Therapy of Calcineurin Inhibitor-Induced Thrombotic Microangiopathy in Renal Allografts

Abstract

Although thrombotic microangiopathy (TM) is a well recognized albeit rare complication of calcineurin inhibitor (CNI) therapy, its treatment is not well established. We report a case of tacrolimus (Tac)-induced TM and propose a course of treatment for this entity. Mr MN, a 32 year old teacher developed ESRD due to obstructive uropathy and hypertension and was commenced on CAPD in June 2006. In March 2007, he received a kidney donated by his spouse. Basiliximab and methylprednisolone (MP) were used for induction followed by prednisolone-Tac-mycophenolate mofetil. He was discharged 10 days post-surgery with a serum creatinine of 95 umol/L and a daily urine output of 5-7 L. On follow-up, his serum creatinine vascillated between 120-145 umol/L depending on hydration status and serum Tac levels were kept within therapeutic ranges. On the 95th day post-transplant, his serum creatinine rose steeply from 132 to 162 umol/L despite euvolaemia. Physical examination was unremarkable and his blood pressure was 117/63 mmHg, lying and standing. Results of the usual investigations were all within normal limits. However, echodoppler ultrasound of the graft showed a rise in the resistive index from 0.68 (fi rst week post-transplant) to 0.8. IV pulse methylprednisolone (500 mg daily x3 days) was commenced whilst awaiting results of the urgent graft biopsy and Tac was reduced. Graft biopsy showed 9 glomeruli, 4 of which demonstrated capillary occlusion by microthrombi. The tubules, interstitium and other blood vessels were normal and C4d staining was negative. A diagnosis of thrombotic microangiopathy (TM) consistent with CNI nephrotoxicity was made. Tacrolimus was substituted with sirolimus. The 3-day course of pulse IV MP was completed. Plasmapheresis daily for 3 days was instituted followed by IV Gammaglobulins at 10 gm daily for 3 days. Aspirin and dipyridamole were also added. His serum creatinine held at 162 umol/L for 2 days then dropped progressively to 126 umol/L by 2 weeks post-and 114 umol/L by 50 days postevent. At last review in February 2008, his serum creatinine was 123 umol/L. Given our extensive experience with this sequential protocol for the remissioninduction treatment of severe lupus nephritis, we are emboldened to propose that this may indeed be a reasonable solution for CCNI-induced TM. Early diagnosis is the key to success. Introduction: Calcineurin toxicity signifi cantly contributes to chronic allograft dysfunction. We retrospectively analyzed patients who were shifted from cyclosporine-MMF-steroid to sirolimus (SRL)-MMF-steroid regimen. Methods: There were total of 16 patients. Repeated measure ANOVA design was done to fi nd signifi cant difference between s. creatinine at conversion and six time points 2, 7, 30, 91,182 and 365 days post conversion. Patients were divided into 3 sub groups: period of post transplant at conversion (less than or equal to 200 weeks (n=11) v/s more than 200 weeks (n=5)); diabetics (n=7) v/s non diabetics (n=9); and pre-conversion s. creatinine (less than or equal to 2.2 (n=10) ...