pathophysiology and therapy of diabetic nephropathy


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this lecture is about the pathophysiology of proteinuria and therapy of diabetic nephropathy

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pathophysiology and therapy of diabetic nephropathy

  1. 1. Diabetic Nephropathy pathophysiology ..pathology… therapy Dr. Muhamed Al Rohani,MD
  2. 2. Complications of Type 2 Diabetes Microvascular Complications Diabetic Retinopathy Leading cause of blindness in working-age adults Diabetic Nephropathy Leading cause of end-stage renal disease Macrovascular Complications Stroke 2- to 4-fold increase in cardiovascular mortality and stroke Heart Disease Diabetic Neuropathy Leading cause of nontraumatic lower extremity amputations Peripheral Vascular Disease Harris MI. Clin Invest Med. 1995;18:231-239. Nelson RG, et al. Adv Nephrol Necker Hosp. 1995;24:145-156. World Health Organization. Diabetes Mellitus Fact Sheet 138. 2002. ADA. National diabetes fact sheet. Available at:
  3. 3. Natural history of DN
  4. 4. Definition progressive rise in urine albumin excretion coupled with increasing BP and leading to declining GFR and CKD Abnormal urine albumin excretion • >30 mg/24 hours and/or diabetic glomerular lesions and/or loss of glomerular filtration rate ADA recommendations, Diabetes Care, January 2012
  5. 5. Epidemiology Diabetic nephropathy affects approximately one third of people with type 1 or type 2 diabetes mellitus. Increase prevalence of DM USA 4% 1995 – 5.4% 2025 Now: USA 7% (20.8 million) Worldwide: 2.8 % 171 million 2000 – 4.4% 366 million 2030 DN prevalence In India: 5.5% and 8.9% Asian Indians in UK 22.3% Incident ESRD patients. Adj: age/gender/race; ref: 2010 ESRD patients.
  6. 6. Epidemiology Type 1 Diabetic  25 - 45% will develop diabetic nephropathy  80- 90% with microalbuminuria will progress to overt diabetic nephropathy in 5 - 10 years  nearly 100% with gross proteinuria will progress to ESRD in 7 - 10 yrs Type 2 Diabetic  50% will have microalbuminuria at the time of presentation with hypertension  10-20% with microalbuminuria will progress to overt nephropathy. Risk factors for DN: Family history Hypertension Dyslipidemia Obese Male smokers 1/26/2014 6
  7. 7. Pathology and pathophysiology
  8. 8. Pathophysiological stages Stage increased GFR Increased filtration pressure as result of increased intraglolerular pressure Increased UOP and low s.cra, urea Pathological change but no clinically evident disease Proteinuria Mesangial expansion and increased matrix change in pore sizes leading to leakage of protein Starling Foces: increased plasma flow, increased glomerular capillary hydrostatic pressure Microhematuria Ischemic injury of tubules due to construction and stenosis of efferent arteriole Decreased GFR Atrophy and death of nephrons CKD and ESKD Loss of compensation mechanisms of nephrons
  9. 9. Endothelium Fenestration (60 – 100 nm) Glycocalyx (network of proteoglycans with neg. charge Endothelial cell injury: Increased permeability Impaired nitric oxide production Upregulation of adhesion molecules Defects of the glycocalyx: Decrease of negativity associated with increased albumin clearance GBM: It is 300 – 400 nm tick gel like structure and 90% water It contains: collagen IV, heparan sulfate proteoglucans, laminin, nidogen Heparan sulfate reduction correlates with degree of proteinuria Its degradation is mediated by heparanase This theory approved in Type 1 and 2 DM but in advanced human cases but not in the early stage where there is also proteinuria. Thickening of GBM: Accumulation of extracellular matrix Reduction in matrix degradation due to decreased metalloproteinase
  10. 10. Systemic HTN, RAS and hyperinsuliemia  Efferent vasocostruction  intraglomerular HTN Cytokines High blood glucose Free radicals Mesangial cell expansion inflammation Atherosclerosis of efferent arteriole Mesangial matrix expansion Fibrin collagens deposition in GBM Intraglomerular mesangial cells: Axis holding the edothelial and epithelial cells Construction and dilatation leading to fenestration change the filtration
  11. 11. Hyaline subendothelial deposition GBM thickening by collagens : IV (α3,α4,α5) Mesangial expansion By collagens : IV (α1,α2) V, VI
  12. 12. Pores Barrier size Electric charge Molecular weight MW: < 40 kDa free to pass > 100 kDa totally restricted Albumin mw 69 kDa Microalbuminuria: Change in elecric charge Macroalbuminuria: Change in elecric charge Increased pores size Electric charge: Anionic ferritin restricted Cationic ferritin pass to podocyte Positively charged Dextran permeable more than neg. or neutral charged dextran
  13. 13. Synthesis and maintenance of the GBM Counteraction of hydrostatic pressure Critical membrane of the filtration barrier (last frontier) The narrow gaps 30 – 40 nm premeable for water and solutes It contains cytoskeleton The apical membrane contains podocalyxin, podoplanin and podoendin which are responable of the negative charge Podocytopenia: Loss of negative charge (loss of podocalyxin) Change in the pores size due to damage in the diagram integrity Causes of reduced number of podocytes: Podocyte detacement Podocyte apoptosis Inability to proliferate and restore podocyte number Silt diaphragm abnormalities: Abnormalities of nephrin Foot process widening and effacement
  14. 14. Pathological classification of DN Class I Description Inclusion Criteria Biopsy does not meet any of the criteria mentioned below Mild or nonspecific LM changes and for class II, III, or IV EM-proven GBM thickening GBM > 395 nm in female and >430 nm in male individuals 9 years of age and older, Podocyte hypertrophy IIa Biopsy does not meet criteria for class III or IV Mild mesangial expansion IIb Mild mesangial expansion in >25% of the observed mesangium Biopsy does not meet criteria for class III or IV Severe mesangial expansion III Severe mesangial expansion in >25% of the observed mesangium Nodular sclerosis (Kimmelstiel– Wilson lesion) Biopsy does not meet criteria for class IV At least one convincing Kimmelstiel–Wilson lesion IV Advanced diabetic glomerulosclerosis Global glomerular sclerosis in >50% of glomeruli Lesions from classes I through III
  15. 15. Mechanisms of proteinuria Site of injury Glomerular hemodynamics glomerular endothelial cell GBM podocyte Glomerular hyperfiltration Endothelial cell injury Diminished Hyperglycemia< AGE, ROS Endothelial cell injury or endothelial glycocalyx enzymatic cleavage Altered VEGF signaling Podocyte injury or loss Irregular thickening Decreased negative charge Podocytopenia Loss of slit diaphragm integrity Foot process widening and effacement Loss negative charge proximal tubule Afferent arteriole vasodilatation Efferent arteriole vasoconstriction glomerular capillary pressure Decrease protein reabsorption production and/or degradation of extracellular matrix proteins production and/or degradation of HSPG Detachment, apoptosis, lack of proliferation Decrease or changes in subcellular localization of nephrin Disrupted actin cytoskeleton Loss of slit diaphragm integrity Impaired podocyte GBM interaction Podocalyxin Tubular injury and interstitial fibrosis AGE, advanced glycosylation end products; HSPG, heparan sulfate proteoglycan; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.
  16. 16. Proteinuria Is an Independent Risk Factor for Mortality in Type 2 Diabetes 1.0 Normoalbuminuria (n=191) Survival (all-cause mortality) 0.9 Microalbuminuria (n=86) 0.8 0.7 Macroalbuminuria (n=51) 0.6 0.5 0 1 2 3 Years Gall et al. Diabetes. 1995;44:1303. 4 5 6
  17. 17. Factors affecting urinary albumin excretion Increases AER Decreases AER  Strenuous exercise  Poorly controlled DM  Heart failure  UTI  Acute febrile illness  Uncontrolled HPT  Haematuria  Menstruation  Pregnancy  NSAIDs  ACE inhibitors
  18. 18. SCREENING FOR NEPHROPATHY WHEN: Type 1 - annually after puberty and 5 years of DM Type 2 - at diagnosis and then annually WHAT: random urine ACR; and random urine dipstick Suspicion of nondiabetic renal disease? No Normal < 2.0 mg/mmol men < 2.8 mg/mmol women Rescreen in 1 year Check ACR results Microalbuminuria 2.0 - 20 mg/mmol men 2.8 - 28 mg/mmol women Only 1 abnormal ACR: Repeat screen in 1 year 1/26/2014 Up to 2 repeat random urine ACRs performed 1 week to 2 months apart Yes Workup or referral for nondiabetic renal disease Macroalbuminuria > 20 mg/mmol men > 28 mg/mmol women Diabetic nephropathy diagnosed Any 2 abnormal out of 3 ACRs: Diabetic nephropathy diagnosed 21
  19. 19. Stages of Renal Involvement According to the Urinary Albumin Level SPECIMEN COLLECTED First voided morning specimen Albumin Excretion 24hr collection (mg/24h) Timed collection (μg/min) Normoalbuminuria <30 Microalbuminuria Overt proteinuria Urine Albumin concentration (mg/l) Urine Albumin:Creatinine ratio* (mg/mmol) <20 <20 <3.5 (F) <2.5 (M) 30-300 20-200 20-200 3.5 to 35 (F) 2.5 to 25 (M) >300 >200 >200 >35 (F) >25 (M)
  20. 20. TREATMENT OF NEPHROPATHY Already on ACE inhibitor? Choose 2nd line therapy: ACE or ARB and add non-DHP CCB YES NO On first-line nephropathy drug? NO Add first-line drug; Recheck ACR in 2 weeks to 2 months YES YES NO ACR normal? Yes First line drug at maximum dose? NO Titrate up; recheck ACR in 2 weeks to 2 months Remeasure ACR in 1 year First line drugs: Type 1- ACE inhibitor Type 2 with Cr Cl > 60 mL/min - ACE inhibitor or ARB Type 2 with Cr Cl 60 mL/min - ARB 1/26/2014 23
  21. 21. Table 2. Recommendations for the Comprehensive Management of T2DM Patients with CKD Factor Recommendations Lifestyle factors diet, exercise, smoking,and alcohol intake Blood glucose Treatment goal: HbA1c <6.5% Preprandial plasma glucose 90-130 mg/dl Postprandial plasma glucose <180 mg/dl Blood pressure Goal ≤130/80 mm Hg Use maximal tolerated dose of ACE inhibitor or ARB before adding a second agent Cholesterol Goal <4.0 mmol/L for total cholesterol and <2.0 mmol/L for LDL-C Consider use of a statin irrespective of baseline lipid values for the secondary prevention of cardiovascular disease Platelets Consider use of low dose aspirin for the secondary prevention of cardiovascular disease Monitoring Annual monitoring of eGFR and ACR
  22. 22. The glycemic control studies A1c Target : Outcome UKPDS 10 yrs > 7% The clinical lesson from the UKPDS follow-up studies is that, although the risks of complications of hypertension might be mitigated with initiation of treatment even after a prolonged elevation of blood pressure, it is particularly necessary to treat hyperglycemia appropriately from the outset of type 2 diabetes. ADVANCE study Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes 6.5% A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. ACCORD Study: Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes <6% As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes.
  23. 23. KDIGO recommendation for proteinuria ACE inhibitors and ARBs are effective in slowing progression of kidney disease characterized by microalbuminuria in hypertensive patients with type 1 or type 2 diabetes. (Moderate) ACE inhibitors, ARBs, and nondihydropyridine calcium channel blockers have a greater antiproteinuric effect than other antihypertensive classes in hypertensive patients with DKD. (Strong) Dihydropyridine calcium channel blockers, when used to treat hypertension in the absence of ACE inhibitors or ARBs, are less effective than other agents in slowing progression of DKD. (Strong) • ARBs are more effective than other antihypertensive classes in slowing progression of kidney disease characterized by macroalbuminuria in hypertensive patients with type 2 diabetes. (Strong) • • ACE inhibitors are more effective than other antihypertensive classes in slowing progression of kidney disease characterized by macroalbuminuria in hypertensive patients with type 1 diabetes. (Strong) ACE inhibitors may be more effective than other antihypertensive classes in slowing the progression of kidney disease characterized by macroalbuminuria in hypertensive patients with type 2 diabetes. (Weak)
  24. 24. ACE Inhibitors can prevent progression of renal failure Risk reduction is 51% Reduce microalbuminuria All causes of mortality Normotensive Type 2 Diabetics 400 110 Proteinuria 350 320 % Initial GFR 105 Placebo (mg/day) 100 280 Enalapril 240 95 200 90 160 Placebo Enalapril 85 120 80 80 0 1 2 3 Years Ann Intern Med 118 577-581.1993 J Am Soc Nephrol 2006 4 5 6 0 1 2 3 Years 4 5 6
  25. 25. Incidence of Progression to Diabetic Nephropathy during Treatment with 150 mg of Irbesartan Daily, 300 mg of Irbesartan Daily, or Placebo in Hypertensive Patients with Type 2 Diabetes and Persistent Microalbuminuria. Parving H et al. N Engl J Med 2001;345:870-878.
  26. 26. Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes in 4447 patients Conclusion: • Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control • The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy in 1448 patients Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. There was no benefit with respect to mortality or cardiovascular events. Combination therapy increased the risk of hyperkalemia and acute kidney injury.
  27. 27. Metformin in Patients with T2DM and CKD • The recommendation of the ADA/EASD metformin can be used – down to an eGFR of 30 mL/min/1.73 m2, – the dose of metformin should be reduced when eGFR is less than 45 mL/min/1.73 m2. – Kidney function should be checked regularly (every 6 months) – discontinued if eGFR falls below 30 mL/min/1.73 m2. – prescribed with caution in patients with an eGFR less than 45 mL/min/1.73 m2, which is rapidly deteriorating. – All patients should be warned that if they develop a condition that can lead to dehydration.
  28. 28. KDIGO lipid control in DM • • • • Target LDL-C in people with diabetes and CKD stages 1-4 should be < 100 mg/dL; <70 mg/dL is a therapeutic option. (B) People with diabetes, CKD stages 1-4, and LDL-C > 100 mg/dL should be treated with a statin. (B) Treatment with a statin should not be initiated in patients with type 2 diabetes on maintenance hemodialysis who do not have a specific cardiovascular indication for treatment. (A) Atorvastatin treatment in patients with type 2 diabetes on maintenance treatment does not improve cardiovascular outcomes. (Strong)
  29. 29. Other oral antidiabetic drugs : DPP-4 inhibitors: Choices of antidiabetic agents for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are limited. Available data suggest that the use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be safe in patients at various stages of renal insufficiency. However, except for linagliptin, dosage adjustment is necessary. patients with moderate renal impairment (defined in the label as a creatinine clearance ≥ 30 to < 50 ml/min). In severe renal impairment (creatinine clearance < 30 ml/min) or end-stage renal disease requiring dialysis, the dose is further reduced to 25 mg once daily. Gliclazide In patients with mild to moderate renal insufficiency the same dosing regimen can be used as in patients with normal renal function with careful patient monitoring. These data have been confirmed in clinical trials. glimepiride A multiple-dose titration using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine clearance ranged from 10–60 mL/min.
  30. 30. Insulin Metabolism of insulin: 30– 80% of systemic insulin in the kidney 40–50% of the endogenous insulin metabolized by the liver Insulin effect on the kidney : Na reabsorption Increase glucose and phosphate higher risk of hypoglycaemia Intensive glucose control with HbA1c around 7% is associated with: Reduction of microalbuminuria by 39% and marcroalbuminuria by 54%
  31. 31. Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. RESULTS: A total of 9,438 CKD patients were randomized, of whom 3,056 were on dialysis. Mean age was 61 years, two thirds were male, one fifth had diabetes mellitus, and one sixth had vascular disease. Compared with either placebo or simvastatin alone, allocation to ezetimibe plus simvastatin was not associated with any excess of myopathy, hepatic toxicity, or biliary complications during the first year of follow-up. Compared with placebo, allocation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL cholesterol differences of 43 mg/dL (1.10 mmol/L) at 1 year and 33 mg/dL (0.85 mmol/L) at 2.5 years. Follow-up is scheduled to continue until August 2010, when all patients will have been followed for at least 4 years. CONCLUSIONS: SHARP should provide evidence about the efficacy and safety of lowering LDL cholesterol with the combination of ezetimibe and simvastatin among a wide range of patients with CKD (SHARP; Lancet. 2011;377:2181-2192).
  32. 32. Bardoxolyne methyl, has been shown to significantly improve the creatinine GFR and cystatin C GFR in patients with DKD after only 4 weeks (Schwartz, Denham, Hurwitz, Meyer, & Pergola, 2009). Recent landmark phase 2 trial of 227 adults with CKD and type 2 DM demonstrated that bardoxolone methyl ( 75 mg is the optimal dose) improved GFR by at least 8.2 +/-1.5 ml/min over placebo after 24 weeks of treatment and that this effect was maintained after a year of therapy. (Pergola, et al., 2011). BUT Bardoxolone methyl did not improve urinary albumin excretion. The results in 3 phase study (BEACON) were disappointing because of elevated rate of CVD including HTN, HF, and increased heart rate PIRFENIDONE: Paricalcitol Ruboxistaurtin Allopurinol
  33. 33. Thank you The End