Calcitriol-Mediated Hypercalcemia in Fungal Granulomas: When Steroids Are Not the Answer

Introduction: Cryptococcosis is an opportunistic fungal infection caused by Cryptococcus neoformans, affecting ~2.8% of solid organ transplant recipients. Granulomatous inflammation, a hallmark of cryptococcal infection, can cause hypercalcemia via increased 1α-hydroxylase production in activated macrophages, converting 25-OH Vitamin D to 1,25-(OH)2 Vitamin D (calcitriol). Although glucocorticoids typically suppress this pathway, they may paradoxically worsen it by impairing host immunity and promoting granuloma formation. We present a case where steroid therapy for IgA Nephropathy led to cryptococcosis and subsequent hypercalcemia, ultimately managed with ketoconazole. Case Description: A 55-year-old man with kidney failure from diabetic nephropathy underwent kidney transplantation. Eight months later, biopsy for proteinuria showed de novo IgA nephropathy, and he was started on prednisone 60 mg daily. Ten weeks later, he presented with fever and tender generalized subcutaneous nodules. Serum cryptococcal antigen titer was >1:2560. Skin biopsy and CSF confirmed cryptococcal organisms. Amphotericin B and flucytosine were initiated; anti-metabolite was discontinued and prednisone tapered. On admission, adjusted calcium was slightly elevated at 10.9 mg/dL, PTH was suppressed (12.4 pg/mL), and 1,25-(OH)2 vitamin D was elevated (103 pg/mL). Despite clinical improvement, adjusted calcium increased to 12.3 mg/dL by day 5. We started Ketoconazole 600 mg daily to inhibit 1α-hydroxylase and augment antifungal activity. Calcium improved to 11 mg/dL by day 3 and normalized by day 20. Repeat calcitriol level had decreased to 19.3 pg/mL. Retrospective staining of the kidney biopsy did not show cryptococcus. Discussion: The macrophages associated with the granulomatous inflammation in cryptococcal infection exhibit high 1α-hydroxylase activity, increasing calcitriol production. In this case, reduction in immunosuppression led to worsening of hypercalcemia by allowing the host to increase granuloma formation to fight the infection. Escalating steroid therapy risked worsening of the infection and was therefore not an appropriate choice. Instead, ketoconazole was employed to inhibit 1α-hydroxylase activity, highlighting it’s role as a viable therapeutic alternative for the treatment of calcitriol-mediated hypercalcemia when steroids are contraindicated.