1.SPEAKERDR. ANKUR NANDAN VARSHNEY

2. DefinitionDiabetic nephropathy, is a chronic conditiondeveloping over many years, characterized by: gradually increasing urinary albumin excretion (UAE) High blood pressure (BP) Declining glomerular filtration rate Absence of other renal/renal tract disease Presence of diabetic retinopathy. ( Brenner 9th edition ) 3. IncidenceAccording to US RENAL DISEASE REGISTRY: In 2006, the proportion of individuals with diabetesbeginning renal replacement therapy (RRT) was 20 44% The number of people with diabetes requiring RRTincreased by 50% between 1996 and 2006. A European report covering 1998 2002 demonstrated a9.9% per year increase.According to ICMR study, India has largest number of diabetics in the world withprevalence of 3.8% in rural and 11.8% in urban adults 25-40% of these develop End Stage Renal Disease . (Anjana RM et al J Diabetes Sci Technol 2011 Jul 1;5(4):906-14) 4. Pathophysiology Usually Multifactorial1. Metabolic pathway2. Hemodynamic pathway3. Genetic 5. Hyperglycemia Duration and magnitude of hyperglycemia stronglycorrelated with the extent and progression ofmicrovascular complications as DN Hyperglycemic damage occur to those cell types thatdevelop intracellular hyperglycemia such asendothelial cells and vascular smooth muscle cells (Lachin JM, Genuth S, Nathan DM, et al, DCCT/EDIC Research Group. Effect ofglycemic exposure on the risk of microvascular complications in the DiabetesControl and Complications Trialrevisted. Diabetes. 2008;57:995-1001.) 6. Mechanism of hyperglycemiainduced damage Four major hypothesis have been generated1. Increased polyol pathway flux2. Increased hexosamine pathway flux3. Increased intracellular formation of advanced glycation end products4. Activation of protein kinase C 7. POLYOL PATHWAY 8. Earlier thought1. Sorbitol induced osmotic distress Recent thought decreased GSH increase in ratio of NADPH/NAD+, that inhibits theactivity of glyceraldehyde-3-phosphate dehydrogenase.(Vikramadithyan RK, Hu Y, Noh HL, et al. Human aldose reductase expressionin transgenic mice. J Clin Invest. 2005 Sep;115:2434-2443.) 9. HEXOSAMINE PATHWAY- 10. O-linked N-acetylglucosamine , reducing expression of insulin responsive genes, leading to selective insulin resistance in vascular endothelial cells. (Yang X, Ongusaha PP, Miles PD, et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964-969. ) 11. Activation of Protein Kinase C 12. In experimental studies , PKC activation had beenshown to produce following effects:-1. Renal blood flow abnormalities2. Glomerular mesangial proliferation3. Increased endothelial cell permeability(Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, et al. Activation of PKC-delta and SHP-1 by hyperglycemia. Nat Med. 2009;15:1298-1306.) 13. Advanced Glycation End products Earlier, it was thought that they arise from nonenzymaticreaction between extracellular proteins and glucose. Now, it is thought they arises by1. Intracellular autooxidation of glucose to glyoxal2. Decomposition of the amadori product to 3- deoxyglucosone3. Fragmentation of glyceraldehyde phosphate to methylglyoxal (most common) (Monnier VM et al. The role of the amadori product in the complications of diabetes Ann N Y Acad Sci. 2008 Apr;1126:81-8.) 14. mechanism of damage 15. Methylglyoxal enhances antiapoptotic by directmodification of heat shock protein repressingcytochrome C mediated caspase activation ( Sakamoto H, Mashima T, Yamamoto K, et al. Modulation of heat-shock protein 27 (Hsp27) anti-apoptotic activity by methylglyoxal modification. J Biol Chem. 2002;277:45770-45775 ) AGE inhibit lateral association of molecules ofbasement membrane ,increasing its premeability toalbumin.(Dobler D, Ahmed N, Song L, et al. Increased dicarbonyl metabolism inendothelial cells in hyperglycemia . Diabetes. 2006;55:1961-1969. ) 16. Hemodynamic pathway Earlier it was thought that systemic hypertensioncauses adverse effect on renal function throughvasoconstriction and arteriolar nephrosclerosis. Now, studies revealed that systemic hypertension leadsto increase in glomerular hydrostatic pressure in sucha way that lead to hyperperfusion , increased capillarypressure , hyperfilteration and proteinuria The direct pressure effect causes stretch of mesangiumcausing protien kinase C activation activates- TGF-B1, fibrinonectine(Rossing K, Christensen PK, Hovind P, et al. Progression of nephropathy in type 2 diabetic patients. Kidney Int. 2004;66(4):1596-1605.) 17. Impaired or abolished renal autoregulation of GFR and renal plasma flow increases vulnerability to hypertension or ischemic injury to glomerular capillaries.(Reich HN, Oudit GY, Penninger JM, et al. Decreased glomerular and tubularphysiology in patients with type 2 diabetes and kidney disease. Kidney Int.2008;74(12):1610-1616.) Succinate, formed by the tricaboxylic acid cycle, provides a direct link between high glucose and renin release in the kidney through G protein coupled receptor for succinate. (Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest. 2008;118(7):2526-2534.) 18. Role of aldosterone Had widespread genomic and non genomic effects Besides electrolyte and fluid homeostasis, its roleinclude1. Upregulation of prosclerotic growth factors asplasminogen activator inhibitor-1 and transforminggrowth factor beta2. Promotion of macrophage infiltration Ultimately leads to renal fibrosis(Ritz E, Tomaschitz A. Aldosterone, a vasculotoxic agentnovel functions for anold hormone. Nephrol Dial Transplant. 2009;24(8):2302-2305.) 19. Genetics Different patients with similar duration and degree ofhyperglycemia differ markedly in their susceptibility tomicro vascular complications. Only 25-40% of patients with hyperglycemia and other riskfactors develop diabetic nephropathy suggesting a geneticrole Family studies reveal that first degree relatives of patientswith DN has higher incidence of DN (83%) than diabeticwithout these complications.(17%) Chromosome 3, 7 and 20 have shown susceptibility loci fordiabetic nephropathy(Pezzolesi MG, Poznik GD, Mychaleckyj JC, et al. Genome-wideassociation scan for diabetic nephropathy susceptibility genes in type1diabetes. Diabetes. 2009;58(6):1403-1410) 20. ACE(I/D) polymorphism 282 nucleotide repetitive sequence 3 phenotypes DD, ID, II Strongly associated with level of circulating ACE level D allele has been found to have deleterious effect on kidneyfunctions with 95% of DD developing ESRD within 10 yrs Act as progression promoter, independently influencedsustained rate of decline in GFR Increased risk of coronary heart disease (Parving H-H, de Zeeuw D, Cooper ME, et al. ACE gene polymorphism andlosartan treatment in type 2 diabetic patients with nephropathy. J Am SocNephrol. 2008;19(4):771-779.) 21. Multiple variations in superoxide dismutase 1 were significantly associated with persistent macroalbuminuria and severe nephropathy.(Al-Kateb H, et al. Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants areassociated with the development and progression of diabetic nephropathy: the Diabetes Control andComplications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study.Diabetes. 2008;57:218-228.) Three EPO promoter genes were found to be associated with increased chances of PDR and ESRD(Tong Zet al, Genetics of Diabetes and Diabetic Complication Study Group. Promoter polymorphism ofthe erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A.2008;105:6998-7003. ) 22. Osteoprotegerin , a secretory glycoprotein of tumor necrosis factor receptor superfamily, involved in vascular calcification, has been found elevated in diabetic with microvascular complications.(Rasmussen LMet al. Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients. Eur J Endocrinol.2006;154(1):75-81.) Adiponectin , shown to possess antiinflammatory and antiatherogenic properties , affects podocyte and levels are increased in patients with diabetic nephropathy. (Sharma K, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest.2008;118(5):1645-1656.) 23. Risk factors associated withprogression 24. Proteinuria induced renaldamage 25. Anemia and DN In patients with DN, anemia is an independent riskfactor associated with decline in GFR. Renal hypoxia resulting from anemia aggravatesinterstitial fibrosis by the stimulation of factors likeTGF- and VEGF. Hypoxia-inducing factor-1 (HIF-1), and ANG-II alsoplays a major role in this.(Thomas MC, Cooper ME, Rossing K, et al. Anaemia in diabetes: isthere a rationale to TREAT? Diabetologia. 2006;49(6):1151-1157.) 26. Obesity, BMI> 40 kg/m2, considered as an independent risk factor for progression of nephropathy. ( Krikken JA, Bakker SJ, Navis GJ. Role of renal haemodynamics in the renal risks of overweight. Nephrol Dial Transplant. 2009;24(6):1708-1711) Smoking, may act as progression promoter in patients with diabetes and proteinuria. (Hovind P, Rossing P, Tarnow L, et al. Smoking and progression of diabetic nephropathy in type 1 diabetes. Diabetologia. 2002;45:A361:abstract.) 27. Mogensons classification Stage 1: Hyperfiltration Increased Glomerular Filtration Rate (GFR >90ml/min) Result of concomitant renal hypertrophy (glomerular andtubular) Various factors contributing:1. Intra renal hemodynamic abnormalities2. TGF-beta3. Increased salt absorption 28. Stage 2 : The Silent Stage The GFR has returned to normal (GFR 60-89ml/min) with no evidence of albuminuria Glomerular damage occur in the form of basement membrane thickening and mesangial expansion. Ambulatory BP monitoring studies have shownmodest rise in BP and absence of nocturnal dip 29. Stage 3: Incipient nephropathy /Microalbuminuria Urine AER has increased upto 30 to 300 mg/24 hrs Renal functions could be normal or reduced. 30-50% of patients may show reversal ofmicroalbuminuria. Persistent microalbuminuria , if untreated, will progress toend-stage renal disease (ESRD). Therefore, all diabetes patients should be screened formicroalbuminuria on a routine basis.(Perkins BAet al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med.2003;348:2285-2293. ) 30. Stage 4 : Macroalbuminuria/Overt Nephropathy The urine AER more than 300 mg of albumin in a 24-hour period. Two peaks of incidences defined as SLOW and FASTTRACKERS Over two thirds of patient in this stage haveHypertension . If untreated a vicious cycle of progressive renalimpairment develops leading to ESRD. 31. Stage 5: Uremia GFR has fallen to