Combination of everolimus with calcineurin inhibitor medication resulted in post-transplant haemolytic uraemic syndrome in lung transplant recipients—a case series

Combination of everolimus with calcineurin inhibitor medication resulted in post-transplant haemolytic uraemic syndrome in lung transplant recipients—a case series Svjetlana Lovric1,*, Jan T. Kielstein1,*, Daniel Kayser1, Verena Bröcker2, Jan U. Becker2, Marcus Hiss1, Mario Schiffer1, Urte Sommerwerck3, Hermann Haller1, Martin Strüber4, Tobias Welte5 and Jens Gottlieb5 1 Department of Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany, 2Department of Pathology, Hannover Medical School, Hannover, Germany, 3Department of Respiratory Medicine, Ruhrlandklinik, Essen, Germany, 4 Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany and 5 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany Correspondence and offprint requests to: Jan T. Kielstein; E-mail: *Both authors contributed equally to this work. Abstract Background. Post-transplant haemolytic uraemic syndrome (HUS) is a rare but serious disease with a high mortality rate, when left untreated. Immunosuppressive drugs like calcineurin inhibitors as well as mammalian tar- get of rapamycin inhibitors have been reported as causative agents for post-transplant HUS. Methods. A retrospective observational study was performed in lung transplant recipients, who took part in an
The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: Nephrol Dial Transplant (2011) 26: 3032–3038 doi: 10.1093/ndt/gfq842 Advance Access publication 10 February 2011 Post-transplant HUS in lung transplant recipients Keywords: adverse effects; everolimus; lung transplantation; posttransplant haemolytic uraemic syndrome; thrombotic microangiopathy Introduction The term ‘thrombotic microangiopathy’ (TMA) describes a variety of pathological conditions characterized by thrombosis in capillaries, arterioles and arteries. The process leads to thrombocytopaenia and symptoms, such as anaemia, purpura and renal failure. Major categories of TMA are haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS is characterized by the appearance of several clinical and laboratory findings, such as microangiopathic haemolytic anaemia, thrombocytopaenia and acute renal failure due to endothelial cell injury with consecutive platelet aggregation and development of intravascular microthrombi in the affected organs. In addition, several neurologic abnormalities and fever can be observed in some patients. The incidence of TMA is 11 cases/million population/year [1]. HUS can be classified into typical and atypical (tHUS and aHUS, respectively). tHUS is associated with Shiga toxin-producing entaerohaemorrhagic Escherichia coli, predominantly in children. The causes of aHUS are variable and include drug toxicity, autoimmune diseases, pregnancy and postpartum and HIV Infection. Furthermore, mutations of complement factors can be found in aHUS. Mutations of complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP) deficiency [2, 3], complement factor B (CFB) and C3, which promote alternative pathway activation have been reported. Also, in ~5% of patients with aHUS, mutations occur that impair the function of thrombomodulin [4]. Not only mutations in the complement system but also genetic polymorphisms are associated with HUS. These polymorphisms were found for CFH-related proteins (CFHR), C4b-binding protein (C4b-BP), MCP and CFH genes. Some drug-induced forms of post-transplant HUS can be triggered by immunosuppressive agents such as cyclosporine and sirolimus [5]. Young recipient age, older donor age, female gender and immunosuppressive regimens including tacrolimus or cyclosporine are predictors of post-transplant HUS after transplantation [6, 7]. The combination of sirolimus and cyclosporine seems to play a major role in the development of post-transplant HUS. The exact pathogenesis of this phenomenon remains unclear. Cyclosporine may increase platelet aggregation, but direct endothelial cell injury seems to be the most important step in this setting. In reference to everolimus, a similar mechanism is certainly possible, however, there is no evidence of an endothelium damaging or blood clotting effect [8]. Posttransplant HUS can be diagnosed based on clinical and laboratory findings, such as anaemia, thrombocytopaenia, elevated lactate dehydrogenase (LDH), decreased haptoglobin and the presence of schistocytosis in peripheral blood smear. In addition, renal function parameters, blood pressure and urine excretion should be monitored. So far, there are various reports of cyclosporine-, tacrolimus- or sirolimus-induced TMA. An increased risk of post-transplant HUS associated with the combination of cyclosporine and everolimus has not been reported in lung transplantation. However, two studies showed unexplained anaemia in liver- and kidney-transplanted patients treated with mammalian target of rapamycin (mTOR) inhibitors [9, 10]. Therefore, we retrospectively searched our database on lung transplant patients for a possible link between everolimus and HUS. Patients and treatment We report a series of five lung transplant recipients who were admitted to two tertiary care centres in a period of 12 months with a newly diagnosed severe impairment of renal function of unknown etiology. Two to twentyfour months prior to admission, the patients had undergone lung transplantation. The initial immunosuppressive regimen after lung transplantation in all these patients included cyclosporine, mycophenolate mofetil (MMF) and prednisolone. Four weeks after transplantation, patients were switched to everolimus in combination with a calcineurin inhibitor or remained on standard immunosuppression with cyclosporine, MMF and prednisolone. Target trough levels of cyclosporine in conjunction with MMF were 200– 250 ng/mL during the first postoperative year, 150–200 ng/mL during the second year and 100–150 ng/mL thereafter. Everolimus target trough levels were 5–7 ng/mL. Prednisolone was tapered in all recipients during the first 3 postoperative months to a maintenance dose of 0.1 mg/kg there after. The immunosuppressive therapy and patient characteristics are shown in Table 1. Furthermore, the patients were treated with anti-infective prophylaxis after lung transplantation including acyclovir, itraconazole and cotrimoxazole. Disease was assessed on clinical and laboratory findings. Post-transplant HUS was assumed if haemolytic anaemia, thrombocytopaenia, deteriorating renal function with elevated LDH, decreased haptoglobin and schistocytosis in peripheral blood smear were evident or renal biopsy interventional study, in two centres. Haemoglobin, platelets, creatinine and lactate dehydrogenase levels were monitored during routine follow-up and patients with deteriorating kidney function were screened for post-transplant HUS. All (...truncated)