The hemolytic–uremic syndrome, which is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment, occurs most frequently in young children. Most cases are secondary to infection with Escherichia coli O157:H7 and other Shiga-toxin–producing strains. However, approximately 10% of cases are atypical and not associated with infection. This article reviews current concepts about the pathobiology of atypical hemolytic–uremic syndrome and its diagnosis and management.

https://www.nejm.org/doi/suppl/10.1056/NEJMra0902814/suppl_file/nejm_noris_1676sa1.pdf

Atypical Hemolytic–Uremic Syndrome

The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us We define six categories of autoinflammatory disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside

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Horror Autoinflammaticus: The Molecular Pathophysiology of Autoinflammatory Disease

Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin–producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS. Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases. Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H ( CFH ) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein ( MCP ) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH , C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations. Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

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Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.

Summary Background and objectives Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease that was first recognized in children but also affects adults. This study assessed the disease presentation and outcome in a nationwide cohort of patients with aHUS according to the age at onset and the underlying complement abnormalities. Design, setting, participants, & measurements A total of 214 patients with aHUS were enrolled between 2000 and 2008 and screened for mutations in the six susceptibility factors for aHUS and for anti–factor H antibodies. Results Onset of aHUS occurred as frequently during adulthood (58.4%) as during childhood (41.6%). The percentages of patients who developed the disease were 23%, 40%, 70%, and 98% by age 2, 18, 40, and 60 years, respectively. Mortality was higher in children than in adults (6.7% versus 0.8% at 1 year) ( P =0.02), but progression to ESRD after the first aHUS episode was more frequent in adults (46% versus 16%; P Conclusion Mortality rate was higher in children than adults with aHUS, but renal prognosis was worse in adults than children. In children, the prognosis strongly depends on the genetic background.

/pdf/genetics-and-outcome-of-atypical-hemolytic-uremic-syndrome-a-192g9zcfvt.pdf

Genetics and Outcome of Atypical Hemolytic Uremic Syndrome: A Nationwide French Series Comparing Children and Adults

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

Mutations in Complement Factor I Predispose to Development of Atypical Hemolytic Uremic Syndrome

Background. The AshSplit catheter has recently been introduced as an alternative permanent tunnelled haemodialysis catheter, combining ease of insertion with good long-term patency and flow rates. Methods. Data were collected prospectively on all the long-term tunnelled haemodialysis (AshSplit) catheters inserted radiologically between January 1998 and March 1999. Information was obtained regarding the initial insertion, ongoing catheter function and re-intervention up to September 1999. Results. A total of 118 catheters were inserted in 88 patients (50 male), median (range) age 64 (20‐86) years. Ultrasound guidance was used routinely and the right internal jugular vein was used in 80 (68%) cases. Initial complications occurred in 14 (11.9%) cases, which included local haemorrhage, carotid artery puncture, and air embolism. Infection occurred in 34% of catheters (2.4u1000 catheter days). Line thrombosis was documented in 20% (1.2u1000 catheter days). Satisfactory mean urea reduction ratio (URR) of 63 was obtained for all catheters. There were 47 re-interventions, mainly for fibrin sheath stripping (34) anduor thrombectomy (25). Total catheter duration was 21600 days with a 1 month cumulative survival of 87% (Kaplan‐Meier probability 85%). At the end of the study, 20 (17%) catheters were still functioning, 39 (33%) had been removed electively, and 22 (18%) patients had died with a functioning catheter in situ. Catheter infection was implicated in four deaths. Conclusions. Radiological insertion of the AshSplit catheter is well tolerated, providing reliable shortand long-term dialysis access. Radiology also has a role in maintaining patency. As with all tunnelled catheters, infection remains a problem.

Radiological placement of the AshSplit haemodialysis catheter: a prospective analysis of outcome and complications

Pure red-cell aplasia (PRCA) is an uncommon condition. It has been reported to occur in dialysis patients following recombinant erythropoietin therapy, initiated for treatment of anaemia of chronic renal failure [1–3]. In those patients, anti-erythropoietin antibodies have been recorded. Little is known of the natural history of this disease or the safest, most efficacious therapy. Here we describe a patient with only moderate renal impairment, who also developed epoetin-induced PRCA. Initial bone marrow histology failed to make a clear diagnosis. There was no spontaneous remission, but the patient was managed successfully with lowdose cyclosporin alone without compromising renal function.

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Low-dose cyclosporin therapy for recombinant erythropoietin-induced pure red-cell aplasia

/pdf/exercise-induced-anuria-in-a-renal-allograft-recipient-2ejt5uzvb6.pdf

Robin J. Winney

Papers

Mutations in Complement Factor I Predispose to Development of Atypical Hemolytic Uremic Syndrome

Radiological placement of the AshSplit haemodialysis catheter: a prospective analysis of outcome and complications

Low-dose cyclosporin therapy for recombinant erythropoietin-induced pure red-cell aplasia

Exercise‐induced anuria in a renal allograft recipient