Abstract
Background
Maternal vitamin D deficiency during pregnancy may influence offspring kidney health. We aimed to examine the associations of 25-hydroxyvitamin D (25(OH)D) blood levels during fetal life with kidney outcomes at school-age.
Methods
This study was embedded in a population-based prospective cohort study among 4,212 mother-child pairs. We measured maternal second trimester (18-25 weeks) and fetal cord blood (at birth) 25(OH)D levels. At a median age of 6.0 years, we measured children’s combined kidney volume, glomerular filtration rate (eGFR) from creatinine and cystatin C serum levels and microalbuminuria from albumin and creatinine urine levels.
Results
Of all mothers, 21.9% had severely deficient levels (25(OH)D <25.0 nmol/L), 25.7% had deficient levels (25.0 to 49.9 nmol/L), 25% had sufficient levels (50.0 to 74.9 nmol/L), and 27.4% had optimal levels (≥75.0 nmol/L). Maternal 25(OH)D levels were not consistently associated with childhood combined kidney volume. Higher maternal 25(OH)D levels were associated with lower childhood eGFR (difference -0.94 ml/min/1.73m2 (95% CI -1.73; -0.15) per 1 standard deviation increase in 25(OH)D). Maternal 25(OH)D levels were not associated with microalbuminuria. Cord blood 25(OH)D levels were not associated with childhood kidney outcomes. The associations of maternal 25(OH)D levels with childhood eGFR were partly explained by childhood vitamin D status.
Conclusion
Our findings suggest that maternal 25(OH)D levels during pregnancy may influence childhood kidney outcomes. These results should be considered hypothesis-generating. Further studies are needed to replicate the observations, to examine the underlying mechanisms, and to identify the long term-clinical consequences.
Keywords: vitamin D, kidney function, kidney volume, kidney development, pediatrics
Introduction
Vitamin D deficiency is related to various adverse health outcomes in early and later life.1–4 An accumulating body of evidence suggest than vitamin D status during pregnancy may persistently affect offspring health including poor weight gain, impaired development and rickets.5, 6 Maternal vitamin D deficiency during pregnancy may also affect offspring kidney health. An experimental study in rats observed that maternal vitamin D deficiency leads to an increase in nephron number in the offspring, suggesting a stimulated nephrogenesis.7 In line with these findings, another study in mice has shown that offspring of mothers who received a vitamin D deficient diet during pregnancy had a higher number of glomeruli and a delayed maturity of the glomeruli 8. However, in contrast to these findings, another study in rats suggests that maternal vitamin D deficiency leads to lower kidney mass and a compromised kidney function.9 As nephrogenesis continues until 36 weeks of gestation and largely ceases afterwards, suboptimal maternal vitamin D levels during specifically second half of pregnancy influence kidney development.10, 11 Smaller kidneys in early life with a reduced number of nephrons lead to glomerular hyperfiltration and sclerosis and predispose to kidney disease in adulthood.12 To the best of our knowledge there are no studies that have observed the effects of fetal life vitamin D levels on kidney function in healthy children.
Therefore, we examined in a population-based prospective cohort study among 4,212 mother-child pairs, the associations of circulating vitamin 25-hydroxyvitamin D (25(OH)D) levels during mid-pregnancy and in cord blood at birth with childhood kidney outcomes. Additionally, we explored whether any association was explained by child’s current 25(OH)D levels.
Methods
Design and study population
This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands.13, 14 All children were born between April 2002 and January 2006. Enrolment in the study was aimed at early pregnancy, but was allowed until the birth of the child. The study was conducted according to the guidelines of the Helsinki Declaration and approved by the Medical Ethics Committee of Erasmus Medical Center, Rotterdam. Written informed consent was obtained from parents. Maternal 25(OH)D blood levels were measured in 7,176 pregnant women. In total, 4,251 of their singleton live born children participated in the kidney follow-up measurements at the age of 6 years. Children with evidence of congenital kidney abnormalities on ultrasound examination (n=7) or with abnormally high urinary albumin-creatinine ratio (>25) (n=12) were excluded from the study. Measurements on kidney ultrasound, creatinine and cystatin C from blood and albumin and creatinine from urine samples were available on 4,212 children. (Figure 1. Flowchart).
Figure 1. Flowchart of the study participants.
Maternal and cord 25(OH)D blood levels
Maternal venous blood samples were collected in mid-pregnancy (median gestational age 20.3 weeks, range 18.5-23.3 weeks). Umbilical cord blood samples were taken immediately after delivery (median 40.1 weeks of gestation, range 35.9-42.3 weeks) by midwives and obstetricians. Measurements of 25(OH)D levels were conducted at the Eyles Laboratory at the Queensland Brain Institute, University of Queensland, Australia.
Total 25(OH)D was reported as the sum of 25(OH)D2 and 25(OH)D3 measured in plasma using a modification of a method previously described.15 Samples were quantified using isotope dilution liquid chromatography-tandem mass spectrometry. Linearity was assessed using matrix-matched calibration standards, with R2 values of >0.99 across the calibration range (10 – 125 nmol/L). Inter-assay inaccuracy and imprecision were assessed at four concentration levels for 25(OH)D3 (48.3, 49.4, 76.4, 139.2 nmol/L) and a single level (32.3 nmol/L) for 25(OH)D2 using certified reference materials and were excellent at all concentration levels tested. Inter-assay inaccuracy and imprecision were both <10% for 25(OH)D3 and <17% for 25(OH)D2, respectively. On the basis of recommendations and previous studies, we defined the following categories for vitamin D status: <25.0 nmol/L (<10.0 mg/L), severely deficient; 25 to 49.9 nmol/L (10.0 to 19.9 mg/L), deficient; 50.0 to 74.9 nmol/L (20.0 to 29.9 mg/L), sufficient; and ≥75.0 nmol/L (≥30.0 mg/L), optimal.16–19 In children circulating 25(OH)D levels were measured at a median age of 6.0 years (range 5.6-7.4), at the Endocrine Laboratory of the VU University Medical Center, Amsterdam as described previously in detail.20 Child’s current 25(OH)D status was available in a subgroup of 2,644 subjects.
Childhood kidney outcomes
Children’s kidney outcomes were assessed at a median age of 6.0 (95% range 5.6 to 7.4) years in a dedicated research center in the Erasmus MC - Sophia Children’s Hospital in Rotterdam.21 We measured kidney volume with ultrasound. Left and right kidneys were identified in the sagittal plane along its longitudinal axis. We performed measurements of maximal bipolar kidney length, width and depth. Kidney width and depth were measured at the level of the hilum. The cross-sectional area in which the kidney appeared symmetrically round at its maximum width was used. Using the equation for a prolate ellipsoid we calculated kidney volume: volume (cm3) = 0.523 x length (cm) x width (cm) x depth (cm).22 Combined kidney volume was calculated by summing right and left kidney volume. Previously, we have reported good intra-observer and inter-observer correlation coefficients.23
We measured creatinine and cystatin C levels from non-fasting blood samples drawn by antecubital venipuncture. Creatinine levels were measured with enzymatic methods and cystatin C levels with a particle enhanced immunoturbidimetric assay (using Cobas 8000 analyzers, Roche, Almere, the Netherlands). Quality control samples demonstrated intra-assay and inter-assay coefficients of variation ranging from 0.51 to 1.37%, and 1.13 to 1.65%, respectively. Estimated glomerular filtration rate (eGFR) was calculated according to the revised Schwartz 2009 formula: eGFRcreat = 36.5 * (height (cm)/serum creatinine (µmol/L).24 Additionally, we calculated eGFR using Zappitelli’s formula based on cystatin C levels: eGFRcystC = 75.94/[CysC1.17].25 We calculated the albumin-creatinine ratio using urine creatinine (mmol/L) and urine albumin (mg/l) levels. These levels were determined with a Beckman Coulter AU analyser, creatinine levels were measured with the Jaffe reaction. In line with clinical cut-offs, microalbuminuria was defined as an albumin-creatinine ratio >2.5 mg/mmol for boys and > 3.5 mg/mmol for girls.26
Covariates
We used questionnaires at enrollment in the study (median 13.5 weeks of gestation) to collect information about maternal age, ethnicity, educational level, and on smoking, alcohol usage and folic acid supplementation during pregnancy.13 The presence of high cholesterol, diabetes, hypertension was available from the same questionnaires. Maternal energy intake during pregnancy was measured at enrollment with a validated semi-quantitative food frequency questionnaire.27 Ethnicity and educational level were defined according to the classification of Statistics Netherlands.28, 29 We measured maternal height and weight at enrollment and calculated body mass index (kg/m2). The date of blood sampling was categorized into summer, fall, winter, and spring based on the Dutch standard seasons. Infant sex, gestational age, weight and length at birth were obtained from midwifes, medical records and hospital registries. We calculated sex- and gestational age-specific SD scores for birth weight.30 Information on breastfeeding was collected using postnatal questionnaires as previously reported.21 At the age of 6 years, child height was determined in standing position to the nearest millimeter without shoes by a Harpenden stadiometer (Holtain Limited, Dyfed, U.K.). Weight was measured using a mechanical personal scale (SECA, Almere, the Netherlands). We calculated body mass index (kg/m2) and body surface area (BSA) (m2) (using DuBois formula BSA = weight (kg)0.425x height (cm)0.725x 0.007184).
Statistical analysis
We performed a non-response analysis by comparing subject characteristics between children with and without follow-up kidney measurements. We used multivariable linear and logistic regression models to assess the associations of maternal and cord 25(OH)D levels with combined kidney volume, creatinine and cystatin C levels, eGFRcreat and eGFRcystC, and risk of microalbuminuria in childhood. Levels of 25(OH)D were analysed both continuously per standard deviation (SD)- increase and using clinical cut-offs.16–18 The regression models were first adjusted for child’s sex, child’s age at kidney measurements, season when blood samples were drawn and maternal ethnicity (basic models), and subsequently additionally for maternal age, education, body mass index at enrolment, smoking, alcohol use, folic acid supplement use and energy intake during pregnancy, and pre-pregnancy comorbidities, and for child’s gestational age-adjusted birth weight, breastfeeding in early life, and body surface area at the age of 6 years. These covariates were included in the models based on their associations with kidney outcomes in previous studies, or a change in effect estimates of >10%. Since the interactions of maternal 25(OH)D with child sex were not significant, we did not stratify our analyses on child sex. To explore if childhood 25(OH)D status explain the associations between fetal 25(OH)D and childhood kidney outcomes, we performed a sensitivity analysis in the subgroup of children with 25(OH)D levels available. To diminish potential bias associated with attrition, missing values of covariates (less than 24%), were multiple imputed by generating 10 independent datasets using the Markov Chain Monte Carlo (MCMC) method. The multiple imputation procedure was based on the correlation between each variable with missing values and the other subject characteristics.31, 32 Statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA).
Results
Participant characteristics
Table 1 shows that in mothers median (95% range) 25(OH)D levels were 51.9 nmol/L (7.7, 122.1). Of all mothers, 21.9% had severely deficient levels (25(OH)D <25.0 nmol/L), 25.7% had deficient levels (25.0 to 49.9 nmol/L), 25% had sufficient levels (50.0 to 74.9 nmol/L), and 27.4% had optimal levels (≥75.0 nmol/L). In cord blood median 25(OH)D levels were 29.3 nmol/L (5.6, 81.5). At the age of 6 years, mean (± SD) combined kidney volume was 120 cm3 (± 22.8), and mean eGFRcreat was 119 ml/min/1.73m2 (± 16.4). Of all children, 7.6% had microalbuminuria. Subjects characteristics before and after imputation are shown in [Electronic Supplementary Material (ESM) Table S1]. Results from the non-response analysis showed that as compared to children who did not have kidney measurements at the age of 6 years, those who did have kidney measurements had mothers with a higher educational level and higher 25(OH)D levels during pregnancy. Children with kidney measurements also had higher 25(OH)D levels at birth (EMS Table S2).
Table 1. Subject characteristics (N = 4,212).
| Maternal characteristics | |
| Age (y) | 31.3 (20.2, 39.4) |
| Body mass index at enrolment (kg/m2) | 22.6 (18.1, 34.3) |
| Education level (%) | |
| - No higher education | 51.2 |
| - Higher education | 48.8 |
| Ethnicity (%) | |
| - European | 63.2 |
| - Cape Verdean | 4.1 |
| - Dutch Antillean | 2.0 |
| - Moroccan | 5.6 |
| - Turkish | 8.2 |
| - Surinamese | 7.6 |
| - Other | 9.3 |
| Smoking during pregnancy (%) | |
| - Never | 75 |
| - Until pregnancy was known | 9.9 |
| - Continued | 15.1 |
| Alcohol consumption during pregnancy (%) | |
| - Never | 42.8 |
| - Until pregnancy was known | 14.3 |
| - Continued | 42.9 |
| Folic acid supplement use (%) | |
| - No | 24.5 |
| - Start in the first 10 weeks | 31.2 |
| - Start periconceptional | 44.3 |
| Maternal energy intake (kcal) | 2,062 (485) |
| Maternal blood levels of 25(OH)D (nmol/L) | 51.9 (7.7, 122.1) |
| Season when blood sample was taken (%) | |
| - Spring | 27.8 |
| - Summer | 22.6 |
| - Autumn | 25.5 |
| - Winter | 24.1 |
| Infant characteristics | |
| Girls (%) | 50.4 |
| Gestational age at birth (wk) | 40.1 (35.9, 42.3) |
| Birth weight (g) | 3,449 (545) |
| Breastfeeding in the first 4 months (%) | |
| - Exclusive | 31.7 |
| - Partial | 61.1 |
| - Never | 7.2 |
| Child 25(OH)D level in cord blood at birth (nmol/L) | 29.3 (5.2, 81.5) |
| Season when cord blood sample was taken (%) | |
| - Spring | 28.2 |
| - Summer | 26.5 |
| - Autumn | 21.4 |
| - Winter | 23.9 |
| Child characteristics at 6 years visit | |
| Age (y) | 6.0 (5.6, 7.4) |
| Height (cm) | 119 (5.6) |
| Weight (kg) | 22.2 (17.4, 32.4) |
| Body mass index (kg/m2) | 15.8 (13.6, 20.7) |
| Body surface area (m2) | 0.86 (0.7, 1.1) |
| Childhood 25(OH)D levels (nmol/L) | 64.4 (18.0, 134.0) |
| Combined kidney volume (cm3) | 120 (22.8) |
| Creatinine (µmol/L) | 37.2 (5.5) |
| Cystatin C (µg/L) | 784 (80.2) |
| eGFRcreat (ml/min/1.73m2) | 119 (16.4) |
| eGFRcystC(ml/min/1.73m2) | 102.5 (14.5) |
| Microalbuminuria (%) | 7.6 |
Values are percentages for categorical variables, means (SD) for continuous variables with a normal distribution, or medians (95% range) for continuous variables with a skewed distribution.
Abbreviations: eGFRcreat estimated glomerular filtration rate calculated based on creatinine blood levels and eGFRcystC estimated glomerular filtration rate calculated based on cystatin C blood levels.
Maternal and cord 25(OH)D levels and childhood kidney outcomes
Table 2 gives the results from the multivariable regression models for the associations of maternal 25(OH)D levels and childhood kidney outcomes. Children of mothers who were vitamin D deficient during pregnancy had a 1.92 cm3 (95% Confidence Interval (CI) 0.11, 3.74) larger combined kidney volume compared to children of mothers who had optimal 25(OH)D levels. However, the overall trend analysis based on continuous data for 25(OH)D was not significant. Maternal 25(OH)D levels were inversely associated with lower childhood eGFRcreat (difference -0.94 (95% CI -1.73; -0.15) ml/min/1.73m2 per 1 SD increase in 25(OH)D). Maternal 25(OH)D levels were not associated with eGFRcystC or risk of microalbuminuria. Results from the crude models are shown in the EMS Table S3 & S4. In line with the results for eGFRcreat and eGFRcystC, maternal 25(OH)D levels were associated with 0.32 µmol/L (95% CI 0.07; 0.58) higher childhood creatinine levels per 1 SD increase in 25(OH)D, but not with childhood cystatin C levels (EMS Table S5). We performed a sensitivity analysis among a subgroup of 2,644 children to explore whether any association was explained by childhood 25(OH)D status. Results from this analysis are given in EMS Table S6, and suggest that the association of maternal 25(OH)D levels with childhood eGFRcreat were at least partly explained by child 25(OH)D status.
Table 2. Associations of maternal 25(OH)D levels during pregnancy with child kidney outcomes at the age of 6 years (N = 4,212).
| Difference in outcome measure (95% Confidence Interval) | ||||
|---|---|---|---|---|
| Kidney volume (cm3) | eGFRcreat (ml/min/1.73m2) | eGFRcystC (ml/min/1.73m2) | Microalbuminuria (odds ratio) | |
| N = 3,897 | N= 2,833 | N=2,836 | N = 4,068 | |
| Multivariable model£ | ||||
| < 25.0 nmol/L (N = 921) | -0.76 (-3.11, 1.59) | 1.52 (-0.83, 3.86) | -0.33 (-2.39, 1.72) | 1.31 (0.83, 2.06) |
| 25.0 to 49.9 nmol/L (N = 1,083) | 1.92 (0.11, 3.74)* | 1.39 (-0.37, 3.15) | 0.66 (-0.93, 2.24) | 0.91 (0.63, 1.32) |
| 50.0 to 74.9 nmol/L (N = 1,055) | 0.90 (-0.82, 2.62) | 1.44 (-0.24, 3.12) | 0.64 (-0.87, 2.15) | 1.15 (0.83, 1.59) |
| ≥ 75.0 nmol/L (N = 1,153) | Reference | Reference | Reference | Reference |
| Continuously (per SD) | -0.55 (-1.35, 0.25) | -0.94 (-1.73, -0.15)* | -0.29 (-0.99, 0.41) | 0.93 (0.80, 1.09) |
Values are linear and logistic regression coefficients (95% confidence interval). Multivariable adjusted model £ is adjusted for child’s sex, age at 6 year visit, maternal characteristics (age, body mass index at intake, alcohol consumption, smoking during pregnancy, folic acid and energy intake during pregnancy, education, ethnicity, prepregnancy comorbidities, season when blood samples were drawn) and child characteristics (birthweight adjusted for gestational age, breastfeeding, and body surface area at the age of 6y). * p < 0.05. Continuously = Maternal vitamin D levels analyzed per 1 standard deviation in 25(OH)D.
Abbreviations: SD standard deviation; eGFRcreat estimated glomerular filtration rate calculated based on creatinine blood levels; eGFRcystC estimated glomerular filtration rate calculated based on cystatin C blood levels.
Table 3 gives the results from the multivariable regression models for the associations of cord 25(OH)D levels at birth and childhood kidney outcomes. Using the same cut-offs for vitamin D status, 42.2% of the children were categorized as severely vitamin D deficient, 36.4% as deficient, 17.3% as sufficient, and 4.1% as optimal. Cord 25(OH)D levels were not associated with any of the childhood kidney outcomes.
Table 3. Associations of 25(OH)D cord blood levels with kidney outcomes at the age of 6 years (N =2,689).
| Difference in outcome measure (95% Confidence Interval) | ||||
|---|---|---|---|---|
| Kidney volume (cm3) | eGFRcreat (ml/min/1.73m2) | eGFRcystC (ml/min/1.73m2) | Microalbuminuria (odds ratio) | |
| N = 2,480 | N= 1,810 | N=1,814 | N = 2,598 | |
| Multivariable model£ | ||||
| < 25.0 nmol/L (N = 1,136) | 0.80 (-3.50, 5.11) | -0.11 (-4.30, 4.09) | -0.33 (-4.23, 3.57) | 0.68 (0.33, 1.41) |
| 25.0 to 49.9 nmol/L (N = 980) | 0.70 (-3.41, 4.81) | -1.64 (-5.62, 2.33) | -0.14 (-3.85, 3.58) | 0.61 (0.31, 1.20) |
| 50.0 to 74.9 nmol/L (N = 464) | -0.34 (-4.58, 3.80) | -0.85 (-4.97, 3.26) | -1.14 (-4.98, 2.71) | 0.56 (0.27, 1.15) |
| ≥ 75.0 nmol/L (N = 109) | Reference | Reference | Reference | Reference |
| Continuously (per SD) | -0.44 (-1.43, 0.55) | -0.20 (-1.18, 0.79) | 0.17 (-0.73, 1.08) | 0.91 (0.75, 1.11) |
Values are linear and logistic regression coefficients (95% confidence interval). Multivariable adjusted model £ is adjusted for child’s sex, age at 6 year visit, maternal characteristics (age, body mass index at intake, alcohol consumption, smoking during pregnancy, folic acid and energy intake during pregnancy, education, ethnicity, prepregnancy comorbidities) and child characteristics (birthweight adjusted for gestational age, breastfeeding, season when blood samples were drawn and body surface area at the age of 6y). *p < 0.05. Continuously = Cord vitamin D levels of analyzed per 1 standard deviation in 25(OH)D. Abbreviations: SD standard deviation; eGFRcreat estimated glomerular filtration rate calculated based on creatinine blood levels; eGFRcystC estimated glomerular filtration rate calculated based on cystatin C blood levels.
Discussion
In this population-based prospective cohort study, we observed that lower maternal, but not cord, 25(OH)D levels in blood, tended to be associated with higher eGFR and larger combined kidney volume in school-age children. The associations may be partly explained by childhood 25(OH)D levels.
Strength and limitations
A major strength of our study the prospective design from fetal life onwards within a large population-based cohort. This study is among the first that examined the association of fetal vitamin D status with kidney health in a large multi-ethnic sample of school-age children. We used 25(OH)D levels, which are the best and most widely used indicator of vitamin D status.33 Furthermore, we used well-established methods to measure kidney size and function.23, 34 Kidney volume was measured by ultrasound. Kidney size is correlated with the number of glomeruli and can be used in epidemiological studies as measure of kidney development.35 In children the estimation of GFR is challenging. Blood creatinine is most commonly used to calculate eGFR, and Schwartz formula has been validated in a pediatric population.24 In addition to blood creatinine levels, we also calculated eGFR based on cystatin C levels using Zappitelli’s formula.25, 36 It has been suggested that blood cystatin C levels might be a better biomarker to estimate GFR because the production rate is constant, it is freely filtered, and less dependent on child weight, height and sex compared to creatinine.37, 38 However in this study we observe that maternal 25(OH)D levels are associated with eGFRcreat but not with eGFRcystC. This study also has some limitations to consider. Of all children with maternal levels of 25(OH)D available, 74% had successful kidney measurements. Mothers of the children that were lost to follow up had on average higher 25(OH)D levels and were on average lower educated, suggesting that our study population had a selection towards a more healthy population. Furthermore, we used the same cut-offs of 25(OH)D for pregnant woman as the documented levels for general population, while it is still not well known what optimal 25(OH)D levels are during pregnancy.33 A limitation of our study is that we did not have information about childhood dietary data at the age of 6 years. Dietary composition can impact childhood microalbuminuria. Moreover, microalbuminuria was evaluated using urine albumin-creatinine ratio from a random urine sample, still we did not have first-morning void samples. Finally, although we performed adjustment for a large number of potential maternal and childhood confounders, residual confounding by other lifestyle factors, might still be present, as in any observational study.
We hypothesized that maternal vitamin D levels may affect offspring kidney health, by reducing the number of nephrons, which in turn lead to glomerular hyperfiltration and sclerosis, thus predisposing the individual to renal damage and subsequent development of higher blood pressure, impaired kidney function and end-stage kidney disease in adulthood.39 The observed effect estimates in the present study are small, but important from an etiological perspective. They provide further insights into pathways leading to changes in kidney function from the earliest phase of life.
Interpretation and comparison with previous studies
In adults, vitamin D deficiency is associated with an increased risk of having microalbuminuria.40 In a study among 15,068 individuals aged 20 years and older in the U.S., it was observed that adults who had 25(OH)D levels in the lowest quartile had an increased risk of microalbuminuria.40 We did not observe any association between maternal or cord 25(OH)D levels and the risk of childhood microalbuminuria. It might be that differences in this clinical marker of kidney dysfunction appear at older ages. The Cardiovascular Health Study, a prospective community-based cohort among 1,705 participants aged 65 years and older in the U.S. reported that lower 25(OH)D levels were associated with a lower eGFR.41 In contrast, we observed that higher maternal 25(OH)D levels were associated with lower eGFR in childhood. Additionally, we observed that the effect of maternal 25(OH)D levels on childhood eGFR was at least partly explained by child’s current 25(OH)D levels. Childhood 25(OH)D and maternal 25(OH)D levels are correlated due to similar dietary and lifestyle factors.
Our findings are in line with animal studies. Studies in rats observed no differences in kidney volume in rats whose mothers were fed with a vitamin D deplete diet.7 However, maternal vitamin D deficiency was associated with an increase in the number of glomeruli at 7 weeks.7 Still, it is not known whether these additional nephrons are functional, and thus confer an advantage to renal function. Interestingly, another study comparing two generations of mice from mothers fed either standard chow or vitamin D-deficient diet, suggests that maternal vitamin D deficiency accompanies changes in the renal expression of important factors that may delay the maturation of glomeruli by extending the period of nephrogenesis.8 In line with these observations, we observed that mothers who were 25(OH)D deficient had children with larger combined kidney volume. Also, lower maternal 25(OH)D levels were associated with an increased eGFR in school-age children. We observed no associations between cord 25(OH)D levels and childhood kidney outcomes. Our results suggest that different periods of fetal 25(OH)D exposure may have different impact on childhood kidney outcomes.
The mechanisms by which maternal vitamin D levels during pregnancy affect childhood kidney function are not known yet. Vitamin D is an important component, during cell proliferation for differentiation and maturation processes.42 Renal proximal tubules are the major site for the conversion of the 25(OH)D to the active hormone, and thus any early changes to renal function may have consequences for later vitamin D physiology. Maka et al. suggests that vitamin D deficient offspring may have prolonged nephrogenic proliferation, without the appropriate switch to nephron maturation. If this is the case, it is likely that the nephrons, although more numerous, may not be fully matured and may be functionally impaired.7
Conclusion
Results from this population-based prospective cohort study suggest that maternal 25(OH)D levels during pregnancy may influence childhood kidney function. Part of the observed effect may be explained by childhood 25(OH)D levels. These results should be considered as hypothesis generating. Further studies are needed to replicate the observations, to examine the underlying mechanisms and to identify the long term-clinical consequences.
Supplementary Information
Supplementary information is available at EJCN's website.
Acknowledgments
The Generation R Study is conducted by the Erasmus University Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond (STAR), Rotterdam. We gratefully acknowledge the contribution of participating mothers, general practitioners, hospitals, midwives and pharmacies in Rotterdam.
Financial support
The general design of the Generation R Study was made possible by financial support from Erasmus Medical Center, Rotterdam; Erasmus University, Rotterdam; the Dutch Ministry of Health, Welfare and Sport; and the Netherlands Organization for Health Research and Development (ZonMw). K.Miliku has been financially supported through Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission. T. Voortman and O Franco work in ErasmusAGE, a research center funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA. The vitamin D assay was supported by the Australian National Health and Medical Research Council (NHMRC APP1062846). Dr John McGrath received a NHMRC John Cade Fellowship (APP1056929). V.W.V. Jaddoe received an additional grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and an European Research Council Consolidator Grant (ERC-2014-CoG-648916). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript.
Footnotes
Author contributions
KM, TV and VWVJ designed the research and wrote the paper; AH, HT, OHF and VWVJ were involved in the design and planning of the study and data collection; JM, DE, TB performed the vitamin D assays on maternal and cord blood. KM and TV analysed the data; JM, DE, TB, AH, HT, OHF and VWVJ provided comments and consultation regarding the analyses and manuscript; KM and VWVJ had primary responsibility for final content. All authors critically reviewed and gave final approval of the version to be published.
Conflict of interest
The authors declare no conflict of interest.
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