Dm nephropathy

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DIABETIC NEPHROPATHYBY DR MALLUM C.BNEPHROLOGY UNITDEPT OF INTERNAL MEDICINEJUTHINTRODUCTIONDN (overt nephropathy): clinical syndrome characterized by persistent albuminuria (>300mg/d or 200g/min), on at least two occasions separated by 3-6 months (attributable to DM)Relentless decline in GFRElevated arterial BP

HISTORYProteinuria was 1st recognized in DM in the late 18th century.The syndrome was discovered by British physician Clifford wilson(1906-1997) and American physician Paul Kimmelstiel (1900-1970) and published for the first time in 1936.

EPIDEMIOLOGYLeading cause of CRF in US & other western countries.(30-40% of all ESRD in US)The syndrome can be seen in patients with chronic diabetes(>15yrs after onset)Approx 50% of patients with DM > 20yrs have this syndrome.Majority of patients have NIDDM.Rarely develops before 10 yrs duration of Type 1 DM

Approx 3-5% of Type 2 DM have overt nephropathyMore common in males.High prevalence in Pima indians,blacks,people of carribean descent.More common in older age group(50-70yrs)Nearly half of newly diagnosed T2DM have microalbuminuria in JosEPIDEMIOLOGYIncidence of microalbuminuria in type 1 DM was 12.6% over 7.3 yrs according to European Diabetes prospective complications Study group . Incidence was 33% in an 18yr follow up in a study in Denmark.In the UK prospective diabetes study(UKPDS)Incidence of microalbuminuria was 2% per year.Prevalence 10 yrs after diagnosis was 25%RISK FACTORS IN UKPDS 74Renal impairmentIncreased SBPUAEPlasma creatinineIndian-Asian ethnicityFemale sex, Decreased waist circumference,Age, Increased insulin sensitivity, Previous sensory neuropathyRISK FACTORS IN UKPDS 74AlbuminuriaIncreased SBPUAEPlasma creatinineIndian-Asian ethnicityMale sex, Increased waist circumference,Plasma triglycerides, LDL cholesterol, HbA1c,Increased white cell count,Ever having smoked,Previous retinopathyPATHOGENESISVarious mechanisms postulated-Metabolic pathway-Mechanical/hormonal pathway

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

METABOLIC PATHWAYHyperglycemia-Glucotoxicity alters expression of glycoprotein synthesisDe Novo synthesis of Heparan sulfate and total GAG content of GBM is reduced resulting in loss of negative charge of GBM and thus proteinuria

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Brownlee M. Nature 2001;414:813-820.Potential Mechanism by Which Hyperglycemia-Induced SuperoxideOverproduction May Activate Pathways of Hyperglycemic Damage HYPERGLYCEMIAAdvanced glycosylation Endproducts(AGE)-Non enzymatic glycosylation of amino groups on protein.Structural and circulating proteins.-AGEs cross-link proteins and alter extracellular matrix structureAGEs accumulates in arterial wall and GBM.Reduced degradation of glycosylated proteins leads to their accumulation in and expansion of GBM and mesangial matrixAccumulation of GBM parallels renal insufficiency.

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Brownlee M. Nature 2001;414:813-820.Mechanism by Which Intracellular Production of Advanced GlycationEndproduct (AGE) Precursors Damage Vascular CellsCytokines(IL 1 & TNF) synthesized by membrane bound receptor which scavenges denatured proteins.These cytokines increase vascular permeability, cellular proliferation,protein synthesisHYPERGLYCEMIAAldose reductase(AR)- present in papillae, glomerular epithelial cells,distal tubular cells,mesangial cells.Converts intracellular glucose to sorbitol leading to cellular dysfunctionSorbitol depletes myoinositol & NADPH leading to oxidative injury.Increased GFR,decreased proteinuria induced experimentally by inhibitors of AR & myoinositol supplementation

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Increased Aldose Reductase Activity and thePolyol Pathway Contribute to Cellular Oxidative StressBrownlee M. Nature 2001;414:813-820.HYPERGLYCEMIADAG- activates protein kinase C(Beta & delta isoforms) and affects gene transcription for collagen and extracellular matrixDecreased eNOS-Increased Endothelin-1-Increased VEGF-Increased TGF-BIncreased PAI-IIncreased NF-kappa BIncreased NADPH oxidase

Three major histologic changes occur1.Mesangial expansion : AGEs2.GBM thickening- augmented thickening or diminished removal.GBM turnover usu takes a year. Inc alpha-2 macroglobulin inhibits mesangial proteases.3.Glomerular sclerosis

HAEMODYNAMIC/HORMONAL PATHWAYElevated GFR,Renal plasma flow,glomerular capillary pressure mediate hyperfiltration.Elevated glomerular pressure causes physical stress which damages endothelial and epithelial surface.Disruption of glomerular barrier leads to accumulation of plasma and lipo- proteins in mesangium.There is mesangial expansion secondary to mesangial matrix production from mesangial proteins & suppression of matrix degradation.Vasoactive hormones like AG2 and Endothelins mediate these haemodynamic events.Increased Renal expression of TGF-alpha causes renal hypertrophy in DN.

Hyperfiltration-Afferent arteriolar vasodilation- secondary to hyperglycemiaIntraglomerular pressure increases local shearing forces and mesangial cell hypertrophy and extracellular matrix secretion.Glomerular sclerosis (Hyalinization)Renal hypertrophy in early stagesNigerian Society of Endocrinology & Metabolism, Jos, 2006

NATURAL HISTORYTYPE 1 DMFirst few yrs-Hyperfiltration, Renal hypertrophy: Raised GFR0-5 yrs-GBM thickening,mesangial volume expansion:GFR returns to normal5-10 yrs-40% microalbuminuria ,hypertension15-25yrs-Overt proteinuria,steady decline in GFR, 50% reach ESRD in 7-10 yrsNATURAL HISTORY (TYPE 2)Differs from type 1 in that,-overt proteinuria may be present at diagnosis-More commonly assoc with hypertension-Microalbuminuria less predictive of progressionr/o other causes of proteinuria Hypertension,CCF Prostate disease Infection

CLINICAL FEATURESHistory-Known diabeticMay present with other complicationsUsually also have concurrent diabetic retinopathy virtually all Type 1, and 50-60% of Type 2(if no retinopathy, doubt DN)Oedema secondary to Nephrotic syndromeOther assoc features like hypertension,vascular occlusive disease,coronary artery diseaseRisk factors for parenteral disease- HIV,Hep B,Hep CUrinary symptoms- UTI,obstruction,stone

Family history of kidney disease-PKDHypertension during childhood, past history of coke coloured urine or proteinuria-GlomerulonephritisPHYSICAL EXAMINATIONHypertensionFundoscopy or fluorescein angiography-diabetic retinopathyPeripheral vascular occlusive disease(decreased pulses,carotid bruits)Diabetic neuropathy(decreased sensations,diminished tendon reflexes)Non healing ulcers/osteomyelitisDIFFERENTIAL DIAGNOSISOther glomerulopathiesInterstitial nephritisNephrotic syndromeAmyloidosisMultiple myelomaRenovascular disease

INVESTIGATIONSUrinalysis-Annual urinalysis recommendedScreening at diagnosis in type 2 DM(7% microalbuminuria)5 yrs after diagnosis in type 1 DM-except puberty or poor glycemic control(18%)With microalbuminuria disease is potentially reversible.Proteinuria -150mg/dl to >300mg/dl (overt nephropathy)

INVESTIGATIONS24 hour & timed urine samples cumbersomeSpot urine sample- Results of albumin measured as urine albumin conc(mg/L) or urine albumin/creatinine(mg/g or mg/mmol)Cut off of 17mg/L or 20mg/L(European policy diabetes group)2 or 3 abnormal samples over 3-6mth periodImmunoassays for albumin measurement(may not detect unreactive fraction of albumin)High performance Liquid Chromatography- measures both immunoreactive & non-immunoreactive albuminSemiquantitative dipstick(Micral strips)Some patients noticed to have decreased GFR in the absence of UAE-Type 1 DM female patients with longstanding DM,HTN,RetinopathyType 2 DM 30% of patients without albuminuria or retinopathy (NHANES III)Therefore GFR estimation makes for proper evaluation of DN using Cockcroft-Gault formulaNigerian Society of Endocrinology & Metabolism, Jos, 2006

Nigerian Society of Endocrinology & Metabolism, Jos, 2006Screening for microalbuminuria

Nigerian Society of Endocrinology & Metabolism, Jos, 2006Albumin creatinine ratio (ACR)ACR (mg/mmol)Microalbuminuria: Women: ACR > 3.5mg/mmol ( 50mg/g)Men: ACR > 2.5mg/mmol (35mg/g)Proteinuria: 25mg/mmolUrine m/c/s- r/o UTISerology- ANCA, anti-DNA, C3,C4Renal USSKidneys enlarged in early stagesShrunken in late stagesr/o obstruction

Renal biopsyif diagnosis is in doubtIf other kidney disease suggestedIf atypical features present egType 1 DM< 10yrsNo retinopathyNephrotic range proteinuria without progressing through microalbuminuriaMacroscopic haematuria Red cell castsLight microscopy-Increase in solid spaces in the tuft with coarse branching of Solid PAS +ve material (Diffuse glomerulopathy)Large acellular accumulations that are circular on cross section are Kimmelstiel-wilson nodules.ImmunofluorescenceDeposition of IgG along the BM in a linear pattern(not diagnostic),no immune depositsFeatures of atherosclerosis in renal vasculature-Concomitant hyperlipidemia,hypertensive arteriosclerosis.Electron microscopyMesangial expansion within the tuft with increased matrix.thickening of capillary wall BM.Urine microscopy-r/o nephritic picture.r/o other primary glomerulopathiesSerum and urine electrophoresis-Exclude multiple myelomaClassify proteinuria(mainly glomerular)MANAGEMENTGoals are to slow progression of kidney damage and control related complicationsMANAGEMENT Glycemic control-Intensive therapy can partially reverse glomerular hypertrophy & hyperfiltration.Delays development of microalbuminuriaStabilize or even decrease protein levels in microalbuminuriaMANAGEMENTGlycemic control-Hyperglycemia has been shown to be a major determinant of the progression of diabetic nephropathyDCCT: 39% reduction in