DIABETIC NEPHROPAHTY

BY

Syed Rizwan, MD

1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 20100

100

200

300

400

500

600

700

IncidenceR2 = 99.8%

Point prevalenceR2 = 99.7%

Projection

Number of Patients

95% Confidence Interval

326,217

372,407

661,330

86,82598,953

172,667

Adjusted for age, gender, race350

300

250

200

150

100

50

0

AII

Diabetes

Hypertension

Cystic Kidney

1992 1994 1996 1998 2000

Chronic Kidney Disease

• Increase in incidence due to,– age of population– increase in diabetes– Decrease in Cardiovascular Mortality

Diabetic Nephropathy

• will increase with more Diabetics all over world.

• Higher morbididty and mortality compared to non-Diabetics.

• Higher cost of health care

Diabetic Nephropathy

• What to do?– prevent or slow progression of disease– decrease morbidity/ mortality– Prepare for RRT(renal replacement

Therapy

prevent or slow progression of Diabetic Nephropahty

– diet,exercise, life style modifications– Glycemic control– HTN control– ACEI/ARBs– Protein restriction– Hyperlipidemia management

Glycemic control in DN

• Stage- earlier the better

• Degree- tighter the better

• Renal disease in Type1 Diabetic may be decreasing.

                                                     

  

Glycemic control in DN

• Is game over once Proteinuric?

• Pancreatic Transplantation can reverse proteinuria and establised Glomerular pathology.

HTN control in DN

• Most important

• Most practical

For Individuals With: BP Goal:

Hypertension(no diabetes or renal disease)

Diabetes Mellitus

Renal Diseasewith proteinuria >1 gram/24 hours or diabetic kidney disease

<140/90 mmHg(JNC 7)

<130/80 mmHg(ADA, JNC 7)

<135/85 mmHg<125/75 mmHg

(NKF)

Target Blood Pressure

Chobanian AV et al. JAMA. 2003;289:2560–2571. American Diabetes Association. Diabetes Care. 2002;25:134–147.National Kidney Foundatrion. Am J Kidn Dis.

2002;39(suppl 1):S1–S266.

ACEI/ARBs in DN

• RAS activated in Diabetic Kidney.

• Strict Glycemic contron in overt Nephropathy- not as helpful in DN.

• Glomerular Hyperfiltration injures kidney.

• Lowering intraglomerular pressure is beneficial

ACEI/ARBs in DN

• Is ACEI effective in slowing DN in Type 2 Diabetics?

• No clear evidence that ACEIs are renoprotective in Type 2 Diabetics

• Drug companies would not research on generic medicine.

ACEI/ARBs in DN

• ACE escape phenomenon.

• Biological action of Ang11 are not completley prevented by ACEI.

• Biological actions of Ang11 are mediated by AT-1 receptor.

Acronym Diagnosis Randomization PrimaryEndpoint Duration

IDNT1

N = 1,715Type 2 DM with nephropathy

Irbesartan/amlodipine/placebo + AHT*

•ESRD•2x creatinine•mortality

2.6 yrs

*AHT = other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs).†AHT = other antihypertensive therapy (excluding ACEIs and ARBs).

RENAAL Type 2 DM with nephropathy

Losartan/placebo + AHT†

•ESRD•2x creatinine•mortality

3.4 yrs

N = 1,513

Effect of ARBs on Diabetic Nephropathy

Multicenter (210 sites), prospective, randomized, double-blind trial in 1,715 hypertensive patients with nephropathy due to type 2 diabetes

Composite of doubling of serum creatinine, onset of ESRD, or death from any cause

Usual AHT* + placebo

Usual AHT* + irbesartan 300 mg/day

Usual AHT* + amlodipine 10 mg/day

2.6 yrs

135/85 mmHg

*Antihypertensive therapy (excluding ACEIs, ARBs, CCBs).

Design:

Duration:

Primary Endpoint:

Randomization:

Target BP:

IDNT: Study Design

Doubling of Serum Creatinine, ESRD, and/or Death

32.6%

41.1%39.0%

20

25

30

35

40

45

Irbesartan Amlodipine Placebo

*

*P = 0.02 vs placebo; P = 0.006 vs amlodipine.

20% - irb vs pbo

23% - irb vs aml

Pat

ien

ts, %

IDNT: Primary Composite Endpoint

Multicenter, randomized, double-blind, placebo-controlled trial in 1,513 patients with type 2 diabetes and nephropathy

Composite of doubling of serum creatinine, onset of ESRD, or death from any cause

Usual AHT* + placebo

Usual AHT* + losartan 50–100 mg/day

3.4 yrs

SBP <140 mmHg

DBP <90 mmHg

Brenner BM et al. N Engl J Med. 2001;345:861–869.

*Antihypertensive therapy (excluding ACEIs or other ARBs).

Design:

Duration:

Primary Endpoint:

Target BP:

RENAAL: Study Design

Doubling of Serum Creatinine, ESRD, and/or Death

43.5%

47.1%

30

34

38

42

46

50

Losartan Placebo

(16% )

P = 0.02.

Pat

ien

ts, %

RENAAL: Primary Composite Endpoint

Brenner BM et al. N Engl J Med. 2001;345:861–869

ACEI/ARBs in DN

• Stronger evidence to use ARBs than ACEI in type2 Diabetic Nephropahty.

• ACEI use is warranted because of cost, BP control and beneficial effects on CVS.

Effect of ARBs on Type 2 Diabetic Nephropathy: Conclusions

• Losartan/irbesartan significantly slow deterioration of renal function in nephropathy

• ARBs significantly reduce the risk of doubling serum creatinine or progressing to ESRD

• In type 2 diabetics with nephropathy, ARBs provide renal benefits independent of their BP-lowering effect

Lewis EJ et al. N Engl J Med. 2001;345:851–860. Brenner BM et al. N Engl J Med. 2001;345:861–869.

Mogensen CE et al. BMJ. 2000;321:1440–1444.

CALM: Study Design

Primary OutcomeMeasures:

Multicenter, randomized, double-blind, placebo-controlled trial in 199 patients with type 2 diabetes, hypertension, and microalbuminuria

BP and urinary albumin:creatinine ratio

Group 1: candesartan 16 mg for 24 weeks (n = 66)

Group 2: lisinopril 20 mg for 24 weeks (n = 64)

Group 3: C16 for 12 weeks with add-on L20 for 2 weeks (n = 34)

Group 4: L20 for 12 weeks with add-on C16 for 12 weeks (n = 35)

Design:

Randomization:

Ch

an

ge

in U

rin

ary

Alb

um

in:

Cre

ati

nin

e R

atio

, %

Candesartan 16 mg

Lisinopril 20 mg

Both

*P = 0.05 from baseline.†P < 0.001 from baseline.

–60

–50

–40

–30

–20

–10

0

*

†

†

Mogensen CE et al. BMJ. 2000;321:1440–1444.

CALM: Reductions From Baseline in Urinary Albumin:Creatinine Ratio (Week 24)

*P = 0.05 from baseline.†P < 0.001 from baseline.

Mogensen CE et al. BMJ. 2000;321:1440–1444.

Ch

an

ge

in B

P, m

mH

g

Candesartan 16 mg

Lisinopril 20 mg

Both–30

–25

–20

–15

–10

–5

0

†

SBPDBP

†

*

† †

†

CALM: Reductions From Baseline in BP

Design: Randomized, double-blind trial in 263 patients with nondiabetic renal

disease

Primary Composite of time to doubling of serum Endpoint: creatinine concentration or ESRD

Randomization: Losartan 100 mg/day + AHT* as neededTrandolapril 3 mg/day + AHT* as

needed

Duration: 3 yrs

Target BP: SBP <130 mmHgDBP <80 mmHg

Nakao N et al. Lancet. 2003;361:117–124.

*Antihypertensive therapy (excluding other ACEIs or other ARBs).

COOPERATE: Study Design

Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124.

Doubling of Serum Creatinine or Progression to ESRD

0

5

10

15

0 5 12 18 24 30 36

20

25

30

Pro

po

rtio

n R

each

ing

En

dp

oin

t, %

Months After Randomization

737683868788Combination

637275838586Trandolapril

596579848889Losartan

Number at Risk

Trandolapril

Losartan

Combination

P = 0.02

COOPERATE: Primary Endpoint

0

1

2

3

0 5 15 20 30 35

Trandolapril

Losartan

Combination

Months After Randomization

Med

ian

Uri

nar

y P

rote

in E

xcre

tio

n,

g/d

ay

Baseline

10 25 40

COOPERATE: UAER

Management of Hyperkalemia in Patients Treated With ACEIs or ARBs

•Discontinue other meds that interfere in K excretion•Low K diet (70 mEq/d)•Effective diuretic therapy: loop diuretics when creatinine >1.8 mg/dl•NaHCO3 tablets (650-mg tablet, 8 mEq)•Decrease dose of ACEI•Consider change to ARB

Palmer BF. N Engl J Med. 2002;347:1256–1261.

ACEI and ARB combination

• No good study in Diabetic Nephropathy.

• Overall use is safer and seems beneficial

• Hyperkalemia is a major concern.

• Benefit proven in Non-Diabetic CKD Pts.

Protein restriction in DN

• Unproven.

• Uncertain.

• Problems with compliance.

• Risk of Malnutrition.

• Avoid High Protein diet.

• About 1gm/kg/day.

Hyperlipidemia and DN

• Common in Diabetics.

• Can cause Glomerular injury.

• Lowering lipid can slow renal disease

Proteinuria in DN

• Proteinuria in Diabetes means more than Glomerular damage.

• Proteinuria in DM points to widespread endothelial and epithelial cell injury.

• High association with,– Retinopathy– Neuropathy– Coronary Artery disease

ANEMIA

AND

DIABETIC NEPHROPATHY

Anemia

• Independent risk factor for ESRD.

• Associated with higher mortality & moebidity.

• Correcting anemia could delay progression of DM.

• Do not ignore ANEMIA in your Diabetic Patients.

Cardiovascular Disease

and

Diabetic Nephropathy

Renal Osteodystrophy

• Almost all Patient with advanced CKD have Renal Bone disease.

• Vitamin D3 deficiency

• Hypocalcemia

• Hyperphosphatemia

• Hyperparathyroidism

• Phosphate Binders used for years are Calcium(PhosLo=Ca acetate)

Diabetic Nephropathy

• What to do?– prevent or slow progression of disease– decrease morbidity/ mortality– Prepare for RRT(renal replacement

Therapy

Vascular Access Placement

As early as possible and indicated

CKD and Diabetes

• Outcome(Morbididty and Mortality) is better if Patient wirh DN started on dilalysis earlier.

• Indication for Dialysis,• Diabetics- Cr. Cl < 15 cc/min.

• Non- Diabetics- Cr.Cl < 10cc/min

Transplantation

• Renal Transplant- graft survival> 90%- 1yr.• Simultaneous Kid./Pancrease(SKP) 92%• Pancease after Kid. TX(PAK) 93%

• Pancrease Transplant alone(PTA) 97%

• Islet Transplant- results encouraging