| Abstract|| |
Vitamin D deficiency state is endemic in the Kashmir valley of the Indian subcontinent. Clinicians frequently treat patients with Vitamin D for diverse clinical symptoms to improve the general health and to reduce the frailty of elderly and these doses may at times be inappropriately high. Vitamin D toxicity-induced acute kidney injury (AKI), often considered rare, can be life-threatening and associated with substantial morbidity if not identified promptly. We aimed to describe clinical and biochemical features, risk factors, and management of AKI patients with Vitamin D toxicity seen at a single tertiary care centre in Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India, between January 2014 and January 2016. Evaluation included detailed clinical history and biochemical tests including serum calcium, phosphorus, creatinine, intact parathyroid hormone, and 25-hydroxyvitamin D [25(OH)D]. Nineteen patients with Vitamin D toxicity-induced AKI could be identified. Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, AKI, acute on chronic kidney disease, and weight loss. Median (range) age was 64 (45–89) years. Median (range) serum 25(OH)D level and median (range) total serum calcium level were 99 (190–988) ng/mL and 139 (119–152) mg/dL, respectively. Overdose of Vitamin D caused by prescription of megadoses of Vitamin D was the cause of AKI in all cases. Median (range) cumulative Vitamin D dose was 6,000,000 (3,600,000–9,000,000) IU. On three- and six-month follow-up, the creatinine and estimated glomerular filtration rate normalized and returned to baseline in all patients except three cases who had underlying chronic kidney disease. Three patients needed rehospitalization for another episode of AKI. Our data demonstrate an emergence of Vitamin D toxicity as a cause of AKI in this part of the world. Irrational use of Vitamin D in megadoses resulted in AKI in all cases. Persistence of Vitamin D in the body for longer time resulted in rehospitalization of patients with AKI. Awareness among health-care providers regarding the toxic potential of high doses of Vitamin D and cautious use of Vitamin D supplements can have immense value to prevent this AKI.
|How to cite this article:|
Chowdry AM, Azad H, Najar MS, Mir I. Acute kidney injury due to overcorrection of hypovitaminosis D: A tertiary center experience in the Kashmir Valley of India. Saudi J Kidney Dis Transpl 2017;28:1321-9
|How to cite this URL:|
Chowdry AM, Azad H, Najar MS, Mir I. Acute kidney injury due to overcorrection of hypovitaminosis D: A tertiary center experience in the Kashmir Valley of India. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 May 23];28:1321-9. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1321/220873
| Introduction|| |
First identified as a vitamin early in the 20th century, the dominant function of Vitamin D in its hormonal form (calcitriol or 1,25-dihydroxyvitamin D [25(OH)D]) is the elevation of plasma calcium to normal levels which is required for the functioning of the neuromuscular junction as well as vasodilatation, nerve transmission, and hormonal secretion. Reports from India and across the world indicate that hypovitaminosis D is widespread in all age-groups., Increasing interest in Vitamin D, partly fueled by pharmaceutical interests, has led to a surge in Vitamin D prescription in recent years. The optimum dose schedule and route of administration of Vitamin D in asymptomatic Vitamin D deficiency, however, remains controversial. Clear recommendations are lacking, particularly in the Indian setting. Physicians are often unable to appreciate the different approaches required for asymptomatic Vitamin D deficiency on the one hand and Vitamin D deficiency-induced osteomalacia on the other. Overzealous correction of low Vitamin D in individuals not having metabolic bone disease has led to the emergence of an increasing number of cases of Vitamin D toxicity-induced acute kidney injury (AKI) over recent years. The Kashmir valley of the Indian subcontinent is situated at an altitude of 1574–5425 feet above the sea level at latitudes 320 20'–340 50' N and longitude 730 45'-750 35' E in the Northern mountainous regions of India. The valley is known to be a vitamin deficient area with Vitamin D deficiency seen in about 69.6% of individuals exposed to the outdoors and 100% of those confined indoors. We report a case series of 19 patients with Vitamin D toxicity-induced AKI seen between January 2014 and January 2016 and discuss in detail the clinical presentation, risk factors, management and prevention of Vitamin D toxicity-induced AKI.
| Methodology|| |
We collected data of 19 patients with Vitamin D toxicity-induced AKI seen over two years (January 2014–January 2016) from a single tertiary care centre in Sher-i Kashmir Institute of Medical Sciences, Srinagar, India. Patients were referred to the Nephrology department to diagnose the cause of AKI, and of these, patients fulfilling the criteria for Vitamin D toxicity were included. Vitamin D toxicity was defined as elevated serum calcium level (>105 mg/dL) with 25(OH)D level >150 ng/mL. Detailed clinical history was obtained in all patients. Laboratory evaluation included measurement of serum calcium, 25(OH)D, intact parathyroid hormone (iPTH), phosphorus, blood urea, and serum creatinine. Serum iPTH was measured using a chemiluminescent microparticle assay (Abbott architect i1000 SR; normal laboratory range 15–70 pg/mL), and serum 25(OH)D was measured using a chemiluminescent microparticle assay (Abbott architect i1000 SR). We also searched electronic laboratory database at our center for a total number of 25(OH)D estimations made and their results between years 2014 to 2016.
| Results|| |
Of the 19 patients studied, eight were male, and 11 were female. Median (range) age was 64 (45–89) years. [Table 1] summarizes the clinical and biochemical characteristics of the 19 patients.
The presenting clinical manifestations were nausea and vomiting (n = 11), altered sensorium (n = 7), constipation (n = 9), acute pancreatitis (n = 2), AKI (n = 16), acute on chronic kidney disease (n = 3), and weight loss (n = 2).
Biochemical parameters are shown in [Table 2]. Median (range) serum 25(OH)D level and median (range) total serum calcium level were 371 (190–988) ng/mL and 13 (11.9–15.2) mg/dL, respectively. Median iPTH was 16 (9–234) pg/mL. Three patients had elevated iPTH which was explained by coexisting chronic kidney disease. Serum 1,25(OH)2D levels were not available in any of our patients, since the test is not performed in our hospital.
Enteral or parenteral overcorrection of Vitamin D deficiency was the cause of Vitamin D toxicity-induced AKI in all cases. All the patients were prescribed Vitamin D by their primary care doctor for various indications: bone pains (n = 6), generalized aches and pains (n = 6), fatigue (n = 5), and myalgias (n = 2). Routine biochemical checkup for low serum 25(OH)D levels was performed in only seven patients before prescribing Vitamin D. Mode of Vitamin D administration was intramuscular injections of Vitamin D3 (each containing 600,000 IU) in seven patients, oral sachets/capsules (each containing 60,000 IU) in seven patients and combined oral and intramuscular in five patients. None of the patients presented with clinical or laboratory evidence of malignancy or any granulomatous disease, either during evaluation at hospital or during subsequent follow-up, for the next three months. They had no history of consumption of foods fortified with Vitamin D3. All patients had normal computerized scan/magnetic resonance imaging scans of the brain.
Details of route of Vitamin D administration and cumulative dose in each case are shown in [Table 1]. Median (range) cumulative Vitamin D dose received was 6000000 (3600000–9,000,000) IU.
[Table 3] shows the total number of 25(OH)D estimations made at our center by various specialties and total number of cases with 25(OH)D beyond toxic level (>150 ng/mL) between years 2014 to 2016. As these data were obtained by reviewing the electronic laboratory database, indications for testing serum 25(OH)D by various specialties cannot be commented on.
Management and course
A total of 19 patients were hospitalized for the management of AKI associated with Vitamin D toxicity. Management of AKI and hypercalcemia primarily included volume expansion with intravenous fluids (0.9% normal saline), judicious use of loop diuretics to enhance sodium and calcium excretion, subcutaneous administration of calcitonin and glucocorticoids. None of the patients required dialysis. The average duration of hospital stay in these patients was two weeks, ranging from one to three weeks. One patient who presented with altered sensorium died during the hospital stay from aspiration pneumonia.
At discharge, all the patients were instructed to maintain oral hydration, avoid calcium and Vitamin D supplements for the next six months and repeat serum calcium monthly for the initial three months and then three-monthly for another one year.
Three patients out of the total 19 had rehospitalization due to hypercalcemia-induced AKI without the history of subsequent Vitamin D ingestion. Of these three patients, one was admitted with altered sensorium and two presented with nausea, vomiting, and constipation.
| Discussion|| |
Vitamin D toxicity-induced AKI is almost always an iatrogenic problem and is totally preventable. There are unusual case reports of Vitamin D intoxication and renal failure secondary to the use of over-the-counter supplements and even milk fortification.,,,, Accidental consumption of very high doses of Vitamin D has also been reported to cause AKI. Our case series is an example of an overambitious attempt to correct Vitamin D deficiency. All the cases were prescribed Vitamin D much beyond the recommended pharmacological doses. Moreover, most of the patients were prescribed intramuscular injections of Vitamin D containing very high dose (600,000 IU) at frequent intervals (daily, alternate day or weekly, etc). Parenteral preparations of Vitamin D should be avoided unless there is evidence of malabsorption, and none of our patients had any suggestion of malabsorption. Seven patients developed AKI with only oral intake of Vitamin D, and another seven developed AKI with only injectable preparation of Vitamin D, but they received very high doses, such as 60,000 IU oral daily or on alternate days over one to three months and 600,000 IU of intramuscular Vitamin D daily or alternate day or weekly.
The exact toxic dose of Vitamin D has not been established. The Institute of Medicine report concluded that doses below 10,000 IU/day are not usually associated with toxicity, whereas doses equal to or above 50,000 IU/day for several weeks or months are frequently associated with toxic side effects including documented hypercalcemia-induced AKI. Most of the reports of Vitamin D toxicity have documented Vitamin D intake of >40,000 IU/day. Single high doses in the pediatric population (Stoss therapy) were associated with hypercalcemia and probably hypervitaminosis D. Hypercalcemia and Vitamin D toxicity were noted in children when they received total dose of 240,000–4,500,000 IU of Vitamin D. In this report, significant variability was noticed in the amount of Vitamin D intake and serum 25(OH)D, and we found no relationship between serum 25(OH)D and calcium levels and clinical status. In this case series, the cumulative Vitamin D dose was above 240000 IU. The mean cumulative Vitamin D dose received in our case series was 6274737 IU over a mean period of nine weeks (range: 5 weeks to 14 weeks), which corresponds to a mean Vitamin D intake of 99599 IU/day. This highlights that high doses may be associated with Vitamin D toxicity.
Vitamin D intoxication results in elevation of the plasma concentrations of various metabolites of Vitamin D3: 25(OH)D3, 24,25(OH) 2D3, 25,26(OH)2D3 and 25(OH)D3-26,23-lactone. The mechanism of Vitamin D toxicity is explained by an overwhelming of the vitamin D signal transduction process, whereby the catabolic system involving the CYP24A1 is unable to keep up with the target cell levels of activated Vitamin D metabolites. Three major theories have been postulated to explain the mechanisms of Vitamin D toxicity. All involve increased concentrations of a Vitamin D metabolite reaching the Vitamin D receptor in the nucleus of target cells and causing exaggerated gene expression. At issue is the offending Vitamin D metabolite and how it becomes elevated. The three hypotheses to explain this are as follows:
- Vitamin D intake raises plasma 1-alpha-25(OH)2D concentrations, which increase cellular 1-alpha 25(OH)2D concentrations
- Vitamin D intake raises plasma 25(OH)D to concentrations that exceed the capacity of the Vitamin D-binding protein (DBP), and “free 25(OH)D” enters the cell, where it has direct effects on gene expression
- Vitamin D intake raises the concentrations of many Vitamin D metabolites, especially Vitamin D itself and 25(OH)D. These concentrations exceed the DBP-binding capacity and cause release of “free” 1-alpha 25(OH)2D, which enters target cells.
Of the three hypotheses put forward, increase in total 25(OH)D and free 1-alpha-25(OH)2D concentrations are the most plausible, although they remain unproven. However, even in the absence of definitive evidence to establish the responsible metabolite, the wealth of animal studies and human anecdotal reports of Vitamin D intoxication indicate that plasma 25(OH)D3 is a good biomarker for toxicity.
Too much Vitamin D can be as dangerous as too little. All 19 cases in this series presented with Vitamin D-induced hypercalcemia and AKI. Accurate clinical and drug history, along with the finding of renal failure, elevated 25(OH)D level (>150 ng/mL) and suppressed iPTH, in the presence of hypercalcemia, confirmed the diagnosis of AKI with Vitamin D toxicity in all our cases. Three cases had elevated iPTH levels, which could be explained by coexisting chronic kidney disease.
The clinical manifestations of Vitamin D toxicity are a consequence of hypercalcemia and include fatigue, generalized weakness, anorexia, polyuria/polydipsia and dehydration, constipation, nausea, vomiting, confusion, difficulty in concentration, irritability, drowsiness, and coma. Hypercalcemia is a known etiologic factor for human acute pancreatitis and AKI. Two patients presented with acute pancreatitis in this series.
In our experience, not all cases with high serum 25(OH)D levels (>150 ng/mL) manifested Vitamin D toxicity. Over a two-year period, 167 patients had serum 25(OH)D levels >150 ng/mL (data taken from the laboratory), of which 19 patients developed Vitamin D toxicity with AKI (data shown in this paper), whereas nine patients were asymptomatic with no AKI. This is supported by other case reports in the literature, which have shown that patients may have levels of serum 25(OH)D above 100 and up to 150 ng/mL without associated hypercalcemia., Significant variability in serum 25(OH)D and calcium levels following oral or intramuscular administration of Vitamin D has been reported. The factors include compliance and adherence to regimen, types of Vitamin D used (D2 vs. D3), route of administration (oral vs. parenteral), body weight and methods of Vitamin D estimation. Further, genes regulating the metabolism of vitamin DBP, and conditions associated with intestinal absorption may influence serum 25(OH)D or serum calcium status., Other risk factors for Vitamin D toxicity include extremes of age, concurrent use of thiazide diuretics, parenteral use of Vitamin D, impaired renal function, and coexisting disorders such as sarcoidosis and tuberculosis. In our case series, 14 of 19 patients were elderly (age >60 years), three patients had coexisting chronic kidney disease, and 12 patients received parenteral Vitamin D.
Vitamin D toxicity is an emergency, which, if not managed promptly, can be life-threatening. Intravenous hydration with normal saline is the mainstay of treatment of hypercalcemia. Loop diuretics should be administered judiciously, as their use can exacerbate preexisting dehydration. In patients with 1,25(OH)2D-mediated hypercalcemia and AKI, glucocorticoids are the preferred therapy. All our patients were hospitalized and received glucocorticoids. Other drugs such as ketoconazole, chloroquine, and hydroxychloroquine, may also decrease 1,25(OH)2D production and are used occasionally. None of our patients needed these additional drugs. Hypercalcemia caused by parenteral Vitamin D overdose can take a long time to normalize due to slow release of Vitamin D from fat deposits. Three of our patients needed rehospitalization for the second episode of hypercalcemia and AKI. Therefore, the patients should be followed up regularly with monitoring of serum calcium and 25(OH)D for six months to one year. The patient should also be instructed to avoid intake of any calcium or Vitamin D supplements.
Case reports and small case series of Vitamin D intoxication and AKI from India have started to appear recently in the literature.,,, The poison seems to be in the dose. Recent awareness of the importance of Vitamin D deficiency, coupled with a lack of understanding of rational pharmacotherapeutics, has led to an increase in inappropriate use of Vitamin D and calcium supplements. Vitamin D supplements given empirically under the garb of wellness and bone health prescriptions, for nonspecific body aches and pains, by several specialties, are passed off unscrupulously as healthy and safe in the patients. To our dismay, a low serum 25(OH)D level diagnosed in routine health screening is often treated with megadoses of calcium and vitamin D supplements by enthusiastic physicians. This has resulted in Vitamin D toxicity as an uncommon cause of hypercalcemia-induced AKI, or not so uncommon cause of hypercalcemia-induced AKI. We anticipate this problem to get only worse as there is a skyrocketing trend in the number of Vitamin D estimations in the past few years. [Table 3] shows the total number of 25(OH)D estimations made at our center and total number of cases with 25(OH)D beyond toxic level (>150 ng/mL) between years 2014 and 2016. A clear increasing trend in number of Vitamin D estimations, along with the number of cases with toxic levels of Vitamin D can be seen. This is purely the result of overenthusiastic correction of low Vitamin D in individuals not having the metabolic bone disease. In addition, marketing of Vitamin D supplements has multiplied 20 times over the past five years with number of brands of Vitamin D increasing from just four in 2010 to 241 in 2014 [data obtained from (All Indian Origin Chemists and Distributors Ltd.) Pharmasofttech (Airborne Warning and Control System) Pvt. Ltd)].
There are some limitations of the study:
- It is a hospital-based study, and hence, the burden of Vitamin D intoxication-induced AKI in the whole Kashmir valley cannot be commented on
- Serum creatinine and calcium levels of all cases with 25(OH)D levels >150 ng/mL, searched from electronic laboratory database of SKIMS, were not looked into
- Although clinical experience and the present case series suggest that the number of cases of Vitamin D toxicity has gone up in recent years, it is not possible to comment on the community incidence of Vitamin D toxicity and AKI. In addition, data from previous decades are not available to make a meaningful comparison.
Vitamin D toxicity is completely a preventable condition. Key preventive measures include the following: (i) awareness among health-care providers regarding the toxic potential of high doses of Vitamin D, (ii) cautious use of Vitamin D supplements and avoidance of empirical treatment of non-specific bony pains with mega-doses of Vitamin D, and (iii) avoidance of parenteral preparation of Vitamin D unless there is evidence of malabsorption.
| Conclusion|| |
Our case series demonstrates the emergence of reversible AKI due to Vitamin D toxicity as an increasingly common clinical problem. Irrational use of Vitamin D in megadoses resulted in AKI in all cases. To prevent iatrogenic Vitamin D toxicity, awareness should be increased among health-care providers regarding the toxic potential of mega doses of Vitamin D, despite its wide margin of safety. Anything that is overdone becomes dangerous.
Conflict of interest: None declared.
| References|| |
Mithal A, Wahl DA, Bonjour JP, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int 2009;20:1807-20.
Hilger J, Friedel A, Herr R, et al. A systematic review of vitamin D status in populations worldwide. Br J Nutr 2014;111:23-45.
Zargar AH, Ahmad S, Masoodi SR, et al. Vitamin D status in apparently healthy adults in Kashmir Valley of Indian subcontinent. Postgrad Med J 2007;83:713-6.
Chiricone D, De Santo NG, Cirillo M. Unusual cases of chronic intoxication by vitamin D. J Nephrol 2003;16:917-21.
Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med 1992;326:1173-7.
Klontz KC, Acheson DW. Dietary supplement-induced vitamin D intoxication. N Engl J Med 2007;357:308-9.
Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med 2001;345: 66-7.
Leu JP, Weiner A, Barzel US. Vitamin D toxicity: Caveat emptor. Endocr Pract 2008; 14:1188-90.
Chambellan-Tison C, Horen B, Plat-Wilson G, Moulin P, Claudet I. Severe hypercalcemia due to vitamin D intoxication. Arch Pediatr 2007; 14:1328-32.
Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Washington (DC): National Academies Press (US). 2011. Available from: http://www.ncbi.nlm.nih.gov/books/NBK56070/
. [Last accessed on 2015 Jan 03].
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842-56.
Jeans PC, Stearns G. The effect of vitamin D on linear growth in infancy: II. The effect of intakes above 1,800 U.S.P. Units daily. J Pediatr 1938;13;730-40.
Vogiatzi MG, Jacobson-Dickman E, DeBoer MD, Drugs, and Therapeutics Committee of The Pediatric Endocrine Society. Vitamin D supplementation and risk of toxicity in pediatrics: A review of current literature. J Clin Endocrinol Metab 2014;99:1132-41.
Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88:582S-586S.
Maalouf J, Nabulsi M, Vieth R, et al. Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children. J Clin Endocrinol Metab 2008;93:2693-701.
Autier P, Gandini S, Mullie P. A systematic review: Influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol Metab 2012;97: 2606-13.
Joshi R. Hypercalcemia due to hypervitaminosis D: Report of seven patients. J Trop Pediatr 2009;55:396-8.
Koul PA, Ahmad SH, Ahmad F, et al. Vitamin d toxicity in adults: A case series from an area with endemic hypovitaminosis d. Oman Med J 2011;26:201-4.
Pandita KK, Razdan S, Kudyar RP, et al. “Excess good can be Dangerous”. A case series of iatrogenic symptomatic hypercalcemia due to hypervitaminosis D. Clin Cases Miner Bone Metab 2012;9:118-20.
Maji D. Vitamin D toxicity. Indian J Endocrinol Metab 2012;16:295-6.
Abdul Majeed Chowdry
Department of Nephrology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir
[Table 1], [Table 2], [Table 3]