aHUS

- Introduction

Unlike typical HUS, which is often associated with Shiga toxin-producing Escherichia coli infections, aHUS is primarily linked to dysregulation of the alternative complement pathway [1]. This uncontrolled activation leads to systemic thrombotic microangiopathy (TMA), resulting in widespread microvascular thrombosis and subsequent organ damage, particularly in the kidneys [2]. Kidneys are the main target organs of HUS, with fibrin and platelet thrombi in glomerular capillaries, endothelial cell swelling, detachment from the glomerular basement membrane, and consequent severe renal impairment [3].

The etiology of aHUS is multifactorial, involving both genetic and acquired factors. Genetic dysregulation of the alternative complement pathway, resulting in endothelial cell dysfunction and microvascular thrombi formation, can be identified in 40–60% of aHUS patients [4]. This dysregulation follows mutations in genes coding for complement regulatory proteins, such as factor H (CFH), factor I (CFI), membrane cofactor protein (MCP), complement 3 (C3), factor B (CFB), or thrombomodulin (THBD), or by the presence of anti–complement factor H (anti-CFH) antibodies with consequent hyperactivation of the complement system [5].

Genetically determined aHUS can be familial or sporadic. The familial form represents about 20% of cases and it is defined by at least two members of the same family being diagnosed with aHUS in a maximum period of 6 months [6]. Genetic mutations predisposing to aHUS can be inherited in either an autosomal dominant or autosomal recessive manner or, rarely, as polygenic inheritance [6].

The development of aHUS is multifactorial. In fact, a second hit is necessary for the disease to manifest itself: different triggers are associated such as drugs (cisplatin, gemcitabine, mitomycin, clopidogrel, quinine, interferon-alfa/beta, anti-vascular endothelial growth factor, alemtuzumab, cyclosporin tacrolimus, ciprofloxacin, oral contraceptives, and vaccines) [6], infections (such as influenza, SARS-CoV-2), malignant hypertension, and pregnancy [7]. All these factors can lead to an onset of aHUS in genetically predisposed individuals. Generally, mutations affect a single gene; however, the combination of two or more mutations has been described in about 12% of patients [6].

Atypical hemolytic uremic syndrome (aHUS) is classified as an ultra-rare disease. Estimates suggest an annual incidence ranging from 0.23 to 1.9 cases per million people globally [8]. The prevalence is challenging to ascertain due to underdiagnosis and misclassification; however, some studies estimate it to be approximately 2 to 9 cases per million population. These figures underscore the rarity of the condition and the necessity for heightened clinical awareness.

The clinical burden of aHUS is substantial. Patients often experience severe complications, including chronic kidney disease, hypertension, neurological deficits, and cardiovascular events [9,10]. The disease's unpredictable nature and potential for rapid progression to end-stage renal disease necessitate intensive medical interventions, including plasma exchange, dialysis, and, in some cases, kidney transplantation [11]. These treatments not only impose significant physical and emotional strain on patients and families but also contribute to considerable healthcare expenditures.