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

Author

Barbour, Sean J., Coppo, Rosanna, Zhang, Hong, Liu, Zhi-Hong, 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., 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., Fellström, Bengt, Smerud, Hilde Kloster, Ferrario, F., Stellato, T., Egido, J., Martin, C., Floege, J., Eitner, F., 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., 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., Ljubanovic, D. Galesic, Gakiopoulou, H., Bertoni, E., 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., 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, M., 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, Cai-Hong, Shi, Sufang, 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., Barbour, Sean J., Coppo, Rosanna, Zhang, Hong, Liu, Zhi-Hong, 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., 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., Fellström, Bengt, Smerud, Hilde Kloster, Ferrario, F., Stellato, T., Egido, J., Martin, C., Floege, J., Eitner, F., 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., 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., Ljubanovic, D. Galesic, Gakiopoulou, H., Bertoni, E., 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., 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, M., 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, Cai-Hong, Shi, Sufang, 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., and Trimarchi, H.

Abstract

Importance 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. Objective 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. Design, Setting, and Participants 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. Main Outcomes and Measures 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 R2D measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. Results 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 R2D (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

Published
2019
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5. Risk factors for progression in children and young adults with IgA nephropathy : an analysis of 261 cases from the VALIGA European cohort

Author

Coppo, Rosanna, Lofaro, Danilo, Camilla, Roberta R., Bellur, Shubha, Cattran, Daniel, Cook, H. Terence, Roberts, Ian S. D., Peruzzi, Licia, Amore, Alessandro, Emma, Francesco, Fuiano, Laura, Berg, Ulla, Topaloglu, Rezan, Bilginer, Yelda., Gesualdo, Loreto, Polci, Rosaria, Mizerska-Wasiak, Malgorzata, Caliskan, Yasar, Lundberg, Sigrid, Cancarini, Giovanni, Geddes, Colin, Wetzels, Jack, Wiecek, Andrzej, Durlik, Magdalena, Cusinato, Stefano, Rollino, Cristiana, Maggio, Milena, Praga, Manuel, Smerud, Hilde Kloster, Tesar, Vladimir, Maixnerova, Dita, Barratt, Jonathan, Papalia, Teresa, Bonofiglio, Renzo, Mazzucco, Gianna, Giannakakis, Costantinos, Söderberg, Magnus, Orhan, Diclehan, Di Palma, Anna Maria, Maldyk, Jadwiga, Ozluk, Yasemin, Sudelin, Birgitta, Tardanico, Regina, Kipgen, David, Steenbergen, Eric, Karkoszka, Henryk, Perkowska-Ptasinska, Agnieszka, Ferrario, Franco, Gutierrez, Eduardo, Honsova, Eva, Coppo, Rosanna, Lofaro, Danilo, Camilla, Roberta R., Bellur, Shubha, Cattran, Daniel, Cook, H. Terence, Roberts, Ian S. D., Peruzzi, Licia, Amore, Alessandro, Emma, Francesco, Fuiano, Laura, Berg, Ulla, Topaloglu, Rezan, Bilginer, Yelda., Gesualdo, Loreto, Polci, Rosaria, Mizerska-Wasiak, Malgorzata, Caliskan, Yasar, Lundberg, Sigrid, Cancarini, Giovanni, Geddes, Colin, Wetzels, Jack, Wiecek, Andrzej, Durlik, Magdalena, Cusinato, Stefano, Rollino, Cristiana, Maggio, Milena, Praga, Manuel, Smerud, Hilde Kloster, Tesar, Vladimir, Maixnerova, Dita, Barratt, Jonathan, Papalia, Teresa, Bonofiglio, Renzo, Mazzucco, Gianna, Giannakakis, Costantinos, Söderberg, Magnus, Orhan, Diclehan, Di Palma, Anna Maria, Maldyk, Jadwiga, Ozluk, Yasemin, Sudelin, Birgitta, Tardanico, Regina, Kipgen, David, Steenbergen, Eric, Karkoszka, Henryk, Perkowska-Ptasinska, Agnieszka, Ferrario, Franco, Gutierrez, Eduardo, and Honsova, Eva

Abstract

There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. Data on 261 young patients [age < 23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. In this cohort of 261 subjects aged < 23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged < 18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ae0.4 g/day/1.73 m(2) and an eGFR of < 90 ml/min/1.73 m(2) were determined to be risk factors in subjects with M0. Children aged < 16 years with M0 and well-preserved eGFR (> 90 ml/min/1.73 m(2)) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN., Erratum in: Pediatric nephrology Vol 32 (1) pp: 193-194. DOI: 10.1007/s00467-016-3506-2

Published
2017
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6. IgA Nephropathy – Mucosal Immunity and Treatment Options

Author

Smerud, Hilde Kloster

Subjects
food allergens, budesonide, recurrence, pharmacological treatment, statin, mucosal immunity, clinical trial, IgA nephropathy, gastrointestinal sensitivity, renal transplantation, urologic and male genital diseases
Abstract

In the present studies we have explored the link between food hypersensitivity and IgA nephropathy (IgAN) and evaluated treatment options in primary and recurrent disease. Approximately one third of our IgAN patients had a rectal mucosal sensitivity to gluten, as demonstrated by increased local mucosal nitric oxide production and/or myeloperoxidase release after gluten challenge. The gluten sensitivity seemed to be an innate immune reaction unrelated to the pathogenesis of celiac disease. Approximately half of the patients had a rectal mucosal sensitivity to soy or cow’s milk (CM). The levels of IgG antibodies to alfa-lactalbumin, beta-lactoglobulin and casein were significantly higher in CM sensitive as compared with non-sensitive IgAN patients, indicating that an adaptive immune response might be involved in addition to the innate immune reaction observed. With the knowledge of gastrointestinal reactivity enteric treatment was considered as a potential new treatment approach of IgAN. A 6-month prospective trial demonstrated proof-of-concept for the use of enteric budesonide targeted to the ileocaecal region of IgAN patients. We observed a modest, but significant reduction in urine albumin, a minor reduction of serum creatinine and a modest increase of eGFR calculated by the MDRD equation. eGFR calculated from the Cockcroft-Gault formula and cystatin C was not changed. In a retrospective study recurrence of IgAN and graft loss was evaluated in Norwegian and Swedish patients having received a primary renal transplant due to IgAN. Adjusting for relevant covariates, a multiple Cox-regression analysis on time to IgAN recurrence showed that use of statins was associated with reduced risk of recurrence and reduced risk of graft loss. The time lag from diagnosis to first transplantation and female gender were also associated with lower risk of recurrence. Improved graft survival was associated with related donor, low donor age and no or low number of acute rejection episodes.

Published
2012

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