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Diabetic nephropathy

Diabetic nephropathy. 12/21 中西醫聯合討論會 Nephro Fellow 1 潘恆之. Introduction. Introduction. Diabetic nephropathy occurs in type 1, type 2 diabetes mellitus and other secondary forms of diabetes mellitus

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Diabetic nephropathy

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  1. Diabetic nephropathy 12/21 中西醫聯合討論會 Nephro Fellow 1潘恆之

  2. Introduction

  3. Introduction • Diabetic nephropathy occurs in type 1, type 2 diabetes mellitus and other secondary forms of diabetes mellitus • A glomerulopathy defined by characteristic structural and functional changes：mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis • Major clinical manifestation are albuminuria, progressive chronic kidney disease, and less often hematuria. ~ American Journal of Kidney disease vol 44, No 1, July 2004

  4. Pathogenesis • Glomerulosclerosis result form : a. Intraglomerular hypertension due to renal vasodilatation b. Ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli  and why renal vasodilatation and glomeruli vessels hyaline narrowing ????

  5. Pathogenesis • There appear to be some different pathogenetic processes： 1. Glomerular hyperfiltration 2. Hyperglycemia and AGEs 3. Prorenin 4. Cytokines 5. Nephrin expression 6. Impaired podocyte-specific insulin signaling

  6. Glomerular hyperfiltration • In an animal model of diabetic nephropathy : a. BP, intra-renal Ang II level, and type IV collagen expression are higher in prediabetic rats b. Renin-angiotensin system blockade reduced intrarenal Ang II, type IV collagen expression, risk of proteinuria and improved glomerular structure. Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol. 2005;16(3):703.

  7. Glomerular hyperfiltration => glomerular hypertension and hyperfiltration have roles in diabetic nephropathy => Antagonizing the profibrotic effects of angiotensin II has benefit for diabetic nephropathy Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol. 2005;16(3):703.

  8. Hyperglycemia and AGEs (advanced glycation end products) • Hyperglycemia stimulates mesangial expansion and mesangial cell apoptosis via increased matrix production or glycation of matrix protein • Excess glucose combines with free amino acids on circulating or tissue protein  circulating and tissue AGE accumulation  crosslinking with collagen  renal and microvascular complication • Hyperglycemia activates protein kinase C  upregulation of heparanase expression as a decrease in cell surface heparan sulfate  glomerular basement membrane permeability to albumin Increased expression of heparanase in overt diabetic nephropathy. Kidney Int. 2006;70(12):2100.

  9. Cytokines • Activation of cytokines, profibrotic elements, inflammation, and VEGF maybe involved in the matrix accumulation in diabetic nephropathy. 1. Hyperglycemia stimulates VEGF expression • VEGF blockde improves albuminuria in diabetic nephropathy 2. Hyperglycemia induced decrease in activated protein C --> structural lesion of diabetic nephropathy and worsens proteinuria in mice Blockade of vascular endothelial growth factor ameliorates diabetic albuminuria in mice. J Am Soc Nephrol. 2006;17(11):3093. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med. 2007;13(11):1349.

  10. Cytokines 3. TGF-β contributes to cellular hypertrophy and enhances collagen synthesis  hyperglycemia increases expression of TGF-β in the glomeruli and matrix protein 4. Renal bone morphogenic protein-7 (BMP-7) counter the profibrogenic actions of TGF-β  diabetes is associated with decreased expression of BMP-7 Molecular mechanisms of diabetic renal hypertrophy. Kidney Int. 1999;56(2):393. Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol. 2006;17(9):2504.

  11. Prorenin • Prorenin binds to a specific tissue receptor that promotes activation of the mitogen-activated protein kinases(MAPK)p44/p42A  Prolonged prorenin receptor blockade abolished MAPK activation prevent diabetic nephropathy despite an unaltered increase in angiotension II activity Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol. 2006;17(7):1950.

  12. Nephrin expression • Impaired in diabetic nephropathy and congenital mutations  result in severe nephrotic syndrome • Diabetic nephropathy has markedly lower renal nephrin expression and fewer electron dense slit diaphram than minimal change and controls  podocin and CD2AP expression are similar amont the three groups. Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Kidney Int. 2004;65(6):2193.

  13. Schematic of the slit diaphragm and other important proteins involved in maintaining foot process assembly. Quaggin S E , Kreidberg J A Development 2008;135:609-620

  14. Impaired podocyte-specific insulin signaling • Mouse models (podocyte-specific insulin receptor deficiency): In the absence of hyperglycemia, affected mice developed albuminuria, effacement of foot processes, apoptosis, glomerular basement membrane thickening, accumulation of mesengial matrix and glomerulosclerosis  activation of the insulin receptor remodeling MAPK 42/44 and Phosphatidylinositol 3 (PI3) kinase signaling pathways  proteinuria decrease

  15. clinical implications of basic research Proteinuria, the Podocyte, and Insulin Resistance N Engl J Med 2010; 363:2068-2069 November 18, 2010

  16. Risk factors • Family history of diabetes • Black race, Mexican-American or Pima Indian ancestry • Higher systemic blood pressures • Poor glycemic control • Smoking • Oral contraceptives • Obesity • Old age

  17. Treatment • Glycemic control • Blood pressure control • Lipid control • Salt and protein restriction • Weight reduction • Angiotensin inhibition • Calcium channel blocker • PPAR-gamma agonists • Other agents

  18. Glycemic control • Delay the development of elevated albumin excretion, slow the rate of progressive renal injury • Reverse the glomerular hypertrophy and hyperfiltration, improves glomerular structure : a. mesengial and mesengial matrix volume decrease b. glomerular and tubular basement membranes return to normal, nodular glomerular lesions disappear c. tubular atrophy improves N Engl J Med 1993;329:977

  19. Diabetic nephropathy reverses after pancreas transplantation N Engl J Med 1998; 339:69

  20. Blood pressure control • United Kingdom Prospective Diabetes Study (UKPDS) : a. SBP decrease 10 mmHg  12% risk reduction in diabetic complication (P<0.001) b. the lowest risk occurred at SBP below 120mmHg

  21. Blood pressure control • Irbesartan Diabetic Nephropathy Trial (IDNT) : a. progressively lower SBP to 120mmHg was associated with decreased cardiovascular death, heart failure, serum creatinine doubling and ESRD risk b. BP < 120/85 mmHg increased the risk of all-cause mortality, cardiovascular death and heart failure Strict BP control is important for preventing progression of diabetic nephropathy in type 2 DM, but the optimal lower limit for BP is unclear.

  22. Lipid control • Elevation in lipid levels lead to promote systemic atherosclerosis and glomerulosclerosis in CKD patient. • In type 1 diabetes mellitus patient, plasma cholesterol > 220mg/dL was an important risk factor for progressive renal disease, particularly if the diastolic pressure > 85 mmHg. Hypercholesterolemia--a determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int Suppl. 1994;45:S125.

  23. Lipid control • The rate of progression from normal albumin excretion to microalbuminuria decreases with fenofibrate (a peroxisome proliferator activated receptor (PPAR)-alpha specific ligand) * Possible mechanisms of fenofibrate benefit : PPAR-α activity --> inflammation and production of type 1 collagen in mesangial cells PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int. 2006;69(9):1511.

  24. Salt restriction • High salt intake blunt the antiproteinuric effects of angiotensin inhibitors • Salt restriction and/or diuretics enhance the effect of renin-angiotensin blockade on proteinuria. • Salt restriction to < 70 meq /day enhance the antiproteinuric effects of ARB in T2DM patient => If it is difficult to achieve: a. restrict sodium intake to 100 < 100meq/d b. give diuretic partially corrects the loss of antiproteinuric effect due to high sodium intake

  25. Protein restriction • Protein reduction reduce the rate of progression in DM patient with overt nerphropathy. => Suggest: avoid a high protein diet (1g/kg/d) Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int. 2002;62(1):220.

  26. Weight reduction • Marked decreases in proteinuria may be observed in obese diabetics who lose weight • Proteinuria significantly decreased at five months among dieters versus the non-dieters control group ( mean weight loss of 4% in the diet group) • No significant differences in renal function were reported in either group. Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am J Kidney Dis. 2003;41(2):319. the length of follow-up was probably too short to have observed renoprotection effect.

  27. Angiotensin inhibition • Primary prevention for diabetic nephropathy • Preservation of renal function

  28. Angiotensin inhibition Primary prevention for diabetic nephropathy * Diabetes induces renal vasodilation, intraglomerular hypertension and glomerular hypertrophy • ACEI and ARB reduce intrarenal vascular resistance and inhibit TGF-β  reduce intraglomerular pressure, minimize glomerular injury, inhibit cellular hypertrophy and collagen synthesis Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Am Soc Nephrol. 2005;16(4):1135.

  29. Captopril reduces (intra)renal vascular resistance in patients with type 2 diabetes Kidney Int 1989;36:526.

  30. Angiotensin inhibition • Preservation of renal function * T1DM: a. ACEI decreases albumin excretion, CKD progression rate, risk of overt nephropathy, ESRD or death. NEJM 1993;329:1456.

  31. Angiotensin inhibition b. ACEI + ARB produces a greater reduction in protein excretion (in 2 short-term studies, 8 wks) --- due to better BP control ??? Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int. 2003;63(5):1874.

  32. * T2DM – renal protection with ARBs a. Irbesartan Diabetic Nephropathy Trial (IDNT): @Irbesartan has lower risk (23%) in doubling of Scr, proteinuria, ESRD or death than amlodipine (and placebo) @Renal failure risk doubles with each doubling of baseline protein excretion @The renal outcomes are best at SBP <134mmHg

  33. b. RENAAL study: @Losartan reduced the albuminuia, incidence of creatinine doubling and ESRD by 25% and 28% @ SBP every 10mmHg => ESRD or death risk 6.7% @ Albuminuria every 50% => CV risk 18%, ESRD risk @ Baseline retinopathy has poor renal outcome • Both of studies show ARB has clear benefits in T2DM patients with overt nephropathy • ARB had significant reductions in the development of heart faliure. However, CV mortality has no obvious reduction.  too short duration of the studies??

  34. * T2DM – renal protection with ACEIs a. ADVANCE trial : perindopril-indapamide combination vs placebo: @ significant reduction of new onset microalbuminuria or worsening of protienuria (19.6% vs 23.6% ) @ significant decrease in mean BP (5.6/2.2 mmHg) @ no significant defference in CKD progression => the renal benefits are due to the ACEI or BP control ??

  35. b. DETAIL trial : enalapril vs. telmisartan vs. placebo @ at 5 yrs, enalapril has smaller GFR decline (NS) @ similar findings of BP, Scr, albuminuria, ESRD, CV events and mortality. • ACEIs are at least as effective as ARBs in diabetic patient with microalbuminuria • ACEIs or ARBs has renoprotection in patient with diabetic nephropathy (progress slowly) • 1/3 of renoprotective effect with ACEI or ARB is due to proteinuria reduction in first 12 months of therapy

  36. ACEI + ARB ??? * small studies – decrease proteinuria in T1DM & T2DM * ONTARGET study – proteinuria and GFR => ESRD and mortality rate => CKD progression => NS

  37. ARB + aliskiren @ AVOID trial – aliskiren + losartan vs. losartan * aliskiren + losartan has 20% greater reduction in proteinuria (no significant on BP) * role of aliskiren in preventing CKD progression ??

  38. Aldosterone antagonism • small study – 81 patient, f/u 48weeks lisinopril + sprionolactone or losartan or placebo * spironolactone + lisinopril –urine ACR decre 34% (S) losartan + lisinopril – urine ACR 17% (NS) * no long term data about CKD progression with ACEI/ARB + aldosterone blockade * Serum pottasium is significant high in both group Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis. 2005;46(1):45.

  39. Another small studies – 268 patient, f/u 40wks ACEI + eplerenone or placebo  eplerenone has additive antiproteinuria effect, similar hyperkalemia rate • Aldosterone antagonists appear to reduce proteinuria when used alone or combination with ACEI/ARB in type 1 and type 2 diabetes. => suggestion : avoid NSAID, combine kaliuretic diuretic therapy Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 2005;68(6):2829.

  40. Calcium channel blocker • Non-dihydropyridine calcium channel blockers slow the rate of progression of diabetic nephropathy * diltiazem and verapamil is as effective as ACEI/ARB in lowering protein excretion in diabetic patients * the antiproteinuric effects of verapamil and ACEI may be addictive * However, diltiazem increases tubulointerstitial fibrosis andglobal glomerulosclerosis. The effect was prevented by combined an ACE inhibitor. Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs. Kidney Int. 1994;46(1):161.

  41. Antihypertensives and urinary protein excretion in diabetic nephropathy Kidney Int. 1992;46(1):161. Superior antiproteinuric effect with combination of antihypertensive therapy Kidney Int. 1998;57(1):193.

  42. Superior antiproteinuric effect with combination of antihypertensive therapy Kidney Int. 1993;51(5):129.

  43. The antiproteinuric mechanism of nondihydropyridine calcium channel blockers: 1. possible reduction in intraglomerular pressure 2. reduce the associated glomerular hypertrophy 3. diltiazem may improve glomerular size permselectivity. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int. 1998;54(3):889. * Uncertain clinical relevance. * The efficacy in the preservation of renal fucntion in relation to ACEI has not yet been evaluated in humans

  44. Dihydropyridine calcium channel blockers ( such as amlodipine, nifedipine, nitrendipine) have a variable effect ranging from increased protein excretion to no effect to a fall in protein excretion in different studies. • Beta-blockers have shown a variable response of protein excretion decrease

  45. PPAR-ϒ agonists • Peroxisome proliferator-activated receptors (PPAR) which are ligand-activated transcritption factors, have a role in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, blood pressure, and development of T2DM nephropathy. • PPAR-ϒ agonists, such as the thiazolidinediones (eg, pioglitazone and rosiglitazone), induce reductions in fibrosis, mesangial cell proliferation, and inflammation in animal models of diabetic nephropathy . Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol. 2008;19(1):182.

  46. PPAR-ϒ agonists • In small studies, PPAR-gamma agonists reduce urinary albumin excretion at various stages of nephropathy and to reduce blood pressure.  Larger studies are required to detect a renoprotective effect • A post hoc analysis of the PROACTIVE trial failed to show a definitive benefit on cardiovascular risk reduction with pioglitazone in people with stage 3 or higher nephropathy Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol. 2008;19(1):182.

  47. Other agents

  48. Bardoxolone methyl • An antioxidant inflammatory modulator that may also have prostaglandin-like effects. It has been beneficial in animal models of drug-induced or ischemic acute kidney injury. • In the Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) trial, Bardoxolone methyl therapy at all three doses significantly increased eGFR at 52 weeks of follow-up by 6 to 10 mL/min per 1.73 m2, while placebo therapy had no effect.

  49. Bardoxolone methyl • The disadvantages of Bardoxolone methyl therapy : a. significantly increased albuminuria  The change in albuminuria was significantly correlated with the change in eGFR.  Increase in eGFR may be mediated by increase in intraglomerular hydrostatic pressure b. significantly increased adverse events -- muscle spasms, nausea, and SBP 2~4 mmHg. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327.

  50. Other agents • limited data, including a meta-analysis, suggest that pentoxifylline lowers proteinuria and may have similar antiproteinuric effects as ACE inhibitors. • Endothelin receptor antagonists, protein kinase C inhibitors,), sulodexide, and fish oil. • There are insufficient data on any of these agents to advocate their use for the treatment or prevention of diabetic nephropathy. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am J Kidney Dis. 2008;52(3):454. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Am J Kidney Dis. 2005;45(3):485.

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