Diabetic Nephropathy:You can't cure it so you have to endure itKing, et al. Qual Health Res. 2002;12:329-46

Persistent albuminuria (>300 mg/d or >200 ug/min) that is confirmed on at least 2 occasion 3-6 months apart.Progeressive decline in the glomerular filtration rate (GFR)Elevated arterial blood pressure

Mesangial expansionThickening of Glomerular Base MembraneGlomerular Sclerosis

Grading

Gambar Glomerulus

PathophysiologyGlomerular Hiperfiltrasion and HiperperfusionAGEs (advance glycosilation end-products)Accumulate of Polyols increase Sorbitol cause by aldose reductaseActivation Protein Kinase C

HiperglicemiaOncotic pressure HiperfiltrationDiluted State, Sodium LossAfferen VasodilatationReninGlomerular HipertensionGlomerular Hiperfiltration dan hiperperfusionSRAA

Pathology of DM nephropathyNormal GlomerulusEarly Diabetic GlomerulusCapillary lumenMesangial cellThickened BMExpanded mesangiumMesangiumPodocyte damage & lossBasement membrane Afferent and efferent hyaline arteriolosclerosis Interstitial fibrosis and tubular atrophy

Renal preglomerular vasodilationSystemic hypertensionGlomerular hypertensionGlomerular sclerosisHyperglycemiaGenetic factorsD metabolism of glom. cellsSimpleminded model of pathogenesis of DM nephropathy

TGF-bAIIstretchglucosePotential mechanisms for increased matrix production in hyperglycemiaMesangial cell

Renal preglomerular vasodilationGlomerular hypertensionTreatment of DM nephropathy: Glucose controlfrom T. Hostetter

Renal preglomerular vasodilationGlomerular hypertensionTreatment of DM nephropathy: Hypertension controlfrom T. Hostetter

DMACEI or ARB

Renal preglomerular vasodilationGlomerular hypertensionTreatment of DM nephropathy: Effect of dietary protein restrictionfrom T. Hostetter

Effect of dietary protein restriction on progression of DM nephropathyGFR(ml/min)

Treatment of DM nephropathy: Effect of statins from T. HostetterRenal preglomerular vasodilationSystemic hypertensionGlomerular hypertensionGlomerular sclerosisHyperglycemiaROSGenetic factorsD metabolism of glom. cells

Renal preglomerular vasodilationSystemic hypertensionGlomerular hypertensionGlomerular sclerosisHyperglycemiaROSGenetic factorsD metabolism of glom. cellsfrom T. HostetterTreatment of DM nephropathy: All together!

The Renin-Angiotensin-SystemAngiotensinogen

RAS in cardiovascular pathologyAdapted from: Chung O. & Unger T., Am J Hypertens 1999;12:150S156SRisk factors: diabetes, obesity, smoking, ageVasoconstrictionVascular hypertrophyEndothelial dysfunctionAtherosclerosisHypertensionPro-thrombotic stateVascular diseaseApoptosisLVHFibrosisArrhythmiaHeart failureMIStrokeCognitive dysfunctionRenal failureDeathDecreased GFRProteinuria/albuminuriaGlomerulosclerosis

ANG II: Progression of Chronic Renal DiseaseRenal diseaseANG IIAngiotensinogenNF- kBTNF-aFibroblastsProfibroticCytokinesMatrixProliferationDifferentationFibrosisTubule CellsChemoattractantsAdhesion proteinsInflammationDirect CytotoxicityVasoconstrictionInflammationGrowth EffectANG II

ANG IIANG IIKlahr et al., 2000Oxidative Stress

Angiotensin-ReceptorsVasoconstrictionNa+-RetentionAldosterone-ReleaseProliferationFibrosisInflammationAnti-ProliferationAnti-FibrosisAnti-InflammationVasodilation (Neuro-)regeneration

mentsFragACEBradykininReninACEAT1ANG IIANG IIAT2ANG IIANG IAngiotensinogenAT1 Receptor BlockersRenin inhibitorsAldosterone antagonistsAldosterone+Drugs inhibiting the renin-angiotensin-aldosterone system

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