Vitamin D-induced hypercalcaemia and acute kidney injury in sarcoidosis

Abstract

Vitamin D deficiency is relatively common, and its management in patients with sarcoidosis is challenging due to the risk of hypercalcaemia. Our patient had an autologous stem cell transplant for multiple sclerosis and was given high-dose vitamin D concurrently with immunosuppressive therapy. The patient subsequently presented with symptomatic hypercalcaemia and an acute kidney injury. A clinical and biochemical recovery was reached by withdrawing vitamin D and administering intravenous fluids. Interestingly, new evidence suggests that activated vitamin D can actually dampen the inflammatory process in sarcoidosis, and this was reflected in a reduction of our patient’s serological markers of sarcoidosis activity. One large study found no significant risk of hypercalcaemia when low doses of vitamin D were used in sarcoidosis. Where indicated, and until clear guidelines are established, we suggest using low doses of vitamin D with cautious monitoring of calcium and renal function.

Background

Patients with sarcoidosis are susceptible to osteoporosis, likely due to the chronic inflammatory nature of the disease.¹ Physicians are faced with a clinical conundrum when contemplating prescribing bone protection, vitamin D and calcium supplements, given the propensity for patients with sarcoidosis to develop hypercalcaemia. Our case highlights this very risk in one patient who suffered hypercalcaemia and acute kidney injury after receiving high-dose vitamin D. Manifestations of hypercalcaemia range from dehydration, nephrolithiasis, constipation and mental alteration to, in extreme cases, acute renal failure, cardiac arrhythmias and death.² Vitamin D deficiency has a considerably high prevalence rate and in the absence of definitive clinical guidelines our case serves to remind us that vitamin D supplementation should be used judiciously and with cautious monitoring in patients with sarcoidosis.

Case presentation

A man in his 30s was referred by his general practitioner (GP) to our acute medical assessment unit due to abnormal serological findings of raised calcium and raised creatinine. His only symptoms were dehydration and polydipsia for 1 week. The patient had a medical history of secondary progressive multiple sclerosis, sarcoidosis diagnosed 1 year prior, type one diabetes, asthma and coeliac disease. He was attending his GP for routine phlebotomy after reportedly receiving an autologous stem cell transplant and high-dose immunosuppressive therapy which was delivered abroad 7 weeks before his presentation to our institution. In addition, he was being administered 5000 units of vitamin D daily—making the total cumulative dose 245 000 units at presentation. The patient had travelled abroad in an attempt to treat his secondary progressive multiple sclerosis. High-dose vitamin D had also been administered as part of this treatment protocol based on emerging hypotheses for its role in treating autoimmune disease.³ His regular medications included insulin degludec 28–32 units once daily subcutaneously, insulin aspart 3–6 units three times a day subcutaneously, tiotropium bromide 2.5 µg once daily inhaled, fluticasone/vilanterol 184/22 µg once daily inhaled, ramipril 1.25 mg once daily and as required salbutamol inhaler. There were no known drug allergies. He was an ex-smoker of 10 years with a three pack-year history. Alcohol intake was minimal at approximately two units per month. He worked in an office and had no occupational exposure history. Family history was significant for having one third-degree relative with multiple sclerosis. Vital signs were stable, and head-to-toe clinical examination was normal.

Investigations

Admission serum calcium was 3.22 mmol/L (normal range 2.25–2.54 mmol/L) and creatinine was 120 µmol/L (normal range 64–104 µmol/L). Previously, these levels were within normal limits. Calcium and creatinine peaked on day 3 of his admission with zeniths of 3.47 mmol/L and 197 µmol/L, respectively. Parathyroid hormone (PTH) level was appropriately low at 8 pg/mL (normal range 15–68 pg/mL) and phosphate was normal at 1.43 (normal range 0.8–1.5 mmol/L). Vitamin D level was found to be markedly raised at 138 nmol/L (normal range 50–125 nmol/L), and had been normal at 58 nmol/L 5 weeks prior to his treatment abroad. His ACE level was elevated at 88 nmol/mL (normal range 18–65 IU/L) previously, but was normal at 34 nmol/mL on admission. Serum magnesium was noted to be below the lower limit of normal at 0.68 mmol/L (normal range 0.7–1 mmol/L). Urine calcium measured 1.58 mmol/L (normal range 1.25–7.5 mmol/24 hours) with calcium:creatinine clearance ratio of 0.049 (normal range <0.14). A renal ultrasound was performed and showed normal kidney size with no hydronephrosis but increased echogenicity of the parenchyma, suggesting intrinsic renal disease. An echocardiogram was performed to assess cardiac function and volume status. It demonstrated normal chamber dimensions and wall thickness with normal systolic function and no valvulopathy. A chest X-ray showed known bihilar enlargement and parenchymal nodularity without fibrosis, and demonstrated stability when compared with chest imaging performed 1 year previously.

Differential diagnosis

Initially, our patient’s hypercalcaemia was suspected to be related to a spontaneous flare of sarcoidosis. A detailed history revealed his recent travel abroad and consequent high-dose course of vitamin D. Hyperparathyroidism, a common cause of hypercalcaemia, was ruled out by an appropriately suppressed PTH level. Therefore, a diagnosis of acute kidney injury and hypercalcaemia secondary to iatrogenic vitamin D toxicity was reached.

Treatment

Vitamin D supplementation was stopped and intravenous fluids were initiated to treat severe hypercalcaemia. Three litres of normal saline were required daily for 1 week with careful monitoring of serum electrolytes. Calcium and creatinine responded similarly to treatment and normalised by 2 weeks (see figure 1). No bisphosphonates, steroids or calcitonin was employed in the treatment strategy.

Figure 1.

Blood test results (figure author: Dominic Doyle).

Outcome and follow-up

We achieved resolution of symptoms and a biochemical response directly proportionate to treatment. Calcium and creatinine levels continued to improve after intravenous fluids were discontinued and remained stable prior to discharge from hospital. Our patient’s renal function, calcium and vitamin D levels were serially monitored for months after discharge and have remained normal.

Discussion

Our case highlights the risk of hypercalcaemia with vitamin D supplementation in sarcoidosis. Physicians should also consider testing for sarcoidosis in patients presenting with hypercalcaemia after receiving vitamin D. We acknowledge one case describing a patient who manifested sarcoidosis only following vitamin D treatment.⁴ Hypercalcaemia in sarcoidosis is caused by the uncontrolled conversion of 25-OH vitamin D to the active form 1,25-OH vitamin D (calcitriol) by high levels of 1-alpha-hydroxylase activity from macrophages in granulomas.⁵ The phosphate level warrants testing in cases of hypercalcaemia as it should be reciprocally low. However, calcitriol increases the absorption of both calcium and phosphate from the intestine and kidney; therefore, phosphate levels may be raised when hypercalcaemia is secondary to vitamin D excess. In our case, the phosphate level was near the upper limit of normal. Evidence of increased PTH-related protein (PTHrP) has also been demonstrated in sarcoidosis macrophages. Unlike PTH, PTHrP expression is not regulated by vitamin D or calcium, but instead by tumour necrosis factor-α and interleukin-6.⁶ Acute hypercalcaemia associated with hypervitaminosis D may lead to direct renal vasoconstriction, decreased extracellular fluid volume and a decreased ability to concentrate urine, which in turn may lead to acute kidney injury as was seen in our patient.⁷ Most case reports of hypervitaminosis D have described intake of a minimum of 40 000 units per day for at least 1 month to reach toxic effects.⁸ However, in our patient’s case, a dose of 5000 units per day for 7 weeks was sufficient to cause renal damage. Although vitamin D supplementation has been recommended for prevention of osteoporosis in patients on maintenance glucocorticoids, the potential risk for patients with sarcoidosis is not factored in these recommendations.⁹ A ‘real-world’ clinical management proposal for patients with sarcoidosis would be to evaluate their bone health with bone densitometry and vitamin D levels. In those who are vitamin D deficient (<25 nmol/L), supplementation should be considered, provided there is no hypercalcaemia or hypercalciuria. Notably, it is recommended measuring 1,25-OH vitamin D in addition to 25-OH vitamin D when screening for vitamin D deficiency. Using low doses of vitamin D, for example 400 IU daily, and aiming for levels at the lower limit of normal in this setting, have been shown to be safer.¹⁰ Serum levels should be repeated within 3 months. Vitamin D is stored in adipose tissue and has a half-life of approximately 2 months but this varies considerably.¹¹ Stopping supplementation in patients with sarcoidosis who develop mild asymptomatic hypercalcaemia is effective.¹² In those with abnormal calcium metabolism, reduced bone mineral density or fragility fractures, treatment with bisphosphonates or other anti-resorptive agents is recommended.¹³ The attendant risks with supplementing vitamin D in patients with sarcoidosis can make physicians hesitant to prescribe it. Yet, this may be detrimental, not just for bone health, as two large studies found correlations between vitamin D deficiency and sarcoidosis activity.^{14 15} Vitamin D attenuates inflammatory immune responses through its downregulation of Th1 lymphocytes.¹⁶ Accordingly, it is inadvisable to forego vitamin D and calcium supplementation when it is indicated. Indeed, our patient’s ACE level was noted to come down with vitamin D supplementation. In summary, the authors advocate restoring vitamin D deficiencies in patients with sarcoidosis on glucocorticoids but with careful prescribing and close patient monitoring.

Patient’s perspective.

I am very interested in furthering my understanding of my chronic condition and so am happy to support the writing of this case and see it published in a prestigious medical journal. My own research has informed me of the importance of monitoring electrolyte balance, particularly including Vitamin D, Calcium and Magnesium. The prevalence of Vitamin D deficiency seems to be grossly underscored, as it is not adequately screened in at-risk groups by medical practitioners. When I enquired about my magnesium levels in hospital they were checked and found to be low. While it may not be a common presentation, I have read that high dose Vitamin D can induce Magnesium depletion in some individuals and it can take many months to correct, assuming dosage and absorption is optimal. As mentioned, the importance of Vitamin D to modulate the immune system in the context of autoimmunity is established and appreciated. The knotty interplay of sarcoidosis in this regard would seem to heighten the need for cautious supplementation and careful monitoring, especially in regard to bone density, for which other co-factors are also crucial. Perhaps it is timely to reintroduce Vitamin D supplementation on a low dose basis going forward as suggested, in tandem with high dose Magnesium if needed. This case report has given me much to reflect on and has encouraged me to consider exploring the possibility of genetic testing and Vitamin D resistance against the backdrop of strong personal and familial autoimmune disease.

Learning points.

• Vitamin D toxicity can be reached with lower doses in patients with sarcoidosis than the general population; therefore, high doses of vitamin D should be avoided in this patient group.

• Only patients with sarcoidosis who have vitamin D deficiency should be treated.

• Close monitoring of renal function, calcium and vitamin D levels is recommended for patients with sarcoidosis taking vitamin D supplementation.

• There is more evidence now showing that vitamin D restoration suppresses sarcoidosis activity.

Ethics statements

Patient consent for publication

Obtained.