Diabetic Nephropathy
Dinkar Kaw, M.D.,
Division of Nephrology
Objectives
Prevalence of diabetic kidney disease
 Pathogenesis of diabetic nephropathy
 Clinical course of diabetic nephropathy
 Slowing the progression of nephropathy
 Screening for early nephropathy

Causes of End Stage Renal Disease
%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Other
Interstit N
Cystic KD
GN
BP
Diabetes
ll
A
USRDS 1993 Annual Data Report
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W
B
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Diabetic Nephropathy
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
The most common cause of ESRD in USA.
Accounts for nearly 40% of ESRD in USA. This
proportion of ESRD due to DN is less in Europe
than in USA.
Incidence is increasing, accounted for 10% in
1973 but now around 40% of USRD populations.
However one needs to keep in mind all diabetic
patients with ESRD do not have DN as underlying
cause of ESRD.
Diabetic Nephropathy



Mortality of ESRD patients with Diabetes Mellitus
is higher than in ESRD patients without Diabetes.
This higher mortality is due to increase in
Cardiovascular, cerebro-vascular, peripheral
vascular and infection related morbidity.
In USA the health care cost for diabetic ESRD
patients has approached to $ 2 billion per year.
Patient Survival on Dialysis by Cause of
Renal Failure
From UpToDate v 6.2; Data from USRDS 1995 Annual Report
Diabetic Nephropathy



DN occurs in 35-40% of patients with type I
diabetes (IDDM) whereas it occurs only in 1520% of patients with type II diabetes (NIDDM).
More frequent in Native Americans, Hispanics and
possibly Asian Indians.
Definition or Criteria for diagnosis of DN
 Presence
of persistent proteinuria in sterile urine of
diabetic patients with concomitant diabetic retinopathy
and hypertension.
D.N.- Pathogenesis

Familial - Genetic
 Only
35-40% patients with IDDM develop DN.
 There is an increased risk of DN in a patient with
family member having DN.
 Increased predisposition of Native Americans, Hispanic
to DN.
D.N.- Pathogenesis

Glycemic Control-in both expt & human
 DN
does not occur in euglycemic patients.
 In early 80s some controversy but DCCT confirmed
role of hyperglycemia in pathogenesis of DN.
 Renal transplant with early DN showed structural
recovery in euglycemic receipient. (Abouna)
Strict Glycemic Control Prevents
Microalbuminuria in Type 1 Diabetes mellitus
From UpToDate v 6.2; Data from the DCCT Research Group, NEJM(1993) 329:977.
D.N.- Pathogenesis





Glomerular Hyperfiltration
Glomerular Hypertension
Glomerular Hypertrophy
GBM thickening
Mesangial Expansion
D.N.- Pathogenesis

Renal lesions mainly related to
extracellular matrix accumulation
- Occurs in glomerular & tubular basement
membrane
- Principal cause of mesangial expansion
- Contributes to interstitium expansion
D.N.- Pathogenesis

Extracellular matrix accumulation
- Imbalance between synthesis & degradation of
ECM components
- Linkage between glucose concentration & ECM
accumulation
- Transforming growth factor-Beta associated with
increased production of ECM molecules
D.N.- Pathogenesis

Extracellular matrix accumulation
- TGF-B can down regulate synthesis of ECM
degrading enzymes & upregulate inhibitors of
these enzymes
- Angiotensin II can stimulate ECM synthesis
through TGF-B activity
- Hyperglycemia activates protein kinase C,
stimulating ECM production through cyclic AMP
Pathway
Diffuse and Nodular Glomerulosclerosis in Diabetic
Nephropathy
From UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Diabetic Nephropathy
Advanced Diabetic Glomerulosclerosis
From: UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Diabetic Nephropathy
Diabetic Nephropathy
Glomerular Basement Membrane Thickening
From: UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Natural Course of D.N.
Stage 1: Renal hypertrophy - hyperfunction
 Stage 2 : Presence of detectable glomerular
lesion with normal albumin excretion rate &
normal blood pressure
 Stage 3 : Microalbuminuria
 Stage 4 : Dipstick positive proteinuria
 Stage 5 : End stage renal disease

Natural History of IDDM
Clinical type 1 diabetes
Functional changes*
Structural changes†
Microalbuminuria
Proteinuria
Rising
blood pressure
Proteinuria
Rising serum
creatinine levels
End-stage
renal disease
CV events
2
5
10
Onset of
diabetes
Years
* Kidney size , GFR .
† GBM thickening , mesangial expansion
20
30
Natural History of NIDDM
Clinical type 2 diabetes
Functional changes*
Structural changes†
Rising blood pressure
Microalbuminuria
Proteinuria
Rising serum
creatinine levels
End-stage
renal disease
Cardiovascular death
Onset of
diabetes
2
5
* Kidney size , GFR .
† GBM thickening , mesangial expansion
10
Years
20
3
0
D.N.- Pathogenesis

Hypertension - in both expt & human
 Hypertension
follows 8-10 years of hyperglycemia
in IDDM patients but it is frequently present at the
diagnosis of NIDDM.
 Many experimental & human studies have shown
HTN accelerating progressive renal injury in DN.
Effect of Angiotensin Blockade
Glomerulus
Bowman’s Capsule
Afferent arteriole
Proteinuria
Efferent arteriole
Angiotensin II
A II blockade:  Glomerular pressure
 AER
( GFR)
ACE-I Is More Renoprotective Than Conventional Therapy
in Type 1 Diabetes
100
% with
doubling of
baseline
creatinine
Baseline creatinine >1.5
mg/dL
75
Placebo
n=202
50
P<.001
25
Captopril
n=207
0
0
1
2
Years of followup
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
3
4
RENAAL
Primary Composite End Point: Doubling of Serum Creatinine,
ESRD or Death (Kaplan – Meier Curve)
Brenner BM et al. N Engl J Med 345:861-869, 2001
RENAAL
dl/mg/yr
Rate of Progression of Renal Disease
(median 1/s Cr slope)
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
Losartan
Placebo
Losartan could delay ESRD by 1.5-2 years.
Brenner BM et al. N Engl J Med 345:861-869, 2001
Irbesartan in patients with type 2 diabetes &
microalbuminuria study
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590 NIDDM patients with HTN and microalbuminuria
with nearly normal GFR.
Randomly assigned to placebo, 150 mg or 300 mg of
irbesartan for 2 years.
Primary outcome was time to the onset of diabetic
nephropathy (urinary albumin excretion rate >200
mcg/min and at least 30% greater albuminuria)
14.9% patients on placebo group, 9.7% of irbesartan
150mg group and 5.2% of irbesartan 300 mg group
reached the primary point.
–
(Parving et al, NEJM, 2001)
ARBs in NIDDM,HTN & microalbuminuria-Parving 2001
Lewis et al NEJM 2001
ACE-I + Verapamil: Additive Reduction of Proteinuria in
Type 2 Diabetes at 1 Year
Trandolapril
Verapamil
(315 mg/d)
Trandolapril (2.9 mg/d)
+ Verapamil (219 mg/d)
n=12
n=11
n=14
(5.5 mg/d)
Percent reduction
0
-10
-27%
-20
-33%
-30
-40
-62%
-50
-60
-70
MAP
Proteinuria
*p <0.001 combination vs either
monotherapy
Bakris GL, et al. Kidney Int. 1998;54:1283-1289.
Reprinted by permission, Blackwell Science, Inc.
*
D.N.-Management

ACEI or AII RB- in both expt & human
 Reduce
glomerular hypertension
 Reduce proteinuria independent of
hemodynamic effects
 Reduce glomerular hypertrophy
 well tolerated apart from hyperkalemia &
worsening of anemia in severe CRF
 Cautious use in presence of severe renovascular
disease
DN: ADA Position Statement
Screening:
Perform an annual test for the presence of microalbuminuria in
1)
type 1 diabetic patients who have had diabetes > 5 years and
2)
all type 2 diabetics patients starting at diagnosis.
Treatment:
•
•
•
•
In the treatment of albuminuria/nephropathy both ACE inhibitors and
ARBs can be used:
In hypertensive and nonhypertensive type 1 diabetic patients with
microalbuminuria or clinical albuminuria, ACE inhibitors are the initial
agents of choice
In hypertensive type 2 diabetic patients with microalbuminuria or
clinical albuminuria, ARBs are the initial agents of choice.
If one class is not tolerated, the other should be substituted
American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002
UK Prospective Diabetes Study (UKPDS) Major Results:
Powerful Risk Reductions
Better blood pressure control reduces…

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Strokes by > one third
Serious deterioration of vision by > one third
Death related to diabetes by one third
Better glucose control reduces…
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Early kidney damage by one third
Major diabetic eye disease by one fourth
Turner RC, et al. BMJ. 1998;317:703713.
Hazard ratio
UKPDS: Relationship Between BP Control And DiabetesRelated Deaths
5
1
p<0.0001
17% decrease per 10 mmHg decrement in
0.5 BP
110 120 130 140 150 160 170
Mean systolic blood pressure (mmHg)
Adler AI, et al. BMJ. 2000;321:412-419.
Reprinted by permission, BMJ Publishing Group.
Diabetes: Tight Glucose vs Tight BP Control and CV
Outcomes in UKPDS
% Reduction In Relative Risk
0
Stroke
Any Diabetic
Endpoint
DM
Deaths
Microvascular
Complications
5%
-10
10%
12%
-20
24%
*
-30
32%
*
-40
-50
32%
*P <0.05 compared to tight glucose control
44%
*
37%
*
Tight Glucose Control Tight BP Control
(Goal <6.0 mmol/l or 108 mg/dL) (Average 144/82 mmHg)
Bakris GL, et al. Am J Kidney Dis.
2000;36(3):646-661.
Reprinted by permission, Harcourt Inc.
National Kidney Foundation Recommendations on
Treatment of HTN and Diabetes
Blood pressure goal: 130/80 mmHg
 Target blood pressure: 125/75 for patients
with >1 gram/day proteinuria
 Blood pressure lowering medications
should reduce both blood pressure +
proteinuria
 Therapies that reduce both blood pressure
and proteinuria have been known to reduce
renal disease progression and incidence of
ischemic heart disease

Bakris GL, et al. Am J Kidney Dis.
2000;36(3):646-661.
Cholesterol Lowering Therapy and
Diabetic Nephropathy

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Randomized singleblinded study
34 NIDDM patients
Lovastatin or PlaceboGFR
ml/mi
n
Followed for 2 years
86
84
82
80
78
76
74
72
70
68
placeb
o
lovasta
tn
0
12
24
Months
Lam, etal. Diabetologia (1995) 38:604-609
Management of ESRD due to DN
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Early planning of Vascular Access
Both HD & PD could be appropriate modalities.
Early initiation of Dialysis at GFR 18-20 mls/min.
Renal Transplantation
 CHD
very common even in absence of symptoms.
 Coronary Angiogram in diabetics under 40 years age.

Combined Renal & Pancreatic Transplantation for
IDDM.
Comparison of Patient Survival on Hemodialysis
and CAPD by Cause of Renal Failure
From UpToDate v 6.2; Data from Nelson, et al JASN(1992)3:1147.
Simultaneous Pancreas-Kidney Transplantation
Patient and Graft Survival
From:
UpToDate
v 6.2
Screening for microalbuminuria in diabetes
Treatment Objectives to Prevent Macrovascular Disease in
Diabetic Patients

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
Hypertension
 BP < 130/80 mmHg
Hypercholesterolemia
 LDL < 100 mg/dL
Hyperglycemia
 Hgb A1C < 7.0 %
American Diabetes Association Clinical Practice
Recommendations. Diabetes Care. 2001;24(suppl1):S1S133.
Management of HTN and Chronic Renal Disease (CRD) in
Diabetics
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Reduce BP to <130/80 mmHg
Use multiple antihypertensive drugs (ACEI, ARB,
diuretic, CCB, beta-blocker)
Maximal reduction of proteinuria
Treat hyperlipidemia (LDL <100 mg/dL)
Control Hgb A1C to <7%
Low salt diet (<2 gm NaCl/day)
Stop cigarette smoking
Thanks for your attention