Complement. First of two parts.

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

/pdf/horror-autoinflammaticus-the-molecular-pathophysiology-of-16vahq02rm.pdf

Horror Autoinflammaticus: The Molecular Pathophysiology of Autoinflammatory Disease

This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs.

/pdf/syndromes-of-thrombotic-microangiopathy-3pa0wmv320.pdf

Syndromes of Thrombotic Microangiopathy

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

https://www.kidney-international.org/article/S0085-2538(15)30481-6/pdf

Genetic studies into inherited and sporadic hemolytic uremic syndrome

Several recent studies have established an association between abnormalities of complement factor H (FH) and the development of hemolytic uremic syndrome (HUS). To identify the relative importance of mutations in FH as a cause of HUS, we have undertaken mutation screening of the FH gene in 19 familial and 31 sporadic patients with FH. Mutations were found in two familial and three sporadic patients, and these clustered in exons 18–20, a domain important for host recognition. Moreover, this study demonstrates that familial HUS is likely to be a heterogeneous condition.

Factor H Mutations in Hemolytic Uremic Syndrome Cluster in Exons 18–20, a Domain Important for Host Cell Recognition

Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.

Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor

the first, aVected individuals, particularly siblings usually residing in regions geographically related to outBackground. In a recent study of three families we have found that inherited haemolytic uraemic syn- breaks of HUS, suVer disease within days or weeks of each other and temporally related to the outbreak. It drome (HUS ) maps to a region of chromosome 1q containing the gene for complement factor H. In one is likely that an infectious agent is responsible. The second familial form of HUS occurs at diVerent times of these families and also in a case of sporadic DHUS, we have identified mutations in the factor H implying an inherited predisposition. In this form prognosis is poor, mortality is high (often over 50%) gene. A further family with inherited HUS has therefore been investigated. and recurrence is not uncommon. In a recent study of three families, we have found that inherited HUS maps Methods. DNA extracted from the family members and DNA extracted from archival post-mortem mat- to a region of chromosome 1q containing the gene for complement factor H. In one of these families, and erial from a deceased family member, was studied. Review of renal biopsies and study of complement also in a case of sporadic D-HUS, we have identified mutations in the factor H gene [2]. components was also undertaken. Results. This family demonstrates an inherited defi- We now present a further family in which an inherited deficiency of complement factor H is associated ciency of complement factor H. Non-diarrhoeal HUS has aVected at least two family members with half with HUS. normal levels of factor H. Conclusion. These findings represent further evidence of the association between factor H dysfunction and Family pedigrees and case histories (Figure 1) HUS. II-4 (Index case)

Rosemary L. Donne

Papers

Genetic studies into inherited and sporadic hemolytic uremic syndrome

Factor H Mutations in Hemolytic Uremic Syndrome Cluster in Exons 18–20, a Domain Important for Host Cell Recognition

Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.

Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor

Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency.