Vitamin D Supplementation in Transplant Patients at Risk of Hypercalcemia

Previous studies have demonstrated a high prevalence (94%) of vitamin D insufficiency among kidney transplant recipients. There are several reasons for this trend, including recommendations to limit sun exposure and advising use of sunscreens with a high sun protection factor (due to increased risk of skin cancer among transplant recipients), inadequate nutritional supplementation of vitamin D both during dialysis and after transplantation, and an increased vitamin D catabolism associated with immunosuppression drugs. Other reasons mirror those among the general population, such as dietary inadequacy, obesity, aging, skin pigmentation, seasonality, and latitude.

Although recent observational studies have demonstrated associations between vitamin D status and various renal transplant outcomes, such as a higher risk of all-cause mortality, a faster annual decrease in renal function, and lower proteinuria in kidney transplant recipients, there is a concern about the potential increase in enteric calcium and phosphate absorption associated with the use of vitamin D supplementation. Hypercalcemia may pose a risk for graft injury and may also contribute to soft tissue and vascular calcification, making normocalcemia a desired target in clinical practice.

There are few available data assessing the use of vitamin D supplementation in a population of hypercalcemic renal transplant recipients. Irene Lynch Cronin, BSc, and colleagues recently conducted a feasibility study to quantify the effect of short-term low-dose cholecalciferol supplementation on serum calcium in a group of renal transplant recipients with a recent history of serum calcium levels >10 mg/dL. Results of the study were reported in the Journal of Renal Nutrition [2019;29(3):181-187].

The study was a 2-week prospective single-arm open-label interventional feasibility study. Eligible adult patients attending the renal transplant follow-up clinic at Cork University Hospital, Cork, Ireland, between October 2014 and May 2015 were invited to participate. Inclusion criteria were tendency toward hypercalcemia (serum calcium >10 mg/dL), vitamin D insufficiency (25[OH] D <30 ng/mL), and >16 years of age. Exclusion criteria were estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², use of nutritional vitamin D supplementation within 3 months prior to the study period, acute illness, and inability to comply with study protocol.

At baseline, an early morning spot urine sample was collected and analyzed for calcium:creatinine ratio (urine calcium

:urine creatinine [mg/L]). Serum creatinine, eGFR, serum total calcium, ionized calcium, serum phosphate, serum intact PTH, and serum albumin were measured via blood samples.

Participants met with the hospital dietitian and received counseling on maintaining their usual diet for the duration of the study to limit alterations in dietary intake of vitamin D or calcium from unduly influencing serum and urine levels. Baseline characteristics recorded were time since transplantation, history of use of vitamin D supplementation, consumption of foods fortified with vitamin D, exposure to sunshine, and use of sunscreen. Weight and height were also recorded and body mass index was calculated.

Each participant was given a 14-day supply of cholecalciferol supplements and asked to take one 1000 IU cholecalciferol supplement (soft gel capsule) per day for 14 days (Adult D3 1000 IU, Shield Health). Spot urinary collection and blood analysis were repeated at the end of the 14-day intervention period. Each participant had a second visit with the renal dietitian who checked for compliance with the supplements/dietary intake.

Standard tabular and graphical methods were used to examine the central tendency, spread, and distribution of variables. The primary analysis was a paired comparison of change in ionized calcium and urine calcium:creatinine ratio at follow-up compared with baseline.

A total of 196 patients attending the clinic were screened. Of those, 45 met eligibility criteria; the final cohort included 18 of the 45. Thirteen patients were men (72%) and all were white. The center’s approach to renal allograft immunosuppression is based on triple therapy using corticosteroids (with a steroid minimization policy in the last 8 years), mycophenolate mofetil, and calcineurin inhibitors (predominantly cyclosporine prior to 2000 and tacrolimus thereafter).

Of the 18 patients, 28% were overweight; 22% of those had body mass index >30 kg/m² (obese). Obesity is linked with vitamin D deficiency due to storage of vitamin D in fat cells and consequent difficulty restoring serum levels. All 18 of the patients were long-term renal transplant recipients (>1 year since transplantation); mean eGFR was 55.7 mL/min/1.73 m² (CKD stage 3). One patient reported use of vitamin D supplementation within the 6 months prior to the study; that patient had discontinued supplementation 3 months prior to joining the study.

At baseline, all albumin levels were >4 g/dL; the analysis assessed uncorrected calcium in addition to ionized calcium. Following the 2-week intervention, the median change in serum calcium from baseline to follow-up was –0.08 mg/dL; P=.3). There was no substantial change in fibroblast growth factor 23 (median change, –1.9 RU/mL). There was a nonsignificant change in the urinary calcium:creatinine ratio (0.001 mg/mg). Mean baseline urine calcium:creatinine ratio was below the threshold for hypercalciuria (0.16 mg/mg). At baseline, parathyroid hormone correlated with ionized calcium r=0.69 (the only correlation of significance). Median change in 25(OH) D was 3.6 ng/dL (P<.05).

The small sample size and short duration of the intervention were cited as limitations to the study. However, the researchers said, “This initial safety study supports the feasibility and safety of conducting, with appropriate monitoring, a longer term interventional trial to quantify the risks and benefits of vitamin D supplementation in this population, particularly in relation to calcium metabolism.”

“As a result of this study, a greater awareness of the prevalence of 25(OH) vitamin D inadequacy in this population has led to routine monitoring of 25(OH)D levels among our transplant patients and appropriate correction of same using a variety of nutritional vitamin D supplements.”

In conclusion, the authors said, “Cautious daily dosing of cholecalciferol appears to safely restore 25(OH) D concentrations in renal transplant patients at risk of hypercalcemia in the short term. Further research is needed to establish long-term safety in this subgroup.”

Takeaway Points

1. Renal transplant recipients often experience vitamin D insufficiency; concerns related to hypercalcemia may lead clinicians to avoid vitamin D supplementation in patients at high risk for hypecalcemia.
2. Researchers in Ireland conducted a 2-week, single-arm, open-label feasibility trial to quantify the effect on serum calcium of short-term low-dose cholecalciferol supplementation in transplant recipients with a recent history of serum calcium levels ≥10 mg/dL.
3. Results of this small sample size study demonstrated that short-term cautious daily dosing of cholecalciferol appears to safely restore vitamin D levels in renal transplant patients at risk of hypercalcemia.