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  • 0 2 5 11-23 13-25 15-27Incipient Nephropathy Predictors?HyperfiltrationMicroalbuminuriaRising BPPoor glycemic contolOnset Of DMOnset of Rising ESRDProteinuria S.CrHTN Functional changes GFR increase (renal hypertrophy) reversible albuminuria increase kidney sizeStructural changes increase GBM thickening Mesangial expansion nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillary glomerulosclerosis capsular drop lesion fibrin cap lesionIDDM, 30-40% DNNIDDM, 10-20% DN

  • Morphologic changesGlomeruli:increase GBM thickeningMesangial expansion nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillary glomerulosclerosiscapsular drop lesionfibrin cap lesionTubulointerstitium,& tubular functional defectsInterstitial scarringImpaired tubular reabsorption of low MW proteins and albuminIncreased Na reabsorption leading to volume expansionHypercalciuriaImpaired excretion of H & K ionsVascular, hyaline thickening of the arteriolar wallGlomerular haemodynamic changesDecreasing Pglom: ACE-I, ARB, low protein diet

  • Transient microalbuminuriaHyperglycemiaHypertensionCongestive heart failureUrinary tract infectionExcessive physical exercise Albumin Excretion Rate / AERNormal < 30 mg/dayMicroalbuminuria 30-300 mg/dOvert proteinuria AER> 300 mg/d

  • Overt Diabetic NephropathyIn early DN the albuminuria is secondary to a loss of the anionic charge barrier of the GCWIn established DN, the proteinuria is due to the presence of an increased number of nonselective and large poresThe presence of persistent proteinuria heralds the overt phase of DN>95% of patients with DN have D RetinopathyRate 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 DMMicrovascularRetinopathyNephropathyMacrovascularPeripheral vascular diseaseCoronary artery diseaseCerebrovascular diseaseDiabetic neuropathy, incl. gastroparesisHyperkalemic RTA

  • Syndrome XObesityDecreased glucose tolerance, Insulin resistance & hyperinsulinemiaHypertensionHyperlipidemia, esp triglycerides Increased risk for atheroscerosis

  • NIDDMPatients on HD in a dialysis unit ~ 30-50% because of NIDDM & diabetic nephropathyMany patients with NIDDM will die of other causes (cardiovascular) before reaching ESRDNatural history less well characterizedHeterogeneous group, with many comorbid conditions, hypertension, obesity10-20% incidence of DN, mostly after 10-20 yFamilial predisposition

  • Management Control of Diabetes, HbA1c

  • usg

  • , a-dsDNA, GBM-Ab

  • Progression of CKDMechanisms of ongoing renal injuryDeposition IC, Ag, Ab, matrix, collagen, fibroblastsIntracapillary coagulationVascular necrosisHypertension & increased PglomMetabolic disturbances, e.g. DM, hyperlipidemiaContinuous inflammationNephrocalcinosis ; dystrophic & metastaticLoss of renal mass / nephronsIschemia; imbalance between renal energy demands and supplyResults inGlomerulosclerosisTubular atrophyInterstitial fibrosis

  • Compensatory renal changes in CKDHypertrophy of residual nephronsIncreased RBF per nephron, but decreased total RBFIncreased Single Nephron GFR / SNGFRIncreased osmotic / solute loadHyperfiltrationIncreased intraglomerular pressure / Pglom

  • ## NEPHRONSPcap +flow Glomerular Protein Glomerular injury flux hyperfiltrationGlomerulosclerosis## NEPHRONS

  • Pattern of excretory adaptationIncreased filtered load; Cr, BUNDecreased tubular reabsorption; Na, H2OIncreased tubular secretion; K+, H+, CrLimitation of nephron adaptationMagnitudeTime, ~response to intake / load, productionAbrupt changes in intake / production may not be toleratedTrade off, expense to other systemsE.g. to preserve P balance PTH increases

  • VolumeUrine,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 kidneyImprovement of anemia by EPO Preservation of peritubular capillary blood flow by blockade of the renin-angiotensin systemProtection of the vascular endotheliumVEGFDextran sulfateAntioxidants to improve the efficiency of cellular respirationHIF-based therapy(hypoxia inducible factor)Prolyl hydroxylase inhibitorsGene transfer of constitutively active HIF

  • Intact nephron hypothesisUsing experimental animals; urine from each kidney was collected seperately Before After End K1 K2 K1 K2 K2

    GFR 50 50 55 14 24NH3 excr 49 51 66 25 40NH3 excr/100mlGFR 100 100 120 121 167K2 was partially K1 removedremovedConclusionNormal 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 SyndromeNervous systemImpaired concentration, perceptual thinking, Peripheral neuropathy; primarily sensory, paresthesias, restless leg syndromeAutonomic neuropathy; impaired baroreceptor function, orthostatic hypotension, impaired sweatingUremic ancephalopathyHematology systemAnemia is invariably present when renal function fall
  • Cardiovascular systemCardiovascular disease is the leading cause of death in patients with CKD stage 4-5Accelerated Atherosclerosis / CAD Hypertension, ~ 80% of all uremic patientsPericarditis Metabolic abnormalitiesLipids; increase in tot. triglycerides, Lp(a), LDL, decrease HDLCarbohydrate metabolism; insulin resistance, decreased need for OAD / insulin in DMHigh prolactin; galactorrheaMen : testosteron is low, FSH / LH normal or highWomen: pg E2 & progesterone are low, FSH /LH normal or slightly elevatedAbnormalities of thyroid gland function test, normal TSH

  • CKD stage 5 (ESRD / GGT)DIALYSIS / Renal Replacement TherapyHemodialysisPeritoneal DialysisContinues Renal Replacement TherapiesKidney TransplantCadaver Living related / unrelated