Multifactorial causes of severe persistent hypercalcemia in an immunosuppressed woman with chronic kidney disease

Abstract

We present the case of a 62-year-old woman with history of chronic kidney disease and birdshot retinochoroidopathy on immune suppression who presented with hypercalcemia, acute kidney injury, and Pneumocystis jirovecii pneumonia (PJP). Despite initial treatment with intravenous (IV) fluids, calcitonin, zoledronic acid, and antimicrobials for her pneumonia, her hypercalcemia persisted. Given her diagnosis of PJP and markedly elevated levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and vitamin A, prednisone (40 mg/day) and IV denosumab (120 mg) were added to her regimen; however, there was no significant improvement in calcium levels. On hospital day 27, intermittent hemodialysis was initiated, resulting in a rapid correction of hypercalcemia, improved kidney function, and better volume status. The patient was discharged on prednisone with stable laboratory parameters.

This case highlights the complex interplay of factors contributing to treatment-refractory hypercalcemia, including vitamin D toxicity, granulomatous infection-driven 1,25-dihydroxyvitamin D excess, and impaired renal clearance. It underscores the importance of early detection of supplement misuse, multidisciplinary care, and the potential need for hemodialysis when conventional treatments fail.

Introduction

Hypercalcemia occurs in about 1% to 6% of hospitalized patients [1, 2]. The most common cause of acute hypercalcemia requiring endocrinology consultation is hypercalcemia of malignancy, followed by hyperparathyroidism. Severe hypercalcemia is often defined as having serum calcium over 14 mg/dL (SI: 3.5 mmol/L) [3]. This case report illustrates the multifactorial causes of hypercalcemia complicated by acute kidney injury on chronic kidney disease (CKD), which resulted in a slow resolution of hypercalcemia despite appropriate treatment.

Case presentation

A 62-year-old woman with a history of birdshot retinochoroidopathy (maintained on chronic prednisone 10 mg/day and methotrexate resulting in immunosuppression), CKD, and recent hospitalization for urosepsis due to obstructive nephrolithiasis presented to the emergency department after a witnessed syncopal episode. She reported generalized weakness, fatigue, and weight loss. Recently, she received stress-dose steroids for septic shock and suspected secondary adrenal insufficiency, which were gradually tapered to hydrocortisone 10 mg in the morning and 5 mg in the evening. Subsequent cosyntropin stimulation testing demonstrated an intact hypothalamic-pituitary-adrenal axis. Notably, the patient did not receive prophylaxis for Pneumocystis jirovecii pneumonia (PJP) during this period of prolonged steroid administration.

On presentation to the hospital, laboratory tests revealed severe acute hypercalcemia with a total serum calcium of 13.9 mg/dL (SI: 3.48 mmol/L) (reference range, 8.5-10.1 mg/dL [SI: 2.1-2.5 mmol/L]) and an albumin level of 2.8 g/dL (SI: 28 g/L) (reference range, 3.5-5.0 g/dL [SI: 35-50 g/L]), corresponding to a corrected calcium of 14.3 mg/dL (SI: 3.58 mmol/L). Her calcium level was 9.5 mg/dL (SI: 2.38 mmol/L) 3 months prior to presentation when she was admitted for sepsis from nephrolithiasis. Serum creatinine was elevated at 3.16 mg/dL (SI: 279 µmol/L) (reference range, 0.5-1.1 mg/dL [SI: 44-97 µmol/L]) compared to a baseline of 1.28 mg/dL (SI: 113 µmol/L), indicating acute kidney injury superimposed on CKD. Parathyroid hormone (PTH) was appropriately low at 10 pg/mL (SI: 1.0 pmol/L) (reference range, 9-73 pg/mL [SI: 0.95-7.73 pmol/L]). Additional laboratory tests showed hyperphosphatemia 6.1 mg/dL (SI: 1.97 mmol/L) (reference range, 2.5-4.5 mg/dL [SI: 0.81-1.45 mmol/L]), markedly elevated 25-hydroxyvitamin D at 243 ng/mL (SI: 607 nmol/L) (reference range, 30-100 ng/mL [SI: 75-250 nmol/L]), and 1,25-dihydroxyvitamin D at 401 pg/mL (SI: 1001 pmol/L) (reference range, 18-72 pg/mL [SI: 45-180 pmol/L]) (see Table 1).

Table 1.

Reference range (conventional and SI units)

Laboratory results	Results	Reference range
Calcium	13.9 mg/dL (3.48 mmol/L)	8.9-10.3 mg/dL (2.23-2.58 mmol/L)
Ionized calcium	7.4 mg/dL (1.85 mmol/L)	4.5-5.3 mg/dL (1.12-1.33 mmol/L)
Phosphorous	4.9 mg/dL (1.58 mmol/L)	2.5-4.7 mg/dL (0.81-1.52 mmol/L)
Albumin	2.8 g/dL (28 g/L)	3.5-4.8 g/dL (35-48 g/L)
Alkaline phosphatase	63 U/L (63 U/L)	38-126 U/L (38-126 U/L)
Creatinine	3.16 mg/dL (279 µmol/L)	0.44-1.03 mg/dL (39-91 µmol/L)
PTH	10 pg/mL (1.06 pmol/L)	9-73 pg/mL (0.95-7.73 pmol/L)
PTH-related peptidea	13 pg/mL (1.38 pmol/L)	11-20 pg/mL (1.17-2.12 pmol/L)
1,25-hydroxyvitamin Da	401 pg/mL (999 pmol/L)	18-72 pg/mL (45-179 pmol/L)
25-hydroxyvitamin D	243 ng/mL (607 nmol/L)	30-100 ng/mL (75-250 nmol/L)
24-h urine calcium	406 mg/24 h (10.15 mmol/24 h)	100-300 mg/24 h (2.5-7.5 mmol/24 h)

Abbreviation: PTH, parathyroid hormone.

^a These laboratory tests are sent to the reference laboratory and are available in about 2 weeks.

On admission, vital signs included blood pressure of 118/67 mm Hg, heart rate 86 beats/minute, respiratory rate 16 breaths/min, oxygen saturation of 95% on 2 L of oxygen, weight 49.3 kg, height 155 cm, and body mass index of 20.5 kg/m². The patient appeared mildly confused, responding to questions slowly and vaguely. Pulmonary examination revealed bilateral crackles, more prominent on the right.

Diagnostic assessment

As part of evaluation for her syncope and hypoxia, an electrocardiogram was performed that demonstrated upsloping ST segments, findings consistent with hypercalcemia. A chest x-ray was performed, revealing nonspecific ill-defined peripheral patchy opacities in the right upper and bilateral lower lobes. A follow-up chest computed tomography scan demonstrated significant interval worsening, with multifocal consolidations and ground-glass opacities (Fig. 1). Due to worsening hypoxia, bronchoscopy was performed, and bronchial lavage tested positive for Pneumocystis jirovecii by direct fluorescent antibody testing.

Figure 1.

Serial computed tomography (CT) image of the chest demonstrating improvement of pulmonary edema and multifocal consolidation. A, Initial CT image acquired on day 4 of hospital admission. B, Follow-up imaging shows improved aeration and resolving pulmonary edema on day 25.

Additional investigations showed a normal serum angiotensin-converting enzyme and no monoclonal protein on serum and urine protein electrophoresis. The patient later revealed that she had been taking at least 3 times the prescribed supplemental dose of vitamin D along with vitamin A for several months because of her concern about bone disease associated with her CKD.

Treatment

On admission, the patient was given a 1-L normal saline bolus. She was then started on continuous intravenous (IV) fluids at a rate of 200 mL/hour as well as empiric antibiotics for presumed community-acquired pneumonia. Due to severe symptomatic hypercalcemia, she received a single dose of zoledronic acid 2 mg and calcitonin 58 IU; however, her encephalopathy persisted. By hospital day 3, worsening hypoxia and volume overload prompted a reduction in the rate of IV fluids and initiation of IV furosemide 40 mg/day. After bronchoscopy results confirmed PJP, treatment with clindamycin, primaquine, and prednisone 40 mg twice daily was initiated on hospital day 5 that was tapered to 40 mg once daily on day 8 and further tapered to 20 mg daily from day 14 to day 18. Notably, the 1,25-dihydroxyvitamin D level had declined to 38 pg/mL (SI: 95 pmol/L) (considered inappropriately normal for suppressed PTH and elevated calcium levels) from initial 401 pg/mL (SI: 1001 pmol/L) after treatment for PJP with antimicrobials and prednisone for a week. The prednisone was subsequently tapered to 20 mg over several days and then discontinued (Fig. 2).

Figure 2.

Serum calcium concentrations after administration of multiple agents to treat persistent hypercalcemia, including hemodialysis.

Given ongoing hypercalcemia, elevated 25-hydroxyvitamin D levels, and persistent PJP, denosumab 120 mg was administered on hospital day 11 and prednisone was restarted at 40 mg daily on day 22. Nephrology was consulted for worsening kidney injury; no major changes in management were initially recommended. Despite 3 additional doses of calcitonin between hospital days 13 and 24, the patient’s calcium levels remained elevated. Vitamin A was also noted to be markedly elevated at 352 µg/dL (SI: 12.3 µmol/L). On hospital day 27, intermittent hemodialysis was initiated, resulting in a rapid decline in serum calcium, normalization of kidney function, and stabilization of volume status. Fig. 2 summarizes calcium trends alongside the treatments administered throughout the hospitalization.

Outcome and follow-up

The patient's creatinine and urine output improved after just 2 sessions of hemodialysis, allowing for removal of the temporary hemodialysis catheter. On hospital day 38, she was discharged home on prednisone 10 mg daily. Approximately 1 month later, during a follow-up visit in the endocrinology clinic, her vitamin D level had decreased to 125 ng/mL (SI: 312 nmol/L); however, her corrected serum calcium had risen from 7.4 mg/dL (SI: 1.9 mmol/L) at discharge to 9.9 mg/dL (SI: 2.5 mmol/L). Additionally, her creatinine had increased from 1.15 mg/dL (SI: 101 μmol/L) to 1.53 mg/dL (SI: 135 μmol/L). The patient was continued on 10 mg of prednisone with a plan for close laboratory follow-up. Five months later, she followed up in the primary care clinic, where her 25-hydroxyvitamin D level had improved to 80 ng/mL (SI: 197 nmol/L), and her serum calcium had normalized to 9.6 mg/dL (SI: 2.4 mmol/L).

Discussion

This case report highlights a diagnostically complex treatment-refractory hypercalcemia in an immunocompromised patient with PJP, vitamin D toxicity, and acute-on-chronic kidney injury. Despite comprehensive medical therapy including IV fluids, zoledronic acid, calcitonin, prednisone, and denosumab, the patient's hypercalcemia remained persistent and required intermittent hemodialysis for resolution.

The patient was diagnosed with PJP from bronchial lavage, a granulomatous infection known to cause PTH-independent hypercalcemia [4]. Activated macrophages within granulomatous tissue express 1α-hydroxylase (cytochrome P450 [CYP]27B1), resulting in extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which increases intestinal calcium absorption and bone resorption [5, 6]. Because of the initially elevated 1,25-dihydroxyvitamin D, the patient's hypercalcemia was thought to be secondary to an infection-driven 1,25-dihydroxyvitamin D overproduction. Management of granulomatous disease-related hypercalcemia includes corticosteroids, which suppresses macrophage 1α-hydroxylase activity and reduces intestinal calcium uptake. The patient's calcium initially decreased in parallel with a reduction in 1,25-dihydroxyvitamin D following initiation of treatment for PJP but subsequently rose again and proved unresponsive to further therapy, including reinitiation of prednisone and the addition of denosumab. Simultaneously, this patient's persistent markedly elevated 25-hydroxyvitamin D concentration of 243 ng/mL (SI: 607 nmol/L) strongly suggested exogenous vitamin D toxicity, from chronic oversupplementation as admitted by the patient on direct questioning. The concurrent elevation in vitamin A, which likely contributed to hypercalcemia via promoting osteoclastogenesis [7], and directly stimulating bone resorption and calcium release raised concern for unsupervised multivitamin use, a common but underrecognized contributor to metabolic disturbances in older or medically complex patients [5, 6]. Although 1,25-dihydroxyvitamin D levels declined with therapy, they remained at 38 pg/mL, an inappropriately normal value in the setting of hypercalcemia and suppressed PTH, suggesting ongoing extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D despite corticosteroid-mediated inhibition of macrophage 1α-hydroxylase activity. Correspondingly, our patient's serum calcium initially improved but later paradoxically worsened with continued steroid use, likely due to the persistently elevated 25-hydroxyvitamin D substrate driving continued 1,25-dihydroxyvitamin D production. This underscores an important clinical point that in patients with coexisting vitamin D toxicity and granulomatous disease, corticosteroids alone may be insufficient unless the excess substrate is reduced, particularly in the setting of impaired renal clearance. Despite receiving multiple pharmacologic interventions [3], the patient's hypercalcemia persisted until hemodialysis was initiated on hospital day 27 [8, 9]. This led to a rapid improvement both in serum calcium and renal function, suggesting that dialysis played a key role in clearing excess calcium and potentially vitamin D metabolites [10]. Although hemodialysis is not commonly required for hypercalcemia, it is indicated in severe, refractory cases, especially when complicated by acute kidney injury, volume overload, or contraindications to medical therapies. In this case, underlying CKD with superimposed acute kidney injury further amplified the metabolic effects of vitamin D toxicity by reducing renal calcium excretion and prolonging metabolite half-lives. This highlights how preexisting renal impairment can exacerbate even moderate levels of vitamin D excess. This case exemplifies how multiple overlapping mechanisms including exogenous vitamin D supplementation, infection-driven enzyme dysregulation, and impaired renal clearance can converge to produce refractory and life-threatening hypercalcemia, requiring escalation to renal replacement therapy. It also emphasizes the importance of identifying all potential contributors early in the course, including nonprescription supplements and granulomatous processes, to guide targeted and effective treatment.

Learning points

• Hypercalcemia often has multiple etiologies. A thorough evaluation should include all potential contributors, including over-the-counter supplement use, as multiple concurrent causes may coexist.

• Steroids may fail to lower calcium if high 25-hydroxyvitamin D substrate continues to drive 1,25-dihydroxyvitamin D production, highlighting the need to address the underlying vitamin D excess.

• Collaborating and discussion with nephrology is crucial if hypercalcemia is persistent and nonresponsive to recommended therapies.

Abbreviations

CKD

chronic kidney disease

IV

intravenous

PJP

Pneumocystis jirovecii pneumonia

PTH

parathyroid hormone

Contributors

All authors made individual contributions to authorship. K.N., G.N., E.G., and C.W. were involved in the diagnosis and management of the patient and contributed to manuscript writing, editing, and submission. T.P. was responsible for procuring images, and contributed to writing the manuscript. All authors were involved in the writing revision of the manuscript and approved the final draft. K.N., E.G., and C.W. were responsible for manuscript submission.

Funding

C.W. is supported by the UCLA Clinical and Translational Science Institute (grant No. UL1TR001881) from the National Center for Advancing Translational Sciences.

Disclosures

The authors have nothing to disclose.

Informed patient consent for publication

Signed informed consent obtained directly from the patient.

Data availability

Original data generated and analyzed for this case report are included in this published article.