Received May 9, 2006
Accepted on February 26, 2007

BASIC SCIENCE ARTICLES: Pathophysiology of Renal Disease and Progression

Albuminuria Is a Target for Renoprotective Therapy Independent from Blood Pressure in Patients with Type 2 Diabetic Nephropathy: Post Hoc Analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Trial

Wouter B.A. Eijkelkamp ^*, Zhongxin Zhang , Giuseppe Remuzzi , Hans-Henrik Parving , Mark E. Cooper ^||, William F. Keane , Shahnaz Shahinfar , Gilbert W. Gleim , Matthew R. Weir ^¶, Barry M. Brenner ^**, and Dick de Zeeuw ^*1

*Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Merck Research Laboratories, Merck & Co., Whitehouse Station, New Jersey; Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Steno Diabetes Center, Gentofte, and Faculty of Health Science, Aarhus University, Aarhus, Denmark; ||Diabetes & Metabolism Division, Baker Medical Research Institute, Melbourne, Australia; ¶Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; and **Department of Medicine, Renal Division, Brigham and Women’s Hospital, and Harvard School of Medicine, Boston, Massachusetts

¹ To whom correspondence should be addressed. E-mail: d.de.zeeuw{at}med.umcg.nl.

	Abstract

Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or albuminuria reduction was associated with a lower risk for ESRD, whereas combined SBP and albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger albuminuria reduction. A lower residual level of albuminuria was also associated with lower ESRD risk. In conclusion, changes in albuminuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on albuminuria reduction. The ESRD risk also showed dependence on the residual level of albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and albuminuria reduction.