MON-180 EVEROLIMUS ASSOCIATED OSTEONECROSIS OF THE JAW IN KIDNEY TRANSPLANT RECIPIENT

Abstract

Mammalian target of rapamycin (mTOR) inhibitors, used in kidney transplant recipients, inhibit T-cell activation and vascular endothelial growth factor (VEGF) pathways, thereby exerting antiproliferative and antiangiogenic effects. Osteonecrosis of the jaw (ONJ) is a serious side-effect of antiresorptive and anti-angiogenic therapies. We report a unique case of osteonecrosis of the jaw associated with use of everolimus in a kidney transplant recipient. A 65-year-old man with polycystic kidney disease and subtotal parathyroidectomy for tertiary hyperparathyroidism, received a deceased donor kidney transplant in 2015 with basiliximab, tacrolimus, mycophenolate and prednisolone immunosuppression. He suffered non-immune delayed graft function and recovered with a 12-month serum creatinine of 230umol/L (eGFR 25ml/min/1.73sq.m). Tacrolimus was changed to everolimus to optimise renal function and retard interstitial fibrosis secondary to CNI use. In November 2017, he presented with swollen gums and left maxillary tenderness with gingival inflammation, exposed maxilla and purulent discharge, indicating infective periodontal disease. He was managed conservatively with antibiotics and dental extractions. His renal function was stable on everolimus 1mg BD with a trough level (C0) at 3.0-4.0 ng/ml. Six months later, he had progressive severe pain limiting oral intake, with 10kg weight loss. A CT head showed progressive bony destruction of maxilla, erosion of the maxillary sinus floor and an oro-antral fistula, consistent with ONJ. Bone biopsy ruled out malignancy, showing necrotic bony trabeculae filled with bacteria. He had never received bisphosphonate, denosumab or radiotherapy. He was on everolimus 0.75mg BD (C0= 3.0ng/ml). Tests revealed relatively low bone turnover markers in the context of active osteonecrosis: parathyroid hormone (PTH) <1.1pmol/L (1.6-6.0pmol/L), procollagen type 1 N propeptide (P1NP) 17ug/L(15-80ug/L), alkaline phosphatase (ALP) 69 U/L (30-110U/L), and C-telopeptide (CTX) 432ng/L (100-600ng/L). In view of its anti-proliferative and possible inhibitory effects on bone turnover, everolimus was ceased. He underwent surgical exploration of the sinuses, debridement of the palate with full upper dental clearance. He was treated with teriparatide 20ug monthly to stimulate bone turnover. Four-months later, the osteonecrotic process had abated, the exposed bone was stable and there were signs of healing. His nutrition status improved and he gained back his lost weight. This is the first case of everolimus associated ONJ in a kidney transplant recipient, despite being on relatively low dose therapy. The suppression of bone resorption via parathyroidectomy and additional inhibitory effect of everolimus resulted in the uncoupling of bone resorption and formation processes. This case not only underlies the importance of considering the potential of ONJ with everolimus in transplant recipients, particularly in those with poor dentition, malignancy, hypoparathyroidism or previous parathyroidectomy, and renal bone disease but also indicates possible therapeutic role of teriparatide in this situation.