First-Morning Void May Be Best Predictor of Renal Events in Diabetic Nephropathy

July 22, 2010 — Albumin-to-creatinine ratio (ACR) in a first-morning void may be the best predictor of renal events in patients with type 2 diabetes and kidney disease, according to the results of the Reduction in Endpoints in Non Insulin Dependent Diabetes Mellitus with the Angiotensin-II Antagonist Losartan (RENAAL) trial reported Online First July 15 in the Journal of the American Society of Nephrology.

"From a clinical point of view, these results are very important, because they imply that collection of first morning voids, which is clearly more convenient than collecting a 24-hour urine, can be used for assessment of proteinuria," said lead author Hiddo J. Lambers Heerspink, PharmD, PhD, from University Medical Center Groningen, in Groningen, the Netherlands, in a news release.

With a study sample of 701 participants with type 2 diabetes and nephropathy enrolled in the RENAAL trial, the goal of the study was to compare prediction of renal events by urinary protein excretion (UPE) and urinary albumin excretion (UAE) from a 24-hour urine collection vs urinary albumin concentration (UAC) and ACR from a first-morning void. Time to a doubling of serum creatinine or end-stage renal disease was the main study endpoint.

There were 202 renal events during follow-up. For each 1-SD increase in the log-transformed measures, the hazard ratios (HRs) for the risk for a renal outcome were 3.16 (95% confidence interval [CI], 2.60 - 3.86) for UAE, 3.02 (95% CI, 2.53 - 3.62) for UPE, 3.23 (95% CI, 2.67 - 3.91) for UAC, and 4.36 (95% CI, 3.50 - 5.45) for ACR. Compared with the other measures, the area under the receiver operating characteristic curve was significantly higher for ACR.

"[F]or predicting renal disease progression in patients with type 2 diabetes and nephropathy, collecting first morning void urine samples and measuring the albumin:creatinine ratio appear to be superior when compared with measuring 24-hour urinary albumin excretion," the study authors write. "These results are clinically important because they imply that collection of first morning voids, which is clearly more convenient than collecting a 24-hour urine, can be used for assessment of proteinuria."

Limitations of this study include inability to directly apply the results to individuals without diabetes or nephropathy. In addition, total protein concentrations were not measured in a first-morning void urine sample, precluding comparison between protein-to-creatinine ratios and ACRs derived from a first-morning void.

In an accompanying editorial, Bryan Kestenbaum, MD, and Ian de Boer, MD, from the University of Washington in Seattle, discuss the implications of this study for clinical practice and for clinical research.

"Given data from this study and the considerable patient effort required for a 24-hour urine collection, we agree with the authors that the first morning albumin:creatinine ratio is in general the logical choice for quantifying proteinuria in clinical practice," they write. "First, urine ACR represents more than simply proteinuria, and associations of urine ACR with disease outcomes should be interpreted in the context of dual contributions of urine albumin excretion and urine creatinine. Second, this study [begs] the questions, 'Why is low urine creatinine excretion associated with adverse kidney and cardiovascular disease outcomes independent of standard measures of body composition?' 'Does a low urine creatinine concentration reflect low muscle mass, low muscle quality, or both?' 'Is a low urine creatinine concentration a modifiable therapeutic target?'"

The RENAAL study was sponsored by Merck & Co, Inc. One of the study authors is an employee of Merck, and 4 other study authors are members of the RENAAL Steering Committee and have received grants from Merck. The editorialists have disclosed no relevant financial relationships.

J Am Soc Nephrol. Published online July 15, 2010.