Predictors of Atrasentan-Associated Fluid Retention and Change in Albuminuria in Patients with Diabetic Nephropathy.
+10 authors
Journal: 2016/June - Clinical Journal of the American Society of Nephrology
ISSN: 1555-905X
Abstract:
OBJECTIVE
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.
METHODS
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.
Open in
PUBMED | DOI | PMC | Google Scholar | Wikipedia
Relations:
Content
Citations
(8)
References
(11)
Clinical trials
(1)
Diseases
(2)
Conditions
(2)
Chemicals
(5)
Organisms
(1)
Anatomy
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Clin J Am Soc Nephrol 10(9): 1568-1574
PMID: 26153128

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

+6 authors

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 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.

Supplementary Material

Supplemental Data:
Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
Corresponding author.
Correspondence: Dr. Donald E. Kohan, Division of Nephrology, University of Utah Health Sciences Center, 1900 East 30 North, Salt Lake City, UT 84132. Email: ude.hatu.csh@nahok.dlanod
Received 2015 Jan 15; Accepted 2015 May 22.
Copyright © 2015 by the American Society of Nephrology

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 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: atrasentan, diabetic nephropathy, albuminuria
Abstract

Values are mean±SD, n (%), or as otherwise indicated. SBP, systolic BP; DBP, diastolic BP; HbA1c, glycated hemoglobin; BNP, B-type natriuretic peptide; Q1, quartile 1; Q3, quartile 3; UACR, urinary albumin to creatinine ratio; RAS, renin-angiotensin system. Modified from reference 5, with permission.

UACR, urinary albumin to creatinine ratio; BNP, B-type natriuretic peptide.

The following covariates were included in the initial backward selection model: treatment assignment, age, sex, body weight, hemoglobin, eGFR, albuminuria, systolic BP, eGFR, log-transformed HOMA product, log-transformed B-type natriuretic peptide, thiazide, and loop diuretic use. Systolic BP and atrasentan dose were not included in the final logistic regression models for body weight and hemoglobin, respectively. HbA1c, glycated hemoglobin; HOMA, homeostatic model assessment; 95% CI, 95% confidence interval.

Click here to view.

Acknowledgments

We greatly appreciate the participation of the many individuals in these studies and the efforts of all of the investigators.

This study was supported by AbbVie.

An abstract containing data from this study was accepted for presentation at the American Society of Nephrology Kidney Week, November 11–16, 2014, in Philadelphia, Pennsylvania.

The sponsor was involved in the design of the study, in the collection and analysis of the data, and in writing the report. All authors had access to study results, and the lead author vouches for the accuracy and completeness of the data reported. The lead author had the final decision to submit the publication.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.cjasn.org.

This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.00570115/-/DCSupplemental.

Footnotes

References

  • 1. Kohan DE, Barton M: Endothelin and endothelin antagonists in chronic kidney disease.Kidney Int86: 896–904, 2014
  • 2. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G, ASCEND Study Group : Avosentan for overt diabetic nephropathy.J Am Soc Nephrol21: 527–535, 2010
  • 3. Wenzel RR, Littke T, Kuranoff S, Jürgens C, Bruck H, Ritz E, Philipp T, Mitchell A, SPP301 (Avosentan) Endothelin Antagonist Evaluation in Diabetic Nephropathy Study Investigators : Avosentan reduces albumin excretion in diabetics with macroalbuminuria.J Am Soc Nephrol20: 655–664, 2009
  • 4. Barton M, Kohan DE: Endothelin antagonists in clinical trials: Lessons learned.Contrib Nephrol172: 255–260, 2011 [[PubMed]
  • 5. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, Correa-Rotter R, Kohan D, Lambers Heerspink HJ, Makino H, Perkovic V, Pritchett Y, Remuzzi G, Tobe SW, Toto R, Viberti G, Parving HH: The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.J Am Soc Nephrol25: 1083–1093, 2014
  • 6. Imai E, Haneda M, Chan JC, Yamasaki T, Kobayashi F, Ito S, Makino H: Reduction and residual proteinuria are therapeutic targets in type 2 diabetes with overt nephropathy: A post hoc analysis (ORIENT-proteinuria).Nephrol Dial Transplant28: 2526–2534, 2013 [[PubMed]
  • 7. Xie D, Hou FF, Fu BL, Zhang X, Liang M: High level of proteinuria during treatment with renin-angiotensin inhibitors is a strong predictor of renal outcome in nondiabetic kidney disease.J Clin Pharmacol51: 1025–1034, 2011 [[PubMed]
  • 8. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL.Kidney Int65: 2309–2320, 2004 [[PubMed]
  • 9. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya P, Andress DL: Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy.J Am Soc Nephrol22: 763–772, 2011
  • 10. Stuart D, Chapman M, Rees S, Woodward S, Kohan DE: Myocardial, smooth muscle, nephron, and collecting duct gene targeting reveals the organ sites of endothelin A receptor antagonist fluid retention.J Pharmacol Exp Ther346: 182–189, 2013 [[PubMed]
  • 11. Stuart D, Rees S, Woodward SK, Koesters R, Strait KA, Kohan DE: Disruption of the endothelin A receptor in the nephron causes mild fluid volume expansion.BMC Nephrol13: 166, 2012
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.