Successful Treatment of De Novo Posttransplant Thrombotic Microangiopathy With Eculizumab

Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by complement hyperactivation secondary to defects in complement genes and acquired autoantibodies against complement regulatory proteins (1). The clinical features include thrombotic microangiopathy (TMA), hemolytic anemia, thrombocytopenia, and acute renal failure. We present a case of this disease that was identified in a simultaneous pancreas kidney transplant recipient successfully treated with the C5a inhibitor eculizumab (Soliris; Alexion Pharmaceuticals, Connecticut). A 46-year-old man with diabetic nephropathy underwent a simultaneous pancreas kidney transplant. The organs were recovered from a 40-year-old brain stem dead donor, and the cold ischemic time for both organs was between 11 and 12 hr. The pretransplant cytotoxic and flow crossmatch were negative and both organs functioned immediately. Initial immunosuppression was with alemtuzumab given after pancreas reperfusion combined with tacrolimus and mycophenolate mofetil as maintenance therapy. On day 17, he developed pyrexia and was started empirically on meropenem. The following day, having identified a potential fungal pathogen from the organ preservation fluid, fluconazole was added and his tacrolimus therapy suspended because of an anticipated augmentation in tacrolimus level. Despite this, his tacrolimus levels increased to 68 ng/dL on day 26 with both grafts showing evidence of dysfunction (Fig. 1a). Biopsies on days 21 and 25 showed borderline and 2B rejection without evidence of complement factor 4 d subunit deposition. There was a low titer of donor reactive antibody (DQ 7 specific) on screening serology without evidence of complement factor 4 d subunit deposition. He was treated with pulsed methylprednisolone (Fig. 1a).FIGURE 1.: (a) Graph of renal and pancreas function with tacrolimus levels posttransplantation. Creatinine, μmol/L; glucose, mmol/L; tacrolimus, ng/dL. Arrows, dialysis sessions; bar, methylprednisolone 500 mg/day. B, renal graft core biopsy. On day 18, his creatinine increased in conjunction with tacrolimus levels to a peak of 1113 μmol/L and 68 ng/dL, respectively, on day 26. Biopsy results: day 21, borderline cellular rejection; day 25, vascular rejection (Banff 2b), no complement factor 4 d subunit deposition; day 41, TMA. (b) High-power detail of day 41 biopsy (Masson's trichrome stain). Oblique section through afferent arteriole with evidence of thrombosis (red, fibrin) in an afferent glomerular arteriole.His renal function continued to deteriorate; a further biopsy performed on day 41 (Fig. 1b) showed evidence of TMA. At this time, his hemoglobin was 7.5 g/dL and platelet count was 186×109/L. A blood film showed evidence of hemolysis. A diagnosis of posttransplant de novo HUS was made and treatment with plasmapheresis (PEX) initiated. Tacrolimus was switched to sirolimus, and his plasma levels of tacrolimus became undetectable on day 46. Pancreas graft function remained excellent, but despite 18 cycles of PEX over the following 3 weeks, he remained oliguric and dependent on hemofiltration to manage uremia. PEX was therefore discontinued and treatment with eculizumab initiated. Within 24 hr of the first infusion of eculizumab (900 mg), his platelet count had increased to 213×109/L and hemoglobin to 13.4 g/dL. In total, four doses of eculizumab were administered at weekly intervals, following the induction protocol of the recently reported trial of eculizumab in aHUS (2). His renal function had improved to an estimated glomerular filtration rate of 40 mL/min/1.73 m2, and currently 1-year posttransplant he has remained stable at this level. He has also remained insulin independent. Mutation screening of both the recipient and donor has not shown any abnormality in complement factor H, complement factor I, complement regulatory protein (membrane cofactor protein), complement factor B, and complement factor 3. De novo aHUS affects approximately 0.8% of patients postrenal transplantation (3) and the majority (≈80% [4]) respond to conventional therapy with PEX and calcineurin inhibitor withdrawal. TMA can be mild and localized to the graft, but in patients with systemic manifestations, there is a significant requirement for dialysis (54%) and graft loss (38%) (5). Approximately 60% of aHUS patients are found to have a mutation in complement regulation genes (6) and, as our analyses have failed to find a defect in any of these genes, we presume that our patient developed aHUS as a result of calcineurin toxicity, possibly in conjunction with other hitherto unidentified predisposing factors. Eculizumab, a humanized murine monoclonal IgG antibody that binds to the complement factor C5, has been used to treat recurrent aHUS after kidney transplant alone. Nurnberger et al. (7) reported on a patient with a complement factor H mutation who was successfully treated with a single dose of eculizumab having been diagnosed with recurrence in the early posttransplant period. To our knowledge, this is the first reported case of the successful use of eculizumab in de novo HUS and highlights an alternative to PEX when this is either unsuccessful or contraindicated. ACKNOWLEDGMENTS The authors acknowledge the support of Alexion Pharmaceuticals and provision of eculizumab. They thank Dr Majo Joachim for the biopsy picture. Colin H. Wilson 1 Alison L. Brown 1 Steve A. White 1 Timothy H.J. Goodship 1,2,3 Neil S. Sheerin 1 Derek M. Manas 1 1Institute of Transplantation The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne, United Kingdom 2Northern Molecular Genetics Service The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne, United Kingdom 3Institute of Genetic Medicine Newcastle University, Newcastle upon Tyne United Kingdom