DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE / CHONIC KIDNEY DISEASE

Incipient Nephropathy Predictors? Hyperfiltration Microalbuminuria Rising BP Poor glycemic contol Onset Of DM Onset of Rising ESRD Proteinuria S.Cr HTN 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 IDDM, 30-40% DN NIDDM, 10-20% DN

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

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

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

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

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

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 y Familial predisposition

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

CHRONIC KIDNEY DISEASE CKD

usg

, a-dsDNA, GBM-Ab

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

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

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

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

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

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).

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

Intact nephron hypothesis Using experimental animals; urine from each kidney was collected seperately Before After End K1 K2 K1 K2 K2 GFR NH3 excr NH3 excr/100mlGFR 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

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

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

CKD stage 5 (ESRD / GGT) DIALYSIS / Renal Replacement Therapy –Hemodialysis –Peritoneal Dialysis –Continues Renal Replacement Therapies Kidney Transplant –Cadaver –Living related / unrelated