Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy

Donald E. Kohan, Hiddo J Lambers Heerspink, Blai Coll, Dennis Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-Rotter, Hirofumi Makino, Vlado Perkovic, Fan Fan Hou, Giuseppe Remuzzi, Sheldon W. Tobe, Robert Toto, Hans Henrik Parving, Dick De Zeeuw

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 patientswith type 2 diabetes, urine albumin/creatinine ratios of 300–3500 mg/g, and eGFRs of 30–75 ml/min per 1.73 m<sup>2</sup> 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 inHb. 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.

Original languageEnglish (US)
Pages (from-to)1568-1574
Number of pages7
JournalClinical Journal of the American Society of Nephrology
Volume10
Issue number9
DOIs
StatePublished - Sep 4 2015

Fingerprint

Albuminuria
Diabetic Nephropathies
Body Weight Changes
Hemoglobins
Type 2 Diabetes Mellitus
atrasentan
Brain Natriuretic Peptide
Glycosylated Hemoglobin A
Weight Gain
Albumins
Creatinine
Therapeutics
Biomarkers
Placebos
Urine

ASJC Scopus subject areas

  • Nephrology
  • Transplantation
  • Epidemiology
  • Critical Care and Intensive Care Medicine

Cite this

Kohan, D. E., Heerspink, H. J. L., Coll, B., Andress, D., Brennan, J. J., Kitzman, D. W., ... De Zeeuw, D. (2015). Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy. Clinical Journal of the American Society of Nephrology, 10(9), 1568-1574. https://doi.org/10.2215/CJN.00570115

Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy. / Kohan, Donald E.; Heerspink, Hiddo J Lambers; Coll, Blai; Andress, Dennis; Brennan, John J.; Kitzman, Dalane W.; Correa-Rotter, Ricardo; Makino, Hirofumi; Perkovic, Vlado; Hou, Fan Fan; Remuzzi, Giuseppe; Tobe, Sheldon W.; Toto, Robert; Parving, Hans Henrik; De Zeeuw, Dick.

In: Clinical Journal of the American Society of Nephrology, Vol. 10, No. 9, 04.09.2015, p. 1568-1574.

Research output: Contribution to journalArticle

Kohan, DE, Heerspink, HJL, Coll, B, Andress, D, Brennan, JJ, Kitzman, DW, Correa-Rotter, R, Makino, H, Perkovic, V, Hou, FF, Remuzzi, G, Tobe, SW, Toto, R, Parving, HH & De Zeeuw, D 2015, 'Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy', Clinical Journal of the American Society of Nephrology, vol. 10, no. 9, pp. 1568-1574. https://doi.org/10.2215/CJN.00570115
Kohan, Donald E. ; Heerspink, Hiddo J Lambers ; Coll, Blai ; Andress, Dennis ; Brennan, John J. ; Kitzman, Dalane W. ; Correa-Rotter, Ricardo ; Makino, Hirofumi ; Perkovic, Vlado ; Hou, Fan Fan ; Remuzzi, Giuseppe ; Tobe, Sheldon W. ; Toto, Robert ; Parving, Hans Henrik ; De Zeeuw, Dick. / Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy. In: Clinical Journal of the American Society of Nephrology. 2015 ; Vol. 10, No. 9. pp. 1568-1574.
@article{d437db187c9444368f5418610ae39ced,
title = "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 patientswith type 2 diabetes, urine albumin/creatinine ratios of 300–3500 mg/g, and eGFRs of 30–75 ml/min per 1.73 m2 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 inHb. 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.",
author = "Kohan, {Donald E.} and Heerspink, {Hiddo J Lambers} and Blai Coll and Dennis Andress and Brennan, {John J.} and Kitzman, {Dalane W.} and Ricardo Correa-Rotter and Hirofumi Makino and Vlado Perkovic and Hou, {Fan Fan} and Giuseppe Remuzzi and Tobe, {Sheldon W.} and Robert Toto and Parving, {Hans Henrik} and {De Zeeuw}, Dick",
year = "2015",
month = "9",
day = "4",
doi = "10.2215/CJN.00570115",
language = "English (US)",
volume = "10",
pages = "1568--1574",
journal = "Clinical Journal of the American Society of Nephrology",
issn = "1555-9041",
publisher = "American Society of Nephrology",
number = "9",

}

TY - JOUR

T1 - Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy

AU - Kohan, Donald E.

AU - Heerspink, Hiddo J Lambers

AU - Coll, Blai

AU - Andress, Dennis

AU - Brennan, John J.

AU - Kitzman, Dalane W.

AU - Correa-Rotter, Ricardo

AU - Makino, Hirofumi

AU - Perkovic, Vlado

AU - Hou, Fan Fan

AU - Remuzzi, Giuseppe

AU - Tobe, Sheldon W.

AU - Toto, Robert

AU - Parving, Hans Henrik

AU - De Zeeuw, Dick

PY - 2015/9/4

Y1 - 2015/9/4

N2 - 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 patientswith type 2 diabetes, urine albumin/creatinine ratios of 300–3500 mg/g, and eGFRs of 30–75 ml/min per 1.73 m2 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 inHb. 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.

AB - 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 patientswith type 2 diabetes, urine albumin/creatinine ratios of 300–3500 mg/g, and eGFRs of 30–75 ml/min per 1.73 m2 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 inHb. 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.

UR - http://www.scopus.com/inward/record.url?scp=84941205359&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941205359&partnerID=8YFLogxK

U2 - 10.2215/CJN.00570115

DO - 10.2215/CJN.00570115

M3 - Article

VL - 10

SP - 1568

EP - 1574

JO - Clinical Journal of the American Society of Nephrology

JF - Clinical Journal of the American Society of Nephrology

SN - 1555-9041

IS - 9

ER -