CENTRO DE CAPACITACIÓN JUDICIAL ELECTORAL
INFORMES DE LABORES
In adults, vitamin D defi ciency is associated with an increased risk of having microalbu- minuria.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 diff erences in this clinical marker of kidney dysfunction appear at older ages. The Cardiovascular Health Study, a pro- spective 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 eff ect 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 fi ndings are in line with animal studies. Studies in rats observed no diff erences in kid- ney volume in rats whose mothers were fed with a vitamin D deplete diet.7
However, maternal vitamin D defi ciency 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-defi cient diet, suggests that maternal vitamin D defi ciency 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 defi cient 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 diff erent periods of fetal 25(OH)D exposure may have diff erent impact on childhood kidney outcomes.
The mechanisms by which maternal vitamin D levels during pregnancy aff ect childhood kidney function are not known yet. Vitamin D is an important component, during cell prolif- eration for diff erentiation 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.7
suggests that vitamin D defi cient off spring 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 infl uence childhood kidney function. Part of the observed ef- fect 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.
REFERENCES
1. Gale CR, Robinson SM, Harvey NC, Javaid MK, Jiang B, Martyn CN et al. Maternal vitamin D status during
pregnancy and child outcomes. Eur J Clin Nutr 2008; 62(1): 68-77.
2. Crozier SR, Harvey NC, Inskip HM, Godfrey KM, Cooper C, Robinson SM et al. Maternal vitamin D status
in pregnancy is associated with adiposity in the off spring: fi ndings from the Southampton Women’s Survey. Am J Clin Nutr 2012; 96(1): 57-63.
3. Hanieh S, Ha TT, Simpson JA, Thuy TT, Khuong NC, Thoang DD et al. Maternal vitamin D status and infant
outcomes in rural Vietnam: a prospective cohort study. PLoS One 2014; 9(6): e99005.
4. Bouvard B, Annweiler C, Salle A, Beauchet O, Chappard D, Audran M et al. Extraskeletal eff ects of vitamin
D: facts, uncertainties, and controversies. Joint Bone Spine 2011; 78(1): 10-16.
5. Robinson PD, Hogler W, Craig ME, Verge CF, Walker JL, Piper AC et al. The re-emerging burden of rickets:
a decade of experience from Sydney. Arch Dis Child 2006; 91(7): 564-568.
6. Harvey NC, Moon RJ, Sayer AA, Ntani G, Davies JH, Javaid MK et al. Maternal antenatal vitamin D status
and off spring muscle development: fi ndings from the Southampton Women’s Survey. J Clin Endocrinol Metab 2014; 99(1): 330-337.
7. Maka N, Makrakis J, Parkington HC, Tare M, Morley R, Black MJ. Vitamin D defi ciency during pregnancy
and lactation stimulates nephrogenesis in rat off spring. Pediatr Nephrol 2008; 23(1): 55-61.
8. Nascimento FA, Ceciliano TC, Aguila MB, Mandarim-de-Lacerda CA. Maternal vitamin D defi ciency
delays glomerular maturity in F1 and F2 off spring. PLoS One 2012; 7(8): e41740.
9. Boyce AC, Palmer-Aronsten BJ, Kim MY, Gibson KJ. Maternal vitamin D defi ciency programmes adult
renal renin gene expression and renal function. J Dev Orig Health Dis 2013; 4(5): 368-376.
10. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Eff ect of in utero and early-life conditions on adult
health and disease. N Engl J Med 2008; 359(1): 61-73.
11. Hinchliff e SA, Sargent PH, Howard CV, Chan YF, van Velzen D. Human intrauterine renal growth ex- pressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest 1991; 64(6): 777-784.
12. Brenner BM, Lawler EV, Mackenzie HS. The hyperfi ltration theory: A paradigm shift in nephrology. Kidney
Int 1996; 49(6): 1774-1777.
13. Jaddoe VWV, van Duijn CM, Franco OH, van der Heijden AJ, van Iizendoorn MH, de Jongste JC et al. The
Generation R Study: design and cohort update 2012. Eur J Epidemiol 2012; 27(9): 739-756.
14. Kruithof CJ, Kooijman MN, van Duijn CM, Franco OH, de Jongste JC, Klaver CC et al. The Generation R
Study: Biobank update 2015. Eur J Epidemiol 2014; 29(12): 911-927.
15. Eyles D, Anderson C, Ko P, Jones A, Thomas A, Burne T et al. A sensitive LC/MS/MS assay of 25OH vitamin
D3 and 25OH vitamin D2 in dried blood spots. Clin Chim Acta 2009; 403(1-2): 145-151.
16. Holick MF. Vitamin D defi ciency. N Engl J Med 2007; 357(3): 266-281.
17. Voortman T, van den Hooven EH, Heijboer AC, Hofman A, Jaddoe VW, Franco OH. Vitamin D Defi ciency in
School-Age Children Is Associated with Sociodemographic and Lifestyle Factors J Nutr 2015. doi: 10.3945/ jn.114.208280
18. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK et al. The 2011 report on dietary refer-
ence intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96(1): 53-58.
19. Sioen I, Mouratidou T, Kaufman JM, Bammann K, Michels N, Pigeot I et al. Determinants of vitamin D
status in young children: results from the Belgian arm of the IDEFICS (Identifi cation and Prevention of Dietary- and Lifestyle-Induced Health Eff ects in Children and Infants) Study. Public Health Nutr 2012; 15(6): 1093-1099.
20. Vogeser M. Quantifi cation of circulating 25-hydroxyvitamin D by liquid chromatography-tandem mass
spectrometry. J Steroid Biochem Mol Biol 2010; 121(3-5): 565-573.
21. Miliku K, Voortman T, Bakker H, Hofman A, Franco OH, Jaddoe VW. Infant Breastfeeding and Kidney
Function in School-Aged Children. Am J Kidney Dis 2015; 10.1053/j.ajkd.2014.12.018.
22. Geelhoed JJM, Taal HR, Steegers EAP, Arends LR, Lequin M, Moll HA et al. Kidney growth curves in
healthy children from the third trimester of pregnancy until the age of two years. The Generation R Study. Pediatr Nephrol 2010; 25(2): 289-298.
23. Geelhoed JJ, Kleyburg-Linkers VE, Snijders SP, Lequin M, Nauta J, Steegers EA et al. Reliability of renal
2.5
24. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA et al. New Equations to Estimate GFR
in Children with CKD. J Am Soc Nephrol 2009; 20(3): 629-637.
25. Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S et al. Derivation and validation of cystatin C-
based prediction equations for GFR in children. Am J Kidney Dis 2006; 48(2): 221-230.
26. Donaghue KC, Chiarelli F, Trotta D, Allgrove J, Dahl-Jorgensen K. Microvascular and macrovascular
complications Microvascular and macrovascular complications. Pediatr Diabetes 2007; 8(3): 163-170.
27. Klipstein-Grobusch K, den Breeijen JH, Goldbohm RA, Geleijnse JM, Hofman A, Grobbee DE et al. Dietary
assessment in the elderly: validation of a semiquantitative food frequency questionnaire. Eur J Clin Nutr 1998; 52(8): 588-596.
28. Centre for Research and Statistics. Centrum voor Onderzoek en Statistiek: Rotterdam, The Netherlands,
2005. Available from http://www.rotterdam.nl/ onderzoek.
29. Statistiek CBvd. Immigrants in the Netherlands 2004. Statistics Netherlands: Netherland, 2004.
30. Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P. An update of the Swedish reference
standards for weight, length and head circumference at birth for given gestational age (1977-1981). Acta Paediatr Scand 1991; 80(8-9): 756-762.
31. Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG et al. Multiple imputation for missing
data in epidemiological and clinical research: potential and pitfalls. BMJ 2009; 338: b2393.
32. Rubin DB, Schenker N. Multiple imputation in health-care databases: an overview and some applica-
tions. Stat Med 1991; 10(4): 585-598.
33. Harvey NC, Holroyd C, Ntani G, Javaid K, Cooper P, Moon R et al. Vitamin D supplementation in preg-
nancy: a systematic review. Health Technol Assess 2014; 18(45): 1-190.
34. Bakker J, Olree M, Kaatee R, de Lange EE, Moons KG, Beutler JJ et al. Renal volume measurements: ac-
curacy and repeatability of US compared with that of MR imaging. Radiology 1999; 211(3): 623-628.
35. Luyckx VA, Brenner BM. The clinical importance of nephron mass. J Am Soc Nephrol 2010; 21(6): 898-910.
36. Bacchetta J, Cochat P, Rognant N, Ranchin B, Hadj-Aissa A, Dubourg L. Which creatinine and cystatin C
equations can be reliably used in children? Clin J Am Soc Nephrol 2011; 6(3): 552-560.
37. Filler G, Bokenkamp A, Hofmann W, Le Bricon T, Martinez-Bru C, Grubb A. Cystatin C as a marker of
GFR--history, indications, and future research. Clin Biochem 2005; 38(1): 1-8.
38. Groesbeck D, Kottgen A, Parekh R, Selvin E, Schwartz GJ, Coresh J et al. Age, gender, and race eff ects on
cystatin C levels in US adolescents. Clin J Am Soc Nephrol 2008; 3(6): 1777-1785.
39. Brenner BM, Chertow GM. Congenital oligonephropathy and the etiology of adult hypertension and
progressive renal injury. Am J Kidney Dis 1994; 23(2): 171-175.
40. de Boer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albumin-
uria in the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 2007; 50(1): 69-77.
41. de Boer IH, Katz R, Chonchol M, Ix JH, Sarnak MJ, Shlipak MG et al. Serum 25-hydroxyvitamin D and
change in estimated glomerular fi ltration rate. Clin J Am Soc Nephrol 2011; 6(9): 2141-2149.
Supplementary Table 2.5.1. Subject characteristics (N=4,212)
Imputed Original Maternal characteristics
Maternal age (y) 31.3 (20.2, 39.4) 31.3 (20.2, 39.4) Maternal body mass index at enrolment (kg/m2
) 22.6 (18.1, 34.3) 22.6 (18.1, 34.2) Education level (%) - No higher education 51.2 49.7 - Higher education 48.8 50.3 Ethnicity (%) - European 63.2 63.8 - Cape Verdean 4.1 4.0 - Dutch Antillean 2.0 2.0 - Moroccan 5.6 5.4 - Turkish 8.2 8.2 - Surinamese 7.6 7.5 - Other 9.3 9.3
Smoking during pregnancy (%)
- Never 75 74.9
- Until pregnancy was known 9.9 9.5
- Continued 15.1 15.6
Alcohol during pregnancy (%)
- Never 42.8 42.2
- Until pregnancy was known 14.3 14.4
- Continued 42.9 43.5
Folic acid supplements use (%)
- No 24.5 22.0
- Start 1st to 10 weeks 31.2 31.3 - Start periconceptional 44.3 46.7 Maternal calories intake (kcal) 2,062 (485) 2,053 (544) Maternal blood levels of 25(OH)D (nmol/L) 51.9 (7.7, 122.1) 51.9 (7.7, 122.1) Season when blood sample was taken (%)
- Spring 27.8 27.8 - Summer 22.6 22.6 - Autumn 25.5 25.5 - Winter 24.1 24.1 Infant characteristics Girls (%) 50.4 50.5
Gestational age at birth (wk) 40.1 (35.9, 42.3) 40.1 (35.9, 42.3) Birth weight (g) 3,449 (545) 3,448 (544) Breastfeeding in the fi rst 4 months (%)
- Exclusive 31.7 25.7
- Partial 61.1 65.7
- Never 7.2 8.6