Predictors of Atrasentan-Associated Fluid Retention and Change in Albuminuria in Patients with Diabetic Nephropathy

Abstract

Background and objectives: Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs.

Design, setting, participants, & measurements: A post hoc analysis was conducted of the phase IIb atrasentan trials assessing albuminuria reduction in 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) who were randomly assigned to receive placebo (n=50) or atrasentan 0.75 mg/d (n=78) or 1.25 mg/d (n=83) for 12 weeks. Changes in body weight and hemoglobin (Hb) after 2 weeks of treatment were used as surrogate markers of fluid retention.

Results: Baseline predictors of weight gain after 2 weeks of atrasentan treatment were higher atrasentan dose, lower eGFR, higher glycated hemoglobin, higher systolic BP, and lower homeostatic metabolic assessment product. Higher atrasentan dose and lower eGFR also predicted decreases in Hb. There were no changes in B-type natriuretic peptide. There was no correlation between reduction in albuminuria after 2 weeks of atrasentan treatment and changes in body weight or Hb.

Conclusions: In the Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With Atrasentan/JAPAN trials, atrasentan-associated fluid retention was more likely in patients with diabetes and nephropathy who had lower eGFR or received a higher dose of atrasentan. Finding that albuminuria reduction was not associated with changes in body weight and Hb suggests that the albuminuria-reducing efficacy of atrasentan is not impaired by fluid retention.

Keywords: albuminuria; atrasentan; diabetic nephropathy.

Copyright © 2015 by the American Society of Nephrology.

Figures

Figure 1.

Distribution of changes in body weight and hemoglobin in subjects taking placebo, atrasentan 0.75 mg/d, or atrasentan 1.25 mg/d. Panel (A) shows changes in body weight and panel (B) shows changes in hemoglobin. Whiskers indicate all data points within 1.5 interquartile range of the upper and lower quartile range.

Figure 2.

Changes in BW and Hb in UACR responders (defined as ≥30% reduction in UACR at week 2) and UACR nonresponders (<30% reduction in UACR at week 2) to placebo, atrasentan 0.75 mg/d, or atrasentan 1.25 mg/d. Error bars represent the SD. BW, body weight; Hb, hemoglobin; UACR, urinary albumin to creatinine ratio.