ASSOCIATION OF SERUM BILIRUBIN AND URIC ACID LEVELS WITH ALBUMINURIA IN TYPE 2 DIABETES PATIENTS

ASSOCIATION OF SERUM BILIRUBIN AND URIC ACID LEVELS WITH ALBUMINURIA IN TYPE 2 DIABETES PATIENTS. BY HAYFORD ATO KWAMENA (10515902) DEPARTMENT OF MEDICAL LABORATORY SCIENCES (CHEMICAL PATHOLOGY UNIT) SCHOOL OF BIOMEDICAL AND ALLIED HEALTH SCIENCES COLLEGE OF HEALTH SCIENCES UNIVERSITY OF GHANA A project work submitted to the Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, College of Health Sciences, University of Ghana, in partial fulfilment for the award of BSc degree in Medical Laboratory Sciences. April, 2018 DECLARATION I, Ato Kwamena Hayford, the author of this dissertation, do hereby declare that with the exception of references to the literature and works of other researchers which have been duly cited, the work in this dissertation is the result of my original work. Ato Kwamena Hayford (Student) . Mr. Brodrick Yeboah Amoah Prof. George Awuku Asare (Supervisor) (Supervisor) .. DEDICATION I wish to dedicate this work of mine to ACKNOWLEDGEMENT I am very grateful to all individuals and groups who contributed to making this study a successful one LIST OF ABBREVIATIONS TABLE OF CONTENTS Item Page TOC h z t Head1,1,Head2,2,Head3,3 HYPERLINK l _Toc511587353 INTRODUCTION PAGEREF _Toc511587353 h 1 HYPERLINK l _Toc511587354 Background PAGEREF _Toc511587354 h 1 HYPERLINK l _Toc511587355 Problem Statement PAGEREF _Toc511587355 h 3 HYPERLINK l _Toc511587356 Significance of Study PAGEREF _Toc511587356 h 4 HYPERLINK l _Toc511587357 AIM OF THE STUDY PAGEREF _Toc511587357 h 4 HYPERLINK l _Toc511587358 Objectives of the study PAGEREF _Toc511587358 h 4 HYPERLINK l _Toc511587359 LITERATURE REVIEW PAGEREF _Toc511587359 h 5 HYPERLINK l _Toc511587360 Type 2 Diabetes PAGEREF _Toc511587360 h 5 HYPERLINK l _Toc511587361 Definition and Description PAGEREF _Toc511587361 h 5 HYPERLINK l _Toc511587362 Symptoms, Screening and Diagnosis of Diabetes PAGEREF _Toc511587362 h 5 HYPERLINK l _Toc511587363 Etiology of Type 2 Diabetes PAGEREF _Toc511587363 h 7 HYPERLINK l _Toc511587364 Complications and Management PAGEREF _Toc511587364 h 7 HYPERLINK l _Toc511587365 The effects of Insulin Resistance and Hyperglycemia PAGEREF _Toc511587365 h 8 HYPERLINK l _Toc511587366 Long term complications PAGEREF _Toc511587366 h 8 HYPERLINK l _Toc511587367 Ketoacidosis PAGEREF _Toc511587367 h 9 HYPERLINK l _Toc511587368 Obesity and its management PAGEREF _Toc511587368 h 9 HYPERLINK l _Toc511587369 Diabetes Prevention and Therapy PAGEREF _Toc511587369 h 9 HYPERLINK l _Toc511587370 Epidemiology PAGEREF _Toc511587370 h 10 HYPERLINK l _Toc511587371 Diabetic Nephropathy PAGEREF _Toc511587371 h 11 HYPERLINK l _Toc511587372 Definition and Description PAGEREF _Toc511587372 h 11 HYPERLINK l _Toc511587373 Screening, Diagnosis and Staging PAGEREF _Toc511587373 h 12 HYPERLINK l _Toc511587374 Stages of Diabetic Kidney Disease progression PAGEREF _Toc511587374 h 13 HYPERLINK l _Toc511587375 Epidemiology PAGEREF _Toc511587375 h 17 HYPERLINK l _Toc511587376 Pathogenesis and disease progression PAGEREF _Toc511587376 h 18 HYPERLINK l _Toc511587377 The Metabolic Syndrome PAGEREF _Toc511587377 h 19 HYPERLINK l _Toc511587378 The Role of Oxidative Stress PAGEREF _Toc511587378 h 19 HYPERLINK l _Toc511587379 Oxidative Stress alters cell signaling and Hemodynamics PAGEREF _Toc511587379 h 22 HYPERLINK l _Toc511587380 Basement Membrane Disruption PAGEREF _Toc511587380 h 23 HYPERLINK l _Toc511587381 Other factors to be considered PAGEREF _Toc511587381 h 23 HYPERLINK l _Toc511587382 Confounders of microalbuminuria estimation PAGEREF _Toc511587382 h 23 HYPERLINK l _Toc511587383 Nephropathy in the absence of Albuminuria PAGEREF _Toc511587383 h 24 HYPERLINK l _Toc511587384 The case of type 2 diabetes specific nephropathy PAGEREF _Toc511587384 h 25 HYPERLINK l _Toc511587385 The Bilirubin Cycle PAGEREF _Toc511587385 h 25 HYPERLINK l _Toc511587386 Uric Acid Cycle PAGEREF _Toc511587386 h 27 HYPERLINK l _Toc511587387 Bilirubin, Uric Acid and the possible link with Diabetic Nephropathy PAGEREF _Toc511587387 h 29 HYPERLINK l _Toc511587388 MATERIALS AND METHODS PAGEREF _Toc511587388 h 30 HYPERLINK l _Toc511587389 Study Site(s) PAGEREF _Toc511587389 h 30 HYPERLINK l _Toc511587390 Study Design PAGEREF _Toc511587390 h 30 HYPERLINK l _Toc511587391 Study Population PAGEREF _Toc511587391 h 30 HYPERLINK l _Toc511587392 Inclusion Criteria PAGEREF _Toc511587392 h 30 HYPERLINK l _Toc511587393 Exclusion Criteria PAGEREF _Toc511587393 h 30 HYPERLINK l _Toc511587394 Sample size determination PAGEREF _Toc511587394 h 31 HYPERLINK l _Toc511587395 Sampling Procedure PAGEREF _Toc511587395 h 31 HYPERLINK l _Toc511587396 Informed Consent PAGEREF _Toc511587396 h 31 HYPERLINK l _Toc511587397 Blood Sample Collection PAGEREF _Toc511587397 h 32 HYPERLINK l _Toc511587398 Urine Sample Collection. PAGEREF _Toc511587398 h 32 HYPERLINK l _Toc511587399 Laboratory Procedures PAGEREF _Toc511587399 h 32 HYPERLINK l _Toc511587400 Data Collection Procedure PAGEREF _Toc511587400 h 33 HYPERLINK l _Toc511587401 Data Analysis PAGEREF _Toc511587401 h 33 HYPERLINK l _Toc511587402 Ethics PAGEREF _Toc511587402 h 34 HYPERLINK l _Toc511587403 Dissemination of Results PAGEREF _Toc511587403 h 34 HYPERLINK l _Toc511587404 REFERENCES PAGEREF _Toc511587404 h 35 HYPERLINK l _Toc511587405 APPENDICES PAGEREF _Toc511587405 h 47 HYPERLINK l _Toc511587406 APPENDIX A PAGEREF _Toc511587406 h 47 HYPERLINK l _Toc511587407 APPENDIX B PAGEREF _Toc511587407 h 49 HYPERLINK l _Toc511587408 APPENDIX C PAGEREF _Toc511587408 h 51 HYPERLINK l _Toc511587409 WORK SCHEDULE PAGEREF _Toc511587409 h 52 HYPERLINK l _Toc511587410 BUDGET PAGEREF _Toc511587410 h 52 LIST OF FIGURES LIST OF TABLES ABSTRACT CHAPTER 1 INTRODUCTION Background Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from a defect in insulin secretion (type 1), insulin action (type 2), or both. In 20-40 of patients with diabetes, the complication of diabetic nephropathy (DN) develops, and is also the most common cause of end-stage renal disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc14-1296, ISBN 1935-5548 (Electronic)r0149-5992 (Linking), ISSN 19355548, PMID 25249672, abstract The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50 of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly 25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD., author dropping-particle , family Tuttle, given Katherine R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bakris, given George L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bilous, given Rudolf W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Chiang, given Jane L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Boer, given Ian H., non-dropping-particle De, parse-names false, suffix , dropping-particle , family Goldstein-Fuchs, given Jordi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hirsch, given Irl B., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kalantar-Zadeh, given Kamyar, non-dropping-particle , parse-names false, suffix , dropping-particle , family Narva, given Andrew S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Navaneethan, given Sankar D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Neumiller, given Joshua J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Patel, given Uptal D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Ratner, given Robert E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Whaley-Connell, given Adam T., non-dropping-particle , parse-names false, suffix , dropping-particle , family Molitch, given Mark E., non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 10, issued date-parts 2014 , page 2864-2883, title Diabetic kidney disease A report from an ADA consensus conference, type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuid7abbec73-7a6e-4090-9924-58144842a47c , mendeley formattedCitation (Tuttle et al., 2014), plainTextFormattedCitation (Tuttle et al., 2014), previouslyFormattedCitation (Tuttle et al., 2014) , properties noteIndex 0 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Tuttle et al., 2014). It is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases, and it increases the risk of mortality, mainly from cardiovascular causes. Sustained hyperglycemia, hypertension, and genetic predisposition are major risk factors for the development of diabetic nephropathy. Increased serum lipids, the amount and origin of dietary protein and smoking also are potential risk factors. The pathogenesis of diabetic nephropathy although not clearly defined and complex, is usually initiated by one or more of the factors above and are expressed as cellular and subcellular mechanisms of which oxidative stress and inflammation play major roles ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1007/s11154-008-9104-2, ISBN 1389-9155 (Print), ISSN 1389-9155, PMID 18709457, abstract Diabetic neuropathy is the most common complication of diabetes, affecting 50 of diabetic patients. Currently, the only treatment for diabetic neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in diabetic neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of diabetic neuropathy and to identify more effective molecular therapeutic targets., author dropping-particle , family Figueroa-Romero, given Claudia, non-dropping-particle , parse-names false, suffix , dropping-particle , family Sadidi, given Mahdieh, non-dropping-particle , parse-names false, suffix , dropping-particle , family Feldman, given Eva L, non-dropping-particle , parse-names false, suffix , container-title Reviews in endocrine metabolic disorders, id ITEM-1, issue 4, issued date-parts 2008 , page 301-14, title Mechanisms of disease the oxidative stress theory of diabetic neuropathy., type article-journal, volume 9 , uris http//www.mendeley.com/documents/uuid02f0aef7-9ef4-4a5a-92f8-f3f3c4d5dc3c , mendeley formattedCitation (Figueroa-Romero, Sadidi, Feldman, 2008), plainTextFormattedCitation (Figueroa-Romero, Sadidi, Feldman, 2008), previouslyFormattedCitation (Figueroa-Romero, Sadidi, Feldman, 2008) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Figueroa-Romero, Sadidi, Feldman, 2008). Although GFR is regarded the best parameter for monitoring renal function ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 200307150-00013 pii, ISBN 1539-3704 (Electronic), ISSN 1539-3704, PMID 12859163, abstract Chronic kidney disease is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. Outcomes of chronic kidney disease include not only kidney failure but also complications of decreased kidney function and cardiovascular disease. Current evidence suggests that some of these adverse outcomes can be prevented or delayed by early detection and treatment. Unfortunately, chronic kidney disease is underdiagnosed and undertreated, in part as a result of lack of agreement on a definition and classification of its stages of pro- gression. Recent clinical practice guidelines by the National Kidney Foundation 1) define chronic kidney disease and classify its stages, regardless of underlying cause, 2) evaluate laboratory measurements for the clinical assessment of kidney disease, 3) associate the level of kidney function with complications of chronic kidney disease, and 4) stratify the risk for loss of kidney function and development of cardiovascular disease. The guide- lines were developed by using an approach based on the proce- dure outlined by the Agency for Healthcare Research and Quality. This paper presents the definition and five-stage classifica- tion system of chronic kidney disease and summarizes the major recommendations on early detection in adults. Recommendations include identifying persons at increased risk (those with diabetes, those with hypertension, those with a family history of chronic kidney disease, those older than 60 years of age, or those with U.S. racial or ethnic minority status), detecting kidney damage by measuring the albuminu2013creatinine ratio in untimed (u201cspotu201d) urine specimens, and estimating the glomerular filtration rate from se- rum creatinine measurements by using prediction equations. Be- cause of the high prevalence of early stages of chronic kidney disease in the general population (approximately 11 of adults), this information is particularly important for general internists and specialists., author dropping-particle , family Levey, given Andrew S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Coresh, given Josef., non-dropping-particle , parse-names false, suffix , dropping-particle , family Balk, given Ethan., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kausz, given Annamaria T., non-dropping-particle , parse-names false, suffix , dropping-particle , family Levin, given Adeera., non-dropping-particle , parse-names false, suffix , dropping-particle , family Steffes, given Michael W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Hogg, given Ronald J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Perrone, given Ronald D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Lau, given Joseph, non-dropping-particle , parse-names false, suffix , dropping-particle , family Eknoya, given Garabed, non-dropping-particle , parse-names false, suffix , container-title Annals of Internal Medicine, id ITEM-1, issued date-parts 2003 , page 137-147, title Clinical Guidelines National Kidney Foundation Practice Guidelines for Chronic Kidney, type article-journal, volume 139 , uris http//www.mendeley.com/documents/uuidae46cc79-d528-49d5-a763-5d6200b7c4bc , mendeley formattedCitation (Levey et al., 2003), plainTextFormattedCitation (Levey et al., 2003), previouslyFormattedCitation (Levey et al., 2003) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Levey et al., 2003), the clinical signature of DN is proteinuria, which is a marker of disease severity and is used as a therapeutic guide. It is also an independent risk factor for cardiovascular disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1001/jama.286.4.421, ISSN 0098-7484, author dropping-particle , family Gerstein, given Hertzel C., non-dropping-particle , parse-names false, suffix , container-title Jama, id ITEM-1, issue 4, issued date-parts 2001 , page 421, title Albuminuria and Risk of Cardiovascular Events, Death, and Heart Failure in Diabetic and Nondiabetic Individuals, type article-journal, volume 286 , uris http//www.mendeley.com/documents/uuid8c87db2f-e4ad-495c-9faf-5423c996c1c7 , id ITEM-2, itemData DOI 10.1111/j.1523-1755.2004.09214.x, ISSN 00986577, PMID 15485419, abstract Studies have shown that albuminuria is associated with increased risk for cardiovascular events. We tested the relationship between albuminuria (UACR) and cardiovascular risk in 8206 hypertensive patients with left ventricular hypertrophy included in the LIFE Study. Follow-up was 39,122 patient years. The risk for the primary composite cardiovascular end point increases continuously from the lowest to the highest decile of baseline UACR. No specific threshold could be identified. In conclusion, albuminuria predicts the outcome in the LIFE Study. The risk for cardiovascular morbidity and mortality among hypertensive patients with left ventricular hypertrophy increases at much lower UACR than has been reported in diabetic patients., author dropping-particle , family Ibsen, given Hans, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wachtell, given Kristian, non-dropping-particle , parse-names false, suffix , dropping-particle , family Olsen, given Michael H., non-dropping-particle , parse-names false, suffix , dropping-particle , family Borch-Johnsen, given Knut, non-dropping-particle , parse-names false, suffix , dropping-particle , family Lindholm, given Lars H., non-dropping-particle , parse-names false, suffix , dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Dahlu00f6f, given Bju00f6rn, non-dropping-particle , parse-names false, suffix , container-title Kidney International, Supplement, id ITEM-2, issue 92, issued date-parts 2004 , page 56-58, title Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy The LIFE Study, type article-journal, volume 66 , uris http//www.mendeley.com/documents/uuid7e521648-3dd9-49c0-94b5-65ba7c7e92f2 , mendeley formattedCitation (Gerstein, 2001 Ibsen et al., 2004), plainTextFormattedCitation (Gerstein, 2001 Ibsen et al., 2004), previouslyFormattedCitation (Gerstein, 2001 Ibsen et al., 2004) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Gerstein, 2001 Ibsen et al., 2004). Thus, in this study, the stage of albuminuria will be used as an assessment of nephropathy (overt proteinuria might be diagnosed in some patients). Bilirubin, produced from heme catabolism, is generally regarded as a toxic compound when accumulated at abnormally high concentrations in biological tissues and is responsible for the clinical symptoms of kernicterus (Sarnat 1984 Odell and Schutta, 1985). However, unconjugated bilirubin, is regarded as an in vitro chain-breaking anti-oxidant and scavenger of hydrogen peroxide, peroxinitrite and peroxyl radicals. It also acts in vivo as an efficient scavenger of other reactive oxygen species and may play a key physiological role in cytoprotection against oxidant mediated damage ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S1357-2725(01)00130-3, ISBN 1357-2725 (Print), ISSN 13572725, PMID 11849989, abstract Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, in the last 10 years, in vitro and in vivo studies, have demonstrated that bilirubin exhibits potent anti-oxidant properties preventing the oxidative damage triggered by a wide range of oxidant-related stimuli. Therefore, the idea of a beneficial and physiological role for bilirubin in cytoprotection against short and long-lasting oxidant-mediated cell injury is highlighted here. u00a9 2002 Elsevier Science Ltd. All rights reserved., author dropping-particle , family Tomaro, given Maru00eda L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Batlle, given Alcira M.Del C., non-dropping-particle , parse-names false, suffix , container-title International Journal of Biochemistry and Cell Biology, id ITEM-1, issue 3, issued date-parts 2002 , page 216-220, title Bilirubin Its role in cytoprotection against oxidative stress, type article-journal, volume 34 , uris http//www.mendeley.com/documents/uuid3e8102b0-8d98-4c3a-9c88-6b6c97899516 , mendeley formattedCitation (Tomaro Batlle, 2002), plainTextFormattedCitation (Tomaro Batlle, 2002), previouslyFormattedCitation (Tomaro Batlle, 2002) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Tomaro Batlle, 2002). Bilirubin is also known to suppress the oxidation of lipids and lipoproteins, especially low-density lipoprotein cholesterol ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1073/pnas.0813132106, ISBN 0027-8424, ISSN 0027-8424, PMID 19286972, abstract AbstractGlutathione (GSH) and bilirubin are prominent endogenous antioxidant cytoprotectants. Despite tissue levels that are thousands of times lower than GSH, bilirubin is effective because of the biosynthetic cycle wherein it is generated from biliverdin by biliverdin reductase (BVR). When bilirubin acts as an antioxidant, it is oxidized to biliverdin, which is immediately reduced by BVR to bilirubin. Why does the body employ both of these 2 distinct antioxidant systems We show that the water-soluble GSH primarily protects water soluble proteins, whereas the lipophilic bilirubin protects lipids from oxidation. Mice with deletion of heme oxygenase-2, which generates biliverdin, display greater lipid than protein oxidation, while the reverse holds for GSH depletion. RNA interference depletion of BVR increases oxidation of lipids more than protein. Depletion of BVR or GSH augments cell death in an oxidant-specific fashion., author dropping-particle , family Sedlak, given T. W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Saleh, given M., non-dropping-particle , parse-names false, suffix , dropping-particle , family Higginson, given D. S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Paul, given B. D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Juluri, given K. R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Snyder, given S. H., non-dropping-particle , parse-names false, suffix , container-title Proceedings of the National Academy of Sciences, id ITEM-1, issue 13, issued date-parts 2009 , page 5171-5176, title Bilirubin and glutathione have complementary antioxidant and cytoprotective roles, type article-journal, volume 106 , uris http//www.mendeley.com/documents/uuid8f119b3d-ceb0-4543-ac87-ead0c7636133 , mendeley formattedCitation (Sedlak et al., 2009), plainTextFormattedCitation (Sedlak et al., 2009), previouslyFormattedCitation (Sedlak et al., 2009) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Sedlak et al., 2009), and is directly related to the total serum antioxidant capacity in humans ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S0021-9150(01)00601-3, ISBN 0021-9150 (Print)r0021-9150 (Linking), ISSN 00219150, PMID 11849670, abstract Background Oxidation processes play an important role in atherogenesis. Bilirubin IX is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). Methods The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n 50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n 2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n 38) and control subjects (n 38). Results The prevalence of IHD in GS subjects (aged 49.7 9.0 years) was 2 (0.05-10.7, 95 confidence interval), compared to 12.1 in a general population (P 0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P 0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. Conclusions In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity. 2002 Elsevier Science Ireland Ltd. All rights reserved., author dropping-particle , family Vitek, given Libor, non-dropping-particle , parse-names false, suffix , dropping-particle , family Jirsa, given Milan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Brodanova, given Marie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kalab, given Milan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Marecek, given Zdenek, non-dropping-particle , parse-names false, suffix , dropping-particle , family Danzig, given Vilm, non-dropping-particle , parse-names false, suffix , dropping-particle , family Novotn, given Ladislav, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kotal, given Petr, non-dropping-particle , parse-names false, suffix , container-title Atherosclerosis, id ITEM-1, issue 2, issued date-parts 2002 , page 449-456, title Gilbert syndrome and ischemic heart disease A protective effect of elevated bilirubin levels, type article-journal, volume 160 , uris http//www.mendeley.com/documents/uuid6fb109bb-766c-4c48-8453-1dd5b2c84774 , mendeley formattedCitation (Vitek et al., 2002), plainTextFormattedCitation (Vitek et al., 2002), previouslyFormattedCitation (Vitek et al., 2002) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Vitek et al., 2002). Fukui et al (2008) reported that serum bilirubin levels were inversely associated with the risk of DN. It has also been indicated from recent prospective studies that higher serum bilirubin levels are a protective factor of DN ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mashitani, given Tsuyoshi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yasuaki, given Hayashino, non-dropping-particle , parse-names false, suffix , dropping-particle , family Okamura, given Yasuaki, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tsujii, given Satoru, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ishii, given Hitoshi, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 1, issued date-parts 2014 , page 252-258, title Correlations between serum bilirubin levels and diabetic nephropathy progression among Japanese type 2 diabetes patients A prospective cohort study Diabetes Distress and Care Registry at Tenri (DDCRT 5), type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuidfff3a559-4aba-4b7d-a770-e25ba5631939 , id ITEM-2, itemData DOI 10.1016/j.metabol.2015.06.006, ISBN 0026-0495, ISSN 15328600, PMID 26142826, abstract Objective Serum bilirubin has been reported to be associated with the progression of kidney disease in patients with diabetic nephropathy. Less is known, however, about the relationship between bilirubin and chronic kidney disease (CKD) of other etiologies. This study was designed to clarify whether serum total bilirubin concentration is associated with kidney disease progression in patients with CKD independent of etiology. Materials and methods This prospective observational study enrolled 279 consecutive patients with stages 3-5 CKD. The renal endpoint was the composite of the doubling of serum creatinine or end-stage renal disease requiring dialysis. Patients were divided into three groups by their serum total bilirubin concentrations 0.3 (lowest), 0.4-0.5 (middle), and 0.6 (highest) mg/dL. A Cox proportional hazards model was applied to determine the risk factors for poor renal outcome. Results The median follow-up period was 21 months. One-hundred and three patients reached renal end points. After multivariable adjustment, a 0.1 mg/dL increase in serum bilirubin was associated negatively with poor renal outcome (hazard ratio HR, 0.73 95 confidence interval CI, 0.60-0.87). In addition, after adjustment for confounding factors, including traditional and nontraditional cardiovascular risk factors, the middle (HR 3.14, 95 CI 1.36-8.57) and lowest (HR 4.22, 95 CI 1.81-11.59) bilirubin groups had significantly higher HRs for renal outcome than the highest bilirubin group. Conclusions Lower serum bilirubin concentration was independently associated with adverse renal outcomes, suggesting that the measurement of serum bilirubin is useful for predicting kidney disease progression in patients with moderate to severe CKD. copy 2015 Elsevier Inc., author dropping-particle , family Sakoh, given Teppei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakayama, given Masaru, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tanaka, given Shigeru, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yoshitomi, given Ryota, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ura, given Yoriko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nishimoto, given Hitomi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Fukui, given Akiko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Shikuwa, given Yui, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tsuruya, given Kazuhiko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kitazono, given Takanari, non-dropping-particle , parse-names false, suffix , container-title Metabolism Clinical and Experimental, id ITEM-2, issue 9, issued date-parts 2015 , page 1096-1102, publisher Elsevier Inc., title Association of serum total bilirubin with renal outcome in Japanese patients with stages 3-5 chronic kidney disease, type article-journal, volume 64 , uris http//www.mendeley.com/documents/uuid816ba05d-e96d-40e9-8df0-54fb91d86bb4 , mendeley formattedCitation (Mashitani, Yasuaki, Okamura, Tsujii, Ishii, 2014 Sakoh et al., 2015), plainTextFormattedCitation (Mashitani, Yasuaki, Okamura, Tsujii, Ishii, 2014 Sakoh et al., 2015), previouslyFormattedCitation (Mashitani, Yasuaki, Okamura, Tsujii, Ishii, 2014 Sakoh et al., 2015) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Mashitani, Yasuaki, Okamura, Tsujii, Ishii, 2014 Sakoh et al., 2015). While it is seen as a potent antioxidant, some epidemiological studies have demonstrated that elevated serum uric acid (UA) is associated with diabetic nephropathy, suggesting a potential role for uric acid in the disease pathogenesis ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.12861/jrip.2012.13, ISSN 2345-2781, PMID 25340102, author dropping-particle , family Momeni, given Ali, non-dropping-particle , parse-names false, suffix , container-title Journal of renal injury prevention, id ITEM-1, issue 1, issued date-parts 2012 , page 37-8, title Serum uric acid and diabetic nephropathy., type article-journal, volume 1 , uris http//www.mendeley.com/documents/uuid6f1e33cd-9931-4670-b0f1-ee8f5a059aa9 , id ITEM-2, itemData DOI 10.3109/03009742.2010.507218, ISBN 1502-7732 (Electronic)r0300-9742 (Linking), ISSN 1502-7732, PMID 20868309, abstract Hyperuricaemia has been linked to reduced renal function, and evidence indicates that it may be associated with acceleration of the decline in glomerular filtration rate (GFR) and progression of chronic kidney disease (CKD)., author dropping-particle , family Kuo, given C-F, non-dropping-particle , parse-names false, suffix , dropping-particle , family Luo, given S-F, non-dropping-particle , parse-names false, suffix , dropping-particle , family See, given L-C, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ko, given Y-S, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Y-M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hwang, given J-S, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chou, given I-J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chang, given H-C, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given H-W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yu, given K-H, non-dropping-particle , parse-names false, suffix , container-title Scandinavian journal of rheumatology, id ITEM-2, issue 2, issued date-parts 2011 , page 116-21, title Hyperuricaemia and accelerated reduction in renal function., type article-journal, volume 40 , uris http//www.mendeley.com/documents/uuidf894a5be-cc68-4fe7-be20-4e6ab4730e68 , mendeley formattedCitation (Kuo et al., 2011 Momeni, 2012), plainTextFormattedCitation (Kuo et al., 2011 Momeni, 2012), previouslyFormattedCitation (Kuo et al., 2011 Momeni, 2012) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kuo et al., 2011 Momeni, 2012). UA is a powerful scavenger of free radicals and provides approximately 60 of free-radical scavenging capacity in plasma ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1073/pnas.78.11.6858, ISBN 0027-8424, ISSN 0027-8424, PMID 6947260, abstract During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate levels in humans (about 300 microM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context., author dropping-particle , family Ames, given B. N., non-dropping-particle , parse-names false, suffix , dropping-particle , family Cathcart, given R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Schwiers, given E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Hochstein, given P., non-dropping-particle , parse-names false, suffix , container-title Proceedings of the National Academy of Sciences, id ITEM-1, issue 11, issued date-parts 1981 , page 6858-6862, title Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer a hypothesis., type article-journal, volume 78 , uris http//www.mendeley.com/documents/uuid1d51bddb-63b5-46f2-89ab-ca7d43ade94f , mendeley formattedCitation (Ames, Cathcart, Schwiers, Hochstein, 1981), plainTextFormattedCitation (Ames, Cathcart, Schwiers, Hochstein, 1981), previouslyFormattedCitation (Ames, Cathcart, Schwiers, Hochstein, 1981) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Ames, Cathcart, Schwiers, Hochstein, 1981). Uric acid is a product of purine metabolism with about two-thirds excretion by the kidneys ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1161/01.HYP.0000069700.62727.C5, ISSN 0194911X, PMID 12707287, abstract Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy., author dropping-particle , family Johnson, given Richard J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kang, given Duk Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Feig, given Daniel, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kivlighn, given Salah, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanellis, given John, non-dropping-particle , parse-names false, suffix , dropping-particle , family Watanabe, given Susumu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tuttle, given Katherine R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Rodriguez-Iturbe, given Bernardo, non-dropping-particle , parse-names false, suffix , dropping-particle , family Herrera-Acosta, given Jaime, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mazzali, given Marilda, non-dropping-particle , parse-names false, suffix , container-title Hypertension, id ITEM-1, issue 6, issued date-parts 2003 , page 1183-1190, title Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease, type article-journal, volume 41 , uris http//www.mendeley.com/documents/uuid476e2c4d-9a2c-4e5c-9e11-ee92273aed66 , mendeley formattedCitation (Johnson et al., 2003), plainTextFormattedCitation (Johnson et al., 2003), previouslyFormattedCitation (Johnson et al., 2003) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Johnson et al., 2003) and some gastrointestinal excretion, especially in patients with renal insufficiency ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Vaziri, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Freel, given W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hatch, given M, non-dropping-particle , parse-names false, suffix , container-title Journal of the American Society of Nephrology, id ITEM-1, issue 4, issued date-parts 1995 , page 1313-1317, title Effect of Chronic Experimental Renal Insufficiency on Urate Metabolism, type article-journal, volume 6 , uris http//www.mendeley.com/documents/uuid29e41c79-3e3b-44b3-8cf4-7f8197c0a091 , mendeley formattedCitation (Vaziri, Freel, Hatch, 1995), plainTextFormattedCitation (Vaziri, Freel, Hatch, 1995), previouslyFormattedCitation (Vaziri, Freel, Hatch, 1995) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Vaziri, Freel, Hatch, 1995). In type 2 diabetics, hyperinsulinemia resulting from insulin resistance can decrease the renal excretion, increase the renal reabsorption, and increase the production of uric acid ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1007/BF00296994, author dropping-particle , family Modan, given Michaela, non-dropping-particle , parse-names false, suffix , dropping-particle , family Halkin, given Hillel, non-dropping-particle , parse-names false, suffix , dropping-particle , family Karasik, given Avraham, non-dropping-particle , parse-names false, suffix , dropping-particle , family Lusky, given A, non-dropping-particle , parse-names false, suffix , container-title Diabetologia, id ITEM-1, issue 9, issued date-parts 1987 , page 713-718, title Elevated serum uric acid – a facet of hyperinsulinaemia, type article-journal, volume 30 , uris http//www.mendeley.com/documents/uuid7499246b-2d1c-40b1-90d7-46dc2e0e3249 , mendeley formattedCitation (Modan, Halkin, Karasik, Lusky, 1987), plainTextFormattedCitation (Modan, Halkin, Karasik, Lusky, 1987), previouslyFormattedCitation (Modan, Halkin, Karasik, Lusky, 1987) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Modan, Halkin, Karasik, Lusky, 1987). Based on some prior studies, UA was identified as a potential mediator/risk factor for the progression of renal disease in rats ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1152/ajprenal.00283.2001, ISBN 1931-857X (Print)r1522-1466, ISSN 0363-6127, PMID 11997315, abstract Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyperuricemia in rats that results in increased blood pressure and mild renal fibrosis. In this study, we examined the effect of hyperuricemia on the renal vasculature. Rats fed 2 oxonic acid and a low-salt diet for 7 wk developed mild hyperuricemia (1.8 vs. 1.4 mg/dl, P 0.05), hypertension 147 vs. 127 mmHg systolic blood pressure (SBP), P 0.05, and afferent arteriolar thickening, with a 35 increase in medial area (P 0.05). Allopurinol or benziodarone prevented the hyperuricemia, hypertension, and arteriolopathy. Hydrochlorothiazide treatment did not prevent the hyperuricemia or arteriolopathy despite controlling blood pressure. In contrast, the arteriolopathy and hypertension were prevented by both enalapril and losartan. Uric acid also directly stimulated vascular smooth muscle cell proliferation in vitro, and this was partially inhibited by losartan. Thus hyperuricemia induces a renal arteriolopathy in rats that is blood pressure independent and involves the renin-angiotensin system., author dropping-particle , family Mazzali, given Marilda, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanellis, given John, non-dropping-particle , parse-names false, suffix , dropping-particle , family Han, given Lin, non-dropping-particle , parse-names false, suffix , dropping-particle , family Feng, given Lili, non-dropping-particle , parse-names false, suffix , dropping-particle , family Xia, given Yi-Yang, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Qiang, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kang, given Duk-Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gordon, given Katherine L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Watanabe, given Susumu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakagawa, given Takahiko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Lan, given Hui Y., non-dropping-particle , parse-names false, suffix , dropping-particle , family Johnson, given Richard J., non-dropping-particle , parse-names false, suffix , container-title American Journal of Physiology – Renal Physiology, id ITEM-1, issue 6, issued date-parts 2002 , page F991-F997, title Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism, type article-journal, volume 282 , uris http//www.mendeley.com/documents/uuidb5b84643-7d6b-4ed4-9e6d-febe3d0afa5b , mendeley formattedCitation (Marilda Mazzali et al., 2002), plainTextFormattedCitation (Marilda Mazzali et al., 2002), previouslyFormattedCitation (Marilda Mazzali et al., 2002) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Marilda Mazzali et al., 2002), while elsewhere it was reported as a marker for progression of renal disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.krcp.2012.07.003, ISSN 22119132, abstract Background The variable clinical and histopathological manifestations of immunoglobulin A nephropathy (IgAN) make it difficult to predict disease progression. A recent study showed that hyperuricemia, a condition common in hypertension and vascular disease, may contribute to renal dysfunction and histological changes including renal arteriosclerosis, tubular atrophy, and interstitial fibrosis. Herein, we investigated the clinical significance of uric acid level at the time of biopsy, as a marker of IgAN progression. Methods We included 193 patients with biopsy-proven IgAN. Renal disease progression was defined as serum creatinine elevation above 1.2 mg/dL or over 20 elevation from baseline. Hyperuricemia was defined as a serum uric acid level 7.3 mg/dL in men and 5.3 mg/dL in women, which were 1 standard deviation above the mean value in the normal subjects. Results The hyperuricemia group (n50) had higher blood pressure, body mass index, and serum creatinine, and a greater amount of proteinuria and a lower glomerular filtration rate than the nonhyperuricemia group (n143). Hyperuricemia increased the risk of IgAN progression (odds ratio, 4.53 95 confidence interval, 1.31-15.66). The disease progression group (n26) had a greater frequency of hyperuricemia, hypertension, and nephrotic range proteinuria than the nonprogression group (n119). The renal survival analysis showed that the hyperuricemia group had a higher rate of IgAN disease progression. Conclusion Hyperuricemia at the time of diagnosis is an important marker for IgAN progression. 2012. The Korean Society of Nephrology. Published by Elsevier. All rights reserved., author dropping-particle , family Kim, given Su Ji, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kim, given Jung Hoon, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gil, given Hyo Wook, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yang, given Jong Oh, non-dropping-particle , parse-names false, suffix , dropping-particle , family Lee, given Eun Young, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hong, given Sae Yong, non-dropping-particle , parse-names false, suffix , container-title Kidney Research and Clinical Practice, id ITEM-1, issue 3, issued date-parts 2012 , page 186-191, publisher Elsevier, title Hyperuricemia as a marker for progression of immunoglobulin A nephropathy, type article-journal, volume 31 , uris http//www.mendeley.com/documents/uuidda503aba-f7ba-4568-a322-3e16bf71241b , mendeley formattedCitation (Kim et al., 2012), plainTextFormattedCitation (Kim et al., 2012), previouslyFormattedCitation (Kim et al., 2012) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kim et al., 2012). Nonetheless, a recent review suggests that UA plays a dual role as a pro-oxidant intracellularly and an anti-oxidant in plasma although extensive molecular studies may be needed to properly examine this fact ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.5049/EBP.2014.12.1.1, ISBN 1738-5997 (Print)r1738-5997, ISSN 20929935, PMID 25061467, abstract Hyperuricemia is known to be associated with the presence of cardiovascular and metabolic syndrome and with the development of incipient kidney disease and an accelerated renal progression. However, an elevated uric acid level was not generally regarded as a true etiology or mediator, but an indicator of these diseases. Uric acid has recently regained the clinical interest and popularity based on emerging data suggesting the causative role of hyperuricemia in cardiovascular and renal disease. Experimental data demonstrates oxidative stress is one of the earliest phenomena observed in vascular, renal, liver cells and adipocytes exposed to uric acid. Since uric acid is one of the major antioxidants of plasma acting as a free radical scavenger and a chelator of transitional metal ion, uric acid-induced oxidative stress seems paradoxical. Data regarding the clinical implication of hyperuricemia is even more confusing, which defines hyperuricemia as a useless parameter to be eliminated from routine follow-up or a major risk factor to be therapeutic target. With a review of experimental and epidemiologic data, the presence of molecular switch to regulate the role of uric acid as anti- or pro-oxidant in different compartment of our body is suggested, which may shed light on understanding the paradoxical role of uric acid and solving the uric acid debate., author dropping-particle , family Kang, given Duk Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ha, given Sung Kyu, non-dropping-particle , parse-names false, suffix , container-title Electrolyte and Blood Pressure, id ITEM-1, issue 1, issued date-parts 2014 , page 1-6, title Uric acid puzzle Dual role as anti-oxidantand pro-oxidant, type article-journal, volume 12 , uris http//www.mendeley.com/documents/uuideee858c1-5c55-4be0-acf3-8e04237c4eb0 , mendeley formattedCitation (D. H. Kang Ha, 2014), plainTextFormattedCitation (D. H. Kang Ha, 2014), previouslyFormattedCitation (D. H. Kang Ha, 2014) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (D. H. Kang Ha, 2014). Even though elevated serum UA level is observed in obesity and insulin resistance ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1253/circj.69.928, ISBN 1346-9843r1347-4820, ISSN 1346-9843, PMID 16041161, abstract Background Associations between hyperuricemia, cardiovascular diseases and diabetes have been reported, but few of the studies have been conducted in the Korean population. The present study examined a Korean adult population with respect to the relationships between serum uric acid concentrations and hypertension, insulin resistance, and the risk factors of metabolic syndrome. Methods and Results A total of 53,477 subjects were divided into 4 groups according to serum uric acid quartiles. The incidence of hypertension in all subjects was higher in the first quartile than in the third plus fourth quartile (odds ratio (OR) 1.192, p0.001). Homeostasis model assessment index was found to be associated with serum uric acid concentration in all subjects (OR 1.193, p0.001), and the serum uric acid concentration was positively correlated with the risk factors of metabolic syndrome. In addition, the number of metabolic syndrome variables increased as serum uric acid concentration increased. Conclusions Serum uric acid concentration was found to be independently correlated with hypertension, insulin resistance and the risk factors of metabolic syndrome. In addition, even those with a serum uric acid concentration in the normal range showed an increased risk of metabolic syndrome as serum uric acid concentration increased., author dropping-particle , family Yoo, given Tae Woo, non-dropping-particle , parse-names false, suffix , dropping-particle , family Sung, given Ki Chul, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hun, given S S, non-dropping-particle , parse-names false, suffix , dropping-particle , family Col, given , non-dropping-particle , parse-names false, suffix , container-title Circulation Journal, id ITEM-1, issue 8, issued date-parts 2005 , page 928-933, title Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome, type article-journal, volume 69 , uris http//www.mendeley.com/documents/uuid6028d4c4-dfa3-4c8d-9886-5873ab370ff4 , mendeley formattedCitation (Yoo, Sung, Hun, Col, 2005), plainTextFormattedCitation (Yoo, Sung, Hun, Col, 2005), previouslyFormattedCitation (Yoo, Sung, Hun, Col, 2005) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Yoo, Sung, Hun, Col, 2005), it may be that the abnormality is an adaptive response against the detrimental effects of the associated excessive free radicals and oxidative stress ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1073/pnas.78.11.6858, ISBN 0027-8424, ISSN 0027-8424, PMID 6947260, abstract During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate levels in humans (about 300 microM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context., author dropping-particle , family Ames, given B. N., non-dropping-particle , parse-names false, suffix , dropping-particle , family Cathcart, given R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Schwiers, given E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Hochstein, given P., non-dropping-particle , parse-names false, suffix , container-title Proceedings of the National Academy of Sciences, id ITEM-1, issue 11, issued date-parts 1981 , page 6858-6862, title Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer a hypothesis., type article-journal, volume 78 , uris http//www.mendeley.com/documents/uuid1d51bddb-63b5-46f2-89ab-ca7d43ade94f , mendeley formattedCitation (Ames et al., 1981), plainTextFormattedCitation (Ames et al., 1981), previouslyFormattedCitation (Ames et al., 1981) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Ames et al., 1981). Problem Statement Diabetic nephropathy occurs in up to 40 of patients diagnosed with either type 1 or type 2 diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc14-1296, ISBN 1935-5548 (Electronic)r0149-5992 (Linking), ISSN 19355548, PMID 25249672, abstract The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50 of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly 25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD., author dropping-particle , family Tuttle, given Katherine R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bakris, given George L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bilous, given Rudolf W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Chiang, given Jane L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Boer, given Ian H., non-dropping-particle De, parse-names false, suffix , dropping-particle , family Goldstein-Fuchs, given Jordi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hirsch, given Irl B., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kalantar-Zadeh, given Kamyar, non-dropping-particle , parse-names false, suffix , dropping-particle , family Narva, given Andrew S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Navaneethan, given Sankar D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Neumiller, given Joshua J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Patel, given Uptal D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Ratner, given Robert E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Whaley-Connell, given Adam T., non-dropping-particle , parse-names false, suffix , dropping-particle , family Molitch, given Mark E., non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 10, issued date-parts 2014 , page 2864-2883, title Diabetic kidney disease A report from an ADA consensus conference, type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuid7abbec73-7a6e-4090-9924-58144842a47c , mendeley formattedCitation (Tuttle et al., 2014), plainTextFormattedCitation (Tuttle et al., 2014), previouslyFormattedCitation (Tuttle et al., 2014) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Tuttle et al., 2014). It is the leading cause of chronic kidney disease and end-stage renal disease. Serum unconjugated bilirubin, a lipid-soluble waste product that needs to be conjugated, further broken down and excreted, has for long been considered as harmful and potentially toxic to cells. However, studies indicate that bilirubin has anti-oxidant properties and could have protective roles. Moreover, bilirubin may act against plaque formation and subsequent atherosclerosis ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Stocker, given Roland, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yamamoto, given Yorihiro, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mcdonagh, given Antony F, non-dropping-particle , parse-names false, suffix , dropping-particle , family Glazer, given Alexander N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ames, given Bruce N, non-dropping-particle , parse-names false, suffix , container-title Science, id ITEM-1, issue 4792, issued date-parts 1987 , page 1043-1046, title Bilirubin is an Antioxidant of Possible Physiological Importance Published by American Association for the Advancement of Science Stable URL http//www.jstor.org/stable/1698769 Accessed 07-06-2016 09 41 UTC, type article-journal, volume 235 , uris http//www.mendeley.com/documents/uuid3b000f7c-5360-42e0-9b6c-feb731251feb , mendeley formattedCitation (Stocker, Yamamoto, Mcdonagh, Glazer, Ames, 1987), plainTextFormattedCitation (Stocker, Yamamoto, Mcdonagh, Glazer, Ames, 1987), previouslyFormattedCitation (Stocker, Yamamoto, Mcdonagh, Glazer, Ames, 1987) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Stocker, Yamamoto, Mcdonagh, Glazer, Ames, 1987). There is limited knowledge on the relationship between circulating unconjugated bilirubin and diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.jdiacomp.2016.05.013, ISSN 1873460X, PMID 27288202, abstract Aims Studies indicate that elevated serum total bilirubin (TBil) levels are associated with lower risk of diabetic kidney disease (DKD). Few studies examined the associations of direct bilirubin (DBil) and indirect bilirubin (IBil) with the development of DKD. Methods Type 2 diabetes patients (nu00a0u00a02,958) with estimated glomerular filtration (eGFR)u00a0u2265u00a060u00a0mlu00a0minu2212u00a01 1.73u00a0mu2212u00a02 from the Dongfengu2013Tongji cohort were selected and followed up for 5u00a0years. Development of DKD was defined as decline in eGFRu00a0u2265u00a030 during follow-up. Generalize linear model was used to assess the associations of bilirubin levels with DKD development. Results Compared with those in the first tertile of serum TBil, the relative risks (RRs) and 95 confidence intervals (CIs) of incident eGFR decline for tertile 2 to 3 were 0.83 (0.64u20131.09) and 0.74 (0.56u20130.98), P trendu00a0u00a00.04. The counterpart RRs (95 CIs) in IBil were 0.74 (0.57u20130.97) and 0.75 (0.57u20130.98), Ptrendu00a0u00a00.04. No significant associations were observed in DBil. Moreover, TBil and IBil interacted with smoking, the bilirubin-DKD associations were evident in ever smokers. Conclusions Our findings suggest that elevation of serum TBil or IBil levels are independent protective factors for development of DKD, particularly in smokers., author dropping-particle , family Wang, given Jing, non-dropping-particle , parse-names false, suffix , dropping-particle , family Li, given Yaru, non-dropping-particle , parse-names false, suffix , dropping-particle , family Han, given Xu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hu, given Hua, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wang, given Fei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yu, given Caizheng, non-dropping-particle , parse-names false, suffix , dropping-particle , family Li, given Xiulou, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yang, given Kun, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yuan, given Jing, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yao, given Ping, non-dropping-particle , parse-names false, suffix , dropping-particle , family Miao, given Xiaoping, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wei, given Sheng, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wang, given Youjie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Weihong, non-dropping-particle , parse-names false, suffix , dropping-particle , family Liang, given Yuan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zhang, given Xiaomin, non-dropping-particle , parse-names false, suffix , dropping-particle , family Guo, given Huan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pan, given An, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yang, given Handong, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wu, given Tangchun, non-dropping-particle , parse-names false, suffix , dropping-particle , family He, given Meian, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes and its Complications, id ITEM-1, issue 7, issued date-parts 2016 , page 1255-1260, publisher Elsevier Inc., title Association between serum bilirubin levels and decline in estimated glomerular filtration rate among patients with type 2 diabetes, type article-journal, volume 30 , uris http//www.mendeley.com/documents/uuid4cd2f529-6ccc-43f3-973f-9252ddf3d772 , mendeley formattedCitation (Wang et al., 2016), plainTextFormattedCitation (Wang et al., 2016), previouslyFormattedCitation (Wang et al., 2016) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Wang et al., 2016). In the Ghanaian diabetic population, there is lack of data on the association between serum antioxidants and the extent of diabetic nephropathy. Moreover, no single study has been conducted to investigate the association between serum uric acid and bilirubin levels, with albuminuria in type 2 diabetics. This study will therefore investigate the relationship between bilirubin (particularly unconjugated bilirubin) and uric acid, and the occurrence of nephropathy in type 2 diabetics. Significance of Study At the time of diagnosis of type 2 diabetes, 7 of affected patients usually would have already developed diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1046/j.1523-1755.2003.00712.x, ISBN 0085-2538 (Print)n0085-2538 (Linking), ISSN 00852538, PMID 12472787, abstract BACKGROUND The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death. METHODS Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease. RESULTS From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0 per year, from microalbuminuria to macroalbuminuria at 2.8 per year, and from macroalbuminuria to elevated plasma creatinine (or175 micromol/L) or renal replacement therapy at 2.3 per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9, of macroalbuminuria was 5.3, and of elevated plasma creatinine or RRT was 0.8. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2 (95 confidence interval, CI, 14.0 to 24.4). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P 0.0001), with an annual rate of 0.7 for subjects in the stage of no nephropathy, 2.0 for those with microalbuminuria, 3.5 for those with macroalbuminuria, and 12.1 with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure. CONCLUSIONS The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy., author dropping-particle , family Adler, given Amanda I., non-dropping-particle , parse-names false, suffix , dropping-particle , family Stevens, given Richard J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Manley, given Sue E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bilous, given Rudy W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Cull, given Carole A., non-dropping-particle , parse-names false, suffix , dropping-particle , family Holman, given Rury R., non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-1, issue 1, issued date-parts 2003 , page 225-232, title Development and progression of nephropathy in type 2 diabetes The United Kingdom Prospective Diabetes Study (UKPDS 64), type article-journal, volume 63 , uris http//www.mendeley.com/documents/uuidfb595757-03a3-4174-9ae1-04e58581999d , mendeley formattedCitation (Adler et al., 2003), plainTextFormattedCitation (Adler et al., 2003), previouslyFormattedCitation (Adler et al., 2003) , properties noteIndex 6 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Adler et al., 2003). Thus, early diagnosis of diabetic nephropathy through microalbuminuria determination greatly influences management of the disease. This study will determine the relationship between serum bilirubin and uric acid, and the extent of albuminuria in type 2 diabetics thereby providing information that will enhance clinical perspectives of type 2 diabetes mellitus with regards to development of diabetic kidney disease and its management. AIM OF THE STUDY The aim of this study is to determine the association of serum unconjugated bilirubin and uric acid levels with albuminuria in patients diagnosed with type 2 diabetes. Objectives of the study The specific objectives are as follows Symptoms, Screening and Diagnosis of Diabetes The symptoms of type 2 diabetes include frequent urination, excessive thirst, weight loss and blurred vision ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 15 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). These are caused by underlying microvascular and macrovascular pathomecanisms (see Complications and Management). The symptoms of the disease often develop over a long period (usually years) and are often less marked than in type 1 diabetes. As such, many people with type 2 diabetes remain unaware of their condition for years. However, while people are unaware, their bodies are already suffering damages due to hyperglycemia and its secondary effects. As a result, many individuals with type 2 diabetes would have already developed some complications at the time of diagnosis of the disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 16 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). Type 2 diabetes is the most common type of diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 16 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). Fasting plasma glucose 6.1-6.9 mmol/L (110-125 mg/ dl) Two-hour plasma glucose 7.8 mmol/L (140) following a 75g oral glucose load.Etiology of Type 2 Diabetes Complications and Management Long term complications Many individuals living with type 2 diabetes remain undiagnosed for many years while the effects of the disease develop undercover. Long-term complications of diabetes include retinopathy with likely loss of vision nephropathy with risk of end-stage renal failure peripheral neuropathy which may lead to foot pain and ulcers that require amputations, and Charcot arthropathy and autonomic neuropathy leading to gastrointestinal, urogenital, and cardiovascular manifestations as well as sexual dysfunction ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc14-S081, ISBN 1935-5548 (Electronic)r0149-5992 (Linking), ISSN 01495992, PMID 24357215, abstract Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the pancreatic u03b2-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia.Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.Long-term complications of diabetes include retinopathy with potential loss of vision nephropathy leading to renal failure peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.The vast majority of cases of diabetes fall into two broad etiopathogenetic categories (discussed in greater detail below). In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue SUPPL.1, issued date-parts 2014 , page 81-90, title Diagnosis and Classification of Diabetes Mellitus, type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuid240aef1a-05e8-4a80-9545-4e71f7fbae45 , mendeley formattedCitation (American Diabetes Association, 2014), plainTextFormattedCitation (American Diabetes Association, 2014), previouslyFormattedCitation (American Diabetes Association, 2014) , properties noteIndex 17 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2014). Hypertension and disorders of lipoprotein metabolism are common in people with diabetes. Ketoacidosis In type 1 diabetes, patients can briefly return to normoglycemia without requiring continuous therapy even after presenting with ketoacidosis ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc14-S081, ISBN 1935-5548 (Electronic)r0149-5992 (Linking), ISSN 01495992, PMID 24357215, abstract Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the pancreatic u03b2-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia.Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.Long-term complications of diabetes include retinopathy with potential loss of vision nephropathy leading to renal failure peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.The vast majority of cases of diabetes fall into two broad etiopathogenetic categories (discussed in greater detail below). In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue SUPPL.1, issued date-parts 2014 , page 81-90, title Diagnosis and Classification of Diabetes Mellitus, type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuid240aef1a-05e8-4a80-9545-4e71f7fbae45 , mendeley formattedCitation (American Diabetes Association, 2014), plainTextFormattedCitation (American Diabetes Association, 2014), previouslyFormattedCitation (American Diabetes Association, 2014) , properties noteIndex 17 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2014). Now, ketoacidosis is not often seen as a first-line or spontaneous occurrence in type 2 diabetes. It usually arises secondary to the stress of another illness such as an infection ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S0140-6736(17)30058-2, ISBN 1846299632, ISSN 1474547X, PMID 28190580, abstract 415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type 2 diabetes accounts for more than 90 of patients with diabetes and leads to microvascular and macrovascular complications that cause profound psychological and physical distress to both patients and carers and put a huge burden on health-care systems. Despite increasing knowledge regarding risk factors for type 2 diabetes and evidence for successful prevention programmes, the incidence and prevalence of the disease continues to rise globally. Early detection through screening programmes and the availability of safe and effective therapies reduces morbidity and mortality by preventing or delaying complications. Increased understanding of specific diabetes phenotypes and genotypes might result in more specific and tailored management of patients with type 2 diabetes, as has been shown in patients with maturity onset diabetes of the young. In this Seminar, we describe recent developments in the diagnosis and management of type 2 diabetes, existing controversies, and future directions of care., author dropping-particle , family Chatterjee, given Sudesna, non-dropping-particle , parse-names false, suffix , dropping-particle , family Khunti, given Kamlesh, non-dropping-particle , parse-names false, suffix , dropping-particle , family Davies, given Melanie J., non-dropping-particle , parse-names false, suffix , container-title The Lancet, id ITEM-1, issue 10085, issued date-parts 2017 , page 2239-2251, publisher Elsevier Ltd, title Type 2 diabetes, type article-journal, volume 389 , uris http//www.mendeley.com/documents/uuidd46dd8ad-139f-41ba-b1ed-739cbdbe27f4 , mendeley formattedCitation (Chatterjee et al., 2017), plainTextFormattedCitation (Chatterjee et al., 2017), previouslyFormattedCitation (Chatterjee et al., 2017) , properties noteIndex 16 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Chatterjee et al., 2017). In some other studies, hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome has been reported as an acute, life-threatening complication of uncontrolled diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc14-S081, ISBN 1935-5548 (Electronic)r0149-5992 (Linking), ISSN 01495992, PMID 24357215, abstract Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the pancreatic u03b2-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia.Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.Long-term complications of diabetes include retinopathy with potential loss of vision nephropathy leading to renal failure peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.The vast majority of cases of diabetes fall into two broad etiopathogenetic categories (discussed in greater detail below). In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue SUPPL.1, issued date-parts 2014 , page 81-90, title Diagnosis and Classification of Diabetes Mellitus, type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuid240aef1a-05e8-4a80-9545-4e71f7fbae45 , mendeley formattedCitation (American Diabetes Association, 2014), plainTextFormattedCitation (American Diabetes Association, 2014), previouslyFormattedCitation (American Diabetes Association, 2014) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2014). Obesity and its management Diabetes Prevention and Therapy Various diabetes prevention and management plans are employed in maintaining a patients blood sugar level in the healthy zone. Physical activity is essential as exercise enhances the usage glucose by the muscles for generation of energy and generally helps the body use insulin more efficiently. Type 2 diabetes may be prevented by managing obesity while regulating impaired glucose tolerance with diet and exercise interventions and using to a lesser extent, metformin and thiazolidinediones in pharmacotherapy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1111/dom.12270, ISSN 1463-1326, abstract Different intervention strategies can prevent type 2 diabetes (T2DM). Aim of the present systematic review and meta-analysis was to evaluate the effectiveness of different strategies. Studies were grouped into 15 different strategies 1 diet plus physical activity 2 physical activity 3u20136 anti-diabetic drugs glitazones, metformin, beta-cell stimulating drugs (sulphanylureas, glinides), alfa-glucosidase inhibitors 7u20138 cardiovascular drugs (ACE inhibitors, ARB, calcium antagonists) 9u201314 diets, lipid-affecting drugs (orlistat, bezafibrate), vitamins, micronutrients, estrogens, alcohol, coffee 15 bariatric surgery. Only controlled studies were included in the analysis, whether randomized, non-randomized, observational studies, whether primarily designed to assess incident cases of diabetes, or performed with other purposes, such as control of hypertension, of ischemic heart disease or prevention of cardiovascular events. Appropriate methodology preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was used. Seventy-one studies (490u2009813 subjects), published as full papers, were analysed to identify predictors of new cases of T2DM, and were included in a meta-analysis (random-effects model) to study the effect of different strategies. Intervention effect (new cases of diabetes) was expressed as odds ratio (OR), with 95 confidence intervals (C.I.s). Publication bias was formally assessed. Body mass index was in the overweight range for 13 groups, obese or morbidly obese in lipid-affecting drugs and in bariatric surgery. Non-surgical strategies, except for beta-cell stimulating drugs, estrogens and vitamins, were able to prevent T2DM, with different effectiveness, from 0.37 (C.I. 0.26u20130.52) to 0.85 (C.I. 0.77u20130.93) the most effective strategy was bariatric surgery in morbidly obese subjects 0.16 (C.I. 0.11,0.24). At meta-regression analysis, age of subjects and amount of weight lost were associated with effectiveness of intervention. These data indicate that several strategies prevent T2DM, making it possible to make a choice for the individual subject., author dropping-particle , family Merlotti, given C, non-dropping-particle , parse-names false, suffix , dropping-particle , family Morabito, given A, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pontiroli, given A E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, Obesity and Metabolism, id ITEM-1, issue 8, issued date-parts 2014 , page 719-727, publisher Wiley Online Library, title Prevention of type 2 diabetes a systematic review and metau2010analysis of different intervention strategies, type article-journal, volume 16 , uris http//www.mendeley.com/documents/uuid5acfa3fb-533f-4474-89af-90a9628854bf , mendeley formattedCitation (Merlotti, Morabito, Pontiroli, 2014), plainTextFormattedCitation (Merlotti, Morabito, Pontiroli, 2014), previouslyFormattedCitation (Merlotti, Morabito, Pontiroli, 2014) , properties noteIndex 17 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Merlotti, Morabito, Pontiroli, 2014). The level of glycemia as measured by HbA1c remains a major focus of diabetic therapy especially because the direct relation between glycemic levels and the risk of microvascular and macrovascular complications has been well demonstrated ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1136/bmj.321.7258.405, ISBN 0959-8138 (Print)r0959-535X (Linking), ISSN 09598138, PMID 10938048, abstract Objective To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design Prospective observational study. Setting 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence of these, 3642 were included in analyses of relative risk. Outcome measures Primary predefined aggregate clinical outcomes any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points non-fatal heart failure and cataract extraction. Risk reduction associated with a 1 reduction in updated mean HbA1c adjusted for possible confounders at diagnosis of diabetes. Results The incidence of clinical complications was significantly associated with glycaemia. Each 1 reduction in updated mean HbA1c was associated with reductions in risk of 21 for any end point related to diabetes (95 confidence interval 17 to 24, P0.0001), 21 for deaths related to diabetes (15 to 27, P0.0001), 14 for myocardial infarction (8 to 21, P0.0001), and 37 for microvascular complications (33 to 41, P0.0001). No threshold of risk was observed for any end point. Conclusions In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (6.0)., author dropping-particle , family Stratton, given I. M, non-dropping-particle , parse-names false, suffix , container-title Bmj, id ITEM-1, issue 7258, issued date-parts 2000 , page 405-412, title Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35) prospective observational study, type article-journal, volume 321 , uris http//www.mendeley.com/documents/uuida684cf9e-d197-453a-89a0-9ff7be71b70b , mendeley formattedCitation (Stratton, 2000), plainTextFormattedCitation (Stratton, 2000), previouslyFormattedCitation (Stratton, 2000) , properties noteIndex 17 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Stratton, 2000). In the UK Prospective Diabetes Study ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family UK Prospective Diabetes Study (UKPDS) Group, given , non-dropping-particle , parse-names false, suffix , container-title Lancet, id ITEM-1, issue 9131, issued date-parts 1998 , page 837-853, title Intensive blood-glucose control with sulphonylureas or insulin UK Prospective Diabetes Study (UKPDS) Group compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), type article-journal, volume 352 , uris http//www.mendeley.com/documents/uuid7e2145f4-2eac-496e-a258-ac4afdf047db , id ITEM-2, itemData DOI 10.1007/BF00400195, ISBN 0012-186X (Print)r0012-186X (Linking), ISSN 0012186X, PMID 1778353, abstract The UK Prospective Diabetes Study (UKPDS) is a multi-centre, prospective, randomised, intervention trial of 5100 newly-diagnosed patients with Type 2 (non-insulin-dependent) diabetes mellitus which aims to determine whether improved blood glucose control will prevent complications and reduce the associated morbidity and mortality. Newly presenting Type 2 diabetic patients aged 25-65 years inclusive, median age 53 years, median body mass index 28 kg/m2 and median fasting plasma glucose 11.3 mmol/l, were recruited and treated initially by diet. Ninety five percent remained hyperglycaemic (fasting plasma glucose greater than 6 mmol/l) and were randomly allocated to different therapies. In the main randomisation, those who were asymptomatic and had fasting plasma glucose under 15 mmol/l were allocated either to diet policy, or to active policy with either insulin or sulphonylurea aiming to reduce the fasting plasma glucose to under 6 mmol/l. Over 3 years, the median fasting plasma glucose in those allocated to diet policy was 8.9 mmol/l compared with 7.0 mmol/l in those allocated to active policy. The Hypertension in Diabetes Study has been included in a factorial design to assess whether improved blood pressure control will be advantageous. Patients with blood pressure greater than or equal to 160/90 mm Hg were randomly allocated to tight control aiming for less than 150/85 mm Hg with either an angiotensin-converting enzyme inhibitor or a Beta-blocker or to less tight control aiming for less than 200/105 mm Hg. The endpoints of the studies are major clinical events which affect the life and well-being of patients, such as heart attacks, angina, strokes, amputations, blindness and renal failure. To date, 728 patients have had at least one clinical endpoint. Surrogate endpoints include indices of macrovascular and microvascular disease detected by ECG with Minnesota Coding, retinal colour photography and microalbuminuria. The studies also aim to evaluate potential risk factors for the development of diabetic complications such as smoking, obesity, central adiposity, plasma LDL- and HDL-cholesterol, triglyceride, insulin, urate and other biochemical variables. The studies are planned to terminate in 1994, with a median follow-up of 9 years (range 3-16 years) for the glucose study and 5 years (range 2-6 years) for the hypertension study., author dropping-particle , family Stratton, given I M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Cull, given C A, non-dropping-particle , parse-names false, suffix , dropping-particle , family Manley, given S E, non-dropping-particle , parse-names false, suffix , dropping-particle , family Frighi, given V, non-dropping-particle , parse-names false, suffix , container-title Diabetologia, id ITEM-2, issue 12, issued date-parts 1991 , page 877-890, title UK prospective diabetes study (UKPDS) – VIII. Study design, progress and performance, type article-journal, volume 34 , uris http//www.mendeley.com/documents/uuid4e9028cd-1932-44b2-8067-4485f5a742e7 , mendeley formattedCitation (Stratton, Cull, Manley, Frighi, 1991 UK Prospective Diabetes Study (UKPDS) Group, 1998), plainTextFormattedCitation (Stratton, Cull, Manley, Frighi, 1991 UK Prospective Diabetes Study (UKPDS) Group, 1998), previouslyFormattedCitation (Stratton, Cull, Manley, Frighi, 1991 UK Prospective Diabetes Study (UKPDS) Group, 1998) , properties noteIndex 17 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Stratton, Cull, Manley, Frighi, 1991 UK Prospective Diabetes Study (UKPDS) Group, 1998), physical and lifestyle intervention was the primary management plan in the standard treatment group with pharmacotherapy used only in severe hyperglycaemic cases. In the more intensive treatment group, patients were randomly assigned to either a sulfonylurea or insulin, with a subset of overweight patients randomly assigned to metformin therapy. Nonetheless, while it may be a frequently required treatment option, type 2 diabetes patients more often than not do not require insulin therapy to survive ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S0140-6736(17)30058-2, ISBN 1846299632, ISSN 1474547X, PMID 28190580, abstract 415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type 2 diabetes accounts for more than 90 of patients with diabetes and leads to microvascular and macrovascular complications that cause profound psychological and physical distress to both patients and carers and put a huge burden on health-care systems. Despite increasing knowledge regarding risk factors for type 2 diabetes and evidence for successful prevention programmes, the incidence and prevalence of the disease continues to rise globally. Early detection through screening programmes and the availability of safe and effective therapies reduces morbidity and mortality by preventing or delaying complications. Increased understanding of specific diabetes phenotypes and genotypes might result in more specific and tailored management of patients with type 2 diabetes, as has been shown in patients with maturity onset diabetes of the young. In this Seminar, we describe recent developments in the diagnosis and management of type 2 diabetes, existing controversies, and future directions of care., author dropping-particle , family Chatterjee, given Sudesna, non-dropping-particle , parse-names false, suffix , dropping-particle , family Khunti, given Kamlesh, non-dropping-particle , parse-names false, suffix , dropping-particle , family Davies, given Melanie J., non-dropping-particle , parse-names false, suffix , container-title The Lancet, id ITEM-1, issue 10085, issued date-parts 2017 , page 2239-2251, publisher Elsevier Ltd, title Type 2 diabetes, type article-journal, volume 389 , uris http//www.mendeley.com/documents/uuidd46dd8ad-139f-41ba-b1ed-739cbdbe27f4 , mendeley formattedCitation (Chatterjee et al., 2017), plainTextFormattedCitation (Chatterjee et al., 2017), previouslyFormattedCitation (Chatterjee et al., 2017) , properties noteIndex 16 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Chatterjee et al., 2017). Epidemiology In 2015, the International Diabetes Federation reported a 5 million deaths worldwide due to diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). Statistics from two years before then indicated that one person died every six seconds of the disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.diabres.2009.10.007, ISBN 2-930229-85-3, ISSN 01688227, PMID 19896746, author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 6, id ITEM-1, issued date-parts 2013 , number-of-pages 1-159, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuidbe0f8fee-1533-4acb-982d-4aab5f0c4de0 , mendeley formattedCitation (International Diabetes Federation, 2013), plainTextFormattedCitation (International Diabetes Federation, 2013), previouslyFormattedCitation (IDF, 2013) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2013). Epidemiology of type 2 diabetes is to a large extent affected by peoples predisposition to genetic and environmental factors. The effects of genetic factors are readily seen following exposure to an obesogenic environment of little physical activity and excessive sugar and fat intake ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S0140-6736(17)30058-2, ISBN 1846299632, ISSN 1474547X, PMID 28190580, abstract 415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type 2 diabetes accounts for more than 90 of patients with diabetes and leads to microvascular and macrovascular complications that cause profound psychological and physical distress to both patients and carers and put a huge burden on health-care systems. Despite increasing knowledge regarding risk factors for type 2 diabetes and evidence for successful prevention programmes, the incidence and prevalence of the disease continues to rise globally. Early detection through screening programmes and the availability of safe and effective therapies reduces morbidity and mortality by preventing or delaying complications. Increased understanding of specific diabetes phenotypes and genotypes might result in more specific and tailored management of patients with type 2 diabetes, as has been shown in patients with maturity onset diabetes of the young. In this Seminar, we describe recent developments in the diagnosis and management of type 2 diabetes, existing controversies, and future directions of care., author dropping-particle , family Chatterjee, given Sudesna, non-dropping-particle , parse-names false, suffix , dropping-particle , family Khunti, given Kamlesh, non-dropping-particle , parse-names false, suffix , dropping-particle , family Davies, given Melanie J., non-dropping-particle , parse-names false, suffix , container-title The Lancet, id ITEM-1, issue 10085, issued date-parts 2017 , page 2239-2251, publisher Elsevier Ltd, title Type 2 diabetes, type article-journal, volume 389 , uris http//www.mendeley.com/documents/uuidd46dd8ad-139f-41ba-b1ed-739cbdbe27f4 , mendeley formattedCitation (Chatterjee et al., 2017), plainTextFormattedCitation (Chatterjee et al., 2017), previouslyFormattedCitation (Chatterjee et al., 2017) , properties noteIndex 17 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Chatterjee et al., 2017). The International Diabetes Federation (IDF) reported that 415million people live with diabetes worldwide ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015) with type 2 diabetes being more prevalent and consuming up to 91 of diabetics in high-income countries ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1111/dme.12791, ISBN 1464-5491 (Electronic)r0742-3071 (Linking), ISSN 14645491, PMID 25962518, abstract Diabet. Med. 32, 1119u20131120 (2015) Last year we published a statement of diabetes prevalence in the UK 1. Accurate information on the number of people with diabetes is essential for the management of diabetes and to understand the epidemiology of the disease and its complications. New data are now published, which allows our data to be updated, and sources of data have been combined to estimate the split of diabetes by type. In autumn 2014 the Quality and Outcomes Framework 2, a financial incentive scheme for general practice based on indicators of the level of care received by patients, provided data on the number of people aged u2265 17 years with diag-nosed diabetes across all four nations of the UK at the end of March 2014. This showed that across the UK there were 3 333 069 people aged u2265 17 years with a recorded diagnosis of diabetes, which equates to a prevalence of 6.2 in this age group. This is up from the equivalent figure of 6 last year 1. The number of children and young people with diagnosed diabetes aged u2264 16 years (and therefore not Table 1 Prevalence of diagnosed diabetes, author dropping-particle , family Holman, given N., non-dropping-particle , parse-names false, suffix , dropping-particle , family Young, given B., non-dropping-particle , parse-names false, suffix , dropping-particle , family Gadsby, given R., non-dropping-particle , parse-names false, suffix , container-title Diabetic Medicine, id ITEM-1, issue 9, issued date-parts 2015 , page 1119-1120, title Current prevalence of Type 1 and Type 2 diabetes in adults and children in the UK, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid9da684c6-c14f-4fc4-a578-4fea4589fb81 , mendeley formattedCitation (N. Holman, Young, Gadsby, 2015), plainTextFormattedCitation (N. Holman, Young, Gadsby, 2015), previouslyFormattedCitation (N. Holman, Young, Gadsby, 2015) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (N. Holman, Young, Gadsby, 2015). In Africa, two thirds of people living with diabetes are undiagnosed ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). The region of Sub-Saharan Africa (SSA) turns out to be one of those having the fastest increasing figures for type 2 diabetes worldwide ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.27.5.1047, ISBN 0149-5992, ISSN 0149-5992, PMID 15111519, abstract OBJECTIVE u2014 The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030. RESEARCH DESIGN AND METHODS u2014 Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries. RESULTS u2014 The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8 in 2000 and 4.4 in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people u03fe65 years of age., author dropping-particle , family Wild Sarah, given , non-dropping-particle , parse-names false, suffix , dropping-particle , family Roglic Gojka, given , non-dropping-particle , parse-names false, suffix , dropping-particle , family Green Anders, given , non-dropping-particle , parse-names false, suffix , dropping-particle , family Sicree Richard, given , non-dropping-particle , parse-names false, suffix , dropping-particle , family Hilary, given King, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 5, issued date-parts 2004 , page 1047-1053, title Global Prevalence of Diabetes Estimates for the year 2000 and projection for 2030, type article-journal, volume 27 , uris http//www.mendeley.com/documents/uuid09ef9b58-daa0-429b-8ea3-c1aca01d8ecc , mendeley formattedCitation (Wild Sarah, Roglic Gojka, Green Anders, Sicree Richard, Hilary, 2004), plainTextFormattedCitation (Wild Sarah, Roglic Gojka, Green Anders, Sicree Richard, Hilary, 2004), previouslyFormattedCitation (Wild Sarah, Roglic Gojka, Green Anders, Sicree Richard, Hilary, 2004) , properties noteIndex 16 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Wild Sarah, Roglic Gojka, Green Anders, Sicree Richard, Hilary, 2004). In 2013, there were an estimated 19.8 million people with type 2 diabetes in SSA and this number is projected to increase to 41.5 million by the year 2035 ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.diabres.2009.10.007, ISBN 2-930229-85-3, ISSN 01688227, PMID 19896746, author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 6, id ITEM-1, issued date-parts 2013 , number-of-pages 1-159, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuidbe0f8fee-1533-4acb-982d-4aab5f0c4de0 , mendeley formattedCitation (International Diabetes Federation, 2013), plainTextFormattedCitation (International Diabetes Federation, 2013), previouslyFormattedCitation (IDF, 2013) , properties noteIndex 16 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2013). In Ghana, 209.2 – 657.5 (averagely 266.2) thousand adults between 20 to 79years live with diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). Diabetic Nephropathy Definition and Description Diabetic nephropathy, the leading cause of chronic kidney disease and end stage renal failure in diabetics, affects up to 40 of both type 1 and type 2 diabetes patients ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc14-1296, ISBN 1935-5548 (Electronic)r0149-5992 (Linking), ISSN 19355548, PMID 25249672, abstract The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50 of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly 25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD., author dropping-particle , family Tuttle, given Katherine R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bakris, given George L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bilous, given Rudolf W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Chiang, given Jane L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Boer, given Ian H., non-dropping-particle De, parse-names false, suffix , dropping-particle , family Goldstein-Fuchs, given Jordi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hirsch, given Irl B., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kalantar-Zadeh, given Kamyar, non-dropping-particle , parse-names false, suffix , dropping-particle , family Narva, given Andrew S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Navaneethan, given Sankar D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Neumiller, given Joshua J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Patel, given Uptal D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Ratner, given Robert E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Whaley-Connell, given Adam T., non-dropping-particle , parse-names false, suffix , dropping-particle , family Molitch, given Mark E., non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 10, issued date-parts 2014 , page 2864-2883, title Diabetic kidney disease A report from an ADA consensus conference, type article-journal, volume 37 , uris http//www.mendeley.com/documents/uuid7abbec73-7a6e-4090-9924-58144842a47c , mendeley formattedCitation (Tuttle et al., 2014), plainTextFormattedCitation (Tuttle et al., 2014), previouslyFormattedCitation (Tuttle et al., 2014) , properties noteIndex 18 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Tuttle et al., 2014). Diabetic kidney disease is far more commonly occurring than the nephropathy that occurs in people without diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1289/image.ehp.v119.i03, ISBN 9782930229812, ISSN 0021-9533, PMID 8529190, abstract The International Diabetes Federation (IDF) is a global umbrella organisation of over 230 national diabetes associations in 170 countries and territories. The IDF Diabetes Atlas, produced in collaboration with global and national health experts, is the foundation and evidence base of IDFu2019s mission to promote diabetes care, prevention and a cure worldwide., author dropping-particle , family International Diabetes Federation, given , non-dropping-particle , parse-names false, suffix , edition 7, id ITEM-1, issued date-parts 2015 , number-of-pages 1-163, title IDF Diabetes Atlas, type book , uris http//www.mendeley.com/documents/uuid908c3407-3ddf-4cf7-925a-9f7a23813273 , mendeley formattedCitation (International Diabetes Federation, 2015), plainTextFormattedCitation (International Diabetes Federation, 2015), previouslyFormattedCitation (IDF, 2015) , properties noteIndex 21 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (International Diabetes Federation, 2015). In the U.S. and Europe, this finding is attributed to the facts that i) diabetes, particularly type 2, is increasing in prevalence ii) diabetes patients do live longer of late and iii) diabetic ESRD patients are now being enrolled in ESRD treatment programs where previously they had been excluded ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.27.2007.s79, ISBN 0065-2598, ISSN 0149-5992, PMID 14693934, abstract Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe this is due to the facts that 1 ) diabetes, particularly type 2, is increasing in prevalence 2 ) diabetes patients now live longer and 3 ) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40 of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of 15.6 billion. About 20u201330 of patients with type 1 or type 2 diabetes develop evidence of nephropathy, but in type 2 diabetes, a considerably smaller fraction of these progress to ESRD. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis. There is considerable racial/ethnic variability in this regard, with Native Americans, Hispanics (especially Mexican-Americans), and African-Americans having much higher risks of developing ESRD than non-Hispanic whites with type 2 diabetes. Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy.nnThe earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (u2265 30 mg/day or 20 u03bcg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Without specific interventions, u223c80 of subjects with u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes care, id ITEM-1, issue suppl 1, issued date-parts 2004 , page S79-83, title Nephropathy in diabetes., type article-journal, volume 27 Suppl 1 , uris http//www.mendeley.com/documents/uuid75909499-bade-47db-82fa-e60f22f9c9dc , mendeley formattedCitation (American Diabetes Association, 2004), plainTextFormattedCitation (American Diabetes Association, 2004), previouslyFormattedCitation (American Diabetes Association, 2004) , properties noteIndex 18 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2004). Diabetic nephropathy is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases and it stimulates cardiovascular disorders and events increasing the risk of death ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.28.1.164, ISBN 0149-5992, ISSN 0149-5992, PMID 15616252, abstract Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects u03f340 of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages mi-croalbuminuria (UAE u03fe20 u242eg/min and u0545199 u242eg/min) and macroalbuminuria (UAE u0546200 u242eg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro-and macroalbuminuria should undergo an evaluation regarding the presence of comor-bid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c u03fd7), treating hypertension (u03fd130/80 mmHg or u03fd125/75 mmHg if proteinuria u03fe1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol u03fd100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the pro-gression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes., author dropping-particle , family Gross, given Jorge L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Azevedo, given Mirela J, non-dropping-particle De, parse-names false, suffix , dropping-particle , family Silveiro, given Sandra P, non-dropping-particle , parse-names false, suffix , dropping-particle , family Canani, given Henrique, non-dropping-particle , parse-names false, suffix , dropping-particle , family Caramori, given Maria Luiza, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zelmanovitz, given Themis, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issued date-parts 2005 , page 176-188, title Diabetic Nephropathy Diagnosis, Prevention, and Treatment, type article-journal, volume 28 , uris http//www.mendeley.com/documents/uuid8228bd2b-1071-4001-b91b-468325331ebe , mendeley formattedCitation (Jorge L Gross et al., 2005), plainTextFormattedCitation (Jorge L Gross et al., 2005), previouslyFormattedCitation (Jorge L Gross et al., 2005) , properties noteIndex 18 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Jorge L Gross et al., 2005). Screening, Diagnosis and Staging Three methods are described in screening for the presence of microalbuminuria (i) measurement of the albumin-to-creatinine ratio in a random or spot urine sample (ii) 24-h urine collection with creatinine determination and simultaneous measurement of creatinine clearance and (iii) timed (e.g., 4-h or overnight) urine collection ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.27.2007.s79, ISBN 0065-2598, ISSN 0149-5992, PMID 14693934, abstract Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe this is due to the facts that 1 ) diabetes, particularly type 2, is increasing in prevalence 2 ) diabetes patients now live longer and 3 ) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40 of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of 15.6 billion. About 20u201330 of patients with type 1 or type 2 diabetes develop evidence of nephropathy, but in type 2 diabetes, a considerably smaller fraction of these progress to ESRD. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis. There is considerable racial/ethnic variability in this regard, with Native Americans, Hispanics (especially Mexican-Americans), and African-Americans having much higher risks of developing ESRD than non-Hispanic whites with type 2 diabetes. Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy.nnThe earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (u2265 30 mg/day or 20 u03bcg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Without specific interventions, u223c80 of subjects with u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes care, id ITEM-1, issue suppl 1, issued date-parts 2004 , page S79-83, title Nephropathy in diabetes., type article-journal, volume 27 Suppl 1 , uris http//www.mendeley.com/documents/uuid75909499-bade-47db-82fa-e60f22f9c9dc , mendeley formattedCitation (American Diabetes Association, 2004), plainTextFormattedCitation (American Diabetes Association, 2004), previouslyFormattedCitation (American Diabetes Association, 2004) , properties noteIndex 18 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2004). The American Diabetes Association (ADA) recommends measuring albumin in a spot urine sample as the first step in the screening and diagnosis of diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.27.2007.s79, ISBN 0065-2598, ISSN 0149-5992, PMID 14693934, abstract Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe this is due to the facts that 1 ) diabetes, particularly type 2, is increasing in prevalence 2 ) diabetes patients now live longer and 3 ) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40 of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of 15.6 billion. About 20u201330 of patients with type 1 or type 2 diabetes develop evidence of nephropathy, but in type 2 diabetes, a considerably smaller fraction of these progress to ESRD. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis. There is considerable racial/ethnic variability in this regard, with Native Americans, Hispanics (especially Mexican-Americans), and African-Americans having much higher risks of developing ESRD than non-Hispanic whites with type 2 diabetes. Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy.nnThe earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (u2265 30 mg/day or 20 u03bcg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Without specific interventions, u223c80 of subjects with u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes care, id ITEM-1, issue suppl 1, issued date-parts 2004 , page S79-83, title Nephropathy in diabetes., type article-journal, volume 27 Suppl 1 , uris http//www.mendeley.com/documents/uuid75909499-bade-47db-82fa-e60f22f9c9dc , mendeley formattedCitation (American Diabetes Association, 2004), plainTextFormattedCitation (American Diabetes Association, 2004), previouslyFormattedCitation (American Diabetes Association, 2004) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2004). This is easy to perform and accurate. Working with 24-hour and timed urine collections are rather clumsy and usually prone to sample collection errors or those errors associated with recording of time. UAE values of spot urine collections may be expressed as urinary albumin concentration (mg/l) ADDIN CSL_CITATION citationItems id ITEM-1, itemData abstract 300 Multiple ChoicesThis is a pdf-only article and there is no markup to show you.full-text.pdf, author dropping-particle , family Gross, given J L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zelmanovitz, given T, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oliveira, given J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Azevedo, given M J, non-dropping-particle de, parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 9, issued date-parts 1999, 9, 1 , page 1599 LP – 1600, title Screening for diabetic nephropathy is measurement of urinary albumin-to-creatinine ratio worthwhile, type article-journal, volume 22 , uris http//www.mendeley.com/documents/uuid1df68f1e-1584-4883-a00a-b2441b5d9be2 , mendeley formattedCitation (J L Gross, Zelmanovitz, Oliveira, de Azevedo, 1999), plainTextFormattedCitation (J L Gross, Zelmanovitz, Oliveira, de Azevedo, 1999), previouslyFormattedCitation (J L Gross, Zelmanovitz, Oliveira, de Azevedo, 1999) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (J L Gross, Zelmanovitz, Oliveira, de Azevedo, 1999) or as urinary albumin-to-creatinine ratio (mg/g or mg/mmol) ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.27.2007.s79, ISBN 0065-2598, ISSN 0149-5992, PMID 14693934, abstract Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe this is due to the facts that 1 ) diabetes, particularly type 2, is increasing in prevalence 2 ) diabetes patients now live longer and 3 ) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40 of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of 15.6 billion. About 20u201330 of patients with type 1 or type 2 diabetes develop evidence of nephropathy, but in type 2 diabetes, a considerably smaller fraction of these progress to ESRD. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis. There is considerable racial/ethnic variability in this regard, with Native Americans, Hispanics (especially Mexican-Americans), and African-Americans having much higher risks of developing ESRD than non-Hispanic whites with type 2 diabetes. Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy.nnThe earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (u2265 30 mg/day or 20 u03bcg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Without specific interventions, u223c80 of subjects with u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes care, id ITEM-1, issue suppl 1, issued date-parts 2004 , page S79-83, title Nephropathy in diabetes., type article-journal, volume 27 Suppl 1 , uris http//www.mendeley.com/documents/uuid75909499-bade-47db-82fa-e60f22f9c9dc , id ITEM-2, itemData DOI 10.1016/S0272-6386(03)00826-6, ISSN 0272-6386, author dropping-particle , family Eknoyan, given Garabed, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hostetter, given Thomas, non-dropping-particle , parse-names false, suffix , dropping-particle , family Bakris, given George L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hebert, given Lee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Levey, given Andrew S, non-dropping-particle , parse-names false, suffix , dropping-particle , family Parving, given Hans-Henrik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Steffes, given Michael W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Toto, given Robert, non-dropping-particle , parse-names false, suffix , container-title American Journal of Kidney Diseases, id ITEM-2, issue 4, issued date-parts 2003, 4, 2 , note doi 10.1016/S0272-6386(03)00826-6, page 617-622, publisher Elsevier, title Proteinuria and other markers of chronic kidney disease a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK) 1, type article-journal, volume 42 , uris http//www.mendeley.com/documents/uuiddc49790f-c156-4e36-b3d6-df93016e62ca , mendeley formattedCitation (American Diabetes Association, 2004 Eknoyan et al., 2003), plainTextFormattedCitation (American Diabetes Association, 2004 Eknoyan et al., 2003), previouslyFormattedCitation (American Diabetes Association, 2004 Eknoyan et al., 2003) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2004 Eknoyan et al., 2003). Although still accurate and less expensive, expressing UAE as albumin concentration (mg/l) might be affected by dilution or concentration of the urine sample ADDIN CSL_CITATION citationItems id ITEM-1, itemData abstract 300 Multiple ChoicesThis is a pdf-only article and there is no markup to show you.full-text.pdf, author dropping-particle , family Gross, given J L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zelmanovitz, given T, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oliveira, given J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Azevedo, given M J, non-dropping-particle de, parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 9, issued date-parts 1999, 9, 1 , page 1599 LP – 1600, title Screening for diabetic nephropathy is measurement of urinary albumin-to-creatinine ratio worthwhile, type article-journal, volume 22 , uris http//www.mendeley.com/documents/uuid1df68f1e-1584-4883-a00a-b2441b5d9be2 , mendeley formattedCitation (J L Gross et al., 1999), plainTextFormattedCitation (J L Gross et al., 1999), previouslyFormattedCitation (J L Gross et al., 1999) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (J L Gross et al., 1999). Screening for nephropathy should be done in the absence of conditions such as urinary tract infection, hematuria, acute febrile illness, vigorous exercise, short-term pronounced hyperglycemia, uncontrolled hypertension, and heart failure as these falsely increase UAE ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vestro, given Else, non-dropping-particle , parse-names false, suffix , dropping-particle , family Poulsen, given Per Logstrup, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christiansen, given Christian, non-dropping-particle , parse-names false, suffix , dropping-particle , family Damsgaard, given Else Marie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Elskjaer, given Hans, non-dropping-particle , parse-names false, suffix , dropping-particle , family Froland, given Anders, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hansen, given Klavs Wurgler, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nielsen, given Steen, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pedersen, given Margrethe Mau, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 4, issued date-parts 1995 , page 572-581, title Microalbuminuria and Potential Confounders, type article-journal, volume 18 , uris http//www.mendeley.com/documents/uuidc1a59cb3-555a-408f-ad63-448da1c7a151 , mendeley formattedCitation (Carl Erik Mogensen et al., 1995), plainTextFormattedCitation (Carl Erik Mogensen et al., 1995), previouslyFormattedCitation (Carl Erik Mogensen et al., 1995) , properties noteIndex 0 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Carl Erik Mogensen et al., 1995). Categorization of diabetic nephropathy (DN) is established based on the extent of urinary albumin excretion (UAE) using timed, 24hour or spot urine collection as indicated in the table below Table 1Definitions of abnormalities in albumin excretion CategorySpot collection (g/mg creatinine)24-h collection (mg/24 h)Timed collection Stage 1 – Early hypertrophy-hyperfunction This marks the initial phase of the progression of diabetic nephropathy. However, pathologic changes that affect the structure, biochemistry, and function of the kidneys are found to have been occurring before clinical onset and diagnosis of diabetes before insulin treatment is started ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given C E, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christensen, given C K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vittinghus, given E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue June, issued date-parts 1983 , page 64-78, title The Stages in Diabetic Renal Disease With Emphasis on the Stage of Incipient Diabetic Nephropathy, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid07040b25-c189-4e72-916d-b176e4c3b4a2 , mendeley formattedCitation (C E Mogensen, Christensen, Vittinghus, 1983), plainTextFormattedCitation (C E Mogensen, Christensen, Vittinghus, 1983), previouslyFormattedCitation (C E Mogensen, Christensen, Vittinghus, 1983) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (C E Mogensen, Christensen, Vittinghus, 1983). Investigations carried out in both human and animal diabetic models revealed that renal tissues increased in size and rate of function, and this increase is marked early in the course of the disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Steffes, given Michael W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Deckert, given T., non-dropping-particle , parse-names false, suffix , dropping-particle , family Christiansen, given Sandahl J., non-dropping-particle , parse-names false, suffix , container-title Diabetologia, id ITEM-1, issued date-parts 1981 , page 89-93, title Functional and Morphological Renal Manifestations in Diabetes Mellitus, type article-journal, volume 21 , uris http//www.mendeley.com/documents/uuid51fc6565-f9ad-4c54-9b61-1bc7231189a7 , id ITEM-2, itemData ISSN 0012-1797 (Print), PMID 7160536, abstract Diabetic glomerulosclerosis in man and in all spontaneous-onset and chemically induced diabetes in experimental models is characterized by diffuse increase in mesangial matrix and glomerular basement membrane thickening. The most prominent features of the biochemical changes in the glomerular basement membrane are increase in the collagen-like components, decreased sialic acid, and increased glucosylation. However, the heterogeneity of the various glycoprotein components of the glomerular basement membrane and related components of the mesangium make comparative biochemistry difficult. Increased glomerular blood flow with no apparent alterations in the glomerular filtration coefficient in diabetes may be attributed to altered vascular control mechanisms which may include both hormonal mediation as well as changes in end-organ responsiveness. Although proteinuria is a common manifestation of diabetic involvement of the glomerulus, there is little biochemical or physiologic evidence as to the specific causes of increased glomerular filtration apparatus permeability. Further information as to the pathogenesis of diabetic vascular disease of the kidney and the ability to reverse pathologic changes by correction of the metabolic milieu will require analysis of carefully selected animal models. Particular care in experimental design must include the ability to integrate pathology, physiology, and biochemistry in each model in order to relate the information to human renal diabetic complications., author dropping-particle , family Brown, given D M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Andres, given G A, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hostetter, given T H, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mauer, given S M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Price, given R, non-dropping-particle , parse-names false, suffix , dropping-particle , family Venkatachalam, given M A, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-2, issue Suppl 1 Pt 2, issued date-parts 1982 , language eng, page 71-81, publisher-place United States, title Kidney complications., type article-journal, volume 31 , uris http//www.mendeley.com/documents/uuid70ad1cc7-0e3e-4046-8cea-ed9f0e2357d7 , mendeley formattedCitation (Brown et al., 1982 Carl Erik Mogensen, Steffes, Deckert, Christiansen, 1981), plainTextFormattedCitation (Brown et al., 1982 Carl Erik Mogensen, Steffes, Deckert, Christiansen, 1981), previouslyFormattedCitation (Brown et al., 1982 Carl Erik Mogensen, Steffes, Deckert, Christiansen, 1981) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Brown et al., 1982 Carl Erik Mogensen, Steffes, Deckert, Christiansen, 1981). It was suggested that the abnormality results from slowly reversible metabolic defects and renal hypertrophy and hyperfunction is gradually corrected over a few months using standard insulin therapy with partial restoration of renal function (as measured by eGFR) occurring first ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1038/ki.1982.81, ISSN 00852538, PMID 7050506, abstract GFR, RPF, and kidney size were measured in nine young recently diagnosed insulin-dependent diabetics before (days 0) and 3 and 8 days after the beginning of the initial insulin treatment and in comparable control subjects. Kidney function was measured by a constant infusion technique using I-125-iothalamate and 131-I-hippuran. Kidney size was determined by means of ultrasound. Before insulin treatment elevated values for GFR (44, P less than 0.01), RPF (18, P less than 0.05), and kidney size (29, P less than 0.01) were found. Near-normal metabolic control was achieved in all patients using either multiple subcutaneous injections of insulin or an artificial betacell. GFR decreased from 160 /- 9 SEM to 141 /- 6 ml/min X 1.73 m2 (P less than 0.01) and further to 133 /- 5 ml/min X 1.73 m2 (P less than 0.01, compared to day 0). Renal plasma flow was 601 /- 33 and 588 /- 44 ml x 1.73 m2 at days 0 and 3, respectively (NS) and decreased to 558 /- 35 ml/min x 1.73 m2 at day 0 (P less than 0.01). By contrast no statistically significant changes in kidney volume were observed the results on day 0, 3 and 8 were 145 /- 7, 162 /- 11 and 143 /- 9 ml/1.73 m2, respectively. The present study demonstrates that kidney size and function are elevated at the onset of insulin-dependent diabetes. Near-normal metabolic control for 8 days induces a reduction but not a complete normalization in kidney function. From the present observations it is suggested that the rapidly reversible part of the elevation in GFR cannot be explained by concomitant changes in kidney and glomerular size (morphological origin) but is probably due to a reduction in renal plasma flow and to a decreased transglomerular pressure (functional origin)., author dropping-particle , family Christiansen, given J. S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Gammelgaard, given J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Tronier, given B., non-dropping-particle , parse-names false, suffix , dropping-particle , family Svendsen, given P. A., non-dropping-particle , parse-names false, suffix , dropping-particle , family Parving, given H. H., non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-1, issue 5, issued date-parts 1982 , page 683-688, publisher Elsevier Masson SAS, title Kidney function and size in diabetics before and during initial insulin treatment, type article-journal, volume 21 , uris http//www.mendeley.com/documents/uuid0d109eb6-ab9b-4b40-9859-c4a72c17cb4d , mendeley formattedCitation (Christiansen, Gammelgaard, Tronier, Svendsen, Parving, 1982), plainTextFormattedCitation (Christiansen, Gammelgaard, Tronier, Svendsen, Parving, 1982), previouslyFormattedCitation (Christiansen, Gammelgaard, Tronier, Svendsen, Parving, 1982) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Christiansen, Gammelgaard, Tronier, Svendsen, Parving, 1982). In a study using the rate of dextran clearance expressed as GFR ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , chapter-number Pathophysi, container-title Handbook of Diabetes Biochemical Pathology., edition 4th, editor dropping-particle , family Brownlee, given M, non-dropping-particle , parse-names false, suffix , id ITEM-1, issued date-parts 1981 , page 23-85, publisher Garland STPM Press, publisher-place New York, London, title Pathophysiology of diabetic complications. Abnormal physiological processes in kidney, type chapter, volume 4 , uris http//www.mendeley.com/documents/uuid4ac1a04e-a616-4e9f-bf13-62431aa85eab , mendeley formattedCitation (Carl Erik Mogensen, 1981), plainTextFormattedCitation (Carl Erik Mogensen, 1981), previouslyFormattedCitation (Carl Erik Mogensen, 1981) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Carl Erik Mogensen, 1981), it was reported that dextran clearance was normal in patients at stage 1 of diabetic nephropathy. Stage 2 Asymptomatic Glomerular Lesions The fenestrated endothelium, glomerular basement membrane, podocyte foot processes and slit diaphragms together form the glomerular filtration barrier. Proteinuria often develops after one or more of these components is compromised in structural integrity and/or function and in some cases, may be ultimately associated with podocyte effacement ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1681/ASN.2006060628, ISSN 1046-6673 (Print), PMID 16914535, abstract Renal biopsies of patients with proteinuria and kidney disease most often are associated with podocyte foot process effacement. For several decades, nephrologists have wondered whether proteinuria is a result of podocyte foot process effacement or the cause of it. In the past few years, the authors laboratory has addressed this issue using different mouse models of proteinuria. Although in most cases, podocyte effacement is associated with proteinuria and glomerular disease, in three different mouse models, it was demonstrated that proteinuria can be observed without podocyte foot process effacement. The first model is generated by injection of antibodies to vascular endothelial growth factor or soluble vascular endothelial growth factor receptor 1. The second model is a mouse with deletion of type IV collagen alpha3 chain in the glomerular basement membrane. The third model was generated by genetic deletion of a slit diaphragm protein known as nephrin. Collectively, these experiments and the supporting evidence from several human studies demonstrate that severe defects in either the glomerular basement membrane or the glomerular endothelium can lead to proteinuria without foot process effacement., author dropping-particle , family Kalluri, given Raghu, non-dropping-particle , parse-names false, suffix , container-title Journal of the American Society of Nephrology JASN, id ITEM-1, issue 9, issued date-parts 2006, 9 , language eng, page 2383-2389, publisher-place United States, title Proteinuria with and without renal glomerular podocyte effacement., type article, volume 17 , uris http//www.mendeley.com/documents/uuidff3477ef-352b-4a55-a648-009ed1d9aa30 , mendeley formattedCitation (Kalluri, 2006), plainTextFormattedCitation (Kalluri, 2006), previouslyFormattedCitation (Kalluri, 2006) , properties noteIndex 25 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kalluri, 2006). Despite the fact that most patients with type 2 diabetes and microalbuminuria usually develop the classic lesions of the KimmelstielWilson syndrome, a significant proportion tend to develop nonspecific vascular and interstitial lesions with little or no glomerular changes ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Ritz, given Eberhard, non-dropping-particle , parse-names false, suffix , dropping-particle , family Orth, given Stephan Reinhold, non-dropping-particle , parse-names false, suffix , container-title The New England Journal of Medicine, id ITEM-1, issue 15, issued date-parts 1999 , page 1127-1133, title Nephropathy in patients with type 2 diabetes mellitus, type article-journal, volume 341 , uris http//www.mendeley.com/documents/uuid165cae9a-b1cc-4e9d-b207-6b89ef4a68d3 , mendeley formattedCitation (Ritz Orth, 1999), plainTextFormattedCitation (Ritz Orth, 1999), previouslyFormattedCitation (Ritz Orth, 1999) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Ritz Orth, 1999). Naturally, it is expected that after standard insulin treatment and glycemic control is started, renal function will be normalized. However, some studies based on the classical renal function test put forward by Homer Smith, have demonstrated a trend of increased glomerular filtration rate of about 20-30 in controlled cases and about 30-40 increase in cases where standard insulin treatment is absent ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1142/9789814340816_0017, ISBN 9789814340816, ISSN 0092-2900 (Print), PMID 55997, author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-1, issue 5, issued date-parts 1982 , page 673-675, publisher Elsevier Masson SAS, title Diabetes mellitus and the kidney, type article-journal, volume 21 , uris http//www.mendeley.com/documents/uuided67c334-1b1c-4057-8185-0c9e8928e90f , id ITEM-2, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , chapter-number Pathophysi, container-title Handbook of Diabetes Biochemical Pathology., edition 4th, editor dropping-particle , family Brownlee, given M, non-dropping-particle , parse-names false, suffix , id ITEM-2, issued date-parts 1981 , page 23-85, publisher Garland STPM Press, publisher-place New York, London, title Pathophysiology of diabetic complications. Abnormal physiological processes in kidney, type chapter, volume 4 , uris http//www.mendeley.com/documents/uuid4ac1a04e-a616-4e9f-bf13-62431aa85eab , id ITEM-3, itemData DOI 10.1038/ki.1982.81, ISSN 00852538, PMID 7050506, abstract GFR, RPF, and kidney size were measured in nine young recently diagnosed insulin-dependent diabetics before (days 0) and 3 and 8 days after the beginning of the initial insulin treatment and in comparable control subjects. Kidney function was measured by a constant infusion technique using I-125-iothalamate and 131-I-hippuran. Kidney size was determined by means of ultrasound. Before insulin treatment elevated values for GFR (44, P less than 0.01), RPF (18, P less than 0.05), and kidney size (29, P less than 0.01) were found. Near-normal metabolic control was achieved in all patients using either multiple subcutaneous injections of insulin or an artificial betacell. GFR decreased from 160 /- 9 SEM to 141 /- 6 ml/min X 1.73 m2 (P less than 0.01) and further to 133 /- 5 ml/min X 1.73 m2 (P less than 0.01, compared to day 0). Renal plasma flow was 601 /- 33 and 588 /- 44 ml x 1.73 m2 at days 0 and 3, respectively (NS) and decreased to 558 /- 35 ml/min x 1.73 m2 at day 0 (P less than 0.01). By contrast no statistically significant changes in kidney volume were observed the results on day 0, 3 and 8 were 145 /- 7, 162 /- 11 and 143 /- 9 ml/1.73 m2, respectively. The present study demonstrates that kidney size and function are elevated at the onset of insulin-dependent diabetes. Near-normal metabolic control for 8 days induces a reduction but not a complete normalization in kidney function. From the present observations it is suggested that the rapidly reversible part of the elevation in GFR cannot be explained by concomitant changes in kidney and glomerular size (morphological origin) but is probably due to a reduction in renal plasma flow and to a decreased transglomerular pressure (functional origin)., author dropping-particle , family Christiansen, given J. S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Gammelgaard, given J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Tronier, given B., non-dropping-particle , parse-names false, suffix , dropping-particle , family Svendsen, given P. A., non-dropping-particle , parse-names false, suffix , dropping-particle , family Parving, given H. H., non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-3, issue 5, issued date-parts 1982 , page 683-688, publisher Elsevier Masson SAS, title Kidney function and size in diabetics before and during initial insulin treatment, type article-journal, volume 21 , uris http//www.mendeley.com/documents/uuid0d109eb6-ab9b-4b40-9859-c4a72c17cb4d , mendeley formattedCitation (Christiansen et al., 1982 Carl Erik Mogensen, 1981, 1982), plainTextFormattedCitation (Christiansen et al., 1982 Carl Erik Mogensen, 1981, 1982), previouslyFormattedCitation (Christiansen et al., 1982 Carl Erik Mogensen, 1981, 1982) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Christiansen et al., 1982 Carl Erik Mogensen, 1981, 1982). The inability of standard insulin therapy to obtain a perfect metabolic control is thought of as a likely reason for this observation ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given C E, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christensen, given C K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vittinghus, given E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue June, issued date-parts 1983 , page 64-78, title The Stages in Diabetic Renal Disease With Emphasis on the Stage of Incipient Diabetic Nephropathy, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid07040b25-c189-4e72-916d-b176e4c3b4a2 , mendeley formattedCitation (C E Mogensen et al., 1983), plainTextFormattedCitation (C E Mogensen et al., 1983), previouslyFormattedCitation (C E Mogensen et al., 1983) , properties noteIndex 25 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (C E Mogensen et al., 1983). Stage 3 Incipient diabetic nephropathy Stage 4 Overt Diabetic Nephropathy This stage which seems to be neither reversible nor arrestable by standard insulin therapy, but its rate of advancement reduced by early antihypertensive therapy, is characterized by progressive clinical proteinuria with concomitant decline in GFR and abnormal blood pressure of about 160/105mmHg ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given C E, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christensen, given C K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vittinghus, given E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue June, issued date-parts 1983 , page 64-78, title The Stages in Diabetic Renal Disease With Emphasis on the Stage of Incipient Diabetic Nephropathy, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid07040b25-c189-4e72-916d-b176e4c3b4a2 , mendeley formattedCitation (C E Mogensen et al., 1983), plainTextFormattedCitation (C E Mogensen et al., 1983), previouslyFormattedCitation (C E Mogensen et al., 1983) , properties noteIndex 25 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (C E Mogensen et al., 1983). At the level of overt diabetic nephropathy, urine albumin excretions increase up to 300mg/ and beyond. Now, the stage of incipient diabetic nephropathy is of great interest due to the fact that with consistent metabolic and hypertensive control, not all patients who show early changes in renal structure and function will progress to the stage of overt diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given C E, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christensen, given C K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vittinghus, given E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue June, issued date-parts 1983 , page 64-78, title The Stages in Diabetic Renal Disease With Emphasis on the Stage of Incipient Diabetic Nephropathy, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid07040b25-c189-4e72-916d-b176e4c3b4a2 , mendeley formattedCitation (C E Mogensen et al., 1983), plainTextFormattedCitation (C E Mogensen et al., 1983), previouslyFormattedCitation (C E Mogensen et al., 1983) , properties noteIndex 25 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (C E Mogensen et al., 1983). In using the rate of clearance of high molecular weight dextran, it was reported that the late changes of renal functional and structure that occur in patients who had developed overt dabetic nephropathy are somewhat nonspecific and may be similar to changes that occur in advanced nephropathy due to other renal disorders ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given C E, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christensen, given C K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vittinghus, given E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue June, issued date-parts 1983 , page 64-78, title The Stages in Diabetic Renal Disease With Emphasis on the Stage of Incipient Diabetic Nephropathy, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid07040b25-c189-4e72-916d-b176e4c3b4a2 , mendeley formattedCitation (C E Mogensen et al., 1983), plainTextFormattedCitation (C E Mogensen et al., 1983), previouslyFormattedCitation (C E Mogensen et al., 1983) , properties noteIndex 25 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (C E Mogensen et al., 1983). Certain changes that occur in early diabetes lead to the more advanced changes that are observed later in the course of diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1142/9789814340816_0017, ISBN 9789814340816, ISSN 0092-2900 (Print), PMID 55997, author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-1, issue 5, issued date-parts 1982 , page 673-675, publisher Elsevier Masson SAS, title Diabetes mellitus and the kidney, type article-journal, volume 21 , uris http//www.mendeley.com/documents/uuided67c334-1b1c-4057-8185-0c9e8928e90f , id ITEM-2, itemData ISSN 0002-9343 (Print), PMID 7036732, author dropping-particle , family Hostetter, given T H, non-dropping-particle , parse-names false, suffix , dropping-particle , family Rennke, given H G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Brenner, given B M, non-dropping-particle , parse-names false, suffix , container-title The American journal of medicine, id ITEM-2, issue 3, issued date-parts 1982, 3 , language eng, page 375-380, publisher-place United States, title The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies., type article-journal, volume 72 , uris http//www.mendeley.com/documents/uuidcf0c4ef7-4dfb-4b90-ba12-cfee7057ca73 , mendeley formattedCitation (Hostetter, Rennke, Brenner, 1982 Carl Erik Mogensen, 1982), plainTextFormattedCitation (Hostetter, Rennke, Brenner, 1982 Carl Erik Mogensen, 1982), previouslyFormattedCitation (Hostetter, Rennke, Brenner, 1982 Carl Erik Mogensen, 1982) , properties noteIndex 26 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Hostetter, Rennke, Brenner, 1982 Carl Erik Mogensen, 1982). These changes include thickening of the glomerular basement membrane due to increased tissue contents which is seen in the early stages as an increase in the glomerular filtration surface area. hemodynamic abnormalities usually confirmed by an increase in glomerular filtration pressure which may eventually lead to disruption of glomerular tissue structure. abnormal extravasation of plasma protein, which is likely due to the increased glomerular filtration pressure. These underlying mechanisms may either function alone or as a network. End-stage renal disease Final Outcome Proteinuria is a strong risk factor for the development of ESRD and tits incidence has been shown to increase proportionally with the extent of proteinuria ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1046/j.1523-1755.2003.00868.x, ISSN 0085-2538, author dropping-particle , family Iseki, given Kunitoshi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ikemiya, given Yoshiharu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Iseki, given Chiho, non-dropping-particle , parse-names false, suffix , dropping-particle , family Takishita, given Shuichi, non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-1, issue 4, issued date-parts 2002, 4, 14 , note doi 10.1046/j.1523-1755.2003.00868.x, page 1468-1474, publisher Elsevier, title Proteinuria and the risk of developing end-stage renal disease, type article-journal, volume 63 , uris http//www.mendeley.com/documents/uuid6a60df6d-4c2f-4424-99bc-4775db25d9c9 , mendeley formattedCitation (Iseki, Ikemiya, Iseki, Takishita, 2002), plainTextFormattedCitation (Iseki, Ikemiya, Iseki, Takishita, 2002), previouslyFormattedCitation (Iseki, Ikemiya, Iseki, Takishita, 2002) , properties noteIndex 27 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Iseki, Ikemiya, Iseki, Takishita, 2002). People who reach this stage require periodic hemodialysis as the filtration system of the kidneys fail. In the course of ESRD, diabetic foot problems occur more frequently although developing cardiovascular disease may be asymptomatic in such patients ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Ritz, given Eberhard, non-dropping-particle , parse-names false, suffix , dropping-particle , family Orth, given Stephan Reinhold, non-dropping-particle , parse-names false, suffix , container-title The New England Journal of Medicine, id ITEM-1, issue 15, issued date-parts 1999 , page 1127-1133, title Nephropathy in patients with type 2 diabetes mellitus, type article-journal, volume 341 , uris http//www.mendeley.com/documents/uuid165cae9a-b1cc-4e9d-b207-6b89ef4a68d3 , mendeley formattedCitation (Ritz Orth, 1999), plainTextFormattedCitation (Ritz Orth, 1999), previouslyFormattedCitation (Ritz Orth, 1999) , properties noteIndex 27 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Ritz Orth, 1999). Progression of DN especially to the stage of ESRD is associated with cardiovascular morbidity and mortality. Thus, it is important to adopt patient-specific therapy that takes into consideration factors such as age, type and duration of diabetes to achieve maximum results ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 1872-9061 (Electronic), PMID 24218418, abstract Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and development of end-stage renal disease (ESRD) remain major concerns in diabetes. In addition, diabetic patients with microalbuminuria have an increased cardiovascular mortality. Therefore, new treatment modalities or strategies are needed to prevent or slow the progression of diabetic nephropathy and prevent cardiovascular disease in diabetes. In this review we describe current concepts in pathophysiology, treatment goals and we discuss future developments in the treatment of diabetic nephropathy. Common risk factors for diabetic nephropathy and its progression are longer duration, poor glycaemic control, hypertension and the presence of albuminuria. Available treatment options, especially renin-angiotensin aldosterone system (RAAS) blockade, but also better blood pressure and blood glucose control, decrease the incidence of cardiovascular disease and renal disease in diabetes. It is important that treatment goals are tailored to the individual patient with individual treatment goals of glycaemic control and blood pressure, depending on age, type of diabetes and diabetes duration. Aggressive treatment of glucose control and blood pressure might not always be best practice for every patient. Since the proportion of ESRD due to diabetic nephropathy remains high, optimisation of RAAS blockade is advocated and can be achieved by adequate sodium restriction and/or diuretic treatment. Moreover, aldosterone blockade might be a valuable strategy, which has potency to slow the progression of diabetic renal disease. Other possible future interventions are under investigation, but large clinical trials have to be awaited to confirm the safety and efficacy of these drugs., author dropping-particle , family Waanders, given F, non-dropping-particle , parse-names false, suffix , dropping-particle , family Visser, given F W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gans, given R O B, non-dropping-particle , parse-names false, suffix , container-title The Netherlands journal of medicine, id ITEM-1, issue 9, issued date-parts 2013, 11 , language eng, page 448-458, publisher-place Netherlands, title Current concepts in the management of diabetic nephropathy., type article-journal, volume 71 , uris http//www.mendeley.com/documents/uuid348a390b-5c2e-4093-a15d-5847da99a06f , mendeley formattedCitation (Waanders, Visser, Gans, 2013), plainTextFormattedCitation (Waanders, Visser, Gans, 2013), previouslyFormattedCitation (Waanders, Visser, Gans, 2013) , properties noteIndex 28 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Waanders, Visser, Gans, 2013). Measurement of endogenous creatinine clearance instead of serum creatinine is recommended in assessing elderly female patients due to their reduced muscle mass which may yield an underestimated GFR ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Ritz, given Eberhard, non-dropping-particle , parse-names false, suffix , dropping-particle , family Orth, given Stephan Reinhold, non-dropping-particle , parse-names false, suffix , container-title The New England Journal of Medicine, id ITEM-1, issue 15, issued date-parts 1999 , page 1127-1133, title Nephropathy in patients with type 2 diabetes mellitus, type article-journal, volume 341 , uris http//www.mendeley.com/documents/uuid165cae9a-b1cc-4e9d-b207-6b89ef4a68d3 , mendeley formattedCitation (Ritz Orth, 1999), plainTextFormattedCitation (Ritz Orth, 1999), previouslyFormattedCitation (Ritz Orth, 1999) , properties noteIndex 27 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Ritz Orth, 1999). Epidemiology Up to 30 of patients with type 1 or type 2 diabetes develop evidence of diabetic nephropathy, but in type 2 diabetes, a considerably lesser proportion of patients progress to end stage renal failure ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.27.2007.s79, ISBN 0065-2598, ISSN 0149-5992, PMID 14693934, abstract Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe this is due to the facts that 1 ) diabetes, particularly type 2, is increasing in prevalence 2 ) diabetes patients now live longer and 3 ) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40 of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of 15.6 billion. About 20u201330 of patients with type 1 or type 2 diabetes develop evidence of nephropathy, but in type 2 diabetes, a considerably smaller fraction of these progress to ESRD. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis. There is considerable racial/ethnic variability in this regard, with Native Americans, Hispanics (especially Mexican-Americans), and African-Americans having much higher risks of developing ESRD than non-Hispanic whites with type 2 diabetes. Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy.nnThe earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (u2265 30 mg/day or 20 u03bcg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Without specific interventions, u223c80 of subjects with u2026, author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes care, id ITEM-1, issue suppl 1, issued date-parts 2004 , page S79-83, title Nephropathy in diabetes., type article-journal, volume 27 Suppl 1 , uris http//www.mendeley.com/documents/uuid75909499-bade-47db-82fa-e60f22f9c9dc , mendeley formattedCitation (American Diabetes Association, 2004), plainTextFormattedCitation (American Diabetes Association, 2004), previouslyFormattedCitation (American Diabetes Association, 2004) , properties noteIndex 19 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2004). However, the relatively higher prevalence of type 2 diabetes claims over half of all diabetic patients starting on dialysis. Moreover, there is significant racial and/or ethnic variability when it comes to the epidemiology of diabetic nephropathy. DN is more common among African Americans, Asians, and Native Americans than Caucasians (U.S. Renal Data System, 2003 ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Young, given Bessie A., non-dropping-particle , parse-names false, suffix , dropping-particle , family Maynard, given Charles, non-dropping-particle , parse-names false, suffix , dropping-particle , family Boyko, given Edward J., non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 8, issued date-parts 2003 , page 2392-2399, title Nephropathy , Cardiovascular Disease , and Mortality in a National Population, type article-journal, volume 26 , uris http//www.mendeley.com/documents/uuidc5bc0a06-b746-47e3-98ac-eb9616489e6b , mendeley formattedCitation (Young, Maynard, Boyko, 2003), manualFormatting Young, Maynard and Boyko, 2003), plainTextFormattedCitation (Young, Maynard, Boyko, 2003), previouslyFormattedCitation (Young, Maynard, Boyko, 2003) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json Young, Maynard and Boyko, 2003). Statistical figures on the prevalence of DN vary at rather large intervals. Depending on the definition of the disease and the method of assessment adapted in various studies, prevalence rates range from 10 to 40 for both type 1 and type 2 diabetes patient groups ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diacare.28.1.164, ISBN 0149-5992, ISSN 0149-5992, PMID 15616252, abstract Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects u03f340 of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages mi-croalbuminuria (UAE u03fe20 u242eg/min and u0545199 u242eg/min) and macroalbuminuria (UAE u0546200 u242eg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro-and macroalbuminuria should undergo an evaluation regarding the presence of comor-bid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c u03fd7), treating hypertension (u03fd130/80 mmHg or u03fd125/75 mmHg if proteinuria u03fe1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol u03fd100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the pro-gression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes., author dropping-particle , family Gross, given Jorge L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Azevedo, given Mirela J, non-dropping-particle De, parse-names false, suffix , dropping-particle , family Silveiro, given Sandra P, non-dropping-particle , parse-names false, suffix , dropping-particle , family Canani, given Henrique, non-dropping-particle , parse-names false, suffix , dropping-particle , family Caramori, given Maria Luiza, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zelmanovitz, given Themis, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issued date-parts 2005 , page 176-188, title Diabetic Nephropathy Diagnosis, Prevention, and Treatment, type article-journal, volume 28 , uris http//www.mendeley.com/documents/uuid8228bd2b-1071-4001-b91b-468325331ebe , id ITEM-2, itemData author dropping-particle , family Ritz, given Eberhard, non-dropping-particle , parse-names false, suffix , dropping-particle , family Orth, given Stephan Reinhold, non-dropping-particle , parse-names false, suffix , container-title The New England Journal of Medicine, id ITEM-2, issue 15, issued date-parts 1999 , page 1127-1133, title Nephropathy in patients with type 2 diabetes mellitus, type article-journal, volume 341 , uris http//www.mendeley.com/documents/uuid165cae9a-b1cc-4e9d-b207-6b89ef4a68d3 , mendeley formattedCitation (Jorge L Gross et al., 2005 Ritz Orth, 1999), plainTextFormattedCitation (Jorge L Gross et al., 2005 Ritz Orth, 1999), previouslyFormattedCitation (Jorge L Gross et al., 2005 Ritz Orth, 1999) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Jorge L Gross et al., 2005 Ritz Orth, 1999). In the U.K. Prospective Diabetes Study (UKPDS), the incidence of microalbuminuria in patients with type 2 diabetes was 2.0 per year and the prevalence 10 years after diagnosis was 25 while proteinuria ranges from 5 to 20 ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1046/j.1523-1755.2003.00712.x, ISBN 0085-2538 (Print)n0085-2538 (Linking), ISSN 00852538, PMID 12472787, abstract BACKGROUND The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death. METHODS Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease. RESULTS From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0 per year, from microalbuminuria to macroalbuminuria at 2.8 per year, and from macroalbuminuria to elevated plasma creatinine (or175 micromol/L) or renal replacement therapy at 2.3 per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9, of macroalbuminuria was 5.3, and of elevated plasma creatinine or RRT was 0.8. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2 (95 confidence interval, CI, 14.0 to 24.4). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P 0.0001), with an annual rate of 0.7 for subjects in the stage of no nephropathy, 2.0 for those with microalbuminuria, 3.5 for those with macroalbuminuria, and 12.1 with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure. CONCLUSIONS The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy., author dropping-particle , family Adler, given Amanda I., non-dropping-particle , parse-names false, suffix , dropping-particle , family Stevens, given Richard J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Manley, given Sue E., non-dropping-particle , parse-names false, suffix , dropping-particle , family Bilous, given Rudy W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Cull, given Carole A., non-dropping-particle , parse-names false, suffix , dropping-particle , family Holman, given Rury R., non-dropping-particle , parse-names false, suffix , container-title Kidney International, id ITEM-1, issue 1, issued date-parts 2003 , page 225-232, title Development and progression of nephropathy in type 2 diabetes The United Kingdom Prospective Diabetes Study (UKPDS 64), type article-journal, volume 63 , uris http//www.mendeley.com/documents/uuidfb595757-03a3-4174-9ae1-04e58581999d , mendeley formattedCitation (Adler et al., 2003), plainTextFormattedCitation (Adler et al., 2003), previouslyFormattedCitation (Adler et al., 2003) , properties noteIndex 7 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Adler et al., 2003). Pathogenesis and disease progression The readily proposed causes of DN include both metabolic alterations (hyperglycaemia and possibly hyperlipidaemia) and haemodynamic alterations (systemic and glomerular hypertension) ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Bennett, given Katie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Aditya, given Bhandari Sumer, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes Nursing, id ITEM-1, issue 2, issued date-parts 2015 , page 61-67, title An overview of diabetic nephropathy Epidemiology, pathophysiology and treatment., type article-journal, volume 19 , uris http//www.mendeley.com/documents/uuid87198b2b-365b-4372-8485-cc821b1c282f , mendeley formattedCitation (Bennett Aditya, 2015), plainTextFormattedCitation (Bennett Aditya, 2015), previouslyFormattedCitation (Bennett Aditya, 2015) , properties noteIndex 22 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Bennett Aditya, 2015). Nonetheless, other causes such as oxidative stress ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1007/s11154-008-9104-2, ISBN 1389-9155 (Print), ISSN 1389-9155, PMID 18709457, abstract Diabetic neuropathy is the most common complication of diabetes, affecting 50 of diabetic patients. Currently, the only treatment for diabetic neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in diabetic neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of diabetic neuropathy and to identify more effective molecular therapeutic targets., author dropping-particle , family Figueroa-Romero, given Claudia, non-dropping-particle , parse-names false, suffix , dropping-particle , family Sadidi, given Mahdieh, non-dropping-particle , parse-names false, suffix , dropping-particle , family Feldman, given Eva L, non-dropping-particle , parse-names false, suffix , container-title Reviews in endocrine metabolic disorders, id ITEM-1, issue 4, issued date-parts 2008 , page 301-14, title Mechanisms of disease the oxidative stress theory of diabetic neuropathy., type article-journal, volume 9 , uris http//www.mendeley.com/documents/uuid02f0aef7-9ef4-4a5a-92f8-f3f3c4d5dc3c , mendeley formattedCitation (Figueroa-Romero et al., 2008), plainTextFormattedCitation (Figueroa-Romero et al., 2008), previouslyFormattedCitation (Figueroa-Romero et al., 2008) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Figueroa-Romero et al., 2008) and microinflammation ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.diabres.2010.01.012, ISSN 01688227, PMID 20138680, abstract Aim This study aimed to evaluate the change of serum levels of proinflammatory molecules in patients with type 2 diabetes and clarify the involvement of these molecules in diabetic nephropathy and atherosclerosis. Methods Sixty-six Japanese type 2 diabetic patients (T2DM) and 39 healthy control subjects were enrolled. We assessed clinical parameters, urinary albumin excretion rate (AER), brachial-ankle pulse wave velocity (baPWV), intima media thickness (IMT) and serum levels of proinflammatory molecules. Results Serum levels of IL-6, IP-10 and MCP-1 were significantly higher in T2DM than in control subjects. In T2DM, serum levels of high-sensitivity (hs) CRP, IP-10, hsTNF-, VCAM-1 and E-selectin were positively correlated with AER. Serum levels of IP-10, hsTNF- and VCAM-1 were positively correlated with baPWV. Serum levels of hsCRP, IL-6, IP-10 and hsTNF- were positively correlated with IMT. Multiple linear regression analysis revealed that serum levels of hsTNF- were independently associated with AER (0.235, P0.038) and serum levels of IP-10 were independently associated with baPWV (0.209, P0.047) and IMT (0.303, P0.032). Conclusion Our results suggest that low-grade inflammation, microinflammation, may be a common risk factor for diabetic nephropathy and atherosclerosis in Japanese type 2 diabetic patients. 2010 Elsevier Ireland Ltd., author dropping-particle , family Kajitani, given Nobuo, non-dropping-particle , parse-names false, suffix , dropping-particle , family Shikata, given Kenichi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakamura, given Akihiko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakatou, given Tatsuaki, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hiramatsu, given Makoto, non-dropping-particle , parse-names false, suffix , dropping-particle , family Makino, given Hirofumi, non-dropping-particle , parse-names false, suffix , container-title Diabetes Research and Clinical Practice, id ITEM-1, issue 2, issued date-parts 2010 , page 171-176, publisher Elsevier Ireland Ltd, title Microinflammation is a common risk factor for progression of nephropathy and atherosclerosis in Japanese patients with type 2 diabetes, type article-journal, volume 88 , uris http//www.mendeley.com/documents/uuiddc7d75ba-5992-4bfb-a502-e54017743dab , mendeley formattedCitation (Kajitani et al., 2010), plainTextFormattedCitation (Kajitani et al., 2010), previouslyFormattedCitation (Kajitani et al., 2010) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kajitani et al., 2010) on which bilirubin and uric acid may have some effect, as well as endothelial dysfunction, are still under investigation. It has also been indicated that hyperglycemia and concomitant glucotoxicity initiates NADPH-oxidase dependent generation of reactive oxygen species (ROS) which induces podocyte apoptosis and this precedes significant levels of UAE, podocyte depletion, and mesangial matrix expansion ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/diabetes.55.01.06.db05-0894, ISSN 0012-1797, PMID 16380497, abstract Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demon-strate that podocyte apoptosis increased sharply with on-set of hyperglycemia in Ins2 Akita (Akita) mice with type 1 diabetes and Lepr db/db (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37 reduction) and db/db (27 reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular re-active oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapop-totic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apo-ptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic ne-phropathy in murine type 1 and type 2 diabetic models. Diabetes 55225u2013233, 2006 D iabetic nephropathy is a serious and common complication of type 1 and type 2 diabetes leading to end-stage renal disease (ESRD) in up to 30 of individuals with diabetes (1). The natural history of diabetic nephropathy has been delin-eated in particular in type 1 diabetes (2u2013 4). A latent period of several years after onset of diabetes is characterized by increased glomerular filtration rate without overt clinical signs and symptoms. The first manifestation of diabetic nephropathy in humans is increased urinary albumin ex-cretion, which usually progresses to nephrotic-range proteinuria. The morphological substrates for these func-tional abnormalities of the glomerular filter apparatus include glomerular hypertrophy, thickening of glomerular basement membrane, and expansion of mesangial extra-cellular matrix. Advanced diabetic nephropathy is charac-terized by glomerulosclerosis, demise of glomerular capillaries, tubulointerstitial degenerau2026, author dropping-particle , family Susztak, given Katalin, non-dropping-particle , parse-names false, suffix , dropping-particle , family Raff, given Amanda C, non-dropping-particle , parse-names false, suffix , dropping-particle , family Schiffer, given Mario, non-dropping-particle , parse-names false, suffix , dropping-particle , family Bu00f6ttinger, given Erwin P, non-dropping-particle , parse-names false, suffix , container-title Diabetes., id ITEM-1, issue January, issued date-parts 2006 , page 225-233, title Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and Podo …, type article-journal, volume 55 , uris http//www.mendeley.com/documents/uuidf110e80f-6b56-4d1d-b932-9b3879e1451f , mendeley formattedCitation (Susztak et al., 2006), plainTextFormattedCitation (Susztak et al., 2006), previouslyFormattedCitation (Susztak et al., 2006) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Susztak et al., 2006). A possible molecular link between ROS and p38 Mitogen-Activated Protein Kinase (MAP-K) proapoptotic pathway activation due to oxidative stress was also indicated ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1074/jbc.M311129200, ISBN 0021-9258 (Print), ISSN 00219258, PMID 14688258, abstract Oxidative stress has been indicated in a variety of pathological processes such as atherosclerosis, diabetes, and neurodegenerative diseases. Understanding how intracellular signaling pathways respond to oxidative insults such as hydrogen peroxide (H(2)O(2)) would have significant therapeutic implications. Recent genetic studies have placed apoptosis signal-regulating kinase 1 (ASK1) in a pivotal position in transmitting H(2)O(2)-initiated signals. How ASK1 is activated by H(2)O(2), though, remains a subject of intense investigation. Here we report a mechanism by which H(2)O(2) induces ASK1 activation through dynamic control of its phosphorylation at serine 967. We found that treatment of COS7 cells with H(2)O(2) triggers dephosphorylation of Ser-967 through an okadaic acid-sensitive phosphatase, resulting in dissociation of the ASK1.14-3-3 complex with concomitant increase of ASK1 catalytic activity and ASK1-mediated activation of JNK and p38 pathways., author dropping-particle , family Goldman, given Erinn H., non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Lei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Fu, given Haian, non-dropping-particle , parse-names false, suffix , container-title Journal of Biological Chemistry, id ITEM-1, issue 11, issued date-parts 2004 , page 10442-10449, title Activation of Apoptosis Signal-regulating Kinase 1 by Reactive Oxygen Species through Dephosphorylation at Serine 967 and 14-3-3 Dissociation, type article-journal, volume 279 , uris http//www.mendeley.com/documents/uuidd6220f06-a906-427d-9934-215820dc996c , mendeley formattedCitation (Goldman, Chen, Fu, 2004), plainTextFormattedCitation (Goldman, Chen, Fu, 2004), previouslyFormattedCitation (Goldman, Chen, Fu, 2004) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Goldman, Chen, Fu, 2004). The Metabolic Syndrome In about a third of patients with type 2 diabetes, hypertension is present at the time of diagnosis of diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Bennett, given Katie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Aditya, given Bhandari Sumer, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes Nursing, id ITEM-1, issue 2, issued date-parts 2015 , page 61-67, title An overview of diabetic nephropathy Epidemiology, pathophysiology and treatment., type article-journal, volume 19 , uris http//www.mendeley.com/documents/uuid87198b2b-365b-4372-8485-cc821b1c282f , mendeley formattedCitation (Bennett Aditya, 2015), plainTextFormattedCitation (Bennett Aditya, 2015), previouslyFormattedCitation (Bennett Aditya, 2015) , properties noteIndex 22 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Bennett Aditya, 2015). The usual finding of syndrome X or the metabolic syndrome characterized by glucose intolerance, elevated LDL cholesterol and triglycerides, and a reduction in HDL cholesterol, obesity, hypertension, and susceptibility to cardiovascular disease, indicates that a common abnormality such as insulin resistance may be the root cause ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue November 1996, issued date-parts 2002 , page 585-589, title Diabetic Nephropathy, type article-journal, volume 25 , uris http//www.mendeley.com/documents/uuidf6903ec9-bf46-4415-913f-3c7bdea14b04 , mendeley formattedCitation (American Diabetes Association, 2002), plainTextFormattedCitation (American Diabetes Association, 2002), previouslyFormattedCitation (American Diabetes Association, 2002) , properties noteIndex 22 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2002). Hypertension may also be associated with underlying diabetic nephropathy in type 2 diabetes patients ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family American Diabetes Association, given , non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue November 1996, issued date-parts 2002 , page 585-589, title Diabetic Nephropathy, type article-journal, volume 25 , uris http//www.mendeley.com/documents/uuidf6903ec9-bf46-4415-913f-3c7bdea14b04 , mendeley formattedCitation (American Diabetes Association, 2002), plainTextFormattedCitation (American Diabetes Association, 2002), previouslyFormattedCitation (American Diabetes Association, 2002) , properties noteIndex 22 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (American Diabetes Association, 2002). The Role of Oxidative Stress Nitric Oxide Depletion Nitric oxide released by endothelial cells as blood flow increases in an artery are depleted by oxidative stress thereby inhibiting flow-mediated dilation (FMD) of blood vessels as is seen in endothelial dysfunction which leads to endothelial injury ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Bennett, given Katie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Aditya, given Bhandari Sumer, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes Nursing, id ITEM-1, issue 2, issued date-parts 2015 , page 61-67, title An overview of diabetic nephropathy Epidemiology, pathophysiology and treatment., type article-journal, volume 19 , uris http//www.mendeley.com/documents/uuid87198b2b-365b-4372-8485-cc821b1c282f , mendeley formattedCitation (Bennett Aditya, 2015), plainTextFormattedCitation (Bennett Aditya, 2015), previouslyFormattedCitation (Bennett Aditya, 2015) , properties noteIndex 23 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Bennett Aditya, 2015). This is followed by the production of cytokines, acceleration of inflammation, worsening of blood vessel rigidity due to atherosclerosis, and further impairment of FMD and susceptibility to oxidative stress mediated tissue damage ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Bennett, given Katie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Aditya, given Bhandari Sumer, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes Nursing, id ITEM-1, issue 2, issued date-parts 2015 , page 61-67, title An overview of diabetic nephropathy Epidemiology, pathophysiology and treatment., type article-journal, volume 19 , uris http//www.mendeley.com/documents/uuid87198b2b-365b-4372-8485-cc821b1c282f , mendeley formattedCitation (Bennett Aditya, 2015), plainTextFormattedCitation (Bennett Aditya, 2015), previouslyFormattedCitation (Bennett Aditya, 2015) , properties noteIndex 23 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Bennett Aditya, 2015). Inflammation, endothelial dysfunction and oxidative stress can thus be considered as interrelated factors that leads to significant kidney damage and cardiovascular events. ROS from the Mitochondria Under physiological conditions, large proportions of the glucose that inflows cells are metabolized to pyruvate via glycolysis. Pyruvate then enters the Krebs cycle for the production of ATP, NADH and FADH2. Transport of the generated coenzymes (NADH and FADH2) from the cytosol into the mitochondria occurs via the malate-aspartate or the glycerol phosphate shuttle mechanisms, where they function as electron donors in the oxidative phosphorylation of other biomolecules ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0929-8673, abstract Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. , author dropping-particle , family Kashihara, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Haruna, given Y, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kondeti, given V K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanwar, given Y S, non-dropping-particle , parse-names false, suffix , container-title Current medicinal chemistry, id ITEM-1, issue 34, issued date-parts 2010 , page 4256-4269, title Oxidative Stress in Diabetic Nephropathy, type article-journal, volume 17 , uris http//www.mendeley.com/documents/uuid6ba79ae1-2d50-4229-9a16-67f94c523483 , mendeley formattedCitation (Kashihara et al., 2010), plainTextFormattedCitation (Kashihara et al., 2010), previouslyFormattedCitation (Kashihara et al., 2010) , properties noteIndex 31 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kashihara et al., 2010). Mitochondrial DNA (mtDNA) is considered more vulnerable to persistent and extensive damage due to oxidative stress since it is more deficient in histones as compared to nuclear DNA ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0929-8673, abstract Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. , author dropping-particle , family Kashihara, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Haruna, given Y, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kondeti, given V K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanwar, given Y S, non-dropping-particle , parse-names false, suffix , container-title Current medicinal chemistry, id ITEM-1, issue 34, issued date-parts 2010 , page 4256-4269, title Oxidative Stress in Diabetic Nephropathy, type article-journal, volume 17 , uris http//www.mendeley.com/documents/uuid6ba79ae1-2d50-4229-9a16-67f94c523483 , mendeley formattedCitation (Kashihara et al., 2010), plainTextFormattedCitation (Kashihara et al., 2010), previouslyFormattedCitation (Kashihara et al., 2010) , properties noteIndex 31 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kashihara et al., 2010). Oxidative Stress alters cell signaling and Hemodynamics In the typical hyperglycemic state due to diabetes, cells of the glomerular mesangium, retinal capillary endothelium and neuronal tissue are incapable of regulating intracellular glucose levels properly ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/db08-0057, ISSN 1939-327X (Electronic), PMID 18511445, abstract It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes., author dropping-particle , family Forbes, given Josephine M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Coughlan, given Melinda T, non-dropping-particle , parse-names false, suffix , dropping-particle , family Cooper, given Mark E, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue 6, issued date-parts 2008, 6 , language eng, page 1446-1454, publisher-place United States, title Oxidative stress as a major culprit in kidney disease in diabetes., type article-journal, volume 57 , uris http//www.mendeley.com/documents/uuid38edff0e-b989-4ca5-881a-0b9330f372f9 , mendeley formattedCitation (Forbes, Coughlan, Cooper, 2008), plainTextFormattedCitation (Forbes, Coughlan, Cooper, 2008), previouslyFormattedCitation (Forbes, Coughlan, Cooper, 2008) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Forbes, Coughlan, Cooper, 2008). Mitogen-Activated Protein Kinases (MAP-Ks) are a superfamily of threonine or serine kinases that control various cellular processes and cell-to-cell interactions including cell motility, apoptosis and survival, cell proliferation and differentiation ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0929-8673, abstract Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. , author dropping-particle , family Kashihara, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Haruna, given Y, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kondeti, given V K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanwar, given Y S, non-dropping-particle , parse-names false, suffix , container-title Current medicinal chemistry, id ITEM-1, issue 34, issued date-parts 2010 , page 4256-4269, title Oxidative Stress in Diabetic Nephropathy, type article-journal, volume 17 , uris http//www.mendeley.com/documents/uuid6ba79ae1-2d50-4229-9a16-67f94c523483 , mendeley formattedCitation (Kashihara et al., 2010), plainTextFormattedCitation (Kashihara et al., 2010), previouslyFormattedCitation (Kashihara et al., 2010) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kashihara et al., 2010). However, in a state of oxidative stress, the activities of MAP-Ks are altered. Among others, p38MAP-K itself is connected with the pathomechanisms that lead to diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1074/jbc.M311129200, ISBN 0021-9258 (Print), ISSN 00219258, PMID 14688258, abstract Oxidative stress has been indicated in a variety of pathological processes such as atherosclerosis, diabetes, and neurodegenerative diseases. Understanding how intracellular signaling pathways respond to oxidative insults such as hydrogen peroxide (H(2)O(2)) would have significant therapeutic implications. Recent genetic studies have placed apoptosis signal-regulating kinase 1 (ASK1) in a pivotal position in transmitting H(2)O(2)-initiated signals. How ASK1 is activated by H(2)O(2), though, remains a subject of intense investigation. Here we report a mechanism by which H(2)O(2) induces ASK1 activation through dynamic control of its phosphorylation at serine 967. We found that treatment of COS7 cells with H(2)O(2) triggers dephosphorylation of Ser-967 through an okadaic acid-sensitive phosphatase, resulting in dissociation of the ASK1.14-3-3 complex with concomitant increase of ASK1 catalytic activity and ASK1-mediated activation of JNK and p38 pathways., author dropping-particle , family Goldman, given Erinn H., non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Lei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Fu, given Haian, non-dropping-particle , parse-names false, suffix , container-title Journal of Biological Chemistry, id ITEM-1, issue 11, issued date-parts 2004 , page 10442-10449, title Activation of Apoptosis Signal-regulating Kinase 1 by Reactive Oxygen Species through Dephosphorylation at Serine 967 and 14-3-3 Dissociation, type article-journal, volume 279 , uris http//www.mendeley.com/documents/uuidd6220f06-a906-427d-9934-215820dc996c , id ITEM-2, itemData DOI 10.1046/j.1523-1755.2001.060002543.x, ISSN 0085-2538 (Print), PMID 11473637, abstract BACKGROUND The p38 mitogen-activated protein kinase (MAPK) pathway is activated by several stress factors, potentially leading to cellular apoptosis and growth. Little is known about the pattern of glomerular p38 MAPK pathway activation during the course of diabetic nephropathy (DN). We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MKP-1), in experimental DN in rats over the course of four months. METHODS Control (C N 16) and diabetic (DM N 16) rats were studied. Four rats from each group were sacrificed monthly, and competitive reverse transcription-polymerase chain reaction and Western blot were performed with microdissected and sieved glomeruli, respectively. RESULTS Glomerular p38 MAPK mRNA expression was significantly higher in DM than C (P 0.01) throughout the four-month period. Western blot revealed an average 3.1-fold increase in p38 MAPK protein throughout the study period (P 0.05). However, p38 MAPK activity was significantly increased only in one- and two-month diabetic glomeruli. Glomerular MKK3/6 and CREB mRNA as well as activity were significantly increased only in one- and two-month DM compared with C. MKP-1 mRNA showed a similar pattern. CONCLUSIONS Glomerular p38 MAPK activity was increased in early DN. Parallel to this, we also showed, to our knowledge for the first time, that there were increased MKK3/6 and CREB activities and mRNA expression. This activated p38 MAPK pathway in diabetic glomeruli may, in part, play a role in the pathogenesis of early hypertrophy and extracellular matrix accumulation., author dropping-particle , family Kang, given S W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Adler, given S G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Lapage, given J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Natarajan, given R, non-dropping-particle , parse-names false, suffix , container-title Kidney international, id ITEM-2, issue 2, issued date-parts 2001, 8 , language eng, page 543-552, publisher-place United States, title p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli., type article-journal, volume 60 , uris http//www.mendeley.com/documents/uuid3d785827-08b0-4a17-b4e6-35981a674984 , mendeley formattedCitation (Goldman et al., 2004 S. W. Kang, Adler, Lapage, Natarajan, 2001), plainTextFormattedCitation (Goldman et al., 2004 S. W. Kang, Adler, Lapage, Natarajan, 2001), previouslyFormattedCitation (Goldman et al., 2004 S. W. Kang, Adler, Lapage, Natarajan, 2001) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Goldman et al., 2004 S. W. Kang, Adler, Lapage, Natarajan, 2001). The p38MAP-K and c-Jun NH2-terminal kinase (JNK) are referred to as stress-activated protein kinases because they are readily activated by exogenous and endogenous stress stimuli including cytokine stimulation, ionizing radiation, osmotic shock and oxidative stress ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0929-8673, abstract Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. , author dropping-particle , family Kashihara, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Haruna, given Y, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kondeti, given V K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanwar, given Y S, non-dropping-particle , parse-names false, suffix , container-title Current medicinal chemistry, id ITEM-1, issue 34, issued date-parts 2010 , page 4256-4269, title Oxidative Stress in Diabetic Nephropathy, type article-journal, volume 17 , uris http//www.mendeley.com/documents/uuid6ba79ae1-2d50-4229-9a16-67f94c523483 , mendeley formattedCitation (Kashihara et al., 2010), plainTextFormattedCitation (Kashihara et al., 2010), previouslyFormattedCitation (Kashihara et al., 2010) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kashihara et al., 2010). Intraglomerular hypertension has been well demonstrated as an early abnormality in the course of diabetic nephropathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0027-8424 (Print), PMID 3862110, abstract Six groups of Munich-Wistar rats underwent micropuncture study 2-10 weeks and morphologic studies 11-13 months after induction of streptozotocin diabetes or after sham treatment. Diabetic rats received diets containing 6 (group D6), 12 (D12), or 50 protein (D50) and were maintained under similar conditions of moderate hyperglycemia by daily injections of ultralente insulin. Age- and weight-matched normal control rats were also given 6 (Group N6), 12 (N12), or 50 protein (N50). Kidney weight, whole-kidney and single-nephron glomerular filtration rate, glomerular plasma flow, and mean glomerular transcapillary hydraulic pressure difference were higher in D50 rats than in all other groups and predisposed this group to marked and progressive albuminuria. Likewise, histological examination of the kidneys disclosed areas of sclerosis in 19.6 of glomeruli in D50 rats the frequency of such lesions was less than 2.5 in all other groups. These findings indicate that the metabolic disorder seen in stable, moderately hyperglycemic diabetic rats does not lead to glomerulopathy as long as elevations in glomerular pressures and flows are prevented., author dropping-particle , family Zatz, given R, non-dropping-particle , parse-names false, suffix , dropping-particle , family Meyer, given T W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Rennke, given H G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Brenner, given B M, non-dropping-particle , parse-names false, suffix , container-title Proceedings of the National Academy of Sciences of the United States of America, id ITEM-1, issue 17, issued date-parts 1985, 9 , language eng, page 5963-5967, publisher-place United States, title Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy., type article-journal, volume 82 , uris http//www.mendeley.com/documents/uuidb56ce2d3-e1a4-404b-bc7b-5f1c3d37aa56 , id ITEM-2, itemData ISSN 0002-9343 (Print), PMID 7036732, author dropping-particle , family Hostetter, given T H, non-dropping-particle , parse-names false, suffix , dropping-particle , family Rennke, given H G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Brenner, given B M, non-dropping-particle , parse-names false, suffix , container-title The American journal of medicine, id ITEM-2, issue 3, issued date-parts 1982, 3 , language eng, page 375-380, publisher-place United States, title The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies., type article-journal, volume 72 , uris http//www.mendeley.com/documents/uuidcf0c4ef7-4dfb-4b90-ba12-cfee7057ca73 , mendeley formattedCitation (Hostetter et al., 1982 Zatz, Meyer, Rennke, Brenner, 1985), plainTextFormattedCitation (Hostetter et al., 1982 Zatz, Meyer, Rennke, Brenner, 1985), previouslyFormattedCitation (Hostetter et al., 1982 Zatz, Meyer, Rennke, Brenner, 1985) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Hostetter et al., 1982 Zatz, Meyer, Rennke, Brenner, 1985). However, fluctuations in the systemic circulatory pressure is usually normalized in the glomerulus especially because of the autoregulatory mechanisms of the afferent arterioles ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0929-8673, abstract Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. , author dropping-particle , family Kashihara, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Haruna, given Y, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kondeti, given V K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanwar, given Y S, non-dropping-particle , parse-names false, suffix , container-title Current medicinal chemistry, id ITEM-1, issue 34, issued date-parts 2010 , page 4256-4269, title Oxidative Stress in Diabetic Nephropathy, type article-journal, volume 17 , uris http//www.mendeley.com/documents/uuid6ba79ae1-2d50-4229-9a16-67f94c523483 , mendeley formattedCitation (Kashihara et al., 2010), plainTextFormattedCitation (Kashihara et al., 2010), previouslyFormattedCitation (Kashihara et al., 2010) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kashihara et al., 2010). Moreover, it appears that the autoregulatory mechanisms of the glomerulus are impaired and glomerular capillary pressure raised in diabetes ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0002-9343 (Print), PMID 7036732, author dropping-particle , family Hostetter, given T H, non-dropping-particle , parse-names false, suffix , dropping-particle , family Rennke, given H G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Brenner, given B M, non-dropping-particle , parse-names false, suffix , container-title The American journal of medicine, id ITEM-1, issue 3, issued date-parts 1982, 3 , language eng, page 375-380, publisher-place United States, title The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies., type article-journal, volume 72 , uris http//www.mendeley.com/documents/uuidcf0c4ef7-4dfb-4b90-ba12-cfee7057ca73 , mendeley formattedCitation (Hostetter et al., 1982), plainTextFormattedCitation (Hostetter et al., 1982), previouslyFormattedCitation (Hostetter et al., 1982) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Hostetter et al., 1982) leading to markedly increased renal plasma flow (RPF) and GFR ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0085-2538 (Print), PMID 3295358, abstract Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by constant inulin and PAH infusion during euglycemia and intravenous dextrose-induced moderate hyperglycemia in seven insulin-dependent diabetics with persistently elevated GFR, seven diabetics with normal GFR, and in six normal control subjects. In euglycemia, RPF was higher and calculated renal vascular resistance (RVR) lower in the hyperfiltering than the normofiltering group (P less than 0.05 for both variables), but filtration fraction (FF) was similar in all groups. During hyperglycemia, mean GFR rose significantly from 157 /- 20 to 174 /- 30 ml/min/1.73 m2 (11.9 P less than 0.05) in the hyperfiltering group only. There was no statistically significant change in mean GFR in the normofiltering diabetic (116 /- 6 vs. 114 /- 13 ml/min/1.73 m2) and the normal control groups (117 /- 15 vs. 113 /- 14 ml/min/1.73 m2). RPF and FF rose by 5.8 and 9.2, respectively, in the hyperfiltering group only, with no change in the normofiltering or normal control groups. No change in RVR was found in any group. Total tubular sodium reabsorption was higher during euglycemia in the hyperfiltering diabetics (P less than 0.01), and rose significantly during hyperglycemia (P less than 0.05) in this group only. Overnight euglycemia did not remove the increased glomerular filtration and flow of hyperfiltering diabetics. Hyperglycemia further accentuated hyperfiltration by elevating renal plasma flow and filtration fraction., author dropping-particle , family Wiseman, given M J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mangili, given R, non-dropping-particle , parse-names false, suffix , dropping-particle , family Alberetto, given M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Keen, given H, non-dropping-particle , parse-names false, suffix , dropping-particle , family Viberti, given G, non-dropping-particle , parse-names false, suffix , container-title Kidney international, id ITEM-1, issue 4, issued date-parts 1987, 4 , language eng, page 1012-1018, publisher-place United States, title Glomerular response mechanisms to glycemic changes in insulin-dependent diabetics., type article-journal, volume 31 , uris http//www.mendeley.com/documents/uuide78f0b4b-51d3-4287-ace0-32cdc9a0bbb6 , mendeley formattedCitation (Wiseman, Mangili, Alberetto, Keen, Viberti, 1987), plainTextFormattedCitation (Wiseman, Mangili, Alberetto, Keen, Viberti, 1987), previouslyFormattedCitation (Wiseman, Mangili, Alberetto, Keen, Viberti, 1987) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Wiseman, Mangili, Alberetto, Keen, Viberti, 1987). Hyperglycemia also contributes to glomerular hyperfiltration as a result of vasoconstriction of efferent arterioles, by activating the renin-angiotensin system (RAS) either locally or across the glomerulus ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0929-8673, abstract Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. , author dropping-particle , family Kashihara, given N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Haruna, given Y, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kondeti, given V K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanwar, given Y S, non-dropping-particle , parse-names false, suffix , container-title Current medicinal chemistry, id ITEM-1, issue 34, issued date-parts 2010 , page 4256-4269, title Oxidative Stress in Diabetic Nephropathy, type article-journal, volume 17 , uris http//www.mendeley.com/documents/uuid6ba79ae1-2d50-4229-9a16-67f94c523483 , mendeley formattedCitation (Kashihara et al., 2010), plainTextFormattedCitation (Kashihara et al., 2010), previouslyFormattedCitation (Kashihara et al., 2010) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kashihara et al., 2010). These abnormalities are reduced by administration of angiotensin converting enzyme (ACE) inhibitors, RAS inhibiting agents, and Angiotensin II receptor blockers (ARBs). Basement Membrane Disruption The progressive damage of the basement membrane forms an essential part of the disease pathogenesis. Macromolecules eventually seep through the basement membrane and this initiates secondary inflammatory pathways that contribute to the overall damage. The mechanisms that cause the destruction of the basement membrane integrity include basement membrane thickening due to underlying microangiopathy, abnormal change in mesangial and vascular cells, formation of Advanced Glycation End products (AGEs), accumulation of polyols via the aldose reductase pathway, and activation of protein kinase C ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Bennett, given Katie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Aditya, given Bhandari Sumer, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes Nursing, id ITEM-1, issue 2, issued date-parts 2015 , page 61-67, title An overview of diabetic nephropathy Epidemiology, pathophysiology and treatment., type article-journal, volume 19 , uris http//www.mendeley.com/documents/uuid87198b2b-365b-4372-8485-cc821b1c282f , mendeley formattedCitation (Bennett Aditya, 2015), plainTextFormattedCitation (Bennett Aditya, 2015), previouslyFormattedCitation (Bennett Aditya, 2015) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Bennett Aditya, 2015). Other factors to be considered Confounders of microalbuminuria estimation Possible confounders such as urinary tract infection, congestive heart failure, hypertension, exercise, and poor metabolic control yield apparent increases in microalbuminuria estimations only when they are clinically overt ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vestro, given Else, non-dropping-particle , parse-names false, suffix , dropping-particle , family Poulsen, given Per Logstrup, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christiansen, given Christian, non-dropping-particle , parse-names false, suffix , dropping-particle , family Damsgaard, given Else Marie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Elskjaer, given Hans, non-dropping-particle , parse-names false, suffix , dropping-particle , family Froland, given Anders, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hansen, given Klavs Wurgler, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nielsen, given Steen, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pedersen, given Margrethe Mau, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 4, issued date-parts 1995 , page 572-581, title Microalbuminuria and Potential Confounders, type article-journal, volume 18 , uris http//www.mendeley.com/documents/uuidc1a59cb3-555a-408f-ad63-448da1c7a151 , mendeley formattedCitation (Carl Erik Mogensen et al., 1995), plainTextFormattedCitation (Carl Erik Mogensen et al., 1995), previouslyFormattedCitation (Carl Erik Mogensen et al., 1995) , properties noteIndex 27 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Carl Erik Mogensen et al., 1995). Nonetheless, controlling these factors are somewhat easily achieved in a standard diabetic clinic. In the advent of delays, it is strongly recommended that urine samples be refrigerated whether they are to be used the same day or the next day ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S0272-6386(03)00826-6, ISSN 0272-6386, author dropping-particle , family Eknoyan, given Garabed, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hostetter, given Thomas, non-dropping-particle , parse-names false, suffix , dropping-particle , family Bakris, given George L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hebert, given Lee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Levey, given Andrew S, non-dropping-particle , parse-names false, suffix , dropping-particle , family Parving, given Hans-Henrik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Steffes, given Michael W, non-dropping-particle , parse-names false, suffix , dropping-particle , family Toto, given Robert, non-dropping-particle , parse-names false, suffix , container-title American Journal of Kidney Diseases, id ITEM-1, issue 4, issued date-parts 2003, 4, 2 , note doi 10.1016/S0272-6386(03)00826-6, page 617-622, publisher Elsevier, title Proteinuria and other markers of chronic kidney disease a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK) 1, type article-journal, volume 42 , uris http//www.mendeley.com/documents/uuiddc49790f-c156-4e36-b3d6-df93016e62ca , mendeley formattedCitation (Eknoyan et al., 2003), plainTextFormattedCitation (Eknoyan et al., 2003), previouslyFormattedCitation (Eknoyan et al., 2003) , properties noteIndex 32 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Eknoyan et al., 2003). Other factors ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vestro, given Else, non-dropping-particle , parse-names false, suffix , dropping-particle , family Poulsen, given Per Logstrup, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christiansen, given Christian, non-dropping-particle , parse-names false, suffix , dropping-particle , family Damsgaard, given Else Marie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Elskjaer, given Hans, non-dropping-particle , parse-names false, suffix , dropping-particle , family Froland, given Anders, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hansen, given Klavs Wurgler, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nielsen, given Steen, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pedersen, given Margrethe Mau, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 4, issued date-parts 1995 , page 572-581, title Microalbuminuria and Potential Confounders, type article-journal, volume 18 , uris http//www.mendeley.com/documents/uuidc1a59cb3-555a-408f-ad63-448da1c7a151 , mendeley formattedCitation (Carl Erik Mogensen et al., 1995), plainTextFormattedCitation (Carl Erik Mogensen et al., 1995), previouslyFormattedCitation (Carl Erik Mogensen et al., 1995) , properties noteIndex 31 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Carl Erik Mogensen et al., 1995) that could affect measurement of microalbuminuria include acute illness with fever, hematuria, dietary protein intake, menstruation and vaginal discharge, pregnancy and water consumption. Measuring UAE as albumin concentration (mg/l) may also be affected by diluting or concentrating the urine sample ADDIN CSL_CITATION citationItems id ITEM-1, itemData abstract 300 Multiple ChoicesThis is a pdf-only article and there is no markup to show you.full-text.pdf, author dropping-particle , family Gross, given J L, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zelmanovitz, given T, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oliveira, given J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Azevedo, given M J, non-dropping-particle de, parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 9, issued date-parts 1999, 9, 1 , page 1599 LP – 1600, title Screening for diabetic nephropathy is measurement of urinary albumin-to-creatinine ratio worthwhile, type article-journal, volume 22 , uris http//www.mendeley.com/documents/uuid1df68f1e-1584-4883-a00a-b2441b5d9be2 , mendeley formattedCitation (J L Gross et al., 1999), plainTextFormattedCitation (J L Gross et al., 1999), previouslyFormattedCitation (J L Gross et al., 1999) , properties noteIndex 33 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (J L Gross et al., 1999). Thus, the most vital confounder to be carefully evaluated remains the intrinsic variability of UAE rate, and as such, multiple tests are recommended in the continuous monitoring and follow-up of patients ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Mogensen, given Carl Erik, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vestro, given Else, non-dropping-particle , parse-names false, suffix , dropping-particle , family Poulsen, given Per Logstrup, non-dropping-particle , parse-names false, suffix , dropping-particle , family Christiansen, given Christian, non-dropping-particle , parse-names false, suffix , dropping-particle , family Damsgaard, given Else Marie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Elskjaer, given Hans, non-dropping-particle , parse-names false, suffix , dropping-particle , family Froland, given Anders, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hansen, given Klavs Wurgler, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nielsen, given Steen, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pedersen, given Margrethe Mau, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 4, issued date-parts 1995 , page 572-581, title Microalbuminuria and Potential Confounders, type article-journal, volume 18 , uris http//www.mendeley.com/documents/uuidc1a59cb3-555a-408f-ad63-448da1c7a151 , mendeley formattedCitation (Carl Erik Mogensen et al., 1995), plainTextFormattedCitation (Carl Erik Mogensen et al., 1995), previouslyFormattedCitation (Carl Erik Mogensen et al., 1995) , properties noteIndex 33 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Carl Erik Mogensen et al., 1995). Nephropathy in the absence of Albuminuria Measurement of UAE is still the first line diagnostic method for the early detection of diabetic nephropathy. What is more, it has been demonstrated ADDIN CSL_CITATION citationItems id ITEM-1, itemData abstract Objective To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. Design Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of amplt150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a u03b2 blocker atenolol as main treatment) with less tight control aiming at a blood pressure of amplt180/105 mm Hg. Setting 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg) 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. Main outcome measures Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. Results Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (Pamplt0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24 in diabetes related end points (95 confidence interval 8 to 38) (P0.0046), 32 in deaths related to diabetes (6 to 51) (P0.019), 44 in strokes (11 to 65) (P0.013), and 37 in microvascular end points (11 to 56) (P0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34 reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99 confidence interval 11 to 50) (P0.0004) and a 47 reduced risk (7 to 70) (P0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29 of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. Conclusion Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of u2026, author dropping-particle , family UK Prospective Diabetes Study Group, given , non-dropping-particle , parse-names false, suffix , container-title BMJ, id ITEM-1, issue 7160, issued date-parts 1998, 9, 12 , page 703 LP – 713, title Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes UKPDS 38, type article-journal, volume 317 , uris http//www.mendeley.com/documents/uuiddc9fc7b8-26b8-4059-9f74-8fb08636332b , mendeley formattedCitation (UK Prospective Diabetes Study Group, 1998), plainTextFormattedCitation (UK Prospective Diabetes Study Group, 1998), previouslyFormattedCitation (UK Prospective Diabetes Study Group, 1998) , properties noteIndex 30 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (UK Prospective Diabetes Study Group, 1998) that the risk of developing microalbuminuria in a cohort of type 2 diabetes patients correlated with i) waist circumference, ii) elevated systolic blood pressure, iii) Indian-Asian ethnicity, iv) history of cardiovascular disease, v) history of retinopathy, vi) smoking history, vii) male gender and viii) plasma triglycerides while factors like elevated LDL cholesterol added to the development of macroalbuminuria. Nonetheless, there are some patients with either type 1 or type 2 diabetes who have decreased glomerular filtration rate (GFR) in the presence of normal UAE ADDIN CSL_CITATION citationItems id ITEM-1, itemData abstract Increased urinary albumin excretion rate is widely accepted as the first clinical sign of diabetic nephropathy. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. The aim of this study was to identify a group of normoalbuminuric type 1 diabetic patients with low GFR and compare them with normoalbuminuric patients with normal GFR. Altogether, 105 normoalbuminuric type 1 diabetic patients with at least 10 years of diabetes duration that had a renal biopsy performed for research purposes were studied. Patients were divided according to GFR into groups with normal (u226590 ml u00b7 minu22121 u00b7 1.73 mu22122) or reduced (amplt90 ml u00b7 minu22121 u00b7 1.73 mu22122) GFR. Clinical and renal structural parameters were compared between these two groups. Glomerular structural parameters were estimated by electron microscopic morphometry. The 23 patients with reduced GFR had more advanced diabetic glomerular lesions. The finding of reduced GFR was much more common among female patients, particularly if retinopathy and/or hypertension were also present. This report confirms that reduced GFR occurs among long-standing normoalbuminuric type 1 diabetic patients and is associated with more advanced diabetic glomerular lesions and, probably, with increased risk of progression. For these reasons, we suggest that regular measurements of GFR be performed in long-standing normoalbuminuric type 1 diabetic female diabetic patients, especially in those with retinopathy or hypertension., author dropping-particle , family Caramori, given M Luiza, non-dropping-particle , parse-names false, suffix , dropping-particle , family Fioretto, given Paola, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mauer, given Michael, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue 4, issued date-parts 2003, 4, 1 , page 1036 LP – 1040, title Low Glomerular Filtration Rate in Normoalbuminuric Type 1 Diabetic Patients, type article-journal, volume 52 , uris http//www.mendeley.com/documents/uuid0535c6c4-0b8f-4408-98d4-2e5d082d942c , id ITEM-2, itemData abstract OBJECTIVEu2014To determine the prevalence and characteristics of patients with type 2 diabetes who have impaired renal function, defined as a glomerular filtration rate (GFR) amplt60 ml u00b7 minu22121 u00b7 1.73 mu22122, and normoalbuminuria.RESEARCH DESIGN AND METHODSu2014A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic 99mTc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria.RESULTSu2014A total of 109 patients (36) had a GFR amplt60 ml u00b7 minu22121 u00b7 1.73 mu22122. The overall prevalence of normo-, micro-, and macroalbuminuria was 43 of 109 (39), 38 of 109 (35), and 28 of 109 (26), respectively. Compared with patients with macroalbuminuria, those with normoalbuminuria were more likely to be older and female. After excluding patients whose normoalbuminuric status was possibly related to the initiation of a renin-angiotensin system (RAS) inhibitor before the start of the study, the prevalence of a GFR amplt60 ml u00b7 minu22121 u00b7 1.73 mu22122 and normoalbuminuria was 23. Temporal changes in GFR in a subset of 34 of 109 (32) unselected patients with impaired renal function were available for comparison over a 3- to 10-year period. The rates of decline in GFR (ml u00b7 minu22121 u00b7 1.73 mu22122 u00b7 yearu22121) of u22124.6 u00b1 1.0, u22122.8 u00b1 1.0, and u22123.0 u00b1 07 were not significantly different for normo- (n 12), micro- (n 12), and macroalbuminuric (n 10) patients, respectively.CONCLUSIONSu2014These results suggest that patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric., author dropping-particle , family MacIsaac, given Richard J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tsalamandris, given Con, non-dropping-particle , parse-names false, suffix , dropping-particle , family Panagiotopoulos, given Sianna, non-dropping-particle , parse-names false, suffix , dropping-particle , family Smith, given Trudy J, non-dropping-particle , parse-names false, suffix , dropping-particle , family McNeil, given Karen J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Jerums, given George, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-2, issue 1, issued date-parts 2004, 1, 1 , page 195 LP – 200, title Nonalbuminuric Renal Insufficiency in Type 2 Diabetes, type article-journal, volume 27 , uris http//www.mendeley.com/documents/uuidca3cd1f7-e4ac-463b-8eaf-e0419355bf0a , mendeley formattedCitation (Caramori, Fioretto, Mauer, 2003 MacIsaac et al., 2004), plainTextFormattedCitation (Caramori, Fioretto, Mauer, 2003 MacIsaac et al., 2004), previouslyFormattedCitation (Caramori, Fioretto, Mauer, 2003 MacIsaac et al., 2004) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Caramori, Fioretto, Mauer, 2003 MacIsaac et al., 2004) and the disease may be initiated when UAE levels are still within the normal range. This process seems to be more common among female type 1 diabetes patients with longstanding diabetes, hypertension, and/or retinopathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData abstract Increased urinary albumin excretion rate is widely accepted as the first clinical sign of diabetic nephropathy. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. The aim of this study was to identify a group of normoalbuminuric type 1 diabetic patients with low GFR and compare them with normoalbuminuric patients with normal GFR. Altogether, 105 normoalbuminuric type 1 diabetic patients with at least 10 years of diabetes duration that had a renal biopsy performed for research purposes were studied. Patients were divided according to GFR into groups with normal (u226590 ml u00b7 minu22121 u00b7 1.73 mu22122) or reduced (amplt90 ml u00b7 minu22121 u00b7 1.73 mu22122) GFR. Clinical and renal structural parameters were compared between these two groups. Glomerular structural parameters were estimated by electron microscopic morphometry. The 23 patients with reduced GFR had more advanced diabetic glomerular lesions. The finding of reduced GFR was much more common among female patients, particularly if retinopathy and/or hypertension were also present. This report confirms that reduced GFR occurs among long-standing normoalbuminuric type 1 diabetic patients and is associated with more advanced diabetic glomerular lesions and, probably, with increased risk of progression. For these reasons, we suggest that regular measurements of GFR be performed in long-standing normoalbuminuric type 1 diabetic female diabetic patients, especially in those with retinopathy or hypertension., author dropping-particle , family Caramori, given M Luiza, non-dropping-particle , parse-names false, suffix , dropping-particle , family Fioretto, given Paola, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mauer, given Michael, non-dropping-particle , parse-names false, suffix , container-title Diabetes, id ITEM-1, issue 4, issued date-parts 2003, 4, 1 , page 1036 LP – 1040, title Low Glomerular Filtration Rate in Normoalbuminuric Type 1 Diabetic Patients, type article-journal, volume 52 , uris http//www.mendeley.com/documents/uuid0535c6c4-0b8f-4408-98d4-2e5d082d942c , mendeley formattedCitation (Caramori et al., 2003), plainTextFormattedCitation (Caramori et al., 2003), previouslyFormattedCitation (Caramori et al., 2003) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Caramori et al., 2003). In type 2 diabetes, the Third National Health and Nutrition Examination Survey (NHANES III) reported that decreased GFR affected 30 of patients in the absence of micro- or macroalbuminuria and retinopathy ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1001/jama.289.24.3273, ISSN 0098-7484, author dropping-particle , family Kramer, given Holly J., non-dropping-particle , parse-names false, suffix , container-title Jama, id ITEM-1, issue 24, issued date-parts 2003 , page 3273, title Renal Insufficiency in the Absence of Albuminuria and Retinopathy Among Adults With Type 2 Diabetes Mellitus, type article-journal, volume 289 , uris http//www.mendeley.com/documents/uuid276e9f9c-a022-49ea-9112-1ec4381475f9 , mendeley formattedCitation (Kramer, 2003), plainTextFormattedCitation (Kramer, 2003), previouslyFormattedCitation (Kramer, 2003) , properties noteIndex 24 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kramer, 2003) and that in both type 1 and type 2 diabetic patients, normoalbuminuria may not prevent a fall in GFR. It is advisable that routine estimation of GFR and UAE should be done to ensure a proper screening of diabetic nephropathy. The case of type 2 diabetes specific nephropathy The characteristic symptoms of long standing type 1 diabetes include retinopathy, microalbuminuria without clinical overt proteinuria and hematuria while kidney size is preserved. Diabetic kidney disease can be more precisely diagnosed in more than 95 of type 1 diabetes patients ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI https//doi.org/10.1016/S0272-6386(12)80561-0, ISSN 0272-6386, author dropping-particle , family Mauer, given S Michael, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chavers, given Blanche M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Steffes, given Michael W, non-dropping-particle , parse-names false, suffix , container-title American Journal of Kidney Diseases, id ITEM-1, issue 2, issued date-parts 1990 , page 96-100, title Should There Be an Expanded Role for Kidney Biopsy in the Management of Patients With Type I Diabetes, type article-journal, volume 16 , uris http//www.mendeley.com/documents/uuidb7428fae-66b0-4e6d-9512-c552a242fccd , id ITEM-2, itemData DOI 10.1001/jama.289.24.3273, ISSN 0098-7484, author dropping-particle , family Kramer, given Holly J., non-dropping-particle , parse-names false, suffix , container-title Jama, id ITEM-2, issue 24, issued date-parts 2003 , page 3273, title Renal Insufficiency in the Absence of Albuminuria and Retinopathy Among Adults With Type 2 Diabetes Mellitus, type article-journal, volume 289 , uris http//www.mendeley.com/documents/uuid276e9f9c-a022-49ea-9112-1ec4381475f9 , mendeley formattedCitation (Kramer, 2003 Mauer, Chavers, Steffes, 1990), plainTextFormattedCitation (Kramer, 2003 Mauer, Chavers, Steffes, 1990), previouslyFormattedCitation (Kramer, 2003 Mauer, Chavers, Steffes, 1990) , properties noteIndex 35 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Kramer, 2003 Mauer, Chavers, Steffes, 1990). In type 2 diabetes, however, clinical renal disease is compounded by other associated diseases and not entirely due to diabetic nephropathy thereby making diagnosis much more complex ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.4093/dmj.2014.38.4.252, ISSN 2233-6079, PMID 25215271, abstract With worldwide epidemic of diabetes mellitus, diabetic nephropathy which is one of the major causes of microvascular complication has become a serious concern in Korea as well as the rest of the world. In view of its significance, there is an urgent and paramount need for proper managements that could either deter or slow the progression of diabetic nephropathy. Despite advances in care, ever increasing number of patients suffering from diabetic kidney disease and from end-stage renal disease implies that the current management is not adequate in many aspects. The reasons for these inadequacies compromise lack of early diagnosis, failure to intervene with timely and aggressive manner, and lack of understanding on the kind of interventions required. Another issue equally important for the adequate care of patients with diabetic nephropathy is an understanding of past, present and future epidemiology of diabetic nephropathy which serves, especially in Korea, as a material determining standard diagnosis and treatment and a national health-policy decision., author dropping-particle , family Park, given Cheol Whee, non-dropping-particle , parse-names false, suffix , container-title Diabetes Metabolism Journal, id ITEM-1, issue 4, issued date-parts 2014 , page 252, title Diabetic Kidney Disease From Epidemiology to Clinical Perspectives, type article-journal, volume 38 , uris http//www.mendeley.com/documents/uuid55987724-33b9-41f9-a423-140ca51cec8c , mendeley formattedCitation (Park, 2014), plainTextFormattedCitation (Park, 2014), previouslyFormattedCitation (Park, 2014) , properties noteIndex 31 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Park, 2014). The Bilirubin Cycle Structure, Synthesis and Conjugation Following the breakdown of red blood cells, the hemoglobin (Hb) molecule is broken apart into heme and globin portions with the heme portion proceeding into the reticuloendothelial system. Although the most abundant source of heme is Hb, heme may also be obtained from myoglobin of muscle, and the enzymatic activities of cytochromes and catalases also lead to the production of bilirubin ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S1357-2725(01)00130-3, ISBN 1357-2725 (Print), ISSN 13572725, PMID 11849989, abstract Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, in the last 10 years, in vitro and in vivo studies, have demonstrated that bilirubin exhibits potent anti-oxidant properties preventing the oxidative damage triggered by a wide range of oxidant-related stimuli. Therefore, the idea of a beneficial and physiological role for bilirubin in cytoprotection against short and long-lasting oxidant-mediated cell injury is highlighted here. u00a9 2002 Elsevier Science Ltd. All rights reserved., author dropping-particle , family Tomaro, given Maru00eda L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Batlle, given Alcira M.Del C., non-dropping-particle , parse-names false, suffix , container-title International Journal of Biochemistry and Cell Biology, id ITEM-1, issue 3, issued date-parts 2002 , page 216-220, title Bilirubin Its role in cytoprotection against oxidative stress, type article-journal, volume 34 , uris http//www.mendeley.com/documents/uuid3e8102b0-8d98-4c3a-9c88-6b6c97899516 , mendeley formattedCitation (Tomaro Batlle, 2002), plainTextFormattedCitation (Tomaro Batlle, 2002), previouslyFormattedCitation (Tomaro Batlle, 2002) , properties noteIndex 36 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Tomaro Batlle, 2002). The basic structure of bilirubin consists of four covalently linked pyrrole (tetrapyrrole) rings in a linear chain as illustrated. below Figure 2.1 Bilirubin in the E,E isomeric form The role in preventing oxidative stress Bilirubin at micromolar concentrations has been demonstrated as a potent scavenger of chain-carrying peroxyl radicals by donating the H atom attached to the C10 resulting in the production of a carbon-centered radical (BR-) ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Stocker, given Roland, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yamamoto, given Yorihiro, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mcdonagh, given Antony F, non-dropping-particle , parse-names false, suffix , dropping-particle , family Glazer, given Alexander N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ames, given Bruce N, non-dropping-particle , parse-names false, suffix , container-title Science, id ITEM-1, issue 4792, issued date-parts 1987 , page 1043-1046, title Bilirubin is an Antioxidant of Possible Physiological Importance Published by American Association for the Advancement of Science Stable URL http//www.jstor.org/stable/1698769 Accessed 07-06-2016 09 41 UTC, type article-journal, volume 235 , uris http//www.mendeley.com/documents/uuid3b000f7c-5360-42e0-9b6c-feb731251feb , mendeley formattedCitation (Stocker et al., 1987), plainTextFormattedCitation (Stocker et al., 1987), previouslyFormattedCitation (Stocker et al., 1987) , properties noteIndex 37 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Stocker et al., 1987). Bilirubin also inhibits the oxidation of lipids and lipoproteins, especially low-density lipoprotein cholesterol ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1073/pnas.0813132106, ISBN 0027-8424, ISSN 0027-8424, PMID 19286972, abstract AbstractGlutathione (GSH) and bilirubin are prominent endogenous antioxidant cytoprotectants. Despite tissue levels that are thousands of times lower than GSH, bilirubin is effective because of the biosynthetic cycle wherein it is generated from biliverdin by biliverdin reductase (BVR). When bilirubin acts as an antioxidant, it is oxidized to biliverdin, which is immediately reduced by BVR to bilirubin. Why does the body employ both of these 2 distinct antioxidant systems We show that the water-soluble GSH primarily protects water soluble proteins, whereas the lipophilic bilirubin protects lipids from oxidation. Mice with deletion of heme oxygenase-2, which generates biliverdin, display greater lipid than protein oxidation, while the reverse holds for GSH depletion. RNA interference depletion of BVR increases oxidation of lipids more than protein. Depletion of BVR or GSH augments cell death in an oxidant-specific fashion., author dropping-particle , family Sedlak, given T. W., non-dropping-particle , parse-names false, suffix , dropping-particle , family Saleh, given M., non-dropping-particle , parse-names false, suffix , dropping-particle , family Higginson, given D. S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Paul, given B. D., non-dropping-particle , parse-names false, suffix , dropping-particle , family Juluri, given K. R., non-dropping-particle , parse-names false, suffix , dropping-particle , family Snyder, given S. H., non-dropping-particle , parse-names false, suffix , container-title Proceedings of the National Academy of Sciences, id ITEM-1, issue 13, issued date-parts 2009 , page 5171-5176, title Bilirubin and glutathione have complementary antioxidant and cytoprotective roles, type article-journal, volume 106 , uris http//www.mendeley.com/documents/uuid8f119b3d-ceb0-4543-ac87-ead0c7636133 , mendeley formattedCitation (Sedlak et al., 2009), plainTextFormattedCitation (Sedlak et al., 2009), previouslyFormattedCitation (Sedlak et al., 2009) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Sedlak et al., 2009), and is proportional to the total serum antioxidant capacity in humans ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/S0021-9150(01)00601-3, ISBN 0021-9150 (Print)r0021-9150 (Linking), ISSN 00219150, PMID 11849670, abstract Background Oxidation processes play an important role in atherogenesis. Bilirubin IX is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). Methods The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n 50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n 2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n 38) and control subjects (n 38). Results The prevalence of IHD in GS subjects (aged 49.7 9.0 years) was 2 (0.05-10.7, 95 confidence interval), compared to 12.1 in a general population (P 0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P 0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. Conclusions In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity. 2002 Elsevier Science Ireland Ltd. All rights reserved., author dropping-particle , family Vitek, given Libor, non-dropping-particle , parse-names false, suffix , dropping-particle , family Jirsa, given Milan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Brodanova, given Marie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kalab, given Milan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Marecek, given Zdenek, non-dropping-particle , parse-names false, suffix , dropping-particle , family Danzig, given Vilm, non-dropping-particle , parse-names false, suffix , dropping-particle , family Novotn, given Ladislav, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kotal, given Petr, non-dropping-particle , parse-names false, suffix , container-title Atherosclerosis, id ITEM-1, issue 2, issued date-parts 2002 , page 449-456, title Gilbert syndrome and ischemic heart disease A protective effect of elevated bilirubin levels, type article-journal, volume 160 , uris http//www.mendeley.com/documents/uuid6fb109bb-766c-4c48-8453-1dd5b2c84774 , mendeley formattedCitation (Vitek et al., 2002), plainTextFormattedCitation (Vitek et al., 2002), previouslyFormattedCitation (Vitek et al., 2002) , properties noteIndex 4 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Vitek et al., 2002). Furthermore, research indicated that the antioxidant properties of bilirubin exceeded that of carotene and linoleic acid ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Stocker, given Roland, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yamamoto, given Yorihiro, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mcdonagh, given Antony F, non-dropping-particle , parse-names false, suffix , dropping-particle , family Glazer, given Alexander N, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ames, given Bruce N, non-dropping-particle , parse-names false, suffix , container-title Science, id ITEM-1, issue 4792, issued date-parts 1987 , page 1043-1046, title Bilirubin is an Antioxidant of Possible Physiological Importance Published by American Association for the Advancement of Science Stable URL http//www.jstor.org/stable/1698769 Accessed 07-06-2016 09 41 UTC, type article-journal, volume 235 , uris http//www.mendeley.com/documents/uuid3b000f7c-5360-42e0-9b6c-feb731251feb , mendeley formattedCitation (Stocker et al., 1987), plainTextFormattedCitation (Stocker et al., 1987), previouslyFormattedCitation (Stocker et al., 1987) , properties noteIndex 37 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Stocker et al., 1987). Figure 2.2 Illustration of bilirubin metabolism in neonates ADDIN CSL_CITATION citationItems id ITEM-1, itemData author dropping-particle , family Hansen, given JF, non-dropping-particle , parse-names false, suffix , dropping-particle , family Maisels, given MJ, non-dropping-particle , parse-names false, suffix , dropping-particle , family Watchko, given TWR, non-dropping-particle , parse-names false, suffix , container-title Fetal and neonatal bilirubin metabolism, editor dropping-particle , family Maisels, given MJ, non-dropping-particle , parse-names false, suffix , dropping-particle , family Watchko, given JF, non-dropping-particle , parse-names false, suffix , id ITEM-1, issued date-parts 2000 , page 3-20, publisher Harwood Academic Publishers, publisher-place London, United Kingdom, title Neonatal Jaundice, type chapter , uris http//www.mendeley.com/documents/uuide09f7de7-9f29-40db-9dfc-6a048fd4bb54 , mendeley formattedCitation (Hansen, Maisels, Watchko, 2000), plainTextFormattedCitation (Hansen, Maisels, Watchko, 2000), previouslyFormattedCitation (Hansen, Maisels, Watchko, 2000) , properties noteIndex 37 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Hansen, Maisels, Watchko, 2000) Uric Acid Cycle Uric acid is generated by the metabolism of either dietary (usually from animal protein) or endogenous pool of purines in the liver, muscle, kidneys, vasculature and intestine. Uric acid exists majorly as salts known as urates and as urate concentration increases in circulation, uric acid crystal formation increases and vice versa. Two purine nucleic acids, adenine monophosphate (AMP) and guanine monophosphate (GMP) are the main reactants in the production of UA by enzymatic activity ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI https//doi.org/10.1016/j.ijcard.2015.08.109, ISSN 0167-5273, author dropping-particle , family Maiuolo, given Jessica, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oppedisano, given Francesca, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gratteri, given Santo, non-dropping-particle , parse-names false, suffix , dropping-particle , family Muscoli, given Carolina, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mollace, given Vincenzo, non-dropping-particle , parse-names false, suffix , container-title International Journal of Cardiology, id ITEM-1, issued date-parts 2016 , page 8-14, title Regulation of uric acid metabolism and excretion, type article-journal, volume 213 , uris http//www.mendeley.com/documents/uuid5f9e6125-1f0c-4ac6-981b-3346a98223ae , mendeley formattedCitation (Maiuolo, Oppedisano, Gratteri, Muscoli, Mollace, 2016), plainTextFormattedCitation (Maiuolo, Oppedisano, Gratteri, Muscoli, Mollace, 2016), previouslyFormattedCitation (Maiuolo, Oppedisano, Gratteri, Muscoli, Mollace, 2016) , properties noteIndex 39 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Maiuolo, Oppedisano, Gratteri, Muscoli, Mollace, 2016). AMP is first converted to inosine either by deaminase-mediated deamination to form inosine monophosphate (IMP) and subsequent dephosphorylation by nucleotidase to form inosine, or the reverse dephosphorylation followed by deamination to form inosine ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI https//doi.org/10.1016/j.ijcard.2015.08.109, ISSN 0167-5273, author dropping-particle , family Maiuolo, given Jessica, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oppedisano, given Francesca, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gratteri, given Santo, non-dropping-particle , parse-names false, suffix , dropping-particle , family Muscoli, given Carolina, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mollace, given Vincenzo, non-dropping-particle , parse-names false, suffix , container-title International Journal of Cardiology, id ITEM-1, issued date-parts 2016 , page 8-14, title Regulation of uric acid metabolism and excretion, type article-journal, volume 213 , uris http//www.mendeley.com/documents/uuid5f9e6125-1f0c-4ac6-981b-3346a98223ae , mendeley formattedCitation (Maiuolo et al., 2016), plainTextFormattedCitation (Maiuolo et al., 2016), previouslyFormattedCitation (Maiuolo et al., 2016) , properties noteIndex 39 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Maiuolo et al., 2016), while GMP is readily converted to guanosine by nucleotidase. Inosine and guanosine are then converted to hypoxanthine and guanine respectively by purine nucleoside phosphorylase (PNP). Hypoxanthine proceeds through oxidation by xanthine-oxidase (XO) to form xanthine, and guanine is deaminated to form xanthine by guanine deaminase. Xanthine, the immediate precursor of UA converted to uric acid by the enzyme xanthine oxidoreductase ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.5049/EBP.2014.12.1.1, ISBN 1738-5997 (Print)r1738-5997, ISSN 20929935, PMID 25061467, abstract Hyperuricemia is known to be associated with the presence of cardiovascular and metabolic syndrome and with the development of incipient kidney disease and an accelerated renal progression. However, an elevated uric acid level was not generally regarded as a true etiology or mediator, but an indicator of these diseases. Uric acid has recently regained the clinical interest and popularity based on emerging data suggesting the causative role of hyperuricemia in cardiovascular and renal disease. Experimental data demonstrates oxidative stress is one of the earliest phenomena observed in vascular, renal, liver cells and adipocytes exposed to uric acid. Since uric acid is one of the major antioxidants of plasma acting as a free radical scavenger and a chelator of transitional metal ion, uric acid-induced oxidative stress seems paradoxical. Data regarding the clinical implication of hyperuricemia is even more confusing, which defines hyperuricemia as a useless parameter to be eliminated from routine follow-up or a major risk factor to be therapeutic target. With a review of experimental and epidemiologic data, the presence of molecular switch to regulate the role of uric acid as anti- or pro-oxidant in different compartment of our body is suggested, which may shed light on understanding the paradoxical role of uric acid and solving the uric acid debate., author dropping-particle , family Kang, given Duk Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ha, given Sung Kyu, non-dropping-particle , parse-names false, suffix , container-title Electrolyte and Blood Pressure, id ITEM-1, issue 1, issued date-parts 2014 , page 1-6, title Uric acid puzzle Dual role as anti-oxidantand pro-oxidant, type article-journal, volume 12 , uris http//www.mendeley.com/documents/uuideee858c1-5c55-4be0-acf3-8e04237c4eb0 , mendeley formattedCitation (D. H. Kang Ha, 2014), plainTextFormattedCitation (D. H. Kang Ha, 2014), previouslyFormattedCitation (D. H. Kang Ha, 2014) , properties noteIndex 39 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (D. H. Kang Ha, 2014). Uric acid cannot be further oxidized to the more soluble compound allantoin by humans due to the absence the uricase enzyme. The kidneys excrete about two-thirds of daily UA, while the gastrointestinal tract eliminates about one-third and hyperuricemia occurs when UA production rate overwhelms excretion rate ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI https//doi.org/10.1016/j.ijcard.2015.08.109, ISSN 0167-5273, author dropping-particle , family Maiuolo, given Jessica, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oppedisano, given Francesca, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gratteri, given Santo, non-dropping-particle , parse-names false, suffix , dropping-particle , family Muscoli, given Carolina, non-dropping-particle , parse-names false, suffix , dropping-particle , family Mollace, given Vincenzo, non-dropping-particle , parse-names false, suffix , container-title International Journal of Cardiology, id ITEM-1, issued date-parts 2016 , page 8-14, title Regulation of uric acid metabolism and excretion, type article-journal, volume 213 , uris http//www.mendeley.com/documents/uuid5f9e6125-1f0c-4ac6-981b-3346a98223ae , mendeley formattedCitation (Maiuolo et al., 2016), plainTextFormattedCitation (Maiuolo et al., 2016), previouslyFormattedCitation (Maiuolo et al., 2016) , properties noteIndex 39 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Maiuolo et al., 2016). Hyperuricemia is characterized by UA levels 7.0mg/dL in men and 6.5mg/dL in women although this range seems to have risen over the years likely due to increased dietary protein intake ADDIN CSL_CITATION citationItems id ITEM-1, itemData ISSN 0270-9295 (Print), PMID 15660328, abstract Hypertension is epidemic and currently affects 25 of the worlds population and is a major cause of stroke, congestive heart failure, and end-stage renal disease. Interestingly, there is evidence that the increased frequency of hypertension is a recent event in human history and correlates with dietary changes associated with Westernization. In this article, we review the evidence that links uric acid to the cause and epidemiology of hypertension. Specifically, we review the evidence that the mutation of uricase that occurred in the Miocene that resulted in a higher serum uric acid in humans compared with most other mammals may have occurred as a means to increase blood pressure in early hominoids in response to a low-sodium and low-purine diet. We then review the evidence that the epidemic of hypertension that evolved with Westernization was associated with an increase in the intake of red meat with a marked increase in serum uric acid levels. Indeed, gout and hyperuricemia should be considered a part of the obesity, type 2 diabetes, and hypertension epidemic that is occurring worldwide. Although other mechanisms certainly contribute to the pathogenesis of hypertension, the possibility that serum uric acid level may have a major role is suggested by these studies., author dropping-particle , family Johnson, given Richard J, non-dropping-particle , parse-names false, suffix , dropping-particle , family Titte, given Srinivas, non-dropping-particle , parse-names false, suffix , dropping-particle , family Cade, given J Robert, non-dropping-particle , parse-names false, suffix , dropping-particle , family Rideout, given Bruce A, non-dropping-particle , parse-names false, suffix , dropping-particle , family Oliver, given William J, non-dropping-particle , parse-names false, suffix , container-title Seminars in nephrology, id ITEM-1, issue 1, issued date-parts 2005, 1 , language eng, page 3-8, publisher-place United States, title Uric acid, evolution and primitive cultures., type article-journal, volume 25 , uris http//www.mendeley.com/documents/uuid2c392e91-69f8-4ea6-b89e-69d2ac2fe92a , id ITEM-2, itemData DOI 10.5049/EBP.2014.12.1.1, ISBN 1738-5997 (Print)r1738-5997, ISSN 20929935, PMID 25061467, abstract Hyperuricemia is known to be associated with the presence of cardiovascular and metabolic syndrome and with the development of incipient kidney disease and an accelerated renal progression. However, an elevated uric acid level was not generally regarded as a true etiology or mediator, but an indicator of these diseases. Uric acid has recently regained the clinical interest and popularity based on emerging data suggesting the causative role of hyperuricemia in cardiovascular and renal disease. Experimental data demonstrates oxidative stress is one of the earliest phenomena observed in vascular, renal, liver cells and adipocytes exposed to uric acid. Since uric acid is one of the major antioxidants of plasma acting as a free radical scavenger and a chelator of transitional metal ion, uric acid-induced oxidative stress seems paradoxical. Data regarding the clinical implication of hyperuricemia is even more confusing, which defines hyperuricemia as a useless parameter to be eliminated from routine follow-up or a major risk factor to be therapeutic target. With a review of experimental and epidemiologic data, the presence of molecular switch to regulate the role of uric acid as anti- or pro-oxidant in different compartment of our body is suggested, which may shed light on understanding the paradoxical role of uric acid and solving the uric acid debate., author dropping-particle , family Kang, given Duk Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ha, given Sung Kyu, non-dropping-particle , parse-names false, suffix , container-title Electrolyte and Blood Pressure, id ITEM-2, issue 1, issued date-parts 2014 , page 1-6, title Uric acid puzzle Dual role as anti-oxidantand pro-oxidant, type article-journal, volume 12 , uris http//www.mendeley.com/documents/uuideee858c1-5c55-4be0-acf3-8e04237c4eb0 , mendeley formattedCitation (Johnson, Titte, Cade, Rideout, Oliver, 2005 D. H. Kang Ha, 2014), plainTextFormattedCitation (Johnson, Titte, Cade, Rideout, Oliver, 2005 D. H. Kang Ha, 2014), previouslyFormattedCitation (Johnson, Titte, Cade, Rideout, Oliver, 2005 D. H. Kang Ha, 2014) , properties noteIndex 40 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Johnson, Titte, Cade, Rideout, Oliver, 2005 D. H. Kang Ha, 2014). Bilirubin, Uric Acid and the possible link with Diabetic Nephropathy A recent study suggests that low serum bilirubin concentration could be a novel risk factor for the development of albuminuria ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.metabol.2013.11.011, ISBN 1532-8600 (Electronic) 0026-0495 (Linking), ISSN 00260495, PMID 24332706, abstract Objective Bilirubin has been recognized as an important endogeneous antioxidant. Previous studies reported that bilirubin could prevent atherosclerosis. The aim of this study was to investigate if serum bilirubin concentration could be a predictor for the development of albuminuria in patients with type 2 diabetes. Materials and Methods We measured serum bilirubin in 320 consecutive patients with normoalbuminuria. We performed follow-up study to assess the development of albuminuria, mean interval of which was 3.2 u00b1 0.9 years. Cox proportional hazards regression was used to examine the relationship between serum bilirubin concentration and the development of albuminuria. Results During follow-up duration, 43 patients have developed albuminuria. In multivariate analysis, after adjusting for comprehensive risk factors, the risk of developing albuminuria was higher in the lowest quartile of serum bilirubin concentrations than that in the highest quartile of serum bilirubin concentrations (Hazard ratio, 5.76 95 CI, 1.65 to 24.93). Conclusions Low serum bilirubin concentration could be a novel risk factor for the development of albuminuria in patients with type 2 diabetes. u00a9 2014 Elsevier Inc., author dropping-particle , family Okada, given Hiroshi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Fukui, given Michiaki, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tanaka, given Muhei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Matsumoto, given Shinobu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kobayashi, given Kanae, non-dropping-particle , parse-names false, suffix , dropping-particle , family Iwase, given Hiroya, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tomiyasu, given Kiichiro, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakano, given Koji, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hasegawa, given Goji, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakamura, given Naoto, non-dropping-particle , parse-names false, suffix , container-title Metabolism Clinical and Experimental, id ITEM-1, issue 3, issued date-parts 2014 , page 409-414, publisher Elsevier Inc., title Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes, type article-journal, volume 63 , uris http//www.mendeley.com/documents/uuidc5094896-f3a2-435d-84bf-d89bad5ea7c8 , mendeley formattedCitation (Okada et al., 2014), plainTextFormattedCitation (Okada et al., 2014), previouslyFormattedCitation (Okada et al., 2014) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Okada et al., 2014). Wang et al (2016) went further to emphasize that particularly unconjugated bilirubin, could be a potential biomarker and therapeutic target for DN. Some cross-sectional studies also indicated an inverse relationship between serum bilirubin level and risk of diabetic kidney disease ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1038/ki.2008.398, ISBN 1523-1755 (Electronic)r0085-2538 (Linking), ISSN 1523-1755, PMID 18854849, abstract Previous studies showed that low serum bilirubin concentrations are associated with increased risk of cardiovascular disease. To explore this further, we evaluated the relationships between serum bilirubin concentrations and the degree of urinary albumin excretion and other markers of subclinical atherosclerosis in 633 consecutive patients with type 2 diabetes. Multiple regression analysis showed that the serum bilirubin concentration was an independent determinant of and had a significant inverse correlation to the log urinary albumin excretion. Serum bilirubin concentrations were significantly lower in patients with than in those without cardiovascular disease. A significant inverse correlation was found between the serum bilirubin concentration and pulse wave velocity, while a significant positive correlation was found to the ankle-brachial index in a subgroup of 386 patients. Our study shows that the serum bilirubin level is associated with microalbuminuria and subclinical atherosclerosis in patients with type 2 diabetes., author dropping-particle , family Fukui, given Michiaki, non-dropping-particle , parse-names false, suffix , dropping-particle , family Tanaka, given Muhei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Shiraishi, given Emi, non-dropping-particle , parse-names false, suffix , dropping-particle , family Harusato, given Ichiko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hosoda, given Hiroko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Asano, given Mai, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hasegawa, given Goji, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakamura, given Naoto, non-dropping-particle , parse-names false, suffix , container-title Kidney international, id ITEM-1, issue 9, issued date-parts 2008 , page 1197-201, publisher Elsevier Masson SAS, title Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes., type article-journal, volume 74 , uris http//www.mendeley.com/documents/uuidb14bd181-a303-4a9f-b032-b1d4e4aff8a6 , id ITEM-2, itemData ISSN 0098-7484, author dropping-particle , family Inoguchi, given T, non-dropping-particle , parse-names false, suffix , dropping-particle , family Sasaki, given S, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kobayashi, given K, non-dropping-particle , parse-names false, suffix , dropping-particle , family Takayanagi, given R, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yamada, given T, non-dropping-particle , parse-names false, suffix , container-title JAMA, id ITEM-2, issue 12, issued date-parts 2007, 9, 26 , note 10.1001/jama.298.12.1398-b, page 1396-1400, title Relationship between gilbert syndrome and prevalence of vascular complications in patients with diabetes, type article-journal, volume 298 , uris http//www.mendeley.com/documents/uuid94f08a34-8f40-4274-a8c7-a645943481f7 , mendeley formattedCitation (Fukui et al., 2008 Inoguchi, Sasaki, Kobayashi, Takayanagi, Yamada, 2007), plainTextFormattedCitation (Fukui et al., 2008 Inoguchi, Sasaki, Kobayashi, Takayanagi, Yamada, 2007), previouslyFormattedCitation (Fukui et al., 2008 Inoguchi, Sasaki, Kobayashi, Takayanagi, Yamada, 2007) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Fukui et al., 2008 Inoguchi, Sasaki, Kobayashi, Takayanagi, Yamada, 2007). It has been reported that higher serum uric acid levels are associated with increased risk of CVD mortality in type 2 diabetic individuals ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.2337/dc09-0625.G.Z., ISSN 1935-5548, PMID 19542211, abstract OBJECTIVE There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals. RESEARCH DESIGN AND METHODS The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders. RESULTS During follow-up, 329 (12.1) patients died, 44.1 (n 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 95 CI 1.12-1.27, P 0.001) and cardiovascular (1.25 1.16-1.34, P 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 1.01-1.61, P 0.046), whereas the association of serum uric acid with all-cause mortality did not. CONCLUSIONS Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures., author dropping-particle , family Zoppini, given G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Targher, given G, non-dropping-particle , parse-names false, suffix , dropping-particle , family Negri, given C, non-dropping-particle , parse-names false, suffix , dropping-particle , family Stoico, given V, non-dropping-particle , parse-names false, suffix , dropping-particle , family Perrone, given F, non-dropping-particle , parse-names false, suffix , dropping-particle , family Muggeo, given M, non-dropping-particle , parse-names false, suffix , dropping-particle , family Bonora, given E, non-dropping-particle , parse-names false, suffix , container-title Diabetes Care, id ITEM-1, issue 9, issued date-parts 2009 , page 1716-1720, title Elevated Serum Uric Acid Concentrations Independently Predict Cardiovascular Mortality in Type 2 Diabetic Patients, type article-journal, volume 32 , uris http//www.mendeley.com/documents/uuid1f666d76-4d04-472b-973b-99a1ee63f391 , mendeley formattedCitation (Zoppini et al., 2009), plainTextFormattedCitation (Zoppini et al., 2009), previouslyFormattedCitation (Zoppini et al., 2009) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Zoppini et al., 2009). In some other studies, it was reported that hyperuricemia and microalbuminuria were both significant predictors of chronic vascular complications in type 2 diabetes patients ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.jdiacomp.2013.12.002, ISBN 1873-460X (Electronic)r1056-8727 (Linking), ISSN 10568727, PMID 24412514, abstract Aims To investigate an association between serum uric acid/microalbuminuria and chronic micro/macro-vascular complications in type 2 diabetic patients. Methods This cross-sectional study enrolled 608 patients with type 2 diabetes. All subjects were examined and basic information on health of the subjects was recorded for inclusion criteria. Several chemical parameters (fasting plasma glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, and microalbuminuria), and related chronic vascular complications were measured and recorded in data forms. Results Logistic regressions were used to analyse odds ratios between uric acid/microalbuminuria levels and several chronic vascular complications. Prevalence of chronic vascular complications in T2DM patients, namely coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy was significantly correlated with increase of uric acid level 2.29 (1.01-5.2), 16.01 (4.74-54.09), 9.99 (4.4-22.8), 4.43 (1.3-15.1), 4.37 (1.5-12.9), and of microalbuminuria level 7.0 (3.6-13.8), 3.2 (1.2-8.7), NA, 14.7 (5.1-42.7), 7.2 (2.9-17.7). Conclusion Both elevated uric acid and microalbuminuria levels were significantly associated with diabetic chronic micro/macro-vascular complications. Monitoring of uric acid and microalbuminuria levels provides a predictive value for a presence of chronic micro/macro-vascular complications in patients with type 2 diabetes. u00a9 2014 Elsevier Inc. All rights reserved., author dropping-particle , family Chuengsamarn, given Somlak, non-dropping-particle , parse-names false, suffix , dropping-particle , family Rattanamongkolgul, given Suthee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Jirawatnotai, given Siwanon, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes and its Complications, id ITEM-1, issue 2, issued date-parts 2014 , page 124-129, publisher Elsevier Inc., title Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes, type article-journal, volume 28 , uris http//www.mendeley.com/documents/uuidd9a6bb5c-96cd-4a4b-9eea-f6a8a5e6758f , mendeley formattedCitation (Chuengsamarn, Rattanamongkolgul, Jirawatnotai, 2014), plainTextFormattedCitation (Chuengsamarn, Rattanamongkolgul, Jirawatnotai, 2014), previouslyFormattedCitation (Chuengsamarn, Rattanamongkolgul, Jirawatnotai, 2014) , properties noteIndex 40 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Chuengsamarn, Rattanamongkolgul, Jirawatnotai, 2014). A close link between UA and increased UAE rate in type 2 diabetes patients in Taiwan was also reported ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1111/j.1523-1755.2005.00459.x, ISSN 0085-2538, PMID 16014058, abstract BACKGROUND Uric acid is detrimental to the kidneys in animal models. However, its role in human diabetic nephropathy has not been extensively studied. This study evaluated the association between serum uric acid and urinary albumin-to-creatinine ratio (ACR) among patients with type 2 diabetes mellitus in Taiwan. METHODS A total of 343 patients (144 men and 199 women), aged 62.8 /- 10.8 years and not using uric acid-lowering agents, diuretics, or alcohol, were recruited. Serum uric acid and urinary ACR were determined. Normoalbuminuria, microalbuminuria, and macroalbuminuria were defined as ACR 30.0, 30.0 to 299.9, and or 300.0 microg/mg, respectively. RESULTS The respective uric acid levels for normoalbuminuria (N 166), microalbuminuria (N 130), and macroalbuminuria (N 47) were 5.2 /- 1.6 mg/dL, 5.6 /- 1.9 mg/dL, and 6.7 /- 2.1 mg/dL (P 0.001). The mean /- SD (minimum-maximum) values of uric acid for the first to the fourth quartile were 3.4 /- 0.6 (1.7-4.2), 4.9 /- 0.4 (4.3-5.4), 6.0 /- 0.3 (5.5-6.5), and 8.1 /- 1.2 (6.6-12.2), respectively. Prevalence of abnormal albuminuria (microalbuminuria plus macroalbuminuria) for the respective quartiles were 38.4, 51.2, 50.6, and 66.3 (P trend 0.01). In men, uric acid correlated positively with triglycerides and natural logarithmic ln (ACR) (gamma 0.168, P 0.05). In women, uric acid correlated positively with triglycerides, ln (ACR) (gamma 0.277, P 0.01) and body mass index (borderline significant P 0.1), but negatively with calculated creatinine clearance. The standardized regression coefficient for ln (ACR) and the odds ratio for abnormal albuminuria for every 1 mg/dL increment of uric acid after adjusting for calculated creatinine clearance and other confounders were 0.138 (P 0.05) and 1.183 (1.025-1.364), respectively. The results after excluding 127 cases with a history of hypertension were similar. CONCLUSION Serum uric acid is an independent correlate of urinary ACR in Taiwanese patients with type 2 diabetes mellitus., author dropping-particle , family Tseng, given Chin-Hsiao, non-dropping-particle , parse-names false, suffix , container-title Kidney international, id ITEM-1, issue 2, issued date-parts 2005 , page 796-801, title Correlation of uric acid and urinary albumin excretion rate in patients with type 2 diabetes mellitus in Taiwan., type article-journal, volume 68 , uris http//www.mendeley.com/documents/uuidad161743-9dce-4555-acfd-55484f40631c , mendeley formattedCitation (Tseng, 2005), plainTextFormattedCitation (Tseng, 2005), previouslyFormattedCitation (Tseng, 2005) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Tseng, 2005). This observation, however, was not made in hypertensive patients and those undergoing treatment for hypertension, as ACE inhibitors used in these patients blocked uric acid-mediated effects ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1152/ajprenal.00283.2001, ISBN 1931-857X (Print)r1522-1466, ISSN 0363-6127, PMID 11997315, abstract Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyperuricemia in rats that results in increased blood pressure and mild renal fibrosis. In this study, we examined the effect of hyperuricemia on the renal vasculature. Rats fed 2 oxonic acid and a low-salt diet for 7 wk developed mild hyperuricemia (1.8 vs. 1.4 mg/dl, P 0.05), hypertension 147 vs. 127 mmHg systolic blood pressure (SBP), P 0.05, and afferent arteriolar thickening, with a 35 increase in medial area (P 0.05). Allopurinol or benziodarone prevented the hyperuricemia, hypertension, and arteriolopathy. Hydrochlorothiazide treatment did not prevent the hyperuricemia or arteriolopathy despite controlling blood pressure. In contrast, the arteriolopathy and hypertension were prevented by both enalapril and losartan. Uric acid also directly stimulated vascular smooth muscle cell proliferation in vitro, and this was partially inhibited by losartan. Thus hyperuricemia induces a renal arteriolopathy in rats that is blood pressure independent and involves the renin-angiotensin system., author dropping-particle , family Mazzali, given Marilda, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kanellis, given John, non-dropping-particle , parse-names false, suffix , dropping-particle , family Han, given Lin, non-dropping-particle , parse-names false, suffix , dropping-particle , family Feng, given Lili, non-dropping-particle , parse-names false, suffix , dropping-particle , family Xia, given Yi-Yang, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Qiang, non-dropping-particle , parse-names false, suffix , dropping-particle , family Kang, given Duk-Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Gordon, given Katherine L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Watanabe, given Susumu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Nakagawa, given Takahiko, non-dropping-particle , parse-names false, suffix , dropping-particle , family Lan, given Hui Y., non-dropping-particle , parse-names false, suffix , dropping-particle , family Johnson, given Richard J., non-dropping-particle , parse-names false, suffix , container-title American Journal of Physiology – Renal Physiology, id ITEM-1, issue 6, issued date-parts 2002 , page F991-F997, title Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism, type article-journal, volume 282 , uris http//www.mendeley.com/documents/uuidb5b84643-7d6b-4ed4-9e6d-febe3d0afa5b , id ITEM-2, itemData DOI 10.1161/hy1101.092839, ISBN 1524-4563 (Electronic)n0194-911X (Linking), ISSN 0194-911X, PMID 11711505, abstract An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (r0.75, n69), with a 10-mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase., author dropping-particle , family Mazzali, given M., non-dropping-particle , parse-names false, suffix , dropping-particle , family Hughes, given J., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kim, given Y.-G., non-dropping-particle , parse-names false, suffix , dropping-particle , family Jefferson, given J. A., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kang, given D.-H., non-dropping-particle , parse-names false, suffix , dropping-particle , family Gordon, given K. L., non-dropping-particle , parse-names false, suffix , dropping-particle , family Lan, given H. Y., non-dropping-particle , parse-names false, suffix , dropping-particle , family Kivlighn, given S., non-dropping-particle , parse-names false, suffix , dropping-particle , family Johnson, given R. J., non-dropping-particle , parse-names false, suffix , container-title Hypertension, id ITEM-2, issue 5, issued date-parts 2001 , page 1101-1106, title Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism, type article-journal, volume 38 , uris http//www.mendeley.com/documents/uuided5a6791-e3ba-4829-a20c-13e7e72c075c , mendeley formattedCitation (M. Mazzali et al., 2001 Marilda Mazzali et al., 2002), plainTextFormattedCitation (M. Mazzali et al., 2001 Marilda Mazzali et al., 2002), previouslyFormattedCitation (M. Mazzali et al., 2001 Marilda Mazzali et al., 2002) , properties noteIndex 8 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (M. Mazzali et al., 2001 Marilda Mazzali et al., 2002). What is more, a recent review of various studies on UA revealed that it plays a dual role intracellularly a pro-oxidant and an anti-oxidant in plasma although more investigations would be required to confirm this conclusion ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.5049/EBP.2014.12.1.1, ISBN 1738-5997 (Print)r1738-5997, ISSN 20929935, PMID 25061467, abstract Hyperuricemia is known to be associated with the presence of cardiovascular and metabolic syndrome and with the development of incipient kidney disease and an accelerated renal progression. However, an elevated uric acid level was not generally regarded as a true etiology or mediator, but an indicator of these diseases. Uric acid has recently regained the clinical interest and popularity based on emerging data suggesting the causative role of hyperuricemia in cardiovascular and renal disease. Experimental data demonstrates oxidative stress is one of the earliest phenomena observed in vascular, renal, liver cells and adipocytes exposed to uric acid. Since uric acid is one of the major antioxidants of plasma acting as a free radical scavenger and a chelator of transitional metal ion, uric acid-induced oxidative stress seems paradoxical. Data regarding the clinical implication of hyperuricemia is even more confusing, which defines hyperuricemia as a useless parameter to be eliminated from routine follow-up or a major risk factor to be therapeutic target. With a review of experimental and epidemiologic data, the presence of molecular switch to regulate the role of uric acid as anti- or pro-oxidant in different compartment of our body is suggested, which may shed light on understanding the paradoxical role of uric acid and solving the uric acid debate., author dropping-particle , family Kang, given Duk Hee, non-dropping-particle , parse-names false, suffix , dropping-particle , family Ha, given Sung Kyu, non-dropping-particle , parse-names false, suffix , container-title Electrolyte and Blood Pressure, id ITEM-1, issue 1, issued date-parts 2014 , page 1-6, title Uric acid puzzle Dual role as anti-oxidantand pro-oxidant, type article-journal, volume 12 , uris http//www.mendeley.com/documents/uuideee858c1-5c55-4be0-acf3-8e04237c4eb0 , mendeley formattedCitation (D. H. Kang Ha, 2014), plainTextFormattedCitation (D. H. Kang Ha, 2014), previouslyFormattedCitation (D. H. Kang Ha, 2014) , properties noteIndex 5 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (D. H. Kang Ha, 2014). CHAPTER 3 MATERIALS AND METHODS Study Site(s) The study was carried out at the Diabetes Clinic of Korle Bu Teaching Hospital (KBTH). Study Design A cross-sectional study was conducted at the Diabetes Clinic of Korle Bu Teaching Hospital, Accra. Study Population Inclusion Criteria The study included type 2 diabetes patients of both sexes. The study included type 2 diabetes patients who were not more than 65 years. Exclusion Criteria The study excluded patients with urinary tract infection, hematuria, bacteriuria, heart failure, uncontrolled hypertension, liver cirrhosis, malignancy or hematologic disease, and those with major cardiovascular events as these may falsely increase albuminuria estimations. The study excluded patients on any medication that might affect serum uric acid concentrations such as, thiazides, salicylates, pyrazinamide, ethambutol, nicotinic acid, and cyclosporine. This study excluded patients with end-stage renal disease/failure (eGFR 10mL/min), and/or those on dialysis. Sample size determination Sample size was calculated using n zp (1-p) / e Where n the minimum sample size, z the standard score, p the known prevalence of microalbuminuria and e the allowable error margin. Using the prevalence of 10.7 ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1186/1471-2369-8-2, ISSN 1471-2369 (Electronic), PMID 17224056, abstract BACKGROUND The prevalences and risk factors of microalbuminuria are not full described among black African diabetic patients. This study aimed at determining the prevalence of microalbuminuria among African diabetes patients in Dar es Salaam, Tanzania, and relate to socio-demographic features as well as clinical parameters. METHODS Cross sectional study on 91 Type 1 and 153 Type 2 diabetic patients. Two overnight urine samples per patient were analysed. Albumin concentration was measured by an automated immunoturbidity assay. Average albumin excretion rate (AER) was used and were categorised as normalbuminuria (AER 20 ug/min), microalbuminuria (AER 20-200 ug/min), and macroalbuminuria (AER 200 ug/min). Information obtained also included age, diabetes duration, sex, body mass index, blood pressure, serum total cholesterol, high-density and low-density lipoprotein cholesterol, triglycerides, serum creatinine, and glycated hemoglobin A1c. RESULTS Overall prevalence of microalbuminuria was 10.7 and macroalbuminuria 4.9. In Type 1 patients microalbuminuria was 12 and macroalbuminuria 1. Among Type 2 patients, 9.8 had microalbuminuria, and 7.2 had macroalbuminuria. Type 2 patients with abnormal albumin excretion rate had significantly longer diabetes duration 7.5 (0.2-24 yrs) than those with normal albumin excretion rate 3 (0-25 yrs), p 0.001. Systolic and diastolic blood pressure among Type 2 patients with abnormal albumin excretion rate were significantly higher than in those with normal albumin excretion rate, (p 0.001). No significant differences in body mass index, glycaemic control, and cholesterol levels was found among patients with normal compared with those with elevated albumin excretion rate either in Type 1 or Type 2 patients. A stepwise multiple linear regression analysis among Type 2 patients, revealed AER (natural log AER) as the dependent variable to be predicted by odds ratio (95 confidence interval) diabetes duration 0.090 (0.049, 0.131), p 0.0001, systolic blood pressure 0.012 (0.003-0.021), p 0.010 and serum creatinine 0.021 (0.012, 0.030). CONCLUSION The prevalence of micro and macroalbuminuria is higher among African Type 1 patients with relatively short diabetes duration compared with prevalences among Caucasians. In Type 2 patients, the prevalence is in accordance with findings in Caucasians. The present study detects, however, a much lower prevalence than previously demonstrated in studies from sub-Saharan Afu2026, author dropping-particle , family Lutale, given Janet Joy Kachuchuru, non-dropping-particle , parse-names false, suffix , dropping-particle , family Thordarson, given Hrafnkell, non-dropping-particle , parse-names false, suffix , dropping-particle , family Abbas, given Zulfiqarali Gulam, non-dropping-particle , parse-names false, suffix , dropping-particle , family Vetvik, given Kare, non-dropping-particle , parse-names false, suffix , container-title BMC nephrology, id ITEM-1, issued date-parts 2007, 1 , language eng, page 2, publisher-place England, title Microalbuminuria among Type 1 and Type 2 diabetic patients of African origin in Dar Es Salaam, Tanzania., type article-journal, volume 8 , uris http//www.mendeley.com/documents/uuide2de48c3-b624-4d40-a2fe-5a56a6edad7a , mendeley formattedCitation (Lutale, Thordarson, Abbas, Vetvik, 2007), plainTextFormattedCitation (Lutale, Thordarson, Abbas, Vetvik, 2007), previouslyFormattedCitation (Lutale, Thordarson, Abbas, Vetvik, 2007) , properties noteIndex 38 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Lutale, Thordarson, Abbas, Vetvik, 2007) at 95 Confidence level (z 1.96, e 10), the minimum number of study participants required for the study was 37. Sampling Procedure Informed Consent Informed consent was sought from the type 2 diabetes patients through the administration of a consent form. Patients who consented to partake in the study were briefed on the content and requirements of the study. Afterwards, data from patients medical records and administered questionnaires was retrieved and reviewed socio-demographic characteristics, comorbidities and health-related habits. No patient was compelled to participate and participants were assured of their freedom to withdraw from the study at any time with or without reason (see Appendix I informed consent). Blood Sample Collection Following an 8-10 hour overnight fast, four milliliters (4 ml) of venous blood sample was collected from each study participant. The appropriate venipuncture site was selected and wiped with 70 alcohol in a circular manner and in an outward fashion and allowed to air-dry. With a tourniquet applied to the participants arm, the blood sample was collected using needle and syringe, the tourniquet released and the needle gently withdrawn. Pressure was immediately applied to the puncture site with the aid of cotton wool. The blood sample was quickly dispensed into a serum-separator tube and labelled appropriately. Urine Sample Collection. The specimen used for albuminuria determination was an early morning spot urine sample. Participants were given clean urine sample containers into which urine was voided and tightly capped. The samples were received and labelled appropriately and with safety precautions by the study team. Laboratory Procedures Blood and urine samples were transported within 2 hours to Central Laboratory, KBTH, and the blood samples quickly centrifuged to obtain and separate sera from red cells. The dates and times of sample collection and arrival at the laboratory were all documented. Analyses included the primary dipstick screening of urine for indicators of urinary tract infection (leukocytes, nitrites), overt proteinuria and glycosuria. Serum uric acid and bilirubin concentrations as well as urine albumin concentrations were determined using the VITROS 5.1 chemistry analyzer (New York, USA) according to the manufacturers instructions. Data Collection Procedure Demographic data including age, sex, weight, height and waist circumference/BMI (where applicable) were collected from patient records. A recent study indicated that the association between low serum bilirubin and decline in GFR in type 2 diabetics was stronger among smokers ADDIN CSL_CITATION citationItems id ITEM-1, itemData DOI 10.1016/j.jdiacomp.2016.05.013, ISSN 1873460X, PMID 27288202, abstract Aims Studies indicate that elevated serum total bilirubin (TBil) levels are associated with lower risk of diabetic kidney disease (DKD). Few studies examined the associations of direct bilirubin (DBil) and indirect bilirubin (IBil) with the development of DKD. Methods Type 2 diabetes patients (nu00a0u00a02,958) with estimated glomerular filtration (eGFR)u00a0u2265u00a060u00a0mlu00a0minu2212u00a01 1.73u00a0mu2212u00a02 from the Dongfengu2013Tongji cohort were selected and followed up for 5u00a0years. Development of DKD was defined as decline in eGFRu00a0u2265u00a030 during follow-up. Generalize linear model was used to assess the associations of bilirubin levels with DKD development. Results Compared with those in the first tertile of serum TBil, the relative risks (RRs) and 95 confidence intervals (CIs) of incident eGFR decline for tertile 2 to 3 were 0.83 (0.64u20131.09) and 0.74 (0.56u20130.98), P trendu00a0u00a00.04. The counterpart RRs (95 CIs) in IBil were 0.74 (0.57u20130.97) and 0.75 (0.57u20130.98), Ptrendu00a0u00a00.04. No significant associations were observed in DBil. Moreover, TBil and IBil interacted with smoking, the bilirubin-DKD associations were evident in ever smokers. Conclusions Our findings suggest that elevation of serum TBil or IBil levels are independent protective factors for development of DKD, particularly in smokers., author dropping-particle , family Wang, given Jing, non-dropping-particle , parse-names false, suffix , dropping-particle , family Li, given Yaru, non-dropping-particle , parse-names false, suffix , dropping-particle , family Han, given Xu, non-dropping-particle , parse-names false, suffix , dropping-particle , family Hu, given Hua, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wang, given Fei, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yu, given Caizheng, non-dropping-particle , parse-names false, suffix , dropping-particle , family Li, given Xiulou, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yang, given Kun, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yuan, given Jing, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yao, given Ping, non-dropping-particle , parse-names false, suffix , dropping-particle , family Miao, given Xiaoping, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wei, given Sheng, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wang, given Youjie, non-dropping-particle , parse-names false, suffix , dropping-particle , family Chen, given Weihong, non-dropping-particle , parse-names false, suffix , dropping-particle , family Liang, given Yuan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Zhang, given Xiaomin, non-dropping-particle , parse-names false, suffix , dropping-particle , family Guo, given Huan, non-dropping-particle , parse-names false, suffix , dropping-particle , family Pan, given An, non-dropping-particle , parse-names false, suffix , dropping-particle , family Yang, given Handong, non-dropping-particle , parse-names false, suffix , dropping-particle , family Wu, given Tangchun, non-dropping-particle , parse-names false, suffix , dropping-particle , family He, given Meian, non-dropping-particle , parse-names false, suffix , container-title Journal of Diabetes and its Complications, id ITEM-1, issue 7, issued date-parts 2016 , page 1255-1260, publisher Elsevier Inc., title Association between serum bilirubin levels and decline in estimated glomerular filtration rate among patients with type 2 diabetes, type article-journal, volume 30 , uris http//www.mendeley.com/documents/uuid4cd2f529-6ccc-43f3-973f-9252ddf3d772 , mendeley formattedCitation (Wang et al., 2016), plainTextFormattedCitation (Wang et al., 2016), previouslyFormattedCitation (Wang et al., 2016) , properties noteIndex 10 , schema https//github.com/citation-style-language/schema/raw/master/csl-citation.json (Wang et al., 2016). Thus, based on a questionnaire, recruited participants were classified as smokers, previously smokers or never smokers and same done for drinking status. Data on the health status of participants such as duration of diabetes, hypertension status and treatment, history of cardiovascular disease (CVD), dyslipidemia status, and haemoglobin A1C (HbA1C) were gathered as well. Data Analysis Ethics Ethical approval was sought from the Ethics and Protocol Review Committee of the School of Biomedical and Allied Health Sciences of the University of Ghana, as well as that of Korle Bu Teaching Hospital. Permission was obtained from the management of the Diabetes Clinic of Korle Bu Teaching Hospital. Participants were informed of the possible physical discomfort of venipuncture procedures. Participants were also assured of patient confidentiality codes instead of names, were used as the means of identification. Patients were reassured that results obtained from analyzing the samples would be kept confidential and used only for the purposes of this research. Dissemination of Results A hardcopy report of this study would be kept at the library of the School of Biomedical and Allied Health Sciences as well as the library of the College of Health Sciences, both of the University of Ghana. The findings generated from this study would be disseminated through publications in health-related journals of international standard as well as by presentations during scientific conferences and other related gatherings. REFERENCES ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY Adler, A. I., Stevens, R. J., Manley, S. E., Bilous, R. W., Cull, C. A., Holman, R. R. (2003). Development and progression of nephropathy in type 2 diabetes The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney International, 63(1), 225232. https//doi.org/10.1046/j.1523-1755.2003.00712.x American Diabetes Association. (2002). Diabetic Nephropathy. Diabetes Care, 25(November 1996), 585589. American Diabetes Association. (2004). Nephropathy in diabetes. Diabetes Care, 27 Suppl 1(suppl 1), S79-83. https//doi.org/10.2337/diacare.27.2007.s79 American Diabetes Association. (2014). Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 37(SUPPL.1), 8190. https//doi.org/10.2337/dc14-S081 Ames, B. N., Cathcart, R., Schwiers, E., Hochstein, P. (1981). Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer a hypothesis. Proceedings of the National Academy of Sciences, 78(11), 68586862. https//doi.org/10.1073/pnas.78.11.6858 Bennett, K., Aditya, B. S. (2015). An overview of diabetic nephropathy Epidemiology, pathophysiology and treatment. Journal of Diabetes Nursing, 19(2), 6167. Brown, D. M., Andres, G. A., Hostetter, T. H., Mauer, S. M., Price, R., Venkatachalam, M. A. (1982). Kidney complications. Diabetes, 31(Suppl 1 Pt 2), 7181. Caramori, M. L., Fioretto, P., Mauer, M. (2003). Low Glomerular Filtration Rate in Normoalbuminuric Type 1 Diabetic Patients. Diabetes, 52(4), 1036 LP-1040. Retrieved from http//diabetes.diabetesjournals.org/content/52/4/1036.abstract Chatterjee, S., Khunti, K., Davies, M. J. (2017). Type 2 diabetes. The Lancet, 389(10085), 22392251. https//doi.org/10.1016/S0140-6736(17)30058-2 Christiansen, J. S., Gammelgaard, J., Tronier, B., Svendsen, P. A., Parving, H. H. (1982). Kidney function and size in diabetics before and during initial insulin treatment. Kidney International, 21(5), 683688. https//doi.org/10.1038/ki.1982.81 Chuengsamarn, S., Rattanamongkolgul, S., Jirawatnotai, S. (2014). Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes. Journal of Diabetes and Its Complications, 28(2), 124129. https//doi.org/10.1016/j.jdiacomp.2013.12.002 Eknoyan, G., Hostetter, T., Bakris, G. L., Hebert, L., Levey, A. S., Parving, H.-H., Toto, R. (2003). Proteinuria and other markers of chronic kidney disease a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK) 1. American Journal of Kidney Diseases, 42(4), 617622. https//doi.org/10.1016/S0272-6386(03)00826-6 Figueroa-Romero, C., Sadidi, M., Feldman, E. L. (2008). Mechanisms of disease the oxidative stress theory of diabetic neuropathy. Reviews in Endocrine Metabolic Disorders, 9(4), 30114. https//doi.org/10.1007/s11154-008-9104-2 Forbes, J. M., Coughlan, M. T., Cooper, M. E. (2008). Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes, 57(6), 14461454. https//doi.org/10.2337/db08-0057 Fukui, M., Tanaka, M., Shiraishi, E., Harusato, I., Hosoda, H., Asano, M., Nakamura, N. (2008). Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. 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Journal of the American Society of Nephrology, 15(90010), 55S57. https//doi.org/10.1097/01.ASN.0000093460.24823.5B Zoppini, G., Targher, G., Negri, C., Stoico, V., Perrone, F., Muggeo, M., Bonora, E. (2009). Elevated Serum Uric Acid Concentrations Independently Predict Cardiovascular Mortality in Type 2 Diabetic Patients. Diabetes Care, 32(9), 17161720. https//doi.org/10.2337/dc09-0625.G.Z. APPENDICES APPENDIX A Information sheet for participants. You are invited to take part in this research. You have the right to either agree or refuse to take part in the study. If you want to take part, kindly read the following information on the purposes and procedures of the study. You can freely decide later to no longer take part of your choice. Title ASSOCIATION OF SERUM BILIRUBIN AND URIC ACID LEVELS WITH ALBUMINURIA IN TYPE 2 DIABETES PATIENTS. Researcher HAYFORD ATO KWAMENA, a final year student at the University of Ghana School of Biomedical and Allied Health Sciences, Korle Bu. Background The levels of glucose (sugar) in the blood are controlled by insulin because it transfers blood sugar into cells of the body. In diabetes, enough insulin is not produced (type 1 diabetes) or the body cant respond normally to the insulin that is made (type 2 diabetes) and this causes blood glucose levels to rise. High glucose level will produce reactive oxygen species chemicals that can attack your kidney cells leading to diabetic kidney disease. This disease is shown by abnormal amounts of protein in urine (albuminuria). It is the most common cause of kidney failure. Bilirubin and uric acid, however, are both end-products of breaking down certain chemicals in the body. Studies have shown that their levels in the blood can affect the development of kidney disease in type 2 diabetes patients. Aim To determine the association of serum bilirubin and uric acid levels with the incidence of albuminuria in type 2 diabetes patients. Procedures 4ml of fasting blood sample would be collected from your arm using a sterile syringe and needle, into gel separator tubes. You would also be given urine containers and required to bring to the clinic a urine sample. Samples would be taken only once. Benefits The information obtained in this study will greatly improve the diagnosis, monitoring and management of diabetes and diabetic kidney disease. Risks and discomfort There is very little risk associated with this study. You might feel a little discomfort when the blood sample is taken while bringing along a urine sample may be quite unpleasant. You might also have a little bruising at the site of blood draw, which will be cared for by qualified health personnel. Participation and Right to Withdraw You are to understand that partaking in this study is entirely voluntary and you may ask questions to which you will receive answers. Hence, you can refuse to take part. If you take part now but change your mind later, you are free to withdraw from the study at any time. Confidentiality The information from your clinical records and the details you provide as well as those obtained by testing your samples in this study will be kept confidential and secure. For further clarification, you may contact the researcher on 0261739244 or via email HYPERLINK [email protected] [email protected] APPENDIX B Consent form. I ____________________________have read (or it has been read to me) and understood the invitation to take part in the research study ASSOCIATION OF SERUM BILIRUBIN AND URIC ACID LEVELS WITH ALBUMINURIA IN TYPE 2 DIABETES PATIENTS. I have received enough information regarding the nature of the study and understand what will be required of me. I have had the opportunity to ask questions concerning the study and I have been answered to my satisfaction. I am aware of my right to withdraw at any point during the study without penalty. I hereby consent to participate in this research study. Participants Signature/Thumbprint ______________________ Date __________ Researchers Signature ______________________ Date __________ APPENDIX C QUESTIONNAIRE FOR INVESTIGATING THE ASSOCIATION OF SERUM BILIRUBIN AND URIC ACID LEVELS WITH ALBUMINURIA IN TYPE 2 DIABETES PATIENTS. The questionnaire is in three sections A, B C. Please tick or fill in the appropriate space provided. Patient Code SECTION A SOCIO DEMOGRAPHIC DATA. Sex Male Female If yes, how recent . Are you on hypertensive treatment Yes No If yes, please specify ACE blockers Diuretics Other Are you on medication for Gout Yes No Are you on dialysis Yes No Are you on cathetherization Yes No SECTION C HEALTH RELATED HABITS Have you engaged in at least 30mins exercise recently Yes No If yes, how recent 24hrs 72hrs 1Week 1Week I am a current smoker I used to smoke I was never a smoker I am a current drinker I used to drink I was never a drinker WORK SCHEDULE ACTIVITYDURATIONProposal WritingAugust – September, 2017Submission of ProposalSeptember, 2017Sample CollectionJanuary – February, 2018Laboratory AnalysisJanuary – February, 2018Analysis of ResultsMarch, 2018Report WritingMarch – April, 2018Submission of projectApril, 2018 BUDGET ITEMQUANTITYAMOUNT IN GHANA CEDISGloves1 pack20Cotton wool1 roll 10Alcohol1 bottle10Needle and Syringe100pieces40Serum separator tubes1 pack50Urine chemistry test strips1 pack30Uric acid Bilirubin tests60 serum samples300Microalbumin tests60 serum samples800Printing and binding100TOTAL1360 PAGE MERGEFORMAT xi PAGE MERGEFORMAT 10 0YfJQ L/5US1C nEudqZqw4)[email protected] 7McB2J,JB)i YQ [email protected]/x7LzPges9dez4iP-2W)HvJflSKzsycQ0598,v)PRjT -n7yfbglc1v)vMkay3 KgBy,_GO/[email protected] 1-wu7QN0E1K44 [email protected] 4D

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