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  2. 2. Definition Diabetic nephropathy, is a chronic condition developing 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. 3. Incidence According to US RENAL DISEASE REGISTRY:  In 2006, the proportion of individuals with diabetes beginning renal replacement therapy (RRT) was 20 – 44%  The number of people with diabetes requiring RRT increased by 50% between 1996 and 2006.  A European report covering 1998 – 2002 demonstrated a 9.9% per year increase. According to ICMR study,  India has largest number of diabetics in the world with prevalence 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. 4. Pathophysiology  Usually Multifactorial 1. Metabolic pathway 2. Hemodynamic pathway 3. Genetic
  5. 5. Hyperglycemia  Duration and magnitude of hyperglycemia strongly correlated with the extent and progression of microvascular complications as DN  Hyperglycemic damage occur to those cell types that develop intracellular hyperglycemia such as endothelial cells and vascular smooth muscle cells (Lachin JM, Genuth S, Nathan DM, et al, DCCT/EDIC Research Group. Effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trial–revisted. Diabetes. 2008;57:995-1001.)
  6. 6. Mechanism of hyperglycemia induced damage  Four major hypothesis have been generated 1. Increased polyol pathway flux 2. Increased hexosamine pathway flux 3. Increased intracellular formation of advanced glycation end products 4. Activation of protein kinase C
  8. 8.  Earlier thought 1. Sorbitol induced osmotic distress  Recent thought  decreased GSH  increase in ratio of NADPH/NAD+, that inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase. (Vikramadithyan RK, Hu Y, Noh HL, et al. Human aldose reductase expression in transgenic mice. J Clin Invest. 2005 Sep;115:2434-2443.)
  10. 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. 11. Activation of Protein Kinase C
  12. 12.  In experimental studies , PKC activation had been shown to produce following effects:- 1. Renal blood flow abnormalities 2. Glomerular mesangial proliferation 3. 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. 13. Advanced Glycation End products  Earlier, it was thought that they arise from nonenzymatic reaction between extracellular proteins and glucose.  Now, it is thought they arises by 1. Intracellular autooxidation of glucose to glyoxal 2. Decomposition of the amadori product to 3- deoxyglucosone 3. 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. 14. mechanism of damage
  15. 15.  Methylglyoxal enhances antiapoptotic by direct modification of heat shock protein repressing cytochrome 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 of basement membrane ,increasing it’s premeability to albumin. (Dobler D, Ahmed N, Song L, et al. Increased dicarbonyl metabolism in endothelial cells in hyperglycemia . Diabetes. 2006;55:1961-1969. )
  16. 16. Hemodynamic pathway  Earlier it was thought that systemic hypertension causes adverse effect on renal function through vasoconstriction and arteriolar nephrosclerosis.  Now, studies revealed that systemic hypertension leads to increase in glomerular hydrostatic pressure in such a way that lead to hyperperfusion , increased capillary pressure , hyperfilteration and proteinuria  The direct pressure effect causes stretch of mesangium causing 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. 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 tubular physiology 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. 18. Role of aldosterone  Had widespread genomic and non genomic effects  Besides electrolyte and fluid homeostasis, it’s role include 1. Upregulation of prosclerotic growth factors as plasminogen activator inhibitor-1 and transforming growth factor beta 2. Promotion of macrophage infiltration  Ultimately leads to renal fibrosis (Ritz E, Tomaschitz A. Aldosterone, a vasculotoxic agent—novel functions for an old hormone. Nephrol Dial Transplant. 2009;24(8):2302-2305.)
  19. 19. Genetics  Different patients with similar duration and degree of hyperglycemia differ markedly in their susceptibility to micro vascular complications.  Only 25-40% of patients with hyperglycemia and other risk factors develop diabetic nephropathy suggesting a genetic role  Family studies reveal that first degree relatives of patients with DN has higher incidence of DN (83%) than diabetic without these complications.(17%)  Chromosome 3, 7 and 20 have shown susceptibility loci for diabetic nephropathy (Pezzolesi MG, Poznik GD, Mychaleckyj JC, et al. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1diabetes. Diabetes. 2009;58(6):1403-1410)
  20. 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 kidney functions with 95% of DD developing ESRD within 10 yrs  Act as progression promoter, independently influenced sustained rate of decline in GFR  Increased risk of coronary heart disease (Parving H-H, de Zeeuw D, Cooper ME, et al. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. J Am Soc Nephrol. 2008;19(4):771-779.)
  21. 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 are associated with the development and progression of diabetic nephropathy: the Diabetes Control and Complications 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 of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A. 2008;105:6998-7003. )
  22. 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. 23. Risk factors associated with progression
  24. 24. Proteinuria induced renal damage
  25. 25. Anemia and DN  In patients with DN, anemia is an independent risk factor associated with decline in GFR.  Renal hypoxia resulting from anemia aggravates interstitial fibrosis by the stimulation of factors like TGF-β and VEGF.  Hypoxia-inducing factor-1 (HIF-1), and ANG-II also plays a major role in this. (Thomas MC, Cooper ME, Rossing K, et al. Anaemia in diabetes: is there a rationale to TREAT? Diabetologia. 2006;49(6):1151-1157.)
  26. 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. 27. Mogenson’s classification  Stage 1: Hyperfiltration • Increased Glomerular Filtration Rate (GFR >90ml/min) • Result of concomitant renal hypertrophy (glomerular and tubular) • Various factors contributing: 1. Intra renal hemodynamic abnormalities 2. TGF-beta 3. Increased salt absorption
  28. 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 shown modest rise in BP and absence of nocturnal dip
  29. 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 of microalbuminuria. • Persistent microalbuminuria , if untreated, will progress to end-stage renal disease (ESRD). • Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis. (Perkins BAet al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 2003;348:2285-2293. )
  30. 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 FAST TRACKERS • Over two thirds of patient in this stage have Hypertension .  If untreated a vicious cycle of progressive renal impairment develops leading to ESRD.
  31. 31.  Stage 5: Uremia  GFR has fallen to <15 ml/min and renal replacement therapy (i.e., haemodialysis, peritoneal dialysis, kidney transplantation) is needed.
  32. 32. Screening
  33. 33.  Screening should be done when the person is free from acute illness and in stable glucose control  Early morning urine sample must be preferred  Serum creatinine level should also be measured annually  Recently serum cystatin C , a naturally circulating protein , freely filtered by glomerulus ,has been suggested as an alternative to creatinine measurement. (MacIsaac RJ , Tsalamandris C , Thomas MC , Premaratne E ,Panagiotopoulos S , Smith TJ , et al. Estimating glomerular fi ltration rate in diabetes: a comparison of cystatin C and creatinine – based methods . Diabetologia 2006 ; 49 : 1686 – 1689 .)
  34. 34. Treatment  Major therapeutic interventions include- 1. Control of blood glucose to near normal level 2. Antihypertensive treatment 3. Lipid lowering therapy 4. Restriction of dietary proteins 5. Cessation of smoking
  35. 35. Glycemic control  Primary prevention:-  Diabetic Control and Complications Trial showed that intensive glycemic control reduces the occurrence of microalbuminuria  ADVANCE study and VETERAN trial recently confirmed similar findings. (ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2diabetes. N Engl J Med. 2008;358(24):2560-2572) (Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med.2009;360(2):129- 139)  The HbA1c level to be kept 1. < 7.5 % in patients receiving insulin 2. <6.5 % in patients not on insulin
  36. 36.  Secondary prevention :-  UKPDS proves that tight glycemic control reduces progression from microalbuminuria to overt nephropathy A recent trial also confirms that ESRD development was retarded by multifactorial interventions (Gaede P, Lund-Andersen H, Parving H-H, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med.2008;358(6):580- 591.)  Nephropathy:-  once overt nephropathy develops , results are disappointing regarding metabolic control preventing furthur progression of disease. (Breyer JA, Bain P, Evans JK, et al. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. Kidney Int. 1996;50:1651-1658.)
  37. 37. Blood pressure control  Primary prevention:-  Initial trials showed that normotensive diabetics treated with ACE inhibitors had a beneficial effect on microalbuminuria.(The EUCLID. Study Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin- dependent diabetes and normoalbuminuria or microalbuminuria. Lancet. 1997;349:1787-1792.)  but recent trials showed that RAS blockade has been effective in reducing development of microalbuminuria in hypertensive normoalbuminuric patients, not in normotensive patients (Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus(the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-840)  ADA does not recommend antihypertensive agents for primary prevention of nephropathy in normotensive normoalbuminuric patients.(American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care. 2009;32(suppl 1):S13-S61)  BP to be reduced to 1. <125/75 mm of Hg if proteinuric or GFR < 60 2. < 130/80 mm of Hg
  38. 38.  Secondary prevention:-  IRMA trial showed that irbesartan is renoprotective independent of it’s blood pressure lowering effect in patients with type 2 diabetes and microalbuminuria (Parving H-H, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type2 diabetes. N Engl J Med. 2001;345:870-878)  STENO2 study also gives similar results with risk reduction made upto 50%(Gaede P, Tarnow L, Vedel P, et al. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2diabetes and microalbuminuria. Nephrol Dial Transplant. 2004;19(11):2784-2788)  ADA states that in patients with diabetes, hypertension and microalbuminuria, both ACE inhibitors and ARB has shown to delay progression to macroalbuminuria (American Diabetes Association. Standards of medical care indiabetes—2009. Diabetes Care. 2009;32(suppl 1):S13-S61.)
  39. 39.  Nephropathy:-  RENAAL study and IDNT trial showed that losartan and irbesartan conferred significant renal benefits independent of it’s blood pressure lowering effect. (Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes andnephropathy. N Engl J Med. 2001;345:861-869.) (Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860)  ADA states “ in patients with type 2 diabetes, hypertension, macroalbuminuria and renal insufficiency ARBs have been shown to delay progression”
  40. 40. Lipid lowering agents  Increased risk of cardiovascular diseases  FIELD STUDY showed improved regression microalbuminaria to normoalbuminuria in pts with type 2 diabetes (Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849-1861.)  A meta analysis shows a small positive effect on urinary albumin excretion and renal function (Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ. 2008;336(7645):645-651.)
  41. 41. Dietary Protein Restriction  A low protein diet reduces urinary albumin excretion and hyperfiltration independently of changes I glucose control and blood pressure changes. (Hansen HP, Tauber-Lassen E, Jensen BR, et al. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int.2002;62(1):220-228.) (Pedrini MT, Levey AS, Lau J, et al. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: meta- analysis.Ann Intern Med. 1996;124:627-632)  Kidney Disease Outcomes Quality Initiative Guidelines currently recommends dietary protein intake of 0.8 g/kg bodyweight per day (KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49(2 suppl 2):S12-S154.)
  42. 42. ALISKERIN  Mechanism of action: a direct renin inhibitor, binds to S3 binding pocket of renin, blocks conversion of angiotensinogen to angiotensin 1  Was FDA approved in 2007 for hypertension  In 2008, AVOID (n= 599) trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy ( Parving et al.N Engl J Med 2008; 358:2433-2446)  But in December 2011, ALTITUDE 8606 study a phase 3 trial was withdrawn prematurely due to side effects of the drug.
  43. 43. Ruboxistaurin  an inhibitor of protein kinase C –beta  Was FDA approved in 2006 for diabetic retinopathy  A pilot study (n=123) over 1 year showed that In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR (Tuttle KR et al.Diabetes Care. 2005 Nov;28(11):2686-90.)  Phase 3 studies are going on, results awaited
  44. 44. Pentoxifyllin  competitive nonselective phosphodiesterase inhibitor and inhibits synthesis TNF-ALFA, IL 1, IL-6  Role of inflammatory markers in pathogenesis of DN (Navarro JF et al. Am J Nephrol 2006;26:562–570)  Studies showed that administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion. (Lin SL et al. Kidney Int. 2006 Apr;69(8):1410-5.)  Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) study , clinical trial is going on, results awaited (Navarro-González JF et al. J Diabetes Complications. 2011 Sep-Oct;25(5):314-9. Epub 2010 Dec 8)
  45. 45. Advanced glycation end-products inhibitor  Benfotiamine leads to increased intracellular thiamine diphosphate levels a cofactor of transketolase. This enzyme directs advanced glycation and lipoxidation end products (AGE's, ALE's) substrates to the pentose phosphate pathway. benfotiamine lowered AGE by 40% (Sourris KC, Forbes JM, Cooper ME. Therapeutic interruption of advanced glycation in diabetic nephropathy: do all roads lead to Rome? Ann N Y Acad Sci.2008;1126:101-106  Alagebrium break some important AGE crosslinks ,does not disrupt the natural carbohydrate modification to proteins, intra- molecular crosslinking or peptide bonds that are responsible for maintaining the normal integrity of the collagen (Park J et al.Nephrol Dial Transplant.2011 Nov;26(11):3474-84) (Watson AM et al.Diabetes. 2012 Aug;61(8):2105-13. Epub 2012 Jun 14)
  46. 46. Advanced glycation end-products inhibitor  Pyridoxamine (a vitamin B6 derivative) an effective scavenger of reactive oxygen species and a potent inhibitor of advanced glycation end products by scavenging reactive carbonyl molecules halting disease process (Chen JL et al.J Am Soc Nephrol. 2012 Jan;23(1):6-8. Epub 2011 Dec 8.)
  47. 47. Kremezin  Kremezin(AST-120) is an oral adsorbent charcoal that absorbs uremic toxins through GI tract and excrte them in faeces, slows down the progression of chronic renal failure (CRF) by removing uremic toxins. (Oral administration of AST-120Kremezin) is a promising therapeutic strategy for advanced glycation end product (AGE)- related disorders. In: Med Hypotheses. 2007;69(3):666-8. Epub 2007 Feb 28.)  A clinical trial (NCT00860431) is going on , results to be declared in september 2013.
  48. 48. Paricalcitol  Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism is unclear.  A phase 2 trial (n=24) showed paricalcitol-induced reduction in albuminuria in patients with diabetic nephropathy (Alborzi P et al. Hypertension. 2008; 52: 249-255 )  Selective Vitamin D Receptor Activator for Albuminuria Lowering (VITAL) Study is undergoing and results are awaited. (Lambers Heerspink HJ, Agarwal R, Coyne DW, et al. The Selective Vitamin D Receptor Activator for Albuminuria Lowering (VITAL)Study: study design and baseline characteristics. Am J Nephrol.2009;30(3):280-286.)
  49. 49.  Soludexide, glycosaminoglycan ,mixture of heparin sulfate and dermatan sulfate, is also found to reduce albuminuria in a pilot study (Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria. Nephrol Dial Transplant.2008;23(6):1946-1954) However in a RCT ,the drug fail to achieve it’s primary goal. (Lewis EJ et al. Am J Kidney Dis. 2011 Nov;58(5):729-36. Epub 2011 Aug 26.)  Tranilast , an antifibrotic agent that reduces collagen synthesis in fibroblasts and inhibit production of IL-6 in endothelial cells, has also been found to reduce albuminuria (Soma J, Sato K, Saito H, et al. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant. 2006;21(10):2795-2799.)
  50. 50. Take Home Message  Diabetic nephropathy is a disease that develops over a long duration .  If early intervention done, progression can be delayed.  There are no signs and symptoms of early disease so screening of all patients is important.  Aggressive treatment of Blood glucose, BP, Lipids helps in prevention of renal function and can improve the outcome