Importance of Baseline Distribution of Proteinuria in Renal Outcomes Trials: Lessons from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study

Abstract

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria <2000 mg/g or >2000 mg/g, within the higher proteinuria stratum (>2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

Effects of Pitavastatin (LIVALO Tablet) on the Estimated Glomerular Filtration Rate (eGFR) in Hypercholesterolemic Patients with Chronic Kidney Disease

“…Proteinuria is known as a major factor related to the decline of eGFR and the progression of renal disease 14,24) ; therefore, it is understandable why patients with proteinuria showed a less pronounced effect of pitavastatin in increasing the eGFR in this study. Diabetes was identified as a factor attenuating the elevation of eGFR during pitavastatin treatment with borderline significance (p 0.0512).…”

Role of Remission Clinics in the Longitudinal Treatment of CKD

“…26 This is consistent with finding that in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), losartan decreased by almost 50% the risk for ESRD in those with baseline proteinuria/creatininuria ratios Ͻ2000 mg/g but had no significant effect in those with more severe proteinuria. 33 These findings combined with consistent evidence from several trials 24,34 -36 of a remarkable renoprotective effect of RAS inhibitor therapy in earlier stages of renal disease should be taken to emphasize the importance of early intervention in patients with type 2 diabetes.…”

Impact of the Preintervention Rate of Renal Function Decline on Outcome of Renoprotective Intervention

“…By randomizing, it is presumed to achieve an equal distribution of renal risk markers over the treatment arms; however, apparently, such an equal distribution is not always obtained: In the RENAAL study, for instance, there was a baseline difference in proteinuria that was calculated to affect its outcome (12). Our data suggest that inclusion of data on preintervention rate of renal function decline may serve to obtain groups with a comparable renal risk during intervention, thereby increasing the validity of the study.…”