Transcript Diabetic Nephropathy - Stanford University

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:
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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
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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
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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. placebo
50% 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
}
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
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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