Renin-Angiotensin-Aldosterone System and Nephropathy

Issa Kawalit,MD

Arab Renal Care Group

Development of Nephropathy

Jamison, Wilkinson. Nephrology, 1997.

Renin-Angiotensin System

AngiotensinogenAng I Ang II Ang Receptor renin ACE binds to

• Angiotensinogen produced and released by the liver

• Renin produced by JG cells in response to glomerular hypoperfusion or changes in lytes

• ACE produced mainly in pulmonary vasculature endothelium

• Angiotensin II binds to its specific receptors in heart, brain, adrenal

glands, kidneys, and vascular smooth muscle wall

CVD Risk Factors

Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria Estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD

(men under age 55 or women under age 65)

Chobanian A et.al Hypertension, Dec. 2003

Comparison of Anti-Hypertensive Regimens on

Proteinuria With similar reductions of blood

pressure…

• Dihydropyridine calcium channel blockers (DHPCCB) increase proteinuria− Ref: Mimran A, et al. Diabetes Care. 1988;11:850-853.− Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113:987-

988.− Ref: Agodoa L, et al. JAMA. 2001;285(21):2719-2728.

• Non-DHPCCB reduces proteinuria when a DHPCCB produces no change or increase in proteinuria– Ref: Smith AC, et al. Kidney Int. 1998;54:889-896.– Ref: Kloke H, et al. Kidney Int. 1998; 53:1559-1573.

IDNT Proportion of Patients with the Primary Composite Endpoint*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Pro

port

ion

wit

hp

rim

ary

en

dp

oin

t

0 6 12 18 24 30 36 42 48 54

579 555 528 496 400 304 216 146 65

565 542 508 474 385 287 187 128 46

568 551 512 471 401 280 190 122 53

Irbesartan (n)

Amlodipine (n)

Placebo (n)

Months of Follow-up

*Composite of a doubling of serum creatinine, end stage renal disease, or death

P=0.02 for irbesartan compared to placebo

Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.©2001 Massachusetts Medical Society. All rights reserved.

Landmark ACE Inhibitor Trials in Diabetics

Study Drug N Dosing Study years

Endpoint P-value

Lewis Captopril

409 25 mg tid ~ 3Doubling of

serum creatinine

P=0.007

Lebovitz

Enalapril 165

5-40 mg qd

~ 3

Correlation of MAP w/ rate of change in

GFR

P=0.026

ABCD Trial

Enalapril

4705-40 mg qd

524-hr

creatinine clearance

NS

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155.Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.

ABCD = Appropriate Blood Pressure Control in Diabetes Trial

ACE-I Provides Greater Renoprotection

Than Non-ACE-I in Patients with Diabetic and Non-Diabetic

NephropathyStudy YearConclusions about

ACE inhibitors (ACE-I)

Bjork et al 1992 ACE-I reduced both the rate of decline in GFR and the amount of albuminuria.

Lewis et al 1993In Type I diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.

REIN 1997In non-diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.

MicroHOPE 2000ACE-I reduced progression of proteinuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria.

AASK 2001ACE-I was superior to amlodipine in reducing proteinuria among non-diabetic African Americans with hypertension and kidney disease.

Clinical Trials and Renal Outcomes Based on

Proteinuria ReductionIncreased Time to Dialysis(30-35% proteinuria reduction)

• Captopril Trial-N Engl J Med, 1993

• AASK Trial-JAMA, 2001

• RENAAL-N Engl J Med, 2001

• IDNT-N Engl J Med, 2001

• COOPERATE-Lancet, 2003

No Change in Time to Dialysis

(NO proteinuria reduction)

DHPCCB arm-IDNT

DHPCCB arm-AASK

Hart P & Bakris GL Managing Hypertension in the Diabetic Patient. IN: Egan BM, Basile JN, and Lackland DT (eds.) Hot Topics in Hypertension Hanley and Belfus, Philadelphia, 2004, pp.249-252.

Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2

Diabetes and Nephropathy

• DETAIL, a prospective, multicenter trial randomized 250 patients with type 2 diabetes, hypertension (BP <180/95 mm Hg), and evidence of early nephropathy (GFR >70 mL/min/1.73 m2) to either telmisartan or enalapril.

Followed for 5 yearsBarnett AH et.al N Engl J Med 2004;351:1952-1961.

Barnett AH et.al N Engl J Med 2004;351:1952-1961.

Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2

Diabetes and Nephropathy-RESULTS

Baseline GFR 91 ml/min

Renoprotective Effect of Irbesartan

Design:• randomized, double-blind, placebo

controlled • 96 centers worldwide • Followed pts for 2 yrs • Parving HH, et al. The Effect of Irbesartan on the Development of

Diabetic Nephropathy in Patients with Type II Diabetes. NEJM. 2001.

Renoprotective Effect of Irbesartan

Patient Population:

• Men and women age 30-70

• Type II diabetes

• Hypertension- 2 of 3 blood pressure readings of SBP>135 and/or DBP>85 in one week

• Persistent microalbuminuria- AER between 2 and 200 μg/min in 2 of 3 overnight urine specimens

• SCr<1.6 mg/dl in men, <1.2 mg/dl in women

• Exclusion of patients with nondiabetic renal disease, cancer, life expectancy<2yrs, or indication for ACE I

Renoprotective Effect of Irbesartan

-128 patientsexcluded for medical reasons

-643 patientsalbuminuria/BP out of range

-18 patientsno albuminuria

PlaceboN=201

Irbesartan 150 mg QDN=195

Irbesartan 300 mg QDN=194

590 patients left for randomization

1469 Patients3 wk screening process

Renoprotective Effect of Irbesartan

• Primary Endpoint: progression to overt nephropathy (AER>200 μg/min and 30% higher than baseline on 2 consecutive visits)

• Secondary Endpoint: change in level of albuminuria, change in creatinine clearance, or normalization of albuminuria (to <20 μg/min)

Renoprotective Effect of Irbesartan

Results

End Point Placebo (N=201)

Irbesartan 150 mg daily (N=195)

Irbesartan 300 mg daily (N=194)

Nephropathy 30 (14.9%) 19 (9.7%) (P=0.08) 10 (5.2%) (P<0.001)

Change in albuminuria -2% (P<0.001) -24% -38%

Decline in Cr Clearance During initial 3 months

3 months – 1 year

0.9 0.1

1.0 0.2

1.9 0.2

Normal. of albuminuria 42 (20.9%) 47 (24.1%) 66 (34.0%) (P=0.006)

Nonfatal CV events 18 (8.7%) 9 (4.5%)

Renoprotective Effect of Irbesartan

Irb 300mg vs. Placebo ARR/ABI NNT

Overt Nephropathy 9.7% 10

Normal. of Albuminuria 13.1% 8

Renoprotective Effect of Irbesartan

Kaplan-Meier Curve showing the Incidence of

Progression to Diabetic Nephropathy

Parving HH, et al. NEJM. Sept., 2001

Renoprotective Effect of Irbesartan

Conclusions:

• Irbesartan 300 mg QD reduced risk of progressing to overt nephropathy and greater reduction in AER

• Irbesartan 300 mg QD led to normalization of albuminuria in more patients

• No significant difference in decline in creatinine clearance between the 3 groups

Irbesartan Diabetic Nephropathy Trial (IDNT)

Design:

• Randomized, double-blind, placebo controlled

• 210 clinical centers

• Mean duration of F/U 2.6 years

• 1715 patients

• Lewis EJ, et al. Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy due to Type II Diabetes. NEJM. 2001

IDNT

Patient Population:

• Type II diabetic men and women age 30-70

• Hypertension SBP>135 and/or DBP>85

• Proteinuria >900 mg/24 hrs

• Serum creatinine 1.0-3.0 mg/dl (women) and 1.2-3.0 mg/dl (men)

IDNT

Primary Endpoint:

• Doubling SCr

• ESRD

• Death (any cause)

Secondary Endpoint:

• Death (CV causes)

• MI

• CHF hospitalization

• CVA

• Above ankle amputation

IDNT - Results

Endpoint Irbesartan(N=579)

Amlodipine(N=567)

Placebo(N=569)

Primary Outcome 189 (32.6%) 233 (41.1%) 222 (39.0%)

Doubling of SCr 98 (16.9%) 144 (25.4%) 135 (23.7%)

ESRD 82 (14.2%) 104 (18.3%) 101 (17.8%)

Death (any cause) 87 (15.0%) 83 (14.6%) 93 (16.3%)

SecondaryOutcome 138 (23.8%) 128 (22.6%) 144 (25.3%)

Lost to F/U or noncompliant

7 (1.2%) 10 (1.8%) 10 (1.8%)

Completed study w/o 1º outcome

385 (66.5%) 332 (58.6%) 343 (60.3%)

Mean duration-F/U 952 days 924 days 921 days

Mean BP 140/70 141/77 144/80

IDNT - Results

Irbesartan vs. Amlodipine Irbesartan vs. Placebo

Endpoint ARR NNT P value ARR NNT P value

Primary Outcome 8.5% 12 0.006 6.4% 16 0.02

Double Creatinine 8.5% 12 0.003 6.8% 15 <0.001

ESRD 4.1% 24 0.07 3.6% 28 0.07

Death N/A N/A N/S N/A N/A N/S

SecondaryOutcome N/A N/A N/S N/A N/A N/S

IDNT - Results

Patients in Irbesartan group had:

• 23% lower rate of CHF than placebo

• Increase in SCr 23% slower than placebo and 21% slower than amlodipine

• 33% reduction of proteinuria compared to 6% in amlodipine group and 10% in placebo

IDNT - Results

Adverse Events:

Overall, irbesartan group had lower rate of adverse events/1000 days (P=0.002)

Irbesartan Amlodipine Placebo

D/C Study Drug

27% of patients – evenly distributed

Hyper-kalemia

11 (1.9%)P=0.02

3 (0.5%) 2 (0.4%)

IDNT -Conclusions

• Irbesartan assoc. with slowing of progression to nephropathy (decreased time to doubling of creatinine)

• Results independent of blood pressure

• Irbesartan assoc. with 23% lower rate of CHF

• Lower adverse events in irbesartan group (but higher rate of hyperkalemia)

IDNT - Limitations

• Bristol Myer Squibb performed data handling

• Amlodipine used as comparison instead of diltiazem or verapamil

• Patients in placebo group required more non-study antihypertensives, so more likely to receive B-blockers (United Kingdom Prospective Diabetic Study)

Angiotensin II Antagonist Losartan Study (RENAAL)

Design:

• Randomized, double-blind, placebo controlled

• 250 centers in 28 countries

• Followed 1513 patients for a mean of 3.4 years

• Brenner BM, et al. Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type II Diabetes and Nephropathy. NEJM. 2001

RENALL

Patient Population:

• Men and women age 31-70

• Type II diabetes

• Nephropathy (alb/Cr ratio > 300 or AER>0.5 g/day on 24° urine)

• SCr 1.3-3.0 mg/dl

• Excluded-type I DM, nondiabetic renal dz, MI or CABG in last month, CVA or PTCA w/in 6 months, TIA in last year, or CHF

RENALL

Primary Endpoint:

• Doubling of SCr

• ESRD

• Death

Secondary Endpoint:

• MI

• Stroke

• Hospitalization for CHF or USA

• Vascular intervention

• Death from CV cause

RENALL - Results

Endpoint Losartan(N=751)

Placebo(N=762)

P value ARR NNT

Primary Outcome 327 (43.5%) 359 (47.1%) 0.02 3.6% 28

Doubling SCr 162 (21.6%) 198 (26.9%) 0.006 4.4% 23

ESRD 147 (19.6%) 194 (25.5%) 0.002 5.9% 17

Death 158 (21.0%) 155 (20.3%) 0.88 N/A N/A

SecondaryOutcome 247 (32.9%) 268 (35.2%) 0.26 N/A N/A

1st admission–CHF 89 (11.9%) 127 (16.7%) 0.005 4.8% 21

MI 50 (6.7%) 68 (8.9%) 0.08 N/A N/A

RENALL – Results

Patients in the losartan group had a reduction in proteinuria of 35%, while the patients in the placebo group had an increase in proteinuria (P=<0.001)

Brenner et al. NEJM. 2001.

RENALL – Conclusions

• Losartan has renoprotective effects by reducing risk of doubling creatinine AND by reducing progression to ESRD

• Losartan reduces episodes of CHF

• Effects reported as independent of blood pressure

ACE I versus ARBs

Design:

• Randomized, double-blind, placebo controlled

• 4 centers in Canada

• 122 patients followed for 52 weeks

• Muirhead N, et al. The Effects of Valsartan and Captopril on Reducing Microalbuminuria in Patients with Type II Diabetes: A Placebo Controlled Trial. Current Therapeutic Research. 1999.

ACE I versus ARBs

Patient Population:

• Males and females > age 17

• Average age 50’s in all groups

• Type II Diabetes

• AER 20-300 μg/min, GFR > 60 ml/min

• SBP<160 mmHg

• Excluded-brittle DM, hypotension, DBP>95

ACE I versus ARBs

P laceb oN = 3 1

F em ale = 3 (9 .7 % )A E R = 6 4 .0 m g/m in

C ap to p ril 2 5 m g tidN = 2 9

F em ale = 8 (2 7 .6 % )A E R = 4 0 .9 m g/m in

V alsartan 8 0 m g Q DN = 3 1

F em ale = 9 (2 9 .0 % )A E R = 6 0 .5 m g/m in

V alsartan 1 6 0 m g Q DN = 3 1

F em ale = 1 3 (4 1 .9 % )A E R = 5 8 .1 m g/m in

To tal P atien tsN = 1 2 2

ACE I versus ARBs

Results: Primary Endpoint- Overt Nephropathy

Secondary Endpoint- Change in GFR

Most common adverse experience- cough (captopril)

Endpoint PlaceboN=31

Captopril 25mgN=29

Valsartan 80mgN=31

Valsartan160mgN=31

Withdrawn 7 (22.6%) 4 (13.8%) 7 (22.6%) 1 (3.2%)

Nephropathy 3 (10.7%) 1 (3.4%) 1 (3.7%) 0

Change in GFR No signif ∆ No signif ∆ No signif ∆ No signif ∆

Adverse exper. 24 (82.8%) 28 (96.6%) 25 (80.6%) 27 (87.1%)

ACE I versus ARBs

1º Endpoint: Nephropathy P value ARR NNT

Valsartan 80 mg vs Placebo 0.018 7.0% 14

Valsartan 160 mg vs Placebo 0.043 10.7% 9

Valsartan 80 mg vs Captopril 0.831 N/A N/A

Valsartan 160 mg vs Captopril 0.503 N/A N/A

Captopril vs Placebo 0.009 7.3% 14

ACE I versus ARBs

Conclusions:

• Patients in valsartan and captopril groups less likely to reach endpoint

• No statistically significant difference between the valsartan and captopril groups

ACE I versus ARBs

Limitations:

• Small study population size

• Differences among the groups

• Lower AER initially in the captopril group

• Short follow-up period

Final Conclusions

Need for more evidence:

• Unfortunate that these studies didn’t have ACE I as a treatment arm

• HOPE and MICRO-HOPE show that ACE inhibitors reduce risk of CV events in patients with diabetes and one other risk factor for CV disease

Final Conclusions

ARBs in heart failure:• ELITE II and Val-HeFT• Ongoing trials

Dickstein. Current Controlled Trials in Cardiovascular Medicine. 2001.

Final Conclusions

• ARBs are renoprotective in patients with diabetes

• ARBs reduce risk of progression to overt nephropathy, rise in creatinine and ESRD

• More evidence comparing ARBs and ACE I, and ARBs in diabetic patients at risk for CV disease is needed

• ACE inhibitors still first line

Acknowledgments

Special Thanks to:

Dr. Pirouz Daeihagh

Dr. Paul J. Laurienti