Diabetic Nephropathy

Yiming Lit, M.D.

May 5, 2009

Epidemiology

• Diabetic nephropathy is the leading cause of ESRD in the US.

• It accounts for 43% of all patients on dialysis

• Cost to Medicare > $ 2 billion per year

Definition

• A microvascular complication of diabetes marked by albuminuria and a deteriorating course from normal renal function to ESRD.

Albuminuria 30 - 300 mg/day got called

“Microalbuminuria”

• it predicts the development of clinical nephropathy

• one “positive” is not enough in the low range

• detected by measuring the albumin/creatinine ratio on a spot urine sample

Epidemiology

• About 20-30% of patients with type I DM develop microalbuminuria, less than half progress to overt nephropathy

• Incidence of ESRD is 16% at 30 years.

• 5-60% of type II DM patients develop DN, depending on ethnicity

Epidemiology

• 63% of patients with diabetic nephropathy have type II DM

• The risk of developing diabetic nephropathy is not constant over the duration of diabetes

Epidemiology

• Risk factors:– Hypertension– Hyperglycemia– Microalbuminuria– Ethnicity– Male gender– Family history– Cigarette smoking

Natural History

Pathology

• Expansion of mesangial matrix with diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)

• Thickening of glomerular and tubular BM

• Arteriosclerosis and hyalinosis of afferent and efferent arterioles

• Tubulointerstitial fibrosis

Pathogenesis

• Exposure to the diabetic milieu• Hyperglycemia

– Induce mesangial expansion and injury– Increased activity of growth factors– Activation of cytokines– Formation of ROS– accumulation of advanced glycosylation endproducts in

tissues• Accumulation of ECM components, such as

collagen

Pathogenesis

• Genetic predisposition to or protection from diabetic nephropathy– Differences in prevalence of microalbuminuria,

ESRD in different patient populations– Only half of patients with poor glycemic

control will develop diabetic nephropathy– Family studies

• Multiple genes may be involved

Diagnosis/Screening

• Spot urine albumin : creatinine ratio

• 24 hour urine collection

• dipstick

Treatment

• Glycemic control

• Hypertension control

• Dietary protein restriction

• RAS blockade

“ Insulin was first isolated from the pancreas in 1922 by Banting and Best, and almost overnight the outlook for the severely diabetic patient changed from one of rapid decline and death to that of a nearly normal person.”

Guyton, 1991

Elizabeth Hughes (1907 - 1981)

Treatment

• Glycemic control– DCCT

• 1441 patients with type I DM randomly assigned to intensive therapy vs. conventional therapy

• Intensive therapy reduced microalbuminuria by 39%

• Reduced albuminuria by 54%

Treatment

• Hypertension control:– Lower the BP, slower the decline in GFR in

patients with diabetic nephropathy– JNC VI recommended BP < 130/85 mmHg in

patients with renal insufficiency– Patients with CKD and > 1g proteinuria, BP

goal should be < 125-130/75-80 mmHg

Treatment

• ACE inhibitors:– Type I diabetes with nephropathy:

• Lewis et al. NEJM, 1993. captopril vs. placebo50% RR of combined end points of death, dialysis and

transplantation in ACEI group independent of BP

Treatment

• Angiotensin-receptor blockers:– RENAAL study(2001)

• 1513 pts with type II DM and nephropathy. Losartan vs. placebo. Losartan reduced the rate of doubling of cr by 16% but no effect on the rate of death.

– IDNT(2001)• 1715 type II DM pts with nephropathy. Irbesartan vs.

amlodipine vs. placebo. Irbesartan has 20% lower risk of reaching endpoints compared to placebo and 23% lower incidence than that in the amlodipine group

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Treatment

Conclusions:• ACE inhibitors or ARB have a strong

antiproteinuric effect apart from their antihypertensive actions

• Increasing the dose of the ACEI or ARB beyond the optimum antihypertensive doses further reduces proteinuria

• Antiproteinuric effect is enhanced by a low Na diet or diuretic

Treatment

• Early screening• Tight glycemic control• HTN management• Use ACEI as first line, if not tolerated, use

ARB. Use the maximum dose as tolerated• If still hypertensive or proteinuric, consider

using combination ACEI and ARB, or ACEI and diuretics