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Riccardo MAGISTRONI

Professore Associato
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa

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Pubblicazioni

2023 - #5187 GREASE II: A PHASE II RANDOMIZED, 24-MONTH, PARALLEL-GROUP, SUPERIORITY STUDY TO EVALUATE THE EFFICACY OF A KETOGENIC DIET IN ADPKD PATIENTS [Abstract in Rivista]
Pezzuoli, Carla; Testa, Francesca; Giovanella, Silvia; Ligabue, Giulia; Marchiò, Maddalena; Biagini, Giuseppe; Magistroni, Riccardo
abstract

2023 - EPIDEMIOLOGICAL AND CLINICAL CHARACTERISTICS OF MIGRANTS ON CHRONIC HEMODIALYSIS TREATMENT [Abstract in Rivista]
Alfano, Gaetano; Fontana, Francesco; Magistroni, Riccardo; Donati, Gabriele
abstract

2023 - Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy [Articolo su rivista]
Kiryluk, K.; Sanchez-Rodriguez, E.; Zhou, X. J.; Zanoni, F.; Liu, L.; Mladkova, N.; Khan, A.; Marasa, M.; Zhang, J. Y.; Balderes, O.; Sanna-Cherchi, S.; Bomback, A. S.; Canetta, P. A.; Appel, G. B.; Radhakrishnan, J.; Trimarchi, H.; Sprangers, B.; Cattran, D. C.; Reich, H.; Pei, Y.; Ravani, P.; Galesic, K.; Maixnerova, D.; Tesar, V.; Stengel, B.; Metzger, M.; Canaud, G.; Maillard, N.; Berthoux, F.; Berthelot, L.; Pillebout, E.; Monteiro, R.; Nelson, R.; Wyatt, R. J.; Smoyer, W.; Mahan, J.; Samhar, A. A.; Hidalgo, G.; Quiroga, A.; Weng, P.; Sreedharan, R.; Selewski, D.; Davis, K.; Kallash, M.; Vasylyeva, T. L.; Rheault, M.; Chishti, A.; Ranch, D.; Wenderfer, S. E.; Samsonov, D.; Claes, D. J.; Akchurin, O.; Goumenos, D.; Stangou, M.; Nagy, J.; Kovacs, T.; Fiaccadori, E.; Amoroso, A.; Barlassina, C.; Cusi, D.; Del Vecchio, L.; Battaglia, G. G.; Bodria, M.; Boer, E.; Bono, L.; Boscutti, G.; Caridi, G.; Lugani, F.; Ghiggeri, G. M.; Coppo, R.; Peruzzi, L.; Esposito, V.; Esposito, C.; Feriozzi, S.; Polci, R.; Frasca, G.; Galliani, M.; Garozzo, M.; Mitrotti, A.; Gesualdo, L.; Granata, S.; Zaza, G.; Londrino, F.; Magistroni, R.; Pisani, I.; Magnano, A.; Marcantoni, C.; Messa, P.; Mignani, R.; Pani, A.; Ponticelli, C.; Roccatello, D.; Salvadori, M.; Salvi, E.; Santoro, D.; Gembillo, G.; Savoldi, S.; Spotti, D.; Zamboli, P.; Izzi, C.
abstract

Genome-wide association analyses identify 30 risk loci for IgA nephropathy. Functional annotations of putative causal genes converge on inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

2023 - Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome [Articolo su rivista]
Barry, Alexandra; Mcnulty, Michelle T; Jia, Xiaoyuan; Gupta, Yask; Debiec, Hanna; Luo, Yang; Nagano, China; Horinouchi, Tomoko; Jung, Seulgi; Colucci, Manuela; Ahram, Dina F; Mitrotti, Adele; Sinha, Aditi; Teeninga, Nynke; Jin, Gina; Shril, Shirlee; Caridi, Gianluca; Bodria, Monica; Lim, Tze Y; Westland, Rik; Zanoni, Francesca; Marasa, Maddalena; Turudic, Daniel; Giordano, Mario; Gesualdo, Loreto; Magistroni, Riccardo; Pisani, Isabella; Fiaccadori, Enrico; Reiterova, Jana; Maringhini, Silvio; Morello, William; Montini, Giovanni; Weng, Patricia L; Scolari, Francesco; Saraga, Marijan; Tasic, Velibor; Santoro, Domenica; van Wijk, Joanna A E; Milošević, Danko; Kawai, Yosuke; Kiryluk, Krzysztof; Pollak, Martin R; Gharavi, Ali; Lin, Fangmin; Simœs E Silva, Ana Cristina; Loos, Ruth J F; Kenny, Eimear E; Schreuder, Michiel F; Zurowska, Aleksandra; Dossier, Claire; Ariceta, Gema; Drozynska-Duklas, Magdalena; Hogan, Julien; Jankauskiene, Augustina; Hildebrandt, Friedhelm; Prikhodina, Larisa; Song, Kyuyoung; Bagga, Arvind; Cheong, Hae; Ghiggeri, Gian Marco; Vachvanichsanong, Prayong; Nozu, Kandai; Lee, Dongwon; Vivarelli, Marina; Raychaudhuri, Soumya; Tokunaga, Katsushi; Sanna-Cherchi, Simone; Ronco, Pierre; Iijima, Kazumoto; Sampson, Matthew G
abstract

: Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

2023 - Mycophenolate mofetil plus steroids compared to steroids alone in IgA nephropathy: a retrospective study [Articolo su rivista]
Fontana, Francesco; Delsante, Marco; Vicari, Manuela; Pala, Chiara; Alfano, Gaetano; Giovanella, Silvia; Ligabue, Giulia; Leonelli, Marco; Manenti, Lucio; Rossi, Giovanni Maria; Magistroni, Riccardo; Fiaccadori, Enrico; Donati, Gabriele
abstract

2023 - PATIENT AND TECHNIQUE SURVIVAL ON PERITONEAL DIALYSIS: A RETROSPECTIVE STUDY [Abstract in Rivista]
Scarmignan, Roberta; Alfano, Gaetano; Fontana, Francesco; Magistroni, Riccardo; Donati, Gabriele
abstract

2023 - PAX2/Renal Coloboma Syndrome Expresses Extreme Intrafamilial Phenotypic Variability [Articolo su rivista]
Giovanella, Silvia; Pasini, Andrea; Ligabue, Giulia; Testa, Francesca; Mori, Giacomo; Tagliafico, Enrico; Magistroni, Riccardo
abstract

Renal coloboma syndrome (RCS) is a disease characterized by kidney and ocular anomalies (kidney hypodysplasia and coloboma). RCS is caused, in half of the cases, by mutations in the paired box 2 (PAX2) gene, a critical organogenesis transcriptional factor. We report the case of a newborn with kidney hypodysplasia in a negative parental context where mother and father were phenotypically unaffected at the initial evaluation. The maternal family presented an important history of kidney disease with undefined diagnosis. Molecular characterization identified a PAX2 variant, classified as likely pathogenic. This variant segregates with the disease, and it was also found in the newborn, explaining his severe symptoms. It is noteworthy that the mother shows the same PAX2 variant, with an apparently negative kidney phenotype, displaying the possibility of an extreme variable expressivity of the disease. This feature suggests extreme caution in segregation analysis and family counseling of PAX2 pedigrees.

2023 - Prevalence, clinical course and outcomes of COVID-19 in peritoneal dialysis (PD) patients: a single-center experience [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Giovanella, Silvia; Morisi, Niccolo; Amurri, Alessio; Ligabue, Giulia; Guaraldi, Giovanni; Ferrari, Annachiara; Cappelli, Gianni; Magistroni, Riccardo; Gregorini, Mariacristina; Donati, Gabriele
abstract

Introduction There are limited data on the effects of COVID-19 on peritoneal dialysis (PD) patients. This study aimed to describe the impact of COVID-19 on the PD population. Methods A monocentric retrospective observational study was conducted on 146 consecutive PD patients followed from January 2020 to March 2022 at the University Hospital of Modena, Italy. Results Twenty-seven (18.4%) PD patients experienced 29 episodes of SARS-CoV-2 infection, corresponding to an incidence rate of 0.16 episodes/patient-year. Median age of COVID-19 patients was 60.4 (interquartile range [IQR] 50.2-66.5) years. In unvaccinated patients (n. 9), COVID-19 was always symptomatic and manifested with fever (100%) and cough (77.7%). COVID-19 caused hospital admission of three (33.3%) patients and two (22.2%) died of septic shock. COVID-19 was symptomatic in 83.3% of vaccinated subjects (n.18) and manifested with fever (61.1%) and cough (55.6%). Hospital admission occurred in 27.8% of the subjects but all were discharged home. Median SARS-CoV-2 shedding was 32 and 26 days in the unvaccinated and vaccinated groups, respectively. At the end of the follow-up, COVID-19 triggered the shift from PD to HD in two subjects without affecting the residual renal function of the remaining patients. Overall, COVID-19 caused an excess death of 22.2%. COVID-19 vaccination refusal accounted for only 1.6% in this cohort of patients. Conclusion COVID-19 incident rate was 0.16 episodes/patient-year in the PD population. About one-third of the patients were hospitalized for severe infection. Fatal outcome occurred in two (7.4%) unvaccinated patients. A low vaccination refusal rate was observed in this population.

2023 - Prolonged RT-PCR test positivity in hemodialysis patients with COVID-19 [Articolo su rivista]
Alfano, G.; Morisi, N.; Ferri, C.; Fontana, F.; Giovanella, S.; Ligabue, G.; Mori, G.; Franceschini, E.; Ferrari, A.; Gregorini, M.; Cappelli, G.; Tagliazucchi, S.; Pecorari, M.; Guaraldi, G.; Magistroni, R.; Donati, G.
abstract

Background: The weakened immune system of patients on hemodialysis (HD) may prolong SARS-CoV-2 infection compared to the general population. Current international guidelines recommend ending isolation in conjunction with serial testing in moderately and severely immunocompromised subjects. This study aimed to estimate SARS-CoV-2 infectivity by measuring RT-PCR test positivity in HD patients. A comparison between RT-PCR test and cycle threshold (Ct) value has been performed as a secondary endpoint. Methods: A single-center retrospective study was conducted at the University of Modena (Italy) from March 2020 to October 2022. Only patients on chronic HD therapy with COVID-19 were enrolled in the study. In our HD Center, two negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) results were used to end quarantine in this population. SARS-CoV-2 RT-PCR test positivity duration measured the time elapsed from a positive RT-PCR to a second negative test. Ct cut-off of 35 cycles was used to definite “high Ct value,” a condition characterized by a large number of cycles of PCR amplification to register a positive RT-PCR test. Results: During the observational period, 159 cases of SARS-CoV-2 infections were diagnosed in 151 patients. Median age was 70.1 (54.3–81.6) years and males accounted for 59.6% of the COVID-19 population. Median duration of SARS-CoV-2 RT-PCR test positivity on the nasal mucosa accounted for 30 (IQR, 21–40.5) days. Unvaccinated patients experienced significantly longer RT-PCR test positivity compared to vaccinated patients (42 [IQR,31–56] vs. 28 [IQR,20–35.7] days; p = < 0.001). The use of high Ct value, a laboratory surrogate of SARS-CoV-2 replication, anticipated a negative RT-PCR test of 9 (IQR, 6–12) days. Multivariate linear regression analysis showed that increased age (β coefficient 0.31; confidence interval [CI] 95%, 0.14—0.43; p = < 0.001) and the lack of anti-SARS-CoV-2 vaccination (β 0.49 CI95%, 11.9–22.5; p = < 0.001) were predictors of a prolonged RT-PCR positivity. Conclusions: Patients with COVID-19 on HD had prolonged RT-PCR test positivity. The adoption of “high Ct value” criteria led to a significant reduction in the duration of RT-PCR test positivity compared to the use of the classical nucleic acid amplification test. In our study, the lack of SARS-CoV-2 vaccination and older age were independently associated with a longer RT-PCR positivity.

2023 - Risk of bleeding after percutaneous native kidney biopsy in patients receiving low-dose aspirin: a single-center retrospective study [Articolo su rivista]
Fontana, Francesco; Cazzato, Silvia; Giaroni, Francesco; Bertolini, Fabrizio; Alfano, Gaetano; Mori, Giacomo; Giovanella, Silvia; Ligabue, Giulia; Magistroni, Riccardo; Cappelli, Gianni; Donati, Gabriele
abstract

Background Although discontinuation of antiplatelet agents at least 5 days before kidney biopsy is commonly recommended, the evidence behind this practice is of low level. Indeed, few non-randomized studies previously showed an equivalent risk of bleeding in patients receiving aspirin therapy.Methods We conducted a single center retrospective study comparing the risk of complications after percutaneous native kidney biopsy in patients who received low-dose aspirin (ASA) within 5 days from biopsy and those who did not. The main outcome was the difference in the incidence of major complications (red blood cell transfusion, need for selective arterial embolization, surgery, nephrectomy). Secondary outcomes included difference in minor complications, comparison between patients who received ASA within 48 h or within 3-5 days, identification of independent factors predictive of major complications.Results We analyzed data on 750 patients, of whom 94 received ASA within 5 days from biopsy. There were no significant differences in the proportion of major complications in patients receiving or not receiving ASA (2.59% and 3.19%, respectively, percentage point difference 1%, 95% CI - 3 to 4%, p = 0.74). Groups were also comparable for minor complications; among patients receiving ASA, there were no differences in major bleeding between those who received ASA within 48 h or 3-5 days from biopsy. Significant baseline predictors of major bleeding in our cohort were platelet count lower than 120*10(3)/ microliter, higher diastolic blood pressure and higher blood urea.Conclusions Treatment with low-dose ASA within 5 days from kidney biopsy did not increase the risk of complications after the procedure.[GRAPHICS].

2023 - Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease [Articolo su rivista]
Gupta, Y.; Friedman, D. J.; Mcnulty, M. T.; Khan, A.; Lane, B.; Wang, C.; Ke, J.; Jin, G.; Wooden, B.; Knob, A. L.; Lim, T. Y.; Appel, G. B.; Huggins, K.; Liu, L.; Mitrotti, A.; Stangl, M. C.; Bomback, A.; Westland, R.; Bodria, M.; Marasa, M.; Shang, N.; Cohen, D. J.; Crew, R. J.; Morello, W.; Canetta, P.; Radhakrishnan, J.; Martino, J.; Liu, Q.; Chung, W. K.; Espinoza, A.; Luo, Y.; Wei, W. -Q.; Feng, Q.; Weng, C.; Fang, Y.; Kullo, I. J.; Naderian, M.; Limdi, N.; Irvin, M. R.; Tiwari, H.; Mohan, S.; Rao, M.; Dube, G. K.; Chaudhary, N. S.; Gutierrez, O. M.; Judd, S. E.; Cushman, M.; Lange, L. A.; Lange, E. M.; Bivona, D. L.; Verbitsky, M.; Winkler, C. A.; Kopp, J. B.; Santoriello, D.; Batal, I.; Pinheiro, S. V. B.; Oliveira, E. A.; Simoes e Silva, A. C.; Pisani, I.; Fiaccadori, E.; Lin, F.; Gesualdo, L.; Amoroso, A.; Ghiggeri, G. M.; D'Agati, V. D.; Magistroni, R.; Kenny, E. E.; Loos, R. J. F.; Montini, G.; Hildebrandt, F.; Paul, D. S.; Petrovski, S.; Goldstein, D. B.; Kretzler, M.; Gbadegesin, R.; Gharavi, A. G.; Kiryluk, K.; Sampson, M. G.; Pollak, M. R.; Sanna-Cherchi, S.
abstract

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

2022 - Acid base disorders in patients with COVID-19 [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Mori, Giacomo; Giaroni, Francesco; Ferrari, Annachiara; Giovanella, Silvia; Ligabue, Giulia; Ascione, Elisabetta; Cazzato, Silvia; Ballestri, Marco; Di Gaetano, Margherita; Meschiari, Marianna; Menozzi, Marianna; Milic, Jovana; Andrea, Bedini; Franceschini, Erica; Cuomo, Gianluca; Magistroni, Riccardo; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni; De Biasi, Sara; Cossarizza, Andrea; Gibellini, Lara
abstract

Purpose Acid-base derangement has been poorly described in patients with coronavirus disease 2019 (COVID-19). Considering the high prevalence of pneumonia and kidneys injury in COVID-19, frequent acid-base alterations are expected in patients admitted with SARS-Cov-2 infection. The study aimed to assess the prevalence of acid-base disorders in symptomatic patients with a diagnosis of COVID-19. Methods The retrospective study enrolled COVID-19 patients hospitalized at the University Hospital of Modena from 4 March to 20 June 2020. Baseline arterial blood gas (ABG) analysis was collected in 211 patients. In subjects with multiple ABG analysis, we selected only the first measurement. A pH of less than 7.37 was categorized as acidemia and a pH of more than 7.43 was categorized as alkalemia. Results ABG analyses revealed a low arterial partial pressure of oxygen (PO2, 70.2 +/- 25.1 mmHg), oxygen saturation (SO2, 92%) and a mild reduction of PO2/FiO(2) ratio (231 +/- 129). Acid-base alterations were found in 79.7% of the patient. Metabolic alkalosis (33.6%) was the main alteration followed by respiratory alkalosis (30.3%), combined alkalosis (9.4%), respiratory acidosis (3.3%), metabolic acidosis (2.8%) and other compensated acid-base disturbances (3.6%). All six patients with metabolic acidosis died at the end of the follow-up. Conclusion Variations of pH occurred in the majority (79.7%) of patients admitted with COVID-19. The patients experienced all the type of acid-base disorders, notably metabolic and respiratory alkalosis were the most common alterations in this group of patients.

2022 - Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy [Articolo su rivista]
Barbour, S. J.; Coppo, R.; Zhang, H.; Liu, Z. -H.; Suzuki, Y.; Matsuzaki, K.; Er, L.; Reich, H. N.; Barratt, J.; Cattran, D. C.; Russo, M. L.; Troyanov, S.; Cook, H. T.; Roberts, I.; Tesar, V.; Maixnerova, D.; Lundberg, S.; Gesualdo, L.; Emma, F.; Fuiano, L.; Beltrame, G.; Rollino, C.; Amore, A.; Camilla, R.; Peruzzi, L.; Praga, M.; Feriozzi, S.; Polci, R.; Segoloni, G.; Colla, L.; Pani, A.; Piras, D.; Angioi, A.; Cancarini, G.; Ravera, S.; Durlik, M.; Moggia, E.; Ballarin, J.; 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.; Geddes, C.; Siamopoulos, K.; Balafa, O.; Galliani, M.; Stratta, P.; Quaglia, M.; Bergia, R.; Cravero, R.; Salvadori, M.; Cirami, L.; Fellstrom, B.; Smerud, H. K.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Boria Grinyo, J. M.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska-Wasiak, M.; Martina, G.; Messuerotti, A.; Dal Canton, A.; Esposito, C.; Migotto, C.; Triolo, G.; Mariano, F.; Pozzi, C.; Boero, R.; Bellur, S.; Mazzucco, G.; Giannakakis, C.; Honsova, E.; Sundelin, B.; Di Palma, A. M.; Gutierrez, E.; Asunis, A. M.; Tardanico, R.; Perkowska-Ptasinska, A.; Terroba, J. A.; Fortunato, M.; Pantzaki, A.; Ozluk, Y.; Steenbergen, E.; Soderberg, M.; Riispere, Z.; Furci, L.; Orhan, D.; Kipgen, D.; Casartelli, D.; Ljubanovic, D. G.; Gakiopoulou, H.; Bertoni, E.; Cannata Ortiz, P.; Karkoszka, H.; Groene, H. J.; Stoppacciaro, A.; Bajema, I.; Bruijn, J.; Fulladosa Oliveras, X.; Maldyk, J.; Ioachim, E.; Bavbek, N.; Cook, T.; Alpers, C.; 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, C. -H.; Shi, S.; Nogi, C.; Suzuki, H.; Koike, K.; Hirano, K.; Yokoo, T.; Hanai, M.; Fukami, K.; Takahashi, K.; Yuzawa, Y.; Niwa, M.; Yasuda, Y.; Maruyama, S.; Ichikawa, D.; Suzuki, T.; Shirai, S.; Fukuda, A.; Fujimoto, S.; Trimarchi, H.
abstract

The International IgA Nephropathy (IgAN) Prediction Tool is the preferred method in the 2021 KDIGO guidelines to predict, at the time of kidney biopsy, the risk of a 50% drop in estimated glomerular filtration rate or kidney failure. However, it is not known if the Prediction Tool can be accurately applied after a period of observation post-biopsy. Using an international multi-ethnic derivation cohort of 2,507 adults with IgAN, we updated the Prediction Tool for use one year after biopsy, and externally validated this in a cohort of 722 adults. The original Prediction Tool applied at one-year without modification had a coefficient of variation (R2) of 55% and 54% and four-year concordance (C statistic) of 0.82 but poor calibration with under-prediction of risk (integrated calibration index (ICI) 1.54 and 2.11, with and without race, respectively). Our updated Prediction Tool had a better model fit with higher R2 (61% and 60%), significant increase in four-year C-statistic (0.87 and 0.86) and better four-year calibration with lower ICI (0.75 and 0.35). On external validation, the updated Prediction Tool had similar R2 (60% and 58%) and four-year C-statistics (both 0.85) compared to the derivation analysis, with excellent four-year calibration (ICI 0.62 and 0.56). This updated Prediction Tool had similar prediction performance when used two years after biopsy. Thus, the original Prediction Tool should be used only at the time of biopsy whereas our updated Prediction Tool can be used for risk stratification one or two years post-biopsy.

2022 - Artificial intelligence in glomerular diseases [Articolo su rivista]
Schena, F. P.; Magistroni, R.; Narducci, F.; Abbrescia, D. I.; Anelli, V. W.; Di Noia, T.
abstract

In this narrative review, we focus on the application of artificial intelligence in the clinical history of patients with glomerular disease, digital pathology in kidney biopsy, renal ultrasonography imaging, and prediction of chronic kidney disease (CKD). With the development of natural language processing, the clinical history of a patient can be used to identify a computable phenotype. In kidney pathology, digital imaging has adopted innovative deep learning algorithms (DLAs) that can improve the predictive capability of the examined lesions. However, at this time, these applications can only be used in research because there is no recognized validation to replace the conventional diagnostic applications. Kidney ultrasonography, used in the clinical examination of patients, provides information about the progression of kidney damage. Machine learning algorithms (MLAs) with promising results for the early detection of CKD have been proposed, but, still, they are not solid enough to be incorporated into the clinical practice. A few tools for glomerulonephritis, based on MLAs, are available in clinical practice. They can be downloaded on computers and cellular phones but can only be applied to uniracial cohorts of patients. To improve their performance, it is necessary to organize large consortia with multiracial cohorts. Finally, in many studies MLA development has been carried out using retrospective cohorts. The performance of the models might differ in retrospective cohorts compared to real-world data. Therefore, the models should be validated in prospective external large cohorts.

2022 - Automated Prediction of Kidney Failure in IgA Nephropathy with Deep Learning from Biopsy Images [Articolo su rivista]
Testa, F.; Fontana, F.; Pollastri, F.; Chester, J.; Leonelli, M.; Giaroni, F.; Gualtieri, F.; Bolelli, F.; Mancini, E.; Nordio, M.; Sacco, P.; Ligabue, G.; Giovanella, S.; Ferri, M.; Alfano, G.; Gesualdo, L.; Cimino, S.; Donati, G.; Grana, C.; Magistroni, R.
abstract

Background and objectives Digital pathology and artificial intelligence offer new opportunities for automatic histologic scoring. We applied a deep learning approach to IgA nephropathy biopsy images to develop an automatic histologic prognostic score, assessed against ground truth (kidney failure) among patients with IgA nephropathy who were treated over 39 years. We assessed noninferiority in comparison with the histologic component of currently validated predictive tools. We correlated additional histologic features with our deep learning predictive score to identify potential additional predictive features. Design, setting, participants, & measurements Training for deep learning was performed with randomly selected, digitalized, cortical Periodic acid–Schiff–stained sections images (363 kidney biopsy specimens) to develop our deep learning predictive score. We estimated noninferiority using the area under the receiver operating characteristic curve (AUC) in a randomly selected group (95 biopsy specimens) against the gold standard Oxford classification (MEST-C) scores used by the International IgA Nephropathy Prediction Tool and the clinical decision supporting system for estimating the risk of kidney failure in IgA nephropathy. We assessed additional potential predictive histologic features against a subset (20 kidney biopsy specimens) with the strongest and weakest deep learning predictive scores. Results We enrolled 442 patients; the 10-year kidney survival was 78%, and the study median follow-up was 6.7 years. Manual MEST-C showed no prognostic relationship for the endocapillary parameter only. The deep learning predictive score was not inferior to MEST-C applied using the International IgA Nephropathy Prediction Tool and the clinical decision supporting system (AUC of 0.84 versus 0.77 and 0.74, respectively) and confirmed a good correlation with the tubolointerstitial score (r50.41, P,0.01). We observed no correlations between the deep learning prognostic score and the mesangial, endocapillary, segmental sclerosis, and crescent parameters. Additional potential predictive histopathologic features incorporated by the deep learning predictive score included (1)inflammation within areas of interstitial fibrosis and tubular atrophy and (2) hyaline casts. Conclusions The deep learning approach was noninferior to manual histopathologic reporting and considered prognostic features not currently included in MEST-C assessment.

2022 - COVID-19 Rapid Antigen Test Screening in Patients on Hemodialysis [Articolo su rivista]
Alfano, Gaetano; Scarmignan, Roberta; Morisi, Niccolò; Fontana, Francesco; Giovanella, Silvia; Ligabue, Giulia; Rofrano, Laura; Gennari, William; Pecorari, Monica; Gregorini, Mariacristina; Cappelli, Gianni; Magistroni, Riccardo; Donati, Gabriele
abstract

Introduction. Patients receiving in-center hemodialysis are extremely vulnerable to COVID-19. It is unclear if routine screening of asymptomatic hemodialysis patients is an effective strategy to prevent COVID-19 outbreaks within the dialysis unit. Methods. We conducted a retrospective analysis of in-center hemodialysis patients who underwent bimonthly COVID-19 rapid antigen test screening from February 15(th) to December 26(th), 2021. Nasal rapid antigen testing was performed in all asymptomatic patients. All rapid antigen-positive tests were confirmed by RT-PCR nasopharyngeal swab. Besides universal rapid antigen screening, RT-PCR testing was conducted in all symptomatic patients and contacts of COVID-19 subjects. Results. Overall, 4079 rapid antigen tests were performed in 277 hemodialysis patients on chronic hemodialysis with a mean age of 68.4 +/- 14.6 years. Thirty-eight (0.9%) rapid antigen tests resulted positive. Only five (13.8%) positive-rapid antigen tests were also positive by RT-PCR testing. During the same period, 219 patients regularly screened by rapid antigen tests bimonthly underwent 442 RT-PCR nasopharyngeal swabs for clinical reasons. RT-PCR testing yielded a positive result in 13 (5.9%) patients. The time elapsed between PCR and the negative-rapid antigen test was 7.7 +/- 4.6 days (range 1.8-13.9 days). At the end of the follow-up, 6.4% of the population on in-center hemodialysis contracted COVID-19, and routine rapid antigen tests detected only 5 out of 18 (27.7%) COVID-19 cases. No outbreaks of COVID-19 were identified within the dialysis unit. Conclusion. Bimonthly rapid antigen screening led to the early diagnosis of COVID-19 in less than one-third of cases. The short incubation period of the new SARS-CoV-2 variants makes bimonthly test screening inadequate for an early diagnosis of COVID-19. More frequent tests are probably necessary to improve the utility of COVID-19 nasal rapid antigen test in patients on hemodialysis.

2022 - COVID-19 in patients on Peritoneal Dialysis: a case series [Abstract in Rivista]
Alfano, G; Fontana, F; Morisi, N; Cappelli, G; Magistroni, R; Donati, G.
abstract

2022 - Ethical challenges in managing unvaccinated patients receiving chronic in-centre haemodialysis [Articolo su rivista]
Alfano, G.; Fontana, F.; Morisi, N.; Mori, G.; Cappelli, G.; Magistroni, R.; Donati, G.
abstract

Insufficient vaccine coverage and dominance of the more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are the leading causes of the continued spread of coronavirus disease 2019 (COVID-19) worldwide. To curb the surge in infections, COVID-19 vaccination has been advocated as a priority measure, especially for frail populations and people at high risk of exposure. Patients on in-centre maintenance haemodialysis (HD) embody both conditions. They are at high risk of severe COVID-19 consequences due to their advanced age and weakened immune system and carry an increased risk of SARS-CoV-2 transmission within shared dialysis rooms and public vehicles. Vaccination of the entire HD population is therefore the most effective strategy to protect patients from the dire consequences of COVID-19. Unfortunately, a minority of patients still express COVID-19 vaccine hesitancy. The management of this group of patients, who have the full right to HD treatment, poses demanding problems from a patient safety perspective. The placement of unvaccinated patients within the dialysis room and the protection of all vaccinated patients are some of the most urgent problems the nephrologist faces during the COVID-19 pandemic. In light of these COVID-19-driven changes, an ethical reflection on the management of unvaccinated patients appears crucial to act responsibly and contribute to the health promotion of dialysis patients.

2022 - Reactogenicity of COVID-19 vaccine in hemodialysis patients: a single-center retrospective study [Articolo su rivista]
Alfano, Gaetano; Morisi, Niccolò; Fontana, Francesco; Scarmignan, Roberta; Tonelli, Laura; Ferri, Camilla; Montani, Martina; Melluso, Andrea; Giovanella, Silvia; Ligabue, Giulia; Mori, Giacomo; Franceschini, Erica; Guaraldi, Giovanni; Cappelli, Gianni; Magistroni, Riccardo; Donati, Gabriele
abstract

: Introduction: Some hemodialysis patients are reluctant to undergo COVID-19 vaccination for the fear of developing adverse events (AEs). The aim of this study was to verify the safety of the mRNA-1273 vaccine in hemodialysis patients. Methods: We conducted a retrospective analysis of in-center hemodialysis patients who underwent mRNA-1273 vaccine from March 1st to April 30th, 2021. All AEs occurring after the first and the second doses were collected and classified as local or systemic. Results: Overall, 126 patients on chronic maintenance dialysis without a prior COVID-19 diagnosis were vaccinated with two doses of mRNA-1273 vaccine. Mean age was 68 (IQR, 54,7-76) years and 53.6% of patients were aged ≥65 years. During the observational period of 68 (IQR, 66-70) days, AEs occurred in 57.9% and 61.9% of patients after the first dose and second dose, respectively. The most common AEs were: injection-site pain (61.9%), erythema (4.8%), itching (4.8%), swelling (16.7%), axillary swelling/tenderness (2.4%), fever (17.5%) headache (7.9%), fatigue (23.8%), myalgia (17.5%), arthralgia (12.7%), dyspnoea (2.4%), nausea/vomiting (7.1%), diarrhoea (5.6%), shivers (4%) and vertigo (1.6%). The rates of local AEs were similar after the first and second doses (P=0.8), whereas systemic AEs occurred more frequently after the second dose (P=0.001). Fever (P=0.03), fatigue (P=0.02) and nausea/vomiting (P=0.03) were significantly more frequent after the second dose of the vaccine. There were no age-related differences in the rate of AEs. Overall, vaccine-related AEs in hemodialysis patients seem to be lower than in the general population. Conclusion: The RNA-1273 vaccine was associated with the development of transient AEs after the first and second doses in patients on chronic maintenance hemodialysis. They were mostly local, whereas systemic AEs were more prevalent after the second dose. Overall, all AEs lasted for a few days, without any apparent sequelae.

2022 - Reactogenicity of MRNA-1273 vaccine in patients on hemodialysis [Abstract in Rivista]
Alfano, G; Fontana, F; Morisi, N; Scarmignan, R; Tonelli, L; Cappelli, G; Magistroni, R; Donati, G.
abstract

2022 - Rethinking Chronic Kidney Disease in the Aging Population [Articolo su rivista]
Alfano, Gaetano; Perrone, Rossella; Fontana, Francesco; Ligabue, Giulia; Giovanella, Silvia; Ferrari, Annachiara; Gregorini, Mariacristina; Cappelli, Gianni; Magistroni, Riccardo; Donati, Gabriele
abstract

The process of aging population will inevitably increase age-related comorbidities including chronic kidney disease (CKD). In light of this demographic transition, the lack of an age-adjusted CKD classification may enormously increase the number of new diagnoses of CKD in old subjects with an indolent decline in kidney function. Overdiagnosis of CKD will inevitably lead to important clinical consequences and pronounced negative effects on the health-related quality of life of these patients. Based on these data, an appropriate workup for the diagnosis of CKD is critical in reducing the burden of CKD worldwide. Optimal management of CKD should be based on prevention and reduction of risk factors associated with kidney injury. Once the diagnosis of CKD has been made, an appropriate staging of kidney disease and timely prescriptions of promising nephroprotective drugs (e.g., RAAS, SGLT-2 inhibitors, finerenone) appear crucial to slow down the progression toward end-stage kidney disease (ESKD). The management of elderly, comorbid and frail patients also opens new questions on the appropriate renal replacement therapy for this subset of the population. The non-dialytic management of CKD in old subjects with short life expectancy features as a valid option in patient-centered care programs. Considering the multiple implications of CKD for global public health, this review examines the prevalence, diagnosis and principles of treatment of kidney disease in the aging population.

2022 - Sarcoidosis in a living donor candidate: case report and review of the literature [Abstract in Rivista]
Mori, G; Tei, L; Alfano, G; Fontana, F; Magistroni, R; Donati, G.
abstract

2022 - Skin reaction with Eosinophilia and Systemic Symptoms after lenalidomide in peritoneal Dialysis [Articolo su rivista]
Cazzato, S.; Fontana, F.; Maccaferri, M.; Leonelli, M.; Ascione, E.; Magistroni, R.; Alfano, G.
abstract

The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a fatal and immunemediated idiosyncratic drug reaction, with symptoms of fever, skin eruptions (that involves more than half of the body surface), facial oedema and hematological disorders, all presenting within the latent period following drug intake. Effects can also be seen on multiple organs, most notably hepatitis in liver and acute interstitial nephritis in kidney, generally post-administration of allopurinol. The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) classifies the DRESS Syndrome cases as “definite”, “probable” or “possible”, based on clinical and laboratory features. Different pathogenetic mechanisms have been involved in this disease, including immunological reactions and HHV-6 reactivation. In our experience, a 72-year-old male, affected by myeloma in peritoneal dialysis, developed a rare case of DRESS syndrome after lenalidomide administration (less than ten cases are known) with HHV-6 reactivation. According to literature, we withdrew the drug and gave methylprednisolone 0,8 mg/kg orally and IVIG 1 gr/kg for two days. Despite this therapy, DRESS syndrome relapsed during steroid taper with rash, thrombocytopenia, hepatitis and high troponin level. A single cycle of intravenous immunoglobulin 0,5 g/kg for four days was enough for syndrome remission. Only few cases are reported in literature, but because of the increasing use of lenalidomide and the autoimmune sequelae of DRESS syndrome, a broad workup and a multidisciplinar careful approach could help in diagnosis, treatment and follow-up.

2022 - Weekly Rapid Antigen Test Screening for COVID-19 in Patients on Hemodialysis [Articolo su rivista]
Alfano, Gaetano; Scarmignan, Roberta; Amurri, Alessio; Fontana, Francesco; Giovanella, Silvia; Ligabue, Giulia; Gennari, William; Pecorari, Monica; Sarti, Mario; Guaraldi, Giovanni; Cappelli, Gianni; Gregorini, Mariacristina; Magistroni, Riccardo; Donati, Gabriele
abstract

COVID-19 is a concerning issue among in-center hemodialysis (HD) patients. To prevent COVID-19 diffusion in our HD facility, weekly rapid nasal antigen test screening was performed for all asymptomatic patients on chronic HD. This study aimed to assess the performance of weekly rapid antigen test in detecting SARS-CoV-2 infection among asymptomatic patients receiving HD.

2022 - Which criteria should we use to end isolation in hemodialysis patients with COVID-19? [Articolo su rivista]
Alfano, G.; Fontana, F.; Ferrari, A.; Morisi, N.; Gregorini, M.; Cappelli, G.; Magistroni, R.; Guaraldi, G.; Donati, G.
abstract

Safe and timely discontinuation of quarantine of in-center hemodialysis (HD) patients with a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a challenging issue for the nephrological community because current guidelines for ending isolation do not mention dialysis patients. To prevent potentially fatal outbreaks of coronavirus disease 2019 (COVID-19), a cautionary approach has been adopted by most dialysis units. The criteria for ending the isolation in the HD population generally coincide with those recommended for immunocompromised people. Thus, a test-based strategy relying on two consecutive negative reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal swabs has been adopted to terminate quarantine. This strategy has the disadvantage of prolonging isolation as RT-PCR positivity does not equate to SARS-CoV-2 infectivity. Consequentially, prolonged positivity of SARS-CoV-2 results in excessive workload for the HD staff who must face an increasing number of COVID-19 patients requiring isolation. This condition leads also to serious implications for the patients and their households including work productivity loss, postponement of health-care appointments and an increased risk of COVID-19 reinfection. To counteract this problem, other diagnostic tests should be used to provide the best care to HD patients. Recent results seem to encourage the use of RT-PCR cycle threshold (Ct) values and rapid antigen tests given their better correlation with cell culture for SARS-CoV-2 than RT-PCR testing. Here, we provide an overview of the current scientific evidence on the tests used to verify the infectiousness of the virus in order to stimulate the nephrological community to adopt a streamlined and pragmatic procedure to end isolation in COVID-19 patients on HD.

2021 - AKI in hospitalized patients with COVID-19: a single-center experience [Articolo su rivista]
Alfano, Gaetano; Giovanella, Silvia; Fontana, Francesco; Milic, Jovana; Ligabue, Giulia; Morisi, Niccolò; Giaroni, Francesco; Mori, Giacomo; Magistroni, Riccardo; Franceschini, Erica; Bedini, Andrea; Cuomo, Giacomo; Digaetano, Margherita; Meschiari, Marianna; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni
abstract

2021 - Clinical Predictors of Nondiabetic Kidney Disease in Patients with Diabetes: A Single-Center Study [Articolo su rivista]
Fontana, F.; Perrone, R.; Giaroni, F.; Alfano, G.; Giovanella, S.; Ligabue, G.; Magistroni, R.; Cappelli, G.
abstract

Background. Although diabetic kidney disease (DKD) could affect up to one-third of patients with diabetes mellitus (DM), these patients can develop kidney diseases different from DKD, or these conditions can superimpose on DKD. Several potential predictors of nondiabetic kidney disease (NDKD) have been proposed, but there are no definitive indications available for kidney biopsy in diabetic patients. Methods. We designed a single-center, cross-sectional, and retrospective cohort study to identify clinical and laboratory factors associated with a diagnosis of NDKD after native kidney biopsy in diabetic patients and to investigate differences in time to end-stage kidney disease (ESKD) in patients with a diagnosis of DKD and NDKD. Results. Of 142 patients included in our analysis, 89 (62.68%) had a histopathological diagnosis of NDKD or mixed NDKD + DKD. Patients in the NDKD group had significantly lower HbA1C, lower prevalence of diabetic retinopathy (DR), and less severe proteinuria, and there was a lower proportion of patients with nephrotic syndrome; the DKD group had significantly lower proportion of patients with hematological conditions. In the multivariate binary logistic regression, only absence of DR and presence of a hematological condition significantly predicted NDKD after adjustment for age and sex. Time to ESKD was significantly higher in patients with NDKD or mixed forms than in those with DKD. Conclusions. After a careful selection, more than half of kidney biopsies performed in diabetic patients can identify NDKD (alone or with concomitant DKD). Absence of DR and coexistence of a hematological condition (especially MGUS) were strong predictors of NDKD in our cohort.

2021 - Clinical Presentation, Renal Histopathological Findings, and Outcome in Patients with Monoclonal Gammopathy and Kidney Disease [Articolo su rivista]
Alfano, G.; Delrio, A.; Fontana, F.; Mori, G.; Cazzato, S.; Ferrari, A.; Perrone, R.; Giovanella, S.; Ligabue, G.; Magistroni, R.; Cappelli, G.
abstract

Monoclonal gammopathies are associated with acute and chronic kidney injury. Nephrotoxicity of the secreted monoclonal (M)-protein is related to its biological properties and blood concentration. Little is known about epidemiology, clinical manifestations, and outcome of monoclonal gammopathies in patients with kidney disease. We retrospectively collected data about demographics, clinical manifestations, and renal histological lesions of all patients (n = 1334) who underwent kidney biopsy between January 2000 and March 2017. Monoclonal gammopathy was detected in 174 (13%) patients with a mean age of 66.4 ± 13.1 years. The spectrum of monoclonal gammopathies comprised monoclonal gammopathy of undetermined significate (MGUS) (52.8%), multiple myeloma (MM) (25.2%), primary amyloidosis (AL) (9.1%), smoldering MM (SMM) (4%), non-Hodgkin lymphoma (NHL) (6.8%), and Hodgkin lymphoma (HL) (1.7%). Monoclonal gammopathy of renal significance (MGRS) accounted for 6.5% in patients with MGUS and 14.2% in patients with SMM. Evaluation of kidney biopsy revealed that M-protein was directly involved in causing kidney injury in MM (93.1%). MM was the only gammopathy significantly associated with an increased risk of kidney injury (odds ratio [OR] = 47.5, CI 95%, 13.7-164.9; P≤0.001). While there were no significant differences in the progression toward end-stage renal disease or dialysis P=0.776, monoclonal gammopathies were associated with a different risk of death P=0.047 at the end of the follow-up. In conclusion, monoclonal gammopathy was a frequent finding (13%) in patients who underwent kidney biopsy. M-protein was secreted by both premalignant (56.8%) and malignant (43.2%) lymphoproliferative clones. Kidney biopsy had a key role in identifying MGRS in patients with MGUS (6.5%) and SMM (14.2%). Among monoclonal gammopathies, only MM was significantly associated with biopsy-proven kidney injury. The rate of end-stage renal disease or dialysis was similar among monoclonal gammopathies, whereas NHL, MM, and SMM showed a higher rate of deaths.

2021 - Confidence Calibration for Deep Renal Biopsy Immunofluorescence Image Classification [Relazione in Atti di Convegno]
Pollastri, Federico; Maroñas, Juan; Bolelli, Federico; Ligabue, Giulia; Paredes, Roberto; Magistroni, Riccardo; Grana, Costantino
abstract

With this work we tackle immunofluorescence classification in renal biopsy, employing state-of-the-art Convolutional Neural Networks. In this setting, the aim of the probabilistic model is to assist an expert practitioner towards identifying the location pattern of antibody deposits within a glomerulus. Since modern neural networks often provide overconfident outputs, we stress the importance of having a reliable prediction, demonstrating that Temperature Scaling (TS), a recently introduced re-calibration technique, can be successfully applied to immunofluorescence classification in renal biopsy. Experimental results demonstrate that the designed model yields good accuracy on the specific task, and that TS is able to provide reliable probabilities, which are highly valuable for such a task given the low inter-rater agreement.

2021 - Development and testing of an artificial intelligence tool for predicting end-stage kidney disease in patients with immunoglobulin A nephropathy [Articolo su rivista]
Schena, F. P.; Anelli, V. W.; Trotta, J.; Di Noia, T.; Manno, C.; Tripepi, G.; D'Arrigo, G.; Chesnaye, N. C.; Russo, M. L.; Stangou, M.; Papagianni, A.; Zoccali, C.; Tesar, V.; Coppo, R.; 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. K.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Rauen, T.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Grinyo, J. M. B.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska-Wasiak, M.; Roszkowska-Blaim, M.; Martina, G.; Messuerotti, A.; Canton, A. D.; Esposito, C.; Migotto, C.; Triolo, G.; Mariano, F.; Pozzi, C.; Boero, R.; Mazzucco, Michele; Giannakakis, C.; Honsova, E.; Sundelin, B.; Di Palma, A. M.; Gutierrez, E.; Asunis, A. M.; Barratt, J.; Tardanico, R.; Perkowska-Ptasinska, A.; Terroba, J. A.; Fortunato, M.; Pantzaki, A.; Ozluk, Y.; Steenbergen, E.; Soderberg, M.; Riispere, Z.; Furci, L.; Orhan, D.; Kipgen, D.; Casartelli, D.; Galesicljubanovic, D.; Gakiopoulou, H.; Bertoni, E.; Ortiz, P. C.; Karkoszka, H.; Groene, H. J.; Stoppacciaro, A.; Bajema, I.; Bruijn, J.; Fulladosaoliveras, X.; Maldyk, J.; Ioachim, E.; Abbrescia, D.; Kouri, N.; Scolari, F.; Delbarba, E.; Bonomini, M.; Piscitani, L.; Stallone, G.; Infante, B.; Godeas, G.; Madio, D.; Biancone, L.; Campagna, M.; Zaza, G.; Squarzoni, I.; Cangemi, C.
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.

2021 - Erratum: SARS-CoV-2 infection in dialysis patients in northern Italy: A single-centre experience (Clinical Kidney Journal (2020) 13:3 (334-339) DOI: 10.1093/ckj/sfaa084) [Articolo su rivista]
Fontana, F.; Giaroni, F.; Frisina, M.; Alfano, G.; Mori, G.; Lucchi, L.; Magistroni, R.; Cappelli, G.
abstract

The title of the article has been corrected to: SARS-CoV-2 infection in dialysis patients in northern Italy: a single-centre experience.

2021 - Hypokalemia in Patients with COVID-19 [Articolo su rivista]
Alfano, G.; Ferrari, A.; Fontana, F.; Perrone, R.; Mori, G.; Ascione, E.; Magistroni, R.; Venturi, G.; Pederzoli, S.; Margiotta, G.; Romeo, M.; Piccinini, F.; Franceschi, G.; Volpi, S.; Faltoni, M.; Ciusa, G.; Bacca, E.; Tutone, M.; Raimondi, A.; Menozzi, M.; Franceschini, E.; Cuomo, G.; Orlando, G.; Santoro, A.; Di Gaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Milic, J.; Meschiari, M.; Mussini, C.; Cappelli, G.; Guaraldi, G.; Borghi, V.; Burastero, G.; Corradi, L.; Di Gaetano, M.; Dolci, G.; Fantini, R.; Iadisernia, V.; Larne, D.; Pellegrino, F.; Rogati, C.; Santoro, A.; Tonelli, R.; Yaacoub, D.; Alfan, S.; Marco, B.; Pulizzi, R.; Leonelli, M.; Facchini, F.; Damiano, F.; Girardis, M.; Andreotti, A.; Biagioni, E.; Bondi, F.; Busani, S.; Chierego, G.; Scotti, M.; Cossarizza, L. S. A.; Bellinazzi, C.; Borella, R.; De Biasi, S.; De Gaetano, A.; Fidanza, L.; Gibellini, L.; Iannone, A.; Tartaro, D. L.; Mattioli, M.; Nasi, M.; Paolini, A.; Pinti, M.
abstract

Background: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19. Methods: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020. Results: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3–3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36–4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08–3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228–1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170–1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222–1.047; P = 0.065) in our cohort of patients. Conclusions: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.

2021 - Immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19 [Articolo su rivista]
Alfano, Gaetano; Damiano, Francesca; Fontana, Francesco; Ferri, Camilla; Melluso, Andrea; Montani, Martina; Morisi, Niccolò; Tei, Lorenzo; Plessi, Jessica; Giovanella, Silvia; Ligabue, Giulia; Mori, Giacomo; Guaraldi, Giovanni; Magistroni, Riccardo; Cappelli, Gianni; Donati, Gabriele
abstract

: Background: Kidney transplant (KT) recipients with COVID-19 are at high risk of poor outcomes due to the high burden of comorbidities and immunosuppression. The effects of immunosuppressive therapy (IST) reduction are unclear in patients with COVID-19. Methods: A retrospective study on 45 KT recipients followed at the University Hospital of Modena (Italy) who tested positive for COVID-19 by RT-PCR analysis. Results: The median age was 56.1 years (interquartile range,[IQR] 47.3-61.1), with a predominance of males (64.4%). Kidney transplantation vintage was 10.1 (2.7-16) years, and 55.6 % of patients were on triple IST before COVID-19. Early immunosuppression minimization occurred in 27 (60%) patients (reduced-dose IST group) and included antimetabolite (88.8%) and calcineurin inhibitor withdrawal (22.2%). After SARS-CoV-2 infection, 88.9% of patients became symptomatic and 42.2% required hospitalization. One patient experienced irreversible graft failure. There were no differences in serum creatinine level and proteinuria in non-hospitalized patients before and post-COVID-19, whereas hospitalized patients experienced better kidney function after hospital discharge (P=0.019). Overall mortality was 17.8%. without differences between full- and reduced-dose IST. Risk factors for death were age (odds ratio [OR]: 1.19; 95%CI: 1.01-1.39), and duration of kidney transplant (OR: 1.17; 95%CI: 1.01-1.35). One KT recipient developed IgA glomerulonephritis and two ones experienced symptomatic COVID-19 after primary infection and SARS-CoV-2 mRNA vaccine, respectively. Conclusions: Despite the reduction of immunosuppression, COVID-19 affected the survival of KT recipients. Age of patients and time elapsed from kidney transplantation were independent predictors of death . Early kidney function was favorable in most survivors after COVID-19.

2021 - Incidence, risk factors and outcome of acute kidney injury (AKI) in patients with COVID-19 [Articolo su rivista]
Alfano, Gaetano; Ferrari, Annachiara; Fontana, Francesco; Mori, Giacomo; Magistroni, Riccardo; Meschiari, Marianna; Franceschini, Erica; Menozzi, Marianna; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Digaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Milic, Jovana; Coloretti, Irene; Raggi, Paolo; Mussini, Cristina; Girardis, Massimo; Cappelli, Gianni; Guaraldi, Giovanni
abstract

Background Acute kidney injury (AKI) is a severe complication of coronavirus disease-2019 (COVID-19). This study aims to evaluate incidence, risk factors and case-fatality rate of AKI in patients with COVID-19. Methods We reviewed the health medical records of 307 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy. Results AKI was diagnosed in 69 out of 307 (22.4%) COVID-19 patients. Stages 1, 2, or 3 AKI accounted for 57.9%, 24.6% and 17.3%, respectively. AKI patients had a mean age of 74.7 +/- 9.9 years. These patients showed higher serum levels of the main markers of inflammation and higher rate of severe pneumonia than non-AKI patients. Kidney injury was associated with a higher rate of urinary abnormalities including proteinuria (0.44 +/- 0.85 vs 0.18 +/- 0.29 mg/mg; P = < 0.0001) and microscopic hematuria (P = 0.032) compared to non-AKI patients. Hemodialysis was performed in 7.2% of the subjects and 33.3% of the survivors did not recover kidney function after AKI. Risk factors for kidney injury were age, male sex, CKD and higher non-renal SOFA score. Patients with AKI had a mortality rate of 56.5%. Adjusted Cox regression analysis revealed that COVID-19-associated AKI was independently associated with in-hospital death (hazard ratio [HR] = 4.82; CI 95%, 1.36-17.08) compared to non-AKI patients. Conclusion AKI was a common and harmful consequence of COVID-19. It manifested with urinary abnormalities (proteinuria, microscopic hematuria) and conferred an increased risk for death. Given the well-known short-term sequelae of AKI, prevention of kidney injury is imperative in this vulnerable cohort of patients.

2021 - Methicillin-Resistant Staphylococcus aureus Peritonitis due to Hematogenous Dissemination from Central Venous Catheter in a Maintenance Dialysis Patient [Articolo su rivista]
Alfano, G.; Frisina, M.; Morisi, N.; Ascione, E.; Fontana, F.; Mori, G.; Cerami, C.; Serra, F.; Cabry, F.; Bonucchi, D.; Gelmini, R.; Guaraldi, G.; Magistroni, R.; Cappelli, G.
abstract

Staphylococcus aureus is a Gram-positive bacterium commonly associated with severe infections in hospitalized patients. S. aureus produces many virulence factors leading to local and distant pathological processes. Invasiveness of S. aureus generally induces metastatic infections such as bacteremia, infective endocarditis, osteomyelitis, arthritis, and endophthalmitis. Peritoneal localization from extra-abdominal infection can be a potential consequence of S. aureus infection. Two cases of metastatic peritonitis have been described in patients on peritoneal dialysis with concomitant peripheral vascular catheter-related bloodstream infection. We reported a case of peritoneal metastatic infection caused by methicillin-resistant Staphylococcus aureus (MRSA) in a patient on maintenance hemodialysis. A 37-year-old man was admitted with fever and chill due to jugular central vascular catheter (CVC)-related bloodstream infection caused by MRSA. CVC was placed after switching the patient from peritoneal dialysis to hemodialysis for scarce adherence to fluid restriction. Detection of MRSA on the peritoneal effluent combined with a total white blood cell count of 554 cells/mm3 prompted the diagnosis of satellite MRSA peritonitis. Antibiotic treatment with daptomycin and simultaneous CVC and peritoneal catheter removal resolved the infectious process. No further metastatic localizations were detected elsewhere. In conclusion, S. aureus can induce metastatic infections far from the site of primary infection. As reported in this case, peritonitis can be secondary to the hematogenous dissemination of S. aureus especially in hospitalized patients having a central line.

2021 - Monoclonal B lymphocytosis in a kidney transplant recipient [Articolo su rivista]
Plessi, J.; Mori, G.; Magistroni, R.; Cappelli, G.
abstract

Monoclonal B lymphocytosis (MBL) is a lymphoproliferative condition characterised by expansion of a B-cell clone in peripheral blood, with an often indolent clinical course. The presence of a B clonal population alone is several hundred times more common in the general population than chronic lymphocytic leukaemia and other non-Hodgkin's lymphoma subtypes, it usually does not represent a malignant condition and it requires follow-up only, without specific treatment. There are few studies describing MBL in solid organ transplant recipients, thus, the concern is raised when enrolling MBL affected subjects in waiting lists. We report the experience of a patient affected by MBL who underwent kidney transplantation, with particular attention to preoperative screening and immunosuppressants impact on post-transplant lymphoproliferative disease risk, to aid clinicians in the evaluation process of transplant candidates affected by similar conditions. 2021 BMJ Publishing Group Limited. Published by BMJ.

2021 - One-year persistence of neutralizing anti-SARS-CoV-2 antibodies in dialysis patients recovered from COVID-19 [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Morisi, Niccolò; Giaroni, Francesco; Mori, Giacomo; Guaraldi, Giovanni; Magistroni, Riccardo; Cappelli, Gianni; Cossarizza, Andrea; Gibellini, Lara
abstract

The immunological mechanisms that modulate immune response to SARS-CoV-2 infection remain elusive. Little is known on the magnitude and the durability of antibody response against COVID-19. There is consensus that patients with immune dysfunction, such as dialysis patients, may be unable to mount a robust and durable humoral immunity after infections. Recent studies showed that dialysis patients seroconverted after COVID-19, but data on the durability of the immune response are missing. We reported the data of a durable anti-spike protein seroconversion after natural SARS-CoV-2 infection in three patients on hemodialysis with a mean age of 67.2 +/- 13.8 years. A mean antibody titer of 212.6 +/- 174.9 UA/ml (Liaison (R), DiaSorin) was found after one year (range, 366-374 days) from the diagnosis of COVID-19. In conclusion, this case series provided evidence that patients receiving hemodialysis who recovered from severe COVID-19 were able to mount a long-lasting immune response against SARS-CoV-2. Although the protective capacity of this long-term immunity remains to be determined, these patients did not report signs of reinfection after recovery from COVID-19.

2021 - Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy [Articolo su rivista]
Canney, M.; Barbour, S. J.; Zheng, Y.; Coppo, R.; Zhang, H.; Liu, Z. -H.; Matsuzaki, K.; Suzuki, Y.; Katafuchi, R.; Reich, H. N.; Cattran, D.; Russo, M. L.; Troyanov, S.; Cook, H. T.; Roberts, I.; Tesar, V.; Maixnerova, D.; Lundberg, S.; Gesualdo, L.; Emma, F.; Fuiano, L.; Beltrame, G.; Rollino, C.; Amore, A.; Camilla, R.; Peruzzi, L.; Praga, M.; Feriozzi, S.; Polci, R.; Segoloni, G.; Colla, L.; Pani, A.; Piras, D.; Angioi, A.; Cancarini, G.; Ravera, S.; Durlik, M.; Moggia, E.; Ballarin, J.; Di Giulio, S.; Pugliese, F.; Serriello, I.; Caliskan, Y.; Sever, M.; Kilicaslan, I.; Locatelli, F.; Del Vecchio, L.; Wetzels, J. F. M.; Peters, H.; Berg, U.; Carvalho, F.; da Costa Ferreira, A. C.; Maggio, M.; Wiecek, A.; Ots-Rosenberg, M.; Magistroni, R.; Topaloglu, R.; Bilginer, Y.; D'Amico, M.; Stangou, M.; Giacchino, F.; Goumenos, D.; Kalliakmani, P.; Gerolymos, M.; Galesic, K.; Geddes, C.; Siamopoulos, K.; Balafa, O.; Galliani, M.; Stratta, P.; Quaglia, M.; Bergia, R.; Cravero, R.; Salvadori, M.; Cirami, L.; Fellstrom, B.; Kloster Smerud, H.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Boria Grinyo, J. M.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska-Wasiak, M.; Martina, G.; Messuerotti, A.; Dal Canton, A.; Esposito, C.; Migotto, C.; Triolo, G.; Mariano, F.; Pozzi, C.; Boero, R.; Bellur, S.; Mazzucco, G.; Giannakakis, C.; Honsova, E.; Sundelin, B.; Di Palma, A. M.; Gutierrez, E.; Asunis, A. M.; Barratt, J.; Tardanico, R.; Perkowska-Ptasinska, A.; Arce Terroba, J.; Fortunato, M.; Pantzaki, A.; Ozluk, Y.; Steenbergen, E.; Soderberg, M.; Riispere, Z.; Furci, L.; Orhan, D.; Kipgen, D.; Casartelli, D.; Galesic Ljubanovic, D.; Gakiopoulou, H.; Bertoni, E.; Cannata Ortiz, P.; Karkoszka, H.; Groene, H. J.; Stoppacciaro, A.; Bajema, I.; Bruijn, J.; Fulladosa Oliveras, X.; Maldyk, J.; Ioachim, E.; Bavbek, N.; Cook, T.; Alpers, C.; Feehally, J.; Berthoux, F.; Bonsib, S.; D'Agati, V.; D'Amico, G.; Emancipator, S.; Emmal, F.; Fervenza, F.; Florquin, S.; Fogo, A.; Groene, H.; Haas, M.; Hill, P.; Hogg, R.; Hsu, S.; Hunley, T.; Hladunewich, ; Jennette, C.; Joh, K.; Julian, B.; Kawamura, T.; Lai, F.; Leung, C.; Li, L.; Li, P.; Liu, Z.; Massat, A.; Mackinnon, B.; Mezzano, S.; Schena, F.; Tomino, Y.; Walker, P.; Wang, H.; Weening, J.; Yoshikawa, N.; Zeng, C. -H.; Shi, S.; Nogi, C.; Suzuki, H.; Koike, K.; Hirano, K.; Yokoo, T.; Hanai, M.; Fukami, K.; Takahashi, K.; Yuzawa, Y.; Niwa, M.; Yasuda, Y.; Maruyama, S.; Ichikawa, D.; Suzuki, T.; Shirai, S.; Fukuda, A.; Fujimoto, S.; Trimarchi, H.
abstract

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

2021 - Response letter to the Editorial: "Ketogenic diet in ADPKD patients" [Articolo su rivista]
Magistroni, Riccardo; Biagini, Giuseppe
abstract

2021 - Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial [Articolo su rivista]
Scolari, F.; Delbarba, E.; Santoro, D.; Gesualdo, L.; Pani, A.; Dallera, N.; Mani, L. -Y.; Santostefano, M.; Feriozzi, S.; Quaglia, M.; Boscutti, G.; Ferrantelli, A.; Marcantoni, C.; Passerini, P.; Magistroni, R.; Alberici, F.; Ghiggeri, G. M.; Ponticelli, C.; Ravani, P.
abstract

Background A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. Methods We randomly assigned 74 adults with membranous nephropathy and proteinuria .3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. Results At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. Conclusions This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-tohead, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial.

2021 - Seroconversion after COVID-19 vaccine in a dialysis patient on immunosuppressants [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Mori, Giacomo; Giovanella, Silvia; Giaroni, Francesco; Ligabue, Giulia; Guaraldi, Giovanni; Magistroni, Riccardo; Cappelli, Gianni
abstract

2021 - The frail world of haemodialysis patients in the COVID-19 pandemic era: a systematic scoping review [Articolo su rivista]
Alfano, G.; Ferrari, A.; Magistroni, R.; Fontana, F.; Cappelli, G.; Basile, C.
abstract

Background: Patients undergoing in-centre haemodialysis (HD) are particularly exposed to the dire consequences of COVID-19. The present systematic scoping review aims to identify the extent, range, and nature of articles related to COVID-19 and maintenance HD: it reports specifically the prevalence of the COVID-19 pandemic in the HD population, implementation of strategies for the prevention, mitigation and containment of the COVID-19 pandemic in HD centres, demographic and clinical characteristics, and outcomes of the pediatric and adult HD patients. Methods: A multi-step systematic search of the literature in Pubmed, Scopus, Ovid Medline, Embase and Web of Science, published between December 1, 2019, and January 30, 2021 was performed. Two authors separately screened the titles and abstracts of the documents and ruled out irrelevant articles. A report of the papers that met inclusion criteria was performed; then, a descriptive analysis of the characteristics of the included articles and a narrative synthesis of the results were performed. Results: The review process ended with the inclusion of 145 articles. Most of them were based on single-centre experiences, which spontaneously developed best practices. Most studies were conducted in high-income countries (69.7%) and a part of them (9.6%) were not in English. Prevalence of COVID-19 among dialysis patients accounted for 0%-37.6%. Preventive measures were reported in 54% of the included articles, with particular emphasis on education, triage, hygiene, and containment measures. Patients experienced a heterogeneous spectrum of symptoms that led 35%-88.2% of them to hospital admission. Median and mean hospital length of stay ranged from 8 to 28.5 and 16.2 to 22 days, respectively. Admission to intensive care units varied widely across studies (from 2.6% to 70.5%) and was associated with high mortality (42.8%–100%). Overall, prognosis was poor in 0%–47% of the hospitalized patients. Conclusions: This systematic scoping review provides an overview of the current knowledge on the impact of COVID-19 on the frail world of HD patients. Furthermore, it may help to implement the existing strategies of COVID-19 prevention and provide a list of unmet needs (safe transport, testing, shelter). Finally, it may be a stimulus for performing systematic reviews and meta-analyses which will form the basis for evidence-based guidelines. Graphic abstract: [Figure not available: see fulltext.]

2021 - Twenty-four-hour serum creatinine variation is associated with poor outcome in the novel coronavirus disease 2019 (COVID-19) patients [Articolo su rivista]
Alfano, Gaetano; Ferrari, Annachiara; Fontana, Francesco; Mori, Giacomo; Ligabue, Giulia; Giovanella, Silvia; Magistroni, Riccardo; Meschiari, Marianna; Franceschini, Erica; Menozzi, Marianna; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Di Gaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Milic, Jovana; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni
abstract

Background: The prognostic value of within-day sCr variation serum creatinine variation is unknown in the setting of the novel coronavirus disease 2019 (COVID-19). We evaluated the prognostic significance of 24-hour serum creatinine variation in COVID-19 patients.Methods: A monocentric retrospective analysis was conducted in COVID-19 patients not admitted to the intensive care unit. Three groups were subdivided based on 24 hours serum creatinine variation from admission. In the stable kidney function group, 24-hour serum creatinine variation ranged from +0.05 to -0.05 mg/dL; in the decreased kidney function group, 24-hour serum creatinine variation was >0.05 mg/dL; in the improved kidney function group, 24-hour serum creatinine variation was <-0.05 mg/dL.Results: The study population included 224 patients with a median age of 66.5 years and a predominance of males (72.3%). Within 24 hours of admission, renal function remained stable in 37.1% of the subjects, whereas it displayed improved and deteriorated patterns in 45.5% and 17.4%, respectively. Patients with decreased kidney function were older and had more severe COVID-19 symptoms than patients with stable or improved kidney function. About half of patients with decreased kidney function developed an episode of acute kidney injury (AKI) during hospitalization. Decreased kidney function was significantly associated with AKI during hospitalization (hazard ratio [HR], 4.6; 95% confidence interval [CI], 1.9-10.8; p < 0.001) and was an independent risk factor for 30-day in-hospital mortality (HR, 5.5; 95% CI, 1.1-28; p = 0.037).Conclusion: COVID-19 patients with decreased kidney function within 24 hours of admission were at high risk of AKI and 30-day in-hospital mortality.

2020 - ADPKD current management and ongoing trials [Articolo su rivista]
Testa, F.; Magistroni, R.
abstract

Among the diseases that require renal replacement therapy (RRT), ADPKD is the fourth for incidence and prevalence. In Italy, there are at least 32,000 patients affected by ADPKD, of which about 2900 in dialysis. The pure costs of dialysis treatment for the Italian National Health Service can be conservatively estimated at 87 million euros per year. Even a modest slowdown in the evolution of the disease would obtain an important result in terms of reduction of health expenditure. In recent years, many new or repurposed drugs have been evaluated in clinical trials for ADPKD. In this review we will mainly focus on advanced stage clinical trials (phase 2 and 3). We have grouped these studies according to the molecular pathway addressed by the experimental drug or the therapeutic strategy. More than 10 years after the start of the first Phase III clinical trials in ADPKD, the first drug active in slowing disease progression is finally available. It cannot be considered a goal but only the beginning of a journey because of the significant side effects and the high cost of Tolvaptan. An exuberant basic research activity in the field, together with the large number of ongoing protocols, keep the nephrologists and their patients positive with regard to the discovery of new and better therapies in a not-too-distant future. © 2019, Italian Society of Nephrology.

2020 - COVID-19 pneumonia in a kidney transplant recipient successfully treated with tocilizumab and hydroxychloroquine [Articolo su rivista]
Fontana, Francesco; Alfano, Gaetano; Mori, Giacomo; Amurri, Alessio; Tei, Lorenzo; Ballestri, Marco; Leonelli, Marco; Facchini, Francesca; Damiano, Francesca; Magistroni, Riccardo; Cappelli, Gianni
abstract

Coronavirus disease 2019 (COVID-19) pneumonia has been poorly reported in solid organ transplanted patients; prognosis is uncertain and best management unclear. We describe the case of a 61-year-old kidney transplant recipient with several comorbidities who was hospitalized and later received a diagnosis of COVID-19 pneumonia; the infection was successfully managed with the use of hydroxychloroquine and a single administration of tocilizumab, after immunosuppression reduction; the patient did not require mechanical ventilation. During the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, transplant clinicians should be readily informed about new cases of COVID-19 pneumonia in solid organ transplant recipients, with focus on therapeutic strategies employed and their outcome.

2020 - Erratum: The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection (Journal of Physical Chemistry DOI: 10.1159/000507914) [Articolo su rivista]
Alfano, G.; Guaraldi, G.; Fontana, F.; Ferrari, A.; Magistroni, R.; Mussini, C.; Cappelli, G.
abstract

In the article by Alfano et al. entitled “The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection” [Blood Purif. DOI: 10.1159/000507914], the affiliations should be indicated as follows:.

2020 - Evaluation of the Classification Accuracy of the Kidney Biopsy Direct Immunofluorescence through Convolutional Neural Networks [Articolo su rivista]
Ligabue, Giulia; Pollastri, Federico; Fontana, Francesco; Leonelli, Marco; Furci, Luciana; Giovanella, Silvia; Alfano, Gaetano; Cappelli, Gianni; Testa, Francesca; Bolelli, Federico; Grana, Costantino; Magistroni, Riccardo
abstract

Background and objectives: Immunohistopathology is an essential technique in the diagnostic workflow of a kidney biopsy. Deep learning is an effective tool in the elaboration of medical imaging. We wanted to evaluate the role of a convolutional neural network as a support tool for kidney immunofluorescence reporting. Design, setting, participants, & measurements: High-magnification (×400) immunofluorescence images of kidney biopsies performed from the year 2001 to 2018 were collected. The report, adopted at the Division of Nephrology of the AOU Policlinico di Modena, describes the specimen in terms of “appearance,” “distribution,” “location,” and “intensity” of the glomerular deposits identified with fluorescent antibodies against IgG, IgA, IgM, C1q and C3 complement fractions, fibrinogen, and κ- and λ-light chains. The report was used as ground truth for the training of the convolutional neural networks. Results: In total, 12,259 immunofluorescence images of 2542 subjects undergoing kidney biopsy were collected. The test set analysis showed accuracy values between 0.79 (“irregular capillary wall” feature) and 0.94 (“fine granular” feature). The agreement test of the results obtained by the convolutional neural networks with respect to the ground truth showed similar values to three pathologists of our center. Convolutional neural networks were 117 times faster than human evaluators in analyzing 180 test images. A web platform, where it is possible to upload digitized images of immunofluorescence specimens, is available to evaluate the potential of our approach. Conclusions: The data showed that the accuracy of convolutional neural networks is comparable with that of pathologists experienced in the field.

2020 - GREASE II. A phase II randomized, 12-month, parallel-group, superiority study to evaluate the efficacy of a Modified Atkins Diet in Autosomal Dominant Polycystic Kidney Disease patients [Articolo su rivista]
Testa, Francesca; Marchiò, Maddalena; D’Amico, Roberto; Giovanella, Silvia; Ligabue, Giulia; Fontana, Francesco; Alfano, Gaetano; Cappelli, Gianni; Biagini, Giuseppe; Magistroni, Riccardo
abstract

Introduction Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a condition that causes progressive renal function decline. Preclinical data suggest the presence of a profound metabolic derangement in ADPKD. Cystic cells shift their energy metabolism from oxidative phosphorylation to aerobic glycolysis, show inhibition of fatty acid oxidation and become glutamine and arginine dependent. Recent preclinical experiences have suggested beneficial effect in terms of reduction of cystic size, interstitial fibrosis and disease progression, targeting these deregulated metabolic pathways by ketosis induction. The dietetic approach to ADPKD, because of low cost and absence of toxicity, represents an interesting therapeutic strategy. Methods and analysis The protocol describes a phase II clinical trial that will evaluate the effect on Total Kidney Volume, safety and tolerability of a ketogenic diet in a selected ADPKD population. The trial will have, as secondary objective, the evaluation of the ability of the ketogenic diet to slow down the renal function decline. This will be a 12-month randomized, parallel group, two arm, superiority trial with 1:1 allocation to evaluate the efficacy of a Modified Atkins Diet protocol compared to a balanced normocaloric diet on 90 ADPKD patients. Dissemination The study results will be released to the patients and the medical community.

2020 - Hybrid dialysis: A promising strategy to reduce hospital access during the SARS-CoV-2 pandemic [Articolo su rivista]
Mori, G.; Alfano, G.; Fontana, F.; Magistroni, R.
abstract

In March 2020, a 74-year-old man affected by end-stage renal disease and on peritoneal dialysis was referred to an emergency room in Modena, Northern Italy, due to fever and respiratory symptoms. After ruling out COVID-19 infection, a diagnosis of chronic obstructive pulmonary disease exacerbation was confirmed and he was thus transferred to the nephrology division. Physical examination and blood tests revealed a positive fluid balance and insufficient correction of the uraemic syndrome, although peritoneal dialysis prescription was maximised. After discussion with the patient and his family, the staff decided to start hybrid dialysis, consisting of once-weekly in-hospital haemodialysis and home peritoneal dialysis for the remaining days. He was discharged at the end of the antibiotic course, after an internal jugular vein central venous catheter placement and the first haemodialysis session. This strategy allowed improvement of depuration parameters and avoidance of frequent access to the hospital, which is crucial in limiting exposure to SARS-CoV-2 in an endemic setting.

2020 - Improving treatment decisions using personalized risk assessment from the International IgA Nephropathy Prediction Tool [Articolo su rivista]
Barbour, Sean J; Canney, Mark; Coppo, Rosanna; Zhang, Hong; Liu, Zhi-Hong; Suzuki, Yusuke; Matsuzaki, Keiichi; Katafuchi, Ritsuko; Induruwage, Dilshani; Er, Lee; Reich, Heather N; Feehally, John; Barratt, Jonathan; For The International IgA, Nephropathy; Magistroni, Riccardo; Cattran, Daniel C
abstract

Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria οϕ 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

2020 - Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update [Articolo su rivista]
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.; 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.; Papastirou, 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.; Rauen, T.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; Van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Boria Grinyo, J. M.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska-Wasiak, M.; 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.; Di Palma, A. M.; Ferrario, F.; Gutierrez, E.; Asunis, A. M.; Barratt, J.; Tardanico, R.; Perkowska-Ptasinska, A.; Arce Terroba, J.; Fortunato, M.; Pantzaki, A.; Ozluk, Y.; Steenbergen, E.; Soderberg, M.; Riispere, Z.; Furci, L.; Orhan, D.; Kipgen, D.; Casartelli, D.; Galesic Ljubanovic, D.; 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.
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 < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). 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.

2020 - Long-term effects of COVID-19 in a patient on maintenance dialysis [Articolo su rivista]
Alfano, G.; Perrone, R.; Fontana, F.; Mori, G.; Lucchi, L.; Guaraldi, G.; Magistroni, R.; Cappelli, G.
abstract

Coronavirus infectious disease (COVID-19) is a novel respiratory infection highly associated with severe complications in elderly subjects affected by cardiovascular disease. Patients on maintenance dialysis are exceptionally vulnerable because most of them are old and have multiple comorbidities. We report the complex clinical course of SARS-CoV-2 infection in a patient on maintenance dialysis who presented with fever and lung edema. After 41 days from the primary infection, the clinically recovered patient experienced symptomatic reactivation of SARS-COV-2 infection documented by positive polymerase chain reaction (PCR) result on nasal/oropharyngeal swab with immunoglobulin M seroconversion. The recurrence of PCR positivity forced us to perform hemodialysis in a separate isolation room for a prolonged period of time. Close monitoring of previously infected patients and restructuring of dialysis facilities are necessary to avoid new outbreaks of this concerning disease.

2020 - Oxalate Nephropathy Caused by Excessive Vitamin C Administration in 2 Patients With COVID-19 [Articolo su rivista]
Fontana, F.; Cazzato, S.; Giovanella, S.; Ballestri, M.; Leonelli, M.; Mori, G.; Alfano, G.; Ligabue, G.; Magistroni, R.; Cenacchi, G.; Antoniotti, R.; Bonucchi, D.; Cappelli, G.
abstract

2020 - Peritoneal dialysis in the time of coronavirus disease 2019 [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Ferrari, Annachiara; Guaraldi, Giovanni; Mussini, Cristina; Magistroni, Riccardo; Cappelli, Gianni; Bacca, Erica; Bedini, Andrea; Borghi, Vanni; Burastero, Giulia; Carli, Federica; Ciusa, Giacomo; Corradi, Luca; Cuomo, Gianluca; Digaetano, Margherita; Dolci, Giovanni; Faltoni, Matteo; Fantini, Riccardo; Franceschi, Giacomo; Franceschini, Ericad; Iadisernia, Vittorio; Larnõ, Damiano; Menozzi, Marianna; Meschiari, Marianna; Milic, Jovana; Orlando, Gabriella; Pellegrino, Francesco; Raimondi, Alessandro; Rogati, Carlotta; Santoro, Antonella; Tonelli, Roberto; Tutone, Marco; Volpi, Sara; Yaacoub, Dina; Aten, G.; Marco, Ballestri; Mori, Giacomo; Girardis, Massimo; Andreotti, Alberto; Biagioni, Emanuela; Bondi, Filippo; Busani, Stefano; Chierego, Giovanni; Scotti, Marzia; Serio, Lucia; Cossarizza, Andrea; Bellinazzi, Caterina; Borella, Rebecca; de Biasi, Sara; de Gaetano, Anna; Fidanza, Lucia; Gibellini, Lara; Iannone, Anna; Lo Tartaro, Domenico; Mattioli, Marco; Nasi, Milena; Paolini, Annamariag; Pinti, Marcello
abstract

In the current setting of global containment, peritoneal dialysis (PD) and home haemodialysis are the best modalities of renal replacement therapy (RRT) to reduce the rate of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the shorter and easier training programme of PD compared to home haemodialysis, PD appears a practical solution for patients with end-stage renal disease to reduce the risk of hospital-acquired infection. PD offers the advantage of minimizing the risk of viral transmission through interpersonal contact that commonly occurs during the haemodialysis session and while travelling from home to the haemodialysis facility using public transport services. To overcome barriers to health care access due to the containment measures for this emerging disease, telemedicine is a useful and reliable tool for delivering health care without exposing patients to the risk of contact. However, novel issues including handling of potentially infected dialysate, caregivers' infectious risk and adequacy of PD in critically ill patients with acute respiratory distress syndrome remain to be clarified. In conclusion, PD should be preferred to the other modalities of RRT during the coronavirus disease 2019 (COVID-19) outbreak because it can be a solution to cope with the increased number of infected patients worldwide.

2020 - SARS-CoV-2 infection in dialysis patients in northern Italy: A single-centre experience [Articolo su rivista]
Fontana, F.; Giaroni, F.; Frisina, M.; Alfano, G.; Mori, G.; Lucchi, L.; Magistroni, R.; Cappelli, G.
abstract

Background. Dialysis patients are considered at high risk for COVID-19 and the infection can easily spread in dialysis units. Methods. We conducted an observational single-centre cohort study to describe clinical characteristics, treatments and outcomes of dialysis patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We tested patients who presented symptoms or had contact with a confirmed case. We enrolled 15 patients positive for SARS-CoV-2. Results. We tested 37 of 306 dialysis patients. Patients with SARS-CoV-2 infection were older (mean age 75.96 6 11.09 years) and all had comorbidities. At presentation, most had interstitial infiltrates on chest X-ray, three-quarters had leucopenia and none had respiratory insufficiency. During follow-up, there was an increase in serum C-reactive protein and interleukin-6. Eighty percent of patients received supplemental oxygen; none received non-invasive ventilation, one was intubated. Most patients (80%) were treated with oral hydroxychloroquine for a median time of 6.5 days [interquartile range (IQR) 5-14.5] and 40% received azithromycin; two patients received a short course of antivirals and one received a single dose of tocilizumab. Only two patients did not require hospitalization. Of the nine survivors, eight still tested positive for SARS-CoV-2 a median of 19 days (IQR 9.25-23) after diagnosis. Six patients died (case fatality rate 40%) a median of 5.5 days (IQR 1.75-9.75) after diagnosis. The main reported cause of death was respiratory failure related to COVID-19 (five patients). Conclusions. We report a single-centre experience of SARS-CoV-2 infection in dialysis patients. The disease showed a high case fatality rate and most patients required hospitalization. Survivors show prolonged viral shedding.

2020 - The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection [Articolo su rivista]
Alfano, Gaetano; Guaraldi, Giovanni; Fontana, Francesco; Ferrari, Annachiara; Magistroni, Riccardo; Mussini, Cristina; Cappelli, Gianni
abstract

2020 - The definition of chronic kidney disease in a context of aging population [Articolo su rivista]
Alfano, G.; Fontana, F.; Mori, G.; Magistroni, R.; Cappelli, G.
abstract

Chronic kidney disease (CKD) is a progressively chronic disease that carries a high burden of morbidity and mortality and is associated with significant healthcare utilization and costs. Recent trends shown that the prevalence of CKD is stable in Europe and USA, whereas tends to decline in some countries with a high standard of care. According to international guidelines, chronic kidney disease (CKD) is defined as the presence of kidney damage or a glomerular filtration rate (eGFR) less than 60 ml/min. This staging method has a main drawback, its imprecise assessment of renal function at the extremes of the age bracket: the use of a fixed threshold value (glomerular filtration rate [GFR <60 ml /min]) to define chronic renal failure appears an imprecise measure in the young and in the elderly. In these two groups, in fact, the measurement of GFR is difficult to categorize in a "rigid" system of classification. The reduction of the GFR with aging is due to a complex process that leads to a steady reduction of the functioning nephrons over 40 years of age. Taken together, these findings should spur us to adopt a new definition of CKD. An age-adapted definition of CKD could be a good solution to avoid a diagnosis of CKD in elderly patients (GFR >45 ml/min) when there are no prognostic implications on survival. The adoption of this new definition would also reduce the high prevalence of the disease in the general population, with a beneficial reduction of the costs associated with monitoring a mildly decreased eGFR.

2020 - The underlying cause of kidney disease is often unknown in dialysis patients: a possible genomic approach [Articolo su rivista]
Testa, F.; Scalabrini, D.; Perrone, R.; Ligabue, G.; Cappelli, G.; Magistroni, R.
abstract

As much as 16-17% European and American patients on renal replacement therapy do not have a conclusive diagnosis of the cause of their renal failure. This may have important implications on the types of morbidity they can develop in case of systemic diseases with extrarenal involvement, or recurrent renal diseases in transplanted patients. A better knowledge of the underlying disease can have important prognostic and therapeutic repercussions. In this study we evaluated the rate of uremic patients who can benefit from a genomic diagnostic approach. Patients liable to a future genomic diagnostic study were selected based on two criteria: (i) age of dialysis entry less or equal to 55 years, and (ii) presence of a non-conclusive diagnosis. Based on the data extracted from the REGDIAL registry, we analyzed 534 patients undergoing renal replacement therapy. We identified 300 patients with age of entry into replacement therapy <55 years (56.2% of the overall study population). Among these, we identified 107 patients with missing or inconclusive diagnosis, which was equal to 20% of the overall population. Of these patients, 32.8% reported a positive family history of kidney disease. This study confirms that a significant proportion of patients on renal replacement therapy do not have an etiological diagnosis and may be subject to a genomic evaluation. With the increasing availability of genomic sequencing technology and the falling of related costs, nephrologists will be increasingly inclined to incorporate clinical genetic testing into their diagnostic armamentarium. There is therefore a need for in-depth, multicenter studies aimed at developing evidence-based guidelines, clear indications and at confirming the usefulness of genetic testing in nephrology.

2019 - A pilot study to evaluate Tolerability and Safety of a Modified Atkins Diet in ADPKD patients [Articolo su rivista]
Testa, Francesca; Marchiò, Maddalena; Belli, Michela; Giovanella, Silvia; Ligabue, Giulia; Cappelli, Gianni; Biagini, Giuseppe; Magistroni, Riccardo
abstract

Background Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the fourth cause of end stage renal disease (ESRD) and urgently requires the development of effective therapeutic treatments. The presence of a shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis in ADPKD prompted us to explore the possibility to limit glucose availability by a nutritional approach. Methods We performed a single arm interventional pilot study to administer the modified Atkins diet to ADPKD patients, evaluating tolerability and safety by a questionnaire, along with glycemia and other biological parameters for 3 months. Results Satisfaction about the administered diet was high (median score of 4, IRQ 4–5). Compliance was also more than satisfactory (3, IRQ 2–5). Wellness reached the highest score (5, IRQ 4–5). Main side effect was the increase in cholesterol levels (mean net increase of 34 ± 13.1 mg/dl). Glycemia was reduced from the mean value of 105.8 ± 8.5 mg/dl (first week) to 92 ± 8.8 mg/dl (after 12ve weeks). Conclusions Our study showed the modified Atkins diet is able to reduce glucose availability and it, is well tolerated by adult patients with ADPKD.

2019 - Evaluating a New International Risk-Prediction Tool in IgA Nephropathy [Articolo su rivista]
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; For The International IgA, Nephropathy; Magistroni, Riccardo; Cattran, Daniel C.
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.

2019 - Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: Evidence from the VALidation of IGA study cohort [Articolo su rivista]
Bellur, S. S.; Roberts, I. S. D.; Troyanov, S.; Royal, V.; Coppo, R.; Cook, H. T.; Cattran, D.; Terroba, Y. A.; Asunis, A. M.; Bajema, I.; Bertoni, E.; Bruijn, J. A.; Cannata-Ortiz, P.; Casartelli, D.; Di Palma, A. M.; Ferrario, F.; Fortunato, M.; Furci, L.; Gakiopoulou, H.; Ljubanovic, D. G.; Giannakakis, K.; Goma, M.; Grone, H. -J.; Gutierrez, E.; Haider, S. A.; 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. P.; Steenbergen, E.; Stoppacciaro, A.; Von Feilitzen, B. S.; Tardanico, R.; 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.; Barratt, J.; Cancarini, G.; Ravera, S.; Durlik, M.; Moggia, E.; Ballarin, J.; Di Giulio, S.; Pugliese, F.; Serriello, I.; Caliskan, Y.; Sever, M.; Locatelli, F.; Del Vecchio, L.; Wetzels, J. F. M.; Peters, H.; Berg, U.; Carvalho, F.; da Costa Ferreira, A. C.; Maggio, M.; Wiecek, A.; Ots-Rosenberg, M.; Magistroni, R.; Topaloglu, R.; Bilginer, Y.; D'Amico, M.; Stangou, M.; Giacchino, F.; Goumenos, D.; Kalliakmani, P.; Gerolymos, M.; Galesic, K.; Geddes, C.; Siamopoulos, K.; Balafa, O.; Galliani, M.; Stratta, P.; Quaglia, M.; Bergia, R.; Cravero, R.; Salvadori, M.; Cirami, L.; Fellstrom, B.; Kloster Smerud, H.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Grinyo, J. M.; Fulladosa, X.; Cusinato, S.; 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.; Boero, R.; Kilicaslan, I.
abstract

Background: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. 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 (CS/IS) treatments, 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 and central absent, local absent and 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, while 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. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with 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 a 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.

2019 - Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: Protocol of a pilot randomised controlled trial [Articolo su rivista]
Scolari, F.; Dallera, N.; Gesualdo, L.; Santoro, D.; Pani, A.; Santostefano, M.; Feriozzi, S.; Mani, L. -Y.; Boscutti, G.; Messa, P.; Magistroni, R.; Quaglia, M.; Ponticelli, C.; Ravani, P.
abstract

Introduction Primary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease may have different long-term outcomes. After 10 years of follow-up, 35%-50% of the untreated patients with persistent nephrotic syndrome may die or progress to end stage renal disease. The 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend that initial therapy should consist of alternating steroids and an alkylating agent for 6 months. Recent observational studies showed that the anti-CD20 antibody rituximab may be effective in inducing remission. We designed a pilot multicentre randomised trial to inform the design of a larger trial testing the efficacy and safety of treatment with steroids and cyclophosphamide versus rituximab in patients with primary MN and heavy proteinuria (>3.5 g/24 hours). Methods and analysis This pilot, open-label, two-parallel-arm, randomised clinical trial will enrol 70 patients with primary MN and heavy proteinuria. Patients will be randomised in a 1:1 ratio to either the intervention arm (rituximab) or the active comparator arm (corticosteroid/alkylating-agent therapy). The study will provide estimates of the probability of complete remission of proteinuria and risk of serious side effects at 12 months to inform the design of a larger trial. We will also assess the recruitment potential of each participating centre to address study feasibility. Ethics and dissemination The trial received ethics approval from the local ethics boards. We will publish pilot data to inform the design of a larger clinical trial. Trial registration numbers NCT03018535; 2011-006115-59. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

2019 - TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes [Articolo su rivista]
Magistroni, R.; Mangolini, A.; Guzzo, S.; Testa, F.; Rapanà, M. R.; Mignani, R.; Russo, G.; Di Virgilio, F.; Aguiari, G.
abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is mainly characterised by the development and enlargement of renal cysts that lead to end-stage renal disease (ESRD) in adult patients. Other clinical manifestations of this pathology include hypertension, haematuria, abdominal pain, cardiovascular system alterations and intracranial aneurysms. ADPKD is linked to mutations in either PKD1 or PKD2 that codifies polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. PC1 and TRPP2 are membrane proteins that function as receptor-channel elements able to regulate calcium homeostasis. The function of polycystins has been mainly studied in kidney cells; but the role of these proteins in T lymphocytes is not well defined. Methods: T lymphocytes were produced from ADPKD1 and ADPKD2 patients as well as from non-ADPKD subjects undergoing renal replacement therapy (RRT) and healthy controls. Protein expression and phosphorylation levels were analysed by western blotting, cell proliferation was calculated by direct counting using trypan blue assay and intracellular calcium concentration was measured by Fura-2 method. Results: PKD2 mutations lead to the significant reduction of TRPP2 expression in T lymphocytes derived from ADPKD patients. Furthermore, a smaller TRPP2 truncated protein in T lymphocytes of patients carrying the mutation R872X in PKD2 was also observed, suggesting that TRPP2 mutated proteins may be stably expressed. The silencing or mutation of PKD2 causes a strong reduction of ATP-evoked calcium in Jurkat cells and ADPKD2 T lymphocytes, respectively. Moreover, T lymphocytes derived from both ADPKD1 and ADPKD2 patients show increased cell proliferation, basal chemotaxis and cell aggregation compared with T lymphocytes from non-ADPKD subjects. Similarly to observations made in kidney cells, mutations in PKD1 and PKD2 dysregulate ERK, mTOR, NFkB and MIF pathways in T lymphocytes. Conclusions: Because the alteration of ERK, mTOR, NFkB and MIF signalling found in T lymphocytes of ADPKD patients may contribute to the development of interstitial inflammation promoting cyst growth and kidney failure (ESRD), the targeting of inflammasome proteins could be an intriguing option to delay the progression of ADPKD. © 2019 The Author(s).

2018 - A Review of the Imaging Techniques for Measuring Kidney and Cyst Volume in Establishing Autosomal Dominant Polycystic Kidney Disease Progression [Articolo su rivista]
Magistroni, R.; Corsi, C.; Martí, T.; Torra, R.
abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited renal disorder; it is defined by progressive renal cyst formation and subsequent renal enlargement that leads to end-stage renal disease. Until recently, only symptomatic treatments for ADPKD existed. However, therapies that address the underlying pathophysiology of ADPKD are now available and accurate identification of the rate of disease progression is essential. Summary: Published data on the different imaging modalities for measuring kidney and cyst volumes in ADPKD are reviewed. The advantages and drawbacks of the different techniques for calculating kidney volume from renal imaging are also examined, including the use of manual planimetry, stereology, and the ellipsoid equation, as well as the prospect of semi- and fully automatic techniques. The translation of these approaches into clinical practice and their role in informing treatment decisions is discussed. Key Messages: These new therapies require the accurate monitoring of disease progression, which along with diagnosis and prognosis, relies on the effective use of renal imaging techniques. There is growing support for the use of total kidney volume as a measure of cyst burden and as a prognostic predictor of renal function in ADPKD, showing promise as a marker of disease progression. © 2018 S. Karger AG, Basel. Copyright: All rights reserved.

2018 - Approccio pratico alla terapia del paziente affetto da Rene Policistico Autosomico Dominante [Articolo su rivista]
Esposito, Ciro; La Milia, Vincenzo; Altobelli, Claudia; Cerutti, Roberta; Manunta, Paolo; Dallera, Nadia; Piscopo, Giovanni; Magistroni, Riccardo
abstract

Il Rene Policistico Autosomico Dominante (ADPKD) è la più frequente patologia genetica di interesse nefrologico e coinvolge dal 7 al 10% dei soggetti in trattamento sostitutivo renale. Si stima che un numero compreso tra 24.000 e 34.000 soggetti in Italia siano affetti da questa condizione. In una patologia che è stata a lungo negletta per mancanza di opzioni terapeutiche è ora disponibile una attraente possibilità di trattamento: tolvaptan ha dimostrato in due trial clinici (pazienti ADPKD con insufficienza renale precoce e pazienti ADPKD con insufficienza renale avanzata) una efficacia clinica nel rallentare la progressione di malattia. La possibile tossicità epatica espressa in circa il 4% dei soggetti esposti al farmaco e un importante effetto acquaretico suggeriscono prudenza e attenzione nell’utilizzo di questa nuova molecola. Sulla base di queste criticità, alcuni medici con una diretta esperienza nell’uso del farmaco hanno brevemente raccolto nelle pagine a seguire le principali raccomandazioni cliniche al trattamento dei pazienti ADPKD. Le raccomandazioni riguardano l’approccio generale al paziente affetto da ADPKD ma con una attenzione particolare agli aspetti legati al nuovo trattamento. Sarà approfondito il delicato compito di introdurre al paziente le opportunità e i limiti della terapia offerta. Infine il documento vuole suggerire come meglio organizzare un ambulatorio dedicato a questa condizione.

2018 - Practical approach to patient therapy affected by Autosomal Dominant Autosomic Polycystic Kidney Disease [Articolo su rivista]
Esposito, C.; La Milia, V.; Altobelli, C.; Cerutti, R.; Manunta, P.; Dallera, N.; Piscopo, G.; Magistroni, R.
abstract

The Autosomal Dominant Polycystic Kidney Disease(ADPKD) is the most frequent renal genetic condition and involves 7 to 10% of subjects undergoing renal replacement therapy. It is estimated that between 24,000 and 34,000 subjects in Italy are affected by this condition. For an illness that has long been neglected due to a lack of treatment options, an attractive treatment possibility is now available: tolvaptan has shown clinical efficacy regarding disease progression in two clinical trials (ADPKD patients with mild renal failure and ADPKD patients with advanced renal failure). The possible liver toxicity expressed in about 4% of the subjects exposed to the drug and an important aquaretic effect suggest prudence and attention in the use of this new molecule. Based on these critical points, some clinicians with direct experience in the use of the drug have briefly collected in the pages to follow the main clinical recommendations for the treatment of ADPKD patints. The recommendations concern the general approach to the patient affected by ADPKD but with particular attention to the aspects related to the new treatment. The delicate task of introducing the opportunities and limitations of the offered therapy to the patient will be deepened. Finally, the document wants to suggest how best to organize a clinic dedicated to this condition.

2018 - The prevalence of autosomal dominant polycystic kidney disease (ADPKD): A meta-analysis of European literature and prevalence evaluation in the Italian province of Modena suggest that ADPKD is a rare and underdiagnosed condition [Articolo su rivista]
Solazzo, Andrea; Testa, Francesca; Giovanella, Silvia; Busutti, Marco; Furci, Luciana; Carrera, Paola; Ferrari, Maurizio; Ligabue, Giulia; Mori, Giacomo; Leonelli, Marco; Cappelli, Gianni; Magistroni, Riccardo
abstract

ADPKD is erroneously perceived as a not rare condition, which is mainly due to the repeated citation of a mistaken interpretation of old epidemiological data, as reported in the Dalgaard's work (1957). Even if ADPKD is not a common condition, the correct prevalence of ADPKD in the general population is uncertain, with a wide range of estimations reported by different authors. In this work, we have performed a meta-analysis of available epidemiological data in the European literature. Furthermore we collected the diagnosis and clinical data of ADPKD in a province in the north of Italy (Modena). We describe the point and predicted prevalence of ADPKD, as well as the main clinical characteristics of ADPKD in this region.

2017 - Comparison of Total Kidney Volume Quantification Methods in Autosomal Dominant Polycystic Disease for a Comprehensive Disease Assessment [Articolo su rivista]
Turco, Dario; Busutti, Marco; Mignani, Renzo; Magistroni, Riccardo; Corsi, Cristiana
abstract

Background: In recent times, the scientific community has been showing increasing interest in the treatments aimed at slowing the progression of the autosomal dominant polycystic kidney disease (ADPKD). Therefore, in this paper, we test and evaluate the performance of several available methods for total kidney volume (TKV) computation in ADPKD patients - from echography to MRI - in order to optimize patient classification. Methods: Two methods based on geometric assumptions (mid-slice [MS], ellipsoid [EL]) and a third one on true contour detection were tested on 40 ADPKD patients at different disease stage using MRI. The EL method was also tested using ultrasound images in a subset of 14 patients. Their performance was compared against TKVs derived from reference manual segmentation of MR images. Patient clinical classification was also performed based on computed volumes. Results: Kidney volumes derived from echography significantly underestimated reference volumes. Geometric-based methods applied to MR images had similar acceptable results. The highly automated method showed better performance. Volume assessment was accurate and reproducible. Importantly, classification resulted in 79, 13, 10, and 2.5% of misclassification using kidney volumes obtained from echo and MRI applying the EL, the MS and the highly automated method respectively. Conclusion: Considering the fact that the image-based technique is the only approach providing a 3D patient-specific kidney model and allowing further analysis including cyst volume computation and monitoring disease progression, we suggest that geometric assumption (e.g., EL method) should be avoided. The contour-detection approach should be used for a reproducible and precise morphologic classification of the renal volume of ADPKD patients.

2017 - Defective glycolysis and the use of 2-deoxy-d-glucose in polycystic kidney disease: from animal models to humans [Articolo su rivista]
Magistroni, Riccardo; Boletta, Alessandra
abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by bilateral renal cyst formation. ADPKD is one of the most common rare disorders, accounting for ~10% of all patients with end-stage renal disease (ESRD). ADPKD is a chronic disorder in which the gradual expansion of cysts that form in a minority of nephrons eventually causes loss of renal function due to the compression and degeneration of the surrounding normal parenchyma. Numerous deranged pathways have been identified in the cyst-lining epithelia, prompting the design of potential therapies. Several of these potential treatments have proved effective in slowing down disease progression in pre-clinical animal studies, while only one has subsequently been proven to effectively slow down disease progression in patients, and it has recently been approved for therapy in Europe, Canada and Japan. Among the affected cellular functions and pathways, recent investigations have described metabolic derangement in ADPKD as a major trait offering additional opportunities for targeted therapies. In particular, increased aerobic glycolysis (the Warburg effect) has been described as a prominent feature of ADPKD kidneys and its inhibition using the glucose analogue 2-deoxy-d-glucose (2DG) proved effective in slowing down disease progression in preclinical models of the disease. At the same time, previous clinical experiences have been reported with 2DG, showing that this compound is well tolerated in humans with minimal and reversible side effects. In this work, we review the literature and speculate that 2DG could be a good candidate for a clinical trial in humans affected by ADPKD.

2017 - Tolvaptan: Clinical Evidence for Slowing the Progression of Autosomal Dominant Polycystic Kidney Disease [Articolo su rivista]
Magistroni, Riccardo
abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal failure and the causative condition in approximately 8% of patients requiring renal replacement therapy in Europe. According to the latest epidemiological data in Italy, about 25,000 individuals are affected by ADPKD. In February 2015, the European Medicines Agency (EMA) approved the use of tolvaptan (JINARC®) for the treatment of ADPKD. Tolvaptan is a selective antagonist for the V2 receptor of vasopressin. It induces the reduction of renal cyst size and kidney volume; furthermore, it restrains cystic cell proliferation. TEMPO 3:4 is a large phase III study that demonstrated the clinical efficacy of tolvaptan in reducing renal volume and slowing renal function loss. The TEMPO 4:4 extension study evaluated for a further two years tolvaptan's safety features and efficacy in patients previously enrolled in TEMPO 3:4. The safety profile emerging from TEMPO 4:4 confirmed the safety and tolerability of this molecule. The most significant clinical safety issue concerns liver toxicity; this occurs in less than 4% of subjects and requires specific monitoring. Post hoc analysis adjusted for major confounders suggested the ability of tolvaptan to retain its therapeutic efficacy even in the extension period. Tolvaptan is the first molecule with proven efficacy in ADPKD; in view of the potential toxicity and the significant aquaretic effect, which reduces the patient's quality of life, the treatment should be directed to a selected population with evidence of rapidly progressive disease.

2016 - Advances in genetics of Immunoglobulin A Nephropathy. [Capitolo/Saggio]
Zhang, Hong; Magistroni, Riccardo; Gharavi, Ali
abstract

In the chapter genetic characteristics of IgA Nephropathy are discussed

2016 - Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) [Articolo su rivista]
Carrera, Paola; Calzavara, Silvia; Magistroni, Riccardo; den Dunnen, Johan T; Rigo, Francesca; Stenirri, Stefania; Testa, Francesca; Messa, Piergiorgio; Cerutti, Roberta; Scolari, Francesco; Izzi, Claudia; Edefonti, Alberto; Negrisolo, Susanna; Benetti, Elisa; Alibrandi, Maria Teresa Sciarrone; Manunta, Paolo; Boletta, Alessandra; Ferrari, Maurizio
abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial.

2016 - Insufficienza renale gestione della uremia e della terapia sostitutiva [Articolo su rivista]
Magistroni, Riccardo; Capolongo, Giovanna; Piscopo, Giovanni
abstract

Replacement therapy implemented by renal transplantation is preferable to dialysis treatment and also in uremic population with ADPKD. In preparation for the transplant nephrectomy is a procedure associated with morbidity and mortality in patient with ADPKD, it should be performed on the basis of stringent clinical indications. When the kidney transplant is not possible, peritoneal dialysis in appropriate patients is not contraindicated with comparable results to the extracorporeal dialytic treatment. The therapeutic targets in substitution treatment with respect to pressure levels, lipids, hemoglobin, anticoagulation regime are comparable to the non ADPKD uremic population.

2016 - The MEST score provides earlier risk prediction in lgA nephropathy [Articolo su rivista]
Barbour, Sean J.; Espino Hernandez, Gabriela; Reich, Heather N.; Coppo, Rosanna; Roberts, Ian S. D.; Feehally, John; Herzenberg, Andrew M.; Cattran, Daniel C; Bavbek, N.; Cook, T.; Troyanov, S.; Alpers, C.; Amore, A.; Barratt, J.; Berthoux, F.; Bonsib, S.; Bruijn, J.; D'Agati, V.; D'Amico, G.; Emancipator, S.; Emmal, F.; Ferrario, F.; Fervenza, F.; Florquin, S.; Fogo, A.; Geddes, C.; 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.; Zhang, H.; Coppo, R.; Troyanov, S.; Cattran, D. C.; Cook, H. T.; Feehally, J.; 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.; Angioi, A.; Piras, L.; 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, Riccardo; Topaloglu, R.; Bilginer, Y.; D'Amico, M.; Stangou, M.; Giacchino, F.; Goumenos, D.; Kalliakmani, P.; Gerolymos, M.; Galesic, K.; Geddes, C.; Siamopoulos, K.; Balafa, O.; Galliani, M.; Stratta, P.; Quaglia, M.; Bergia, R.; Cravero, R.; Salvadori, M.; Cirami, L.; Fellstrom, B.; Kloster Smerud, H.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Lupo, A.; Bernich, P.; Menè, P.; Morosetti, M.; Van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Boria Grinyo, J. M.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska Wasiak, M.; Martina, G.; Messuerotti, A.; Dal Canton, A.; Esposito, C.; Migotto, C.; Triolo, G.; Mariano, F.; Pozzi, C.; Boero, R.; Bellur, S.; Mazzucco, G.; Giannakakis, C.; Honsova, E.; Sundelin, B.; Di Palma, A. M.; Ferrario, 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.
abstract

The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods.

2016 - Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy [Articolo su rivista]
Feehally, John; Coppo, Rosanna; Troyanov, Stéphan; Bellur, Shubha S; Cattran, Daniel; Cook, Terence; Roberts, Ian S. D; Verhave, Jacobien C; Camilla, Roberta; Vergano, Luca; Egido, Jesus; Wiecek, Andrzej; Karkoszka, Henryk; Tesar, Vladimir; Maixnerova, Dita; Ots Rosenberg, Mai; Quaglia, Marco; Rollino, Cristiana; Magistroni, Riccardo; Cusinato, Stefano; Cravero, Raffaella; Peruzzi, Licia; Lundberg, Sigrid; Gesualdo, Loreto; Cancarini, Giovanni; Feriozzi, Sandro; Ferrario, Franco
abstract

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.

2016 - [Clinical diagnosis of Autosomal Dominant Polycystic Kidney Disease] [Articolo su rivista]
Magistroni, Riccardo; Izzi, Claudia; Scolari, Francesco
abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder related to kidney. ADPKD is usually easy to diagnose in people who have a family history of ADPKDs developing typical symptoms, including flank, abdominal pain or macroscopic hematuria. In this setting, diagnosis in adults at risk for ADPKD is commonly performed by ultrasonography, which reveals two enlarged kidneys with multiple bilateral cysts. ADPKD may be more difficult to diagnose in the absence of family history or in subjects with atypical presentation, including asymmetric or focal renal imaging findings, discordant disease within family, early onset of ADPKD and development of ESRD before 30 yr of age. The presence of a total of three or more renal cysts for at-risk subjects aged 15-39 years and two cysts or more in each kidney for at-risk subjects aged 40-59 years are sufficient for the diagnosis of ADPKD. The absence of any renal cyst is sufficient for disease exclusion only for at-risk subjects aged 40 years or older. If the family history is negative, the diagnosis of ADPKD can be made in a patient with enlarged kidneys, numerous cysts, presence of liver cysts and absence of findings suggesting a different cystic disease. If the imaging diagnosis is not clear or showing atypical manifestations in subjects, molecular genetic testing should be performed.

2016 - [Diagnosis in Polycystic Kidney Disease] [Articolo su rivista]
Magistroni, Riccardo
abstract

The diagnosis of ADPKD should be based on a thorough assessment of the family history, radiological study and when indicated, genetic study. The anamnestic definition of 'negative family history' should be accepted only after a full clinical-instrumental assessment of close relatives of the subject . Ultrasound is the diagnostic modality of choice in at-risk patients with a positive family history of ADPKD. In some clinical scenarios (screening kidney donation, family planning and others) misdiagnosis based on morphological criteria may be too high. For this reason, it is not recommended to use the kidney ultrasound in order to rule out the diagnosis in patients younger than 40 years. In the cases with a positive family history in which the renal ultrasonography has not been able to clarify the diagnosis, either as confirmation or exclusion, MRI is indicated, given the increased sensitivity and specificity of the technology. The molecular genetic analysis can help establish the diagnosis. In the cases with negative family history, it is necessary to evaluate the presence of syndromic elements non-characteristic of ADPKD. In the presence of these elements, it is recommended to send the patient to a tertiary center for a differential diagnosis based on clinical and molecular assessment.

2016 - [Genetics and genetic counseling] [Articolo su rivista]
Izzi, Claudia; Liut, Francesca; Dallera, Nadia; Mazza, Cinzia; Magistroni, Riccardo; Savoldi, Gianfranco; Scolari, Francesco
abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic disease, characterized by progressive development of bilateral renal cysts. Two causative genes have been identified: PKD1 and PKD2. ADPKD phenotype is highly variable. Typically, ADPKD is an adult onset disease. However, occasionally, ADPKD manifests as very early onset disease. The phenotypic variability of ADPKD can be explained at three genetic levels: genic, allelic and gene modifier effects. Recent advances in molecular screening for PKD gene mutations and the introduction of the new next generation sequencing (NGS)- based genotyping approach have generated considerable improvement regarding the knowledge of genetic basis of ADPKD. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, focusing on new insights in genotype-phenotype correlation and exploring novel clinical approach to genetic testing. Evaluation of these new genetic information requires a multidisciplinary approach involving a nephrologist and a clinical geneticist.

2015 - Corticosteroids in IgA nephropathy: A retrospective analysis from the VALIGA study [Articolo su rivista]
Vladimir, Tesar; Stéphan, Troyanov; Shubha, Bellur; Jacobien C., Verhave; H., Terence Cook; John, Feehally; Ian S. D., Roberts; Daniel, Cattran; Rosanna, Coppo; on behalf of the VALIGA study of the ERA EDTA Immunonephrology Working, Group; Magistroni, Riccardo
abstract

Current guidelines suggest treatment with corticosteroids (CS) in IgA nephropathy (IgAN) when proteinuria is persistently ≥1 g/d despite 3-6 months of supportive care and when eGFR is >50 ml/min per 1.73 m2.Whether the benefits of this treatment extend to patients with an eGFR ≤50 ml/min per 1.73 m2, other levels of proteinuria, or different renal pathologic lesions remains unknown. We retrospectively studied 1147 patients with IgAN from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification and medication used, with details of duration but not dosing. Overall, 46% of patients received immunosuppression, of which 98% received CS. Treated individuals presented with greater clinical and pathologic risk factors of progression. They also received more antihypertensive medication, and a greater proportion received renin angiotensin system blockade (RASB) compared with individuals without immunosuppressive therapy. Immunosuppression was associated with a significant reduction in proteinuria, a slower rate of renal function decline, and greater renal survival. Using a propensity score, we matched 184 subjects who received CS and RASB to 184 patients with a similar risk profile of progression who received only RASB. Within this group, CS reduced proteinuria and the rate of renal function decline and increased renal survival. These benefits extended to those with an eGFR#50 ml/min per 1.73 m2, and the benefits increased proportionally with the level of proteinuria. Thus, CS reduced the risk of progression regardless of initial eGFR and in direct proportion to the extent of proteinuria in this cohort.

2015 - Geometry-independent assessment of renal volume in polycystic kidney disease from magnetic resonance imaging [Relazione in Atti di Convegno]
Turco, Dario; Severi, Stefano; Mignani, Renzo; Magistroni, Riccardo; Corsi, Cristiana
abstract

Total renal volume (TRV) is an important quantitative indicator of the progression of autosomal dominant polycystic kidney disease (ADPKD). The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease proposes a method for TRV computation based on manual tracing and geometric modeling. We developed a fast and nearly-automated technique for kidney segmentation and automatically compute TRV. In this study we aim to compare TRV estimates derived from these two different approaches. The highly-automated technique for the analysis of MR images was tested on 30 ADPKD patients. TRV was computed from both axial and coronal acquisitions, and compared to measurements based on geometric modeling by linear regression and Bland Altman analysis. In addition, to assess reproducibility, intra-observer and inter-observer variabilities were computed. The results of this study provide the feasibility of using a nearly-automated approach for accurate and fast evaluation of TRV also in markedly enlarged ADPKD kidneys.

2015 - New developments in the genetics, pathogenesis, and therapy of IgA nephropathy [Articolo su rivista]
Magistroni, Riccardo; D'Agati, Vivette D.; Appel, Gerald B.; Kiryluk, Krzysztof
abstract

Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multihit pathogenesis model, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geoethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of interpopulation allelic differentiation across all genetic loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multilocus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the 'Intestinal Immune Network for IgA Production' emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multihit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.Kidney International advance online publication, 16 September 2015; doi:10.1038/ki.2015.252.

2015 - Reliability of Total Renal Volume Computation in Polycystic Kidney Disease From Magnetic Resonance Imaging [Articolo su rivista]
Turco, Dario; Severi, Stefano; Mignani, Renzo; Aiello, Valeria; Magistroni, Riccardo; Corsi, Cristiana
abstract

RATIONALE AND OBJECTIVES: Total renal volume (TRV) is an important quantitative indicator of the progression of autosomal dominant polycystic kidney disease (ADPKD). The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease proposes a method for TRV computation based on manual tracing and geometric modeling. Alternative approaches for TRV computation are represented by the application of advanced image processing techniques. In this study, we aimed to compare TRV estimates derived from these two different approaches. MATERIALS AND METHODS: The nearly automated technique for the analysis of magnetic resonance (MR) images was tested on 30 ADPKD patients. TRV was computed from both axial (KVax) and coronal (KVcor) acquisitions and compared to measurements based on geometric modeling (KVap) by linear regression and Bland-Altman analysis. In addition, to assess reproducibility, intraobserver and interobserver variabilities were computed. RESULTS: Linear regression analysis between KVax and KVcor resulted in an excellent correlation (KVax = 1KVcor - 0.78; r2 = 0.997). Bland-Altman analysis showed a negligible bias and narrow limits of agreement (bias: -11.7 mL; SD: 54.3 mL). Similar results were obtained by comparison of volumes obtained applying the nearly automated method and the one based on geometric modeling (y = 0.98x + 75.9; r2 = 0.99; bias: -53.7 mL; SD: 108.1 mL). Importantly, geometric modeling does not provide reliable TRV estimates in huge kidney affected by regional deformation. Intraobserver and interobserver variability resulted in very small percentage error <2%. CONCLUSIONS: The results of this study provide the feasibility of using a nearly automated approach for accurate and fast evaluation of TRV also in markedly enlarged ADPKD kidneys including exophytic cysts.

2014 - Can tonsillectomy modify the innate and adaptive immunity pathways involved in IgA nephropathy? [Articolo su rivista]
Vergano, Luca; Loiacono, Elisa; Albera, Roberto; Coppo, Rosanna; Camilla, Roberta; Peruzzi, Licia; Amore, Alessandro; Donadio, Maria Elena; Chiale, Federica; Boido, Alberto; Mariano, Filippo; Mazzucco, Gianna; Ravera, Sara; Cancarini, Giovanni; Magistroni, Riccardo; Beltrame, Giulietta; Rollino, Cristiana; Stratta, Piero; Quaglia, Marco; Bergia, Roberto; Cravero, Raffaella; Cusinato, Stefano; Benozzi, Luisa; Savoldi, Silvana; Licata, Carola
abstract

The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/β1, p = 0.039; LPM7/β5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin-proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.

2014 - Comment on the paper: 'novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease' [Articolo su rivista]
Corsi, Cristiana; Mignani, Renzo; Turco, Dario; Magistroni, Riccardo; Severi, Stefano
abstract

[Not Available]

2014 - Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens [Articolo su rivista]
Kiryluk, Krzysztof; Li, Yifu; Scolari, Francesco; Sanna Cherchi, Simone; Choi, Murim; Verbitsky, Miguel; Fasel, David; Lata, Sneh; Prakash, Sindhuri; Shapiro, Samantha; Fischman, Clara; Snyder, Holly J; Appel, Gerald; Izzi, Claudia; Viola, Battista Fabio; Dallera, Nadia; Del Vecchio, Lucia; Barlassina, Cristina; Salvi, Erika; Bertinetto, Francesca Eleonora; Amoroso, Antonio; Savoldi, Silvana; Rocchietti, Marcella; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Salvadori, Maurizio; Ravani, Pietro; Magistroni, Riccardo; Ghiggeri, Gian Marco; Caridi, Gianluca; Bodria, Monica; Lugani, Francesca; Allegri, Landino; Delsante, Marco; Maiorana, Mariarosa; Magnano, Andrea; Frasca, Giovanni; Boer, Emanuela; Boscutti, Giuliano; Ponticelli, Claudio; Mignani, Renzo; Marcantoni, Carmelita; Di Landro, Domenico; Santoro, Domenico; Pani, Antonello; Polci, Rosaria; Feriozzi, Sandro; Chicca, Silvana; Galliani, Marco; Gigante, Maddalena; Gesualdo, Loreto; Zamboli, Pasquale; Battaglia, Giovanni Giorgio; Garozzo, Maurizio; Maixnerová, Dita; Tesar, Vladimir; Eitner, Frank; Rauen, Thomas; Floege, Jürgen; Kovacs, Tibor; Nagy, Judit; Mucha, Krzysztof; Pączek, Leszek; Zaniew, Marcin; Mizerska Wasiak, Małgorzata; Roszkowska Blaim, Maria; Pawlaczyk, Krzysztof; Gale, Daniel; Barratt, Jonathan; Thibaudin, Lise; Berthoux, Francois; Canaud, Guillaume; Boland, Anne; Metzger, Marie; Panzer, Ulf; Suzuki, Hitoshi; Goto, Shin; Narita, Ichiei; Caliskan, Yasar; Xie, Jingyuan; Hou, Ping; Chen, Nan; Zhang, Hong; Wyatt, Robert J; Novak, Jan; Julian, Bruce A; Feehally, John; Stengel, Benedicte; Cusi, Daniele; Lifton, Richard P; Gharavi, Ali G.
abstract

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

2014 - HEMOREOLOGIC PROFILE OF KIDNEY TRANSPLANT RECIPIENTS: A ROLE IN CARDIOVASCULAR RISK? [Abstract in Atti di Convegno]
Fontana, Francesco; Ballestri, M; Magistroni, R; Damiano, F; Cappelli, G.
abstract

Introduction and Aims: Hemorheology evaluates blood flow properties and mainly focuses on the study of blood viscosity and erythrocyte’s deformability. Flow properties are main determinants of an adequate tissue perfusion and their alterations play a significant role in cardiovascular diseases occurrence through endothelium damage and subsequent fibrosis with progression to end-organ injury.Patients with end stage renal disease (ESRD) undergoing dialysis present a CV risk of death 10-20 fold higher than the general population but also kidney transplantation (KT), being the optimal therapy for ESRD, keeps an higher CV risk compared to general population.Hemorheologic profile alterations have been described in ESRD patients but comprehensive data on KT recipients are missing. Aim of our study is to characterize the hemorheologic profile of KT recipients, and to compare these data with healthy volunteers and HD patients. Methods: We investigated 47 healthy volunteers, 90 uremic patients undergoing intermittent HD, 108 kidney transplant recipients (KT) testing as hemorheologic parameters: plasma viscosity (ηP), whole blood viscosity (expressed as low shear rate (ηS1) or high shear rate (ηS200), erythrocyte aggregation index (EAI), flow limit (t0: as minimum strenght to be applied to blood fluid in order to start to flow), erythrocyte deformability (ED) evaluated by Taylor factor (Tk) [1-(ηP/ηS200)0.4/Ht], viscous-elastic blood behavior (as elastic module G’: fluid response to a preset and increasing strain using a oscillating pattern). All measurements were performed with a Haake Rotovisco RV20 Rheometer. Results: We confirmed alterations of the hemorheologic profile in HD patients both before and after the dialytic session. KT, when compared to results obtained before HD treatments , normalizes many hemorheological parameters:ηP (1,35 ± 0,13 mPa*s vs 1,57 ± 0,23 mPa*s; p<0,05), ηS1 (12,57 ± 3,87 mPa*s vs 26,45 ± 11,79; p<0,05), ηS200 (3,96 ± 0,46 mPa*s vs 4,74 ± 1,08 mPa*s; p <0,05), EAI (KT 3,11 ± 0,89 vs 6,11 ± 2,25; p<0,05), t0 (0,12 ± 0,08 mPa vs 0,18 ± 0,06; p<0,05).However, KT show a markedly lower ED when compared to HD, as estimated with Tk (0,85 ± 0,10 vs 0,81 ± 0,09; p<0,05), and this data is confirmed by viscous-elastic blood behaviour with higher G’ in KT than in HD as from figure 1. Conclusions: HD patients show various hemorheologic profile alterations; this could support the extremely high incidence of CV complications in these patients, involving large vessels (hS1), myocardial hypertrophy (t0), small vessels and microcirculation (hS200, Tk, EAI).KT improves most hemorheologic alterations found in HD, justifying a global reduction in CV risk. However ED is reduced in KT (higher Tk and G’), and this alteration could act as a detrimental injury at the microcircolatory level, damaging the endothelium and, through its activation, leading to a progression of end-organ damage in KT patients.As a matter of fact an impaired ED could contribute to progression of interstitial fibrosis and tubular atrophy (IFTA); effects of different antirejection drugs represent a further stimulating point to be addressed.

2014 - Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments [Articolo su rivista]
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, Riccardo; 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.
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.

2013 - CD133 and CD24 expression in renal tissue of patients affected by autosomal dominant polcystic kidney disease [Articolo su rivista]
Lodi, Daniele; Ligabue, Giulia; Cavazzini, Fabrizio; Lupo, Valentina; Cappelli, Gianni; Magistroni, Riccardo
abstract

Background: Autosomal dominant polycystic kidney disease is a condition mainly character- ized by the progressive development and enlar- gement of cysts in each kidney. In this process a high rate of proliferation and apoptosis of tubu- lar cells has been documented and interpreted as a futile attempt of tissue repair. In considera- tion of the role of stem cells in reparative proc- esses we investigated the presence and local- ization of CD133 + CD24+ renal progenitors in renal ADPKD tissue and cells. Methods: Two normal kidneys and two ADPKD kidneys were examined. CD133 and CD24 expression was in- vestigated by confocal microscopy and immu- noblotting. Furthermore cystic isolated cells and cultured immortalized cells were characterized. Results: CD133 and CD24 have the same local- ization in ADPKD tissues and in normal kidneys: expression is restricted to a subset of epithelial cells (PEC) of Bowman’s capsule and to tubular cells in a focal and segmental pattern. Further- more, in ADPKD tissue, cysts diffusely express CD133 and CD24. According to a quantitative analysis in ADPKD tissue CD133 + CD24 + cells are statistically more expressed in tubules (p < 0.001) and less expressed in the Bowman’s capsule (p = 0.0016) compared to the same lo- calizations in control tissue. Conclusions: CD133 and CD24 antigens, typically expressed by renal epithelial progenitors, are more expressed in ADPKD tubules and highly expressed in ADPKD cysts. Whether CD133 and CD24 expression would signify renal progenitor recruitment or alternatively an expression pattern of the dedif- ferentiation of ADPKD cells remains unclear.

2013 - HEMORHEOLOGY IN RENAL TRANSPLANTATION [Poster]
Fontana, Francesco; Ballestri, M; Mori, G; Testa, F; Magistroni, Riccardo; Cappelli, Gianni
abstract

NA

2013 - Identification and Characterization of New Proteins in Podocyte Dysfunction of Membranous Nephropathy by Proteomic Analysis of Renal Biopsy [Articolo su rivista]
Ligabue, Giulia; Magistroni, Riccardo; Marco, Cantu'; Lupo, Valentina; Genovese, Filippo; Cavazzini, Fabrizio; Luciana, Furci; Cappelli, Gianni
abstract

Interstitial fluid, obtained by gentle centrifugation of the renal biopsy specimen, is highly enriched in elements directly secreted by the kidney tissue and is suitable for proteomic analysis. Here we describe the first clinical application of renal interstitial fluid analysis in a subset of samples obtained from patients affected by idiopathic membranous nephropathy. We included in the study fifty-one patients with different pathologic diagnoses. We identified the proteomic pattern of idiopathic membranous nephropathy with mass spectrometry analysis by comparing these samples with two controls: normal kidney and IgA nephropathy. Proteomic results were validated by immunofluorescence analysis of renal tissues and Western blot of serum, urines and podocyte cell cultures. We observed an increased expression of PDZ and LIM domain protein 5 (PDLI5) and LIM domain binding protein 3 (LDB3) providing first evidence of the differential expression of these LIM domain-related proteins in kidney and urines of patients with idiopathic membranous nephropathy. Interstitial fluid can be considered a valuable biological fluid in the discovery phase of biomarkers. In order to validate its clinical use, it is pivotal to assess the availability of the biomarkers in ‘usual’ samples: blood and/or urine. PDLI5 and LDB3 share a common LIM domain suggesting a possible role in the cytoskeleton organization and they appear upregulated in glomeruli of patients affected by idiopathic membranous nephropathy. Furthermore the two proteins become highly abundant in the urine of patients affected by idiopathic membranous nephropathy. In conclusion, our approach may be considered a novel method for identifying candidate biomarkers for patients suffering from membranous nephropathy and other glomerulonephrites

2013 - Lipoprotein glomerulopathy associated with a mutation in apolipoprotein e [Articolo su rivista]
Magistroni, Riccardo; Bertolotti, Marco; Furci, Luciana; Fano, Rita Adriana; Leonelli, Marco; Pisciotta, Livia; Pellegrini, Elisa; Calabresi, Laura; Bertolini, Stefano; Calandra, Sebastiano
abstract

Lipoprotein glomerulopathy is a pathological condition characterized by lipid accumulation in the glomerular capillaries that has been associated with the presence of rare mutants of apolipoprotein E (ApoE). We describe a 51-year-old Italian patient presenting Type III hyperlipidemia and proteinuria in whom renal biopsy showed capillary ectasia and intraluminal lipid deposits, suggesting the diagnosis of lipoprotein glomerulopathy. The patient, who had elevated plasma ApoE level, was found to be heterozygous for a mutation in ApoE (Arg150Cys), designated apoEMODENA. This mutation induces the formation of ApoE dimers that are detectable under non-reducing conditions. Treatment with hypolipidemic drugs did not result in a complete remission of the proteinuria and was accompanied by a slow but progressive worsening of renal function with the persistence of intracapillary lipid thrombi. The introduction of low-density lipoprotein aphaeresis combined with a more aggressive lipid lowering and antihypertensive therapy resulted in the remission of proteinuria and a substantial improvement of renal function. Switching from low-density lipoprotein aphaeresis to plasma filtration did not result in an equivalent control of renal damage. The patient died of intracranial hemorrhage during an acute episode of malignant hypertension.

2012 - Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy [Articolo su rivista]
C., Murtas; M., Bruschi; G., Candiano; G., Moroni; Magistroni, Riccardo; A., Magnano; F., Bruno; A., Radice; L., Furci; L., Argentiero; M. L., Carnevali; P., Messa; F., Scolari; R. A., Sinico; L., Gesualdo; F. C., Fervenza; L., Allegri; P., Ravani; G. M., Ghiggeri
abstract

BACKGROUND AND OBJECTIVES: The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum IgG(1), IgG(3), and IgG(4) against aldose reductase (AR), SOD2, and alpha-enolase (alphaENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG(4) were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients. RESULTS: IgG(4) was the most common isotype for all antibodies; IgG(1) and IgG(3) were nearly negligible. IgG(4) levels were positive in a significant proportion of MN patients (AR, 34%; SOD2, 28%; alphaENO, 43%). Antibody titers were higher in MN than in healthy and pathologic controls (P<0.005). Anti-NEP IgG(4) did not differ from normal controls (P=0.12). Anti-PLA2r IgG(4) was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-alphaENO IgG(4) (P<0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P<0.05). CONCLUSIONS: Our data suggest that IgG(4) is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, alphaENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.

2012 - Identification and characterization of a new autoimmune protein in membranous nephropathy by immunoscreening of a renal cDNA library [Articolo su rivista]
Cavazzini, Fabrizio; Magistroni, Riccardo; L., Furci; V., Lupo; Ligabue, Giulia; M., Granito; M., Leonelli; Albertazzi, Alberto; Cappelli, Gianni
abstract

Membranous Nephropathy (MN) represents a large amount of Nephrotic Syndromes in the adult population and its definitive diagnosis is currently carried out through biopsy. An autoimmune condition has been demonstrated in idiopathic MN (iMN) in which some kidney structures are targeted by patient autoantibodies. Some candidate antigens have been described and other likely involved target proteins responsible for the disease are not known yet. In this work our aim is to identify these proteins by screening a lambda-phage library with patients' sera. We enrolled four groups of patients: two MN groups of 12 full iMN patients; one control group of 15 patients suffering from other renal diseases; one control group of 15 healthy individuals. A commercial cDNA phagemide library was screened using the above described sera, in order to detect positive signals due to antigen-antibody bond. We detected one phagemide clone expressing a protein which was shown to be targeted by the antibodies of the iMN sera only. Control sera were negative. The sequence analysis of cDNA matched the Synaptonemal Complex protein 65 (SC65) coding sequence. Further proteomic analyses were carried out to validate our results. We provide evidence of an involvement of SC65 protein as an autoimmune target in iMN. Considering the invasiveness and the resulting risk coming from renal biopsy, our ongoing aim is to set a procedure able to diagnose affected patients through a little- or non-invasive method such as blood sampling rather than biopsy.

2012 - Monoclonal antibodies in nephrology: a delicate balance between curative potential, evidence of effectiveness, and toxicity [Articolo su rivista]
Magistroni, Riccardo
abstract

Rituximab is a chimeric human-murine anti-CD20 monoclonal antibody able to obtain the depletion of B lymphocytes. In recent years significant clinical experience has been gained and literature studies have been carried out investigating the possible role of this drug in autoimmune conditions such as immune-mediated glomerulonephritis and transplant rejection. It must be stressed that at present the drug is not registered for any type of kidney disease and its use in nephrology is to be considered off-label. A recent report showed that rituximab is generously administered in clinical settings where the support of the literature is still debated and inconclusive; in a significant number of cases the drug is used in contexts where the scientific support can be considered substantially inconsistent. This brief report will address the principal findings on the use of rituximab in nephrology. It will also briefly evaluate the role of eculizumab, a novel biological drug active on the complement cascade. Experimental evidence points to a central role for these two new drugs in many immune-mediated conditions of nephrologic interest. This exciting field of research is still in its infancy with regard to the scientific assessment of the clinical applications. In view of the ethical considerations concerning the toxicity of therapeutic interventions and the need to give patients the best available treatment, a great collaborative effort is required by the nephrology community to address these clinical issues in the context of multicenter randomized controlled studies.

2012 - Tolvaptan in patients with autosomal dominant polycystic kidney disease [Articolo su rivista]
Torres, V. E.; Chapman, A. B.; Devuyst, O.; Gansevoort, R. T.; Grantham, J. J.; Higashihara, E.; Perrone, R. D.; Krasa, H. B.; Ouyang, J.; Czerwiec, F. S.; Tempo, Trial Investigators; Magistroni, Riccardo
abstract

BACKGROUND: The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V2-receptor antagonists inhibit cyst growth and slow the decline of kidney function. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V2-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. RESULTS: Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P&lt;0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P = 0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of followup, P&lt;0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P = 0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter]-1 per year vs. -3.81 [mg per milliliter]-1 per year; P&lt;0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). CONCLUSIONS: Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.) Copyright © 2012 Massachusetts Medical Society.

2011 - Direct characterization of target podocyte antigens and auto-antibodies in human membranous glomerulonephritis: Alfa-enolase and borderline antigens [Articolo su rivista]
M., Bruschi; M. L., Carnevali; C., Murtas; G., Candiano; A., Petretto; M., Prunotto; R., Gatti; L., Argentiero; Magistroni, Riccardo; G., Garibotto; F., Scolari; P., Ravani; L., Gesualdo; L., Allegri; G. M., Ghiggeri
abstract

The identification of glomerular auto-antigens in idiopathic human membranous glomerulonephritis (MGN) is a crucial step towards the definition of the mechanisms of the disease. Recent 'in vivo' studies demonstrated a heterogeneous composition of glomerular immune-deposits in MGN biopsies only a part of which have been characterized. We studied with a proteomical approach IgGs eluted from laser capture microdissected glomeruli of 8 MGN patients and showed the existence of other three immune proteins in MGN glomeruli (alpha-enolase, elongation factor 2 and Glycyl Aminoacyl-tRNA Synthetase). One of these, i.e. alpha-enolase, fulfilled all criteria for being considered an auto-antigen. Specific IgG(1) and IgG(4) reacting with podocyte alpha-enolase were, in fact, eluted from microdissected glomeruli and Confocal- and Immuno Electron-Microscopy showed co-localization of alpha-enolase with IgG(4) and C5b-9 in immune-deposits. Serum levels of anti a-enolase IgG4 were determined in 131 MGN patients and were found elevated in 25% of cases. Overall, our data demonstrate that glomerular alpha-enolase is a target antigen of autoimmunity in human MGN. Circulating anti alpha-enolase auto-antibodies can be detected in sera of a significant quota of MGN patients. Like other auto-antigens, alpha-enolase may be implicated in the pathogenesis of human MGN.

2011 - Genome-wide association study identifies susceptibility loci for IgA nephropathy [Articolo su rivista]
A. G., Gharavi; K., Kiryluk; M., Choi; Y., Li; P., Hou; J., Xie; S., Sanna Cherchi; C. J., Men; B. A., Julian; R. J., Wyatt; J., Novak; J. C., He; H., Wang; J., Lv; L., Zhu; W., Wang; Z., Wang; K., Yasuno; M., Gunel; S., Mane; S., Umlauf; I., Tikhonova; I., Beerman; S., Savoldi; Magistroni, Riccardo; G. M., Ghiggeri; M., Bodria; F., Lugani; P., Ravani; C., Ponticelli; L., Allegri; G., Boscutti; G., Frasca; A., Amore; L., Peruzzi; R., Coppo; C., Izzi; B. F., Viola; E., Prati; M., Salvadori; R., Mignani; L., Gesualdo; F., Bertinetto; P., Mesiano; A., Amoroso; F., Scolari; N., Chen; H., Zhang; R. P., Lifton
abstract

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 x 10(2) and 4.84 x 10 and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

2011 - Interstitial fluid obtained from kidney biopsy as new source of renal biomarkers [Articolo su rivista]
Magistroni, Riccardo; Cantu, M.; Ligabue, Giulia; Masellis, M.; Spisni, E.; Furci, L.; Lupo, Valentina; Genovese, F.; Cavazzini, Fabrizio; Albertazzi, Alberto
abstract

Introduction: Development of renal biomarkers is required to improve on diagnostic accuracy, prognosis and prediction of response to therapy in renal disease. We describe a new method of obtaining from renal specimens a biologic fluid potentially enriched in secreted proteins. Methods: A renal biopsy specimen was centrifuged, and the interstitial fluid (IF) obtained was evaluated by SELDI-ToF, 1D and 2D gel electrophoresis. Twelve spots were extracted from the 2D gel and characterized by MALDI-TOF-MS. Results: The SELDI diagrams demonstrated abundant peptide peaks. One-dimensional gel electrophoresis demonstrated the presence of many bands indicating a diversity of proteins in the sample. Comparison of serum to IF demonstrated a number of bands that were not shared, suggesting that the IF is not a simple "replica" of plasma fluid. Employing 2D-PAGE, 418 spots were identified in the IF sample; 12 spots were selected and analyzed by mass spectrometry. Conclusions: We have described a novel technique to obtain a biologic fluid that contains a significant quantity and diversity of proteins from renal tissue. The procedure to obtain the fluid is simple and easily applicable to standard renal biopsy procedures. This fluid has the potential to identify informative proteins that are more concentrated than in any other renal biologic fluid previously analyzed and strictly related to renal pathophysiology. Future work includes the development of a clinical protocol to identify and validate informative biomarkers that have diagnostic and prognostic value.

2011 - [Screening for cerebral aneurysms in the ADPKD population: mandatory or potentially harmful?] [Articolo su rivista]
Magistroni, Riccardo; Palmieri, Lucia; Scolari, F.
abstract

Cerebral aneurysm in autosomal dominant polycystic kidney disease (ADPKD) is an uncommon event (documented in 6-13% of cases) but frequently characterized by severe neurological sequelae and potentially fatal in case of rupture. The arterial vascular wall of the anterior cerebral circulation is most frequently involved. Experimental data showed the expression of polycystins (the proteins modified by the mutation in this disease) in the affected arterial vascular wall and some mutations apparently give rise to greater susceptibility to the complication. The risk factors that cause the predisposition to this condition and the natural history are poorly understood. This lack of information complicates the clinical management of these patients because many pivotal questions still need an answer: Are cerebral aneurysms to be screened for in the ADPKD population? If so, at which intervals? In which cases where an aneurysm has been detected is correction needed? Which type of correction technique is to be preferred, interventional neuroradiology or neurosurgery? The three authors compare their partially discordant positions on this highly controversial topic.

2010 - Genetic variation of DKK3 may modify renal disease severity in ADPKD [Articolo su rivista]
Liu, M.; Shi, S.; Senthilnathan, S.; Yu, J.; Wu, E.; Bergmann, C.; Zerres, K.; Bogdanova, N.; Coto, E.; Deltas, C.; Pierides, A.; Demetriou, K.; Devuyst, O.; Gitomer, B.; Laakso, M.; Lumiaho, A.; Lamnissou, K.; Magistroni, Riccardo; Parfrey, P.; Breuning, M.; Peters, D. J.; Torra, R.; Winearls, C. G.; Torres, V. E.; Harris, P. C.; Paterson, A. D.; Pei, Y.
abstract

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.

2010 - Il Registro Italiano del Rene PolicisticoAutosomico Dominante [Articolo su rivista]
P., Carrera; Palmieri, Lucia; F., Caruso; Lodi, Daniele; F., Rigo; L., Furci; Granito, Maria; Damiano, Francesca; Iatrino, Rossella; A., Boletta; M., Ferrari; G., Aguiari; Magistroni, Riccardo
abstract

Non disponibile

2010 - Lipoprotein glomerulopathy treated with LDL-apheresis (Heparin-induced Extracorporeal Lipoprotein Precipitation system): a case report. [Articolo su rivista]
Russi, G; Furci, L; Leonelli, M; Magistroni, Riccardo; Romano, N; Rivasi, P; Albertazzi, Alberto
abstract

INTRODUCTION: Lipoprotein glomerulopathy is a glomerulonephritis which was described for the first time by Saito in 1989 and is currently acknowledged as a separate nosological entity. It is histologically characterized by a marked dilatation of the glomerular capillaries and the presence of lipoprotein thrombi in the glomerular lumens. The dyslipidemic profile is similar to that of type III dyslipoproteinemia with Apolipoprotein E values that are often high; proteinuria and renal dysfunction are present. Proteinuria often does not respond to steroid and cytostatic treatments. The phenotypic expression of lipoprotein glomerulopathy is most probably correlated to a genetic alteration of the lipoprotein metabolism (mutation of the Apolipoprotein E coding gene). In literature, lipoprotein glomerulopathies have mainly been reported in Japanese and Chinese subjects, except for three cases in the Caucasian race, reported in France and the USA.CASE PRESENTATION: We describe the case of a 60-year-old female, Caucasian patient suffering from lipoprotein glomerulopathy, carrier of a new mutation on the Apolipoprotein E gene (Apolipoprotein E(MODENA)), and treated successfully with low density lipoprotein-apheresis with the Heparin induced extracorporeal lipoprotein precipitation system. After a first phase of therapeutic protocol with statins, the patient was admitted for nephrotic syndrome, renal failure and hypertension. Since conventional treatment alone was not able to control dyslipidemia, aphaeretic treatment with heparin-induced Extracorporeal Lipoprotein Precipitation - apheresis (HELP-apheresis) was started to maintain angiotensin converting enzyme inhibitor therapy for the treatment of hypertension. Treatment with HELP-apheresis led to a complete remission of the proteinuria in a very short time (four months), as well as control of hypercholesterolemia and renal function recovery.CONCLUSION: According to this case of lipoprotein glomerulopathy, we believe that renal damage expressed by proteinuria correlates to the levels of lipids and, furthermore, the treatment with HELP-apheresis, by lowering low-density lipoprotein cholesterol and triglycerides, may be considered as a therapeutic option in synergy with pharmacological treatment in the treatment of lipoprotein glomerulopathy.

2010 - Pregnancy and progression of IgA nephropathy: results of an Italian multicenter study [Articolo su rivista]
Limardo, M.; Imbasciati, E.; Ravani, P.; Surian, M.; Torres, D.; Gregorini, G.; Magistroni, Riccardo; Casellato, D.; Gammaro, L.; Pozzi, C.
abstract

BACKGROUND: Whether pregnancy impacts on the long-term outcome of immunoglobulin A (IgA) nephropathy is unknown. This study aims to compare the long-term outcome of kidney disease in women with IgA nephropathy and preserved kidney function who did and did not become pregnant. STUDY DESIGN: Multicenter longitudinal cohort study. SETTING & PARTICIPANTS: Women of childbearing age with biopsy-proven IgA nephropathy, serum creatinine level<or=1.2 mg/dL at diagnosis, and minimum follow-up of 5 years after biopsy recruited from 35 nephrology centers participating in a national collaborative study group of pregnancy and kidney disease sponsored by the Italian Society of Nephrology. PREDICTORS: Pregnancy, treated as a time-dependent variable; baseline proteinuria; hypertension; and kidney biopsy histologic characteristics. OUTCOME & MEASURES: Rate of change in estimated creatinine clearance, change in proteinuria, and new-onset hypertension. RESULTS: 245 patients were enrolled. Of these, 223 women (136 and 87 in the pregnancy and nonpregnancy groups, respectively) had serum creatinine levels<or=1.2 mg/dL at diagnosis. Baseline data (including age, estimated creatinine clearance, prevalence of hypertension, and histologic grade of kidney damage) were similar between groups with the exception of proteinuria (protein excretion, 1.33 vs 0.95 g/d in the pregnancy vs nonpregnancy groups, respectively; P=0.03). Kidney function decreased 1.31 mL/min/y (95% CI, 0.99-1.63) during a median follow-up of 10 years (range, 5-31 years) and did not differ between groups. Baseline proteinuria predicted a faster decrease, but did not modify the effect of pregnancy. Pregnancy did not affect changes in proteinuria over time or risk of new-onset hypertension. LIMITATIONS: Unrecognized or unmeasured factors associated with the decision of becoming pregnant might have influenced results. CONCLUSIONS: Pregnancy does not seem to affect the long-term outcome of kidney disease in women with IgA nephropathy and preserved kidney function.

2010 - Urine Proteome Analysis May Allow Non-Invasive Differential Diagnosis of Diabetic Nephropathy [Articolo su rivista]
Papale, M.; Di Paolo, S.; Magistroni, Riccardo; Lamacchia, O.; De Mattia, A.; Teresa Rocchetti, M.; Furci, L.; Pasquali, S.; De Cosmo, S.; Cignarelli, M.; Gesualdo, L.
abstract

AbstractObjective: Chronic renal insufficiency and/or proteinuria in type 2 diabetes may stem from chronic renal diseases (CKD) other than classic diabetic nephropathy (DN) in over one third of cases. We interrogated urine proteomic profiles generated by SELDI-TOF/MS with the aim to isolate a set of biomarkers able to reliably identify biopsy-proven DN and to establish a stringent correlation with the different patterns of renal injury. Research design and methods: Ten mug urine proteins from 190 subjects [20 healthy subjects (HS), 20 normoalbuminuric (NAD) and 18 microalbuminuric (MICRO) diabetic patients, and 132 patients with biopsy-proven nephropathy (65 DN, 10 diabetics with non-diabetic CKD (nd-CKD) and 57 non-diabetic patients with CKD)] were run by CM10 ProteinChip array and analysed by supervised learning methods (CART analysis). Results: The classification model correctly identified 75% NAD, 87.5% MICRO and 87.5% DN when applied to a blinded testing set. Most importantly, it was able to reliably differentiate DN from nd-CKD in both diabetic and non-diabetic patients. Among the best predictors of the classification model, we identified and validated 2 proteins, ubiquitin and ss2-microglobulin. Conclusions: Our data suggest the presence of a specific urine proteomic signature able to reliably identify type 2 diabetic patients with diabetic glomerulosclerosis.

2009 - Primary IgA nephropathy is more severe in TGF-beta1 high secretor patients. [Articolo su rivista]
Brezzi, B; Del Prete, D; Lupo, A; Magistroni, Riccardo; Gomez Lira, M; Bernich, P; Anglani, F; Mezzabotta, F; Turco, A; Furci, L; Ceol, M; Antonucci, F; Abaterusso, C; Bonfante, L; D'Angelo, A; Albertazzi, Alberto; Gambaro, G.
abstract

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and is characterized by extremely variable clinical and morphological features and outcome. TGF-beta1 has a key role in fibrogenesis and the progression of renal damage. Its production is under genetic control. Methods: We recruited 105 Italian biopsy-proven IgAN patients for genotyping for the TGF-beta1 C-509T, T869C (COD 10) and G915C (COD 25) polymorphisms; 200 healthy blood donors were used as normal controls. Glomerular and interstitial mRNA levels of TGF-beta1 were assessed by real-time PCR in 34 patients to seek relationships with clinical, renal histopathological features and outcome. Results: The genotype distributions in the IgAN population were not statistically different from the controls. The COD 10 TT genotype was associated with more severe histological damage as assessed by Lee's classification (CC 50%, CT 39.6% and TT 17.2% were graded as mild; CC 35.7%, CT 43.7% and TT 44.8% as moderate, and CC 14.3%, CT 16.7% and TT 37.9% as severe [p=0.0049]) and with severe interstitial infiltrates (CC 10.4%, CT 35.2% and TT 54.2% [p=0.03]). A higher interstitial immunodeposition was observed for TGF-beta1, collagen IV and alpha-SMA in patients with the COD 10 T allele (p=0.045, p=0.049, p=0.032, respectively). The T allele was associated with significantly higher TGF-beta1 mRNA levels in the interstitium (TT+CT vs. CC: 0.52 +/- 0.16 vs. 0.18 +/- 0.10 copies/mL, respectively; p=0.000). The T allele was also associated with higher mRNA levels in glomeruli, though the difference was not statistically significant. Finally, the T allele was significantly associated with a worse prognosis, the end points being reached by 40% of TT+CT and 32% of CC patients (p=0.009). Conclusions: In primary IgA nephropathy, the T allele of the TGF-beta1 COD 10 C/T polymorphism seems to be associated with more severe histological lesions, higher renal TGF-beta1 mRNA levels and a worse prognosis. This polymorphism seems to be functionally relevant and to have a prognostic impact.

2009 - Proteomic analysis of urine from proteinuric patients shows a proteolitic activity directed against albumin [Articolo su rivista]
Magistroni, Riccardo; Ligabue, Giulia; Lupo, Valentina; Furci, L; Leonelli, M; Manganelli, L; Masellis, M; Gatti, V; Cavazzini, Fabrizio; Tizzanini, W; Albertazzi, Alberto
abstract

BACKGROUND: Nephrotic syndrome is a condition that is clinically associated with poor outcome. In this study, we compared different techniques of urine sample preparation in order to develop a robust analytical protocol to define the differential urinary proteome of urinary abnormalities compared to nephrotic proteinuria. METHODS: We recruited 5 normal control subjects, 16 patients with urinary abnormalities and 16 patients with nephrotic syndrome. Proteins from normal urine were processed using three different protocols [acetone, ultrafiltration and trichloroacetic acid (TCA) precipitation], depletion of albumin and IgGs and then analysed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) gels and mass spectrometry. RESULTS: Comparing the three extraction methods by visual inspection of gels after 2D gel electrophoresis, the acetone precipitation and TCA methods yielded the best quality of protein extraction, while the acetone precipitation method was the most efficient. Furthermore, we tested three commercial kits for albumin and IgG depletion. We applied the optimized acetone extraction protocol to compare urinary samples from nephrotic patients (NP) to urinary samples obtained from patients presenting with urinary abnormalities (UAP). We observed a proteolytic activity directed against albumin. This observation was more prevalent in urinary samples from NP than from UAP. Within both groups, there was some inter-individual variability in the observed proteolytic activity. An increased concentration of alpha1 antitrypsin was also observed in urine of NP. We analysed albumin fragmentation by 1D and 2D western blots in the same samples skipping the albumin and IgG depletion steps to avoid the possible confound of albumin fragment removal. The analysis confirmed a stronger proteolytic activity in the nephrotic group. CONCLUSIONS: The proteolytic activity against albumin and the anti-proteolytic activity of alpha1 antitrypsin are likely linked and could play an important role in the nephrotic process. If replicated in larger samples, this methodology may lead to a better understanding of the underlying pathophysiological process of nephrotic syndrome.

2009 - Unified criteria for ultrasonographic diagnosis of ADPKD [Articolo su rivista]
Pei, Y; Obaji, J; Dupuis, A; Paterson, Ad; Magistroni, Riccardo; Dicks, E; Parfrey, P; Cramer, B; Coto, E; Torra, R; San Millan, Jl; Gibson, R; Breuning, M; Peters, D; Ravine, D.
abstract

Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals &gt; or = 60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged &gt; or = 40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.

2008 - APOE MODENA : A NOVEL APOE MUTANT CAUSING LIPOPROTEIN GLOMERULOPATHY [Abstract in Rivista]
Bertolotti, Marco; Elisa, Pellegrini; Magistroni, Riccardo; Juri, Piattoni; Carulli, Lucia; Gian Paolo, Russi; Livia, Pisciotta; Sebastiano, Calandra; Stefano, Bertolini
abstract

Lipoprotein glomerulopathy (LPG) is a rare disease characterized by laminated lipid thrombi in the lumina of dilated glomerular capillaries. Apolipoproteins E and B can be demonstrated in these lipid deposits. The plasma lipid profile of LPG patients is similar to that of dysbetalipoproteinemia with elevated IDL and ApoE. Patients often present nephrotic proteinuria but their lipid profile differs from that of nephrotic syndrome secondary to other kidney diseases. LPG has been mainly reported in Japanese and Chinese subjects, associated with novel mutations in APOE gene encoding ApoE. We have identified LPG in an Italian women who at the age of 47 was found to have a combined hyperlipidemia (TC 376 and TG 306 mg/dl) and subsequently developed proteinuria in the nephrotic range. Renal biopsy demonstrated lipoprotein thrombi in glomerular capillaries suggesting LPG. The sequence of APOE gene showed that the patient was: i) homozygous for 2 allele [Cys112 and Cys158 in the mature protein] and ii) heterozygous for a novel mutation in exon 4: c.502 C>T [Arg 150>Cys in the mature protein]. Since the mutant ApoE has a new cysteine residue it is likely that it forms a disulfide bridge with the other Cys residues of the E2 isoforms, resulting in ApoE polymerization (dominant negative effect). This is probably the cause of both dyslipidemia and lipid thrombi in the glomerular capillaries. In view of the poor response of plasma lipids and renal histology and function to statin treatment, the patient started lipid-apheresis with reduction of both dyslipidemia and proteinuria.

2008 - Autosomal dominant polycystic kidney disease: from genes to cilium. [Articolo su rivista]
Magistroni, Riccardo; Furci, L; Albertazzi, Alberto; G., ITAL NEFROL
abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a quite frequent monogenic hereditary disease. The incidence has been reported to range between 1:400 and 1:1000 life births. The disease is caused by a mutation of the PKD1 gene in 85% of the cases and by a mutation of the PKD2 gene in the remaining 15%. The main characteristic of this condition is the development of renal cysts. Observations regarding various cystic kidney diseases sustained by mutations of different genes are steadily converging to a common point. This unifying element is the primary cilium. The cilium, which has long been considered a mere biological oddity, has lately become the focus of intense scientific attention because it may turn out to be the key to the understanding of cystic degeneration. The cilia can be regarded as sensors projecting out of the cell. In particular in the kidney they are located in an ideal place to capture information from the tubular lumen. One of the roles the cilia may play is the reception of chemical signals. An alternative hypothesis attributes to the cilia the role of mechanosensors capable of detecting variations of the urine flux in the tubular lumen. The cilium projects itself into the lumen where it can readily capture variations in the external environment and transmit them to the cell by as yet undefined pathways. This is the still largely unexplored frontier that will provide the elements needed to understand and treat renal cystic diseases.

2008 - Interstitiome: a novel proteomic discipline applied to renal biopsy [Abstract in Atti di Convegno]
Magistroni, Riccardo; Lupo, Valentina; Ligabue, Giulia; Cantù, M; Cavazzini, Fabrizio; Furci, L; Albertazzi, Alberto
abstract

Introduzione: Nonostante il ruolo centrale nella diagnostica nefrologica, la biopsia renale mostra alcuni limiti. In particolare la risposta morfologica stereotipa ad insulti eziologici di natura diversa non rende sempre agevole la diagnosi differenziale sulla base dei soli dati istologici. Negli ultimi anni la ricerca di marcatori diagnostici ed in particolare gli studi proteomici hanno avuto un’evoluzione esponenziale. I fluidi biologici normalmente utilizzati per tali studi (siero/plasma) presentano il limite di essere composti da migliaia di proteine con un range di concentrazioni di circa 12 ordini di grandezza. Tali caratteristiche, unite al fatto che i marcatori prodotti e liberati dal tessuto vengono diluiti nel sistema circolatorio, rendono queste indagini estremamente difficoltose.Scopi: Nel tentativo di superare questa limitazione e di isolare un fluido biologico con concentrazione di biomarcatori elevata, abbiamo sviluppato una tecnica per estrarre proteine dall’interstizio del frustolo bioptico renale e sottoporle ad analisi proteomica.Metodi: Il frustolo bioptico viene centrifugato su colonna con filtro a fibre di vetro. Il liquido prodotto viene recuperato, mentre il frustolo bioptico viene reidratato in soluzione fisiologica e processato secondo le consuete tecniche istologiche. Il liquido interstiziale viene analizzato, parallelamente a campioni di siero dello stesso paziente, sia attraverso tecnica SELDI-ToF, sia mediante SDS-PAGE con colorazione argentica. Si è proceduto quindi all’analisi delle bande differenziali ed elaborazione statistica dei profili SELDI-ToF di interstizio e siero.Risultati: Abbiamo verificato che il processamento finalizzato all’estrazione del liquido interstiziale non modifica in alcun modo il risultato delle preparazioni istologiche. Le analisi in SELDI-ToF e SDS-PAGE hanno evidenziato numerose proteine presenti nel liquido interstiziale. La comparazione di questo risultato con quello derivante dal siero degli stessi pazienti indica una significativa differenza nella composizione dei due fluidi. In particolare, si rileva la notevole diminuzione dell’albumina nel liquido interstiziale rispetto al siero.Conclusioni: Con questo lavoro si è dimostrata l’applicabilità di un approccio innovativo nell’analisi di un fluido biologico ottenuto da frustoli bioptici renali per studi proteomici. La procedura consente di recuperare il fluido interstiziale da biopsie senza modificarne le caratteristiche istologiche. Il profilo proteico di questo nuovo campione è diverso da quello sierico: la notevole diminuzione di albumina nel liquido interstiziale e la presenza di bande e picchi differenziali tra i due campioni sono indicativi di una diversa composizione.Questo nuovo fluido biologico apre dunque la prospettiva analitica di un nuovo proteoma che abbiamo denominato INTERSTIZIOMA. La ricerca di biomarcatori nell’interstizioma permetterà di aggiungere una nuova dimensione diagnostica alla biopsia renale.

2008 - Screening of a kidney cDNA library for the identification of autoimmune proteins from serum of membranous nephropathy patients. [Abstract in Atti di Convegno]
Cavazzini, Fabrizio; Magistroni, Riccardo; Furci, L; Leonelli, M; Ligabue, Giulia; Lupo, Valentina; Albertazzi, Alberto
abstract

INTRODUCTION AND AIMS: Membranous Nephropathy (MN) represents a large amount of Nephrotic Syndromes in the adult population and its definitive diagnosis is currently carried out through biopsy. An autoimmune condition is suspected in MN in which some glomerular structures are targeted by patient antibodies. We do not know yet the target protein (or proteins) putatively involved and responsible for the disease. The aim of this work is to identify these proteins by screening a lambda-phage library using patient serum pools.METHODS: We set up the following three pools of sera: (i) from 15 MN patients, (ii) from 15 non-MN renal patients (4 with diabetic nephropathy, 4 with focal glomerulosclerosis, 4 with type I membranoproliferative glomerulonephritis, 3 with minimal change disease), and (iii) from 15 healthy individuals. A commercial cDNA phagemide library (from healthy kidney whole mRNA ) was screened using the above described pooled sera, in order to detect positive signals following antigen-antibody recognition.RESULTS: We detected one phagemide clone expressing a protein which was shown to be targeted by the antibodies of the pooled MN sera only. Control sera were both negative. The cDNA insert carried by the phagemide was subsequently sequenced. In particular, by comparing the sequence we isolated with a human DNA database, a complete matching with the synaptonemal complex protein 65 (SC65), also known as No55, was found.CONCLUSIONS: Anti-No55 autoantibodies appear to be involved in MN physiopathology by being present in patient sera. Considering the invasiveness and the resulting risk coming from renal biopsy, our ongoing aim is to set up a procedure able to diagnose affected patients through a little- or non-invasive method such as blood sampling rather than a biopsy. By dosing patient autoantibodies targeting this self-protein, it might be possible to carry out a correct diagnosis thus avoiding biopsy-correlated risks.

2007 - Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36 [Articolo su rivista]
Paterson, Ad; Liu, Xq; Wang, K; Magistroni, Riccardo; Song, X; Kappel, J; Klassen, J; Cattran, D; ST GEORGE HYSLOP, P; Pei, Y.
abstract

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and an important cause of ESRD. Familial clustering of cases suggests genetic predisposition to this disease. Two recent genome-wide studies in IgAN have identified a major susceptibility locus on chromosome 6q22 (IGAN1) and two additional loci with suggestive linkage signals on chromosomes 4q26-31 and 17q12-22. A large four-generation family with 14 affected individuals has been clinically ascertained and excluded from linkage to these loci. A genome-wide linkage scan was performed on this family with GeneChip Mapping 10K 2.0 Arrays using an "affected-only" strategy. By nonparametric analysis, two regions of suggestive linkage (multipoint logarithm of odds [LOD] scores >2) were identified on chromosomes 2q36 and 13p12.3. By parametric analysis (assuming an autosomal dominant inheritance, a disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75%), a significant linkage to chromosome 2q36 (maximum multipoint LOD score 3.47) was found. Nine simple sequence repeat markers then were genotyped in 21 members (included all of the affected individuals), and significant linkage to chromosome 2q36 over a region of 12.2 cM (maximum multipoint LOD score 3.46) was confirmed. Recombination events in two affected individuals, as detected by haplotype analysis, delineated a critical interval of approximately 9 cM (equivalent to approximately 7 Mb) between D2S1323 and D2S362. Taken together, these data provide strong evidence for a novel disease susceptibility locus for familial IgAN.

2007 - Plasma exchange in acute and chronic hyperviscosity syndrome: a rheological approach and guidelines study [Articolo su rivista]
M., Ballestri; F., Ferrari; Magistroni, Riccardo; M., Mariano; Gb, Ceccherelli; G., Milanti; M., DE PALMA; Albertazzi, Alberto
abstract

Therapeutic plasma exchange is an extra-corporeal technique able to remove from blood macromolecules and/or replace deficient plasma factors. It is the treatment of choice in hyperviscosity syndrome, due to the presence of quantitatively or qualitatively abnormal plasma proteins such as paraproteins. In spite of a general consensus on the indications to therapeutic plasma exchange in hyperviscosity syndrome, data or guide lines about the criteria to plan the treatment are still lacking. We studied the rheological effect of plasma exchange in 20 patients with plasma hyperviscosity aiming to give data useful for a rational planning of the treatment. Moreover, we verified the clinical applicability of the estimation of plasma viscosity by means of Kawai's equation. Plasma exchange decreases plasma viscosity about 20-30% for session. Only one session is required to normalize plasma viscosity when it is < 2.2 mPas, whereas a maximum of 3 session are required when it is > 2.2 till to 6 mPas. A fourth session is useless, especially if the inter-session interval is < 15 days. By means of a polynomial equation, knowing basal-plasma viscosity and the disease of a patient, we can calculate the decrease of viscosity obtainable by each session of plasma exchange then the number of session required to normalize the viscosity. Kawai's equation is able to evaluate plasma viscosity in healthy volunteers, but it is not clinically reliable in paraproteinemias. [Pubmed] [Scholar] [EndNote] [BibTex]

2007 - Towards evidence-based nephrology: the seeming paradox of "out-of-line" guidelines. [Articolo su rivista]
Magistroni, Riccardo
abstract

no abstract

2006 - A validated model of disease progression in IgA nephropathy [Articolo su rivista]
Magistroni, Riccardo; L., Furci; M., Leonelli; M., Masellis; Ligabue, Giulia; L., Lucchi; A., Lupo; B., Brezzi; G., Gambaro; L., Manganelli; G., Pedrazzi; M., Ricardi; L., Bormioli; Albertazzi, Alberto
abstract

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the general population. There is accumulating evidence that immunosuppressive treatment is efficacious in IgAN. However, it is critical to define appropriate indicators for this therapy especially in the wake of potentially deleterious side effects to immunosuppressives. Methods: This study retrospectively reviewed IgAN cases collected since 1981 to identify clinical and/or histological parameters for disease progression; 310 patients with biopsy proven IgAN, diagnosed from January 1981 to March 2004, were included. Results: We defined a clinical prognostic index (CPI) using multivariate analysis, which incorporated these clinical/histological parameters. Semiquantitative scores were assigned as follows: 2 points if creatinine (Cr) was >1.4 mg/dL, 1 point if proteinuria was >1 g/24 hr, I point if a patient was affected by hypertension, and 1 point if a patient was older than 30 yrs. Dividing our population into two groups (scores 0-2 = low CPI group; scores 3-5 = high CPI group), we demonstrated a significantly different 10-yr renal survival rate; in the low CPI group, renal survival since time of biopsy at 10 yrs was 91.7%; in the high CPI group the renal survival at 10 yrs was 35%. We validated the CPI in an independent sample from Verona (validation group) and demonstrated similar results for the CPI. Conclusions: The CPI is convenient to use for defining the risk of disease progression.

2006 - Influence of ACE I/D gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease: a meta-analysis [Articolo su rivista]
Tv, Pereira; Ac, Nunes; M., Rudnicki; Magistroni, Riccardo; Albertazzi, Alberto; Ac, Pereira; Je, Krieger
abstract

Background. Autosomal dominant polycystic kidney disease (ADPKD) is a renal disease characterized by an important variability in clinical course, which cannot be fully explained by the genetic heterogeneity of the disease. Although the role for the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a modifier factor in ADPKD renal deterioration has been suggested, direct evidence from genetic association studies remain inconclusive. To provide a more robust estimate of the putative effect of the ACE I/D polymorphism on the renal progression in ADPKD, we performed a meta-analysis pooling data from all relevant studies in which the role of the ACE I/D variant in ADPKD clinical features was evaluated. Methods. We applied a random-effects model to combine odds ratio and 95% confidence intervals. Q-statistic was used to evaluate the homogeneity, and both Egger's and Begg-Mazumdar tests were used to assess publication bias. Results. Altogether, three distinct meta-analyses were generated using data from 13 studies. Despite the absence of publication bias and the presence of homogeneity among study results, the DD genotype failed to show an influence on risk of end-stage renal disease (ESRD), mean age at ESRD or risk of hypertension in ADPKD patients when compared with I-allele carriers (DD vs ID + II). Likewise, meta-analyses carried out separately for Caucasian and Asian studies showed no indication of an association between the DD genotype and a faster renal deterioration in ADPKD. Conclusion. These findings do not support the hypothesis that the enhanced ACE activity associated with the D allele might promote a significantly worse prognosis in patients with ADPKD.

2005 - Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease [Articolo su rivista]
Ad, Paterson; Magistroni, Riccardo; N., He; Kr, Wang; A., Johnson; Pr, Fain; E., Dicks; P., Parfrey; P., St George Hyslop; Y., Pei
abstract

Significant intrafamilial phenotypic variability is well documented in autosomal dominant polycystic kidney disease (ADPKD) and suggests a modifier effect. In this study, variance components analysis was performed to estimate the contribution of genetic factors for within-family renal disease variability in 406 patients from 66 type 1 ADPKD families. Overall, 39% of the study patients had ESRD at their last follow-up, and their renal survival did not differ by gender (P = 0.35, log-rank test). Because their frequency plot of creatinine clearance (Ccr) assumed a bimodal distribution with a marked kurtosis that was not improved by transformations, the study cohort was decomposed into two separate groups (non-ESRD [n = 247] and ESRD [n = 159]) in which the Ccr plots were normally distributed. The heritability (h(2)) of Ccr and age at ESRD (age(ESRD)) and the genetic correlations between these measures and their covariates were estimated. In patients without ESRD, a significant heritability was found for Ccr (h(2) = 0.42; P = 0.0015) after adjusting for age (P = 0.0001), systolic BP (P = 0.0006), and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P = 0.00001). Birth year, gender, BMI, diastolic and mean BP, and pack-years of cigarette smoking did not significantly influence the heritability of this trait. In patients with ESRD, age(ESRD) provides a better measure than Ccr, which was very narrowly distributed. A significant heritability was found for ageESRD (h(2) = 0.78; P = 0.00009) in these latter patients. None of the above covariates influenced the heritability of this trait. It is concluded that a significant modifier gene effect influences the progression of renal disease in type 1 ADPKD.

2003 - Epidermal growth factor receptor polymorphism and autosomal dominant polycystic kidney disease [Articolo su rivista]
Magistroni, Riccardo; Manfredini, P; Furci, L; Ligabue, Giulia; Martino, C; Leonelli, M; Scapoli, C; Albertazzi, Alberto
abstract

BACKGROUND: The clinical variability in the rate of progression of autosomal dominant polycystic kidney disease (ADPKD) has been attributed to genetic heterogeneity, though environmental factors and modifying genes very likely play an important role as well. We examined the association between clinical outcome, defined by age at onset of end-stage renal disease (ESRD) in 46 ADPKD patients, and a polymorphism in the epidermal growth factor receptor (EGFR) gene, a candidate modifying gene. EGFR is a key element in renal tubular proliferation. METHODS: This study comprised 46 unrelated patients with ADPKD and ESRD, and 58 healthy controls. The patients had prevalently PKD 1 mutations. The EGFR microsatellite polymorphism was genotyped according to Gebhardt et al (11). RESULTS: The allele frequencies of the EGFR polymorphism were different in the ADPKD sample and the control population (G2=17.19; P=0.009). In particular, the frequencies of the 122 and 118bp length alleles had a different distribution (P=0.010 and P=0.047 respectively). Patients with the 122bp length polymorphism had ESRD at an earlier age,but this finding was not statistically significant. CONCLUSIONS: These findings suggest an association between the EGFR microsatellite polymorphism and ADPKD. However, it is difficult to establish which alleles are protective and which harmful. A larger, multicenter study may help clarify these results and is also required to replicate our preliminary finding of an association between ADPKD and the EGFR polymorphism.

2003 - Evaluation of coronary artery disease by multislice spiral computed tomography in dialysis patients [Abstract in Atti di Convegno]
Ferramosca, E; Malaguti, V; Di Felice, A; Magistroni, R; Ratti, C; Modena, Mg; Ligabue, G; Romagnoli, R; Bagni, B; Albertazzi, A.
abstract

Evaluation of coronary artery disease by multislice spiral computed tomography in dialysis patients

2003 - Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease [Articolo su rivista]
Magistroni, Riccardo; He, N; Wang, K; Andrew, R; Johnson, A; Gabow, P; Dicks, E; Parfrey, P; Torra, R; SAN MILLAN, Jl; Coto, E; VAN DIJK, M; Breuning, M; Peters, D; Bogdanova, N; Ligabue, Giulia; Albertazzi, Alberto; Hateboer, N; Demetriou, K; Pierides, A; Deltas, C; ST GEORGE HYSLOP, P; Ravine, D; Pei, Y.
abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance < or = 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 to 78.1] versus 68.1 [95% CI, 66.0 to 70.2] yr) and CRF (72.5 [95% CI, 70.1 to 74.9] versus 63.7 [95% CI, 61.4 to 66.0] yr). Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P < 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.

2003 - MALATTIE DEL RENE, DELLE VIE URINARIE E DELL'APPARATO GENITALE MASCHILE : Le Nefropatie Glomerulari: glomerulonefriti primitive; glomerulonefriti secondarie [Capitolo/Saggio]
P. F., Palmieri; Magistroni, Riccardo; Albertazzi, Alberto
abstract

Per glomerulonefrite si intende una malattia infiammatoria che colpisce primitivamente il glomerulo renale

2003 - Precocious activation of genes of the renin-angiotensin system and the fibrogenic cascade in IgA glomerulonephritis [Articolo su rivista]
DEL PRETE, D; Gambaro, G; Lupo, A; Anglani, F; Brezzi, B; Magistroni, Riccardo; Gaziotto, R; Furci, L; Modena, F; Bernich, P; Albertazzi, Alberto; Dangelo, A; Maschio, G.
abstract

BACKGROUND: The renin-angiotensin system (RAS) seems to play a pivotal role in progression of immunoglobulin A (IgA) nephropathy (IgAN). Accordingly, in patients with IgAN a relationship between the RAS and the fibrogenic cascade triggered by transforming growth factor-beta1 (TGF-beta1) should be observed. This study was carried out to obtain deeper insight into the regulation of RAS and the interaction with TGF-beta1 in the diseased kidney. METHODS: Twenty renal biopsies from IgAN patients and five from renal cancer patients (controls) were analyzed in both microdissected glomerular and tubulointerstitial compartments by reverse transcription-polymerase chain reaction (RT-PCR). All patients had normal renal function. The expression of the following genes was determined: angiotensinogen (Agtg), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 and type II (AT1 and AT2 receptors), TGF-beta1, collagen IV (Coll IV), alpha-smooth muscle actin (alpha-SMA). Quantitative data were confirmed for TGF-beta1 and ACE genes by real-time PCR. Results. RAS genes were overexpressed in IgAN patients vs. control subjects. There was no difference between glomerular and tubulointerstitial RAS gene expression levels. On the contrary, the overactivation of fibrogenic cascade genes (TGF-beta1, Coll IV, alpha-SMA) in the tubulointerstitium was observed (TGF-beta1, glomerular 0.14 +/- 0.10 SD; tubulointerstial 0.34 +/- 0.20; P = 0.000) (alpha-SMA, glomerular 0.08 +/- 0.07; tubulointerstitial 0.35 +/- 0.19; P = 0.000) (Coll IV, glomerular 0.12 +/- 0.11; tubulointerstitial 0.22 +/- 0.10; P = 0.03). This fibrogenic cascade seems to be triggered by RAS as indicated by statistically significant correlations between the expression of their respective genes. A direct relationship between the putative Ang II activity and the expression of AT receptor genes was found in the tubulointerstitium, whereas in the glomeruli this relationship was negative. In the interstitium, statistically significant positive relationships emerged between interstitial infiltrates and the gene expression of Agtg, AT1 receptor, Coll IV, and TGF-beta1. CONCLUSION: This study demonstrates that a tight regulation of the intrarenal RAS exists in IgAN and that it follows the general rules disclosed in animal models. Moreover, the RAS seems to be activated early in the diseased kidney and it appears that such activation drives inflammation and a parallel stimulation of the TGF-beta fibrogenic loop, particularly at the tubulointerstitial level.

2001 - I polimorfismi del gene dell’enzima di conversione dell’angiotensina (ACE) nel rene policistico autosomico dominante (ADPKD) [Articolo su rivista]
Magistroni, Riccardo; Furci, L.; Leonelli, M.; Ballestri, M.; Ligabue, Giulia; Martino, C.; Scapoli, C.; Albertazzi, Alberto
abstract

BACKGROUND. In the kidneys of patients with progressive IgA Nephropathy (IgAN) hyperactivation of angiotensin II has been recognized. We analyzed the role of the Renin Angiotensin System (RAS) polymorphisms in relation to renal histology in a Northern Italian population. Furthermore we evaluated the effect of the genetic variants on tissutal expression levels of the respective genes.METHODS. The clinical data at the biopsy time and the histological data of 121 patients affected by IgA nephropathy were collected, 97 of these subjects and 100 healthy control subjects were genotyped for the following polymorphisms: Angiotensinogen (Agt) M235T, Angiotensin Converting Enzyme (ACE) I/D, Angiotensin II type 1 Receptor (AT1R) A1166C variants. Twenty IgAN subjects were randomly selected for the mRNA expression evaluation of the genes Agt, ACE and AT1R.RESULTS. None of the polymorphisms seems associated with the risk of developing IgAN when compared to the control population. The Agt M235T is associated to the mesangial proliferation, (Kruskal-Wallis KW = 7.907 corrected for ties, p value 0.019), the TT variant presents the highest value of mesangioproliferative lesions. The ACE genotype is related to glomerulosclerosis and glomerular volume: patients with the II genotype show a major grade of glomerulosclerosis (Kruskal Wallis χ2 9.225, df 2, p 0.01) and largest glomeruli (p = 0.003). Glomerular ACE mRNA levels are significantly higher in patients with the ACE-II genotype than in carriers of the DD and DI genotypes (p=0.04). CONCLUSION. This study suggests that RAS genetic variants may modulate proliferative and sclerotic phenomena by affecting the tissutal abundance of the RAS components.

2000 - Il rene policistico autosomico dominante (ADPKD): aspetti genetico-molecolari, clinici ed epidemiologici nella provincia di Modena. [Articolo su rivista]
Magistroni, Riccardo; Furci, L.; Ligabue, Giulia; Baraldi, A.; Medici, G.; Olmeda, F.; Ballestri, M.; Miscia, M. C.; Ferrari, Sergio; Albertazzi, Alberto
abstract

non disponibile

2000 - Trattato di Medicina Interna : Le Sindromi Renali. [Capitolo/Saggio]
Furci, L; Magistroni, Riccardo; Albertazzi, Alberto
abstract

In un'epoca di globalizzazione, il sapere medico non può far agio sulla cultura internazionale di spicco nell'avanzamento della medicina, ma nel contempo non può astrarsi dal contesto territoriale in cui avviene l'esercizio della professione medica. In considerazione di ciò, il "Teodori 2004 - Trattato Italiano di Medicina Interna", nella sua VIIª edizione, si è arricchito di 30 nuovi capitoli ed aggiornato secondo i più recenti dettami della medicina, con Autori altamente qualificati nella materia. Inoltre ha preso in considerazione aspetti epidemiologici-clinico-terapeutici particolarmente attintenti alla realtaà della patologia internistica in Italia. Questa simbiosi di universalità dello scibile e di aderenza alla situazione clinica del nostro territorio, costituisce un punto di froza dell'opera che accrescerà il successo editoriale che essa ha sempre avuto. È per queste sue preorogative che ci sentiamo di proporre all'attenzione del corpo docente universitario, degli studenti delle Facoltà Mediche, dei medici professionisti, l'adozione di questo trattato come testo di acculturamento e di formazione per la laurea in Medicina e Chirurgia, nonché per l'esercizio pratico della professione medica. Convinti della validità di questo "Trattato" quale opera innovatrice nella trattatistica medica italiana, sospinti dalle continue richieste di realizzare un'opera rinnovata, sicuri di interpretare la volontà del Prof. Ugo Teodori e desiderosi che il suo nome non venga dimenticato come testimonianza di gratitudine e di fedeltà ai suoi insegnamenti, ci siamo assunti l'impegno di affrontare la preparazione di questa nuova edizione. La nuova opera ha richiesto grande impegno organizzativo e la piena disponibilità da parte dei Coordinatori e degli oltre 250 Collaboratori che hanno accettato anche limiti di spazio per contenere il testo in due volumi. A tutti un vivo ringraziamento. Un particolare ringraziamento va rivolto al nostro staff redazionale per aver curato con la cunsueta professionalità e in piena collaborazione con gli Autori la realizzazione dell'opera. È pertanto con orgoglio che presentiamo il "Teodori 2004-Trattato Italiano di Medicina Interna" che per la sua completezza, organicità, aggiornamento e riferimenti bibliografici, si colloca tra le migliori opere della letteratura scientifica internazionale. Tra i pregi dell'opera non va, peraltro, trascurato il costo veramente interessante per il suo acquisto.