Development of transplant renal artery thrombosis and signs of haemolytic-uraemic syndrome following the change from cyclosporin to tacrolimus in a renal transplant patient

Ahmet Alper Kiykim 2 3 Caner Ozer 1 2 Altan Yildiz 1 2 Naci Tiftik 0 2 Mehmet Senli 2 3 Ebru Kelebek 2 3 Erdal Doruk 2 4 Erdem Akbay 2 4 0 Division of Hematology, Department of Internal Medicine 1 Department of Radiology 2 Kiykim, Nefroloji Bilim Dal 3 Division of Nephrology, Department of Internal Medicine 4 Department of Urology, Faculty of Medicine, University of Mersin , Turkey Introduction The clinical presentation of post-transplantation thrombotic microangiopathy (TMA) is variable. Often, TMA will manifest systemically as haemolytic-uraemic syndrome (HUS), with classic findings of renal failure, haemolytic anaemia, schistocytes and thrombocytopenia [1]. Localized and systemic TMA represent a spectrum of severity of the same disorder, not two different disorders with distinct pathophysiological states. Pre-transplantation HUS, anticardiolipin antibodies, acute rejection, cytomegalovirus (CMV) and some medications are associated with the development of TMA. Herein we report a patient who developed the signs and symptoms of de novo HUS and transplant renal artery thrombosis following switching from cyclosporin to tacrolimus. Case The patient is a 38-year-old Turkish woman whose primary cause of renal failure was bilateral nephrolithiasis. She had a gradual development of end-stage renal disease (ESRD) without a previous renal history of thrombotic microangiopathy. She had been on haemodialysis for 10 months. The renal transplantation had been performed from a 2-antigen mismatched, 74-year-old living related donor (her mother) 10 months earlier. The transplanted kidney had immediate function with excellent urine output but a slowly dropping serum creatinine level. The patient did not require haemodialysis in the post-transplant period. Induction immunosuppressive protocol consisted of daclizumab and a total of 750 mg intravenous methylprednisolone. Maintenance immunosuppression included a prednisone tape, mycophenolate mofetil (MMF) at 1000 mg orally twice daily and cyclosporin at 200 mg orally twice daily. Her serum creatinine level at discharge, post-transplant day 20, was 1.4 mg/dl (normal: 0.81.2 mg/dl). The patient was healthy, except for hypertension during 6 months post-transplant. Her serum creatinine level increased to 1.6 mg/dl gradually during this period, but we did not consider this due to rejection and structural abnormality in graft, guiding laboratory and clinical evaluation. Because the donor was an elderly person and resistant hypertension and cyclosporin nephrotoxicity were considered in the patient, cyclosporin was switched to low dose tacrolimus (4 mg/day, 0.08 mg/kg/day) in the sixth month post-transplant. Tacrolimus dose was subsequently increased to 6 mg/ day (0.1 mg/kg) orally within 3 weeks. The patient was admitted to our hospital at 24 days after switching to tacrolimus, with complaints of sudden and severe local graft pain, complete anuria and weakness for 25 h. At this time, the patient had no additional complaints. On admission, physical examination revealed no abnormal finding, except for elevated blood pressure (200/110 mmHg). There was no tenderness or swelling on the graft region. Obstructive uropathy was not determined. Renal artery blood flow was not observed by Doppler ultrasound examination. Selective transplant renal arteriography was performed. The main transplant renal artery and some peripheral branches were occluded by thrombi (Figures 1 and 2). The main renal artery stenosis and tortuous segmental arteries are shown in Figure 2. Fig. 1. Appearance of the mean renal artery thrombosis. Blood and urine tests that were obtained 25 h before admission were all normal, except the unchanged elevated serum creatinine (1.7 mg/dl). On admission, blood tests revealed the following results: haemoglobin 8.9 g/dl, platelet count 37 000/mm3 and blood smear revealed the features of microangiopathic haemolytic anaemia. Other values were serum glucose 99 mg/dl; blood urea nitrogen 127 mg/dl; serum creatinine 4.9 mg/dl; potassium 6.2 mEq/l; cholesterol 198 mg/dl; low-density lipoprotein 118 mg/dl; high-density lipoprotein 32 mg/dl. Because of anuria, urine tests could not be done. Lactate dehydrogenase (LDH) was 1840 U/l (normal: <480 U/l), aspartate aminotransferase (AST) was 340 U/l (normal: <32 U/l), alanine aminotransferase (ALT) was 42 U/l (normal: <31 U/l) and creatine kinase (CK) was 580 U/l (normal: <145 U/l). Arterial blood gas analysis revealed mild metabolic acidosis. Anticardiolipin antibody-IgG and -IgM were negative. Other antibodies (antinuclear antibodies, antidouble-stranded DNA, antineutrophil cytoplasmic autoantibody) and lupus anticoagulant were all negative. Coombs test was negative. CMV-IgM was negative. Resistance to activated protein C was not determined. She was diagnosed as systemic TMA and HUS, with classic findings of renal failure, haemolytic anaemia, severe thrombocytopenia, elevated LDH, AST and CK and peripheral blood smear that revealed microangiopathic haemolytic anaemia. We did not find other conditions proposed by some to trigger TMA, such as pre-transplantation HUS, anticardiolipin antibodies, acute rejection or CMV. The patient was not on other medications known to be a significant risk for causing medication-induced thrombotic microangiopathy at this time. Fig. 2. Renal artery and tortuous branch are seen after the first dose of rt-PA. Tacrolimus trough levels were not found higher than 13.9 ng/ml during the treatment period. Believing tacrolimus was possibly the inducing agent for this thrombotic microangiopathy, it was discontinued at once. Immunosuppressive therapy was continued with MMF and high dose (1 mg/kg/day) oral steroid. Percutaneous transplant renal angioplasty (PTRA) was performed successfully after thrombolysis (direct infusion into the thrombus of three bolus doses of 5 mg rt-PA followed by 1 mg/h infusion for 8 h) to the stenotic and occluded segments (Figures 13). Low dose rt-PA was administered because of the presence of thrombocytopenia and uraemia. The patient needed to be treated by haemodialysis three times. We could not perform plasmapheresis for considered HUS due to technical insufficiency. Urine output started at once after the thrombolysis and PTRA. Her serum creatinine decreased gradually and was 2.2 mg/dl after 2 weeks. Her blood pressure control was acceptable with a beta-blocker (nebivolol) 3 monotherapy. Platelet count increased to 138 000/mm . Blood smear findings and the serum levels of LDH, AST, CK and ALT returned to normal. The patient was discharged with the treatment regimen, which consists of MMF (2000 mg/day), prednisolone (15 mg/ day), acetylsalicylic acid (100 mg/day), dipridamole (225 mg/day), nebivolol (10 mg/day) and simvastatine (20 mg/day). The patient was healthy and serum creatinine was 2.1 mg/dl after 3 months. Discussion TMA and renal artery thrombosis is a very rare condition. Rates of de novo TMA after renal transConsequences of switc (...truncated)