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1. Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update

Author

Coppo, R., D'Arrigo, G., Tripepi, G., Russo, M. L., Roberts, I. S. D., Bellur, S., Cattran, D., Cook, T. H., Feehally, J., Tesar, V., Maixnerova, D., Peruzzi, L., Amore, A., Lundberg, S., Di Palma, A. M., Gesualdo, L., Emma, F., Rollino, C., Praga, M., Biancone, L., Pani, A., Feriozzi, S., Polci, R., Barratt, J., Del Vecchio, L., Locatelli, F., Pierucci, A., Caliskan, Y., Perkowska-Ptasinska, A., Durlik, M., Moggia, E., Ballarin, J. C., Wetzels, J. F. M., Goumenos, D., Papasotiriou, M., Galesic, K., Toric, L., Papagianni, A., Stangou, M., Benozzi, L., Cusinato, S., Berg, U., Topaloglu, R., Maggio, M., Ots-Rosenberg, M., D'Amico, M., Geddes, C., Balafa, O., Quaglia, M., Cravero, R., Cirami, C. L., Fellstrom, B., Floege, J., Egido, J., Mallamaci, F., Zoccali, C., Fuiano, L., Beltrame, G., Camilla, R., Segoloni, G., Colla, L., Angioi, A., Piras, L., Cancarini, G., Ravera, S., Ballarin, J., Di Giulio, S., Pugliese, F., Serriello, I., Sever, M., Kilicaslan, I., Peters, H., Carvalho, F., Da Costa Ferreira, A. C., Wiecek, A., Magistroni, R., Bilginer, Y., Giacchino, F., Papastirou, M., Siamopoulos, K., Galliani, M., Stratta, P., Bergia, R., Salvadori, M., Cirami, L., Kloster Smerud, H., Ferrario, F., Stellato, T., Martin, C., Eitner, F., Rauen, T., Lupo, A., Bernich, P., Mene, P., Morosetti, M., Van Kooten, C., Rabelink, T., Reinders, M. E. J., Boria Grinyo, J. M., 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., Boero, R., Mazzucco, G., Giannakakis, C., Honsova, E., Sundelin, B., Gutierrez, E., Asunis, A. M., Tardanico, R., 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., Akiopoulou, 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 Internal Medicine

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Adolescent, 030232 urology & nephrology, Renal function, 030204 cardiovascular system & hematology, Kidney, Nephropathy, Cohort Studies, 03 medical and health sciences, Glomerulonephritis, 0302 clinical medicine, renal biopsy, Interquartile range, IgA nephropathy, progression, risk factors, Child, Disease Progression, Female, Follow-Up Studies, Glomerular Filtration Rate, Glomerulonephritis, IGA, Humans, Prognosis, Medicine, Endocapillary hypercellularity, IGA, Transplantation, medicine.diagnostic_test, business.industry, medicine.disease, medicine.anatomical_structure, Renal pathology, Nephrology, Cohort, Renal biopsy, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business
Abstract

Background It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. Methods In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1–10.8)]. Results In this extended analysis, M1, S1 and T1–T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P Conclusion Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Published
2020

2. Reproducibility of the Oxford Classification of IgA nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALIGA study cohort

Author

Bellur, S, Roberts, ISD, Troyanov, S, Royal, V, Coppo, R, Cook, HT, Cattran, D, Terroba, YA, Asunis, AM, Bajema, I, Bertoni, E, Bruijn, JA, Cannata-Ortiz, P, Casartelli, D, Di Palma, AM, Ferrario, F, Fortunato, M, Furci, L, Gakiopoulou, H, Ljubanovic, DG, Giannakakis, K, Gomà, M, Gröne, H-J, Gutiérrez, E, Haider, SA, Honsova, E, Ioachim, E, Karkoszka, H, Kipgen, D, Maldyk, J, Mazzucco, G, Orhan, D, Ozluk, Y, Pantzaki, A, Perkowska-Ptasinska, A, Riispere, Z, Soderberg, M, Steenbergen, E, Stoppacciaro, A, Sundelin, B, and Tardanico, R

Subjects
immunosuppression, kidney biopsy, Oxford classification, 1103 Clinical Sciences, IgA nephropathy, proteinuria, Urology & Nephrology
Abstract

Objective & Methods: The VALIGA study investigated the utility of the Oxford Classification of IgA nephropathy (IgAN) in 1147 patients from 13 European countries. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive treatments (CS/IS), and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present-central absent, local absent-central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy whilst the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity), and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. By contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes compared to central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion: We conclude that differences in the scoring of MEST-C criteria between local pathologists and central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Published
2018

3. 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

4. Effects of complete androgen blockade for 12 and 24 weeks on the pathological stage and resection margin status of prostate cancer

Author

Selli, Aag, C., Montironi, R. b, Bono, A. c, Pagano, F. d, Zattoni, F. e, Manganelli, A. f, Selvaggi, F. P. g, Comeri, G. C. h, Fiaccavento, G. i, Guazzieri, S. j, Lembo, A. k, Cosciani, Cunico, S. l, Potenzoni, D. m, Muto, Nac, G., Mazzucchelli, R. b, Santinelli, A. b, Polito, M. n, Muzzonigro, G. n, Minardi, D. n, Palazzo, S. o, Bufo, P. o, Bertoldin, R. p, Doglioni, C. p, Macrì, E. p, Canclini, L. q, Chinagila, D. q, Zambolin, T. r, Tanello, M. r, Tardanico, R. r, Usoi, E. s, Migliari, R. s, Muscas, G. s, Valdes, E. s, Varsi, C. s, Ferretti, S. t, Palladini, P. t, Digregorio, C. t, Conti, G. u, Lunetta, Q. u, Scola, G. u, Signorelli, G. v, Andretta, E. v, Giordano, R. v, Nisi, E. v, Rizzo, M. w, Bartoletti, R. w, Amorosi, A. w, Martini, E. x, Andreassi, P. x, Ventura, T. x, Artibani, W. y, Piazza, R. y, Gaetoni, De, C. y, Fontana, D. z, Tarabuzzi, R. z, Gulbetta, L. z, Bollito, E. z., Prayer, Galetti, Aa, T., Gardiman, Aa, M., Belmonte, Ab, P., Sacchi, Ab, G., Rocco, Rossetti, Ac, S., Terrone, Ac, C., Palestro, Ac, G., Galliano, Ac, D., Bardari, Ac, F., Campobasso, Ac, O., Pisacane, A. M., Ac, Rubertis, De, Ad, G., Del, Vecchio, M. T., Ad, Gregori, Ae, A., Serra, Ae, L., Anselmo, Af, G., Checchin, Af, A., Arrigoni, G. A, Scott, Cathryn Anne, Beltrami, Carlo Alberto, Galassi, Ag, P., Comeri, Ah, G., Bono, A. V., Ah, Fava, Ah, C., Salvadore, Ah, M., Tasca, Ai, A., Meneghini, Meli, S., and Armani, A.

Subjects
Male, medicine.medical_specialty, Surgical margin, Antineoplastic Agents, Hormonal, Biopsy, Pathological staging, medicine.medical_treatment, Drug Administration Schedule, Pathology and Forensic Medicine, Tosyl Compounds, Prostate cancer, Nitriles, medicine, Humans, Anilides, Prospective Studies, Radical surgery, Neoadjuvant therapy, Aged, Neoplasm Staging, Prostatectomy, business.industry, Prostatic Neoplasms, Androgen Antagonists, Original Articles, General Medicine, Middle Aged, medicine.disease, Neoadjuvant Therapy, Surgery, Chemotherapy, Adjuvant, Goserelin, Resection margin, Histopathology, business
Abstract

Aims: To compare the pathological stage and surgical margin status in patients undergoing either immediate radical prostatectomy or 12 and 24 weeks of neoadjuvant hormonal treatment (NHT) in a prospective, randomised study. Methods: Whole mount sections of 393 radical prostatectomy specimens were evaluated: 128 patients had immediate surgery, 143 were treated for 12 weeks and 122 for 24 weeks with complete androgen blockade. Results: Histopathology revealed organ confined tumours in 40.4% of patients with clinical stage B disease in the immediate surgery group, whereas 12 and 24 weeks of NHT increased the number of organ confined tumours to 54.6% and 64.8%, respectively. Among patients with clinical stage C tumours, pathological staging found organ confined disease in 10.4%, 31.4%, and 61.2% in the immediate surgery, 12 weeks of NHT, and 24 weeks of NHT groups, respectively. Preoperative NHT caused a significant decrease in positive margins both in patients with clinical stage B and C disease. The extent of margin involvement was not influenced by preoperative treatment. Conclusions: Neoadjuvant androgenic suppression is effective in reducing both the pathological stage and the positive margin rate in patients with stage B and C prostatic cancer undergoing radical surgery. Some beneficial effects are evident in those patients treated for 24 weeks, and it is reasonable to assume that the optimal duration of NHT is longer than three months.

Published
2002

5. Allelism of medullary cystic disease, familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease caused by delayed uromodulin trafficking to plasma membrane and endoplasmic reticulum retention

Author

Rampoldi L, Lamorte G, Bernascone I, Caridi G, Santon D, Boaretto F, Tardanico R, Dagnino M, Colussi G, Scolari F, Ghiggeri GM, Amoroso A, MAZZA, DAVIDE, CASARI , GIORGIO NEVIO, Rampoldi, L, Lamorte, G, Bernascone, I, Caridi, G, Santon, D, Boaretto, F, Tardanico, R, Dagnino, M, Colussi, G, Scolari, F, Ghiggeri, Gm, Amoroso, A, Casari, GIORGIO NEVIO, and Mazza, Davide

Published
2006

9. Lymphadenopathic and oropharyngeal Kaposi's sarcoma in a drug addict with acquired immunodeficiency syndrome. Immunological abnormalities in peripheral blood and lymphoid tissue

Author

Facchetti, F, Zorzi, M, Tardanico, R, Salvi, A, Zuccato, F, Franceschini, F, Cattaneo, R, and Callea, F

Subjects
Adult, Male, Acquired Immunodeficiency Syndrome, Histocytochemistry, Lymphoid Tissue, Humans, Immunochemistry, Lymphatic Diseases, Neoplasms, Oropharyngeal Neoplasms, Pharyngeal Neoplasms, Sarcoma, Kaposi, Sarcoma, Kaposi
Abstract

Lymphocyte subsets were analyzed in peripheral blood and lymph nodes from a drug-addict with acquired immunodeficiency syndrome (AIDS) presenting with disseminated lymphadenopathic and oropharyngeal Kaposi's sarcoma. At the onset of disease, hypergammaglobulinemia, increase of OKT8+ T cell subset and reversal of OKT4/OKT8 ratio were found in the blood. At the same time, lymph nodes displayed, besides Kaposi's sarcoma, marked follicular hyperplasia, plasmocytosis and increase of OKT8+/Leu 2a+ T cells within follicular centers. These results are interpreted to indicate that at an early stage of disease the major tissue alterations took place within follicular centers and consisted of both B cell activation and T suppressor cell reaction. These changes correlated with immunological abnormalities observed in peripheral blood. Immunohistochemical investigation of lymphoid tissue may be useful to detect AIDS patients at an early stage.

Published
1984

12. Effects of complete androgen blockade for 12 and 24 weeks on the pathological stage and resection margin status of prostate cancer

Author

Selli, C., Montironi, R., Bono, A., Pagano, F., Zattoni, F., Manganelli, A., Selvaggi, F. P., Comeri, G. C., Fiaccavento, G., Guazzieri, S., Lembo, A., Cosciani-Cunico, S., Potenzoni, D., Muto, G., Mazzucchelli, R., Santinelli, A., Polito, M., Muzzonigro, G., Minardi, D., Palazzo, S., Bufo, P., Bertoldin, R., Doglioni, C., Macrì, E., Canclini, L., Chinagila, D., Zambolin, T., Tanello, M., Tardanico, R., Usoi, E., Migliari, R., Muscas, G., Valdes, E., Varsi, C., Ferretti, S., Palladini, P., Digregorio, C., Conti, G., Lunetta, Q., Scola, G., Signorelli, G., Andretta, E., Giordano, R., Nisi, E., Rizzo, M., Bartoletti, R., Amorosi, A., Martini, E., Andreassi, P., Ventura, T., Artibani, W., Piazza, R., Gaetoni, C., Fontana, D., Tarabuzzi, R., Gulbetta, L., ENRICO BOLLITO, Prayer-Galetti, T., Gardiman, M., Belmonte, P., Sacchi, G., Rocco Rossetti, S., Terrone, C., Palestro, G., Galliano, D., Bardari, F., Campobasso, O., Pisacane, A. M., Rubertis, G., Del Vecchio, M. T., Gregori, A., Serra, L., Anselmo, G., Checchin, A., Arrigoni, G. A., Scott, C., Beltrami, C. A., Galassi, P., Comeri, G., Bono, A. V., Fava, C., Salvadore, M., Tasca, A., Meneghini, A., Meli, S., and Armani, A.

15. Prognostic value of cytogenetic analysis in clear cell renal carcinoma: A study on 131 patients with long-term follow-up

Author

alessandro antonelli, Arrighi, N., Tardanico, R., Balzarini, P., Zanotelli, T., Corti, S., Zani, D., Cozzoli, A., Cunico, S. C., and Simeone, C.

Subjects
Adult, Male, Time Factors, Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell, genetics/secondary/surgery, Chromosome Aberrations, Cytogenetic Analysis, Female, Follow-Up Studies, Humans, Karyotyping, Kidney Neoplasms, genetics/pathology/surgery, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Prognosis, Prospective Studies, Survival Rate, Time Factors, Progosis, 80 and over, Humans, Prospective Studies, Clear cell renal carcinoma, Aged, Neoplasm Staging, Chromosome Aberrations, Carcinoma, renal carcinoma, Middle Aged, Prognosis, genetics/secondary/surgery, Kidney Neoplasms, Chromosome alterations, Karyotype analysis, Survival Rate, genetics/pathology/surgery, Karyotyping, Lymphatic Metastasis, Cytogenetic Analysis, Female, Follow-Up Studies

19. 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

20. Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo (2)

Author

Gabriella Moroni, Corrado Murtas, Piergiorgio Messa, Maricla Galetti, Angela Tincani, Gian Marco Ghiggeri, Giancarlo Barbano, Renato Alberto Sinico, Landino Allegri, Paola Migliorini, Franco Franceschini, Maurizio Bruschi, Alice Bonanni, Pietro Ravani, Giorgio Piaggio, Francesco Scolari, Giovanni Candiano, Federico Pratesi, Alberto Martini, Barbara Trezzi, Antonella Radice, Francesca Brunini, Regina Tardanico, Rita Gatti, Bruschi, M, Galetti, M, Sinico, R, Moroni, G, Bonanni, A, Radice, A, Tincani, A, Pratesi, F, Migliorini, P, Murtas, C, Franceschini, F, Trezzi, B, Brunini, F, Gatti, R, Tardanico, R, Barbano, G, Piaggio, G, Messa, P, Ravani, P, Scolari, F, Candiano, G, Martini, A, Allegri, L, and Ghiggeri, G

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Anti-nuclear antibody, Enolase, SLE, Lupus nephritis, Podocyte, Biology, medicine.disease_cause, Cell Line, Autoimmunity, Histones, Young Adult, chemistry.chemical_compound, Antigen, clinical immunology, immunology and pathology, lupus nephritis, medicine, Humans, Aged, Autoantibodies, Complement C1q, DNA, Female, Lupus Nephritis, Middle Aged, Podocytes, Creatinine, Autoantibody, General Medicine, Lupus Nephriti, medicine.disease, Autoantibodie, Histone, Basic Research, chemistry, Nephrology, Immunology, Nephritis, Human
Abstract

Glomerular planted antigens (histones, DNA, and C1q) are potential targets of autoimmunity in lupus nephritis (LN). However, the characterization of these antigens in human glomeruli in vivo remains inconsistent. We eluted glomerular autoantibodies recognizing planted antigens from laser-microdissected renal biopsy samples of 20 patients with LN. Prevalent antibody isotypes were defined, levels were determined, and glomerular colocalization was investigated. Renal and circulating antibodies were matched, and serum levels were compared in 104 patients with LN, 84 patients with SLE without LN, and 50 patients with rheumatoid arthritis (RA). Autoantibodies against podocyte antigens (anti–α-enolase/antiannexin AI) were also investigated. IgG2 autoantibodies against DNA, histones (H2A, H3, and H4), and C1q were detected in 50%, 55%, and 70% of biopsy samples, respectively. Anti-DNA IgG3 was the unique non-IgG2 anti-DNA deposit, and anti-C1q IgG4 was mainly detected in subepithelial membranous deposits. Anti-H3, anti-DNA, and anti-C1q IgG2 autoantibodies were also prevalent in LN serum, which also contained IgG3 against the antigen panel and anti-C1q IgG4. Serum and glomerular levels of autoantibodies were not strictly associated. High serum levels of all autoantibodies detected, including anti–α-enolase and antiannexin AI, identified LN versus SLE and RA. Anti-H3 and anti–α-enolase IgG2 levels had the most remarkable increase in LN serum and represented a discriminating feature of LN in principal component analysis. The highest levels of these two autoantibodies were also associated with proteinuria>3.5 g/24 hours and creatinine>1.2 mg/dl. Our findings suggest that timely autoantibody characterization might allow outcome prediction and targeted therapies for patients with nephritis.

Published
2015

21. Glomerular autoimmune multicomponents of human lupus nephritis in vivo: α-enolase and annexin AI

Author

Piergiorgio Messa, Maricla Galetti, Maurizio Bruschi, Paola Migliorini, Laura Bianchi, Renato Alberto Sinico, Angela Tincani, Giancarlo Barbano, Andrea Scaloni, Chiara D'Ambrosio, Alice Bonanni, Landino Allegri, Federico Pratesi, Maria Luisa Carnevali, Giovanni Candiano, Gian Marco Ghiggeri, Regina Tardanico, Pietro Ravani, Alberto Martini, Michael P. Madaio, Gabriella Moroni, Francesco Scolari, Agata Giallongo, Franco Franceschini, Barbara Trezzi, Antonella Radice, Rita Gatti, Beatrice Bianco, Corrado Murtas, Bruschi, M, Sinico, R, Moroni, G, Pratesi, F, Migliorini, P, Galetti, M, Murtas, C, Tincani, A, Madaio, M, Radice, A, Franceschini, F, Trezzi, B, Bianchi, L, Giallongo, A, Gatti, R, Tardanico, R, Scaloni, A, D'Ambrosio, C, Carnevali, M, Messa, P, Ravani, P, Barbano, G, Bianco, B, Bonanni, A, Scolari, F, Martini, A, Candiano, G, Allegri, L, and Ghiggeri, G

Subjects
Male, Proteomics, Pathology, Mice, Inbred MRL lpr, Biopsy, Kidney Glomerulus, Lupus nephritis, Mice, SCID, lupus nephriti, medicine.disease_cause, Autoimmunity, Mice, Inbred BALB C, Annexin A1, Mice, Inbred BALB C, Tumor, medicine.diagnostic_test, General Medicine, Middle Aged, Autoantibodie, Lupus Nephritis, DNA-Binding Proteins, Nephrology, GN, Monoclonal, Immunohistochemistry, Female, Human, immunology and pathology, lupus nephritis, Adolescent, Adult, Animals, Autoantibodies, Biomarkers, Tumor, Humans, Immunoglobulin G, Phosphopyruvate Hydratase, Tumor Suppressor Proteins, Young Adult, medicine.medical_specialty, DNA-Binding Protein, Enolase, Biology, SCID, Inbred MRL lpr, medicine, Tumor Suppressor Protein, Animal, Autoantibody, Proteomic, medicine.disease, Basic Research, Immunology, Kidney Glomerulu, Biomarkers
Abstract

Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against α-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of α-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti–α-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti–α-enolase/low anti-annexin AI IgG2 and patients with low anti–α-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti–α-enolase IgG2 recognized specific epitopes of α-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human α-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against α-enolase and annexin AI predominate in the glomerulus and can be detected in serum.

Published
2014

22. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics

Author

Ilenia Bernascone, Regina Tardanico, Gianluca Caridi, Francesca Boaretto, Giuseppe Lamorte, Daniela Santon, Gian Marco Ghiggeri, Luca Rampoldi, Antonio Amoroso, Monica Dagnino, Francesco Scolari, Giacomo Colussi, Giorgio Casari, Rampoldi, L, Caridi, G, Santon, D, Boaretto, F, Bernascone, I, Lamorte, G, Tardanico, R, Dagnino, M, Colussi, G, Scolari, F, Ghiggeri, Gm, Amoroso, A, and Casari, GIORGIO NEVIO

Subjects
Male, medicine.medical_specialty, Tamm–Horsfall protein, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Multicystic dysplastic kidney, Hyperuricemia, Endoplasmic Reticulum, Kidney, Medullary cystic kidney disease, Nephropathy, Alleles, Amino Acid Sequence, Chromosome Mapping, Conserved Sequence, Female, Humans, Kidney Diseases, Kidney Failure, Chronic, Mucoproteins, Pedigree, Polycystic Kidney, Autosomal Dominant, Uromodulin, Molecular Biology, Genetics, Genetics (clinical), Kidney Failure, Internal medicine, medicine, Polycystic Kidney, Missense mutation, Cyst, Chronic, biology, Endoplasmic reticulum, General Medicine, medicine.disease, Endocrinology, medicine.anatomical_structure, Autosomal Dominant, Mutation, biology.protein, Missense
Abstract

The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.

Published
2003

23. Autosomal dominant medullary cystic disease: a disorder with variable clinical pictures and exclusion of linkage with the NPH1 locus

Author

Gianluca Caridi, Antonio Amoroso, Battista Fabio Viola, Gian Marco Ghiggeri, Rosanna Gusmano, Nicola Bossini, Silvana Savoldi, Regina Tardanico, Daniela Puzzer, Valerio Vizzardi, Prati E, Giorgio Casari, Francesco Scolari, Rosario Maiorca, B. Valzorio, Scolari, F, Ghiggeri, Gm, Casari, GIORGIO NEVIO, Amoroso, A, Puzzer, D, Caridi, Gl, Valzorio, B, Tardanico, R, Vizzardi, V, Savoldi, S, Viola, Bf, Bossini, N, Prati, E, Gusmano, R, and Maiorca, R.

Subjects
Male, Pathology, Candidate gene, Gout, Genetic Linkage, Kidney Failure, Nephronophthisis, Fatal Outcome, Polycystic Kidney, Juvenile nephronophthisis, Chronic, Child, Kidney Medulla, Nephritis, Middle Aged, Protein-Serine-Threonine Kinases, Polycystic Kidney, Autosomal Dominant, Pedigree, Hyperuricaemia, Linkage analysis, Medullary cystic disease, NPH1 locus, Adolescent, Adult, Aged, Apoproteins, Chromosomes, Human, Pair 2, DNA, DNA Primers, Female, Follow-Up Studies, Humans, Kidney Failure, Chronic, Nephritis, Interstitial, Phosphoproteins, Retrospective Studies, Arabidopsis Proteins, Nephrology, Autosomal Dominant, Pair 2, Human, medicine.medical_specialty, government.form_of_government, Locus (genetics), Protein Serine-Threonine Kinases, Chromosomes, Genetic linkage, Retinitis pigmentosa, medicine, Transplantation, business.industry, medicine.disease, eye diseases, government, Age of onset, business, Interstitial, Kidney disease
Abstract

failure. The exclusion of linkage to the NPH1 locus suggests the existence of an MCD responsible locus, Background. The nephronophthisis‐medullary cystic disease (NPH/MCD) complex represents a heterogen- still to be mapped. eous group of hereditary tubulointerstitial nephritis. Key words: gout; hyperuricaemia; linkage analysis; The most common variant is juvenile recessive NPH, medullary cystic disease; nephronophthisis; NPH1 for which a gene locus (NPH1) has been mapped on locus chromosome 2q13. MCD is a less common dominant condition usually recognized later in life, which resembles NPH in many aspects, still presenting remarkable clinical diVerences. Nothing is known Introduction about the chromosome locus of MCD. Methods. Five MCD families were studied. Diagnosis The nephronophthisis‐medullary cystic disease was made by inference from family history, type of (NPH/MCD) complex represents a heterogeneous inheritance, clinical signs and histology. Multipoint group of inherited renal diseases sharing some histopalinkage analysis was performed by markers D2S293, thological lesions and a few clinical similarities [1,2]. D2S340 and D2S160 spanning the entire NPH1 locus. The most common variant is juvenile nephronophthisis Results. Diagnosis of MCD was made in 28 aVected (NPH ), a disease with an autosomal recessive inheritmembers (16 males; 12 females), belonging to five ance. Clinical signs of NPH typically are present in families. Histological diagnosis was available in 10 early childhood and invariably lead to end-stage renal patients; clinical diagnosis in 11; seven deceased relat- failure within the second decade of life. A gene locus ives had diagnosis of chronic nephritis. The age at for the purely renal form of NPH (NPH1) has been diagnosis ranged from 8 to 65 years. Renal medullary located on chromosome 2q13, where 65‐75% of cysts were found in a minority of patients. In family NPH1 patients exhibit a large homozygous deletion 1, the disease was associated with hyperuricaemia and (~250 kb) at which site a candidate gene has been gouty arthritis. Progression of renal disease presented identified [3‐7]. NPH occurring in association with intra- and extra-family variability with members of the extrarenal symptoms, such as retinitis pigmentosa, does same family showing mild elevation of creatinine or not map on 2q13 [3‐5]. terminal renal failure. The NPH1 locus associated to Medullary cystic disease (MCD) is a less common recessive NPH was excluded from linkage to the dom- condition, with autosomal dominant inheritance. inant MCD. MCD is recognized later in life, usually in the third Conclusions. MCD might be more common than previ- decade, and leads to end-stage renal failure at the age ously assumed. Variability in clinical presentation and of 40‐50 years [1,2]. Nothing is known about the absence of histopathological hallmarks contribute to chromosome loci or defective gene of the MCD. make the diagnosis uncommon. The most remarkable The clinical heterogeneity of NPH/MCD complex clinical diVerence with NPH is the age of onset in has been a matter of debate. Originally, the diseases some kindreds and a delayed progression towards renal were assumed to be diVerent disorders [8‐10].

Published
1998

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