Atypical hemolytic uremic syndrome (aHUS) is a rare, potentially life-threatening form of thrombotic microangiopathy (TMA) and is characterized by mechanical hemolytic anemia, thrombocytopenia, and renal impairment.1–3 The estimated global annual incidence of aHUS ranges from 0.23 to 1.9 cases per million population.1 It is primarily caused by dysregulation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis, which predominantly affects the kidneys.4,5 Complement abnormalities, either acquired or inherited, have been identified in approximately 50–60% of patients with aHUS.2 Mutations in complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP) or CD46, complement component 3 (C3), complement factor B (CFB), thrombomodulin and CFH-related protein 1 and 3 (CFHR1 and CFHR3) genes or the presence of anti-CFH antibodies have been implicated in the predisposition to the onset and recurrence of aHUS.2,4,6,7 Fatigue, vomiting, dyspnea, hypertension, edema, and heart failure are some of the typical signs and symptoms of aHUS.3–5

Until the early 2010s, treatment of aHUS was limited to plasma infusion or exchange and supportive therapy such as blood pressure control and management of renal injury.5,8,9 However, plasma therapy is associated with procedural risks, risk of end-stage kidney disease, possibility of premature death, and other adverse events (AEs).5 According to the 2013 European guidelines, kidney transplantation was recommended only for aHUS patients with an MCP gene mutation or anti-CFH antibodies,10 due to the high risk of post-transplant recurrence observed in other genetic variants.6 MCP is a kidney-expressed membrane-anchored protein with <20% risk of recurrence after transplantation while anti-CFH antibodies can be managed with plasma therapy and immunosuppression.3,4,10

Recently, advances in understanding complement activation pathways and regulatory proteins led to a paradigm shift in aHUS treatment, specifically with the emergence of complement blockade therapy. Eculizumab is a humanized monoclonal antibody that binds to complement component 5 (C5), preventing its cleavage into C5a and C5b. This inhibition prevents the formation of the membrane attack complex (C5b-9) mediated by C5b.4,7 The pivotal clinical trials by Legendre et al. demonstrated the efficacy of eculizumab in improving aHUS outcomes, including improvement in renal function and TMA outcomes.11 Further, its prophylactic use in kidney transplantation has been reported to reduce the risk of recurrence.12 Although eculizumab is generally well tolerated, it requires frequent intravenous infusions, administered once a week for the first 4 weeks and once every 2 weeks as maintenance therapy thereafter.11,13 This dosing schedule may increase treatment burden and infusion-related AEs.5,14 Moreover, its high cost limits accessibility in certain healthcare settings.12 To address these limitations, ravulizumab, a modified version of eculizumab with structural changes that reduce cellular degradation and extend its half-life was developed.15

Ravulizumab has been approved by the Food and Drug Administration, European Medicines Agency, and recently by the Spanish Drug Agency for the treatment of paroxysmal nocturnal hemoglobinuria and aHUS.16–19 Pivotal studies of ravulizumab in patients with aHUS showed comparable efficacy and safety to eculizumab, with the added benefit of an 8-week dosing interval.16,20–22 Ravulizumab has also demonstrated favorable results in kidney transplant recipients who switched from eculizumab.23–27 A discrete choice experiment study of 2382 individuals across five countries reported that increasing the dosing interval from 2 to 8 weeks was a key factor in influencing treatment preference.28 Similarly, another study reported a stronger preference for ravulizumab over eculizumab due to fewer infusions and hospital visits, which provided more free time for patients and caregivers and benefit to their quality of life.14

While ravulizumab is increasingly used in aHUS management, data on its use in kidney transplant recipients, especially in Spain, remains limited. Therefore, this study in Spain aims to evaluate clinical efficacy and safety of ravulizumab in a national multicenter cohort including patients diagnosed with aHUS before or after undergoing kidney transplantation, when given as prophylaxis (de novo at the time of transplant or maintenance following switch from eculizumab) or as treatment (post-transplant aHUS).

Data were collected from 14 hospitals across Spain, in 68 patients: 35 (51.5%) women and 33 (48.5%) men, with a mean (SD) age of 46.84 (13.44) years (Table 1). Of these, 58 (85.3%) patients received kidney from deceased donors and 10 (14.7%) from living donors. Most patients had received one kidney transplant (n=44; 64.7%), while a minority had received 2 or more transplants (n=24; 35.3%). The most frequent reason for ravulizumab administration was switch (n=51; 75.0%), while 14 patients (20.6%) received ravulizumab as prophylaxis from the time of kidney transplantation and 3 patients (4.4%) received it as treatment for a post-transplant de novo episode or recurrence of aHUS. Approximately 47.1% of the patients were sensitized (cPRA>30%).

Complement genetic testing data was available for all patients, and the most frequently identified variant was factor H (n=24; 35.3%). Overall, 43 (63.2%) patients were classified as high risk, 23 (33.8%) as intermediate or moderate risk, and 2 (2.9%) as low risk (Table 1 and Fig. 2). Data on genetic variants stratified by the type of ravulizumab administration is shown in Fig. 3.

Fig. 2.

Genetic variants according to recurrence risk. C3, complement component 3; MCP, membrane cofactor protein.

Fig. 3.

Genetic variants based on the type of ravulizumab administration. C3, complement component 3; MCP, membrane cofactor protein. High risk: Factor H, C3, Factor H and MCP, C3+others. Moderate risk: Factor I, Thrombomodulin, Not found. Low risk: MCP.

Most patients received induction immunosuppressive therapy with anti-lymphocyte globulin (n=41/66; 62.1%), followed by basiliximab (n=18/66; 27.3%) and rituximab (n=1/66; 1.5%), while a minority of patients did not receive any induction therapy (n=6/66; 9.1%). The maintenance immunosuppressive regimen included immediate-release tacrolimus (n=41/67; 61.2%), extended-release tacrolimus (n=15/67; 22.4%), and LCP tacrolimus (n=11/67; 16.4%). As adjunct immunosuppression, 63 (92.6%) patients received mycophenolic acid derivatives and 5 (7.4%) received mTOR inhibitors. All patients received prednisone according to the local practice.

This national retrospective, observational, multicenter study assessed the clinical efficacy and safety of ravulizumab in adult patients diagnosed with aHUS before or after undergoing kidney transplantation. Treatment with ravulizumab over 6 months showed significant improvements in hematological and renal parameters, including hemoglobin, platelet count, serum creatinine, and eGFR. No meningococcal infections, treatment discontinuations, or deaths were reported during the study period. Our findings are consistent with the results reported in clinical trials and observational studies, including data from global registries.16,20,26,27,30

It should be noted that our study includes a substantial number of patients (n=68), which is higher than that reported in studies with eculizumab conducted in France (Zuber et al., n=52)12 or the UK (Glover et al., n=38).29 Previous studies on ravulizumab, both the German multicenter study (n=10)27 and the global aHUS registry (n=24),31 have focused on the switch population; the results of these studies were similar to our study, where stabilization of renal function and persistent hematological normalization were observed. Literature data regarding de novo ravulizumab prophylaxis are limited to isolated cases23; in this study, we present 14 cases which have demonstrated good post-transplant outcomes.

In our study, the most frequent reason for ravulizumab administration was switch (75.0%), followed by prophylaxis (20.6%), and treatment for post-transplant de novo episode or recurrence of aHUS (4.4%). This switch from eculizumab to ravulizumab is likely driven by the lower infusion frequency of ravulizumab and improved quality of life.14,28

In the switch group, disease activity remained stable over 6 months of treatment, with no statistically significant changes observed in hematological or renal parameters, including haptoglobin, hemoglobin, platelets, LDH, creatinine, eGFR, and proteinuria. These findings are consistent with data reported previously, in patients switching from eculizumab to ravulizumab, by Schönfelder et al. (retrospective study in Germany) and Gaeckler et al. (Global aHUS Registry study),27,31 reinforcing the efficacy of ravulizumab in maintaining disease control. It should however be noted that the study by Gaeckler et al. analyzed only 27 aHUS patients with kidney transplantation, with no data provided on the protocol used. Further, in our study, CH50 levels increased significantly in the switch group; however, this finding should be interpreted with caution since the data was available for only half of the patients. Notably, no significant changes were observed in any of the hematological and renal parameters in this group, likely indicating the limitations of CH50 in monitoring complement blockade. In fact, accruing evidence suggests that CH50 may not be a reliable marker for monitoring complement blockade by ravulizumab.32,33 This is possibly due to the release of C5 by ravulizumab, particularly in assays that use low pH conditions in vitro, which can lead to inaccurate results.32,33

The prophylaxis group demonstrated the most pronounced improvements in both hematological and renal parameters at 3 months and 6 months compared to baseline. Statistically significant improvements were observed in hemoglobin, platelet count, and eGFR, along with reduction in serum creatinine. These findings support the use of ravulizumab as prophylaxis to prevent post-transplant aHUS recurrence and align with the case report by Schmidt et al. which described favorable outcomes with ravulizumab prophylaxis (after switching from eculizumab) in a young kidney transplant recipient, sustained through six months of follow-up post-transplantation.23 Similar results were noted in other case reports with longer follow-up (12–22 months).24,25 The study by Busutti et al. also showed adequate complement control by ravulizumab, indicated by normal C5b-9 deposits.25

In our study, three patients received ravulizumab treatment following a post-transplant de novo episode or recurrence of aHUS. The findings for this group should be interpreted with caution given the small sample size. Improvements in renal and hematological parameters were observed; however, statistical significance was not reached, which could be explained by the small sample size and short follow-up. Prior research has shown ravulizumab to be effective in maintaining aHUS remission after kidney transplantation.23,25

Although genetic testing is not required for diagnosis of aHUS, it plays a vital role in assessing recurrence risk, disease prognosis, and guiding individualized treatment strategies.5,6 In our study, complement genetic testing data was available for all patients. Of the 68 patients in the study, no genetic variant was identified in 14 patients; however, these patients were included in the study based on their clinical profile. The majority of patients were classified in the high-risk group for recurrence. The major genetic variant detected was factor H (35.3%), which has been reported to be associated with a high risk of aHUS recurrence.6 No differences were observed among the three risk groups; further, in all three groups, stabilization or improvement of hematological parameters and renal function was confirmed.

Ten patients received kidneys from living donors in the current study and most of the clinical parameters did not differ significantly between living and deceased donor transplants. However, renal function was better in the living donor transplants as observed by the higher eGFR (p=0.02) and lower serum creatinine (p=0.07) (vs deceased donor transplants), consistent with literature suggesting better patient and graft survival outcomes in living donor transplants than deceased donor transplants.34 Our results provide further evidence that treatment with ravulizumab is safe and feasible in patients with aHUS receiving living donor renal transplant.

Ravulizumab was well tolerated across all groups. Although patients receiving C5 inhibitors are susceptible to meningococcal infections,35,36 no such cases were reported in our study. UTI was the most common infection observed in our study (24.6%), with similar rates across the three groups; the incidence was similar to that reported in other kidney transplant cohorts. In the aHUS ravulizumab pivotal trial with patients receiving ravulizumab as de novo treatment (n=8 transplant patients), Rondeau et al. reported a 17.2% incidence of UTIs within six months.20 Schönfelder et al. reported a total incidence of 27.8% in a cohort of 32 patients, 10 of whom had received a kidney transplant.27 Dixon et al. reported, among adult patients, two cases (3.4%) of UTIs and one case of pyelonephritis, although it is unclear whether these occurred in transplant recipients (n=8).21 In the 2025 global aHUS registry, Gaeckler et al. reported 10 infections (26.3%), including cases of urinary sepsis, pyelonephritis, and bacteremia.31 In earlier studies with eculizumab, Legendre et al. reported only one case of UTI (6% [n=1/17]), although it is not specified whether this was in a renal transplant patient.11 Subsequent studies by Zuber and Glover do not provide data on UTIs among safety outcomes,12,29 and focus solely on meningococcal infections.29 The UTIs in our study occurred within the first six months of ravulizumab treatment. In the prophylaxis group, the peri-transplant period was considered the most significant risk factor. Due to the small number of patients in the treatment group, we cannot draw firm conclusions; however, in the switch group, UTI incidence (10 out of 41 patients) was similar to that observed in the general transplant population.37

Overall, our study findings support the efficacy and safety of ravulizumab in patients with aHUS who have received a kidney transplant. Additionally, its extended dosing interval may reduce healthcare burden and improve quality of life, specifically among transplant recipients requiring lifelong treatment.14,28,38

An economic impact assessment was not performed in the current study. While some studies have reported that ravulizumab is cost-effective, a detailed analysis would require a different protocol from the one used in the present study. It is important to highlight that, during this period, patients received only four doses of ravulizumab (an induction dose plus three maintenance doses), which is substantially fewer than the doses required for eculizumab (four weekly induction doses and ten maintenance doses). This likely resulted in a considerable reduction in hospital resource utilization, less dependence on caregivers, and more time available for patients to dedicate to their own activities. A key strength of this study lies in the considerable number of patients included in this multicenter analysis based on a common protocol, which allowed for a robust evaluation of ravulizumab for switch, prophylaxis, and treatment of aHUS. Given that aHUS is a rare disease, this sample size is particularly notable in a real-world setting.

The limitations of the study need to be acknowledged. Comparisons with eculizumab or placebo, such as incidence of infections and formal cost analyses, were not performed since these were beyond the scope of the study; however, these could be explored in future studies. Our study lacks free C5 measurement since it is not commercially available in routine clinical practice. Additionally, the small sample size in the treatment subgroup limits inference.

Treatment with ravulizumab was effective and safe in adult patients with aHUS who underwent kidney transplantation. No cases of meningococcal infections or treatment discontinuations occurred during the study period. Our findings support the use of ravulizumab as a valid option for the first-line treatment of aHUS in renal transplant settings. In addition to its comparable efficacy and safety to eculizumab, ravulizumab offers fewer infusions which could improve quality of life and reduce treatment burden.

CFR: study design, data curation, data acquisition, statistical analysis, and data interpretation. IR, FM, EG: data acquisition, statistical analysis, and data interpretation. HTC: data acquisition and data interpretation. AM, MLPT, DR, VLJ, MOLO, AIDM, LAVS, MJGS, RHG: data acquisition. All authors read and approved the final manuscript.

This research has not received any external funding.

CFR receives consulting fees from Sobi and Novartis; receives honoraria from Alexion, Sobi, and Chiesi; and support for attending meetings and/or travel from Alexion and Chiesi.

HTC receives consulting fees from Novartis and Sobi; receives honoraria from Alexion, Novartis, and Sobi; and support for attending meetings and/or travel from Chiesi.

IR receives honoraria and support for attending meetings and/or travel from Alexion.

AM receives honoraria from Alexion, Astellas, and Chiesi; and support for attending meetings and/or travel from Chiesi and Astellas.

FM receives honoraria and support for attending meetings and/or travel from Alexion.

MOLO reports support for attending meetings and/or travel from Astellas and Chiesi.

EG, MJGS, AIDM, MLPT, RHG, LAVS, DR, and VLJ have no conflicts of interest to disclose.

The data underlying this article are available in the article and in its online supplementary material.