Pediatr Transplantation 2015: 19: 492–498
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12527
Vitamin D insufficiency and deficiency in pediatric renal transplant recipients Ebbert K, Chow J, Krempien J, Matsuda-Abedini M, Dionne J. (2015) Vitamin D insufficiency and deficiency in pediatric renal transplant recipients. Pediatr Transplant, 19: 492–498. DOI: 10.1111/petr.12527.
Kirsten Ebbert1, Josephine Chow2, Jennifer Krempien2, Mina Matsuda-Abedini3 and Janis Dionne2 1
Abstract: Vitamin D deficiency is prevalent in the pediatric CKD population. Recognizing that renal transplant recipients have CKD, we assessed the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients, compared to a healthy pediatric population. We prospectively studied 25(OH)D levels in 29 pediatric renal transplant recipients and 45 control patients over one yr. The overall prevalence of vitamin D insufficiency and deficiency was common in both populations, at 76% (95% CI: 61, 87%) in the pediatric renal transplant recipients and 91% (95% CI: 80, 98%) in the control group. In the paired renal transplant samples, the mean 25(OH) D level was 52.3 17.9 nmol/L in the winter and 65.6 18.8 nmol/L in the summer (95% CI diff.: 3.9, 22.7), in keeping with a significant seasonal difference. The mean dietary intake of vitamin D in the renal transplant recipients, assessed by three-day dietary record, was 5.7 lg/ day, with a vitamin D intake below the EAR in the majority. We did not find an association between vitamin D intake and 25(OH)D levels in this study, likely due to the low dietary intake of vitamin D within the transplant population, identifying a potential area for intervention and improvement.
Vitamin D is increasingly recognized as an important metabolite for which there is a significant, previously underappreciated, prevalence of deficiency. Vitamin D is a prohormone (1) that may be derived from dietary sources or synthesized in the skin (2). While over 90% of our vitamin D stores are endogenously produced, dietary intake may be a more important factor in settings where sun exposure is limited (3). Health Canada reviewed the vitamin D status of Canadians in the 2007–2009 Canadian Health Measures Survey, finding 25(OH)D levels below 75 nmol/L in 51% of 6- to 11-yr-olds, and 65% of 12- to 19-yr-olds (4). Furthermore, vitamin D deficiency resulting in rickets has been reported in Canadian infants and children, with 104 cases Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CKD, chronic kidney disease; EAR, estimated average requirement; ICH-GCP, International Conference on Harmonization Good Clinical Practice; iPTH, intact parathyroid hormone; LCMSCS, liquid chromatography tandem mass spectrometry; nGFR, nuclear medicine glomerular filtration rate; RDA, recommended daily intake.
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Department of Pediatrics, B.C. Children’s Hospital, Vancouver, BC, Canada, 2Division of Nephrology, University of British Columbia, BC Children’s Hospital,Vancouver, BC, Canada, 3Division of Nephrology, University of Toronto,The Hospital for Sick Children,Toronto, ON, Canada
Key words: vitamin D – 25-hydroxyvitamin D – kidney transplantation – recommended dietary allowances – seasons – pediatric Janis Dionne, MD, Pediatric Nephrology, B.C. Children’s Hospital, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada Tel.: 604 875 2272 Fax: 604 875 3649 E-mail: [email protected] Accepted for publication 15 April 2015
over a two-yr period (5). While vitamin D levels have been shown inadequate in various Canadian populations, to our knowledge there is no reference data specific to the British Columbia pediatric population, despite differences in weather and diet as compared to other regions in Canada. Awareness is increasing regarding the importance of vitamin D in multiple physiologic systems and disease processes. Vitamin D supplementation in infancy has been associated with an 80% decrease in the incidence of type I diabetes mellitus in a 30-yr Finnish birth cohort study (6). Vitamin D levels have been shown to be inversely associated with plasma glucose concentration (7, 8) and insulin resistance (7) and positively correlated with HDL levels (8) in pediatric populations. Vitamin D is also thought to have an important role in innate immunity and decreased infection (9). Vitamin D is particularly important in renal patients, both those with CKD and renal transplants. In CKD, vitamin D deficiency is associated with adverse effects including hyperparathyroidism (10), anemia (11), and an
Vitamin D in pediatric renal transplant
increased risk of cardiovascular disease, including early atherogenesis, vascular calcifications, and heart failure (12). Reduced control of inflammation and altered renin activity may contribute to this increased degree of cardiovascular risk (12). Patients with renal disease have multiple risk factors for developing vitamin D deficiency; these include restricted diet, decreased activity and sunlight exposure, prescribed sun avoidance (13), the need for greater sunlight exposure to produce equivalent vitamin D3 to that produced by a healthy person (14), increased urinary losses of megalin and 25(OH)D bound to vitamin D binding protein (if proteinuric) (15), and use of corticosteroids (16). Vitamin D deficiency has been correlated with poorer graft function postrenal transplantation (17). Literature on the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients is limited; a wide range in prevalence, from 49% to 100%, has been described in the populations studied (18–22). Seasonal variation, a wide range of geographic locations, and a variety of ethnicities have been assessed in these studies. Outside of lower 25 (OH)D levels being associated with winter months, clear trends with respect to these variables have not been consistently reproduced. Without a healthy ethnically comparable control population for comparison, it would be difficult to determine how rates of vitamin D insufficiency and deficiency vary from the expected rate within that geographic population. In the only two studies that included a control group for comparison (21, 22), results were contradictory. The majority of these studies did not compare seasonal variation within individuals, and none of these studies assessed the impact of dietary vitamin D intake. In this study, we aimed to determine the prevalence of vitamin D insufficiency and deficiency in a cross-sectional population of pediatric renal transplant recipients, comparing the prevalence with a control group of healthy children. We also compared seasonal differences in the mean 25 (OH)D level in each group and assessed dietary vitamin D intake as a contributory factor to vitamin D status in the renal transplant recipients. Patients and methods This was a prospective study of pediatric renal transplant recipients, and a cross-sectional control group. Data were collected between August 2009 and August 2010. The study included 29 pediatric renal transplant recipients from the Multi-Organ Transplant Clinic at British Columbia Children’s Hospital, Canada. This is the only pediatric transplant center for all children in British Columbia and the Yukon Territory. All 48 pediatric renal transplant recipients
cared for at our center were eligible. British Columbia and the Yukon are situated at a latitude above 48 degrees north. In the city of Vancouver (the most populated city in British Columbia and the Yukon), sunlight hours range from 54 h per month in December, to 296 h per month in July. Pediatric renal transplant recipients were evaluated at enrollment and approximately six months later for seasonal variation analysis. The control group comprised 45 generally healthy children requiring minor operative procedures through day surgery at BC Children’s Hospital. Patients with chronic illnesses and those requiring a procedure for underlying diagnoses known to be associated with vitamin D deficiency were excluded. All patients in the control group were between the ages of six and 17 yr, to match the typical age range of the renal transplant population. Twenty-four of the control patients were recruited in the winter, and 21 were recruited in the summer, stratified to allow for seasonal comparison. All subjects and/or parents provided informed consent, and subjects aged 7–13 yr provided assent. The research was approved by the University of British Columbia Children and Women’s Hospital Research Ethics Board and was in accordance with the ICH-GCP. All subjects in the renal transplant and control groups had a 25(OH)D level drawn at the time of routine blood work or during intravenous catheter insertion. Study 25 (OH)D3 levels were analyzed at a single laboratory by highperformance LCMSCS. Renal transplant recipients were also requested to complete a three-day dietary record, which was subsequently analyzed by our transplant dietitian for vitamin D intake. Data including ethnicity and current medications or supplements were collected on all participants. Most recent nGFR and underlying renal disease were collected for renal transplant recipients. The KDOQI guideline reference ranges were used to stratify the results in this study. Severe vitamin D deficiency was defined as 75 nmol/L (14). The year was divided into two 6-month periods based on data for local sunlight hours. The six months with the greatest number of sunlight hours, April through September, were designated as “summer”; the six months with the fewest sunlight hours, October through March, were designated as “winter.” Seasonal data were analyzed according to this stratification. Statistical analysis included comparison of the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients to controls. The difference in prevalence between groups was assessed with a 95% confidence interval as a measure of precision. The mean 25(OH) D levels were compared between the renal transplant and control groups, with standard error reported. To assess seasonal variation, mean winter and summer 25(OH)D levels from paired renal transplant recipients were compared, and the mean change was reported with standard error. The mean winter and summer 25(OH)D levels were compared in the control group, and the mean change was reported with standard error. The contribution of dietary vitamin D intake to vitamin D status in renal transplant recipients was analyzed using a linear regression model. The correlation between iPTH and 25(OH)D was analyzed using a linear regression model.
Results
The baseline characteristics of subjects involved in this study are outlined in Table 1. 493
Ebbert et al. Table 1. Renal transplant recipient and control group characteristics
N Age (yr) Male Ethnicity Caucasian Asian Oriental South Asian First Nations Hispanic Other Vitamin D supplement
Renal transplant recipients
Control group
29 16 (4.6–20) 48%
45 9 (6–17) 53%
52% 14% 14% 14% 3% 3% 3%
69% 13% 7% 0% 7% 4% 15%
The median age of renal transplant recipients was higher than controls, but sex and racial background were comparable between renal transplant recipients and controls. The control group had a slightly higher reported use of vitamin D supplements, although the use of supplements was low in both groups. In the renal transplant recipients, the mean time from transplantation was 4.0 yr, and the median 2.6 yr. The mean nGFR in the renal transplant recipients was 70.2 mL/min/1.73 m2, and the median nGFR was 68 mL/min/1.73 m2, falling within CKD stage 2. Our primary objective was to assess the difference in prevalence of vitamin D insufficiency and deficiency between pediatric renal transplant recipients and a population of generally healthy children. The overall prevalence of insufficiency and deficiency in the renal transplant population was 76%, with 49% being insufficient and 27% being deficient. In comparison, the overall prevalence of insufficiency and deficiency in the control population was 91%, with 73% being insufficient and 18% being deficient. No statistically
significant difference was evident in the prevalence of vitamin D insufficiency and deficiency between these two populations, with both groups demonstrating an increased prevalence of low 25 (OH)D levels (Fig. 1). Comparison of mean 25 (OH)D levels showed the renal transplant recipients had an overall mean of 58.8 23.4 nmol/L and the control group to have an overall mean of 55.2 16.0 nmol/L. Our second objective was to compare seasonal differences in mean 25(OH)D levels within each group. In the seasonal paired renal transplant recipients analysis (n = 16), the mean winter 25 (OH)D level was 52.3 17.9 nmol/L, and the mean summer level was significantly higher at 65.6 18.8 nmol/L (95% CI for the difference: 3.9–22.7) (Fig. 2). We found a prevalence of vitamin D insufficiency and deficiency of 84% in the winter and 66% in the summer. In the winter, 37% of the renal transplant recipients were deficient and 47% were insufficient; in the summer, the prevalence of deficiency decreased to 19%, with 48% remaining insufficient. In the control group, the mean winter and summer 25(OH)D levels were not statistically different. To determine whether there was a correlation between dietary intake of vitamin D and the 25(OH)D level, we compared intake with classification of vitamin D status in the renal transplant recipients (Fig. 3). While there seems to be a trend to increased vitamin D intake and better vitamin D status, the correlation was not statistically significant. The mean total vitamin D intake (diet and supplements) in our renal transplant recipients was 5.7 lg/day. The majority (16 of 21) renal transplant recipients completing a dietary record had an inadequate mean intake as compared to the EAR.
100% 90% 80%
Prevalence
70% 60% 50%
73%
49%
Insufficient Deficient
40% 30% 20% 10% 0%
494
27%
Renal transplant
18% Control
Fig. 1. Prevalence of vitamin D insufficiency and deficiency in renal transplant recipients and control group.
Vitamin D in pediatric renal transplant 120
Mean 25(OH)D (nmol/L)
110
Fig. 2. Seasonal variation in mean 25(OH)D levels in renal transplant recipients and control group.
Renal transplant Control
p = 0.02
100 90 80 70 60 50 40 30 20 10 0
Winter renal transplant
Winter control
Summer renal transplant
Summer control
Fig. 3. Total vitamin D intake (l/kg) in renal transplant recipients with deficient, insufficient, and optimal 25(OH) D levels. No statistically significant difference was detected.
Other potential factors related to 25(OH)D levels were reviewed but were not significant. Proteinuria of 1.0 g/L or greater was only present in three renal transplant recipients, which was too small to correlate with 25(OH)D levels. There was an inverse correlation between PTH and 25(OH)D in 17 paired samples, which did not meet statistical significance. Discussion
While there is growing interest in the vitamin D status of both normal children and pediatric patients with CKD, there is a paucity of data on the vitamin D status of pediatric renal transplant recipients. This study determined
that the overall prevalence of vitamin D insufficiency or deficiency in a Canadian pediatric renal transplant recipient population is high. This prevalence was not significantly different from the control pediatric population that also had an unexpectedly high prevalence of vitamin D insufficiency or deficiency. Significant seasonal variation in the mean 25(OH)D levels of the renal transplant recipients was observed. Analysis of the effect of vitamin D dietary intake on vitamin D status was confounded by the very low vitamin D intake in the majority of the transplant recipients. Our study highlights a significant clinical concern within our pediatric renal transplant population that deserves further attention. 495
Ebbert et al.
The mean 25(OH)D in the renal transplant recipients falls below the optimal range recommended by the K/DOQI guidelines (14), and other accepted reference ranges (23). MatsudaAbedini et al. found mean 25(OH)D levels of 40 21 nmol/L and 45 20 nmol/L in a group of 54 pediatric renal transplant recipients at four and eight wk post-transplant, respectively (unpublished data). A total of 92% of recipients were insufficient or deficient with 25(OH)D levels below 75 nmol/L at eight wk post-transplant, and 77% remained insufficient or deficient at 32 wk post-transplant. Our results, at a mean of four yr post-transplantation, are comparable to these findings. In a UK study of renal transplant recipients, the mean winter 25(OH)D levels were 36 nmol/L, also comparable to our results (20). In that study, 25(OH)D deficiency was related to short stature and hyperparathyroidism (20) that we could not confirm with our analysis. Geographic latitude is likely a strong contributing factor to the high rates of vitamin D insufficiency or deficiency demonstrated in our healthy control population. There is inadequate ultraviolet light exposure from sunlight to induce vitamin D conversion in skin above a latitude of 35 degrees north in winter months (2, 24). While quantification of vitamin D status in other pediatric populations in Canada has shown a high prevalence of vitamin D insufficiency and deficiency, no such data have been published for the British Columbia pediatric population. The mean 25(OH)D level in pediatric studies from other provinces have been low, comparable to our control results, at 47.2 nmol/L in a cohort of children presenting to the emergency room in Edmonton, Alberta (25) and 45.9 nmol/L in French–Canadian adolescents (7). Both of these were cross-sectional studies in the winter or early spring, when 25(OH)D status is expected to be lowest. In the nationwide Canadian Health Measures Survey, the 25(OH)D plasma levels were measured as 75.0 nmol/L in children ages 6–11 yr, and of 68.1 nmol/L in children ages 12–19 yr (4). The hypovitaminosis evident in our study group and other Canadian populations is consistent with the known correlation between northern latitudes and low vitamin D levels. The seasonal variation in 25(OH)D levels identified in our paired renal transplant recipients is consistent with other pediatric renal transplant studies which have demonstrated, in multivariate analysis, an increased likelihood of vitamin D deficiency during the winter months (21, 22). Variations in 25(OH)D based on sunlight exposure are well documented in other renal populations. The large pediatric CKD study by 496
Ali et al. also confirmed seasonal variation in vitamin D levels, with summer and fall levels being significantly greater than winter and spring levels (26). Even in Florida, where sunlight was expected to be adequate throughout the year, a pediatric CKD study showed a trend toward lower vitamin D levels in the winter (65 27 nmol/L) than the summer (72 32 nmol/L) (27). Similar seasonal trends have been reported in the adult renal transplant recipient population (28). This consistent seasonal variation would need to be taken into account by researchers planning future studies of vitamin D as well as by clinicians who monitor for and manage vitamin D deficiency within their renal populations. The effect of dietary vitamin D intake on the vitamin D status of renal transplant recipients in this study was likely confounded by the overall poor vitamin D intake within this population, which is an important finding in itself. The EAR of vitamin D is 10 lg (400 IU)/day, and the RDA is 15 lg (600 IU)/day (29). The usual intake from food of children age 9–13 yr in British Columbia is 6.4 lg/day (female) to 7.2 lg/day (male) and in children age 14–18 yr is 5.0 lg/day (female) to 7.9 lg/day (male) (30). Our renal transplant recipients also fell below these usual intakes, despite routine nutritional advice and support. A study of children ages 2–16 yr presenting to the pediatric emergency department in Edmonton, Alberta, Canada, in spring showed that no children with vitamin D intake above 0.45 lg/kg/day had 25(OH)D levels below 40 nmol/L; in their study, dietary vitamin D was the most important independent determinant of 25(OH)D (25). While the appropriate dietary intake for a pediatric renal transplant population is not known, Tuchman et al. demonstrated use of a vitamin D supplement ≥10 lg/day was associated with an 18.7 nmol/L increase in vitamin D level at follow-up (22). When pediatric renal transplant recipients are found to be vitamin D insufficient or deficient, there are early data to suggest more effective repletion with cholecalciferol over ergocalciferol, although larger studies are in need to confirm this finding (21). This study is novel in that it provides an estimate for the prevalence of vitamin D insufficiency and deficiency in a Canadian pediatric renal transplant population, assesses seasonal differences in 25(OH)D levels in pediatric renal transplant recipients through a paired analysis, and provides a dietary analysis of vitamin D intake in this population. It also provides an estimate of the prevalence of vitamin D insufficiency and deficiency in healthy children in
Vitamin D in pediatric renal transplant
British Columbia, Canada, which to our knowledge has not previously been reported. However, the results of this study should be interpreted in light of its inherent limitations. Our patient numbers were small, and while some results seemed to indicate a trend, this could not be confirmed statistically. Recruitment was limited in renal transplant recipients due to the requirement to complete a three-day dietary record in summer and winter; although we suggest this as part of their routine clinical annual assessment, it is often not completed. The cross-sectional assessment of our transplant recipients would not take into account the changes in 25(OH)D reported in some studies as time post-transplant lengthens, although the pediatric studies that have assessed this have found high rates of vitamin D deficiency regardless of time post-transplant. The lack of difference in prevalence of vitamin D insufficiency and deficiency between the renal transplant and control groups, while unexpected, may represent a true lack of difference between these groups. The renal transplant recipients receive regular dietary monitoring and expert dietary advice which may improve their overall vitamin D status, despite their risk factors for lower levels. Given the very high prevalence of insufficiency and deficiency in both groups, a study with higher power may be required to detect any significant difference, although the clinical relevance of a very small difference would have to be considered. In conclusion, we have shown a very high prevalence of vitamin D insufficiency and deficiency in both pediatric renal transplant recipients and a healthy pediatric control population in British Columbia, Canada. The pediatric renal transplant recipients had a dietary vitamin D intake below their EAR, and although the contributing factors were not determined, this could be an important area for intervention and future studies. Remarkable seasonal variation was also noted, in keeping with the results of current vitamin D literature. As we continue to learn more about the importance of vitamin D in many aspects of health and disease, ongoing research to learn more about the effects of low vitamin D and vitamin D supplementation in pediatric renal transplant recipients will be of great importance. Acknowledgments The authors thank Ruth Milner for her expertise in statistical analysis, Simon Whyte and the B.C. Children’s Hospital Department of Anesthesia for their assistance with obtaining samples from the control population, and B.C. Children’s Hospital Telethon for funding this study.
Funding B.C. Children’s Hospital Foundation Telethon.
Authors’ contributions K. Ebbert: Participated in concept/design, data collection, data interpretation, drafting, and critical revision of the article; J. Chow: Research coordinator and participated in participant recruitment, data collection, and critical revision of the article; J. Krempien: Participated in data collection, dietary data analysis, and critical revision of the article; M. Matsuda-Abedini: Participated in concept/design, data interpretation, and critical revision of the article; J. Dionne: Participated in concept/design, data interpretation, drafting, and critical revision of the article.
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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12527
Vitamin D insufficiency and deficiency in pediatric renal transplant recipients Ebbert K, Chow J, Krempien J, Matsuda-Abedini M, Dionne J. (2015) Vitamin D insufficiency and deficiency in pediatric renal transplant recipients. Pediatr Transplant, 19: 492–498. DOI: 10.1111/petr.12527.
Kirsten Ebbert1, Josephine Chow2, Jennifer Krempien2, Mina Matsuda-Abedini3 and Janis Dionne2 1
Abstract: Vitamin D deficiency is prevalent in the pediatric CKD population. Recognizing that renal transplant recipients have CKD, we assessed the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients, compared to a healthy pediatric population. We prospectively studied 25(OH)D levels in 29 pediatric renal transplant recipients and 45 control patients over one yr. The overall prevalence of vitamin D insufficiency and deficiency was common in both populations, at 76% (95% CI: 61, 87%) in the pediatric renal transplant recipients and 91% (95% CI: 80, 98%) in the control group. In the paired renal transplant samples, the mean 25(OH) D level was 52.3 17.9 nmol/L in the winter and 65.6 18.8 nmol/L in the summer (95% CI diff.: 3.9, 22.7), in keeping with a significant seasonal difference. The mean dietary intake of vitamin D in the renal transplant recipients, assessed by three-day dietary record, was 5.7 lg/ day, with a vitamin D intake below the EAR in the majority. We did not find an association between vitamin D intake and 25(OH)D levels in this study, likely due to the low dietary intake of vitamin D within the transplant population, identifying a potential area for intervention and improvement.
Vitamin D is increasingly recognized as an important metabolite for which there is a significant, previously underappreciated, prevalence of deficiency. Vitamin D is a prohormone (1) that may be derived from dietary sources or synthesized in the skin (2). While over 90% of our vitamin D stores are endogenously produced, dietary intake may be a more important factor in settings where sun exposure is limited (3). Health Canada reviewed the vitamin D status of Canadians in the 2007–2009 Canadian Health Measures Survey, finding 25(OH)D levels below 75 nmol/L in 51% of 6- to 11-yr-olds, and 65% of 12- to 19-yr-olds (4). Furthermore, vitamin D deficiency resulting in rickets has been reported in Canadian infants and children, with 104 cases Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CKD, chronic kidney disease; EAR, estimated average requirement; ICH-GCP, International Conference on Harmonization Good Clinical Practice; iPTH, intact parathyroid hormone; LCMSCS, liquid chromatography tandem mass spectrometry; nGFR, nuclear medicine glomerular filtration rate; RDA, recommended daily intake.
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Department of Pediatrics, B.C. Children’s Hospital, Vancouver, BC, Canada, 2Division of Nephrology, University of British Columbia, BC Children’s Hospital,Vancouver, BC, Canada, 3Division of Nephrology, University of Toronto,The Hospital for Sick Children,Toronto, ON, Canada
Key words: vitamin D – 25-hydroxyvitamin D – kidney transplantation – recommended dietary allowances – seasons – pediatric Janis Dionne, MD, Pediatric Nephrology, B.C. Children’s Hospital, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada Tel.: 604 875 2272 Fax: 604 875 3649 E-mail: [email protected] Accepted for publication 15 April 2015
over a two-yr period (5). While vitamin D levels have been shown inadequate in various Canadian populations, to our knowledge there is no reference data specific to the British Columbia pediatric population, despite differences in weather and diet as compared to other regions in Canada. Awareness is increasing regarding the importance of vitamin D in multiple physiologic systems and disease processes. Vitamin D supplementation in infancy has been associated with an 80% decrease in the incidence of type I diabetes mellitus in a 30-yr Finnish birth cohort study (6). Vitamin D levels have been shown to be inversely associated with plasma glucose concentration (7, 8) and insulin resistance (7) and positively correlated with HDL levels (8) in pediatric populations. Vitamin D is also thought to have an important role in innate immunity and decreased infection (9). Vitamin D is particularly important in renal patients, both those with CKD and renal transplants. In CKD, vitamin D deficiency is associated with adverse effects including hyperparathyroidism (10), anemia (11), and an
Vitamin D in pediatric renal transplant
increased risk of cardiovascular disease, including early atherogenesis, vascular calcifications, and heart failure (12). Reduced control of inflammation and altered renin activity may contribute to this increased degree of cardiovascular risk (12). Patients with renal disease have multiple risk factors for developing vitamin D deficiency; these include restricted diet, decreased activity and sunlight exposure, prescribed sun avoidance (13), the need for greater sunlight exposure to produce equivalent vitamin D3 to that produced by a healthy person (14), increased urinary losses of megalin and 25(OH)D bound to vitamin D binding protein (if proteinuric) (15), and use of corticosteroids (16). Vitamin D deficiency has been correlated with poorer graft function postrenal transplantation (17). Literature on the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients is limited; a wide range in prevalence, from 49% to 100%, has been described in the populations studied (18–22). Seasonal variation, a wide range of geographic locations, and a variety of ethnicities have been assessed in these studies. Outside of lower 25 (OH)D levels being associated with winter months, clear trends with respect to these variables have not been consistently reproduced. Without a healthy ethnically comparable control population for comparison, it would be difficult to determine how rates of vitamin D insufficiency and deficiency vary from the expected rate within that geographic population. In the only two studies that included a control group for comparison (21, 22), results were contradictory. The majority of these studies did not compare seasonal variation within individuals, and none of these studies assessed the impact of dietary vitamin D intake. In this study, we aimed to determine the prevalence of vitamin D insufficiency and deficiency in a cross-sectional population of pediatric renal transplant recipients, comparing the prevalence with a control group of healthy children. We also compared seasonal differences in the mean 25 (OH)D level in each group and assessed dietary vitamin D intake as a contributory factor to vitamin D status in the renal transplant recipients. Patients and methods This was a prospective study of pediatric renal transplant recipients, and a cross-sectional control group. Data were collected between August 2009 and August 2010. The study included 29 pediatric renal transplant recipients from the Multi-Organ Transplant Clinic at British Columbia Children’s Hospital, Canada. This is the only pediatric transplant center for all children in British Columbia and the Yukon Territory. All 48 pediatric renal transplant recipients
cared for at our center were eligible. British Columbia and the Yukon are situated at a latitude above 48 degrees north. In the city of Vancouver (the most populated city in British Columbia and the Yukon), sunlight hours range from 54 h per month in December, to 296 h per month in July. Pediatric renal transplant recipients were evaluated at enrollment and approximately six months later for seasonal variation analysis. The control group comprised 45 generally healthy children requiring minor operative procedures through day surgery at BC Children’s Hospital. Patients with chronic illnesses and those requiring a procedure for underlying diagnoses known to be associated with vitamin D deficiency were excluded. All patients in the control group were between the ages of six and 17 yr, to match the typical age range of the renal transplant population. Twenty-four of the control patients were recruited in the winter, and 21 were recruited in the summer, stratified to allow for seasonal comparison. All subjects and/or parents provided informed consent, and subjects aged 7–13 yr provided assent. The research was approved by the University of British Columbia Children and Women’s Hospital Research Ethics Board and was in accordance with the ICH-GCP. All subjects in the renal transplant and control groups had a 25(OH)D level drawn at the time of routine blood work or during intravenous catheter insertion. Study 25 (OH)D3 levels were analyzed at a single laboratory by highperformance LCMSCS. Renal transplant recipients were also requested to complete a three-day dietary record, which was subsequently analyzed by our transplant dietitian for vitamin D intake. Data including ethnicity and current medications or supplements were collected on all participants. Most recent nGFR and underlying renal disease were collected for renal transplant recipients. The KDOQI guideline reference ranges were used to stratify the results in this study. Severe vitamin D deficiency was defined as 75 nmol/L (14). The year was divided into two 6-month periods based on data for local sunlight hours. The six months with the greatest number of sunlight hours, April through September, were designated as “summer”; the six months with the fewest sunlight hours, October through March, were designated as “winter.” Seasonal data were analyzed according to this stratification. Statistical analysis included comparison of the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients to controls. The difference in prevalence between groups was assessed with a 95% confidence interval as a measure of precision. The mean 25(OH) D levels were compared between the renal transplant and control groups, with standard error reported. To assess seasonal variation, mean winter and summer 25(OH)D levels from paired renal transplant recipients were compared, and the mean change was reported with standard error. The mean winter and summer 25(OH)D levels were compared in the control group, and the mean change was reported with standard error. The contribution of dietary vitamin D intake to vitamin D status in renal transplant recipients was analyzed using a linear regression model. The correlation between iPTH and 25(OH)D was analyzed using a linear regression model.
Results
The baseline characteristics of subjects involved in this study are outlined in Table 1. 493
Ebbert et al. Table 1. Renal transplant recipient and control group characteristics
N Age (yr) Male Ethnicity Caucasian Asian Oriental South Asian First Nations Hispanic Other Vitamin D supplement
Renal transplant recipients
Control group
29 16 (4.6–20) 48%
45 9 (6–17) 53%
52% 14% 14% 14% 3% 3% 3%
69% 13% 7% 0% 7% 4% 15%
The median age of renal transplant recipients was higher than controls, but sex and racial background were comparable between renal transplant recipients and controls. The control group had a slightly higher reported use of vitamin D supplements, although the use of supplements was low in both groups. In the renal transplant recipients, the mean time from transplantation was 4.0 yr, and the median 2.6 yr. The mean nGFR in the renal transplant recipients was 70.2 mL/min/1.73 m2, and the median nGFR was 68 mL/min/1.73 m2, falling within CKD stage 2. Our primary objective was to assess the difference in prevalence of vitamin D insufficiency and deficiency between pediatric renal transplant recipients and a population of generally healthy children. The overall prevalence of insufficiency and deficiency in the renal transplant population was 76%, with 49% being insufficient and 27% being deficient. In comparison, the overall prevalence of insufficiency and deficiency in the control population was 91%, with 73% being insufficient and 18% being deficient. No statistically
significant difference was evident in the prevalence of vitamin D insufficiency and deficiency between these two populations, with both groups demonstrating an increased prevalence of low 25 (OH)D levels (Fig. 1). Comparison of mean 25 (OH)D levels showed the renal transplant recipients had an overall mean of 58.8 23.4 nmol/L and the control group to have an overall mean of 55.2 16.0 nmol/L. Our second objective was to compare seasonal differences in mean 25(OH)D levels within each group. In the seasonal paired renal transplant recipients analysis (n = 16), the mean winter 25 (OH)D level was 52.3 17.9 nmol/L, and the mean summer level was significantly higher at 65.6 18.8 nmol/L (95% CI for the difference: 3.9–22.7) (Fig. 2). We found a prevalence of vitamin D insufficiency and deficiency of 84% in the winter and 66% in the summer. In the winter, 37% of the renal transplant recipients were deficient and 47% were insufficient; in the summer, the prevalence of deficiency decreased to 19%, with 48% remaining insufficient. In the control group, the mean winter and summer 25(OH)D levels were not statistically different. To determine whether there was a correlation between dietary intake of vitamin D and the 25(OH)D level, we compared intake with classification of vitamin D status in the renal transplant recipients (Fig. 3). While there seems to be a trend to increased vitamin D intake and better vitamin D status, the correlation was not statistically significant. The mean total vitamin D intake (diet and supplements) in our renal transplant recipients was 5.7 lg/day. The majority (16 of 21) renal transplant recipients completing a dietary record had an inadequate mean intake as compared to the EAR.
100% 90% 80%
Prevalence
70% 60% 50%
73%
49%
Insufficient Deficient
40% 30% 20% 10% 0%
494
27%
Renal transplant
18% Control
Fig. 1. Prevalence of vitamin D insufficiency and deficiency in renal transplant recipients and control group.
Vitamin D in pediatric renal transplant 120
Mean 25(OH)D (nmol/L)
110
Fig. 2. Seasonal variation in mean 25(OH)D levels in renal transplant recipients and control group.
Renal transplant Control
p = 0.02
100 90 80 70 60 50 40 30 20 10 0
Winter renal transplant
Winter control
Summer renal transplant
Summer control
Fig. 3. Total vitamin D intake (l/kg) in renal transplant recipients with deficient, insufficient, and optimal 25(OH) D levels. No statistically significant difference was detected.
Other potential factors related to 25(OH)D levels were reviewed but were not significant. Proteinuria of 1.0 g/L or greater was only present in three renal transplant recipients, which was too small to correlate with 25(OH)D levels. There was an inverse correlation between PTH and 25(OH)D in 17 paired samples, which did not meet statistical significance. Discussion
While there is growing interest in the vitamin D status of both normal children and pediatric patients with CKD, there is a paucity of data on the vitamin D status of pediatric renal transplant recipients. This study determined
that the overall prevalence of vitamin D insufficiency or deficiency in a Canadian pediatric renal transplant recipient population is high. This prevalence was not significantly different from the control pediatric population that also had an unexpectedly high prevalence of vitamin D insufficiency or deficiency. Significant seasonal variation in the mean 25(OH)D levels of the renal transplant recipients was observed. Analysis of the effect of vitamin D dietary intake on vitamin D status was confounded by the very low vitamin D intake in the majority of the transplant recipients. Our study highlights a significant clinical concern within our pediatric renal transplant population that deserves further attention. 495
Ebbert et al.
The mean 25(OH)D in the renal transplant recipients falls below the optimal range recommended by the K/DOQI guidelines (14), and other accepted reference ranges (23). MatsudaAbedini et al. found mean 25(OH)D levels of 40 21 nmol/L and 45 20 nmol/L in a group of 54 pediatric renal transplant recipients at four and eight wk post-transplant, respectively (unpublished data). A total of 92% of recipients were insufficient or deficient with 25(OH)D levels below 75 nmol/L at eight wk post-transplant, and 77% remained insufficient or deficient at 32 wk post-transplant. Our results, at a mean of four yr post-transplantation, are comparable to these findings. In a UK study of renal transplant recipients, the mean winter 25(OH)D levels were 36 nmol/L, also comparable to our results (20). In that study, 25(OH)D deficiency was related to short stature and hyperparathyroidism (20) that we could not confirm with our analysis. Geographic latitude is likely a strong contributing factor to the high rates of vitamin D insufficiency or deficiency demonstrated in our healthy control population. There is inadequate ultraviolet light exposure from sunlight to induce vitamin D conversion in skin above a latitude of 35 degrees north in winter months (2, 24). While quantification of vitamin D status in other pediatric populations in Canada has shown a high prevalence of vitamin D insufficiency and deficiency, no such data have been published for the British Columbia pediatric population. The mean 25(OH)D level in pediatric studies from other provinces have been low, comparable to our control results, at 47.2 nmol/L in a cohort of children presenting to the emergency room in Edmonton, Alberta (25) and 45.9 nmol/L in French–Canadian adolescents (7). Both of these were cross-sectional studies in the winter or early spring, when 25(OH)D status is expected to be lowest. In the nationwide Canadian Health Measures Survey, the 25(OH)D plasma levels were measured as 75.0 nmol/L in children ages 6–11 yr, and of 68.1 nmol/L in children ages 12–19 yr (4). The hypovitaminosis evident in our study group and other Canadian populations is consistent with the known correlation between northern latitudes and low vitamin D levels. The seasonal variation in 25(OH)D levels identified in our paired renal transplant recipients is consistent with other pediatric renal transplant studies which have demonstrated, in multivariate analysis, an increased likelihood of vitamin D deficiency during the winter months (21, 22). Variations in 25(OH)D based on sunlight exposure are well documented in other renal populations. The large pediatric CKD study by 496
Ali et al. also confirmed seasonal variation in vitamin D levels, with summer and fall levels being significantly greater than winter and spring levels (26). Even in Florida, where sunlight was expected to be adequate throughout the year, a pediatric CKD study showed a trend toward lower vitamin D levels in the winter (65 27 nmol/L) than the summer (72 32 nmol/L) (27). Similar seasonal trends have been reported in the adult renal transplant recipient population (28). This consistent seasonal variation would need to be taken into account by researchers planning future studies of vitamin D as well as by clinicians who monitor for and manage vitamin D deficiency within their renal populations. The effect of dietary vitamin D intake on the vitamin D status of renal transplant recipients in this study was likely confounded by the overall poor vitamin D intake within this population, which is an important finding in itself. The EAR of vitamin D is 10 lg (400 IU)/day, and the RDA is 15 lg (600 IU)/day (29). The usual intake from food of children age 9–13 yr in British Columbia is 6.4 lg/day (female) to 7.2 lg/day (male) and in children age 14–18 yr is 5.0 lg/day (female) to 7.9 lg/day (male) (30). Our renal transplant recipients also fell below these usual intakes, despite routine nutritional advice and support. A study of children ages 2–16 yr presenting to the pediatric emergency department in Edmonton, Alberta, Canada, in spring showed that no children with vitamin D intake above 0.45 lg/kg/day had 25(OH)D levels below 40 nmol/L; in their study, dietary vitamin D was the most important independent determinant of 25(OH)D (25). While the appropriate dietary intake for a pediatric renal transplant population is not known, Tuchman et al. demonstrated use of a vitamin D supplement ≥10 lg/day was associated with an 18.7 nmol/L increase in vitamin D level at follow-up (22). When pediatric renal transplant recipients are found to be vitamin D insufficient or deficient, there are early data to suggest more effective repletion with cholecalciferol over ergocalciferol, although larger studies are in need to confirm this finding (21). This study is novel in that it provides an estimate for the prevalence of vitamin D insufficiency and deficiency in a Canadian pediatric renal transplant population, assesses seasonal differences in 25(OH)D levels in pediatric renal transplant recipients through a paired analysis, and provides a dietary analysis of vitamin D intake in this population. It also provides an estimate of the prevalence of vitamin D insufficiency and deficiency in healthy children in
Vitamin D in pediatric renal transplant
British Columbia, Canada, which to our knowledge has not previously been reported. However, the results of this study should be interpreted in light of its inherent limitations. Our patient numbers were small, and while some results seemed to indicate a trend, this could not be confirmed statistically. Recruitment was limited in renal transplant recipients due to the requirement to complete a three-day dietary record in summer and winter; although we suggest this as part of their routine clinical annual assessment, it is often not completed. The cross-sectional assessment of our transplant recipients would not take into account the changes in 25(OH)D reported in some studies as time post-transplant lengthens, although the pediatric studies that have assessed this have found high rates of vitamin D deficiency regardless of time post-transplant. The lack of difference in prevalence of vitamin D insufficiency and deficiency between the renal transplant and control groups, while unexpected, may represent a true lack of difference between these groups. The renal transplant recipients receive regular dietary monitoring and expert dietary advice which may improve their overall vitamin D status, despite their risk factors for lower levels. Given the very high prevalence of insufficiency and deficiency in both groups, a study with higher power may be required to detect any significant difference, although the clinical relevance of a very small difference would have to be considered. In conclusion, we have shown a very high prevalence of vitamin D insufficiency and deficiency in both pediatric renal transplant recipients and a healthy pediatric control population in British Columbia, Canada. The pediatric renal transplant recipients had a dietary vitamin D intake below their EAR, and although the contributing factors were not determined, this could be an important area for intervention and future studies. Remarkable seasonal variation was also noted, in keeping with the results of current vitamin D literature. As we continue to learn more about the importance of vitamin D in many aspects of health and disease, ongoing research to learn more about the effects of low vitamin D and vitamin D supplementation in pediatric renal transplant recipients will be of great importance. Acknowledgments The authors thank Ruth Milner for her expertise in statistical analysis, Simon Whyte and the B.C. Children’s Hospital Department of Anesthesia for their assistance with obtaining samples from the control population, and B.C. Children’s Hospital Telethon for funding this study.
Funding B.C. Children’s Hospital Foundation Telethon.
Authors’ contributions K. Ebbert: Participated in concept/design, data collection, data interpretation, drafting, and critical revision of the article; J. Chow: Research coordinator and participated in participant recruitment, data collection, and critical revision of the article; J. Krempien: Participated in data collection, dietary data analysis, and critical revision of the article; M. Matsuda-Abedini: Participated in concept/design, data interpretation, and critical revision of the article; J. Dionne: Participated in concept/design, data interpretation, drafting, and critical revision of the article.
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