Understanding Diabetic Nephropathy – Is There a Genetic Susceptibility?
Diabetes is rapidly increasing in prevalence,1 resulting in profound socioeconomic impacts in both developed and developing countries. Furthermore, the parallel increase in the prevalence of complications of diabetes, particularly nephropathy, retinopathy and associated cardiovascular disease, is placing enormous demands on healthcare budgets.2
Improved understanding of the aetiology and pathogenesis of these complications is urgently needed. Effective screening strategies to identify individuals with diabetes most likely to develop complications could improve outcomes by focusing resources on those at highest risk.
What Is Diabetic Nephropathy?
Diabetic nephropathy (DN) is a microvascular complication affecting patients with both type 1 and type 2 diabetes. It has become the leading cause of end-stage renal disease (ESRD) in Europe and the US managed by renal replacement therapy (kidney dialysis and/or renal transplantation).3,4 The clinical phenotype includes persistent proteinuria, a decreasing glomerular filtration rate (GFR) and hypertension.5 A sizeable minority of patients with diabetes eventually develop definite DN.6 The earliest clinical manifestation is microalbuminuria (incipient nephropathy), which may progress to overt proteinuria (dipstick urinalysis positive for proteinuria) followed by the emergence of hypertension, a declining GFR and, later, development of ESRD. Nevertheless, microalbuminura is not an absolutely reliable predictor of progression to DN as some patients remain microalbuminuric while others show regression of albuminuria to normal albumin excretion rates.7 Patients with DN have much higher mortality rates than individuals with diabetes with normal albumin excretion rates. The excess mortality is largely attributed to higher rates of coronary artery disease, stroke and amputation,8 and the five-year survival rate for ESRD patients with diabetes is worse than for most cancers.
DN in type 1 and 2 diabetes differs in a number of ways. For example, compared with type 1 diabetes the rate of progression of renal failure in patients with type 2 diabetes is more variable. In patients with type 2 diabetes, microalbuminuria progression to advanced renal disease is less frequent and increases in blood pressure generally occur before onset of microalbuminuria.9 Older patients with type 2 diabetes may also have concurrent hypertensive renal vascular disease, and unlike patients with type 1 diabetes the age at diabetes onset is more difficult to establish. Therefore, phenotypic definition of DN is simpler in patients with type 1 diabetes, which is one reason why efforts to discover genetic variants associated with risk of DN might be more successful in these patients.
Pathophysiological features of DN include glomerular capillary hypertension, glomerular hyperfiltration, mesangial matrix expansion and glomerulosclerosis. Prolonged hyperglycaemia leads to chronic metabolic and haemodynamic changes that modify the activity of various intracellular signalling pathways and transcription factors.10 There is the subsequent induction of cytokines, chemokines and growth factors, particularly transforming growth factor beta (TGFβ). These effects promote structural abnormalities in the kidney such as glomerular basement membrane thickening, podocyte injury and mesangial matrix expansion with the later development of irreversible glomerular sclerosis and tubulointerstitial fibrosis associated with declining GFR. The clinical management of DN includes optimal glycaemic control, treatment of dyslipidaemia and aggressive lowering of blood pressure ideally with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 receptor (ARB) blockers.11–14
- Wild S, Roglic G, Green A, et al., Global prevalence of diabetes: estimates for the year 2000 and projections for 2030, Diabetes Care, 2004;27:1047–53.
- Ray JA, Valentine WJ, Secnik K, et al., Review of the cost of diabetes complications in Australia, Canada, France, Germany, Italy and Spain, Curr Med Res Opin, 2005;21:1617–29.
- UK Renal Registry Report, UK Renal Registry, Bristol, 2007. Available at: www.renalreg.com
- US Renal Data System, USRDS 2007, Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 2007. Available at: www.usrds.org
- Ritz E, Pathogenesis, clinical manifestations and natural history of diabetic nephropathy, Comprehensive Clin Nephrol, 2007;13.
- Krolewski AS, Warram JH, Christlieb AR, et al., The changing natural history of nephropathy in type I diabetes, Am J Med, 1985;78:785–94.
- Perkins BA, Ficociello LH, Silva KH, et al., Regression of microalbuminuria in type 1 diabetes, N Engl J Med, 2003;348: 2285–93.
- Morgan CL, Currie CJ, Stott NC, et al., The prevalence of multiple diabetes-related complications, Diabet Med, 2000;17: 146–51.
- Remuzzi G, Schieppati A, Ruggenenti P, Clinical practice. Nephropathy in patients with type 2 diabetes, N Engl J Med, 2002;346:1145–51.
- Soldatos G, Cooper ME, Diabetic nephropathy: important pathophysiologic mechanisms, Diabetes Res Clin Pract, 2008;82(Suppl. 1):S75–9.
- The Diabetes Control and Complications Research Group, The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus, N Engl J Med, 1993;329: 977–86.
- UK Prospective Diabetes Study (UKPDS) Group, Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet, 1998;352:837–53.
- Nathan DM, Cleary PA, Backlund JY, et al., Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes, N Engl J Med, 2005;353: 2643–53.
- Barnett AH, Treating to goal: challenges of current management, Eur J Endocrinol, 2004;151(Suppl. 2):T3–7.
- Quinn M, Angelico MC, Warram JH, et al., Familial factors determine the development of diabetic nephropathy in patients with IDDM, Diabetologia, 1996;39:940–45.
- Viberti GC, Keen H, Wiseman MJ, Raised arterial pressure in parents of proteinuric insulin dependent diabetics, Br Med J, 1987;295:515–17.
- De Cosmo S, Bacci S, Piras GP, et al., High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria, Diabetologia, 1997;40:1191–6.
- Fogarty DG, Hanna LS, Wantman M, et al., Segregation analysis of urinary albumin excretion in families with type 2 diabetes, Diabetes, 2000;49:1057–63.
- Ng DP, Tai BC, Koh D, et al., Angiotensin-I converting enzyme insertion/deletion polymorphism and its association with diabetic nephropathy, Diabetologia, 2005; 48:1008–16.
- Bain SC, Chowdhury TA, Genetics of diabetic nephropathy and microalbuminuria, J R Soc Med, 2000;93:62–6.
- Ng DP, Krolewski AS, Molecular genetic approaches for studying the etiology of diabetic nephropathy, Curr Mol Med, 2005;5:509–25.
- Savage DA, Bain SC, McKnight AJ, et al., Gene discovery in diabetic nephropathy, Curr Diabetes Report, 2007;7:139–45.
- Freedman BI, Bostrom M, Daeihagh P, et al., Genetic factors in diabetic nephropathy, Clin J Am Soc Nephrol, 2007;2:1306–16.
- Placha G, Canani LH, Warram JH, et al., Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes, Adv Chronic Kidney Dis, 2005;12:155–69.
- Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, Nature, 2007;447:661–78.
- Mohlke KL, Boehnke M, Abecasis GR, Metabolic and cardiovascular traits: an abundance of recently identified common genetic variants, Hum Mol Genet, 2008;17:R102–8.
- Lettre G, Rioux JD, Autoimmune diseases: insights from genome-wide association studies, Hum Mol Genet, 2008;17: R116–21.
- Easton DF, Eeles RA, Genome-wide association studies in cancer, Hum Mol Genet, 2008;17:R109–15.
- McCarthy MI, Abecasis GR, Cardon LR, et al., Genome-wide association studies for complex traits: consensus, uncertainty and challenges, Nat Rev Genet, 2008;9:356–69.
- Bodmer W, Bonilla C, Common and rare variants in multifactorial susceptibility to common diseases, Nat Genet, 2008;40:695–701.
- International HapMap Consortium, A haplotype map of the human genome, Nature, 2005;437:1299–1320.
- McCarthy MI, Hirschhorn JN, Genome-wide association studies: potential next steps on a genetic journey, Hum Mol Genet, 2008;17:R156–65.
- McCarthy MI, Casting a wider net for diabetes susceptibility genes, Nat Genet, 2008;40:1039–40.
- GAIN Collaborative Research Group, New models of collaboration in genome-wide association studies: the Genetic Association Information Network, Nat Genet, 2007;39: 1045–51.
- Mueller PW, Rogus JJ, Cleary PA, et al., Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes, J Am Soc Nephrol, 2006;17: 1782–90.
- Savage DA, Patterson CC, Deloukas P, et al., Genetic association analyses of non-synonymous single nucleotide polymorphisms in diabetic nephropathy, Diabetologia, 2008;51: 1998–2002.
- Thorn LM, Forsblom C, Fagerudd J, et al., Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study), Diabetes Care, 2005;28: 2019–24.
- Murphy M, Godson C, Cannon S, et al., Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells, J Biol Chem, 1999;274:5830–34.
- McMahon R, Murphy M, Clarkson M, et al., IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1, J Biol Chem, 2000;275:9901–4.
- Dolan V, Murphy M, Sadlier D, et al., Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy, Am J Kidney Dis, 2005;45:1034–9.
- Murphy M, Crean J, Brazil DP, et al., Regulation and consequences of differential gene expression in diabetic kidney disease, Biochem Soc Trans, 2008;36:941–5.
- Dolan V, Murphy M, Alarcon P, et al., Gremlin – a putative pathogenic player in progressive renal disease, Expert Opin Ther Targets, 2003;7:523–6.
- Walsh DW, Roxburgh SA, McGettigan P, et al., Co-regulation of Gremlin and Notch signalling in diabetic nephropathy, Biochim Biophys Acta, 2008;1782:10–21.
- Jones PA, Baylin SB, The epigenomics of cancer, Cell, 2007;128:683–92.
- Esteller M, Epigenetics in cancer, N Engl J Med, 2008;358: 1148–59.
- Gray SG, De Meyts P, Role of histone and transcription factor acetylation in diabetes pathogenesis, Diabetes Metab Res Rev, 2005;21:416–33.
- Dong C, Yoon W, Goldschmidt-Clermont PJ, DNA methylation and atherosclerosis, J Nutr, 2002;132:2406–9S.
- Sharma P, Kumar J, Garg G, et al., Detection of altered global DNA methylation in coronary artery disease patients, DNA Cell Biol, 2008;27:357–65.
- Ingrosso D, Cimmino A, Perna AF, et al., Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia, Lancet, 2003;361:1693–9.
- Zaina S, Lindholm MW, Lund G, Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?, J Nutr, 2005;135:5–8.
- Stenvinkel P, Karimi M, Johansson S, et al., Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?, J Intern Med, 2007;261: 488–99.
- Soifer HS, Rossi JJ, Saetrom P, MicroRNAs in disease and potential therapeutic applications, Mol Ther, 2007;15: 2070–79.
- Mattes J, Collison A, Foster PS, Emerging role of microRNAs in disease pathogenesis and strategies for therapeutic modulation. Curr Opin Mol Ther, 2008;10:150–57.
- Couzin J, MicroRNAs make big impression in disease after disease, Science, 2008;319:1782–84.
- Kato M, Zhang J, Wang M, et al., MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors, Proc Natl Acad Sci U S A, 2007;104:3432–7.
- Sethupathy P, Borel C, Gagnebin M, et al., Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3’ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes, Am J Hum Genet, 2007;81:405–13.
- Wang Q, Wang Y, Minto AW, et al., MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy, FASEB J, 2008. Epub ahead of print.
- Gregory PA, Bert AG, Paterson EL, et al., The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1, Nat Cell Biol, 2008;10:593–601.
- Saunders MA, Liang H, Li WH, Human polymorphism at microRNAs and microRNA target sites, Proc Natl Acad Sci U S A, 2007;104:3300–3305.
- Bentley DR, Whole-genome re-sequencing, Curr Opin Genet Dev, 2006;16:545–52.
- Wheeler DA, Srinivasan M, Egholm M, et al., The complete genome of an individual by massively parallel DNA sequencing, Nature, 2008;452:872–6.
- Mardis ER, The impact of next-generation sequencing technology on genetics, Trends Genet, 2008;24:133–41.
- Strausberg RL, Levy S, Rogers YH, Emerging DNA sequencing technologies for human genomic medicine, Drug Discov Today, 2008;13:569–77.
- Craig DW, Pearson JV, Szelinger S, et al., Identification of genetic variants using bar-coded multiplexed sequencing, Nat Methods, 2008;5:887–93.
- Albert TJ, Molla MN, Muzny DM, et al., Direct selection of human genomic loci by microarray hybridization, Nat Methods, 2007;4:903–5.