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Noris M.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | Remuzzi G.,Unit of Nephrology and Dialysis
Nature reviews. Nephrology | Year: 2014

Haemolytic uraemic syndrome (HUS) is characterized by nonimmune haemolytic anaemia, thrombocytopenia and renal impairment-most incidents in childhood are caused by shiga toxin-producing bacteria. Atypical HUS (aHUS) accounts for 10% of cases and has a poor prognosis. About 60% of patients with aHUS have dysregulation of the alternative complement pathway (complement-mediated aHUS). The kidney is the main target organ, but other organs might also be affected. Cardiac complications occur in 3-10% of patients with complement-mediated aHUS, as a consequence of microangiopathic injury in the coronary microvasculature, and can cause sudden death. Emerging evidence also suggests that either thrombosis or stenosis of the medium and large arteries might complicate disease course, and such disorders occur even after renal function is lost. In this Perspectives article we discuss the impact of cardiovascular involvement in complement-mediated aHUS, the role of acute and chronic complement hyperactivation in such events and the implications for treatment. Source

Noris M.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | Remuzzi G.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco
Current Opinion in Nephrology and Hypertension | Year: 2013

PURPOSE OF REVIEW: Several genetic and acquired abnormalities leading to abnormal activation of the alternative pathway of complement have been identified in patients with atypical hemolytic uremic syndrome (aHUS). The purpose of this review is to shed light on how advances in the understanding of aHUS pathogenesis have impacted on prevention and cure of aHUS recurrence after kidney transplantation. RECENT FINDINGS: Studies over the past decade have shown that the risk of posttransplant recurrence of aHUS depends on the underlying genetic abnormality. The risk is high in patients with mutations in genes encoding circulating complement proteins and regulators, whereas patients with mutations in membrane cofactor protein generally show good transplant outcome. Given the poor outcome associated with recurrence, isolated renal transplantation had been contraindicated in aHUS patients. Combined kidney-liver transplantation and prophylactic plasma exchange have been used to prevent posttransplant recurrences. More recent data have provided evidence about the efficacy of the anti-C5 monoclonal antibody eculizumab in the prevention and treatment of posttransplant aHUS recurrences. SUMMARY: This review summarizes recent advances on preventing and managing aHUS recurrence after kidney transplantation and discusses the issues that still need clarification. © 2013 Wolters Kluwer Health / Lippincott Williams & Wilkins. Source

Fagiuoli S.,Ospedale Papa Giovanni XXIII | Daina E.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | D'Antiga L.,Paediatric Hepatology | Colledan M.,Ospedale Papa Giovanni XXIII | Remuzzi G.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco
Journal of Hepatology | Year: 2013

While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management and LT results in both paediatric and adult populations of selected liver-based monogenic diseases, which represent examples of different transplantation strategies, driven by the understanding of the expression of the underlying genetic defect. © 2013 European Association for the Study of the Liver. Source

Cravedi P.,Mount Sinai School of Medicine | Remuzzi G.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | Ruggenenti P.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco
Nephron - Clinical Practice | Year: 2014

The ideal treatment of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) is still a matter of debate. This is a major issue since these patients may progress to end-stage kidney disease (ESKD) in 5-10 years. Steroids, alkylating agents, and calcineurin inhibitors have been suggested to achieve NS remission and prevent ESKD in this population. Treatment benefits, however, are uncertain and are often offset by serious adverse events (SAEs). Evidence that B cells play a crucial role in the pathogenesis of the disease, both as precursors of autoantibody-producing cells and as antigen-presenting cells, provided the background for explorative studies testing the role of B cell-depletion therapy with the monoclonal antibody rituximab. This approach aimed at selectively inhibiting disease mechanisms without the devastating consequences of unspecific immunosuppression. Finding that rituximab safely ameliorated NS in 8 patients with primary MN fueled a series of observational studies that uniformly confirmed the safety/efficacy profile of rituximab in this context. Although head-to-head comparisons in randomized clinical trials are missing, comparative analyses between series of homogeneous patient cohorts clearly show at least similar efficacy of rituximab as compared to steroid plus alkylating agents. Moreover, data confirm the dramatically superior safety profile of rituximab that actually appears to be associated with a rate of SAEs even lower than that observed with conservative therapy. Rituximab is also effective in patients resistant to other treatments and its cost-effectiveness is further increased when treatment is titrated to circulating B cells. Recently identified pathogenic antibodies against the M type phospholipase A2 receptor will likely provide a novel tool to monitor disease activity and drive rituximab therapy, at least in a subset of patients. Newly developed anti-CD20 antibodies could represent a valuable option for those who fail rituximab therapy. Steroids, alkylating agents, and calcineurin inhibitors should likely be abandoned. © 2014 S. Karger AG, Basel. Source

Ruggenenti P.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | Ruggiero B.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | Cravedi P.,Clinical Research Center for Rare Diseases Aldo e Cele Dacco | Vivarelli M.,Childrens Hospital Bambino Gesu | And 12 more authors.
Journal of the American Society of Nephrology | Year: 2014

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic,multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroidinduced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m2 intravenously).At 1 year, allpatientswere in remission: 18were treatment-free and 15 never relapsed.Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults,MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0mg/kg (IQR, 0-0.23) (P,0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2ml/min per 1.73m2 (P=0.01),with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroiddependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children. Copyright © 2014 by the American Society of Nephrology. Source

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