Ayurveda and Diabetic nephropathy

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

Definition

Progressive rise in urine albumin excretion (UAE) coupled with increasing BP and leading to declining GFR and CKD

1. Abnormal urine albumin excretion >30 mg/24 hours

2. Diabetic Glomerular Lesion

3. GFR ↓

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

Appearance

Diabetic Nephropathy

Goals Early Diagnosis1. Routine screening: BP (Systolic and diastolic), Pre-

diabetics and diabetics (Morning hyperglycemia, evening normoglycaemia, PP, HBA1C), Lipid profile

2. Urine Albumin excretion (UAE), ACR Microhaemoglobinuria

3. Sensitization for further work up Treatment: 1. Diet2. Regime3. Drugs Prevention of complications

Susceptible patients/risk factors

Genetics: Pre-hypertensives, Cardiovascular disease, hyperglycaemics

Onset of diabetes – Type 2 – Mild to moderate hypertension

Persistent raise in BP – Lack of nocturnal dipping – Prior to appearance of microalbuminuria

Onset of DM – Raised UAE Inefficient control of hyperglycaemia –

continuous raised HBA1C above 8 Dyslipidaemia Associated Retinopathy and Neuropathy

Risk

Albumin excretion rate – 10mg/24 hr HBA1C - >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 contraceptives Cardiovascular risk factors

Diagnostic protocol

Persistent Proteinuria in DM

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

With Hypertension Diabetic retinopathy Renal function deterioration

05/02/2023

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SCREENING FOR NEPHROPATHYWHEN: Type 1 - annually after puberty and 5 years of DM

Type 2 - at diagnosis and then annually

WHAT: random urine ACR;

and random urine dipstick

Normal< 2.0 mg/mmol men

< 2.8 mg/mmol womenRescreen in 1 year

Microalbuminuria2.0 - 20 mg/mmol men

2.8 - 28 mg/mmol women

Macroalbuminuria> 20 mg/mmol men

> 28 mg/mmol womenDiabetic nephropathy

diagnosed

Up to 2 repeat random urine ACRs performed 1 week to 2

months apart

Suspicion of nondiabetic

renal disease?Yes

Workup or referral fornondiabetic renal

diseaseNo

Check ACR results

Only 1 abnormal ACR: Repeat screen

in 1 year

Any 2 abnormal out of 3 ACRs: Diabetic

nephropathy diagnosed

DN AND DM Type 1 : Rare before 10 years Type 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 UAE

Normoalbuminuria <30mg/day Microalbuminuria : 30 – 300 mg/day Macroalbuminuria: >300 mg /day

Albumin Excretion

SPECIMEN COLLECTED

24hr collection (mg/24h)

Timed collection (μg/min)

First voided morning specimen

Urine Albumin concentration

(mg/l)

Urine Albumin:Creatinine

ratio* (mg/mmol)

Normoalbuminuria <30 <20 <20 <3.5 (F)<2.5 (M)

Microalbuminuria 30-300 20-200 20-200 3.5 to 35 (F) 2.5 to 25 (M)

Overt proteinuria >300 >200 >200 >35 (F)>25 (M)

Stages of Renal Involvement According to the Urinary Albumin Level

Natural history of DN

HYPERTENSION Kidney 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

RETINOPATHY

80% of Type 1 DM with RP – DN 50% of Type 2 DM with RP – DN

PROGRESSIVE DETERIORATION OF KIDNEY FUNCTION

Initially GFR is increased – hyper filtration Serum 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 Pyrexia Infection Pyuria CCF Hyperglycaemia Hypertension Haematuria Menstruation Pregnancy

Decreased in ACE inhibitors and NSAIDS intake

PATHOGENESIS Functional changes कफजन्य Increased renal plasma flow Hyperperfusion Afferent vessel dilatation and efferent vessel

contraction (Atherosclerosis) Intraglomerular hypertension Increased glomerular hydrostatic pressure Hyperfiltration स्रोतोदुष्टि� प्रकार – संग एवं विवमाग�गमन

PATHOPHYSIOLOGICAL STAGESStage increased GFR Increased filtration pressure as result of

increased intraglolerular pressure Increased UOP and low s.cra, ureaPathological change but no clinically evident disease

Proteinuria 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 GFR Atrophy and death of nephrons

CKD and ESKD Loss of compensation mechanisms of nephrons

METABOLIC CHANGES AGEs Advanced glycation end products Pro fibrogenic and pro inflammatory cytokines

(transforming growth factor – beta TGF Beta) Protein kinase C Polyol pathway – Sorbitol aldose reductase

pathway – sorbitol cannot cross cell membrane – accumulation – osmotic stress on cells – insulin entry restricted - hyperinsulinaemia

ROS (Reactive oxygen species) by hypertension Endothelial dysfunction – vascular damage Angiotensin II सभी inflammatory changes वि�त्तजन्य होते हैं

INTRAGLOMERULAR MESANGIAL CELLS: AXIS HOLDING THE EDOTHELIAL AND EPITHELIAL CELLS, CONSTRICTION AND DILATATION LEADING TO FENESTRATION - CHANGE THE FILTRATION

Atherosclerosis of efferent arteriole

Increased HTN in glomerulus

PATHOGENESISROS, hyperinsulinaemia, HTN

AGEs,

Mesangial matrix expansion

Fibrin collagens deposition in GBM

Influence of cytokines C and mesangial expansion

STRUCTURAL CHANGES Mesangial expansion Renal hypertrophy Thickening of GBM (glomerular basement

membrane) Glomerulosclerosis (Kimmelsteil Wilson

nodules) Glomerulus में होने वाले सभी विवकार जिजस्मे वृक्क ऊतक का

क्षय होता है वह वातजन्य हैं

Endothelium Fenestration (60 – 100 nm) Glycocalyx (network of proteoglycans with

neg. charge Endothelial cell injury:

Increased permeability Impaired nitric oxide production Up-regulation of adhesion molecules

Defects of the glycocalyx: Decrease of negativity associated with

increased albumin clearance

GBM It is 300 – 400 nm thick gel like structure and 90% water Critical membrane for filtration barrier The narrow gaps 30 – 40 nm permeable for water and solutes It contains cytoskeleton The apical membrane contains podocalyxin, podoplanin and

podoendin which are responable of the negative charge It contains: collagen IV, heparan sulfate proteoglucans, laminin,

nidogen Podocytopenia:

Loss of negative charge (loss of podocalyxin) Change in the pores size due to damage in the diagram integrity

Causes of reduced number of podocytes: Podocyte detacement Podocyte apoptosis Inability to proliferate and restore podocyte number

Silt diaphragm abnormalities: Abnormalities of nephrin Foot process widening and effacement

GBM Heparan sulfate reduction correlates with

degree of proteinuria Its 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 hyperfiltration

Afferent arteriole vasodilatation Efferent arteriole vasoconstriction glomerular capillary pressure

 glomerular endothelial cell

Endothelial 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 HSPG

 podocyte

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 DNClass Description Inclusion Criteria

I Mild or nonspecific LM changes and EM-proven GBM thickening

Biopsy 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 expansion

Biopsy does not meet criteria for class III or IVMild mesangial expansion in >25% of the observed mesangium

IIb Severe mesangial expansion

Biopsy does not meet criteria for class III or IVSevere mesangial expansion in >25% of the observed mesangium

III Nodular sclerosis (Kimmelstiel–Wilson lesion)

Biopsy does not meet criteria for class IV

At least one convincing Kimmelstiel–Wilson lesion

IV Advanced diabetic glomerulosclerosis

Global 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), Normoalbuminuria

Stage 3: Micro-albuminuria, BP may be raised, Normal serum creatinine

Stage 4: Macro-albuminuria, Hypertension, serum creatinine may be raised or normal

Stage 5: Above and increasing serum creatine, End stage kidney disease

TREATMENT GOAL Screening and prevention of type 2 DM Screening and prevention of DN Screening and prevention of

Microalbuminuria to DN Management of Hypertension Management of dyslipidaemia

PREVENTIVE MEASURES Screening of diabetic nephropathy Prevention of diabetic nephropathy

Screening:1. Blood pressure : <130/802. UAE: Type 2 – Annual after diagnosis, type 1

– annual 5 year post diagnosis (normal range - <30mg/day, <20µg/min, < 30 µg/mg creatinine)

3. Lipid profile – Annual (LDL <100mg/dl, HDL >40mg/dl, TG <150mg/dl)

TABLE 2. RECOMMENDATIONS FOR THE COMPREHENSIVE MANAGEMENT OF T2DM PATIENTS WITH CKDFactor Recommendations Lifestyle factors diet, exercise, smoking,and alcohol intake

Blood glucose Treatment goal: HbA1c <6.5%Preprandial plasma glucose 90-130 mg/dlPostprandial plasma glucose <180 mg/dl

Blood pressure Goal ≤130/80 mm HgUse maximal tolerated dose of ACE inhibitor or ARB before adding a second agent

Cholesterol Goal <4.0 mmol/L for total cholesterol and <2.0 mmol/L for LDL-C Consider use of a statin irrespective of baseline lipid values for the secondary prevention of cardiovascular disease

Platelets Consider use of low dose aspirin for the secondary prevention of cardiovascular disease

Monitoring Annual monitoring of eGFR and ACR

RECOMMENDED TREATMENT Target to keep HBA1C <7% BP < 130/80 Lipid at normal levels Supplements: Stevia rebaudiana : As a sweetner? करेला (Bitter melon - Momordica charantia), सदाबहार

(Vinca rosea/Catharanthus), नीम�त्र (Azadirachta indica), wheetgrass juice /decoction

Juice of root of black pig weed (Trianthema decandra), juice of root of Indian Banyan (Ficus bengalensis) and juice of leaves of Vasa (Adhatoda zeylanica) – to manage DM

मेथी (Fenugreek) and लशुन (garlic) – lipid as well as sugar levels

DIET Oatmeal (यव दलिलया), broccoli (फूलगोभी), green beans (हरी

सेम), strawberries (झडबेर), salmon (मत्स्य), lean meats (अल्� वसा मांस) and cinnamon (दालचीनी)

Avoid high sugar foods and limit protein intake Too much protein intake will increase the kidney burden

and aggravate the kidney damage Limit the salt intake, because too much salt intake will

aggravate hypertension Avoid high potassium content foods such as oranges

and banana Herbal tea - can help repairing kidney damage like

dandelion root tea (ककरौंधा – Taraxicum officinale), nettle leaf tea (विबचू्छ बूटी – Urtica dioica), corn silk tea (मकइ के भुटे्ट के बाल) - Natural diuretics which can remove extra wastes

Drugs

Oral Hypoglycaemics: मेषश्रृंगी (Gymnema sylvestre): Lower blood sugar,

decrease desire of sweet food, maintain lipid levels.

विवजयसार (Pterocarpus marsupium): Hypoglycaemic effect as well as मेदोहर

हरिरद्रा (Turmeric): Hypoglycaemic, anti-inflammatory, Free radical scavenger

दारुहरिरद्रा (Berbaris aristata): Stimulates pancreatic function

मेलिथका (Fenugreek): Hypoglycaemic जम्बू (Syzygium cumini/Eugenia jambolana):

Hypoglycaemic, hypolipidaemic

CONTD आम्र बीज (seeds of Mangifera indica):

Hypoglycaemic , hypolipidaemic नागजिजह्वा (Enicostema littorale): Potent

hypoglycaemic उदुम्बर (Ficus glomerata): Hypoglycaemic विनम्ब लिचरायता

DRUGS FOR PROTEINURIA / RENAL FUNCTION

�ुनन�वा (Boerhavia diffusa): Helps in reducing urea and creatinine as well as renal tissue rejuvenator, hypoglycaemic

गोकु्षर (Tribulus terrestris): Diuretic, renal protector

भूष्टिम आमलकी (Phyllanthus niruri): Anti oxidant and anti infective

मंजिजष्ठा (Rubia cordifolia): Blood detoxifier कासनी (Cichorium intybus): Lowers creatinine

and urea, protects kidney tissue

CONT रुमी मस्तगी (Pistacia lentiscus): Liver and kidney

protector लिशग्रु (Moringa oleifera): Urinary antiseptic

HYPERTENSION अजु�न (Terminalia arjuna) तगर (Valeriana welchii) ब्राह्मी (Bacopa monnieri) स��गन्धा (Rauwolfia serpentina) शंख�ुष्�ी (Convolvulus pluricaulis)

CONTD Diet - 20% carbohydrate, 10 to 15 % protein

and 60-65% vegetables Celery (Ajwain) - lowers pressure by reducing

blood concentration of stress hormones Indian gooseberry (Amla) is effective to lower

it Watermelon - helps in dilating the blood

vessels

योगाभ्यास

सुखासन अथवा वज्रासन में रेचक �ूरक प्राणायाम ध्यान विUया ताडासन, �वनमुक्तासन, भुजंगासन आदिद जलनेवित, शोधन बस्तिस्त वातप्रको� की अवस्था में अनुवासन बस्तिस्त का प्रयोग (गोकु्षरादिद

तैल) से

Thank you