Extrarenal manifestations of atypical hemolytic uremic syndrome: a systematic review and meta-analysis

Background: Atypical Hemolytic Uremic Syndrome (aHUS) is categorized as a thrombotic microangiopathy (TMA), which arises due to abnormal or unregulated complement pathway activation. While the disease frequently affects renal blood vessels, it can also involve multiple other organ systems. This review examines the prevalence and clinical outcomes of aHUS patients with extrarenal involvement.

Methods: A comprehensive literature search was performed using PubMed/Medline, Embase, the Web of Science Core Collection, and CINAHL. Search terms included 'aHUS', 'extrarenal', and specific organ systems such as neurological, gastrointestinal, and cardiovascular. Patient data was collected on clinical characteristics, including extrarenal symptoms, lab findings, genetic mutations, and adverse events. Meta-analysis was conducted using R software, version 3.1.0.

Results: A total of 47 studies were reviewed, comprising 890 aHUS patients, ranging in age from 3 months to 66 years. Common genetic abnormalities included factor H (CFH) mutations, seen in 12% (84/700 patients) across 19 studies, and anti-FH IgG autoantibodies, identified in 27.1% (102/376 patients) from 10 studies. The central nervous system was the most frequently involved extrarenal site [28% (240/858 patients) from 32 studies], with seizures as the predominant CNS symptom. Gastrointestinal symptoms were next most common [31% (230/741 patients) from 25 studies], followed by cardiovascular involvement [16% (97/607) from 23 studies]. Kidney failure was reported in 13.2% (61/463 patients) from 11 studies, with an overall mortality rate of 8.9% (56/632 patients) reported across 27 studies.

Conclusions: Around 20-30% of aHUS patients experience extrarenal manifestations, with neurologic symptoms occurring most frequently. Due to the high costs and limited availability, genetic data is rarely reported, and studies are often small, underscoring the need for larger, multi-center cohort studies.

Prospero registration: 466915.

Impact: Approximately 20-30% of patients with atypical Hemolytic Uremic Syndrome (aHUS) experienced extrarenal manifestations, with neurologic involvement being the most common. Current studies in aHUS patients are heterogeneous and inconsistent in reporting complement mutations with extrarenal manifestations. This systematic review highlights the significance of multi-system assessment in aHUS patients and the need for larger, multi-centered cohort studies.