Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials

Chronic Kidney Disease Epidemiology Collaboration

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. Methods: In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease” “chronic renal insufficiency” “albuminuria” “proteinuria” and “randomized controlled trial”; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. Findings: We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation: Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Funding: US National Kidney Foundation.

Original languageEnglish (US)
Pages (from-to)128-139
Number of pages12
JournalThe Lancet Diabetes and Endocrinology
Volume7
Issue number2
DOIs
StatePublished - Feb 1 2019

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Albuminuria
Kidney Diseases
Meta-Analysis
Randomized Controlled Trials
Biomarkers
Chronic Renal Insufficiency
Therapeutics
Proteinuria
Chronic Kidney Failure
Glomerular Filtration Rate
PubMed

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Change in albuminuria as a surrogate endpoint for progression of kidney disease : a meta-analysis of treatment effects in randomised clinical trials. / Chronic Kidney Disease Epidemiology Collaboration.

In: The Lancet Diabetes and Endocrinology, Vol. 7, No. 2, 01.02.2019, p. 128-139.

Research output: Contribution to journalArticle

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abstract = "Background: Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. Methods: In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease” “chronic renal insufficiency” “albuminuria” “proteinuria” and “randomized controlled trial”; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. Findings: We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71{\%}] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13{\%}) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95{\%} Bayesian credible interval [BCI] 0·13–1·70), each 30{\%} decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27{\%} lower hazard for the clinical endpoint (95{\%} BCI 5–45{\%}; median R2 0·47, 95{\%} BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30{\%} decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95{\%} of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation: Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Funding: US National Kidney Foundation.",
author = "{Chronic Kidney Disease Epidemiology Collaboration} and Heerspink, {Hiddo J.L.} and Tom Greene and Hocine Tighiouart and Gansevoort, {Ron T.} and Josef Coresh and Simon, {Andrew L.} and Chan, {Tak Mao} and Hou, {Fan Fan} and Lewis, {Julia B.} and Francesco Locatelli and Manuel Praga and Schena, {Francesco Paolo} and Levey, {Andrew S.} and Inker, {Lesley A.} and Angel Sevillano and Kamper, {Anne Lise} and {van Zuilen}, {Arjan D.} and Brenner, {Barry M.} and Bart Maes and Ihle, {Benno U.} and Brendan Barret and Leung, {C. B.} and Szeto, {C. C.} and Christina Fitzner and Christoph Wanner and Claudio Pozzi and Montagnino, {Claudio Ponticelli} and Di Xie and {de Zeeuw}, Dick and Edmund Lewis and Eduardo Verde and Eduardo Gutierrez and Enyu Imai and Fernando Caravaca and Fervenza, {Fernando C.} and Fumiaki Kobayashi and Gabriella Moroni and Becker, {Gavin J.} and Beck, {Gerald J.} and Appel, {Gerald B.} and Gershon Frisch and {van Essen}, {G. G.} and Giuseppe Maschio and Giuseppe Remuzzi and Giuseppe Montogrino and Parving, {Hans Henrik} and Heerspink, {Hiddo J.L.} and Hirofumi Makino and Imitiaz Jehan and Toto, {Robert D}",
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T1 - Change in albuminuria as a surrogate endpoint for progression of kidney disease

T2 - a meta-analysis of treatment effects in randomised clinical trials

AU - Chronic Kidney Disease Epidemiology Collaboration

AU - Heerspink, Hiddo J.L.

AU - Greene, Tom

AU - Tighiouart, Hocine

AU - Gansevoort, Ron T.

AU - Coresh, Josef

AU - Simon, Andrew L.

AU - Chan, Tak Mao

AU - Hou, Fan Fan

AU - Lewis, Julia B.

AU - Locatelli, Francesco

AU - Praga, Manuel

AU - Schena, Francesco Paolo

AU - Levey, Andrew S.

AU - Inker, Lesley A.

AU - Sevillano, Angel

AU - Kamper, Anne Lise

AU - van Zuilen, Arjan D.

AU - Brenner, Barry M.

AU - Maes, Bart

AU - Ihle, Benno U.

AU - Barret, Brendan

AU - Leung, C. B.

AU - Szeto, C. C.

AU - Fitzner, Christina

AU - Wanner, Christoph

AU - Pozzi, Claudio

AU - Montagnino, Claudio Ponticelli

AU - Xie, Di

AU - de Zeeuw, Dick

AU - Lewis, Edmund

AU - Verde, Eduardo

AU - Gutierrez, Eduardo

AU - Imai, Enyu

AU - Caravaca, Fernando

AU - Fervenza, Fernando C.

AU - Kobayashi, Fumiaki

AU - Moroni, Gabriella

AU - Becker, Gavin J.

AU - Beck, Gerald J.

AU - Appel, Gerald B.

AU - Frisch, Gershon

AU - van Essen, G. G.

AU - Maschio, Giuseppe

AU - Remuzzi, Giuseppe

AU - Montogrino, Giuseppe

AU - Parving, Hans Henrik

AU - Heerspink, Hiddo J.L.

AU - Makino, Hirofumi

AU - Jehan, Imitiaz

AU - Toto, Robert D

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background: Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. Methods: In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease” “chronic renal insufficiency” “albuminuria” “proteinuria” and “randomized controlled trial”; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. Findings: We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation: Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Funding: US National Kidney Foundation.

AB - Background: Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. Methods: In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease” “chronic renal insufficiency” “albuminuria” “proteinuria” and “randomized controlled trial”; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. Findings: We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation: Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Funding: US National Kidney Foundation.

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