Case Presentation: A 57-year-old male with a history of renal transplant currently on immunosuppressive medication presents to the hospital with fevers and general malaise. Laboratory findings were significant for hypercalcemia (15.6 mg/dL) with suppressed parathyroid hormone (PTH) levels. Infectious investigation including urinalysis, chest x-ray, commuted tomography (CT) of the chest, abdomen, and pelvis, blood cultures, viral panel which included COVID-19, influenza, and respiratory syncytial virus was all unremarkable. Due to his severe hypercalcemia, isotonic saline, calcitonin, and bisphosphonates were administered with no improvement. Further laboratory studies to evaluate refractory hypercalcemia were significant for normal PTH-Related Protein (14 pg/mL), elevated 1,25 dihydroxy vitamin D (133 pg/dL), and normal 25-dihydroxy vitamin D (52 ng/dL). The patient was persistently febrile despite broad spectrum antibiotics in the setting of immunosuppression. Further infectious investigation involved Ebstein Barr virus, Parvovirus, Lyme, tuberculosis, herpes simplex virus, histoplasma and pneumocystis jirovecii. His pneumocystis jirovecci qualitative PCR returned positive. He was promptly treated with systemic steroids and atovaquone for PJP. Serum calcium returned to normal after completion of therapy.

Discussion: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that can occur in solid organ transplant recipients. These transplant patients benefit from primary microbial prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) which significantly reduces the incidence of PJP. PJP can be insidious in clinical expression and difficult to diagnose, and thus remains a life-threatening illness that has increased mortality rates. Hypercalcemia is associated with PJP in renal transplant patients and is often the leading clue to aid in diagnosis. The mechanism of hypercalcemia in renal transplant patients infected with PJP is similar to that of granulomatous diseases. Granulomas are formed and consist of macrophages, monocytes, and other cell types. The macrophages produce 1-alpha hydroxylase, which converts calcidiol to calcitriol, which is an active form of Vitamin D. Calcitriol stimulates calcium absorption in the intestines and kidneys as well as mobilizes calcium from bone tissue. As a result, calcitriol causes hypercalcemia.

Conclusions: Hypercalcemia has many causes and requires a thorough work-up. When working up resistant hypercalcemia in a setting of renal transplant, PJP should be included in the differential diagnosis.