Atypical hemolytic-uremic syndrome (aHUS) is a microangiopathic thrombotic syndrome with a prominent renal involvement. So far, plasma exchange has been the usual treatment although it currently only has a category III indication (not clearly indicated) according to American Society for Apheresis (1). Despite the adult onset, 50% cases are related to mutations in regulatory complement proteins (complement factor H [CFH], factor I, membrane cofactor protein, CFH-related proteins, and C4b-binding protein) (2). Gain-of-function mutations in genes encoding factor B and C3, which promote alternative pathway activation, and antibodies against CFH have been observed in less than 10% of patients. Recently, mutations in the membrane protein, thrombomodulin, have been found in 5% of patients suffering from aHUS (3). A “second hit” event, such as pregnancy, drugs, or infections, seems to be needed to develop aHUS in the presence of some mutations. The current knowledge suggests that because of the deregulated activation of alternative pathway of complement on the normal endothelial cell surfaces, a cascade of inflammation and thrombosis is generated with a subsequent microangiopathic anemia hemolytic, thrombocytopenia, and acute renal failure (4). The recurrence rate of aHUS after renal transplantation is high (20%–80%) and prognosis is poor with a high risk of graft loss (5). A hypothetical utility of complement blockage was supposed and eculizumab, a humanized antibody against C5a approved for paroxysmal nocturnal hemoglobinuria, has been assayed in patients with congenital (6) and adult-onset HUS with mutations in gene encoding CHC (7, 8). However, in another patient with relapsing unclassified aHUS, eculizumab was able to inhibit microangiopathic hemolytic process, but renal damage could not be prevented and end-stage renal failure developed in the patient. The authors suggest that therapeutic success may depend on early administration of eculizumab (9). Here, we report a 22-year-old woman suffering from recurrent aHUS after kidney transplantation with no mutation in complement regulatory proteins who also responded to just one dose of eculizumab. At the age of 20 years, she presented with postpartum aHUS, confirmed by biopsy. Despite 23 packed red blood cell units transfusion, corticoids, and plasma exchange, she finally developed an end-stage renal disease and began hemodialysis. Twenty-six months later, she received a non–heart-beating donor renal transplantation. At that moment, panel reactive antibodies were negative by complement-dependent cytotoxicity. She received induction therapy with thymoglobulin, enteric-coated mycophenolate sodium, sirolimus, and prednisone. The clinical evolution was successful with creatinine levels at discharge of 1.1 mg/dL. Twelve days after transplantation, aUHS recurred in the clinical context of fever and diarrhea. The creatinine level was 1.8 mg/dL, lactate dehydrogenase level was 4272 UI/L, platelets of 91×109/L, and hemoglobin of 113 g/L with six to nine schistocytes per high-power field. Haptoglobin was below technique detection level. ADAMTS-13 activity in plasma was normal and no inhibitory effect was detected. Renal function worsened with creatinine levels reaching 4.7 mg/dL. Renal allograft biopsy showed features of thrombotic microangiopathy in glomeruli and C4d staining of the biopsy was negative. C3 and C4 levels were normal. No mutations were identified in factor H, factor I, and membrane complex proteins genes. The patient was homozygous for H3 factor H; a gene associated to a higher risk of suffering from USH. Five daily plasma exchanges were initiated, sirolimus was stopped and tacrolimus was introduced. But, persistent thrombocytopenia (41×109/L) and progressive impairment of hemolytic anemia (nadir hemoglobin of 58 g/L) with transfusion requirements was observed. In the context of severe recurrent aHUS, the administration of a single dose of 600 mg of eculizumab was decided. After 36 hours of the administration, the hemolysis started to decrease and platelet count increased. Four days later, renal function and platelet count were normal (Fig. 1). Seven months after treatment, her renal function, hemoglobin, and platelet count are normal; no signs of hemolysis are present without any treatment in relation to aHUS.FIGURE 1.: Response to eculizumab in a case of recurrent atypical hemolytic uremic syndrome. The graphs show the time course of the platelet count and laboratory values used to determine the occurrence of hemolysis and renal function. After diagnosis of recurrent atypical hemolytic-uremic syndrome after renal transplantation, plasma exchange was performed five times (vertical black bars indicate treatments). Despite this treatment, atypical hemolytic-uremic syndrome was aggravated. A single dose of 600 mg of eculizumab was administered on 3rd April 3 (arrow). After treatment with eculizumab, creatinine, lactate dehydrogenase (LDH), and platelet count levels normalized in 96 hr. Seven months after, the patient is still in remission.In the patient reported here as in the report by Nürnberger et al., an early single dose of eculizumab was able to induce a sustained disappearance of the microangiopathic hemolytic process and a full recovery of kidney function well after the expected half-life in the circulation of the humanized antibody (11.3±3.4 days) (10). These findings support the potential role of eculizumab in the treatment of aHUS even when no mutations in the complement regulatory proteins are present. Carlos Fernández-de Larrea1 Frederic Cofan2 Federico Oppenheimer2 Josep Maria Campistol2 Gines Escolar1 Miguel Lozano1 1 Department of Hemotherapy and Hemostasis Hospital Clinic, IDIBAPS University of Barcelona Barcelona, Spain 2 Renal Transplantation Unit Hospital Clinic, IDIBAPS University of Barcelona Barcelona, Spain
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Jan 16, 2024
Jaehoon Shin + 9
