Lysinuric Protein Intolerance: Not Only a Disorder for Pediatric Nephrologists - Case Report Miriam Rigoldi, Caterina Mele, Matteo Breno, Marina Noris, Amantia Imeraj, Sara Gamba, Arrigo Schieppati, Erica Daina, on behalf of Italian Undiagnosed Rare Diseases Network (IURDN) Nephron, 2025 Introduction: Lysinuric protein intolerance (LPI) is a multisystemic inborn error of metabolism with a variable clinical expressivity that usually begins in childhood with growth failure and gastroenterological/neurological problems related to the altered urea cycle and, later, with complications involving the renal, pulmonary, and immunohematological systems. Case Report: We present the case of a 40-year-old woman suffering from chronic kidney disease in the context of a LPI, whose diagnosis was challenging because the signs of the disease were always blurred and the patient never manifested critical episodes typical of this multisystemic disease. In addition to renal disease, splenomegaly, thrombocytopenia, elevated lactate dehydrogenase (LDH), hyperferritinemia, and hypertriglyceridemia were also present. A thorough investigation of the patient’s food preferences revealed her spontaneous aversion to protein-containing foods and excessive drowsiness during the occurrence of infectious episodes or on the rare occasions of excessive protein intake, although without ever coming to medical attention. These nuanced signs led us to suspect an impairment of the urea cycle and ultimately allowed us to narrow down the diagnosis to LPI through biochemical and genetic investigations. Conclusion: Nephrologists should consider LPI in the differential diagnosis, whenever a patient presents with mixed proteinuria, tubular dysfunction, and/or chronic kidney disease of unknown origin. In these circumstances, we suggest looking for other signs such as growth failure, signs and symptoms ascribed to urea-cycle impairment, pulmonary involvement, hepatosplenomegaly, and laboratory alterations such as pancytopenia, hyperferritinemia, lipid abnormalities, and elevated LDH.
Exuberant Endothelial C5b-9 Formation in Recurrent and De Novo Posttransplant Thrombotic Microangiopathy Sistiana Aiello, Sara Gastoldi, Elena Bresin, Miriam Galbusera, Caterina Mele, Erica Daina, Donata Santarsiero, Giorgia Comai, Gaetano La Manna, Carolina Martinatto, Ariela Benigni, Giuseppe Remuzzi, Marina Noris Kidney International Reports, 2024 Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation. It may present as a recurrence of atypical hemolytic uremic syndrome (aHUS) or may occur de novo. 1 Kidney graft outcome in patients with recurrent aHUS is poor and strongly dependent on the early initiation of anti-C5 therapy.1 However, diagnosing aHUS recurrence, as well as de novo TMA, is challenging because patients may present without hematological signs.1 A biopsy may not be feasible, particularly in patients with thrombocytopenia. Here, we evaluated whether an ex vivo assay of serum-induced terminal complement complex (C5b-9) formation on human microvascular endothelial cells (HMEC-1), which efficiently detects complement dysregulation in nontransplanted patients with aHUS,2 could also help diagnose posttransplant recurrent aHUS. We also evaluated whether de novo posttransplant TMA is associated with endothelial complement activation, which remains a widely discussed issue,3,4 and whether the C5b-9 formation assay could support diagnosis. Due to the high risk of recurrence, the incidence of TMA in kidney grafts exceeds 36 times in patients with a pretransplant history of aHUS, compared to those with other causes of end-stage renal disease. This underscores the importance of accurately diagnosing native kidney disease.1 Unfortunately, 20% to 30% of patients on transplant waiting lists have no diagnosis.5 To address this additional issue, we investigated whether the C5b-9 assay could help to identify aHUS cases among patients with end-stage renal disease.
“Eculizumab First” in the Management of Posttransplant Thrombotic Microangiopathy Federica Maritati, Valeria Corradetti, Claudia Bini, Michele Provenzano, Vania Cuna, et al. Kidney International Reports, 2024 IntroductionPost-transplant thrombotic microangiopathy (PT-TMA) is an uncommon event that characterizes approximately 3-14% of kidney transplants (KT), and that is associated with a higher risk of delayed graft function and graft loss. PT-TMA occurs more frequently within the first three months after transplant and can be a manifestation of de novo disease or the recurrence of previous atypical hemolytic uremic syndrome (aHUS). Abnormalities in complement regulation genes could explain the increased susceptibility of some patients to PT-TMA. Eculizumab is a humanized monoclonal antibody that inhibits the formation of the membrane attack complex C5b-9. The aim of this study is to evaluate the efficacy of eculizumab as treatment for PT-TMA.MethodsWe retrospectively analyzed clinical records of 45 KT patients who received eculizumab immediately after the clinical diagnosis of PT-TMA.ResultsKidney biopsy was performed in 91.1% of patients and complement genetic study in 64.4%. 85.4% of kidney biopsies showed signs of TMA; genetic analysis revealed one pathogenetic variant, two variants of uncertain significance, one likely benign variant, 8 risk polymorphisms, 27 risk haplotypes.After two weeks from the treatment starting, hemoglobin and platelets significantly increased. A remarkable improvement in kidney function was also observed. After six months, 28.8% of patients had a complete renal recovery while 44.4% had a partial recovery.ConclusionThis is, to our knowledge, the largest series of KT patients with PT-TMA treated with eculizumab. These data suggest that eculizumab is associated with a normalization of hemolysis indices and an important and progressive improvement of graft function.
A GWAS in the pandemic epicenter highlights the severe COVID-19 risk locus introgressed by Neanderthals Matteo Breno, Marina Noris, Nadia Rubis, Aneliya Ilieva Parvanova, Davide Martinetti, Sara Gamba, Lucia Liguori, Caterina Mele, Rossella Piras, Silvia Orisio, Elisabetta Valoti, Marta Alberti, Olimpia Diadei, Elena Bresin, Miriam Rigoldi, Silvia Prandini, Tiziano Gamba, Nadia Stucchi, Fabiola Carrara, Erica Daina, Ariela Benigni, Giuseppe Remuzzi Iscience, 2023 Large GWAS indicated that genetic factors influence the response to SARS-CoV-2. However, sex, age, concomitant diseases, differences in ancestry, and uneven exposure to the virus impacted the interpretation of data. We aimed to perform a GWAS of COVID-19 outcome in a homogeneous population who experienced a high exposure to the virus and with a known infection status. We recruited inhabitants of Bergamo province—that in spring 2020 was the epicenter of the SARS-Cov-2 pandemic in Europe—via an online questionnaire followed by personal interviews. Cases and controls were matched by age, sex and risk factors. We genotyped 1195 individuals and replicated the association at the 3p21.31 locus with severity, but with a stronger effect size that further increased in gravely ill patients. Transcriptome-wide association study highlighted eQTLs for LZTFL1 and CCR9 . We also identified 17 loci not previously reported, suggestive for an association with either COVID-19 severity or susceptibility.
Impact of SARS-CoV-2 Omicron and Delta variants in patients requiring intensive care unit (ICU) admission for COVID-19, Northern Italy, December 2021 to January 2022 Antonio Piralla, Francesco Mojoli, Laura Pellegrinelli, Ferruccio Ceriotti, Antonia Valzano, Giacomo Grasselli, Maria Rita Gismondo, Valeria Micheli, Antonio Castelli, Claudio Farina, Marco Arosio, Ferdinando Luca Lorini, Diana Fanti, Andrea Busni, Matteo Laratta, Fabrizio Maggi, Federica Novazzi, Luca Cabrini, Anna Paola Callegaro, Roberto Keim, Giuseppe Remuzzi, Annalisa Cavallero, Sergio Maria Ivano Malandrin, Roberto Rona, Federica Giardina, Guglielmo Ferrari, Federica Zavaglio, Piera D'angelo, Cristina Galli, Laura Bubba, Sandro Binda, Massimo Oggioni, Sara Colonia Uceda Renteria, Patrizia Bono, Andreina Baj, Francesca Drago Ferrante, Davide Guarneri, Marco Tonelli, Gavino Napolitano, Alice Nava, Lorenzo Romeo, Elena Nicolini, Rea Valaperta, Ludovica Varisano, Caterina Mele, Lucia Liguori, Monica Raggi, Silvia Mongodi, Michele Pagani, Paolo Severgnini, Dario Gasberti, Ezio Bonanomi, Paolo Gritti, Francesco Marrazzo, Ilaria Giovannini, Noemi Sacchi, Orlando Sagliocco, Danilo Cereda, Sabrina Buoro, Fausto Baldanti, Elena Pariani Respiratory Medicine and Research, 2023
An ex vivo test to investigate genetic factors conferring susceptibility to atypical haemolytic uremic syndrome Sara Gastoldi, Sistiana Aiello, Miriam Galbusera, Matteo Breno, Marta Alberti, Elena Bresin, Caterina Mele, Rossella Piras, Lucia Liguori, Donata Santarsiero, Ariela Benigni, Giuseppe Remuzzi, Marina Noris Frontiers in Immunology, 2023 IntroductionComprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains challenging owing to the complexity of functional studies with mutant proteins. This study was designed: 1) To identify a tool for rapid functional determination of complement gene variants; 2) To uncover inherited complement dysregulation in aHUS patients who do not carry identified gene variants.MethodsTo address the above goals, we employed an ex-vivo assay of serum-induced C5b-9 formation on ADP-activated endothelial cells in 223 subjects from 60 aHUS pedigrees (66 patients and 157 unaffected relatives).ResultsSera taken from all aHUS patients in remission induced more C5b-9 deposition than control sera, independently from the presence of complement gene abnormalities. To avoid the possible confounding effects of chronic complement dysregulation related to aHUS status, and considering the incomplete penetrance for all aHUS-associated genes, we used serum from unaffected relatives. In control studies, 92.7% of unaffected relatives with known pathogenic variants exhibited positive serum-induced C5b-9 formation test, documenting a high sensitivity of the assay to identify functional variants. The test was also specific, indeed it was negative in all non-carrier relatives and in relatives with variants non-segregating with aHUS. All but one variants in aHUS-associated genes predicted in-silico as likely pathogenic or of uncertain significance (VUS) or likely benign resulted as pathogenic in the C5b-9 assay. At variance, variants in putative candidate genes did not exhibit a functional effect, with the exception of a CFHR5 variant. The C5b-9 assay in relatives was helpful in defining the relative functional effect of rare variants in 6 pedigrees in which the proband carried more than one genetic abnormality. Finally, for 12 patients without identified rare variants, the C5b-9 test in parents unmasked a genetic liability inherited from an unaffected parent.DiscussionIn conclusion, the serum-induced C5b-9 formation test in unaffected relatives of aHUS patients may be a tool for rapid functional evaluation of rare complement gene variants. When combined with exome sequencing the assay might be of help in variant selection, to identify new aHUS-associated genetic factors.
CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome Rossella Piras, Elisabetta Valoti, Marta Alberti, Elena Bresin, Caterina Mele, Matteo Breno, Lucia Liguori, Roberta Donadelli, Miriam Rigoldi, Ariela Benigni, Giuseppe Remuzzi, Marina Noris Frontiers in Immunology, 2023 IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare disease that manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, and is associated with dysregulation of the alternative complement pathway. The chromosomal region including CFH and CFHR1-5 is rich in repeated sequences, favoring genomic rearrangements that have been reported in several patients with aHUS. However, there are limited data on the prevalence of uncommon CFH-CFHR genomic rearrangements in aHUS and their impact on disease onset and outcomes.MethodsIn this study, we report the results of CFH-CFHR Copy Number Variation (CNV) analysis and the characterization of resulting structural variants (SVs) in a large cohort of patients, including 258 patients with primary aHUS and 92 with secondary forms.ResultsWe found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving CFH alone or CFH and CFHR (group A; n=14), while 30% exhibited rearrangements including only CFHRs (group B; n=6). In group A, 6 patients presented CFH::CFHR1 hybrid genes, 7 patients carried duplications in the CFH-CFHR region that resulted either in the substitution of the last CFHR1 exon(s) with those of CFH (CFHR1::CFH reverse hybrid gene) or in an internal CFH duplication. In group A, the large majority of aHUS acute episodes not treated with eculizumab (12/13) resulted in chronic ESRD; in contrast, anti-complement therapy induced remission in 4/4 acute episodes. aHUS relapse occurred in 6/7 grafts without eculizumab prophylaxis and in 0/3 grafts with eculizumab prophylaxis. In group B, 5 subjects had the CFHR31-5::CFHR410 hybrid gene and one had 4 copies of CFHR1 and CFHR4. Compared with group A, patients in group B exhibited a higher prevalence of additional complement abnormalities and earlier disease onset. However, 4/6 patients in this group underwent complete remission without eculizumab treatment. In secondary forms we identified uncommon SVs in 2 out of 92 patients: the CFHR31-5::CFHR410 hybrid and a new internal duplication of CFH.DiscussionIn conclusion, these data highlight that uncommon CFH-CFHR SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the CFH are associated with a poor prognosis but carriers respond to anti-complement therapy.
Mycoplasma pneumoniae Infection Associated with Anti-Factor H Autoantibodies in Atypical Hemolytic Uremic Syndrome Elisabetta Valoti, Rossella Piras, Caterina Mele, Marta Alberti, Lucia Liguori, Matteo Breno, Cristina Bertulli, Elena Bresin, Roberta Donadelli Nephron, 2022 Hemolytic uremic syndrome (HUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia, and renal impairment mostly triggered by strains of Shiga-like toxin-producing <i>Escherichia coli</i> (STEC-HUS). A rarer form of HUS, defined as atypical HUS (aHUS), is associated with genetic or acquired dysregulation of the alternative pathway of the complement system and presents a poorer prognosis than STEC-HUS. Factor H autoantibodies (anti-FHs) have been reported in aHUS in 5–11% of cases and are strongly associated with the homozygous deletion of <i>CFHR3-CFHR1</i> genes. In the large majority of patients, anti-FH-associated aHUS is commonly preceded by gastrointestinal or respiratory tract infections. Here, we described the clinical case of a 3-year-old boy who was hospitalized for aHUS preceded by <i>Mycoplasma pneumoniae</i> (MP) infection. He resulted positive for anti-FHs and carried the homozygous deletion of <i>CFHR3-CFHR1</i>. Of relevance, he also showed a variant of unknown significance in the <i>C5</i> gene. The patient was successfully treated with eculizumab and achieved hematological and renal remission. The anti-FH titer decreased, became negative after 6 months of mycophenolate mofetil (MMF) treatment, and remained negative for 21-month follow-up indicating that immunosuppression was effective and could prevent the reappearance of anti-FHs. We hypothesized that MP, likely through an evasion strategy of immunosurveillance based on binding of pathogen to FH, triggers anti-FH antibody generation and aHUS in a subject genetically predisposed. In conclusion, to the best of our knowledge, here, we reported the first case of anti-FH-mediated aHUS after an MP infection who benefited from eculizumab and immunosuppressive therapy based on MMF. Hence, monitoring of anti-FHs in patients with post-MP infection glomerulonephritis could be recommended, especially in those with low C3 plasma levels.
IgA nephropathy and atypical hemolytic uremic syndrome: a case series and a literature review Lucio Manenti, Giovanni Maria Rossi, Isabella Pisani, Micaela Gentile, Francesco Fontana, Francesco Paolo Pilato, Marco Delsante, Federico Ricco, Renzo Mignani, Caterina Mele, Elena Bresin, Enrico Fiaccadori Journal of Nephrology, 2022 Our case series and literature review show that the onset of either aHUS or renal TMA in the course of IgAN are associated with very poor renal outcome. Activation of the alternative pathway revealed by consumption of serum C3 seems to play a major role. Our hypothesis is that the presence of a predisposing factor (e.g. dysregualtion of complement alternative pathway and/or other intrarenal precipitating factors) might be at the heart of aHUS-IgAN pathophysiology.
Third-party bone marrow–derived mesenchymal stromal cell infusion before liver transplantation: A randomized controlled trial Federica Casiraghi, Norberto Perico, Manuel A. Podestà, Marta Todeschini, Marco Zambelli, Michele Colledan, Stefania Camagni, Stefano Fagiuoli, Antonio D. Pinna, Matteo Cescon, Valentina Bertuzzo, Lorenzo Maroni, Martino Introna, Chiara Capelli, Josee T. Golay, Marina Buzzi, Marilena Mister, Pamela Y.R. Ordonez, Matteo Breno, Caterina Mele, Alessandro Villa, Giuseppe Remuzzi American Journal of Transplantation, 2021
Rare functional variants in complement genes and anti-FH autoantibodies-associated AHUS Elisabetta Valoti, Marta Alberti, Paraskevas Iatropoulos, Rossella Piras, Caterina Mele, Matteo Breno, Alessandra Cremaschi, Elena Bresin, Roberta Donadelli, Silvia Alizzi, Antonio Amoroso, Ariela Benigni, Giuseppe Remuzzi, Marina Noris Frontiers in Immunology, 2019
Cluster analysis identifies distinct pathogenetic patterns in c3 glomerulopathies/immune complex–Mediated membranoproliferative GN Paraskevas Iatropoulos, Erica Daina, Manuela Curreri, Rossella Piras, Elisabetta Valoti, Caterina Mele, Elena Bresin, Sara Gamba, Marta Alberti, Matteo Breno, Annalisa Perna, Serena Bettoni, Ettore Sabadini, Luisa Murer, Marina Vivarelli, Marina Noris, Giuseppe Remuzzi, for the Registry of Membranoproliferative Glomerulonephritis/C3 Glomerulopathy Journal of the American Society of Nephrology, 2018
Hemolytic Uremic Syndrome Caterina Mele, Marina Noris, Giuseppe Remuzzi Critical Care Nephrology Third Edition, 2017
Hemolytic uremic syndrome in pregnancy and postpartum Alexandra Bruel, David Kavanagh, Marina Noris, Yahsou Delmas, Edwin K.S. Wong, Elena Bresin, François Provôt, Vicky Brocklebank, Caterina Mele, Giuseppe Remuzzi, Chantal Loirat, Véronique Frémeaux-Bacchi, Fadi Fakhouri Clinical Journal of the American Society of Nephrology, 2017
Hemolytic uremic syndrome Caterina Mele, Giuseppe Remuzzi, Marina Noris Seminars in Immunopathology, 2014
Genetic screening in adolescents with steroid-resistant nephrotic syndrome Beata S. Lipska, Paraskevas Iatropoulos, Ramona Maranta, Gianluca Caridi, Fatih Ozaltin, Ali Anarat, Ayse Balat, Jutta Gellermann, Agnes Trautmann, Ozlem Erdogan, Bassam Saeed, Sevinc Emre, Radovan Bogdanovic, Marta Azocar, Irena Balasz-Chmielewska, Elisa Benetti, Salim Caliskan, Sevgi Mir, Anette Melk, Pelin Ertan, Esra Baskin, Helena Jardim, Tinatin Davitaia, Anna Wasilewska, Dorota Drozdz, Maria Szczepanska, Augustina Jankauskiene, Lina Maria Serna Higuita, Gianluigi Ardissino, Ozan Ozkaya, Elzbieta Kuzma-Mroczkowska, Oguz Soylemezoglu, Bruno Ranchin, Anna Medynska, Marcin Tkaczyk, Amira Peco-Antic, Ipek Akil, Tomasz Jarmolinski, Agnieszka Firszt-Adamczyk, Jiri Dusek, Giacomo D. Simonetti, Faysal Gok, Alaleh Gheissari, Francesco Emma, Rafael T. Krmar, Michel Fischbach, Nikoleta Printza, Eva Simkova, Caterina Mele, Gian Marco Ghiggeri, Franz Schaefer Kidney International, 2013
The toll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts Marina Noris, Paola Cassis, Nadia Azzollini, Regiane Cavinato, Daniela Cugini, Federica Casiraghi, Sistiana Aiello, Samantha Solini, Linda Cassis, Marilena Mister, Marta Todeschini, Mauro Abbate, Ariela Benigni, Piera Trionfini, Susanna Tomasoni, Caterina Mele, Cecilia Garlanda, Nadia Polentarutti, Alberto Mantovani, Giuseppe Remuzzi Journal of Immunology, 2009
Hemolytic Uremic Syndrome Caterina Mele, Giuseppe Remuzzi Critical Care Nephrology Second Edition, 2009
Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides Daniela Macconi, Chiara Chiabrando, Silvia Schiarea, Sistiana Aiello, Linda Cassis, Elena Gagliardini, Marina Noris, Simona Buelli, Carla Zoja, Daniela Corna, Caterina Mele, Roberto Fanelli, Giuseppe Remuzzi, Ariela Benigni Journal of the American Society of Nephrology, 2009
Hemolytic Uremic Syndrome Caterina Mele, Giuseppe Remuzzi Critical Care Nephrology Second Edition, 2008
Hemolytic uremic syndrome Giornale Italiano Di Nefrologia Organo Ufficiale Della Societa Italiana Di Nefrologia, 2007
Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome Jessica Caprioli, Marina Noris, Simona Brioschi, Gaia Pianetti, Federica Castelletti, Paola Bettinaglio, Caterina Mele, Elena Bresin, Linda Cassis, Sara Gamba, Francesca Porrati, Sara Bucchioni, Giuseppe Monteferrante, Celia J. Fang, M. K. Liszewski, David Kavanagh, John P. Atkinson, Giuseppe Remuzzi, for the International Registry of Recurrent, Familial HUS/TTP Blood, 2006
