Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease

A Meta-Analysis of Patient-Level Data

  1. Tazeen H. Jafar, MD, MPH;
  2. Christopher H. Schmid, PhD;
  3. Marcia Landa, MA;
  4. Ioannis Giatras, MD;
  5. Robert Toto, MD;
  6. Giuseppe Remuzzi, MD;
  7. Giuseppe Maschio, MD;
  8. Barry M. Brenner, MD;
  9. Annelise Kamper, MD;
  10. Pietro Zucchelli, MD;
  11. Gavin Becker, MD;
  12. Andres Himmelmann, MD;
  13. Kym Bannister, MD;
  14. Paul Landais, MD;
  15. Shahnaz Shahinfar, MD;
  16. Paul E. de Jong, MD, PhD;
  17. Dick de Zeeuw, MD;
  18. Joseph Lau, MD;
  19. Andrew S. Levey, MD; and
  20. the ACE Inhibition in Progressive Renal Disease Study Group*
  1. From New England Medical Center, Tufts University School of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts; University of Texas at Southwestern, Dallas, Texas; Institute di Recherche, Farmacologiche “Mario Negri,” Bergamo, Ospedale Civile Maggiore, Verona, and Ospedale M. Malphigi, Bologna, Italy; Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; The Royal Melbourne Hospital, Melbourne, and Royal Adelaide Hospital, Adelaide, Australia; Sahlgrenska University Hospital, Göteborg, Sweden; Hôpital Necker, Paris, France; Merck Research Laboratories, West Point, Pennsylvania; and University of Groningen, Groningen, the Netherlands.

    Abstract

    Purpose: To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease.

    Data Sources: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease.

    Study Selection: Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997.

    Data Extraction: Data on 1860 nondiabetic patients were analyzed.

    Data Synthesis: Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 and P = 0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d.

    Conclusion: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.

    *For other members of the ACE Inhibition in Progressive Renal Disease Study Group, see Appendix 1.

    Article and Author Information

    • Presented in abstract form at the 31st Annual Meeting of the American Society of Nephrology, 25 October 1998, Philadelphia, Pennsylvania; the 15th Congress of the International Society of Nephrology, 5 May 1999, Buenos Aires, Argentina; and the 32nd Annual Meeting of the American Society of Nephrology, 5 and 7 November 1999, Miami, Florida.

    • Grant Support: By grant RO1 DK53869A from the National Institute of Diabetes and Digestive and Kidney Diseases (Dr. Levey); grants RO1 HS08532 (Drs. Schmid and Lau) and RO1 HS 10064 (Dr. Schmid) from the Agency for Healthcare Research and Quality; grant 1097-5 from the Dialysis Clinic, Inc., Paul Teschan Research Fund (Dr. Jafar); New England Medical Center-St. Elizabeth's Hospital Medical Center Clinical Research Fellowship Program, Boston, Massachusetts (Dr. Jafar); and an unrestricted grant from Merck Research Laboratories, West Point, Pennsylvania (Dr. Levey).

    • Requests for Single Reprints: Andrew S. Levey, MD, Division of Nephrology, New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111.

    • Current Author Addresses: Dr. Jafar: Department of Medicine, The Aga Khan University, Stadium Road, PO Box 3500, Karachi, Pakistan.

    • Dr. Schmid: Division of Clinical Care Research, Biostatistics Research Center, New England Medical Center, Box 63, 750 Washington Street, Boston, MA 02111.

    • Ms. Landa: Division of Clinical Care Research, New England Medical Center, Box 63, 750 Washington Street, Boston, MA 02111.

    • Dr. Giatras: 50 G. Papandreou Street, Nea Erythrea, 14671 Athens, Greece.

    • Dr. Toto: Dallas Nephrology Associates, 6010 Forest Park Road, Suite 100, Dallas, TX 75235.

    • Dr. Remuzzi: Institute di Recherche, Farmacologiche “Mario Negri,” Via Gavezzeni 11, 24125 Bergamo, Italy.

    • Dr. Maschio: Division Nefrologia, Ospedale Civile Maggiore, 37126 Verona, Italy.

    • Dr. Brenner: Renal Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02111.

    • Dr. Kamper: Department of Nephrology, Herlev Hospital, University of Copenhagen, DK 2730 Herlev, Denmark.

    • Dr. Zucchelli: Department of Nephrology, Ospedale M. Malphigi, Via P. Palagi 9, Bologna, Italy.

    • Dr. Becker: Department of Nephrology, The Royal Melbourne Hospital, Grattan Street, Melbourne, Victoria 3050, Australia.

    • Dr. Himmelmann: Department of Clinical Pharmacology, Sahlgrenska University Hospital, S41345 Göteborg, Sweden.

    • Dr. Bannister: Renal Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.

    • Dr. Landais: Service d'Informatique et de Statistiques Médicales, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France.

    • Dr. Shahinfar: Merck Research Laboratories, 10 Sentry Parkway, Walton and Stenton Avenue, BL-1, Blue Bell, PA 19422.

    • Drs. de Jong and de Zeeuw: University of Groningen, Oostersingel 59, 9713 EZ Groningen, the Netherlands.

    • Dr. Lau: Division of Clinical Care Research, New England Medical Center, Box 827, 750 Washington Street, Boston, MA 02111.

    • Dr. Levey: Division of Nephrology, New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111.

    • Author Contributions: Conception and design: C.H. Schmid, I. Giatras, R. Toto, G. Remuzzi, G. Maschio, B.M. Brenner, A. Kamper, P. Zucchelli, G. Becker, A. Himmelmann, K. Bannister, P. Landais, S. Shahinfar, P.E. de Jong, D. de Zeeuw, J. Lau, A.S. Levey.

    • Analysis and interpretation of the data: T.H. Jafar, C.H. Schmid, M. Landa, J. Lau, A.S. Levey.

    • Drafting of the article: T.H. Jafar, C.H. Schmid, A.S. Levey.

    • Critical revision of the article for important intellectual content: T.H. Jafar, C.H. Schmid, M. Landa, R. Toto, P.E. de Jong, A.S. Levey.

    • Final approval of the article: T.H. Jafar, C.H. Schmid, M. Landa, I. Giatras, R. Toto, G. Remuzzi, G. Maschio, B.M. Brenner, A. Kamper, P. Zucchelli, G. Becker, A. Himmelmann, K. Bannister, P. Landais, S. Shahinfar, P.E. de Jong, D. de Zeeuw, J. Lau, A.S. Levey.

    • Provision of study materials or patients: R. Toto, G. Remuzzi, G. Maschio, B.M. Brenner, A. Kamper, P. Zucchelli, G. Becker, A. Himmelmann, K. Bannister, P. Landais, S. Shahinfar, P.E. de Jong, D. de Zeeuw, A.S. Levey.

    • Statistical expertise: C.H. Schmid, J. Lau.

    • Obtaining of funding: T.H. Jafar, C.H. Schmid, S. Shahinfar, J. Lau, A.S. Levey.

    • Administrative, technical, or logistic support: C.H. Schmid, M. Landa, A.S. Levey.

    • Collection and assembly of data: T.H. Jafar, M. Landa, I. Giatras, A.S. Levey.

    Summary for Patients

    • Summaries for Patients:Using a Type of Blood Pressure Medicine, Angiotensin-Converting Enzyme Inhibitors, To Prevent Worsening of Kidney Disease Unrelated to Diabetes Ann Intern Med July 17, 2001 135:S21
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    1. Ann Intern Med July 17, 2001 vol. 135 no. 2 73-87
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