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      Evaluating a New International Risk-Prediction Tool in IgA Nephropathy

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          Abstract

          This modeling study uses international, multi-ethnic derivation and validation cohorts of patients with biopsy-proven IgA nephropathy to evaluate a risk-prediction tool for 50% decline in kidney function or end-stage renal disease. How can we better predict, at the time of kidney biopsy, the risk of a 50% decline in kidney function or end-stage renal disease in patients with IgA nephropathy? Large international multiethnic cohorts including 3927 patients were enrolled to both derive and externally validate 2 prediction models, one that included patient race/ethnicity, and one that did not. Both models outperformed clinical measures for prediction of kidney disease progression and patient risk stratification. The 2 prediction models were shown to be accurate and validated methods to help clinicians improve management and treatment of IgA nephropathy in multi-ethnic cohorts and may aid international researchers in trial recruitment. Although IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. To derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. We derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Cox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R 2 D measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. The study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R 2 D (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (ΔC, 0.04; 95% CI, 0.03-0.04 and ΔC, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R 2 D (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. In this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

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          Most cited references30

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          GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.

          The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
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            Remission of proteinuria improves prognosis in IgA nephropathy.

            Proteinuria has been shown to be an adverse prognostic factor in IgA nephropathy. The benefit of achieving a partial remission of proteinuria, however, has not been well described. We studied 542 patients with biopsy-proven primary IgA nephropathy in the Toronto Glomerulonephritis Registry and found that glomerular filtration rate (GFR) declined at -0.38 +/- 0.61 ml/min per 1.73 m2/mo overall, with 30% of subjects reaching end-stage renal disease. Multivariate analysis revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline. Among the 171 patients with 3 g/d (n = 121) lost renal function 25-fold faster than those with or =3 g/d who achieved a partial remission (<1 g/d) had a similar course to patients who had < or =1 g/d throughout, and fared far better than patients who never achieved remission. These results underscore the relationship between proteinuria and prognosis in IgA nephropathy and establish the importance of remission.
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              IgA nephropathy.

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                Author and article information

                Journal
                JAMA Internal Medicine
                JAMA Intern Med
                American Medical Association (AMA)
                2168-6106
                April 13 2019
                Affiliations
                [1 ]Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
                [2 ]BC Renal, Vancouver, British Columbia, Canada
                [3 ]Regina Margherita Children’s University Hospital, Torino, Italy
                [4 ]Peking University Institute of Nephrology, Beijing, China
                [5 ]Nanjing University School of Medicine, Nanjing, China
                [6 ]Faculty of Medicine, Juntendo University, Tokyo, Japan
                [7 ]National Fukuoka Higashi Medical Center, Fukuoka, Japan
                [8 ]Division of Nephrology, University of Toronto, Toronto, Ontario, Canada
                [9 ]The John Walls Renal Unit, Leicester General Hospital, Leicester, England
                Article
                10.1001/jamainternmed.2019.0600
                6583088
                30980653
                5fdc005d-fd19-4a5a-8438-9f8caf9f67f6
                © 2019
                History

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