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1. Histological predictors of outcome in C3 glomerulopathy and idiopathic immunoglobulin-associated membranoproliferative glomerulonephritis

Author

Medjeral-Thomas, N, Barbour, S, Gisby, J, Han, H, Bomback, A, Fervenza, F, Cairns, T, Szydlo, R, Tan, S-J, Marks, S, Waters, A, Appel, G, D'Agati, V, Sethi, S, Nast, C, Bajema, I, Alpers, C, Fogo, A, Licht, C, Fakhouri, F, Cattran, D, Peters, J, Terence, C, Lomax-Browne, H, Pickering, M, and Alexion Pharmaceuticals Inc.

Subjects
urogenital system, 1103 Clinical Sciences, Urology & Nephrology
Abstract

Background and objectives C3 glomerulopathy and idiopathic immunoglobulin-associated membranoproliferative glomerulonephritis (Ig-MPGN) are kidney diseases characterised by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients reach end stage kidney disease within 10 years. Design, setting, participants and measurements To improve identification of patients with poor prognosis we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histological scoring system, we analysed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-MPGN. We used linear regression, survival analysis and Cox proportional hazards models to assess the relationship between histological and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane (GBM) double contours and endocapillary hypercellularity. Multivariable analysis showed negative associations between estimated glomerular filtration rate (eGFR) and crescents, interstitial inflammation, and interstitial fibrosis and tubular atrophy (IFTA). Proteinuria positively associated with endocapillary hypercellularity and GBM double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at time of biopsy, and cellular/fibrocellular crescents, segmental sclerosis and IFTA scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and IFTA scores were significant determinants of deterioration in kidney function.

Published
2022

2. Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy

Author

Canney, M., Barbour, S. J., Zheng, Y., Coppo, R., Zhang, H., Liu, Z. -H., Matsuzaki, K., Suzuki, Y., Katafuchi, R., Reich, H. N., Cattran, D., Russo, M. L., Troyanov, S., Cook, H. T., Roberts, I., Tesar, V., Maixnerova, D., Lundberg, S., Gesualdo, L., Emma, F., Fuiano, L., Beltrame, G., Rollino, C., Amore, A., Camilla, R., Peruzzi, L., Praga, M., Feriozzi, S., Polci, R., Segoloni, G., Colla, L., Pani, A., Piras, D., Angioi, A., Cancarini, G., Ravera, S., Durlik, M., Moggia, E., Ballarin, J., Di Giulio, S., Pugliese, F., Serriello, I., Caliskan, Y., Sever, M., Kilicaslan, I., Locatelli, F., Del Vecchio, L., Wetzels, J. F. M., Peters, H., Berg, U., Carvalho, F., da Costa Ferreira, A. C., Maggio, M., Wiecek, A., Ots-Rosenberg, M., Magistroni, R., Topaloglu, R., Bilginer, Y., D'Amico, M., Stangou, M., Giacchino, F., Goumenos, D., Kalliakmani, P., Gerolymos, M., Galesic, K., Geddes, C., Siamopoulos, K., Balafa, O., Galliani, M., Stratta, P., Quaglia, M., Bergia, R., Cravero, R., Salvadori, M., Cirami, L., Fellstrom, B., Kloster Smerud, H., Ferrario, F., Stellato, T., Egido, J., Martin, C., Floege, J., Eitner, F., Lupo, A., Bernich, P., Mene, P., Morosetti, M., van Kooten, C., Rabelink, T., Reinders, M. E. J., Boria Grinyo, J. M., Cusinato, S., Benozzi, L., Savoldi, S., Licata, C., Mizerska-Wasiak, M., Martina, G., Messuerotti, A., Dal Canton, A., Esposito, C., Migotto, C., Triolo, G., Mariano, F., Pozzi, C., Boero, R., Bellur, S., Mazzucco, G., Giannakakis, C., Honsova, E., Sundelin, B., Di Palma, A. M., Gutierrez, E., Asunis, A. M., Barratt, J., Tardanico, R., Perkowska-Ptasinska, A., Arce Terroba, J., Fortunato, M., Pantzaki, A., Ozluk, Y., Steenbergen, E., Soderberg, M., Riispere, Z., Furci, L., Orhan, D., Kipgen, D., Casartelli, D., Galesic Ljubanovic, D., Gakiopoulou, H., Bertoni, E., Cannata Ortiz, P., Karkoszka, H., Groene, H. J., Stoppacciaro, A., Bajema, I., Bruijn, J., Fulladosa Oliveras, X., Maldyk, J., Ioachim, E., Bavbek, N., Cook, T., Alpers, C., Feehally, J., Berthoux, F., Bonsib, S., D'Agati, V., D'Amico, G., Emancipator, S., Emmal, F., Fervenza, F., Florquin, S., Fogo, A., Groene, H., Haas, M., Hill, P., Hogg, R., Hsu, S., Hunley, T., Hladunewich, Jennette, C., Joh, K., Julian, B., Kawamura, T., Lai, F., Leung, C., Li, L., Li, P., Liu, Z., Massat, A., Mackinnon, B., Mezzano, S., Schena, F., Tomino, Y., Walker, P., Wang, H., Weening, J., Yoshikawa, N., Zeng, C. -H., Shi, S., Nogi, C., Suzuki, H., Koike, K., Hirano, K., Yokoo, T., Hanai, M., Fukami, K., Takahashi, K., Yuzawa, Y., Niwa, M., Yasuda, Y., Maruyama, S., Ichikawa, D., Suzuki, T., Shirai, S., Fukuda, A., Fujimoto, S., Trimarchi, H., Anesthesiology, Pathology, Graduate School, ACS - Heart failure & arrhythmias, and ACS - Atherosclerosis & ischemic syndromes

Subjects
Male, Time Factors, glomerular disease, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Gastroenterology, 0302 clinical medicine, Outcome Assessment, Health Care, Clinical endpoint, Medicine, Clinical Epidemiology, Proteinuria, medicine.diagnostic_test, Remission Induction, Hazard ratio, IgA nephropathy, General Medicine, Middle Aged, end stage kidney disease, epidemiology and outcomes, proteinuria, renal function decline, renal pathology, 3. Good health, Renal pathology, Nephrology, Disease Progression, Female, medicine.symptom, Glomerular Filtration Rate, Adult, medicine.medical_specialty, Nephropathy, 03 medical and health sciences, Internal medicine, Biopsy, Humans, Proportional Hazards Models, Retrospective Studies, business.industry, Surrogate endpoint, Glomerulonephritis, IGA, medicine.disease, Confidence interval, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Kidney Failure, Chronic, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business
Abstract

Contains fulltext : 232930.pdf (Publisher’s version ) (Closed access) BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to

Published
2021

3. Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy

Author

Canney, M. Barbour, S.J. Zheng, Y. Coppo, R. Zhang, H. Liu, Z.-H. Matsuzaki, K. Suzuki, Y. Katafuchi, R. Reich, H.N. Cattran, D. Russo, M.L. Troyanov, S. Cook, H.T. Roberts, I. Tesar, V. Maixnerova, D. Lundberg, S. Gesualdo, L. Emma, F. Fuiano, L. Beltrame, G. Rollino, C. Amore, A. Camilla, R. Peruzzi, L. Praga, M. Feriozzi, S. Polci, R. Segoloni, G. Colla, L. Pani, A. Piras, D. Angioi, A. Cancarini, G. Ravera, S. Durlik, M. Moggia, E. Ballarin, J. Di Giulio, S. Pugliese, F. Serriello, I. Caliskan, Y. Sever, M. Kilicaslan, I. Locatelli, F. Del Vecchio, L. Wetzels, J.F.M. Peters, H. Berg, U. Carvalho, F. da Costa Ferreira, A.C. Maggio, M. Wiecek, A. Ots-Rosenberg, M. Magistroni, R. Topaloglu, R. Bilginer, Y. D'Amico, M. Stangou, M. Giacchino, F. Goumenos, D. Kalliakmani, P. Gerolymos, M. Galesic, K. Geddes, C. Siamopoulos, K. Balafa, O. Galliani, M. Stratta, P. Quaglia, M. Bergia, R. Cravero, R. Salvadori, M. Cirami, L. Fellstrom, B. Kloster Smerud, H. Ferrario, F. Stellato, T. Egido, J. Martin, C. Floege, J. Eitner, F. Lupo, A. Bernich, P. Menè, P. Morosetti, M. van Kooten, C. Rabelink, T. Reinders, M.E.J. Boria Grinyo, J.M. Cusinato, S. Benozzi, L. Savoldi, S. Licata, C. Mizerska-Wasiak, M. Martina, G. Messuerotti, A. Dal Canton, A. Esposito, C. Migotto, C. Triolo, G. Mariano, F. Pozzi, C. Boero, R. Bellur, S. Mazzucco, G. Giannakakis, C. Honsova, E. Sundelin, B. Di Palma, A.M. Gutiérrez, E. Asunis, A.M. Barratt, J. Tardanico, R. Perkowska-Ptasinska, A. Arce Terroba, J. Fortunato, M. Pantzaki, A. Ozluk, Y. Steenbergen, E. Soderberg, M. Riispere, Z. Furci, L. Orhan, D. Kipgen, D. Casartelli, D. Galesic Ljubanovic, D. Gakiopoulou, H. Bertoni, E. Cannata Ortiz, P. Karkoszka, H. Groene, H.J. Stoppacciaro, A. Bajema, I. Bruijn, J. Fulladosa Oliveras, X. Maldyk, J. Ioachim, E. Bavbek, N. Cook, T. Alpers, C. Feehally, J. Berthoux, F. Bonsib, S. D'Agati, V. D'Amico, G. Emancipator, S. Emmal, F. Fervenza, F. Florquin, S. Fogo, A. Groene, H. Haas, M. Hill, P. Hogg, R. Hsu, S. Hunley, T. Hladunewich Jennette, C. Joh, K. Julian, B. Kawamura, T. Lai, F. Leung, C. Li, L. Li, P. Liu, Z. Massat, A. Mackinnon, B. Mezzano, S. Schena, F. Tomino, Y. Walker, P. Wang, H. Weening, J. Yoshikawa, N. Zeng, C.-H. Shi, S. Nogi, C. Suzuki, H. Koike, K. Hirano, K. Yokoo, T. Hanai, M. Fukami, K. Takahashi, K. Yuzawa, Y. Niwa, M. Yasuda, Y. Maruyama, S. Ichikawa, D. Suzuki, T. Shirai, S. Fukuda, A. Fujimoto, S. Trimarchi, H. International IgA Nephropathy Network

Abstract

Background On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. Methods In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a $25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to,1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). Results During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. Conclusions Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints. Copyright © 2021 by the American Society of Nephrology.

Published
2021

4. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy

Author

Barbour, S.J., Coppo, R., Zhang, H., Liu, Z.H., Suzuki, Y., Matsuzaki, K., Katafuchi, R., Er, L., Espino-Hernandez, G., Kim, S.J., Reich, H.N., Feehally, J., Cattran, D.C., Russo, M.L., Troyanov, S., Cook, H.T., Roberts, I., Tesar, V., Maixnerova, D., Lundberg, S., Gesualdo, L., Emma, F., Fuiano, L., Beltrame, G., Rollino, C., Amore, A., Camilla, R., Peruzzi, L., Praga, M., Feriozzi, S., Polci, R., Segoloni, G., Colla, L., Pani, A., Piras, D., Angioi, A., Cancarini, G., Ravera, S., Durlik, M., Moggia, E., Ballarin, J., Giulio, S. di, Pugliese, F., Serriello, I., Caliskan, Y., Sever, M., Kilicaslan, I., Locatelli, F., Vecchio, L. del, Wetzels, J.F.M., Peters, H., Berg, U., Carvalho, F., Ferreira, A.C.D., Maggio, M., Wiecek, A., Ots-Rosenberg, M., Magistroni, R., Topaloglu, R., Bilginer, Y., D'Amico, M., Stangou, M., Giacchino, F., Goumenos, D., Kalliakmani, P., Gerolymos, M., Galesic, K., Geddes, C., Siamopoulos, K., Balafa, O., Galliani, M., Stratta, P., Quaglia, M., Bergia, R., Cravero, R., Salvadori, M., Cirami, L., Fellstrorn, B., Smerud, H.K., Ferrario, F., Stellato, T., Egido, J., Martin, C., Floege, J., Eitner, F., Lupo, A., Bernich, P., Mene, R., Morosetti, M., Kooten, C. van, Rabelink, T., Reinders, M.E.J., Grinyo, J.M.B., Cusinato, S., Benozzi, L., Savoldi, S., Licata, C., Mizerska-Wasiak, M., Martina, G., Messuerotti, A., Canton, A. dal, Esposito, C., Migotto, C., Triolo, G., Mariano, F., Pozzi, C., Boero, R., Bellur, S., Mazzucco, G., Giannakakis, C., Honsova, E., Sundelin, B., Palma, A.M. di, Gutierrez, E., Asunis, A.M., Barratt, J., Tardanico, R., Perkowska-Ptasinska, A., Terroba, J.A., Fortunato, M., Pantzaki, A., Ozluk, Y., Steenbergen, E., Soderberg, M., Riispere, Z., Furci, L., Orhan, D., Kipgen, D., Casartelli, D., Ljubanovic, D.G., Gakiopoulou, H., Bertoni, E., Ortiz, P.C., Karkoszka, H., Groene, H.J., Stoppacciaro, A., Bajema, I., Bruijn, J., Oliveras, X.F., Maldyk, J., Loachim, E., Bavbek, N., Cook, T., Alpers, C., Berthoux, F., Bonsib, S., D'Agati, V., D'Amico, G., Emancipator, S., Emmal, F., Fervenza, F., Florquin, S., Fogo, A., Groene, H., Haas, M., Hill, P., Hogg, R., Hsu, S., Hunley, T., Hladunewich, Jennette, C., Joh, K., Julian, B., Kawamura, T., Lai, F., Leung, C., Li, L., Li, P., Liu, Z., Massat, A., Mackinnon, B., Mezzano, S., Schena, F., Tomino, Y., Walker, P., Wang, H., Weening, J., Yoshikawa, N., Zeng, C.H., Shi, S.F., Nogi, C., Suzuki, H., Koike, K., Hirano, K., Yokoo, T., Hanai, M., Fukami, K., Takahashi, K., Yuzawa, Y., Niwa, M., Yasuda, Y., Maruyama, S., Ichikawa, D., Suzuki, T., Shirai, S., Fukuda, A., Fujimoto, S., Trimarchi, H., Int IgA Nephropathy Network, and Pathology

Subjects
Adult, Male, medicine.medical_specialty, Risk Assessment, 01 natural sciences, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, Internal Medicine, Humans, Medicine, 030212 general & internal medicine, 0101 mathematics, business.industry, Proportional hazards model, Clinical study design, 010102 general mathematics, Glomerulonephritis, IGA, Middle Aged, Models, Theoretical, medicine.disease, Clinical trial, Cohort, Female, business, Risk assessment, Kidney disease
Abstract

ImportanceAlthough 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. ObjectiveTo 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. Design, Setting, and ParticipantsWe 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. Main Outcomes and MeasuresCox 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-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe 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-D(2) (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 (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 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-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn 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.

Published
2019

5. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy

Author

Barbour, Sean J. Coppo, Rosanna Zhang, Hong Liu, Zhi-Hong and Suzuki, Yusuke Matsuzaki, Keiichi Katafuchi, Ritsuko Er, Lee Espino-Hernandez, Gabriela Kim, S. Joseph Reich, Heather N. Feehally, John Cattran, Daniel C. Russo, M. L. and Troyanov, S. Cook, H. T. Roberts, I. Tesar, V. and Maixnerova, D. Lundberg, S. Gesualdo, L. Emma, F. and Fuiano, L. Beltrame, G. Rollino, C. Amore, A. Camilla, R. Peruzzi, L. Praga, M. Feriozzi, S. Polci, R. and Segoloni, G. Colla, L. Pani, A. Piras, D. Angioi, A. and Cancarini, G. Ravera, S. Durlik, M. Moggia, E. Ballarin, J. Di Giulio, S. Pugliese, F. Serriello, I. Caliskan, Y. and Sever, M. Kilicaslan, I. Locatelli, F. Del Vecchio, L. and Wetzels, J. F. M. Peters, H. Berg, U. Carvalho, F. and da Costa Ferreira, A. C. Maggio, M. Wiecek, A. and Ots-Rosenberg, M. Magistroni, R. Topaloglu, R. Bilginer, Y. and D'Amico, M. Stangou, M. Giacchino, F. Goumenos, D. and Kalliakmani, P. Gerolymos, M. Galesic, K. Geddes, C. and Siamopoulos, K. Balafa, O. Galliani, M. Stratta, P. and Quaglia, M. Bergia, R. Cravero, R. Salvadori, M. Cirami, L. Fellstrorn, B. Smerud, H. Kloster Ferrario, F. and Stellato, T. Egido, J. Martin, C. Floege, J. Eitner, F. and Lupo, A. Bernich, P. Mene, R. Morosetti, M. van Kooten, C. Rabelink, T. Reinders, M. E. J. Boria Grinyo, J. M. Cusinato, S. Benozzi, L. Savoldi, S. Licata, C. and Mizerska-Wasiak, M. Martina, G. Messuerotti, A. Dal Canton, A. Esposito, C. Migotto, C. Triolo, G. Mariano, F. and Pozzi, C. Boero, R. Bellur, S. Mazzucco, G. Giannakakis, C. Honsova, E. Sundelin, B. Di Palma, A. M. Ferrario, F. and Gutierrez, E. Asunis, A. M. Barratt, J. Tardanico, R. and Perkowska-Ptasinska, A. Arce Terroba, J. Fortunato, M. and Pantzaki, A. Ozluk, Y. Steenbergen, E. Soderberg, M. and Riispere, Z. Furci, L. Orhan, D. Kipgen, D. Casartelli, D. Ljubanovic, D. Galesic Gakiopoulou, H. Bertoni, E. and Cannata Ortiz, P. Karkoszka, H. Groene, H. J. Stoppacciaro, A. Bajema, I. Bruijn, J. Fulladosa Oliveras, X. Maldyk, J. Loachim, E. Bavbek, N. Cook, T. Troyanov, S. and Alpers, C. Amore, A. Barratt, J. Berthoux, F. Bonsib, S. and Bruijn, J. D'Agati, V D'Amico, G. Emancipator, S. and Emmal, F. Ferrario, F. Fervenza, F. Florquin, S. Fogo, A. Geddes, C. Groene, H. Haas, M. Hill, P. Hogg, R. and Hsu, S. Hunley, T. Hladunewich Jennette, C. Joh, K. and Julian, B. Kawamura, T. Lai, F. Leung, C. Li, L. and Li, P. Liu, Z. Massat, A. Mackinnon, B. Mezzano, S. and Schena, F. Tomino, Y. Walker, P. Wang, H. Weening, J. and Yoshikawa, N. Zeng, Cai-Hong Shi, Sufang Nogi, C. and Suzuki, H. Koike, K. Hirano, K. Kawamura, T. Yokoo, T. and Hanai, M. Fukami, K. Takahashi, K. Yuzawa, Y. Niwa, M. Yasuda, Y. Maruyama, S. Ichikawa, D. Suzuki, T. and Shirai, S. Fukuda, A. Fujimoto, S. Trimarchi, H. Int IgA Nephropathy Network

Abstract

ImportanceAlthough 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. ObjectiveTo 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. Design, Setting, and ParticipantsWe 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. Main Outcomes and MeasuresCox 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-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe 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-D(2) (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 (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 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-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn 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.

Published
2019

7. The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults

Author

Coppo, R., Troyanov, S., Camilla, R., Hogg, R.J., Cattran, D.C., Cook, H.T., Feehally, J., Roberts, I.S.D., Amore, A., Alpers, C.E., Barratt, J., Berthoux, F., Bonsib, S., Bruijn, J.A., D'Agati, V., D'Amico, G., Emancipator, S.N., Emma, F., Ferrario, F., Fervenza, F.C., Florquin, S., Fogo, A.B., Geddes, C.C., Groene, H.J., Haas, M., Herzenberg, A.M., Hill, P.A., Hsu, S.I., Jennette, J.C., Joh, K., Julian, B.A., Kawamura, T., Lai, F.M., Li, L.S., Li, P.K., Liu, Z.H., Mezzano, S., Schena, F.P., Tomino, Y., Walker, P.D., Wang, H.Y., Weening, J.J., Yoshikawa, N., Zhang, H., Int igA Nephropathy Network, Renal Pathology Soc, Psychiatry, Pathology, AII - Amsterdam institute for Infection and Immunity, and Other departments

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Biopsy, Renal function, Kidney, Kidney Function Tests, urologic and male genital diseases, Gastroenterology, Nephropathy, Glomerulonephritis, children, renal biopsy, Internal medicine, medicine, Humans, Child, children histopathology IgA nephropathy renal biopsy glomerular-filtration-rate prognostic indicators renal biopsies features japanese, Hematuria, Proteinuria, medicine.diagnostic_test, business.industry, Glomerulonephritis, IGA, IgA nephropathy, medicine.disease, Nephrology, Chronic Disease, Cohort, histopathology, Female, Histopathology, Renal biopsy, medicine.symptom, business, Immunosuppressive Agents
Abstract

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults. Kidney International (2010) 77, 921-927; doi: 10.1038/ki.2010.43; published online 3 March 2010

Published
2010

8. The ubiquitin-like protein FAT10 mediates NF-kappaB activation

Author

Gong, Pengfei, Canaan, A, Wang, B, Leventhal, J, Snyder, A, Nair, V, Cohen, C D, Kretzler, M, D'Agati, V, Weissman, S, Ross, M J, and University of Zurich

Subjects
2727 Nephrology, 570 Life sciences, biology, 610 Medicine & health, 10035 Clinic for Nephrology, 10052 Institute of Physiology
Published
2010

10. Glycation and diabetes: The RAGE connection

Author

Hudson, B. I., Hofmann, M. A., Bucciarelli, L., Wendt, T., Bernhard Moser, Lu, Y., Qu, W., Stern, D. M., D Agati, V., Yan, S. D., Yan, S. F., Grant, P. J., and Schmidt, A. M.

12. Le case e la polvere del tempo. Stanze infestate, studi verdi, soffitti anneriti nelle ultime novelle di Luigi Pirandello

Author

C. Carmina, Carmina, C, La Monaca, D, Castello, A, D'Agati, V, Librizzi, N, Gatto, S, Ferlita, S, Inzerillo, G, Spina, G, Pinello, C, Tedesco, L., and C. Carmina

Subjects
House, home, Pirandello, short stories, literary space, Settore L-FIL-LET/11 - Letteratura Italiana Contemporanea
Abstract

The essay analyzes the methods of representation of the house in Pirandello's latest novels. In these short stories, the intimate space of the house becomes an emblem of the dissipation of life, of its disintegrated and fleeting character, in which the destructive flow of time dominates unchallenged.

Published
2022

13. Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy

Author

Sean J. Barbour, Rosanna Coppo, Hong Zhang, Zhi-Hong Liu, Yusuke Suzuki, Keiichi Matsuzaki, Lee Er, Heather N. Reich, Jonathan Barratt, Daniel C. Cattran, M.L. Russo, S. Troyanov, H.T. Cook, I. Roberts, V. Tesar, D. Maixnerova, S. Lundberg, L. Gesualdo, F. Emma, L. Fuiano, G. Beltrame, C. Rollino, A. Amore, R. Camilla, L. Peruzzi, M. Praga, S. Feriozzi, R. Polci, G. Segoloni, L. Colla, A. Pani, D. Piras, A. Angioi, G. Cancarini, S. Ravera, M. Durlik, E. Moggia, J. Ballarin, S. Di Giulio, F. Pugliese, I. Serriello, Y. Caliskan, M. Sever, I. Kilicaslan, F. Locatelli, L. Del Vecchio, J.F.M. Wetzels, H. Peters, U. Berg, F. Carvalho, A.C. da Costa Ferreira, M. Maggio, A. Wiecek, M. Ots-Rosenberg, R. Magistroni, R. Topaloglu, Y. Bilginer, M. D’Amico, M. Stangou, F. Giacchino, D. Goumenos, E. Papachristou, K. Galesic, C. Geddes, K. Siamopoulos, O. Balafa, M. Galliani, P. Stratta, M. Quaglia, R. Bergia, R. Cravero, M. Salvadori, L. Cirami, B. Fellstrom, H. Kloster Smerud, F. Ferrario, T. Stellato, J. Egido, C. Martin, J. Floege, F. Eitner, A. Lupo, P. Bernich, P. Menè, M. Morosetti, C. van Kooten, T. Rabelink, M.E.J. Reinders, J.M. Boria Grinyo, S. Cusinato, L. Benozzi, S. Savoldi, C. Licata, M. Mizerska-Wasiak, G. Martina, A. Messuerotti, A. Dal Canton, C. Esposito, C. Migotto, G. Triolo, F. Mariano, C. Pozzi, R. Boero, S. Bellur, G. Mazzucco, C. Giannakakis, E. Honsova, B. Sundelin, A.M. Di Palma, E. Gutiérrez, A.M. Asunis, J. Barratt, R. Tardanico, A. Perkowska-Ptasinska, J. Arce Terroba, M. Fortunato, A. Pantzaki, Y. Ozluk, E. Steenbergen, M. Soderberg, Z. Riispere, L. Furci, D. Orhan, D. Kipgen, D. Casartelli, D. Galesic Ljubanovic, H. Gakiopoulou, E. Bertoni, P. Cannata Ortiz, H. Karkoszka, H.J. Groene, A. Stoppacciaro, I. Bajema, J. Bruijn, X. Fulladosa Oliveras, J. Maldyk, E. Ioachim, N. Bavbek, T. Cook, C. Alpers, F. Berthoux, S. Bonsib, V. D’Agati, G. D’Amico, S. Emancipator, F. Emmal, F. Fervenza, S. Florquin, A. Fogo, H. Groene, M. Haas, P. Hill, R. Hogg, S. Hsu, T. Hunley, M. Hladunewich, C. Jennette, K. Joh, B. Julian, T. Kawamura, F. Lai, C. Leung, L. Li, P. Li, Z. Liu, A. Massat, B. Mackinnon, S. Mezzano, F. Schena, Y. Tomino, P. Walker, H. Wang, J. Weening, N. Yoshikawa, C.-H. Zeng, S. Shi, C. Nogi, H. Suzuki, K. Koike, K. Hirano, T. Yokoo, M. Hanai, K. Fukami, K. Takahashi, Y. Yuzawa, M. Niwa, Y. Yasuda, S. Maruyama, D. Ichikawa, T. Suzuki, S. Shirai, A. Fukuda, S. Fujimoto, H. Trimarchi, Triolo, G., Mariano, F., Pozzi, C., Boero, R., Bellur, S., Mazzucco, G., Giannakakis, C., Honsova, E., Sundelin, B., Di Palma, A. M., Russo, M. L., Ferrario, F., Gutiérrez, E., Asunis, A. M., Barratt, J., Tardanico, R., Perkowska-Ptasinska, A., Terroba, J. Arce, Fortunato, M., Pantzaki, A., Ozluk, Y., Troyanov, S., Steenbergen, E., Soderberg, M., Riispere, Z., Furci, L., Orhan, D., Kipgen, D., Casartelli, D., Ljubanovic, D. Galesic, Gakiopoulou, H., Bertoni, E., Cook, H. T., Cannata Ortiz, P., Karkoszka, H., Groene, H. J., Stoppacciaro, A., Bajema, I., Bruijn, J., Fulladosa Oliveras, X., Maldyk, J., Ioachim, E., Bavbek, N., Roberts, I., Cook, T., Alpers, C., Amore, A., Berthoux, F., Bonsib, S., D'Agati, V., D'Amico, G., Tesar, V., Emancipator, S., Emmal, F., Fervenza, F., Florquin, S., Fogo, A., Geddes, C., Groene, H., Haas, M., Hill, P., Maixnerova, D., Hogg, R., Hsu, S., Hunley, T., Hladunewich, M., Jennette, C., Joh, K., Julian, B., Kawamura, T., Lai, F., Leung, C., Lundberg, S., Li, L., Li, P., Liu, Z., Massat, A., Mackinnon, B., Mezzano, S., Schena, F., Tomino, Y., Walker, P., Wang, H., Gesualdo, L., Weening, J., Yoshikawa, N., Zeng, C.-H., Shi, S., Nogi, C., Suzuki, H., Koike, K., Hirano, K., Yokoo, T., Emma, F., Hanai, M., Fukami, K., Takahashi, K., Yuzawa, Y., Niwa, M., Yasuda, Y., Maruyama, S., Ichikawa, D., Suzuki, T., Shirai, S., Fuiano, L., Fukuda, A., Fujimoto, S., Trimarchi, H., Beltrame, G., Rollino, C., Camilla, R., Peruzzi, L., Praga, M., Feriozzi, S., Polci, R., Segoloni, G., Colla, L., Pani, A., Piras, D., Angioi, A., Cancarini, G., Ravera, S., Durlik, M., Moggia, E., Ballarin, J., Di Giulio, S., Pugliese, F., Serriello, I., Caliskan, Y., Sever, M., Kilicaslan, I., Locatelli, F., Del Vecchio, L., Wetzels, J. F. M., Peters, H., Berg, U., Carvalho, F., da Costa Ferreira, A. C., Maggio, M., Wiecek, A., Ots-Rosenberg, M., Magistroni, R., Topaloglu, R., Bilginer, Y., D'Amico, M., Stangou, M., Giacchino, F., Goumenos, D., Papachristou, E., Galesic, K., Siamopoulos, K., Balafa, O., Galliani, M., Stratta, P., Quaglia, M., Bergia, R., Cravero, R., Salvadori, M., Cirami, L., Fellstrom, B., Smerud, H. Kloster, Stellato, T., Egido, J., Martin, C., Flöge, Jürgen, Eitner, F., Lupo, A., Bernich, P., Menè, P., Morosetti, M., van Kooten, C., Rabelink, T., Reinders, M. E. J., Boria Grinyo, J. M., Cusinato, S., Benozzi, L., Savoldi, S., Licata, C., Mizerska-Wasiak, M., Martina, G., Messuerotti, A., Dal Canton, A., Esposito, C., Migotto, C., Pathology, Center of Experimental and Molecular Medicine, Graduate School, and ACS - Heart failure & arrhythmias

Subjects
Adult, disease progression, end-stage kidney disease, IgA nephropathy, prediction tool, risk prediction, Biopsy, Glomerulonephritis, IGA, Prognosis, Cohort Studies, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Nephrology, Humans, Renal Insufficiency, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], Glomerular Filtration Rate
Abstract

Kidney international 102(1), 160-172 (2022). doi:10.1016/j.kint.2022.02.042, Published by Elsevier, New York, NY

Published
2022
Full Text
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14. Whole-Exome Sequencing in Adults With Chronic Kidney Disease A Pilot Study

Author

David Fasel, Gerald B. Appel, Corinne Antignac, Hila Milo Rasouly, Andrew S. Bomback, Marcin Zaniew, Aditya Mattoo, Anna Materna-Kiryluk, Francesca Lugani, Glen S. Markowitz, Wooin Ahn, Sneh Lata, Krzysztof Kiryluk, Luca Rampoldi, Vivette D. D'Agati, Maya K. Rao, Miguel Verbitsky, Adele Mitrotti, Chad A. Newton, Ali G. Gharavi, Simone Sanna-Cherchi, Gianluca Caridi, Jai Radhakrishnan, Lindsey M. Slater, Pietro A. Canetta, Rik Westland, Vaidehi Jobanputra, Emily E. Groopman, Maddalena Marasa, Christine Kim Garcia, Jordan G. Nestor, Yifu Li, Lata, S, Marasa, M, Li, Yf, Fasel, Da, Groopman, E, Jobanputra, V, Rasouly, H, Mitrotti, A, Westland, R, Verbitsky, M, Nestor, J, Slater, Lm, D'Agati, V, Zaniew, M, Materna-Kiryluk, A, Lugani, F, Caridi, G, Rampoldi, L, Mattoo, A, Newton, Ca, Rao, Mk, Radhakrishnan, J, Ahn, W, Canetta, Pa, Bomback, A, Appel, Gb, Antignac, C, Markowitz, G, Garcia, Ck, Kiryluk, K, Sanna-Cherchi, S, and Gharavi, Ag

Subjects
Adult, Male, 0301 basic medicine, Proband, medicine.medical_specialty, Population, 030232 urology & nephrology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Exome, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, education, Exome sequencing, education.field_of_study, business.industry, Donor selection, Sequence Analysis, DNA, General Medicine, Middle Aged, medicine.disease, Transplantation, 030104 developmental biology, Mutation, Medical genetics, Female, New York City, business, Kidney disease
Abstract

Background The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown. Objective To study the diagnostic utility of WES in a selected referral population of adults with CKD. Design Observational cohort. Setting A major academic medical center. Patients 92 adults with CKD of unknown cause or familial nephropathy or hypertension. Measurements The diagnostic yield of WES and its potential effect on clinical management. Results Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy. Limitation The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population. Conclusion Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted. Primary funding source New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

Published
2018

15. Letteratura e musica nel Novecento. D'Annunzio, Montale, Zanzotto

Author

INZERILLO, Giovanni, Perrone, D, Tedesco, N, Calina, N, Inzerillo, G, Jansen, M, Arts, C, Lanslot, I, Cergna, S, Cannavacciuolo, L, Farrugia, C, Bastiansen, M, D'Agati, V, O'Connell, D, and Kretschmann, T

Subjects
Comparatistica musico-letteraria, D'Annunzio, Montale, Zanzotto, Settore L-FIL-LET/11 - Letteratura Italiana Contemporanea
Published
2014

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