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

Svjetlana Lovric 2 3 Jan T. Kielstein 2 3 Daniel Kayser 2 3 Verena Bro cker 1 2 Jan U. Becker 1 2 Marcus Hiss 2 3 Mario Schiffer 2 3 Urte Sommerwerck 0 2 Hermann Haller 2 3 Martin Stru ber 2 5 Tobias Welte 2 4 Jens Gottlieb 2 4 0 Department of Respiratory Medicine , Ruhrlandklinik, Essen, Germany 1 Department of Pathology, Hannover Medical School , Hannover, Germany 2 The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions , please 3 Department of Medicine, Division of Nephrology and Hypertension, Hannover Medical School , Hannover, Germany 4 Department of Respiratory Medicine, Hannover Medical School , Hannover, Germany 5 Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School , Hannover, Germany 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 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 cases of post-transplant HUS were identified by clinical and laboratory findings. Outcome was recorded until 6 months after diagnosis. Results. A total of 2188 visits in 512 lung transplant recipients (outpatients) were analysed. Out of those, 126 patients took part in an interventional study. In this study, 67 were switched to everolimus in combination with calcineurin inhibitors 4 weeks after transplantation, 59 patients remained on standard immunosuppression (calcineurin inhibitors, mycophenolate mofetil and prednisolone). Five cases of post-transplant HUS were identified in the everolimus group. None of the patients had evidence of gastrointestinal infection or preexisting renal disease. Posttransplant HUS was treated with therapeutic plasma exchange and methylprednisolone pulse therapy. Everolimus was discontinued in all five patients. This treatment regimen led to normalization of haemoglobin, platelets and improved renal function. Two patients developed end-stage renal failure and were maintained on haemodialysis. One patient died due to multiorgan failure. Improvement of renal function was seen in two patients. No further cases were recorded in patients without everolimus during the study period. Conclusions. Our data should raise the awareness of posttransplant HUS in lung transplant recipients. Post-transplant HUS is a rare disease, but it is a serious cause of acute renal failure in lung transplant recipients treated with a combination of everolimus and calcineurin inhibitors. 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 s (...truncated)