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Diabetic Nephropathy

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Title: Diabetic Nephropathy


1
Diabetic Nephropathy
2
Objectives
  • Prevalence of diabetic kidney disease
  • Pathogenesis of diabetic nephropathy
  • Clinical course of diabetic nephropathy
  • Slowing the progression of nephropathy
  • Screening for early nephropathy

3
Causes of End Stage Renal Disease
USRDS 1993 Annual Data Report
4
Diabetic Nephropathy
  • 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.

5
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.

6
Patient Survival on Dialysis by Cause of Renal
Failure
From UpToDate v 6.2 Data from USRDS 1995 Annual
Report
7
Diabetic Nephropathy
  • DN occurs in 35-40 of patients with type I
    diabetes (IDDM) whereas it occurs only in 15-20
    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.

8
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.

9
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)

10
Strict Glycemic Control PreventsMicroalbuminuria
in Type 1 Diabetes mellitus
From UpToDate v 6.2 Data from the DCCT Research
Group, NEJM(1993) 329977.
11
D.N.- Pathogenesis
  • Glomerular Hyperfiltration
  • Glomerular Hypertension
  • Glomerular Hypertrophy
  • GBM thickening
  • Mesangial Expansion

12
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

13
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

14
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

15
Diffuse and Nodular Glomerulosclerosis in
Diabetic Nephropathy
From UpToDate v 6.2 Courtesy H. Rennke, M.D.
16
Diabetic Nephropathy
17
Advanced Diabetic Glomerulosclerosis
From UpToDate v 6.2 Courtesy H. Rennke, M.D.
18
Diabetic Nephropathy
19
Diabetic NephropathyGlomerular Basement Membrane
Thickening
From UpToDate v 6.2 Courtesy H. Rennke, M.D.
20
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

21
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
20
30
Onset of diabetes
Years
Kidney size , GFR . GBM thickening ,
mesangial expansion
22
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
10
20
30
Years
Kidney size , GFR . GBM thickening ,
mesangial expansion
23
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.

24
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25
Effect of Angiotensin Blockade
Proteinuria
Angiotensin II
A II blockade
26
ACE-I Is More Renoprotective Than Conventional
Therapy in Type 1 Diabetes
100 75 50 25 0
Baseline creatinine gt1.5 mg/dL
with doubling of baseline creatinine
Placebo n202
Plt.001
Captopril n207
0
1
2
3
4
Years of follow-up
Lewis EJ, et al. N Engl J Med. 1993329(20)1456-1
462.
27
RENAAL
Primary Composite End Point Doubling of Serum
Creatinine, ESRD or Death (Kaplan Meier Curve)
Brenner BM et al. N Engl J Med 345861-869, 2001
28
RENAAL
Losartan could delay ESRD by 1.5-2 years.
Brenner BM et al. N Engl J Med 345861-869, 2001
29
Irbesartan in patients with type 2 diabetes
microalbuminuria study
  • 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 gt200
    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)

30
ARBs in NIDDM,HTN microalbuminuria-Parving 2001
31
Lewis et al NEJM 2001
32
ACE-I Verapamil Additive Reduction of
Proteinuria in Type 2 Diabetes at 1 Year
Trandolapril (2.9 mg/d) Verapamil (219 mg/d)
Trandolapril (5.5 mg/d)
Verapamil (315 mg/d)
n12
n11
n14
-27
-33
Percent reduction
-62

p lt0.001 combination vs either monotherapy
Bakris GL, et al. Kidney Int. 1998541283-1289.
Reprinted by permission, Blackwell Science, Inc.
33
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

34
DN ADA Position Statement
  • Screening
  • Perform an annual test for the presence of
    microalbuminuria in
  • type 1 diabetic patients who have had diabetes gt
    5 years and
  • 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 25S85-S89, 2002
35
UK Prospective Diabetes Study (UKPDS) Major
Results Powerful Risk Reductions
  • Better blood pressure control reduces
  • Strokes by gt one third
  • Serious deterioration of vision by gt one third
  • Death related to diabetes by one third
  • Better glucose control reduces
  • Early kidney damage by one third
  • Major diabetic eye disease by one fourth

Turner RC, et al. BMJ. 1998317703-713.
36
UKPDS Relationship Between BP Control And
Diabetes-Related Deaths
Hazard ratio
Mean systolic blood pressure (mmHg)
Adler AI, et al. BMJ. 2000321412-419. Reprinted
by permission, BMJ Publishing Group.
37
Diabetes Tight Glucose vs Tight BP Control and
CV Outcomes in UKPDS
DM Deaths
Microvascular Complications
Stroke
Any Diabetic Endpoint
0
5
10
-10
12
-20
24
Reduction In Relative Risk

-30
32
32

37
P lt0.05 compared to tight glucose control

-40
44
Tight Glucose Control (Goal lt6.0 mmol/l or 108
mg/dL)
Tight BP Control (Average 144/82 mmHg)

-50
Bakris GL, et al. Am J Kidney Dis.
200036(3)646-661. Reprinted by permission,
Harcourt Inc.
38
National Kidney Foundation Recommendations on
Treatment of HTN and Diabetes
  • Blood pressure goal 130/80 mmHg
  • Target blood pressure 125/75 for patients with
    gt1 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.
200036(3)646-661.
39
Cholesterol Lowering Therapy and Diabetic
Nephropathy
  • Randomized single-blinded study
  • 34 NIDDM patients
  • Lovastatin or Placebo
  • Followed for 2 years

GFR ml/min
Months
Lam, etal. Diabetologia (1995) 38604-609
40
Management of ESRD due to DN
  • 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.

41

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)31147.
42
Simultaneous Pancreas-Kidney Transplantation Patie
nt and Graft Survival
From UpToDate v 6.2
43
Screening for microalbuminuria in diabetes
44
Treatment Objectives to Prevent Macrovascular
Disease in Diabetic Patients
  • Hypertension
  • BP lt 130/80 mmHg
  • Hypercholesterolemia
  • LDL lt 100 mg/dL
  • Hyperglycemia
  • Hgb A1C lt 7.0

American Diabetes Association Clinical Practice
Recommendations. Diabetes Care.
200124(suppl1)S1-S133.
45
Management of HTN and Chronic Renal Disease (CRD)
in Diabetics
  • Reduce BP to lt130/80 mmHg
  • Use multiple antihypertensive drugs (ACEI, ARB,
    diuretic, CCB, beta-blocker)
  • Maximal reduction of proteinuria
  • Treat hyperlipidemia (LDL lt100 mg/dL)
  • Control Hgb A1C to lt7
  • Low salt diet (lt2 gm NaCl/day)
  • Stop cigarette smoking

46
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