Atypical Hemolytic Uremic Syndrome

With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.

Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches.

BackgroundAtypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes.MethodsWe conducted a nationwide epidemiological survey of clinically diagnosed aHUS patients and examined 118 patients enrolled from 1998 to 2016 in Japan. We screened variants of seven genes related to complement and coagulation, as well as positivity for anti-CFH antibodies, and assessed clinical manifestations, laboratory findings, and clinical course.ResultsThe most frequent genetic abnormalities were in C3 (31%) and the frequency of CFH variants was relatively low (10%) compared to Western countries. The predominant variant in this cohort was C3 p.I1157T (23%), which was related to favorable outcomes despite frequent relapses. A total of 72% of patients received plasma therapy, while 42% were treated with eculizumab. The prognosis of Japanese aHUS patients was relatively favorable, with a total mortality rate of 5.4% and a renal mortality rate of 15%.ConclusionsThe common occurrence of genotype C3, especially the p.I1157T variant was the characteristic of the genetic backgrounds of Japanese aHUS patients that differed from those of Caucasian patients. In addition, the favorable prognosis of patients with the unique C3 p.I1157T variant indicates that understanding the clinical characteristics of individual gene alterations is important for predicting prognosis and determining therapeutic strategies in aHUS.

BackgroundPregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare, life-threatening condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, elevated liver enzymes, and acute kidney injury. Prompt diagnosis and therapy are crucial due to the high risk of progression to chronic kidney disease (CKD), end-stage kidney disease (ESKD), and dialysis dependency, as well as significant maternal and fetal morbidity and mortality.MethodsA comprehensive literature search was conducted across EMBASE, MEDLINE, and the Cochrane CENTRAL from January 2000 to March 2024. Studies reporting on pregnancy and kidney outcomes in women diagnosed with p-aHUS were included.ResultsTen studies involving 386 pregnancies in 380 patients met the inclusion criteria for the final analysis. Renal outcomes varied, with mean creatinine levels ranging from 0.72 to 8.734 mg/dL. Dialysis was required in 66.6% of patients, and 25% developed ESKD. Maternal complications included preeclampsia (36.4%) and hemolysis, elevated liver enzymes, and low platelets syndrome (29.7%), with a 5% maternal mortality rate. Fetal complications included intrauterine fetal demise (n = 25), intrauterine growth restriction, low birth weight, and prematurity. Treatment with eculizumab significantly reduced the risk of CKD and ESKD, with a pooled risk ratio of 0.20 (95% confidence interval: 0.09-0.44) and low heterogeneity (I² = 0%, P = .43).ConclusionThis analysis highlights the severe kidney and pregnancy outcomes associated with p-aHUS. Eculizumab treatment is significantly beneficial in reducing the risk of CKD and ESKD.