Meggan Mackay1, Maria Dall'Era2, Joanna Fishbein1, Kenneth Kalunian3, Martin Lesser1, Jorge Sanchez-Guerrero4, Deborah M Levy5, Earl Silverman5, Michelle Petri6, Cristina Arriens7, Edmund J Lewis8, Stephen M Korbet8, Fabrizio Conti9, Vladimir Tesar10, Zdenka Hruskova10, Eduardo F Borba11, Eloisa Bonfa11, Tak Mao Chan12, Manish Rathi13, K L Gupta13, Vivekanand Jha14, Sarfaraz Hasni15, Melissa R West16, Neil Solomons17, Frederic A Houssiau18, Juanita Romero-Diaz19, Juan Mejia-Vilet19, Brad H Rovin20. 1. Feinstein Institute for Medical Research, Manhasset, New York. 2. University of California, San Francisco. 3. University of California at San Diego, La Jolla. 4. University of Toronto, Toronto, Ontario, Canada. 5. Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada. 6. Johns Hopkins University, Baltimore, Maryland. 7. Oklahoma Medical Research Foundation, Oklahoma City. 8. Rush University Medical Center, Chicago, Illinois. 9. Sapienza University of Rome, Rome, Italy. 10. Charles University and General University Hospital, Prague, Czech Republic. 11. Hospital das Clinicas da Universidade de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. 12. University of Hong Kong, Queen Mary Hospital, Hong Kong, China. 13. Postgraduate Institute of Medical Education and Research, Chandigarh, India. 14. George Institute for Global Health India, New Delhi, India, and University of Oxford, Oxford, UK. 15. National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. 16. KHI, American Society of Nephrology, Washington, DC. 17. Aurinia Pharmaceuticals Inc., Victoria, British Columbia, Canada. 18. Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. 19. Instituto Nacional de Ciencias Medicas and Nutricion Salvador Zubiran, Mexico City, Mexico. 20. Ohio State University Wexner Medical Center, Columbus.
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.
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.
Authors: Myrto Kostopoulou; Antonis Fanouriakis; Kim Cheema; John Boletis; George Bertsias; David Jayne; Dimitrios T Boumpas Journal: RMD Open Date: 2020-07