Background <p>Antibodies to factor H (anti-FH) are a leading cause of atypical hemolytic uremic syndrome (aHUS) in school-going children. While terminal complement blockade with eculizumab (ECZ) is standard of care for all forms of aHUS, anti-FH associated aHUS is uniquely amenable to combination therapy with plasma exchange (PEX) and immunosuppression. There are no controlled comparisons on the relative short- or medium-term efficacy of the two strategies of management.</p> Objectives <p>The primary objectives were to compare the time from initiation of therapy to hematological remission and renal recovery between patients managed with PEX versus ECZ, with or without immunosuppression, for anti-FH associated aHUS in native kidneys. We also compared the proportions of patients attaining hematological remission or renal recovery by 7, 14 and 28&#xa0;days of therapy, and proportion of patients with chronic kidney disease G1–5, dialysis-dependence, or death. </p> Data sources <p>PubMed and Embase were searched from January 2004 to April 2025. </p> Study eligibility criteria <p>Studies, in English language, were eligible if they reported the time to hematological remission and renal recovery in individual patients with anti-FH antibody-associated aHUS in native kidneys and treated with either PEX or ECZ with or without additional immunosuppression. </p> Participants and interventions <p>Within studies, individual patients were included if they had received either, and not both, PEX or ECZ, and information regarding time to hematological remission and renal recovery was available. </p> Study appraisal and synthesis methods <p>The risk of bias for retrospective cohort studies and case reports or series was assessed using the Newcastle–Ottawa Quality Assessment Scale and Joanna Briggs Institute (JBI) tool for systematic reviews, respectively. Individual patient data were combined by therapy group to report time-to-event outcomes as hazard ratios (95% confidence intervals, CI), compared using the log rank test. Other continuous measures were compared between groups using the rank sum test. </p> Results <p>Fourteen of 57 studies shortlisted from among 403 search results met eligibility criteria, within which 99 patients, including 81 managed with PEX and 18 with ECZ, with/without immunosuppression, were eligible. Patients receiving PEX presented later with more severe anemia and lower eGFR, and more often required dialysis. Median time to hematologic remission was significantly shorter with PEX (9 vs. 20&#xa0;days; <i>P</i> = 0.0007) while time to renal recovery was similar (16 vs. 20&#xa0;days; <i>P</i> = 0.36).&#xa0;The proportion with CKD G3–5 and mortality was insignificantly higher with PEX than ECZ (respective <i>P</i> 0.077 and 0.36). </p> Limitations <p>Our findings are limited by small numbers of participants and studies, lack of comparative studies, heterogeneity in disease severity, and variations in definitions of outcomes. </p> Conclusions and implications of key findings <p>Patients managed with PEX achieved hematological remission faster than those on ECZ; the time to renal recovery was similar. Given the precautions and vigilance necessary with complement blockade, PEX appears to be a satisfactory initial choice for managing anti-FH associated HUS, particularly in low-resource settings. Prospective trials should compare the efficacy, safety and healthcare costs of these strategies in managing patients with anti-FH associated HUS.</p> Systematic review registration number <p>PROSPERO ID: CRD420251033150.</p> Graphical abstract <p></p>