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.

Aurinia Pharmaceuticals Inc Victoria British Columbia Canada

Charles University and General University Hospital Prague Czech Republic

Cliniques Universitaires Saint Luc Universite Catholique de Louvain Brussels Belgium

Feinstein Institute for Medical Research Manhasset New York

George Institute for Global Health India New Delhi India and University of Oxford Oxford UK

Hospital das Clinicas da Universidade de Sao Paulo Faculdade de Medicina da Universidade de Sao Paulo Sao Paulo Brazil

Hospital for Sick Children and University of Toronto Toronto Ontario Canada

Instituto Nacional de Ciencias Medicas and Nutricion Salvador Zubiran Mexico City Mexico

Johns Hopkins University Baltimore Maryland

KHI American Society of Nephrology Washington DC

National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland

Ohio State University Wexner Medical Center Columbus

Oklahoma Medical Research Foundation Oklahoma City

Postgraduate Institute of Medical Education and Research Chandigarh India

Rush University Medical Center Chicago Illinois

Sapienza University of Rome Rome Italy

University of California at San Diego La Jolla

University of California San Francisco

University of Hong Kong Queen Mary Hospital Hong Kong China

University of Toronto Toronto Ontario Canada

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