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.
N1 - Funding Information:
The KHI and the LNTN would like to thank the US Food and Drug Administration, in particular the following individuals whom the KHI workgroup consulted during this effort: Larissa Lapteva, MD, Nikolay Nikolov, MD, Aliza Thompson, MD, and Sarah Yim, MD. We would also like to thank Amrutha Baskaran, MD, MSCR (University of California, San Diego), Laura Straub (Strategic Review and Planning Manager for the Immune Tolerance Network, San Francisco, CA), and Elian D. Silverman (KHI, American Society of Nephrology, Washington, DC) for help with data management, organization, and logistic support for this project.
Funding Information:
1Meggan Mackay, MD, MS, Joanna Fishbein, MPH, Martin Lesser, PhD: Feinstein 阀nstitute for Medical Research, Manhasset, New York2;M aria Dall’Era, MD: University of California, San Francisco; 3Kenneth Kalunian, MD: University of California at San Diego, La Jolla; 4Jorge Sanchez-Guerrero, MD, MS: University of Toronto, Toronto, Ontario, Canada; 5Deborah M. Levy, MD, MS, Earl Silverman, MD: Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada; 6Michelle Petri, MD, MPH: Johns Hopkins University, Baltimore, Maryland; 7Cristina Arriens, MD, MSCS: Oklahoma Medical Research Foundation, Oklahoma City; 8Edmund J. Lewis, MD, Stephen M. Korbet, MD: Rush University Medical Center, Chicago, 阀llinois; The views and opinions expressed in this publication are those of the authors and do not necessarily reflect the official policies of any Kidney Health 阀nitiative (KH 阀ఀ member organization, the Department of Veterans A 贀airs, or the US Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the US Government. Supported in part by the KH 阀 and the Lupus Nephritis Trials Network (LNTN?. The KH 阀 is a public–private partnership between the American Society of Nephrology, the FDA, and more than 90 member organizations and companies to enhance patient safety and foster innovation in kidney disease. The LNTN is comprised of 200 investigators from 40 countries who are committed to collaborative research dedicated to improving outcomes for people with lupus nephritis. KH 阀 and LNTN funds were used to defray costs incurred during the conduct of the project, including project
Funding Information:
management support. Dr. Petri’s work was supported in part by N 阀H grants AR-43737 and AR-69572. Dr. Hasni’s work was supported by the 阀ntramural Research Program, National 阀nstitute of Arthritis and Musculoskeletal and Skin Diseases, N 阀H.
Publisher Copyright:
© 2018, American College of Rheumatology
PY - 2019/3
Y1 - 2019/3
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.
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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 -