Use of vitamin D drops leading to kidney failure in a 54-year-old man

There are many reasons why the diagnosis of vitamin D toxicity of the recent case report by Auguste et al (1) was probably wrong, and was the result of a red herring. The patient had been taking 8,000-10,000 IU/day of vitamin D for 2.5 yrs while serum creatinine was not an issue. When the serum 25-hydroxyvitamin D ( 25(OH)D ) was first measured, and it was 241 nmol/L, consistent with long-term intake of the patient’s reported vitamin D intake but almost double the top of the reference range for people not taking a supplement. However, the serum 1,25-dihydroxyvitamin D ( 1,25(OH)2D ) was exceptionally high along with serum calcium and creatinine.
The Institutes of Medicine specifies 10,000 IU/day as the “No Observed Adverse Effect Level” – an intake that is not advisable, but which is not considered objectively harmful either (2). Doses of vitamin D higher than 10,000 IU/day have been used in clinical trials that achieved higher 25(OH)D values and for longer duration, yet there was not one case of hypercalcemia, and certainly no kidney damage reported from among those hundreds of those study subjects (3–9). The case report described by Auguste et al is not consistent with any previous clinical experience with vitamin D intake. What is unusual is the high serum 1,25(OH)2D level, because even in the most extreme cases of vitamin D toxicity, with 25(OH)D exceeding 2,000 nmol/L, the total serum 1,25(OH)2D was only modestly increased (10). The primary cause of the renal impairment in the case report of Auguste et al was something beyond the vitamin D intake: either a tumor, or sarcoidosis.
Auguste et al speculate that their patient might have been unusually susceptible to vitamin D because of a mutation in the CYP24A1 gene that encodes for the breakdown enzyme of 25(OH)D and 1,25(OH)2D (1). But if that were the case, the condition would not have required 2.5 years of vitamin D supplementation to manifest itself, and it could not have been resolved within a few months. Since several genetic defects can impair the CYP24A1 enzyme, the diagnosis is suitably screened for with a biochemistry-lab test, the ratio of 25(OH)D to 24,25(OH)2D concentrations (11). That test was conducted for my research group at the same hospital laboratory that Auguste et al used for their own 25(OH)D results (12). It is not likely that a rare CYP24A1 defect is pertinent to this case report, because of the duration of vitamin D intake, and by the elevated 1,25(OH)2D, as well as by the recent onset of symptoms.
The high serum 1,25(OH)2D levels, hypercalcemia renal impairment and recent onset are entirely consistent with published case reports on sarcoidosis (13,14). The only difference was that in those, serum 25(OH)D was normal. The high 1,25(OH)2D in the case report of Auguste et al (1) is not a sign of vitamin D toxicity, and likely, a consequence of sarcoidosis (13–15). The renal biopsy used by Auguste et al does not rule out sarcoidosis (16). Hydroxychloroquine is not a conventional treatment for vitamin D toxicity, but it is a first-line treatment for sarcoidosis (13–15). While the case reported by Auguste et al was probably not a primary disease of vitamin D toxicity, it is important to limit sources of vitamin D in patients with sarcoidosis.
The lesson here, is that it is common for patients to take dietary supplements in amounts that may raise test values beyond the laboratory’s reference range. But an abnormally high lab value does not in itself justify a diagnosis of toxicity. The consequence of accepting the false clue of a high vitamin D level was that no serious effort was made at establishing the true cause of the problem.

Literature Cited.

1. Auguste BL, Avila-Casado C, Bargman JM. Use of vitamin D drops leading to kidney failure in a 54-year-old man. CMAJ. 2019 Apr 8;191(14):E390–4.
2. Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D, Calcium. The National Academies Collection: Reports funded by National Institutes of Health. In: Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US) National Academy of Sciences.; 2011.
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The patient reported by Auguste et al (1) suffered from vitamin D intoxication due to an underlying pathologic condition that the authors failed to recognize. They incorrectly concluded that a dose of 8000-12,000 IUs daily can result in vitamin D intoxication. Vitamin D toxicity generally occurs when the level of 25-hydroxyvitamin D is over 375 nmol/L (150 ng/mL).(2) This patient had a 25-hydroxyvitamin D of 241 nmol/L (96 ng/mL). This concentration is considered to be within the normal limit (30 – 100 ng/mL) according to the Endocrine Society’s Clinical Practice Guideline.(3) Ingestion of 10,000 IU/d of vitamin D3 raising blood levels of 25-hydroxyvitamin D above 100 ng/mL was not associated with hypercalcemia.(4) Population studies also reported doses of up to 20,000 IUs daily was not associated with toxicity.(2) 1,25-dihydroxyvitamin D3 levels are not increased in patients with vitamin D intoxication with hypercalcemia, because of the suppression of parathyroid hormone reducing renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D.(2,3) The high levels of 1,25-dihydroxyvitamin D3, and the fact that the authors observed that treatment with hydroxychloroquine resulted in a rapid decline in circulating levels of 1,25-dihydroxyvitamin D3 should have alerted the authors that the likely explanation is due to the unregulated extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. The renal 25-hydroxy vitamin D-1 alpha-hydroxylase (CYP27B1) is not sensitive to hydroxychloroquine, ketoconazole or glucocorticoids as suggested by the authors. Only the extrarenal CYP 27B1 is sensitive to these medications.(4) The authors made a modest effort with imaging studies to rule out granulomatous disorders. However, the authors did not appreciate the patient’s previous history for urothelial carcinoma which has been reported to be associated with vitamin D toxicity associated with unregulated extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. This was the likely cause for his intoxication and renal failure and not the dose of vitamin D.(5)

References

1. Auguste BL, Avila-Casado C, Bargman JM. Use of vitamin D drops leading to kidney failure in a 54-year-old man. Canadian Medical Association Journal. 2019;191(14):E390.
2. Holick MF. Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective. Mayo Clinic Proceedings. 2015;90(5):561-4.
3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-30.
4. Adams JS, Hewison M. Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Archives of biochemistry and biophysics. 2012;523(1):95-102.
5. Asao K, McHugh JB, Miller DC, Esfandiari NH. Hypercalcemia in upper urinary tract urothelial carcinoma: a case report and literature review. Case reports in endocrinology. 2013;2013:470890-.