Successful 13‐year ongoing remission with <scp>C5</scp> inhibitor therapy following renal transplant in atypical hemolytic uremic syndrome
Authors: Mariam A. Mostafa, Martin Zand, Jeremy Taylor, Peter Kouides
Journal: American Journal of Hematology (2024)

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment. Atypical HUS (aHUS) refers to cases of HUS that are caused by defects in the regulation of the alternative complement pathway and unlike other TMA are not associated with Shiga-toxin producing Escherichia coli (STEC) or ADAMTS13 deficiency. While it is a rare disorder, it has poor outcomes with mortality in up to one out of four patients and progression to end-stage renal disease (ESRD) in one out of two patients.1 The advent of complement inhibitors (eculizumab and most recently ravulizumab) in treatment of aHUS has revolutionized management and improved outcomes.2 aHUS occurs due to either genetic mutations or development of autoantibodies against complement regulating proteins, complement proteins itself, or thrombomodulin with the net result of over-activation of the alternative complement pathways and end-organ damage.1 Renal impairment in aHUS is serious with many patients requiring renal replacement therapy and/or progressing to ESRD.1 Extra-renal manifestations and complications can also occur including central nervous system (CNS) manifestations (such as seizures, drowsiness, focal neurological affection, or coma, and posterior reversible encephalopathy syndrome (PRES)), cardiac involvement (such as myocardial infarction), gangrene, pulmonary hemorrhage, gastrointestinal involvement, or even multi-organ failure.2 The complement inhibitor eculizumab has become the cornerstone of management of aHUS. Ravulizumab is a second-generation complement inhibitor with advantage of allowing longer interval of dosing. Complement inhibitor therapy has been administered in the post-renal transplant phase in aHUS patients to reduce the risk of recurrence and allograft rejection. Based on systematic review and meta-analysis of 380 aHUS patients undergoing renal transplant followed by eculizumab post-transplant, the rate of recurrence and allograft rejection, respectively, was 6.3% (95% CI: 2.8%–13.4%, I2 = 0%) and 5.5% (95% CI: 2.9%–10.0%).9 The total duration of post-transplant eculizumab in that review was 4–79 months. We now report one of the longest durations of successful C5 inhibitor therapy of 156 months (13 years) of complement inhibitor therapy following renal transplant for prevention of aHUS recurrence. This case also represents the third documented case of ravulizumab in the prevention of aHUS post-renal transplant.3, 4 We present a 21-year-old female patient without significant past medical history who presented with a partial seizure, hypertension, acute renal failure, and severe thrombocytopenia. Initial workup revealed acute kidney injury (creatinine of 8.5 mg/dL, K 2.8 mEq/L, BUN 70 mg/dL), anemia (hematocrit 19%), and thrombocytopenia (platelets 19 × 103/μL). She was found to have a microangiopathic picture with low haptoglobin (<6 mg/dL), elevated LDH (309 U/L), and schistocytes. Further workup revealed normal C3 (110 mg/dL), C4 (22 mg/dL), C5a (7.2 ng/mL), CH50 (88 U/mL), and ADAMTS13 level (128%). Her seizure was attributed to posterior reversible encephalopathy syndrome (PRES). She was diagnosed with aHUS and subsequent genetic testing identified the CFI and thrombomodulin mutations. Plasma exchange therapy and dialysis were initiated (in 2009) along with phenytoin for the seizures with marked improvement in her labs (normalization of LDH and haptoglobin). The patient continued on dialysis for ESRD. One year later, the patient had a successful living unrelated donor kidney transplant and was put on eculizumab every 2 weeks at 900 mg with immunosuppression with tacrolimus, mycophenolate, mofetil, and prednisone. The patient was kept on eculizumab for 10 years without any recurrence in aHUS with CH50 levels maintained <10% on therapy. In 2020, she was switched from eculizumab infusions every 2 weeks to ravulizumab 3300 mg every 8 weeks following an initial loading dose. The patient noticed improvement in fatigue on discontinuation of eculizumab and has since been kept uneventfully on ravulizumab for the last 3 years. aHUS is a rare but serious TMA disorder that presents with renal impairment. It is imperative to diagnose aHUS in a timely manner and begin treatment as soon as HUS/aHUS is suspected even before confirmation, given the rapid progression with high mortality and morbidity associated with delays in treatment. The advent of complement inhibitors, which received the Food and Drug Administration approval for treatment of aHUS in 2011, has created a paradigm shift in management of the disease with improved outcomes.5 Many aHUS patients undergo renal transplantation, which in the past has had a notoriously high graft failure with 50% of patients developing recurrence after transplantation and 80%–90% of those cases developing graft failure.1 Risk of recurrence after transplantation is higher in aHUS patients with certain gene mutations (C3, CFH, and CFI) and consequently, eculizumab has been used in high-risk aHUS renal transplant patients prophylactically to reduce risk of recurrence and graft failure.5, 6 THBD mutations have been documented in 5% of cases with aHUS and we report an aHUS patient with THBD mutation that underwent renal transplantation. However, studies have called into question the pathogenic potential of THBD mutations suggesting that their prevalence in aHUS reflects their prevalence in the general population.7, 8 Our patient was kept in remission from aHUS with complement inhibitor therapy for 13 years (10 years with eculizumab followed by 3 years of ravulizumab) of remission following renal transplant, the longest case documented in literature to our knowledge as well as the only documented case of aHUS with THBD mutation without relapse following renal transplant. Ravulizumab, which is a new complement inhibitor monoclonal antibody derived from eculizumab, has a longer half-life that allows for administration once every 8 weeks compared to once every 2–3 weeks as in eculizumab.2 The major reported side effects of ravulizumab are headache, diarrhea, and vomiting. Our patient was switched from eculizumab to ravulizumab, which has been maintained for 3 years presently without recurrence of aHUS or development of adverse effects. Incidentally, our case is only the third documented case of aHUS managed with ravulizumab in the setting of renal transplant with only two other documented cases.3, 4 While the current standard of care for aHUS is indefinite therapy with complement inhibitors, this long-term maintenance approach is associated with issues for patients including frequent visits for infusion, financial toxicity, as well as an increased risk of infection. Consequently, there is a growing number of cases reported in the literature of aHUS in remission in which complement inhibitors have been discontinued. In a prospective study by Fakhouri et al., 55 patients (including 19 children) with aHUS discontinued complement inhibitors with almost a quarter of patients (13 patients, 23%) experiencing relapse of whom 11 regained baseline kidney functions while two developed worsening in baseline chronic kidney disease, one of whom progressed to ESRD.8 Chaturvedi et al. reported on another cohort of aHUS in which complement therapy was discontinued. Of the 17 patients with clinician-directed discontinuation due to clinical remission, two patients experienced recurrence (11.1%).9 However, both studies did not include patients with renal transplantation. Another study reviewed the literature for all aHUS cases who discontinued complement therapy and found that of the 280 patients analyzed, the relapse rate was 29.6% with relapse independently associated with CFH variants, MCP/CD46 variants, renal transplant, and decreasing age. Of the 280 cases reported, 25 cases had renal transplantation and while specific data were not reported separately regarding outcomes in patients with renal transplant, three patients had allograft loss in the cohort upon eculizumab discontinuation and the odds ratio of relapse in the multivariable logistic regression model was 4.287 (95% CI 1.428–12.866).10 Consequently, given the paucity of data on discontinuation of complement inhibitors in renal transplant patients as well as the existing data that suggest relapse rate is high in renal transplant patients and in CFI mutation, we decided to continue complement inhibitor therapy indefinitely for our patient. In summary, management and prognosis of aHUS has dramatically improved in the era of complement inhibitors. Our case highlights the successful long-term use of complement inhibitors in patients with aHUS following renal transplantation. While there is increasing interest in discontinuation of complement inhibitor therapy, existing reports show increased risk of aHUS relapse in patients with renal transplant and further studies are needed to clearly delineate risk of relapse in this population. All authors contributed to writing and editing of the manuscript. The authors declare that they have no conflict of interest. Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient. Data sharing is not applicable to this article as no new data were created or analyzed in this study.