DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE / CHONIC KIDNEY DISEASE

1. DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE /CHONIC KIDNEY DISEASE

2. IDDM, 30-40% DN NIDDM, 10-20% DN Incipient Nephropathy Predictors? Hyperfiltration Microalbuminuria Rising BP Poor glycemic contol HTN 0 2 5 11-23 13-25 15-27 Onset of Rising ESRD Proteinuria S.Cr Onset Of DM Functional changes GFR increase (renal hypertrophy) reversible albuminuria increase kidney size Structural changes increase GBM thickening Mesangial expansion nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillary glomerulosclerosis capsular drop lesion fibrin cap lesion

4. Morphologic changes • Glomeruli: • increase GBM thickening • Mesangial expansion • nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillary glomerulosclerosis • capsular drop lesion • fibrin cap lesion • Tubulointerstitium,& tubular functional defects • Interstitial scarring • Impaired tubular reabsorption of low MW proteins and albumin • Increased Na reabsorption leading to volume expansion • Hypercalciuria • Impaired excretion of H & K ions • Vascular, hyaline thickening of the arteriolar wall • Glomerular haemodynamic changes • Decreasing Pglom: ACE-I, ARB, low protein diet

5. Transient microalbuminuria • Hyperglycemia • Hypertension • Congestive heart failure • Urinary tract infection • Excessive physical exercise • Albumin Excretion Rate / AER • Normal < 30 mg/day • Microalbuminuria 30-300 mg/d • Overt proteinuria AER> 300 mg/d

7. Overt Diabetic Nephropathy • In early DN the albuminuria is secondary to a loss of the anionic charge barrier of the GCW • In established DN, the proteinuria is due to the presence of an increased number of nonselective and large pores • The presence of persistent proteinuria heralds the overt phase of DN • >95% of patients with DN have D Retinopathy • Rate of decline in GFR has been reported as linear in a given patient, but wide differing between patients • ~ 1 ml/min per month, with 50% of patients reaching ESRD ~ 7 years after the onset of proteinuria. • Recent reports suggest that is has slowed down ~10 years

8. Complication of DM • Microvascular • Retinopathy • Nephropathy • Macrovascular • Peripheral vascular disease • Coronary artery disease • Cerebrovascular disease • Diabetic neuropathy, incl. gastroparesis • Hyperkalemic RTA

9. Syndrome ‘X’ • Obesity • Decreased glucose tolerance, Insulin resistance & hyperinsulinemia • Hypertension • Hyperlipidemia, esp triglycerides • Increased risk for atheroscerosis

10. NIDDM • Patients on HD in a dialysis unit ~ 30-50% because of NIDDM & diabetic nephropathy • Many patients with NIDDM will die of other causes (cardiovascular) before reaching ESRD • Natural history less well characterized • Heterogeneous group, with many comorbid conditions, hypertension, obesity • 10-20% incidence of DN, mostly after 10-20 y • Familial predisposition

11. Management • Control of Diabetes, HbA1c <7 • Control of hypertension, BP<130/80, if proteinuria BP<125/75 • Low salt diet • Control of hyperlipidemia • Weight control • Smoking cessation • Management of other comorbid conditions; cardiovascular, anemia, cerebrovascular, physical inactivity... • ACE-I, ARB, combination

12. CHRONIC KIDNEY DISEASECKD

13. usg

23. , a-dsDNA, GBM-Ab

33. Progression of CKD • Mechanisms of ongoing renal injury • Deposition IC, Ag, Ab, matrix, collagen, fibroblasts • Intracapillary coagulation • Vascular necrosis • Hypertension & increased Pglom • Metabolic disturbances, e.g. DM, hyperlipidemia • Continuous inflammation • Nephrocalcinosis ; dystrophic & metastatic • Loss of renal mass / nephrons • Ischemia; imbalance between renal energy demands and supply • Results in • Glomerulosclerosis • Tubular atrophy • Interstitial fibrosis

35. Compensatory renal changes in CKD • Hypertrophy of residual nephrons • Increased RBF per nephron, but decreased total RBF • Increased Single Nephron GFR / SNGFR • Increased osmotic / solute load • Hyperfiltration • Increased intraglomerular pressure / Pglom

36. ## NEPHRONS Pcap +flow Glomerular Protein Glomerular injury flux hyperfiltration Glomerulosclerosis ## NEPHRONS

37. Pattern of excretory adaptation • Increased filtered load; Cr, BUN • Decreased tubular reabsorption; Na, H2O • Increased tubular secretion; K+, H+, Cr • Limitation of nephron adaptation • Magnitude • Time, ~response to intake / load, production • Abrupt changes in intake / production may not be tolerated • Trade off, expense to other systems • E.g. to preserve P balance PTH increases

38. Volume Urine, Uosm, U(Na,K,H)

40. Multiple mechanisms of chronic hypoxia in the kidney. • Mechanisms of hypoxia in the kidney of chronic kidney disease include loss of peritubular capillaries (A), • Decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells as a result of fibrosis of the kidney (B), • Stagnation of peritubular capillary blood flow induced by sclerosis of "parent" glomeruli (C), • Decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances (D), • Inappropriate energy usage as a result of uncoupling of mitochondrial respiration induced by oxidative stress (E), • Increased metabolic demands of tubular cells (F), and • Decreased oxygen delivery as a result of anemia (G).

41. Treatment modalities that target chronic hypoxia in the kidney • Improvement of anemia by EPO • Preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system • Protection of the vascular endothelium  • VEGF    • Dextran sulfate • Antioxidants to improve the efficiency of cellular respiration • HIF-based therapy    (hypoxia inducible factor) • Prolyl hydroxylase inhibitors     • Gene transfer of constitutively active HIF

42. Intact nephron hypothesis • Using experimental animals; urine from each kidney was collected seperately Before After End K1 K2 K1 K2 K2 GFR 50 50 55 14 24 NH3 excr 49 51 66 25 40 NH3 excr/100mlGFR 100 100 120 121 167 K2 was partially K1 removed removed • Conclusion • Normal renal tissue undergoes hypertrophy to compensate for loss of • functioning nephrons • -Normal tubules adapt, increase in function as other tubules are lost • -Diseased nephrons / tubules adapt in the same way ~ • increase NH3 excr / 100mlGFR • -Even diseased nephrons can increase their GFR

45. The Uremic Syndrome • Nervous system • Impaired concentration, perceptual thinking, • Peripheral neuropathy; primarily sensory, paresthesias, restless leg syndrome • Autonomic neuropathy; impaired baroreceptor function, orthostatic hypotension, impaired sweating • Uremic ancephalopathy • Hematology system • Anemia is invariably present when renal function fall <30% • Decreased RBC survival, response to EPO, • Deficiencies of Fe, B12, folate, aluminium overload • Blood loss • Hyper PTH • Inflammation – malnutrition • Bone marrow fibrosis • Inadequate dialysis • Bleeding diathesis: easy bruising, slow clotting • Prolonged BT & abnormal platelet function • PF3 concentration are generally low, impaired aggregability • Reduced von Willebrand’s factor HMW multimers • Uremic toxins & PTH • Immune function • Impaired Ab response to viral Ag (not to bacterial) • Decreased T-cells • Cutaneous anergy

46. Cardiovascular system • Cardiovascular disease is the leading cause of death in patients with CKD stage 4-5 • Accelerated Atherosclerosis / CAD • Hypertension, ~ 80% of all uremic patients • Pericarditis • Metabolic abnormalities • Lipids; increase in tot. triglycerides, Lp(a), LDL, decrease HDL • Carbohydrate metabolism; insulin resistance, decreased need for OAD / insulin in DM • High prolactin; galactorrhea • Men : testosteron is low, FSH / LH normal or high • Women: pg E2 & progesterone are low, FSH /LH normal or slightly elevated • Abnormalities of thyroid gland function test, normal TSH