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Excess Vitamin D Linked to Kidney Damage
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Download the PDF here
Veronica Hackethal, MD
April 08, 2019
https://www.medscape.com/viewarticle/911444
Vitamin D has been reported to have a wide range of benefits. However, a recent case study indicates that excessive use of vitamin D can cause kidney damage in people who are not deficient in the vitamin.
The article was published online April 8 in the Canadian Medical Association Journal.
"The aim of this case study is to inform a wider audience that vitamin D at large doses [10,000 IU daily] in patients with normal serum vitamin D levels can lead to toxicity," first author Bourne Auguste, MD, University of Toronto, Ontario, Canada, told Medscape Medical News.
"The public should know that taking more vitamin D than is recommended does not necessarily lead to added benefit. Rather, it can lead to increased harm and specifically kidney failure," he added.
2010 guidelines from Osteoporosis Canada recommend 400–1000 IU of vitamin D daily for most adults, and 800–2000 IU daily for older adults and those at increased risk for osteoporosis. The US recommended daily intake of vitamin D for males and females between the ages of 1 and 70 years is 600 IU daily and 800 IU for those older than 70 years.
Because vitamin D has a wide therapeutic range, toxicity is rare, Auguste and colleagues note. However, as a fat-soluble vitamin, high doses of it taken for extended periods can lead to buildup.
"Many patients think of vitamin D as a simple supplement with no harm and perhaps historically overstated benefits," Auguste said. "Given that it is so readily available in various over-the-counter formulations and the perception that it has many benefits with no harm, other patients [besides the one in this case study] may be at risk for vitamin D toxicity and potentially kidney failure."
Vitamin D toxicity has a wide range of symptoms, which can delay diagnosis. Those symptoms include, among others, fatigue, high blood pressure, frequent urination, confusion, and itchiness. Early recognition of vitamin D toxicity may prevent chronic kidney damage.
"Vitamin D toxicity may go unrecognized for a long period of time, given the nonspecific symptoms patients may have on presentation. Patients may be taking over-the-counter supplements without full disclosure," Auguste explained.
Management includes careful review of prescription and over-the-counter medications, limiting exposure to sunlight, decreasing dietary and supplemental sources of vitamin D, and monitoring vitamin D levels in asymptomatic patients. Because it is fat soluble, it can take several months for levels to return to normal. In addition, after stopping vitamin D supplements, calcium levels may continue to increase before reversing.
"Clinicians should also consider adjunctive therapies beyond cessation of vitamin D and calcium supplements, such as hydroxychloroquine, glucocorticoids, and ketoconazole in those patients who are symptomatic to decrease the active form of vitamin D in the body," Auguste advised.
Supplements and Sunlight Triggered Toxicity
The reported case concerns a 54-year-old man who had recently returned from a trip to Southeast Asia, where he had spent an extended time sunbathing (6–8 hours per day for 2 weeks). Upon returning to Canada, a family physician found that his creatinine level was elevated (132 μmol/L from a baseline of 100 μmol/L). Four weeks later, despite discontinuing antihypertensive medication and diuretics, which could have caused dehydration and elevations in creatinine, the patient's creatinine level was even higher (376 μmol/L), and he was referred to a kidney specialist.
Further questioning revealed that the man had seen a naturopath who had prescribed high doses of vitamin D. Despite no known history of bone loss or vitamin D deficiency, the man took 8000–12000 IU of vitamin D daily for 2.5 years.
Workup disclosed hypercalcemia (ionized calcium, 1.48 mmol/L) and elevated levels of vitamin D (1,25-dihydroxyvitamin D3 level, 274 pmol/L; 25-hydroxyvitamin D3, 241 nmol/L). Renal biopsy results showed kidney damage (nephrosclerosis and microcalcifications without sarcoidosis or light chain deposition).
The nephrologist advised him to stop taking vitamin D supplements and to stop eating calcium-rich foods. His diuretics remained on hold, and the patient resumed taking one antihypertensive medication. At the second visit, physicians found that his levels of 1,25-dihydroxyvitamin D3 (the biologically active form of vitamin D) and calcium had continued to increase. The patient also described new-onset skin itchiness, likely due to his high calcium levels.
The patient declined to receive glucocorticoids because of concerns about weight gain. Upon starting hydroxychloroquine 400 mg daily, his calcium and vitamin D levels decreased. Almost 1 year later, his calcium and vitamin D levels returned to normal, but he has stage 3B chronic kidney disease.
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Use of vitamin D drops leading to kidney failure in a 54-year-old man
http://www.cmaj.ca/content/191/14/E390
CMAJ April 08
KEY POINTS
• Vitamin D toxicity is rare, but clinicians must be aware of the risks of vitamin D use to limit complications related to hypercalcemia.
• Calcium levels may get worse before getting better in patients even after cessation of supplements, as vitamin D is fat soluble.
• Observational data and expert opinion suggest that glucocorticoids, ketoconazole and hydroxychloroquine are reasonable options to treat hypercalcemia related to vitamin D toxicity by decreasing the “active” 1, 25 dihydroxyvitamin D3 levels.
A 54-year-old man was referred urgently to the nephrology clinic by his family physician for suspected acute kidney injury, with a creatinine level of 376 μmol/L. He had recently returned from a trip to Southeast Asia, where he had spent extensive periods sunbathing (6–8 h/d) for 2 weeks. His medical history included hypertension, dyslipidemia and gout, for which he was taking perindopril 8 mg daily, rosuvastatin 10 mg daily, amlodipine 10 mg daily, indapamide 2.5 mg daily and febuxostat 80 mg daily.
On his return to Canada, the patient’s creatinine level had initially increased from his baseline of 100 μmol/L to 132 μmol/L. His family physician instructed him to discontinue his antihypertensive and diuretic agents temporarily on the premise that he had possible extracellular fluid depletion from the heat exposure. Despite this measure, on repeat measurement 4 weeks later, the patient’s creatinine level had risen to 376 μmol/L. During this 4-week period, he had not used nonsteroidal antiinflammatory drugs or new medications, had not been exposed to intravenous contrast and had no acute illnesses. Given that his creatinine level continued to rise rapidly with no clear etiology, the patient was referred to nephrology.
The patient’s family history included autosomal dominant polycystic kidney disease, with 2 first-degree relatives requiring dialysis before age 60. However, he had undergone radiographic screening with abdominal ultrasonography, which was negative for polycystic kidneys.
At the nephrology clinic, the patient’s blood pressure was 149/98 mm Hg, with no urgent clinical indications for dialysis. Renal ultrasonography showed normal-sized kidneys with no hydronephrosis or echogenicity. An incidental 1.2 cm bladder mass was seen on ultrasonography and was later diagnosed as noninvasive urothelial carcinoma. (This was treated with local excision with interval surveillance, requiring no chemotherapy.)
Urine studies at the patient’s initial nephrology visit did not show leukocytes, erythrocytes or protein. There were no cellular casts or crystals seen on urine microscopy. Results of serum and urine protein electrophoresis studies were negative. Complete blood count was normal. However, the patient’s serum calcium and parathyroid hormone (PTH) levels showed a non-PTH-mediated hypercalcemia (Box 1). Testing of 25-hydroxyvitamin D3 and 1,25 dihydroxyvitamin D3 levels was ordered. Imaging studies of the chest and abdomen were unremarkable.
On more detailed questioning, the patient mentioned that he was seeing a naturopathic specialist who had prescribed high doses of vitamin D, advising him to take 8 drops of a specific brand daily. He did not have a history of a fragility fracture or documented vitamin D deficiency. The recommended brand contained 500 IU per drop. Unknowingly, the patient obtained another vitamin D preparation that contained 1000 IU per drop. The patient was not counselled about toxicity risks and, over a period of 2.5 years, he took 8–12 drops of vitamin D daily, for a total daily dose of 8000–12 000 IU.
At the nephrology clinic, the patient’s measured 1,25 dihydroxyvitamin D3 level was 274 pmol/L and his 25-hydroxyvitamin D3 level was 241 nmol/L (Box 1). He was instructed to stop taking all vitamin D supplements and calcium-rich foods. His diuretics remained on hold, but one of his antihypertensive agents (amlodipine) was resumed after his second clinic visit. His 1,25 dihydroxyvitamin D3 and ionized calcium levels continued to increase (Figure 2). His only new symptom related to hypercalcemia was pruritus.
Given his worsening hypercalcemia and increased active vitamin D levels, we counselled the patient about starting glucocorticoid therapy. He was reluctant to start glucocorticoids, given concerns about potential weight gain. As an alternative, we offered oral hydroxychloroquine at 400 mg daily and counselled the patient on adverse effects, including retinal toxicity.
The patient’s calcium and vitamin D levels decreased after initiation of hydroxychloroquine. Almost 1 year after diagnosis, his calcium and vitamin D levels have returned to normal, but he is left with stage 3B (estimated glomerular filtration rate 34 mL/min/1.73m3) chronic kidney disease.
Discussion
Historically, reports have outlined the benefits of vitamin D in relation to bone health.1 Other purported benefits of vitamin D included nonskeletal outcomes, such as cardiovascular benefit, fall prevention, and reduction of infections and malignancies.2 However, an umbrella review of systematic reviews and meta-analyses did not show that vitamin D reduces primary fracture risk or convincingly improves other nonskeletal health outcomes.3 Furthermore, a recent review for the US Preventive Services Task Force showed no benefit of vitamin D in preventing primary fracture in those without known deficiency, osteoporosis or prior fracture.4
In its 2010 guideline, Osteoporosis Canada recommended vitamin D supplementation of 10–25 μg (400–1000 IU) for most low-risk adults under the age of 50 years to achieve serum levels of 25-hydroxyvitamin D3 greater than 75 nmol/L (level 3 evidence),1 arguing that the potential benefits outweigh risks. A daily vitamin D intake of 20–50 μg (800–2000 IU) is recommended for high-risk and older adults (level 2 evidence).1
Mechanism of vitamin D toxicity
Although vitamin D toxicity is rare owing to a large therapeutic range, its widespread availability in various over-the-counter formulations may pose a substantial risk to uninformed patients. After consumption, vitamin D is carried to the liver where it undergoes hydroxylation and is activated by either microsomal CYP2R1 or mitochondrial CYP27A1 to 25-hydroxyvitamin D3.5,6 The resulting 25-hydroxyvitamin D3 binds to the vitamin D binding protein and is carried to the kidneys for further 1α-hydroxylation by CYP27B1 to produce 1,25 dihydroxyvitamin D3.6 This 1,25 dihydroxyvitamin D3 is transported to target cells and enters the nucleus of the vitamin D receptor, leading to an upregulation in gene expression. Although it is transported by vitamin D binding protein, 1,25 dihydroxyvitamin D3 has a lower affinity to binding relative to 25-hydroxyvitamin D3 and its metabolites.5 A leading hypothesis suggests that an oversaturation of the vitamin D binding protein causes an increase in free active Vitamin D (1,25 dihydroxyvitamin D3), resulting in hypercalcemia.
CYP24A1 plays an important role in the deactivation of 1,25 dihydroxyvitamin D3 to calcitroic acid.6 CYP24A1 also breaks down precursor 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3. Loss-of-function mutations in CYP24A1 have been associated with hypercalcemia because of increased vitamin D sensitivity.6 Although we did not perform genetic testing on our patient, it is plausible that he had a CYP24A1 mutation, increasing his susceptibility to vitamin D toxicity.
Manifestations of toxicity
Toxicity can occur over a short period in patients ingesting large doses of vitamin D, either intentionally or inadvertently.7 The literature supports that doses greater than 10 000 IU per day for several months may lead to toxicity (> 200 nmol/L of 25-hydroxyvitamin D3).8 However, differences in patient characteristics such as malabsorption and mutations in CYP24A1 can lead to substantial variation in doses required for toxicity to occur.
Patients may present with symptoms involving the central nervous system and gastrointestinal, genitourinary and cardiovascular systems. Central nervous system manifestations include lethargy, hypotonia, hyporeflexia, confusion and coma. Gastrointestinal symptoms include nausea, vomiting, pancreatitis and constipation; cardiovascular symptoms of toxicity, such as hypertension, arrhythmias and QT segment shortening, may also occur.9 Genitourinary symptoms include polyuria, nephrocalcinosis and renal failure. The symptomatology associated with vitamin D toxicity underscores the suggestion that hypercalcemia may be responsible for most symptoms seen.7 Sustained hypercalcemia can also lead to dysregulation of calcium–phosphate homeostasis leading to PTH suppression and impaired bone turnover.3,5
Importantly, patients may be asymptomatic, delaying diagnosis, and abnormalities related to vitamin D toxicity may be detected only incidentally.
In terms of renal involvement, hypercalcemia can cause kidney injury both acutely and chronically. Hypercalcemia can cause acute kidney injury primarily by 2 mechanisms: afferent arteriolar constriction and intravascular volume depletion from a diuretic effect through activation of calcium-sensing receptor at the sodium–chloride cotransporter in the loop of Henle.10 Our patient’s acute kidney injury was likely worsened by volume depletion from diuretic use, prolonged heat exposure and preexisting hypercalcemia from vitamin D toxicity. We saw some improvement in his renal function as his calcium levels decreased, by discontinuing his vitamin D supplements and temporarily holding his diuretics and antihypertensive agents. However, we believe that our patient developed chronic disease as shown by nephrosclerosis on renal biopsy (Figure 1).
Management of toxicity
In cases where vitamin D toxicity is suspected, patients should have their medications — prescribed and over-the-counter — carefully reviewed. Initial strategies to reduce vitamin D levels should focus on reducing dietary or supplementary sources. Although there is currently no evidence from large trials, observational data suggest that clinicians may consider strategies to reduce active vitamin D levels if hypercalcemia persists, through inhibition of 1α-hydroxylase activity (Figure 3).11,12 If patients are asymptomatic, clinicians may choose to monitor levels expectantly, as vitamin D is very fat soluble and levels may take some time to return to normal.
Several medications have been used successfully to treat hypercalcemia by reducing the active form of vitamin D. Glucocorticoids, ketoconazole and hydroxychloroquine have all been used in cases of hypercalcemia related to sarcoidosis.1,9 Expert opinion suggests that these medications reduce 1α-hydroxylase activity and may be used to manage hypercalcemia by reducing 1,25 dihydroxyvitamin D3 levels.11,12 Given that our patient was reluctant to use glucocorticoid treatment, we used hydroxychloroquine as an alternative to decrease his 1,25 dihydroxyvitamin D3 levels and, in turn, his calcium levels.
Our experience informs us that patients and clinicians should be better informed about the risks regarding the unfettered use of vitamin D. Given new findings from the US Preventive Services Task Force,4 current Canadian guidelines regarding its use in low-risk individuals should be revisited.
Patients with CYP24A1 mutations may be at an increased risk of vitamin D toxicity, and clinicians can consider genetic testing if vitamin D toxicity develops with doses less than 10 000 IU per day. Although vitamin D toxicity is rare, early recognition may prevent chronic complications related to hypercalcemia. In patients who are symptomatic, cessation of supplements along with treatment with glucocorticoids is suggested. In cases where glucocorticoid therapy is not preferred or is contraindicated, ketoconazole or hydroxychloroquine are reasonable alternatives.
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