Diabetic Nephropathy Dr Rahul

8/12/2019 Diabetic Nephropathy Dr Rahul

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DIABETIC NEPHROPATHY

Dr. P. Rahul

Nephrologist


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INTRODUCTION

Microvascular complication

Occurs in upto 40% of diabetes patients

Emerging as a leading cause of ESRD in India Mortality of ESRD patients with Diabetes Mellitus is higher

than in ESRD patients without Diabetes

However all diabetic patients with ESRD do not have DN asunderlying cause of ESRD.


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EPIDEMIOLOGY - DIABETES

Number of diabetics world wide: 171 million.

By 2030 - 334 million.

USA - 8%

Europe - 7%

India - 12-15% (Urban)

Type I ~ 10%

Type II > 90%


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EPIDEMIOLOGY

General incidence of Diabetic Nephropathy:

30-40 % of patients with Type I DM

25-40 % of patients with Type II DM

20 - 30 % of Type I DMProgress to ESRD

1020 % of Type II DMProgress to ESRD

> 30 % of all chronic renal failure patients have Diabetic

Nephropathy

Diabetic Kidney 2007


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EPIDEMIOLOGY

In Type 1 DM with Microalbuminuria:

3080 % develop albuminuria in 10-15 yrs

50-78% develop ESRD in 10-18 yrs

In Type 2 DM :

8-10% have microalbuminuria at diagnosis

20-40% develop albuminuria in 10-15 yrs

20% progress to ESRD in 10-18 yrs

Diabetic Kidney 2007


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Genetic Susceptibility

Likelihood of developing DN is markedly increased in patients

with a diabetic sibling or parent who has diabetic nephropathy.

RISK FACTORS FOR DN


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Age

Increasing age, along with increasing duration of diabetes,

was associated with increased risk for developing

albuminuria.

RISK FACTORS FOR DN


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Blood Pressure

Association between the subsequent development of

nephropathy and higher systemic pressures.

RISK FACTORS FOR DN


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Glycemic Control

Diabetic nephropathy is more likely to develop in patients with

worse glycemic control (higher HbA1c levels).

RISK FACTORS FOR DN


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Race

Increased incidence in African-Americans, Pima Indians,

Asians

RISK FACTORS FOR DN


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Obesity

Associated with an increased risk of chronic kidney disease

among patients with diabetes.

RISK FACTORS FOR DN


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Smoking

Associated with increases in albuminuria and the risk of end-

stage renal disease and of decreased survival once dialysis is

begun.

RISK FACTORS FOR DN


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NATURAL HISTORY

DN develops after a well defined time period and is usually

associated with retinopathy

DN is characterised by certain well defined stages and presents with

proteinuria , hypertension and renal failure.

All renal disease in a diabetic is not Diabetic Nephropathy


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TIME TO ONSET

20 to 30 percent will have microalbuminuria in 15 years

Less than half of these patients will progress to overt

nephropathy.

Onset of overt nephropathy is typically between 10 and 15

years after the onset of the disease.

Those patients who have no proteinuria after 20 to 25 years

have a risk of developing overt renal disease of only about 1

percent per year.


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RELATION BETWEEN DIABETIC

NEPHROPATHY AND RETINOPATHY

Patients with nephropathy and type 1 diabetes almost always

have other signs of diabetic microvascular disease, such as

retinopathy and neuropathy

Relationship between diabetic nephropathy and retinopathy is

less predictable in type 2 diabetes


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Type 2 diabetics with marked proteinuria and retinopathy most

likely have diabetic nephropathy, while those without

retinopathy have a high frequency of non-diabetic glomerular

disease

30 percent of type 2 diabetics with renal insufficiency have non-

diabetic renal disease




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2007 K/DOQI Guidelines for diabetes and chronic kidney

disease suggest that chronic kidney disease should be

attributed to diabetes in most patients with diabetes if

microalbuminuria and diabetic retinopathy are both present.

By comparison, other causes of CKD should be entertained if

diabetic retinopathy is absent




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Non Diabetic renal disease

suspected when.

No retinopathy

Absence of albuminuria

Rapid increase in serum creatinine.

Presence of active urinary sediment.


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Stage Duration Features

I Hypertrophy < 2 yrs Nephromegaly, No laboratory

abnormalities, RPF

II Histological

abnormalities

> 2 yrs Initial morphological lesions :

GBM thickness, Mesangium

III Incipient

nephropathy

10-20

yrs

Microalbuminuia, GFR - N

Hypertension (50%)

IV Overtnephropathy

15-20yrs

Persistent proteinuria, HTN(70%), RPF & GFR

V End stage

renal disease

20-40

yrs

GFR < 10%

Hypertension (90%)

MOGENSENS STAGING


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Stagingwell defined in Type 1 DM

In Type 2

15-30% patients can have Microalbuminuria at diagnosis

(Stage 3)

2-8 % can have Overt proteinuria at diagnosis (Stage 4)


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SCREENINGWhen ?

Type 1 DM

Young patientsfrom puberty

Adults - 5 yrs after diagnosis Type 2 DM

At diagnosis

Yearly thereafter in both


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How ?

Spot Urine albumin-creatinine ratio

24 hour urinegold standard Dipstick/Micral


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ALBUMINTO-CREATININE RATIO

Calculation of albumin-to- creatinine ratio in an untimed urine

specimen.

A value above 30mg/g or 0.03mg/mg suggests that albumin

excretion is above 30mg/d and hence microalbuminuria is

probably present.

Almost 100% sensitivity for detection of microalbuminuria.

Preferred screening strategy for all diabetic patients.


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MICROALBUMINURIA

Persistent albumin excretion between 30 and 300 mg/day (20

to 200 g/min) is called microalbuminuria

At least 2/3 samples positive for microalbuminuria in 6

months.

No e/o infection, hyperglycemia, no prior exertion.


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Significance:

Type I DM:

Predicts overt nephropathy

Type II DM:

Predicts CV mortality

Predicts nephropathy

MICROALBUMINURIA


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MICROALBUMINURIA AND GFR

Loss of renal function - defined as an estimated decrease in

GFR of more than 3.3 percent per yearoccurred in

9% of patients with normoalbuminuria

16% - regression of microalbuminuria.

32% - Stable microalbuminuria

68% - Progressive microalbuminuria


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PROGRESSION TO

MACROALBUMINURIA

Albumin excretion above 300 mg/day (200 g/min) is

considered to represent macroalbuminuria

Rate of progression from microalbuminuria to

macroalbuminuria was 2.8 percent per year

Mean rate of loss of GFR in patients with macroalbuminuria

was 0.93 mL/min per month


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M N GEMENT OF DN

Primaryprevention

Secondaryprevention

Tertiaryprevention

ESRDMADMOvert

nephropathy

Ref. Tobe SW et al. CMAJ 2002; 167(5): 499-503


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LIFE STYLE MODIFICATION

Ideal body weight

Abstinence from alcohol

Cessation of smoking

Regular exercise


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PRIMARY PREVENTION

Glycemic control

Strict glycemic control is recommended in all patients

because of its beneficial effects on microvascular

complications


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L NDM RK TRI LS

Type I DM - DCCT

Type II DM - UKPDS

Tight glycemic control leads to significant decrease in retinopathy,

neuropathy and nephropathy and macrovascular complications


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Adapted from Diabetes Care ,Jan 2007

Key concepts in setting glycemic goals:

A1C is the primary target for glycemic control

Ideal HbA1C < 7%

More stringent glycemic goals (i.e., a normal A1C,


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Glycemic Control

Diet

Exercise

Insulin

Oral hypoglycemic agents


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OHAs in CKD


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OHA s in CKD


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ACE INHIBITORS OR ARBS

Three randomized, placebo-controlled trials of 256 to 3326

patients with diabetes and normoalbuminuria (RASS,

EUCLID, DIRECT) showed no benefit from angiotensin

inhibition

There is no evidence that ACE inhibitors or ARBs are

effective for the primary prevention of microalbuminuria in

patients with diabetes who are normoalbuminuric and

normotensive.


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SECONDARY PREVENTION

How to control proteinuria?

Dietary Management

0.6-0.8 g/kg protein day, normal (1-1.2 gm/kg) if on dialysis

High Biological value proteins

Vegetable protein better

Essential amino acids

Ketoanalogues of essential amino acids


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Salt intake and proteinuria

high salt intake has been shown to blunt the antiproteinuric

effects of angiotensin inhibitors in patients with non-diabetic

kidney disease.

Salt restriction and/or diuretics enhance the effect of renin-

angiotensin blockade on proteinuria

Salt restriction to 70 meq/day has been found to enhance

the antiproteinuric effects of ARB in patients with type 2

diabetes


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ACEI & ARBS

Beyond BP Control

Proteinuria

RAS

Growth factors

Free oxygen radicals

Antifibrotic role

Sodium absorption


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ACE inhibitor plus ARB

The superiority of combination therapy with an ACE inhibitor

and an ARB compared to either therapy alone in decreasing

proteinuria has been established in both type 1 and type 2

diabetes

combination therapy with an ACE inhibitor and ARB is

associated with a higher incidence of adverse effects


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ARB plus aliskiren

The first effective oral direct renin inhibitor

Aliskiren lowers blood pressure to a degree comparable to

most other agents

In the AVOID trial, aliskiren plus losartan was associated with

a significant 20 percent greater reduction in proteinuria

compared to losartan alone


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Aldosterone antagonism

Aldosterone antagonists appear to reduce proteinuria when

used alone, and to have an additive effect on proteinuria

when used in combination with an ACE inhibitor or an ARB in

both type 1 and type 2 diabetes

Spironolactone, Eplerenone


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Other antihypertensive drugs

Diltiazem and verapamil appear to be as consistently effective

as an ACE inhibitor or ARB in lowering protein excretion in

diabetic patients


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Other agents

Pentoxifylline lowers proteinuria


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Weight reduction

Marked decreases in proteinuria may be observed in obese

diabetics who lose weight.


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HYPERTENSION AND

PROGRESSION

Transmission to glomerulusinitiation of sclerosis

DBP > 90 mm hgprogression twice as fast

MAP of 90almost normalizes rate of decline (2

ml/min/year)

In proteinuric hypertensiveseffects more marked


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HYPERTENSION

1. Diet

2. Exercise

3. Drugsicsers

calcium antagonists


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* Lowering BP by any drugbeneficial

ACEI

ARBs

Ca channel blockers

Blockers

Diuretics


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HYPERLIPIDEMIA AND

PROGRESSION Dyslipidemia implicated in the pathogenesis of progression

lipids nephrotoxic.

Increase glomerular capillary pressure.

Mesangial changesstructural and functional (lipid peroxidation

of LDLfoam cells )

Lipoprotein thrombi in the glomerular capillaries


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HYPERLIPIDEMIA TREATMENT

Diet

Exercise

Drugs

Statins

Fibrates


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ANEMIA AND PROGRESSION

Enhances renal hypoxia

Stimulates release of profibrotic cytokines

Target Hb 12 g/dL

Erythropoietin therapy and correction of anemiamay slow CKD prog ress ion


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RENAL REPLACEMENT THERAPY

Dialysis

Hemodialysis

Peritoneal Dialysis

Transplant


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NEWER THERAPIES

Inhibition of TGF-beta (Monoclonal Antibodies to TGF-beta)

appears to ameliorate diabetic nephropathy in experimental

models of diabetes and in preliminary human studies.

Protein Kinase C Inhibitors: Ruboxistaurine

Antifibrotic agents: Tranilast

Endothelin antagonist: Bosentan


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NEWER THERAPIES

PPAR-gamma agonists

thiazolidinediones (eg, pioglitazone and rosiglitazone) -

variety of beneficial effects in animal models of diabetic

nephropathy, such as reductions in fibrosis, mesangial cell

proliferation, and inflammation

reduce urinary albumin excretion at various stages of

nephropathy and reduce blood pressure


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NEWER THERAPIES

Reduction of Advanced Glycation end products: ACE I & ARB

Metformin

Aminoguanidine (Pinagedine)

Pyridoxamine

Lipoic acid

Vitamin E

Benfotiamine

Monoclonal Ab to Amadori glycated albumin


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SUMMARY

Diabetic renal disease reaching epidemic proportions

All renal disease in a diabetic not diabetic nephropathy

Early detection importantSpot urine test/MICRAL

Multi-pronged approach

Diet, Glycemic control, Blood pressure control, ACEI/ARBs

Renal replacement therapies are available but a poor substitute

for prevention


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THANK YOU

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Diabetic Nephropathy Dr Rahul