1. Renin-Angiotensin-Aldosterone System and Nephropathy
Issa Kawalit,MD
Arab Renal Care Group

33. Development of Nephropathy
Jamison, Wilkinson. Nephrology, 1997.

34. Renin-Angiotensin System
AngiotensinogenAng 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

37. 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

39. 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:
Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113:
Ref: Agodoa L, et al. JAMA. 2001;285(21):
Non-DHPCCB reduces proteinuria when a DHPCCB produces no change or increase in proteinuria
Ref: Smith AC, et al. Kidney Int. 1998;54:
Ref: Kloke H, et al. Kidney Int. 1998; 53:
Comparison of Anti-Hypertensive Regimens on Proteinuria
Calcium channel blockers (CCBs) are effective anti-hypertensive drugs, but their safety in patients with proteinuric renal diseases and renal insufficiency may be questioned because of reported untoward effects on urinary protein excretion. CCBs are known to have differential effects on both changes in proteinuria as well as progression of diabetic nephropathy. For patients with proteinuria, the dihydropyridine CCBs do not lower proteinuria despite a reduction of blood pressure. Studies on the effects on the course of renal function are limited, however, the available data do suggest that this class of CCBs may be less advantageous than other antihypertensive drugs, thus arguing against the use of these agents as first-line drugs in patients with proteinuric renal diseases. Information on the effects of the non-dihydropyridine CCBs is limited. Data support the hypothesis that CCBs that provide sustained reductions in proteinuria do so, in part, by improving glomerular size permselectivity. Although the data suggest that these classes of CCBs might be more beneficial, more studies are needed, particularly in patients with non-diabetic renal diseases.
References:
Mimran A, Insua A, Ribstein J, Bringer J, Monnier L. Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care. 1988;11(10):
Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med ;113(12):
Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int. 1998;54(3):

45. IDNT Proportion of Patients with the Primary Composite Endpoint*
P=0.02 for irbesartan compared to placebo
Proportion with primary endpoint
*Composite of a doubling of serum creatinine, end stage renal disease, or death 6 12 18 24 30 36 42 48 54
Months of Follow-up
Irbesartan (n)
579
555
528
496
400
304
216
146 65
Amlodipine (n)
565
542
508
474
385
287
187
128 46
Placebo (n)
568
551
512
471
401
280
190
122 53
Lewis EJ, et al. N Engl J Med. 2001;345(12):
©2001 Massachusetts Medical Society. All rights reserved.

50. Landmark ACE Inhibitor Trials in Diabetics
Study
Drug N
Dosing
Study years
Endpoint
P-value
Lewis
Captopril
409
25 mg tid
~ 3
Doubling of serum creatinine
P=0.007
Lebovitz
Enalapri l
165
5-40
mg qd
Correlation of MAP w/ rate of change in GFR
P=0.026
ABCD Trial
Enalapril
470 5
24-hr creatinine clearance NS
Landmark ACE Inhibitor Trials in Diabetics
Until recently, reductions in proteinuria had not been clearly associated with renal benefit. There are now numerous long-term clinical trials in patients who have lost >35% of their renal function, with or without diabetes, demonstrating that reductions in proteinuria of >30% below baseline correlate with marked reductions in renal disease progression. The 3 landmark trials in diabetes are shown on this slide.
References:
Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338(10):
Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(suppl2):B54-64.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):
Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et al. Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int Suppl. 1994;45:S150-S155.
ABCD = Appropriate Blood Pressure Control in Diabetes Trial
Lewis EJ, et al. N Engl J Med. 1993;329(20):
Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155.
Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.

52. ACE inhibitors (ACE-I)
ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy
Study
Year
Conclusions 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
1993
In Type I diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.
REIN
1997
In non-diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.
MicroHOPE
2000
ACE-I reduced progression of proteinuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria.
AASK
2001
ACE-I was superior to amlodipine in reducing proteinuria among non-diabetic African Americans with hypertension and kidney disease.
ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy
With respect to renoprotection, both diabetic and non-diabetic patients benefit when the actions of angiotensin II are inhibited. ACE inhibition reduces the risk of doubling of serum creatinine and the combined endpoint of end stage renal disease (ESRD) and death. There is also decreased progression of proteinuria from normoalbuminuria to microalbuminuria, and from microalbuminuria to macroalbuminuria. Furthermore, it appears that the ability to prescribe drugs that inhibit the actions of angiotensin II yields superior outcomes compared to other drugs that act through calcium channel blockade or through beta blockade.
References:
Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001; 285(21):
Bjorck S, Mulec H, Johnsen SA, Norden G, Aurell M. Renal protective effect of enalapril in diabetic nephropathy. BMJ. 1992;304(6823):
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet Jan 22;355(9200):253-9.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):
Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):

53. Clinical Trials and Renal Outcomes Based on Proteinuria Reduction
Increased 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

54. 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 years
Barnett AH et.al N Engl J Med 2004;351:

55. Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy-RESULTS
Baseline GFR 91 ml/min
Barnett AH et.al N Engl J Med 2004;351:

70. 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

71. 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

72. Renoprotective Effect of Irbesartan
-128 patients
excluded for medical reasons
-643 patients
albuminuria/BP out of range
-18 patients
no albuminuria
Placebo
N=201
Irbesartan 150 mg QD
N=195
Irbesartan 300 mg QD
N=194
590 patients left for randomization
1469 Patients
3 wk screening process

73. 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)

74. Renoprotective Effect of Irbesartan
Results

75. Renoprotective Effect of Irbesartan
Irb 300mg vs. Placebo
ARR/ABI
NNT
Overt Nephropathy
9.7% 10
Normal. of Albuminuria
13.1% 8

76. Renoprotective Effect of Irbesartan
Kaplan-Meier Curve showing the Incidence of Progression to Diabetic Nephropathy
Parving HH, et al. NEJM. Sept., 2001

77. 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

78. 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

79. 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 mg/dl (women) and mg/dl (men)

80. IDNT Primary Endpoint: Secondary Endpoint: Doubling SCr ESRD
Death (any cause)
Secondary Endpoint:
Death (CV causes) MI
CHF hospitalization
CVA
Above ankle amputation

81. IDNT - Results Endpoint Irbesartan (N=579) Amlodipine (N=567) Placebo
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%)
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

82. Irbesartan vs. Amlodipine
IDNT - Results
Irbesartan vs. Amlodipine
Irbesartan vs. Placebo
Endpoint
ARR
NNT
P value
Primary Outcome
8.5% 12
0.006
6.4% 16
0.02
Double Creatinine
0.003
6.8% 15
<0.001
ESRD
4.1% 24
0.07
3.6% 28
Death
N/A
N/S
SecondaryOutcome

83. 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

84. 27% of patients – evenly distributed
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%)

85. 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)

86. 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)

87. 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

88. 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 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

89. RENALL Primary Endpoint: Secondary Endpoint: Doubling of SCr ESRD
Death
Secondary Endpoint: MI
Stroke
Hospitalization for CHF or USA
Vascular intervention
Death from CV cause

90. 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
SecondaryOutcome
247 (32.9%)
268 (35.2%)
0.26
1st admission–CHF
89 (11.9%)
127 (16.7%)
0.005
4.8% 21 MI
50 (6.7%)
68 (8.9%)
0.08

91. 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

92. 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

93. 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

94. ACE I versus ARBs Patient Population: Males and females > age 17
Average age 50’s in all groups
Type II Diabetes
AER μg/min, GFR > 60 ml/min
SBP<160 mmHg
Excluded-brittle DM, hypotension, DBP>95

95. ACE I versus ARBs

96. ACE I versus ARBs Results: Primary Endpoint- Overt Nephropathy
Secondary Endpoint- Change in GFR
Most common adverse experience- cough (captopril)
Endpoint
Placebo
N=31
Captopril 25mg
N=29
Valsartan 80mg
Valsartan160mg
Withdrawn
7 (22.6%)
4 (13.8%)
1 (3.2%)
Nephropathy
3 (10.7%)
1 (3.4%)
1 (3.7%)
Change in GFR
No signif ∆
Adverse exper.
24 (82.8%)
28 (96.6%)
25 (80.6%)
27 (87.1%)

97. 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
Valsartan 160 mg vs Captopril
0.503
Captopril vs Placebo
0.009
7.3%

98. 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

99. ACE I versus ARBs Limitations: Small study population size
Differences among the groups
Lower AER initially in the captopril group
Short follow-up period

100. 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

101. Dickstein. Current Controlled Trials in Cardiovascular Medicine. 2001.
Final Conclusions
ARBs in heart failure:
ELITE II and Val-HeFT
Ongoing trials
Dickstein. Current Controlled Trials in Cardiovascular Medicine

102. 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

103. Special Thanks to: Dr. Pirouz Daeihagh Dr. Paul J. Laurienti
Acknowledgments
Special Thanks to: Dr. Pirouz Daeihagh Dr. Paul J. Laurienti