Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes

Meggan Mackay, Maria Dall'Era, Joanna Fishbein, Kenneth Kalunian, Martin Lesser, Jorge Sanchez-Guerrero, Deborah M. Levy, Earl Silverman, Michelle Petri, Cristina Arriens, Edmund J. Lewis, Stephen M. Korbet, Fabrizio Conti, Vladimir Tesar, Zdenka Hruskova, Eduardo F. Borba, Eloisa Bonfa, Tak Mao Chan, Manish Rathi, K. L. GuptaVivekanand Jha, Sarfaraz Hasni, Melissa R. West, Neil Solomons, Frederic A. Houssiau, Juanita Romero-Diaz, Juan Mejia-Vilet, Brad H. Rovin

Research output: Contribution to journalArticle

Abstract

Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84–0.92) and in an independent LN cohort (c-indices 0.89–0.92). Conclusion: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.

Original languageEnglish (US)
Pages (from-to)411-419
Number of pages9
JournalArthritis and Rheumatology
Volume71
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Lupus Nephritis
Biomarkers
Clinical Trials
Kidney
Chronic Renal Insufficiency
Proteinuria
Renal Replacement Therapy
Creatinine
Wounds and Injuries
Serum
Pathology
Nephrology
Databases

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials : Development and Validation of a Novel Approach to Predict Future Kidney Outcomes. / Mackay, Meggan; Dall'Era, Maria; Fishbein, Joanna; Kalunian, Kenneth; Lesser, Martin; Sanchez-Guerrero, Jorge; Levy, Deborah M.; Silverman, Earl; Petri, Michelle; Arriens, Cristina; Lewis, Edmund J.; Korbet, Stephen M.; Conti, Fabrizio; Tesar, Vladimir; Hruskova, Zdenka; Borba, Eduardo F.; Bonfa, Eloisa; Chan, Tak Mao; Rathi, Manish; Gupta, K. L.; Jha, Vivekanand; Hasni, Sarfaraz; West, Melissa R.; Solomons, Neil; Houssiau, Frederic A.; Romero-Diaz, Juanita; Mejia-Vilet, Juan; Rovin, Brad H.

In: Arthritis and Rheumatology, Vol. 71, No. 3, 01.03.2019, p. 411-419.

Research output: Contribution to journalArticle

Mackay, M, Dall'Era, M, Fishbein, J, Kalunian, K, Lesser, M, Sanchez-Guerrero, J, Levy, DM, Silverman, E, Petri, M, Arriens, C, Lewis, EJ, Korbet, SM, Conti, F, Tesar, V, Hruskova, Z, Borba, EF, Bonfa, E, Chan, TM, Rathi, M, Gupta, KL, Jha, V, Hasni, S, West, MR, Solomons, N, Houssiau, FA, Romero-Diaz, J, Mejia-Vilet, J & Rovin, BH 2019, 'Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes', Arthritis and Rheumatology, vol. 71, no. 3, pp. 411-419. https://doi.org/10.1002/art.40724
Mackay, Meggan ; Dall'Era, Maria ; Fishbein, Joanna ; Kalunian, Kenneth ; Lesser, Martin ; Sanchez-Guerrero, Jorge ; Levy, Deborah M. ; Silverman, Earl ; Petri, Michelle ; Arriens, Cristina ; Lewis, Edmund J. ; Korbet, Stephen M. ; Conti, Fabrizio ; Tesar, Vladimir ; Hruskova, Zdenka ; Borba, Eduardo F. ; Bonfa, Eloisa ; Chan, Tak Mao ; Rathi, Manish ; Gupta, K. L. ; Jha, Vivekanand ; Hasni, Sarfaraz ; West, Melissa R. ; Solomons, Neil ; Houssiau, Frederic A. ; Romero-Diaz, Juanita ; Mejia-Vilet, Juan ; Rovin, Brad H. / Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials : Development and Validation of a Novel Approach to Predict Future Kidney Outcomes. In: Arthritis and Rheumatology. 2019 ; Vol. 71, No. 3. pp. 411-419.
@article{a960a5cda81b4f9ebd1ead5c371287c3,
title = "Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes",
abstract = "Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84–0.92) and in an independent LN cohort (c-indices 0.89–0.92). Conclusion: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.",
author = "Meggan Mackay and Maria Dall'Era and Joanna Fishbein and Kenneth Kalunian and Martin Lesser and Jorge Sanchez-Guerrero and Levy, {Deborah M.} and Earl Silverman and Michelle Petri and Cristina Arriens and Lewis, {Edmund J.} and Korbet, {Stephen M.} and Fabrizio Conti and Vladimir Tesar and Zdenka Hruskova and Borba, {Eduardo F.} and Eloisa Bonfa and Chan, {Tak Mao} and Manish Rathi and Gupta, {K. L.} and Vivekanand Jha and Sarfaraz Hasni and West, {Melissa R.} and Neil Solomons and Houssiau, {Frederic A.} and Juanita Romero-Diaz and Juan Mejia-Vilet and Rovin, {Brad H.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1002/art.40724",
language = "English (US)",
volume = "71",
pages = "411--419",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials

T2 - Development and Validation of a Novel Approach to Predict Future Kidney Outcomes

AU - Mackay, Meggan

AU - Dall'Era, Maria

AU - Fishbein, Joanna

AU - Kalunian, Kenneth

AU - Lesser, Martin

AU - Sanchez-Guerrero, Jorge

AU - Levy, Deborah M.

AU - Silverman, Earl

AU - Petri, Michelle

AU - Arriens, Cristina

AU - Lewis, Edmund J.

AU - Korbet, Stephen M.

AU - Conti, Fabrizio

AU - Tesar, Vladimir

AU - Hruskova, Zdenka

AU - Borba, Eduardo F.

AU - Bonfa, Eloisa

AU - Chan, Tak Mao

AU - Rathi, Manish

AU - Gupta, K. L.

AU - Jha, Vivekanand

AU - Hasni, Sarfaraz

AU - West, Melissa R.

AU - Solomons, Neil

AU - Houssiau, Frederic A.

AU - Romero-Diaz, Juanita

AU - Mejia-Vilet, Juan

AU - Rovin, Brad H.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84–0.92) and in an independent LN cohort (c-indices 0.89–0.92). Conclusion: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.

AB - Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84–0.92) and in an independent LN cohort (c-indices 0.89–0.92). Conclusion: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.

UR - http://www.scopus.com/inward/record.url?scp=85060877299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060877299&partnerID=8YFLogxK

U2 - 10.1002/art.40724

DO - 10.1002/art.40724

M3 - Article

C2 - 30225865

AN - SCOPUS:85060877299

VL - 71

SP - 411

EP - 419

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 3

ER -