Diabetic Nephropathy

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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
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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.

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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
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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.

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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.

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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.
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D.N.- Pathogenesis

• Glomerular Hyperfiltration
• Glomerular Hypertension
• Glomerular Hypertrophy
• GBM thickening
• Mesangial Expansion

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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

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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

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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

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

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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
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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
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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.

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Effect of Angiotensin Blockade
Proteinuria
Angiotensin II
A II blockade
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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.
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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
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RENAAL
Losartan could delay ESRD by 1.5-2 years.
Brenner BM et al. N Engl J Med 345861-869, 2001
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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)

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ARBs in NIDDM,HTN microalbuminuria-Parving 2001
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Lewis et al NEJM 2001
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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.
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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

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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
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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.
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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.
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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

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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.
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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.
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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
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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.

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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.
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Simultaneous Pancreas-Kidney Transplantation Patie
nt and Graft Survival
From UpToDate v 6.2
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Screening for microalbuminuria in diabetes
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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.
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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

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Thanks for your attention