Supplementary Material for: Thrombotic Microangiopathy in Renal Allograft Induced by Valproic Acid Treatment in addition to Tacrolimus and Everolimus: A Case Report

Thrombotic microangiopathy (TMA) is a known complication in renal transplant recipients and is often associated with drugs like calcineurin inhibitors (CNI) and mammalian target of rapamycin (mTOR) inhibitors. Additionally, toxic levels of valproic acid have been implicated in systemic TMA. This report describes a case of pathologic TMA in a renal allograft that may be induced by the combined use of CNI, mTOR inhibitor, and valproic acid at standard doses. A 37-year-old female diagnosed with glomerulonephritis underwent ABO-compatible living-donor renal transplantation. Following the procedure, the blood concentrations of tacrolimus (CNI) and everolimus (mTOR inhibitor) were maintained at optimal levels. Two and a half years post-transplant, valproic acid therapy was initiated for migraine management and titrated within the therapeutic range. Despite the gradual decline in renal function, there was no evidence of anemia or thrombocytopenia. Four years post-transplant, a graft biopsy identified a necrotic thrombotic microvascular lesion suggestive of acute TMA, despite no signs of rejection. Renal function stabilized after the discontinuation of valproic acid. Pathological TMA may impair renal function in patients receiving multiple drugs known to induce TMA. Hence, an early graft biopsy may be crucial for diagnosis, even when blood levels of immunosuppressive drugs are within the therapeutic range.