Vitamin D Status in Children with Chronic Kidney Disease

Chronic kidney disease (CKD) is defined as an irreversible progressive renal damage lasting for   three or more months [1, 2].  Reported prevalence of CKD in Pakistan varies from 12-29% of renal diseases in pediatric tertiary care centers [3, 4]. Patients with long standing CKD are at high risk of vitamin D deficiency (VDD) and it is a major contributor in the pathogenesis of secondary hyperparathyroidism (SHPT). SHPT in advanced stages of CKD is chiefly attributed to deficiency of 1,25 dihydroxycholecalciferol {1, 25(OH) ₂ D}, and combined with hyperphosphatemia, leads to disordered bone turnover and mineralization, known as mineral bone disorder (MBD). The dysregulated calcium (Ca), phosphorus (P), parathyroid hormone (PTH), and 25-hydroxyvitamin D (25OHD) along with increased fibroblast growth factor – 23 (FGF-23)  result in vascular calcification  which may contribute to high cardiovascular diseases and mortality both in children and adults[1,6-8].  Recent evidence shows that vitamin D has other important biological functions such as modulation of immune system, endocrine system, and cardiovascular protection in addition to its classical function on bone and mineral metabolism [5]. VDD is common in children and its prevalence varies depending on multiple factors [9, 10–13]. Reported prevalence of VDD in CKD ranges from 20-80% depending upon the stage of CKD [9, 14]. Current clinical practice guidelines for management of CKD recommend evaluation for SHPT (serum Ca, P, ALP, PTH) and 25OHD if PTH is high followed by replacement with high dose vitamin D [15, 16]. This approach may delay the onset of secondary hyperparathyroidism. Current evidence shows that 25OHD is the major circulating form of vitamin D with half-life of 2-3 weeks and its levels are the best indicator of vitamin D status [10–13]. Considering the important role of VDD in SHPT in children with CKD, this study was planned with the objective to determine the 25OHD levels in children with CKD.

his cross-sectional study on 90 children, aged 3 months to 17 years with CKD was carried out in the Department of Pediatric Nephrology, National Institute of Child Health (NICH), Karachi from January 2013 to December 2013 after approval from the Hospital Ethics Committee. Patients were enrolled after written/verbal informed consent from parents. National Kidney Foundation-Kidney Disease Outcome Quality Initiative (NKF-KDOQI) guidelines were used to classify CKD into 5 stages based on estimated glomerular filtration rate (GFR) as calculated by Schwartz formula [2, 15, 17]. CKD –stages were defined as stage 1= GFR > 90ml/min/1.73 m2 (with evidence of renal damage), stage 2= GFR between 60-89 ml/min/1.73 m2, 3= GFR between 30-59 ml/min/1.73 m2, 4= GFR between =15-29 ml/min/1.73 m2 and stage 5= GFR< 15 ml/min/1.73m2. Stage 4 and 5 are considered as advanced CKD. Patients with all CKD-stages 1-5 were included without consideration for the treatment modality (conservative or dialysis). Patients who were on vitamin D, 1-alfa-cholecalciferol were included while patients who were on 25OHD treatment were excluded from the study. Serum levels of 25OHD were measured at NICH laboratory by radioimmunoassay method. Vitamin D status was defined as sufficiency (>30-80 ng/ml), insufficiency (16-30 ng/ml), mild to moderate deficiency (5-15ng/ml) and severe deficiency (<5ng/ml) [1, 15] Data including age, gender, height and weight, serum Cr, GFR and CKD-stage, underlying etiology, mode of treatment (dialysis or conservative), bone biochemistry (Ca, P, ALP, PTH), 25OHD levels were collected and analyzed using Statistical Package for Social Sciences (SPSS) version 16. Categorical variables were summarized by frequencies and percentages while continuous variables were summarized with mean + SD. ANOVA was used to determine mean differences whereas chi-square was used for categories like gender and vitamin D status among CKD stages. Pearson correlation test was applied to observe the correlation between 25OHD levels with S. Cr, GFR, and bone biochemistry parameters. P <0.05 was taken as statistically significant.

 Demographic Characteristics (Table 1): Among the 90 patients, there was a male predominance (61.1%) with male to female ratio of 1.5:1. The mean age of study population was 7.4+ 4.6 years and common age groups (table 2) were 6-10 years (n=28, 31%) and above 10 years (n=27; 30%). The mean weight and height of patients was 16.8+9.7 kg and 102.4+29.4 cm respectively.

Etiologies of CKD: Renal hypoplasia –dysplasia was the most common etiology of CKD (33, 36.7%) followed by stone disease (17, 18.9%), posterior urethral valves (15, 16.7%) and juvenile nephronophthisis (11, 12.2%). Other causes of CKD were neurogenic bladder (7.8%), chronic glomerulonephritis (4.4%), reflux nephropathy (2.2%) and polycystic kidney disease (1.1%).

 Renal Function and Staging of CKD (Table 1): The mean blood urea, serum Cr and GFR were 113.5+82.0 mg/dL, 3.9+3.4 mg/dL and 28.8+28.3 ml/min/1.73 m² respectively. CKD stage 5 and 4 was observed in 34(37.8%) and 26(28.9%) patients respectively. Together both constitutes advanced CKD and accounts for 66.7% of all cases. Forty of the 90 (44.44%) patients were undergoing dialysis.

Bone Biochemistry (Table 1): Bone biochemistry showed mean serum Ca, phosphorus, ALP and PTH levels 8.3+1.6 mg/dL, 5.2+1.7 mg/dL, 418.3+298.2 U/L and 370.6+320.7 ng/ml respectively.

Vitamin D Status (Table 1): The overall mean serum 25OHD level in patients with CKD was 18.9+16.8 ng/ml with a range of 1.6–54.4 ng/ml. The mean 25OHD levels in males were 17.7+10.6ng/ml compared to   16.9+ 9.7 ng/ml in females.  This difference (0.82) was not statistically significant (p=0.79). 25OHD levels were quite different (p=.002) being lowest (13.3+8.6ng/ml) in children above 10 years and below one years of age (Table 2). Of the 90 children, 37 (41.1%) had insufficiency, 33 (36.7%) had mild to moderate deficiency and 9 (10%) had severe 25OHD deficiency. Thus suboptimal levels of 25OHD (18.9+16.8 ng/ml) were observed   in 79 cases (87.77 %) and in all the stages of CKD. It was noticeably low (6 out of 9) in CKD -stage 5 (Table 1 vitamin D status).  Similarly high frequency of moderate VDD was also observed in CKD-stage 4 (9, 34.6%) and stage 5 (17, 50%). 25OHD level was also low in 14 patients (15.55%) receiving maintenance dose of 1-alfacalcidol. Pearson correlation revealed a weak direct correlation of 25OHD level with GFR (r=0.125, p=0.112) and indirect correlation with serum Cr(r= -0.169, 0.242), both were not significant. Similarly there was no statistically significant relationship between 25OHD levels with serum Ca (r=0.09, P=0.410), serum P (r=-0.03, P=0.745), serum ALP (r= -0.10, P =0.325) and serum PTH (r = -0.04, P=0.69).

We found a high prevalence (88%) of suboptimal 25OHD levels in children with CKD. Among 90 CKD patients, more than 41% had VD insufficiency, 37% had mild to moderate VDD and 10% presented with severe VDD. This is a first report from Pakistan in which we have documented the 25OHD levels in children with CKD. Similar studies have documented a high prevalence of VDD in children with CKD from many parts of World including India [9, 14, 18 – 21]. Reported prevalence of VDD in CKD children varies from 40-80% in a number of published studies, which is consistent with our findings [9, 14, 18]. The mean 25OHD levels (18.9+16.8) in our study are comparable to a study by Ali FN et al in which it was 21.8 ng/ml [14].  A high frequency of severe VDD in children with advanced uremia (6 out of 9 with severe deficiency) is consistent with a study by Seehermvong W et al [19]. Kalkwarf H et al also found high frequency of VDD (26-74%) in CKD children compared to age matched healthy controls (31%) and this deficiency increased with the severity of CKD, 50 % in advanced CKD and 74% in patients on dialysis [18]. Although majority of patients (66.7%) in our study belonged to advanced CKD and some of them were on dialysis, the frequency of low levels of 25OHD was also high (71.4%) in early stage (CKD-stage 1) and in CKD stage 5(97.7%). Thus, our results are consistent with a study by Kalkwarf H et al [18]. In this study, we did not find significant changes in bone turnover markers  (table 1) like hypocalcaemia (8.3+1.6mg/dl), hyperphosphatemia (5.2+1.7 mg /dl), alkaline phosphatase (418.3 +298.2 U/L) and parathyroid hormone levels (370.6+320.2 pg/ml). Our findings are consistent with the classical findings of secondary hyperparathyroidism in children with CKD [1, 6, 7]. Low 25OHD levels in advanced stages of CKD in the presence of classical bone turnover markers confirm the state of SHPT, which is also consistent with other studies [9, 15, 18]. Vitamin D supplementation may suppress the PTH synthesis and prevent development of SHPT and its associated consequences [6 – 8, 18, 19, 21]. Low 25OH levels in children receiving alfacalcidol in more than 15% in this study suggest that nutritional form of VD is necessary for extra-renal conversion of 25OHD to 1,25hydroxycholecalciferol. Current guidelines recommend measurement of 25OHD in CKD stage 2-4 if PTH is high [15]. We suggest, based on the findings in our study, that these guidelines may be modified as 25OHD levels should be measured in all stages of CKD and supplementation of VD in all patients with suboptimal levels (<30 ng/ml). This strategy   may delay the onset of secondary hyperparathyroidism [21]. There are certain confounding factors such as vitamin D intake in diet, medications and sunlight exposure   which affect 25OHD levels, however, this study did not measure these variables and we cannot examine the effect of these confounding variables on the outcomes.  Further, as there was no control group without CKD, we cannot conclude with certainty that the prevalence of vitamin D deficiency is higher in CKD children than children without CKD.

In this study, a high frequency (87.8%) of suboptimal vitamin D levels suggest that 25OHD levels should be measured in all stages of CKD and fortification strategy of vitamin D may be implemented.

1. VanDeVoorde RG, Warady BA. Management of chronic kidney disease. In: Avner E, Harmon W, Niaudet P, Yoshikawa N (Eds). Pediatric Nephrology. 6th Ed. Springer Berlin Heidelberg 2009; Ch 68:1661-92
2. Eckardt KU, Berns JS, Rocco MV, Kasiske BL. Definition and classification of CKD: the debate should be about patient prognosis–a position statement from KDOQI and KDIGO. Am J Kidney Dis. 2009; 53(6):915-20.
3. Ramzan A, Moorani KN. Pattern of renal diseases in children. J Surg Pak Intern. 2001; 6 (4):9-12
4. Moorani KN, Asim S, Shahid A. Pattern of Kidney Disease in children. Pak Pediatr J. 2013; 37 (1): 26-33
5. Rivera JR, Piedra CDL, Ramos A, Ortiz A, Egido J. The Expanding Spectrum of biological actions of Vitamin D. Nephrol Dial Transplant. 2010; 25 (9):2850-65
6. Wesseling K, Bakkaloglu S, Salusky IB. Chronic Kidney Disease mineral and bone disorder in children. Pediatr Nephrol. 2008;23 (2):195-207
7. Wesseling K. Bone disease in Pediatric chronic kidney disease. Pediatr Nephrol. 2013;28 (4):569-76
8. Portale AA, Wolf M, Juppner H, Messinger S, Kumar J, Wesseling K et al. Disordered FGF-23 and mineral metabolism in children with chronic kidney disease. Clin J Am Soc Nephrol. 2014; 9 (2):344-53
9. Querfeld U, Mak RH. Vitamin D deficiency and toxicity in chronic kidney disease: in search of therapeutic window. Pediatr Nephrol. 2010; 25 (12):2413-30
10. Bal Subramanian S, Dhanalakshmi K, Amperayani S. Vitamin D deficiency in childhood: A Review of current guidelines on diagnosis and management. Indian Pediatr. 2013;50 (7):669–75
11. Holick MF, Binkley NC, Bishoff FHA, Gordon CM, Henley DA, Heanely RP et al. Evaluation, Treatment and prevention of vitamin D deficiency: An Endocrine Society Clinical  Practice Guidelines. Clin Endocrinol Metabol. 2011;96(7):1911-30
12. Melamed ML, Kumar J. Low levels of 25-hydroxyvitamin D in the pediatric populations: prevalence and clinical outcomes. Pub Health. 2010; 4(1): 89–97.
13. Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar D. Vitamin D status in Andhra Pradesh: a population based study. Indian J. Med. Res. 2008; 127(3):211–18
14. Ali FN, Arguelles LM, Langman CB, Price HE. Vitamin D deficiency in children with chronic kidney disease: uncovering an epidemic. 2009; 123(3):791-96
15. Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral bone disorder (CKD-MBD). Kidney Int. 2009; 76( Suppl 113):S1-S130.
16. NKF-KDOQI Clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease. Am J Kid Dis. 2005;46(Suppl 1):S1-S121
17. Schwartz GJ, Haycock GB, Edelman JCM, Spitzer A.A simple estimate of glomerular filtration rate in children derived from body length. Pediatrics. 1976;58 (2):259-63
18. Kalkwarf HJ, Denburg MR, Strife F, Zemel BS, Foerster DL, Wetz Steon RJ et al. Vitamin D deficiency is common in children and adolescents with chronic kidney disease. Kidney Int. 2012; 81 (7):692-97
19. Seeherunvong W, Abitbol CL, Chandar J, Zillernelo G, Freundlich M. Vitamin D insufficiency and deficiency in children with CKD. J Pediatr. 2009; 154 (6) :906 – 11
20. Belostotsky V, Mughal MZ, Berry JL, Webb NJ. Vitamin D deficiency in children with renal disease. Arch Dis Child. 2008; 93 (11):959-62.
21. Shroff R, Wan M, Gullett A, Ledermann S, Shute R, Knott C et al. Ergocalciferol supplementation in children with CKD delays the onset of secondary hyperparathyroidism; A Randomized Trial. Clin J Am Soc Nephrol. 2012; 7 (2):216 –2