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51. 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

58. 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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59. Vascular bioengineering of scaffolds derived from human discarded transplant kidneys using human pluripotent stem cell-derived endothelium

Author

Leuning, DG, Witjas, FMR, Maanaoui, M, de Graaf, AMA, Lievers, E, Geuens, T, Avramut, CM, Wiersma, LE, van den Berg, CW, Sol, WMPJ, de Boer, H, Wang, G, LaPointe, VLS, van der Vlag, J, van Kooten, C, van den Berg, BM, Little, MH, Engelse, MA, Rabelink, TJ, Leuning, DG, Witjas, FMR, Maanaoui, M, de Graaf, AMA, Lievers, E, Geuens, T, Avramut, CM, Wiersma, LE, van den Berg, CW, Sol, WMPJ, de Boer, H, Wang, G, LaPointe, VLS, van der Vlag, J, van Kooten, C, van den Berg, BM, Little, MH, Engelse, MA, and Rabelink, TJ

Abstract

The bioengineering of a replacement kidney has been proposed as an approach to address the growing shortage of donor kidneys for the treatment of chronic kidney disease. One approach being investigated is the recellularization of kidney scaffolds. In this study, we present several key advances toward successful re-endothelialization of whole kidney matrix scaffolds from both rodents and humans. Based on the presence of preserved glycosoaminoglycans within the decelullarized kidney scaffold, we show improved localization of delivered endothelial cells after preloading of the vascular matrix with vascular endothelial growth factor and angiopoietin 1. Using a novel simultaneous arteriovenous delivery system, we report the complete re-endothelialization of the kidney vasculature, including the glomerular and peritubular capillaries, using human inducible pluripotent stem cell -derived endothelial cells. Using this source of endothelial cells, it was possible to generate sufficient endothelial cells to recellularize an entire human kidney scaffold, achieving efficient cell delivery, adherence, and endothelial cell proliferation and survival. Moreover, human re-endothelialized scaffold could, in contrast to the non-re-endothelialized human scaffold, be fully perfused with whole blood. These major advances move the field closer to a human bioengineered kidney.

Published
2019

69. A Restricted Role for FcgammaR in the Regulation of Adaptive Immunity

Author

Fransen, M. F., Benonisson, H., van Maren, W. W., Sow, H. S., Breukel, C., Linssen, M. M., Claassens, J. W. C., Brouwers, C., van der Kaa, J., Camps, M., Kleinovink, J. W., Vonk, K. K., van Heiningen, S., Klar, N., van Beek, L., van Harmelen, V., Daxinger, L., Nandakumar, Kutty Selva, Holmdahl, R., Coward, C., Lin, Q., Hirose, S., Salvatori, D., van Hall, T., van Kooten, C., Mastroeni, P., Ossendorp, F., Verbeek, J. S., Fransen, M. F., Benonisson, H., van Maren, W. W., Sow, H. S., Breukel, C., Linssen, M. M., Claassens, J. W. C., Brouwers, C., van der Kaa, J., Camps, M., Kleinovink, J. W., Vonk, K. K., van Heiningen, S., Klar, N., van Beek, L., van Harmelen, V., Daxinger, L., Nandakumar, Kutty Selva, Holmdahl, R., Coward, C., Lin, Q., Hirose, S., Salvatori, D., van Hall, T., van Kooten, C., Mastroeni, P., Ossendorp, F., and Verbeek, J. S.

Abstract

By their interaction with IgG immune complexes, FcgammaR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcgammaR-knockout mice, it has been concluded that FcgammaRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcgammaRs (FcgammaRI/II/III/IV(-/-) mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcgammaRIIb-deficient mice, FcgammaRI/II/III/IV(-/-) mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcgammaRs in the modulation of the adaptive immune response in vivo. We conclude that FcgammaRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.

Published
2018
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71. FRI0311 The effect of b cell targeted therapies on autoantibodies and excessive neutrophil extracellular trap formation in systemic lupus erythematosus patients

Author

Van Dam, L.S., primary, Osmani, Z., additional, Kraaij, T., additional, Kamerling, S.W., additional, Bakker, J.A., additional, Scherer, H.U., additional, Rabelink, T.J., additional, Voll, R.E., additional, Isenberg, D., additional, van Kooten, C., additional, and Teng, Y.O., additional

Published
2018
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73. PS7:129 Synergetic b-cell immunomodulation with rituximab and belimumab combination treatment in severe, refractory sle

Author

Kraaij, T, primary, Kamerling, SWA, additional, de Rooij, ENM, additional, van Daele, PLA, additional, Bredewold, OW, additional, Bakker, JA, additional, Bajema, IM, additional, Scherer, HU, additional, Toes, REM, additional, Huizinga, TWJ, additional, Rabelink, TJ, additional, van Kooten, C, additional, and Teng, YKO, additional

Published
2018
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74. Development and testing of an artificial intelligence tool for predicting end-stage kidney disease in patients with immunoglobulin A nephropathy

Author

Schena, Francesco Paolo, Anelli, Vito Walter, Trotta, Joseph, Di Noia, Tommaso, Manno, Carlo, Tripepi, Giovanni, D’Arrigo, Graziella, Chesnaye, Nicholas C., Russo, Maria Luisa, Stangou, Maria, Papagianni, Aikaterini, Zoccali, Carmine, Tesar, Vladimir, Coppo, Rosanna, Tesar, V., Maixnerova, D., Lundberg, S., Gesualdo, L., Emma, F., Fuiano, L., Beltrame, G., Rollino, C., Coppo, R., Amore, A., Camilla, R., Peruzzi, L., Praga, M., Feriozzi, S., Polci, R., Segoloni, G., Colla, L., Pani, A., Angioi, A., Piras, L., Feehally, J., 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., Papasotiriou, M., Galesic, K., Toric, L., Geddes, C., Siamopoulos, K., Balafa, O., Galliani, M., Stratta, P., Quaglia, M., Bergia, R., Cravero, R., Salvadori, M., Cirami, L., Fellstrom, B., Smerud, H. Kloster, Ferrario, F., Stellato, T., Egido, J., Martin, C., Floege, J., Eitner, F., Rauen, T., Lupo, A., Bernich, P., Menè, P., Morosetti, M., van Kooten, C., Rabelink, T., Reinders, M.E.J., Grinyo, J.M. Boria, Cusinato, S., Benozzi, L., Savoldi, S., Licata, C., Mizerska-Wasiak, M., Roszkowska-Blaim, M., Martina, G., Messuerotti, A., Canton, A. Dal, Esposito, C., Migotto, C., Triolo, G., Mariano, F., Pozzi, C., Boero, R., Mazzucco, Giannakakis, C., Honsova, E., Sundelin, B., Di Palma, A.M., Ferrario, F., Gutiérrez, E., Asunis, A.M., Barratt, J., Tardanico, R., Perkowska-Ptasinska, A., Terroba, J. Arce, Fortunato, M., Pantzaki, A., Ozluk, Y., Steenbergen, E., Soderberg, M., Riispere, Z., Furci, L., Orhan, D., Kipgen, D., Casartelli, D., GalesicLjubanovic, D., Gakiopoulou, H., Bertoni, E., Ortiz, P. Cannata, Karkoszka, H., Groene, H.J., Stoppacciaro, A., Bajema, I., Bruijn, J., FulladosaOliveras, X., Maldyk, J., Ioachim, E., Abbrescia, Daniela, Kouri, Nikoleta, Stangou, Maria, Papagianni, Aikaterini, Scolari, Francesco, Delbarba, Elisa, Bonomini, Mario, Piscitani, Luca, Stallone, Giovanni, Infante, Barbara, Godeas, Giulia, Madio, Desiree, Biancone, Luigi, Campagna, Marco, Zaza, Gianluigi, Squarzoni, Isabella, and Cangemi, Concetta

Abstract

We have developed an artificial neural network prediction model for end-stage kidney disease (ESKD) in patients with primary immunoglobulin A nephropathy (IgAN) using a retrospective cohort of 948 patients with IgAN. Our tool is based on a two-step procedure of a classifier model that predicts ESKD, and a regression model that predicts development of ESKD over time. The classifier model showed a performance value of 0.82 (area under the receiver operating characteristic curve) in patients with a follow-up of five years, which improved to 0.89 at the ten-year follow-up. Both models had a higher recall rate, which indicated the practicality of the tool. The regression model showed a mean absolute error of 1.78 years and a root mean square error of 2.15 years. Testing in an independent cohort of 167patients with IgAN found successful results for 91% of the patients. Comparison of our system with other mathematical models showed the highest discriminant Harrell C index at five- and ten-years follow-up (81% and 86%, respectively), paralleling the lowest Akaike information criterion values (355.01 and 269.56, respectively). Moreover, our system was the best calibrated model indicating that the predicted and observed outcome probabilities did not significantly differ. Finally, the dynamic discrimination indexes of our artificial neural network, expressed as the weighted average of time-dependent areas under the curve calculated at one and two years, were 0.80 and 0.79, respectively. Similar results were observed over a 25-year follow-up period. Thus, our tool identified individuals who were at a high risk of developing ESKD due to IgAN and predicted the time-to-event endpoint. Accurate prediction is an important step toward introduction of a therapeutic strategy for improving clinical outcomes.

Published
2021
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75. 2 Aangeboren immuniteit en acute ontsteking

Author

van Kooten, C. and Daha, M.R.

Subjects
Article
Abstract

Samenvatting Een van de belangrijkste functies van het immuunsysteem is het beschermen van ons lichaam tegen infecties. Om deze bescherming te kunnen realiseren, moet aan een aantal voorwaarden worden voldaan: 1) het immuunsysteem moet het pathogeen ter plaatse en liefst specifiek kunnen herkennen; 2) het immuunsysteem moet het pathogeen zo snel mogelijk onschadelijk maken en opruimen; en 3) het immuunsysteem moet een geheugen opbouwen, zodat hetzelfde pathogeen een volgende maal sneller en efficiënter geëlimineerd kan worden. Hoewel het derde aspect een speciale eigenschap is van de adaptieve immuniteit, is voor de eerste twee punten een nauwe samenwerking tussen de innate (aangeboren) en de adaptieve (verworven) immuniteit noodzakelijk. Elektronisch aanvullend materiaal De online versie van dit hoofdstuk (doi:10.1007/978-90-368-1613-7_2) bevat aanvullend materiaal, dat beschikbaar is voor geautoriseerde gebruikers.

Published
2013

76. Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy

Author

Feehally, J, Coppo, R, Troyanov, S, Bellur, Ss, Cattran, D, Cook, T, Roberts, Is, Verhave, Jc, Camilla, R, Vergano, L, Egido, J, Wiecek, A, Karkoszka, H, Tesar, V, Maixnerova, D, Ots-Rosenberg, M, Quaglia, M, Rollino, C, Magistroni, R, Cusinato, S, Cravero, R, Peruzzi, L, Lundberg, S, Gesualdo, L, Cancarini, G, Feriozzi, S, Ferrario, F, Emma, F, Fuiano, L, Beltrame, G, Amore, A, Praga, M, Polci, R, Biancone, L, Colla, L, Pani, A, Angioi, A, Piras, D, Ravera, S, Durlik, M, Moggia, E, Ballarin, J, Di Giulio, S, Pierucci, A, Caliskan, Y, Sever, M, Kilicaslan, I, Locatelli, F, Del Vecchio, L, Wetzels, Jf, Peters, H, Berg, U, Carvalho, F, da Costa Ferreira AC, Maggio, M, 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, Bergia, R, Salvadori, M, Cirami, L, Fellstrom, B, Kloster Smerud, H, Stellato, T, Cleary, C, Floege, J, Rauen, T, Lupo, A, Bernich, P, Menè, P, Morosetti, M, van Kooten, C, Rabelink, T, Reinders, Me, Boria Grinyo JM, Benozzi, L, Savoldi, S, Licata, C, Mizerska-Wasiak, M, Roszkowska-Blaim, M, Martina, G, Messuerotti, A, Dal Canton, A, Esposito, C, Migotto, C, Triolo, G, Mariano, F, Pozzi, C, Di Palma AM, Boero, R, Mazzucco, G, Giannakakis, C, Honsova, E, Sundelin, B, Gutiérrez, E, Asunis, Am, 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, Groene, Hj, Stoppacciaro, A, Bajema, I, Bruijn, J, Fulladosa Oliveras, X, Maldyk, J, and Ioachim, E.

Subjects
Male, Physiology, medicine.medical_treatment, IgA nephropathy, Tonsillectomy, Risk factors, Progression of chronic renal failure, 030232 urology & nephrology, 030204 cardiovascular system & hematology, urologic and male genital diseases, Gastroenterology, Progression of chronic renal failure, Cohort Studies, Kidney Failure, Glomerulonephritis, 0302 clinical medicine, Ethnicity, Chronic, Proteinuria, medicine.diagnostic_test, Age Factors, IgA nephropathy, Middle Aged, Europe, Treatment Outcome, Nephrology, Cohort, Disease Progression, Female, Renal biopsy, medicine.symptom, Glomerular Filtration Rate, Cohort study, Adult, medicine.medical_specialty, Urology, Renal function, Ethnic Groups, Nephropathy, iga nephropathy, tonsillectomy, risk factors, progression of chronic renal failure, 03 medical and health sciences, Sex Factors, Physiology (medical), Internal medicine, Risk factors, Tonsillectomy, medicine, Humans, Follow-Up Studies, Glomerulonephritis, IGA, Kidney Failure, Chronic, Propensity Score, Retrospective Studies, IGA, business.industry, Retrospective cohort study, medicine.disease, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business
Abstract

Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.

Published
2016

78. IgG is elevated in obese white adipose tissue but does not induce glucose intolerance via Fcγ-receptor or complement

Author

van Dam, A D, primary, van Beek, L, additional, Pronk, A C M, additional, van den Berg, S M, additional, Van den Bossche, J, additional, de Winther, M P J, additional, Koning, F, additional, van Kooten, C, additional, Rensen, P C N, additional, Boon, M R, additional, Verbeek, J S, additional, van Dijk, K Willems, additional, and van Harmelen, V, additional

Published
2017
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81. Evidence from the large VALIGA cohort validates the subclassification of focal segmental glomerulosclerosis in IgA nephropathy

Author

Bellur, Shubha S., Troyanov, Stéphan, Vorobyeva, Olga, Coppo, Rosanna, Roberts, Ian S.D., Coppo, R., Feehaly, J., Troyanov, S., Cattran, D.C., Cook, H.T., Roberts, I., Radcliffe, John, Russo, M.L., 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., Papagianni, K., Stangou, M., Giacchino, F., Goumenos, D., Papasotirious, M., Kalliakmani, P., Gerolymos, M., Galesic, K., Toric, L., 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., Roszkowska-Blaim, M., Durlik, M., Hryszko, T., Klinger, M., Kamińska, D., Krajewska, M., Martina, G., Messuerotti, A., Dal Canton, A., Esposito, C., Migotto, C., Triolo, G., Mariano, F., Pozzi, C., Boero, R., Cambier, A., Bellur, S., Mazzucco, G., Giannakakis, C., Honsova, E., Sundelin, B., Di Palma, A.M., Ferrario, F., Diomedi-Casadei, F., 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., and Royal, V.

Abstract

Evidence from the Oxford IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S1). Using the larger Validation in IgA (VALIGA) study cohort, we investigated the association between podocytopathic changes and higher proteinuria, kidney outcome and response to immunosuppressive therapy. All biopsies were evaluated for glomeruli with segmental capillary occlusion by matrix (“not otherwise specified”, NOS lesion), simple capsular adhesion without capillary occlusion (Adh), tip lesions, and podocyte hypertrophy (PH). S1 required a NOS lesion and/or Adh. A Chi-Squared Automatic Interaction Detection method was used to identify subgroups of FSGS lesions associated with distinctive proteinuria at biopsy and assessed survival from a combined event (kidney failure or 50% decline in estimated glomerular filtration rate). Finally, we evaluated within each subgroup if immunosuppression was associated with a favorable outcome using propensity analysis. In 1147 patients, S1 was found in 70% of biopsies. Subclassification found NOS lesions in 44%, Adh in 59%, PH in 13%, and tip lesions in 3%, with much overlap. Four subgroups were identified with progressively higher proteinuria: from lowest, S1 without NOS, S1 with NOS but without Adh/PH, to highest, S1 with NOS and Adh but without PH, and S1 with NOS and PH. These four subgroups showed progressively worse kidney survival. Immunosuppression was associated with a better outcome only in the two highest proteinuria subgroups. Propensity analysis in these two groups, adjusted for clinical and pathological findings, found a significant time-dependent hazard of combined outcome with corticosteroids. Podocyte hypertrophy and glomeruli with simple adhesions appeared to reflect active lesions associated with a response to corticosteroids, while other S1 lesions defined chronicity. Thus, our findings support subclassifying S1 lesions in IgAN.

Published
2024
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82. Microarray gene expression analysis to evaluate cell type specific expression of targets relevant for immunotherapy of hematological malignancies

Author

Pont, MJ, Honders, MW, Kremer, AN, Van Kooten, C, Out, C, Hiemstra, PS, De Boer, HC, Jager, MJ, Schmelzer, E, Vries, RG, Al Hinai, AS, Kroes, WG, Monajemi, R, Goeman, JJ, Böhringer, S, Marijt, WAF, Falkenburg, JHF, Griffioen, M, Pont, MJ, Honders, MW, Kremer, AN, Van Kooten, C, Out, C, Hiemstra, PS, De Boer, HC, Jager, MJ, Schmelzer, E, Vries, RG, Al Hinai, AS, Kroes, WG, Monajemi, R, Goeman, JJ, Böhringer, S, Marijt, WAF, Falkenburg, JHF, and Griffioen, M

Abstract

Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers.

Published
2016

83. Microarray gene expression analysis to evaluate cell type specific expression of targets relevant for immunotherapy of hematological malignancies

Author

Pont, M. J., Honders, M. W., Kremer, A. N., Van Kooten, C., Out, C., Hiemstra, P. S., De Boer, H. C., Jager, M. J., Schmelzer, E., Vries, R. G., Al Hinai, A. S., Kroes, W. G., Monajemi, R., Goeman, J. J., Böhringer, S., Marijt, W. A F, Falkenburg, J. H F, Griffioen, M., Pont, M. J., Honders, M. W., Kremer, A. N., Van Kooten, C., Out, C., Hiemstra, P. S., De Boer, H. C., Jager, M. J., Schmelzer, E., Vries, R. G., Al Hinai, A. S., Kroes, W. G., Monajemi, R., Goeman, J. J., Böhringer, S., Marijt, W. A F, Falkenburg, J. H F, and Griffioen, M.

Published
2016

84. Microarray gene expression analysis to evaluate cell type specific expression of targets relevant for immunotherapy of hematological malignancies

Author

Hubrecht Institute with UMC, Pont, M. J., Honders, M. W., Kremer, A. N., Van Kooten, C., Out, C., Hiemstra, P. S., De Boer, H. C., Jager, M. J., Schmelzer, E., Vries, R. G., Al Hinai, A. S., Kroes, W. G., Monajemi, R., Goeman, J. J., Böhringer, S., Marijt, W. A F, Falkenburg, J. H F, Griffioen, M., Hubrecht Institute with UMC, Pont, M. J., Honders, M. W., Kremer, A. N., Van Kooten, C., Out, C., Hiemstra, P. S., De Boer, H. C., Jager, M. J., Schmelzer, E., Vries, R. G., Al Hinai, A. S., Kroes, W. G., Monajemi, R., Goeman, J. J., Böhringer, S., Marijt, W. A F, Falkenburg, J. H F, and Griffioen, M.

Published
2016

85. Blockade of costimulatory pathways of T-cell activation: the solution to acute and chronic rejection?

Author

van Kooten C

Subjects
Graft Rejection, T-Lymphocytes, T cell, chemical and pharmacologic phenomena, Lymphocyte Activation, CD28 Antigens, Internal Medicine, medicine, Humans, Cytotoxic T cell, CD40 Antigens, CD154, CD86, CD40, biology, Chemistry, CD28, hemic and immune systems, Tumor Necrosis Factor Receptor Superfamily, Member 7, Blockade, Cell biology, medicine.anatomical_structure, Nephrology, Acute Disease, Chronic Disease, biology.protein, CD80
Abstract

Understanding of how antigen-specific signals and costimulatory molecules are involved in T-cell activation has resulted in new strategies to interfere with allograft rejection. The present review focuses on the role of two receptor-ligand pairs: CD28 and cytotoxic T lymphocyte associated antigen-4, which interact with the B7 ligands (CD80, CD86); and CD40, which interacts with the CD40L (CD154). On the basis of the extensive tissue distribution of CD40, it is likely that the CD40/CD40L system plays a much broader role.

Published
1999

89. Quaking post-transcriptionally promotes differentiation of monocytes into pro-atherogenic macrophages by controling pre-mRNA splicing and gene expression

Author

de Bruin, R.G., primary, Shiue, L., additional, Prins, J., additional, Djaramshi, A., additional, de Boer, H., additional, Fagg, W.S., additional, van Gils, J., additional, Duijs, J., additional, van Kooten, C., additional, Jukema, J.W., additional, van Esch, H., additional, Rabelink, T.J., additional, Kazan, H., additional, Biessen, E.A.L., additional, Ares, M., additional, van Zonneveld, A.J., additional, and van der Veer, E., additional

Published
2016
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91. Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies

Author

Pont, M. J., primary, Honders, M. W., additional, Kremer, A. N., additional, van Kooten, C., additional, Out, C., additional, Hiemstra, P. S., additional, de Boer, H. C., additional, Jager, M. J., additional, Schmelzer, E., additional, Vries, R. G., additional, Al Hinai, A. S., additional, Kroes, W. G., additional, Monajemi, R., additional, Goeman, J. J., additional, Böhringer, S., additional, Marijt, W. A. F., additional, Falkenburg, J. H. F., additional, and Griffioen, M., additional

Published
2016
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92. Anti-carbamylated protein antibodies: a specific hallmark for rheumatoid arthritis. Comparison to conditions known for enhanced carbamylation; renal failure, smoking and chronic inflammation

Author

Verheul, M K, primary, van Erp, S J H, additional, van der Woude, D, additional, Levarht, E W N, additional, Mallat, M J K, additional, Verspaget, H W, additional, Stolk, J, additional, Toes, R E M, additional, van der Meulen-de Jong, A E, additional, Hiemstra, P S, additional, van Kooten, C, additional, and Trouw, L A, additional

Published
2016
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93. Mannan-Binding Lectin Is Involved in the Protection against Renal Ischemia/Reperfusion Injury by Dietary Restriction

Author

Shushimita, Shushimita, van der Pol, P (Pieter), de Bruin, Ron, IJzermans, J.N.M., van Kooten, C, Dor, Frank, Shushimita, Shushimita, van der Pol, P (Pieter), de Bruin, Ron, IJzermans, J.N.M., van Kooten, C, and Dor, Frank

Abstract

Preoperative fasting and dietary restriction offer robust protection against renal ischemia/reperfusion injury (I/RI) in mice. We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on these findings, we investigated the effect of short-term DR (30% reduction of total food intake) or three days of water only fasting on MBL in 10-12 weeks old male C57/Bl6 mice. Both dietary regimens significantly reduce the circulating levels of MBL as well as its mRNA expression in liver, the sole production site of MBL. Reconstitution of MBL abolished the protection afforded by dietary restriction, whereas in the fasting group the protection persisted. These data show that modulation of MBL is involved in the protection against renal I/RI induced by dietary restriction, and suggest that the mechanisms of protection induced by dietary restriction and fasting may be different.

Published
2015

96. Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

Author

Coppo, Rosanna, Troyanov, Stéphan, Bellur, Shubha, Cattran, Daniel, Cook, H. Terence, Feehally, John, Roberts, Ian S.D., Morando, Laura, Camilla, Roberta, Tesar, Vladimir, Lunberg, Sigrid, Gesualdo, Loreto, Emma, Francesco, Rollino, Cristiana, Amore, Alessandro, Praga, Manuel, Feriozzi, Sandro, Segoloni, Giuseppe, Pani, Antonello, Cancarini, Giovanni, Durlik, Magalena, Moggia, Elisabetta, Mazzucco, Gianna, Giannakakis, Costantinos, Honsova, Eva, Sundelin, B. Brigitta, Palma, Anna Maria Di, Ferrario, Franco, Gutierrez, Eduardo, Asunis, Anna Maria, Barratt, Jonathan, Tardanico, Regina, Perkowska-Ptasinska, Agnieszka, Maixnerova, D., Lundberg, S., Fuiano, L., Beltrame, G., Peruzzi, L., Polci, R., Colla, L., Angioi, A., Piras, D., Ravera, S., Ballarin, J., Di Giulio, S., Pugliese, F., Caliskan, Y., Locatelli, F., Del Vecchio, L., Wetzels, J. F.M., Peters, H., Berg, U., Carvalho, F., 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., 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., Ferrario, F., Gutiérrez, E., Arce Terroba, J., Fortunato, M., Ozluk, Y., Kilicaslan, I., Steenberger, E., Soderberg, M., Da Costa Ferreira, A. C., Riispere, Z., Furci, L., Orhan, D., Kipgen, D., Casartelli, D., Galesic Ljubanovic, D., Bertoni, E., Cannata Ortiz, P., Groene, H. J., Stoppacciaro, A., Bajema, I., Bruijn, J., Fulladosa Oliveras, X., Maldyk, J., Ioachim, E., Coppo, Rosanna, Troyanov, Stéphan, Bellur, Shubha, Cattran, Daniel, Cook, H. Terence, Feehally, John, Roberts, Ian S.D., Morando, Laura, Camilla, Roberta, Tesar, Vladimir, Lunberg, Sigrid, Gesualdo, Loreto, Emma, Francesco, Rollino, Cristiana, Amore, Alessandro, Praga, Manuel, Feriozzi, Sandro, Segoloni, Giuseppe, Pani, Antonello, Cancarini, Giovanni, Durlik, Magalena, Moggia, Elisabetta, Mazzucco, Gianna, Giannakakis, Costantinos, Honsova, Eva, Sundelin, B. Brigitta, Palma, Anna Maria Di, Ferrario, Franco, Gutierrez, Eduardo, Asunis, Anna Maria, Barratt, Jonathan, Tardanico, Regina, Perkowska-Ptasinska, Agnieszka, Maixnerova, D., Lundberg, S., Fuiano, L., Beltrame, G., Peruzzi, L., Polci, R., Colla, L., Angioi, A., Piras, D., Ravera, S., Ballarin, J., Di Giulio, S., Pugliese, F., Caliskan, Y., Locatelli, F., Del Vecchio, L., Wetzels, J. F.M., Peters, H., Berg, U., Carvalho, F., 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., 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., Ferrario, F., Gutiérrez, E., Arce Terroba, J., Fortunato, M., Ozluk, Y., Kilicaslan, I., Steenberger, E., Soderberg, M., Da Costa Ferreira, A. C., Riispere, Z., Furci, L., Orhan, D., Kipgen, D., Casartelli, D., Galesic Ljubanovic, D., Bertoni, E., Cannata Ortiz, P., Groene, H. J., Stoppacciaro, A., Bajema, I., Bruijn, J., Fulladosa Oliveras, X., Maldyk, J., and Ioachim, E.

Abstract

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin-angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m 2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Published
2014

98. The Action of Interleukin 6 on Lymphoid Populations

Author

Aarden La and van Kooten C

Subjects
Interleukin 20, biology, Chemistry, Immunology, biology.protein, Interleukin, Stimulation, Antibody, Interleukin 6, Interleukin 5, Molecular biology, Peripheral blood, Interleukin 3
Abstract

We have analysed the role of IL-6 in activation of human lymphocytes isolated from peripheral blood. We found little effect of IL-6 on proliferation of T cells. IL-6 did stimulate production of IgM by B cells. However, it did not behave as a terminal differentiation factor and was required only during the first two days of the culture. Under most conventional stimulation conditions T cells themselves produce little or no IL-6. High IL-6 production could be induced by stimulating the cells with a combination of phorbol-12-myristate 13-acetate (PMA) and anti-CD28 antibodies.

Published
2007

99. Injection of recombinant Fc alpha RI/CD89 in mice does not induce mesangial IgA deposition

Author

van der Boog, PJM, van Kooten, C, van Zandbergen, G, Klar-Mohamad, N, Oortwijn, B, Bos, NA, van Remoortere, A, Hokke, CH, de Fijter, JW, Daha, MR, and Translational Immunology Groningen (TRIGR)

Subjects
EXPRESSION, IDENTIFICATION, NEPHROPATHY, receptor, GLYCOSYLATION, IgA nephropathy, LYMPHOCYTES, ALPHA-RECEPTOR CD89, IMMUNOGLOBULIN (IG)A1, CELLS, FC-RECEPTOR, COMPLEXES, CD89, IgA, mouse
Abstract

Background. Earlier studies have suggested that complexes of the human IgA receptor FcalphaRI/CD89 with mouse IgA are pathogenic upon deposition in the renal mesangium. Transgenic mice expressing FcalphaRI/CD89 on macrophages/monocytes developed massive mesangial IgA deposition and a clinical picture of IgA nephropathy (IgAN). Based on these findings, the purpose of this study was to design an experimental model of IgAN by injection of human CD89 in mice. The interaction of mouse IgA with CD89 was investigated further. Methods. Recombinant human soluble CD89 and a chimeric CD89-Fc protein were generated, produced, purified and injected in mice. Renal cryosections were stained for IgA and CD89. The interaction of mouse IgA with CD89 was analysed by fluorescence-activated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA) and plasmon resonance technology. Results. Injection of recombinant human CD89 did not result in significant IaA or CD89 deposition in the renal mesangium. However, CD89 staining in the liver was found to be positive. CD89 was rapidly cleared from circulation without signs of complex formation with IgA. FACS analysis, ELISA and plasmon resonance techniques all revealed a dose-dependent binding, of human IgA to recombinant CD89, while no detectable binding was seen of Mouse IgA. either of serum IgA or of different monoclonal mouse IgA preparations. Conclusions. An experimental model for IgAN in mice could not be obtained by injection of recombinant CD89. This is compatible with our in vitro biochemical data showing a lack of binding between recombinant human CD89 and mouse IgA.

Published
2004

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