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A meta-analysis of GFR slope as a surrogate endpoint for kidney failure

Nature Medicine volume 29, pages 1867–1876 (2023)Cite this article

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Abstract

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min−1 per 1.73 m2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82–1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25–0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression.

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Fig. 1: Treatment effect on 3-year total slope, chronic slope and clinical endpoint, overall and by disease group.
Fig. 2: Trial-level analyses for the association between treatment effects on GFR slope and treatment effects on the clinical endpoint.
Fig. 3: Trial-level analyses for the association between treatment effects on GFR slope and treatment effects on the clinical endpoint by disease groups.

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Data availability

All data used in the analysis were obtained by the CKD-EPI Clinical Trials (CT) group through third parties. Data use agreements prohibit CKD-EPI CT from sharing data with parties external to the agreement. See Supplementary Table 1 for the identity of third party providers. The following datasets can be requested through data-sharing platforms: Vivli: CANVAS (NCT01032629), CANVAS-R (NCT01989754), CREDENCE (NCT02065791), EMPA-REG Outcome (NCT01131676), EXAMINE (NCT00968708), Harmony Outcome (NCT02465515) and FIDELIO-DKD (NCT02540993); NIDDK: AASK (NCT04364139), FSGS/FONT (NCT00135811), HALT-PKD Study A and Study B (NCT00283686) and MDRD (NCT03202914); NHLBI BioLINCC: TOPCAT (NCT00094302) and SPRINT (NCT01206062); Clinical Study Data Request: PARADIGM-HF (NCT01035255) and ACCOMPLISH (NCT00170950); and sponsors’ website: LEADER (NCT01179048).

Code availability

The statistical code used for the primary analysis can be found at https://github.com/UofUEpiBio/ckdepict.

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Acknowledgements

We thank the National Kidney Foundation (NKF) and its sponsors for funding this research. The NKF received consortium support from the following companies: AstraZeneca, Bayer, Boehringer Ingelheim, Cerium Pharma, Chinook, CSL Behring, Janssen, Novartis, NovoNordisk, ProKidney and Travere. This work also received support from the Utah Study Design and Biostatistics Center, with funding in part from the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR002538. The support and resources from the Center for High Performance Computing at the University of Utah are also gratefully acknowledged. We thank all investigators, study teams and participants of the studies included in the meta-analysis (Protocol). This analysis includes SPRINT and TOPCAT research materials obtained from the National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of SPRINT or TOPCAT or the NHLBI. The FSGS/FONT trial, HALT-PKD Study A and HALT-PKD Study B were conducted by the investigators of the respective studies and were supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The data from these studies reported here were supplied by the NIDDK Central Repository. This paper does not necessarily reflect the opinions or views of these studies, the NIDDK Central Repository or the NIDDK. We are grateful for data from AstraZeneca, Bayer AG, Boehringer Ingelheim, GlaxoSmithKline (made available through Vivli, Inc.), Novartis (made available through a clinical study data request (CSDR)), Novo Nordisk A/S and Takeda (made available through Vivli, Inc.). Vivli and CSDR have not contributed to or approved, and are not in any way responsible for, the contents of this publication.

Author information

Authors and Affiliations

  1. Division of Nephrology, Tufts Medical Center, Boston, MA, USA

    Lesley A. Inker, Shiyuan Miao, Juhi Chaudhari & Ronald D. Perrone

  2. Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA

    Willem Collier, Tom Greene & Benjamin Haaland

  3. Division of Nephrology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA

    Gerald B. Appel & Pietro Canetta

  4. George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia

    Sunil V. Badve, Brendon L. Neuen, Mark Woodward, John Chalmers, Bruce Neal, Vlado Perkovic, David Johnson & Meg Jardine

  5. Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain

    Fernando Caravaca-Fontán, Hernando Trujillo, Teresa Cavero & Angel Sevillano

  6. Department of Nephrology and Dialysis, Sant’Anna Hospital, ASST Lariana, Como, Italy

    Lucia Del Vecchio

  7. Division of Nephrology, RWTH Aachen University, Aachen, Germany

    Jürgen Floege & Thomas Rauen

  8. Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Marian Goicoechea, Eduardo Verde, Ursula Verdalles & David Arroyo

  9. Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    William G. Herrington

  10. Nakayamadera Imai Clinic, Takarazuka, Japan

    Enyu Imai

  11. Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore

    Tazeen H. Jafar

  12. Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA

    Julia B. Lewis & Jamie Dwyer

  13. Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China

    Philip K. T. Li, Kai-Ming Chow, Cheuk-Chun Szeto & Chi-Bon Leung

  14. Department of Nephrology, AZ Delta, Roeselare, Belgium

    Bart D. Maes

  15. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

    Giuseppe Remuzzi, Piero Ruggenenti, Annalisa Perna & Fabiola Carrara

  16. Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy

    Francesco P. Schena & Carlo Manno

  17. Renal Research Unit, Comprehensive Heart Failure Center, Department of Clinical Research and Epidemiology, University of Würzburg, Würzburg, Germany

    Christoph Wanner

  18. Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands

    Jack F. M. Wetzels

  19. George Institute for Global Health, School of Public Health, Imperial College London, London, UK

    Mark Woodward

  20. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Hiddo J. L. Heerspink

  21. Denver Health, Denver, CO, USA

    Raymond O. Estacio, Rebecca Hanratty, Di Xie & Fan Fan Hou

  22. Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada

    Brendan Barrett

  23. Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA

    Kenneth W. Mahaffey

  24. Boehringer Ingelheim International, Ingelheim, Germany

    Maximilian von Eynatten

  25. Section of Nephrology, University of Chicago School of Medicine, Chicago, IL, USA

    Arlene Chapman

  26. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    Vicente Torres

  27. Department of Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, USA

    Alan Yu

  28. Division of Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA

    Godela Brosnahan

  29. Department of Nephrology Dialysis and Renal Transplantation, Alessandro Manzoni Hospital, Lecco, Italy

    Thierry Hannedouche, Giuseppe Maschio, Francesco Locatelli, Simeone Andrulli, Claudio Pozzi & Donatella Casartelli

  30. Cleveland Clinic Foundation, Cleveland, OH, USA

    Marc A. Pohl

  31. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Itamar Raz

  32. Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA

    Lawrence G. Hunsicker

  33. Department of Nephrology, Heilig Hartziekenhuis Roeselare-Menen, Roeselare, Belgium

    An Vanacker

  34. Renal Division, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium

    Thomas Malfait

  35. Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands

    Peter J. Blankestijn & Arjan van Zuilen

  36. Daiichi Sankyo, Tokyo, Japan

    Fumiaki Kobayashi

  37. Department of Medicine, Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Hirofumi Makino

  38. Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China

    Juliana C. N. Chan

  39. Department of Nephrology, Hospital Universitario 12 de Octubre, Department of Medicine, Complutense University, Madrid, Spain

    Manuel Praga

  40. Merck & Co., Inc., Merck Research Laboratories, Upper Gwynedd, North Wales, PA, USA

    William F. Keane

  41. Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    Richard Haynes, William G. Herrington, Colin Baigent & Martin Landray

  42. Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany

    Claudia Seikrit

  43. Department of Medical Statistics, RWTH Aachen University, Aachen, Germany

    Stefanie Wied

  44. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Robert D. Toto

  45. Departments of Nephrology, University of Groningen, Groningen, The Netherlands

    Paul E. de Jong

  46. Department of Nephrology, St. Donato Hospital, Arezzo, Italy

    Mauro Saddelli

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  1. Lesley A. Inker
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Consortia

the CKD-EPI Clinical Trials Consortium

  • Raymond O. Estacio
  • , Rebecca Hanratty
  • , John Chalmers
  • , Pietro Canetta
  • , Brendan Barrett
  • , Bruce Neal
  • , Vlado Perkovic
  • , Kenneth W. Mahaffey
  • , David Johnson
  • , Meg Jardine
  • , Maximilian von Eynatten
  • , Eduardo Verde
  • , Ursula Verdalles
  • , David Arroyo
  • , Arlene Chapman
  • , Vicente Torres
  • , Alan Yu
  • , Godela Brosnahan
  • , Thierry Hannedouche
  • , Kai-Ming Chow
  • , Cheuk-Chun Szeto
  • , Chi-Bon Leung
  • , Di Xie
  • , Fan Fan Hou
  • , Jamie Dwyer
  • , Marc A. Pohl
  • , Itamar Raz
  • , Lawrence G. Hunsicker
  • , An Vanacker
  • , Thomas Malfait
  • , Giuseppe Maschio
  • , Francesco Locatelli
  • , Peter J. Blankestijn
  • , Arjan van Zuilen
  • , Fumiaki Kobayashi
  • , Hirofumi Makino
  • , Juliana C. N. Chan
  • , Simeone Andrulli
  • , Claudio Pozzi
  • , Donatella Casartelli
  • , Manuel Praga
  • , Hernando Trujillo
  • , Teresa Cavero
  • , Angel Sevillano
  • , Piero Ruggenenti
  • , Annalisa Perna
  • , Fabiola Carrara
  • , William F. Keane
  • , Carlo Manno
  • , Richard Haynes
  • , William G. Herrington
  • , Colin Baigent
  • , Martin Landray
  • , Thomas Rauen
  • , Claudia Seikrit
  • , Stefanie Wied
  • , Robert D. Toto
  • , Paul E. de Jong
  •  & Mauro Saddelli

Contributions

L.A.I., T.G. and H.J.H.L. conceived and designed the study. L.A.I., H.J.L.H. and J.C. conducted the literature search and study screening. G.B.A., S.V.B., F.C.-F., L.D.V., J.F., M.G., W.G.H., E.I., T.H.J., J.B.L., P.K.T.L., B.D.M., B.L.N., R.D.P., G.R., F.P.S., C.W., J.F.M.W. and M.W. collected data in the included studies. W.C., T.G., S.M. and J.C. analyzed the data. L.A.I., W.C., T.G., H.J.L.H. and B.H. wrote the first draft of the manuscript. All authors contributed to the interpretation of the data, provided critical feedback on paper drafts and approved the final draft.

Corresponding author

Correspondence to Lesley A. Inker.

Ethics declarations

Competing interests

L.A.I. reports funding from National Institutes of Health (NIH), National Kidney Foundation (NKF), Omeros, Chinnocks, and Reata Pharmaceuticals for research and contracts to Tufts Medical Center; consulting agreements to Tufts Medical Center with Tricida; and consulting agreements with Diamerix. W.H.C. reports funding from the NKF to his institute for his graduate research assistantship. T.G. reports grant support from the NKF, Janssen Pharmaceuticals, Durect Corporation and Pfizer and statistical consulting from AstraZeneca, CSL and Boehringer Ingleheim. B.H. consults for the NKF, Proxima Clinical Research, Value Analytics Health and Guidepoint Global. G.B.A. reports funding for research studies through Columbia University, Calliditas, Travere, Novartis, Equillium, Roche, Sanofi, Reata, Apellis, Nephronet, Goldfinch and Vertex; consultations for Sanofi-Genzyme, Roche/Genetech, Apellis, Novartis, Travere, Calliditas, Glaxo and Aurinia; and speaker’s honoraria from GlaxoSmithKline and Aurinia, both on lupus nephritis. S.V.B. reports funding from the National Health and Medical Research Council of Australia; has served on the advisory boards of Bayer, AstraZeneca and Vifor Pharma; and has received speaker’s honoraria from Bayer, AstraZeneca, Pfizer and Vifor Pharma, all fees paid to the George Institute for Global Health. L.D.V. was an advisory board member for Travere. L.D.V. is also National Leader for the PROTECT Study and the VISIONARY study. J.F. reports lecture and consulting honoraria from Alynlam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Calliditas, Fresenius, Novartis, Omeros, Travere and Vifor and is a member of the data safety monitoring board in trials for Novo Nordisk and Visterra. W.G.H. reports personal funding from the UK Medical Research Council (MC_UU_00017/3) and Kidney Research UK (MR/R007764/1) and grants to the University of Oxford from Boehringer Ingelheim and Eli Lilly. E.I. received research funding and honoraria for lectures from AstraZeneca, Tanabe Mitsubishi, Boehringer Ingelheim, Daiich Sankyo, Kyowa Kirin and Novo Nordisk. J.B.L. is a consultant for CSL and BioVie. P.K.T.L. received speaker’s honoraria from FibroGen, AstraZeneca and Baxter. B.D.M. is the National Leader of the ASCEND-D and ASCEND-ND trials of GlaxoSmithKline and the PROTECT and DUPLEX trials of Travere and is a steering committee member for the Novartis APPLAUSE trial and the Vera Therapeutics ATACICEPT trial. B.L.N. has received fees for advisory boards, scientific presentations, continuing education, steering committee roles and travel from AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare, Janssen and Medscape, with all honoraria paid to his institution. R.D.P. received research support from Otsuka, Reata, Kadmon, Sanofi Genzyme and the US Department of Defense (TAME PKD); has been a member of steering committees for Sanofi Genzyme, Otsuka and TAME PKD, with fees paid to employing institutions; and has provided consultancy for Navitor, Palladiobio, Reata and Otsuka. G.R. has had consultancy agreements with Alexion Pharmaceuticals, Janssen, Akebia Therapeutics, Biocryst Pharmaceuticals, Menarini Ricerche SpA and AstraZeneca and speaker honoraria/travel reimbursement from Boehringer Ingelheim and Novartis. M.W. reports consulting fees from Amgen and Freeline, paid to him. H.J.L.H. received grant support from the NKF to his institute and is a consultant for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, GoldFinch, Janssen, Merck, Novo Nordisk and Travere Pharmaceuticals. S.M., J.C., M.G., F.C.F., T.H.J., F.P.S., C.W. and J.F.M.W. have no conflicts to report associated with this manuscript.

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Extended data

Extended Data Fig. 1

Flow diagram of studies included in trial-level analyses.

Extended Data Fig. 2 Trial-level analyses for the association between treatment effects on GFR slope and treatment effects on the clinical endpoint.

Circles represent separate studies. Sizes are proportional to the number of events (kidney failure with replacement therapy, GFR <15 mL/min/1.73m2, or doubling of serum creatinine). Colors indicate intervention type. The black line is the line of regression through the studies. Blue lines show the 95% pointwise Bayesian prediction bands computed from the model. Red triangles indicate studies where the estimated treatment effects are beyond the margins.

Extended Data Fig. 3 Trial-level analyses for the association between treatment effects on GFR slope and treatment effects on the secondary clinical endpoint.

Circles represent separate studies. Sizes are proportional to the number of events (kidney failure with replacement therapy, GFR <15 mL/min/1.73m2). Colors indicate intervention type. The black line is the line of regression through the studies. Blue lines show the 95% pointwise Bayesian prediction bands computed from the model. Red triangles indicate studies where the estimated treatment effects are beyond the margins.

Extended Data Table 1 Categories of disease by intervention
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Extended Data Table 2 Mean slopes in treatment and control and treatment effect by intervention, causal disease and subgroups—total slope computed at 3 years, total slope computed at 2 years, chronic slope and acute slope
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Extended Data Table 3 Treatment effects on the clinical endpoint
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Extended Data Table 4 Trial-level analyses for the association between treatment effects on GFR slope over 2 years and treatment effects on the clinical endpoint by subgroups
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Extended Data Table 5 Trial-level results using secondary endpoint (that is, dialysis or GFR < 15 ml min−1 per 1.73 m2)
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Extended Data Table 6 Trial-level analyses for the association between treatment effects on GFR slope and treatment effects on the clinical endpoint by sensitivity excluding disease groups
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Extended Data Table 7 Application of GFR slope as surrogate endpoint in a new RCT: predicted treatment effect on clinical endpoint and PPV for subgroup-specific analyses
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Supplementary information

Supplementary Information

Supplementary Tables 1–11 and References.

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Supplementary Data

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Inker, L.A., Collier, W., Greene, T. et al. A meta-analysis of GFR slope as a surrogate endpoint for kidney failure. Nat Med 29, 1867–1876 (2023). https://doi.org/10.1038/s41591-023-02418-0

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