Atypical Hemolytic Uremic Syndrome: New Challenges in the Complement Blockage Era

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

“…In the majority of patients diagnosed before 16 years of age, aHUS is a rare disease that presents with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure ( 64 ) with a prevalence of 2.2–9.4 per 1,000,000 ( 88 ). A number of genetic deficiencies of complement components lead to impaired regulation of the alternative pathway, either through loss-of-function mutations of regulating proteins, i.e., CFH or CFI, or through gain-of-function mutations of C3, leading to reduced affinity of CFH, or complement factor B, forming a hyperactive C3 convertase, thereby overwhelming regulatory capacity ( 89 ). Moreover, certain genetic variants of CFH induce generation of autoantibodies that neutralize CFH and prevent complement regulation ( 90 ).…”

Genetic atypical hemolytic uremic syndrome in children: a 20-year experience from a tertiary center

“…Treatment with eculizumab reduces CH50 activity below 10% (expected response). CH50 assay is widely available, but it has serious disadvantages as the high diversity between the different tests and a trend to the variability of CH50 in the low range, which limit its clinical utility 6 . One of the most controversial issues concerning the use of eculizumab on aHUS is the duration of therapy.…”

“…In recent years, aHUS has been found to be associated with genetic or autoimmune abnormalities leading to dysregulation of the alternative complement pathway on the surface of the vascular endothelium 1 , 3 . In almost 60% of aHUS patients, mutations in genes encoding complement-regulating proteins are reported, either resulting in loss of function in a complement regulatory gene or in gain of function in an effector gene 1 , 6 . Mutations in 6 genes have been associated with increased susceptibility for aHUS - complement factor H (CFH), complement factor B, complement factor I, membrane cofactor protein (MCP), C3, and thrombomodulin.…”

“…Therapeutic plasma exchange (TPE) was the mainstay of treatment for aHUS until 2014, when new data reveled considerable morbidity associated with plasma therapy in children along with eculizumab approval. Since then, several studies have demonstrated that effective terminal complement blockade with eculizumab can rescue native kidney function and allow successful kidney transplantation after renal function loss due to aHUS 6 , 7 .…”

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

“…Hemolytic-uremic syndrome (HUS) is an ultra-rare disease defined by the triad of mechanical hemolytic anemia, thrombocytopenia, and acute kidney injury (Avila Bernabeu et al, 2020). Typical forms of HUS are related to infection by Shiga toxin-producing E. coli, whereas the atypical form of HUS termed aHUS is due to defects in alternative complement activation pathway (Avila Bernabeu et al, 2020). In 50%-60% of aHUS cases, genetic variants in proteins regulating the alternative pathway of complement are found, but it is a clear consensus that absence of molecular finding does not exclude an alternative pathway deregulation.…”