HUS consisting of hemolytic anemia, thrombocytopenia, and acute renal failure, is clinical manifestation of thrombotic microangiopathy (TMA) diagnosed by histopathologic examination of a biopsied kidney specimen. It occurs in 5-15% of patients who receive cyclosporine and in approximately 1-5% of those who are given tacrolimus (6, 7). TMA is being reported with increasing frequency (8) also in patients receiving sirolimus-based immunosuppressant drugs regimen (9). Recent experimental studies showed that sirolimus itself can cause thrombotic microangiopathy and delay healing process after TMA. We present cases of two patients who developed HUS after treatment of combined FK506/ATG/Sirolimus regimen and fully recovered after discontinuation of sirolimus.

26-years old patient with end stage renal failure caused by chronic pyelonephritis underwent second cadaver renal allograft from 50 year old donor. Due to high immunisation (max. PRA was 74%, last 36%) immunosupression was started with ATG – fresenius (1-st dose 9 mg/kg), methylprednisolone (250 mg for day 0), tacrolimus (initially 0.2 mg/kg per day) and sirolimus ( first dose 6 mg). ATG was reduced to the dose of 3 mg/kg (3 doses) under the control of number of CD 3 plus cells. The graft functioned immediately and serum creatinine dropped from 4 mg/dl to 3.3 mg/dl on post-operative day 6. From that time, no further improvement in graft function was observed. On day 13 post-transplant, graft function started to deteriorate (serum creatinine 3.8 mg/dl) with normal graft perfusion on colored doppler study. Anemia and thrombocytopenia were primary considered to be consistent with ATG myelotoxicity (fall in hemoglobin 9.3-6.2 g/l; fall in platelet count 254-76 x 10 9/l). Whole blood 12-h through tacrolimus, and 24-h through levels of sirolimus were within therapeutic ranges (FK: min. 7.2 ng/dl, max. 10.2 ng/dl, Rapa 4.5). There were no biochemical signs of hemolysis, however there were high LDH levels (1554 U/L, normal range 80-248 U/L). In the first core biopsy vascular changes can be seen. Nearly total occlusion of majority of arteries due to non-inflammatory mucoid-like intimal proliferation was observed (fig. 1). C4d deposits were found; additionally in some vessels homogenic acidophilic deposits interpreted as fibrin were present. These changes of thrombotic angiopathy were not accompanied by acute rejection nor were remarkable chronic interstitial features found. The clinical picture of intravascular haemolysis, thrombocytopenia, and worsening renal function with microangiopathy in histopathology examination was primary assumed to be tacrolimus – inducted haemolytic-uremic syndrome (HUS). Tacrolimus was discontinued and mycophenolate mophetil was started in a dose of 1.0 g per day then raised to 2.0 g per day. Neither plasmapheresis nor fresh frozen plasma was employed, instead methylprednisolone was given as a prophylaxis of acute rejection in highly immunized patient (3 x 500 mg, then 10 x 125 mg). There was no renal graft function improvement; however whole blood sirolimus level was maintained on 3.0 ng/ml. The second biopsy performed on 25 day displayed similar arterial changes of mucoid-like intimal proliferation with nearly complete occlusion of vascular lumen, so the diagnosis of thrombotic angiopathy was sustained (fig. 2), C4d deposits were not found. Vascular disturbances resulted in significant ischaemia that led to cortical necrosis, therefore sirolimus was discontinued and fast normalization of renal function was observed (fall in creatinine to 1.8 mg/dl).