Ayurveda and Diabetic nephropathy

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Dr Praveen Kumar ChoudharyAssociate ProfessorA & U Tibbia College, New Delhi

Progressive rise in urine albumin excretion (UAE) coupled with increasing BP and leading to declining GFR and CKD Abnormal urine albumin excretion >30 mg/24 hours

Diabetic Glomerular Lesion

GFR

American Diabetes Association (ADA) recommendations, Diabetes Care, January 2012

GoalsEarly DiagnosisRoutine screening: BP (Systolic and diastolic), Pre-diabetics and diabetics (Morning hyperglycemia, evening normoglycaemia, PP, HBA1C), Lipid profileUrine Albumin excretion (UAE), ACR Microhaemoglobinuria Sensitization for further work up Treatment: DietRegimeDrugsPrevention of complications

Genetics: Pre-hypertensives, Cardiovascular disease, hyperglycaemicsOnset of diabetes Type 2 Mild to moderate hypertensionPersistent raise in BP Lack of nocturnal dipping Prior to appearance of microalbuminuria Onset of DM Raised UAEInefficient control of hyperglycaemia continuous raised HBA1C above 8 Dyslipidaemia Associated Retinopathy and Neuropathy

Albumin excretion rate 10mg/24 hrHBA1C - >8 Retinopathy

Chances are more over a decade

Chances are very less in absence of these factors

Others Low birth weight (British med. Jour. 2004)Oral contraceptivesCardiovascular risk factors

Persistent Proteinuria in DM

AER > 300mg /day Type 1 : after 10 yearsType 2 : At the time of diagnosis

With HypertensionDiabetic retinopathyRenal function deterioration

SCREENING FOR NEPHROPATHYWHEN: Type 1 - annually after puberty and 5 years of DMType 2 - at diagnosis and then annuallyWHAT: random urine ACR;and random urine dipstickNormal< 2.0 mg/mmol men< 2.8 mg/mmol womenRescreen in 1 yearMicroalbuminuria2.0 - 20 mg/mmol men2.8 - 28 mg/mmol womenMacroalbuminuria> 20 mg/mmol men> 28 mg/mmol womenDiabetic nephropathy diagnosedUp to 2 repeat random urine ACRs performed 1 week to 2 months apartSuspicion of nondiabeticrenal disease?YesWorkup or referral fornondiabetic renal diseaseNoCheck ACR resultsOnly 1 abnormal ACR: Repeat screen in 1 yearAny 2 abnormal out of 3 ACRs: Diabetic nephropathy diagnosed

3/17/20179

DN and DMType 1 : Rare before 10 yearsType 2: May be in newly diagnosed

Peak incidence : 10 to 20 years, starts declining after 20 years

DM > 30 years with normoalbuminuria > Very low risk of Overt DN

Abnormal UAENormoalbuminuria 300 mg /day

Albumin ExcretionSPECIMEN COLLECTED 24hr collection (mg/24h) Timed collection (g/min)First voided morning specimenUrine Albumin concentration (mg/l)Urine Albumin:Creatinine ratio* (mg/mmol)Normoalbuminuria 25 (M)

Stages of Renal Involvement According to the Urinary Albumin Level

HypertensionKidney is a villain and victim More BP more rapid deterioration

Effect on glomerulus:Dilatation of afferent arteriole increase in intra-glomerular pressure hyper-filtration damage

Hypertension is most important aggravating factor for DN

Retinopathy80% of Type 1 DM with RP DN50% of Type 2 DM with RP DN

Progressive deterioration of kidney functionInitially GFR is increased hyper filtrationSerum Creatinine is normal Till overt DN in which macroalbuminuria is present After DN GFR starts to decrease @ 1ml/min/ month

Other causes of increased uae Exercise PyrexiaInfection Pyuria CCFHyperglycaemiaHypertension Haematuria Menstruation Pregnancy Decreased in ACE inhibitors and NSAIDS intake

pathogenesisFunctional changes Increased renal plasma flowHyperperfusion Afferent vessel dilatation and efferent vessel contraction (Atherosclerosis) Intraglomerular hypertension Increased glomerular hydrostatic pressure Hyperfiltration

Pathophysiological stagesStage increased GFRIncreased filtration pressure as result of increased intraglolerular pressure Increased UOP and low s.cra, ureaPathological change but no clinically evident diseaseProteinuria Mesangial expansion and increased matrix change in pore sizes leading to leakage of proteinStarling Foces: increased plasma flow, increased glomerular capillary hydrostatic pressure Microhematuria Ischemic injury of tubules due to constriction and stenosis of efferent arteriole Decreased GFRAtrophy and death of nephrons CKD and ESKD Loss of compensation mechanisms of nephrons

Metabolic changes AGEs Advanced glycation end productsPro fibrogenic and pro inflammatory cytokines (transforming growth factor beta TGF Beta) Protein kinase CPolyol pathway Sorbitol aldose reductase pathway sorbitol cannot cross cell membrane accumulation osmotic stress on cells insulin entry restricted - hyperinsulinaemiaROS (Reactive oxygen species) by hypertension Endothelial dysfunction vascular damageAngiotensin II inflammatory changes

Intraglomerular mesangial cells: Axis holding the edothelial and epithelial cells, Constriction and dilatation leading to fenestration - change the filtration

Atherosclerosis of efferent arterioleIncreased HTN in glomerulus

Pathogenesis

ROS, hyperinsulinaemia, HTN

AGEs, Mesangial matrix expansionFibrin collagens deposition in GBM

Influence of cytokines C and mesangial expansion

Structural changes Mesangial expansion Renal hypertrophyThickening of GBM (glomerular basement membrane)Glomerulosclerosis (Kimmelsteil Wilson nodules)Glomerulus

Endothelium Fenestration (60 100 nm)Glycocalyx (network of proteoglycans with neg. chargeEndothelial cell injury: Increased permeability Impaired nitric oxide productionUp-regulation of adhesion molecules Defects of the glycocalyx: Decrease of negativity associated with increased albumin clearance

GBMIt is 300 400 nm thick gel like structure and 90% waterCritical membrane for filtration barrier The narrow gaps 30 40 nm permeable for water and solutesIt contains cytoskeletonThe apical membrane contains podocalyxin, podoplanin and podoendin which are responable of the negative charge It contains: collagen IV, heparan sulfate proteoglucans, laminin, nidogenPodocytopenia:Loss of negative charge (loss of podocalyxin)Change in the pores size due to damage in the diagram integrityCauses of reduced number of podocytes: Podocyte detacementPodocyte apoptosisInability to proliferate and restore podocyte numberSilt diaphragm abnormalities:Abnormalities of nephrinFoot process widening and effacement

GBMHeparan sulfate reduction correlates with degree of proteinuriaIts degradation is mediated by heparanase This theory approved in Type 1 and 2 DM but in advanced human cases but not in the early stage where there is also proteinuria.

MW: < 40 kDa free to pass > 100 kDa totally restricted Albumin mw 69 kDa

Microalbuminuria:Change in electric charge Macroalbuminuria: Change in electric chargeIncreased pores size

Mechanisms of proteinuria Site of injury Glomerular hemodynamics Glomerular hyperfiltrationAfferent arteriole vasodilatation Efferent arteriole vasoconstriction glomerular capillary pressureglomerular endothelial cellEndothelial cell injury Diminished endothelial glycocalyxAltered VEGF signaling Hyperglycemia< AGE, ROS Endothelial cell injury or enzymatic cleavagePodocyte injury or loss

GBM Irregular thickeningDecreased negative charge production and/or degradation of extracellular matrix proteins production and/or degradation of HSPGpodocyte

proximal tubule PodocytopeniaLoss of slit diaphragm integrity Foot process widening and effacement

Loss negative charge

Decrease protein reabsorption Detachment, apoptosis, lack of proliferation Decrease or changes in subcellular localization of nephrin Disrupted actin cytoskeletonLoss of slit diaphragm integrityImpaired podocyte GBM interaction Podocalyxin

Tubular injury and interstitial fibrosis

AGE, advanced glycosylation end products; HSPG, heparan sulfate proteoglycan; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.

Pathological classification of DNClassDescriptionInclusion CriteriaIMild or nonspecific LM changes and EM-proven GBM thickeningBiopsy does not meet any of the criteria mentioned below for class II, III, or IVGBM > 395 nm in female and >430 nm in male individuals 9 years of age and older, Podocyte hypertrophy IIaMild mesangial expansionBiopsy does not meet criteria for class III or IVMild mesangial expansion in >25% of the observed mesangiumIIbSevere mesangial expansionBiopsy does not meet criteria for class III or IVSevere mesangial expansion in >25% of the observed mesangiumIIINodular sclerosis (KimmelstielWilson lesion)Biopsy does not meet criteria for class IVAt least one convincing KimmelstielWilson lesionIVAdvanced diabetic glomerulosclerosisGlobal glomerular sclerosis in >50% of glomeruliLesions from classes I through III

Stages of diabetic nephropathy Stage 1: Glomerular hypertension and hyperfiltration, Normoalbuminuria, Raised GFR and normal serum creatinine Stage 2: Silent phase (No clinical menifestation, only structural changes detected by biopsy), NormoalbuminuriaStage 3: Micro-albuminuria, BP may be raised, Normal serum creatinineStage 4: Macro-albuminuria, Hypertension, serum creatinine may be raised or normalStage 5: Above and increasing serum creatine, End stage kidney disease

Treatment goalScreening and prevention of type 2 DMScreening and prevention of DNScreening and prevention of Microalbuminuria to DNManagement of Hypertension Management of dyslipidaemia

Preventive measures Screening of diabetic nephropathyPrevention of diabetic nephropathy

Screening:Blood pressure :