Vitamin D has important roles in the function of various organs. Besides controlling calcium and bone homeostasis via the kidney, vitamin D regulates cell interaction, and modulates the immune response, thereby affecting susceptibility to infection via activation of vitamin D receptors expressed throughout the body [1]. Despite lacking renal 1α-hydroxylase, patients with chronic kidney disease (CKD) retain an ability to convert nutritional vitamin D or calcifediol (25-hydroxyvitamin D, 25(OH)D) to active vitamin D (1,25 (OH)2D) using nonrenal la-hydroxylase present in several tissues including skin, breast, colon, prostate, and various cells in the immune system [2]. Therefore, an adequate quantity of 25(OH)D is necessary for production of 1,25 (OH)2D. The best indicator of vitamin D status is serum concentration [25(OH)D] because it correlates with total body store, has a longer half-life, and has a higher blood concentration than 1,25 (OH)2D [3]. The U.S. National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/K/DOQI) Clinical Practice Guidelines suggest that replacement with 25(OH) D should be initiated before treatment with 1,25 (OH)2D in patients with CKD and a serum [25(OH)D] <30 ng/mL [4],
Earlier studies reported the prevalence of 25(OH)D deficiency in as many as 30% to 80% of patients receiving renal replacement therapy (RRT) including hemodialysis (HD) [5,6,7,8,9], peritoneal dialysis (PD) [10,11,12,13,14], and post kidney transplantation (KT) [15,16,17,18,19]
Summary of studies of prevalence of 25(OH)D deficiency in various renal replacement therapy modalitiesAuthors (year) Countries Study design Population (n) Duration of RRT (months) Age (years) [25(OH)D] (ng/mL) Prevalence of low [25(OH)D] (ng/mL) % Saabetal. [5] USA retrospective HD (131) 66.5 [4–303] 59.0 [25–90] 16.9±8.5 Deficient (<15) 51 (2007) Insufficient (<30) 92 Del Valle etal. [9] Argentina cross-sectional HD (84) 41.0±29.6 58.9±16.6 24.4 (5–79) Deficient (<15) 22.6 (2007) Insufficient (15–30) 53.5 Jean et al. [6] France cross-sectional HD (253) 62±74 66.7±14 14.8±10.4 Deficient (<10) 42 (2008) Insufficient (10–30) 47 Blairetal. [7] USA retrospective, HD (344) 37.1±34.5 61.9±16.3 21.0±13.5 Deficiency (<40) 92.4 (2008) multi-centered Porter etal. [8] USA retrospective HD (96) 68.4±55.2 52.5±14.6 14.7±6.0 Deficient (<15) 56 (2013) Insufficient (16–30) 44 Alwakeeletal. [14] Saudi cross-sectional PD (27) 27.5±18.5 46.0±21.0 16.1±8.2 Deficient (<15) 59.2 (2014) Arabia Insufficient (15–25) 29.6 Ewers etal. [16] Denmark cross-sectional KT (173) 88.8 (39.6–152.4) 53.4±11.7 F21.6 (15–31) Deficient (<15) 29.0 (2008) M 18.2 (12–27) Insufficient (16–30) 51.0 Marcenetal. [17] Spain retrospective KT (509) 113.0±76.0 45.4±14.5 20.0±10.6 Deficient (<16) 38.3 (2009) Insufficient (16–30) 46.9 Kulshresthaetal. [18] USA cross-sectional KT (74) 51.2 (47.9–53.5) 46.0±16.0 MS 20.5 ±7.2 Deficient (<16) 29.7 (2013) Without MS 24.8±11.1 Insufficient (16–30) 51.4 Beiqueetal. [19] Canada retrospective KT (331) 80.4 (34.8–129.6) 51.0 (41.5–60.2) 31.3 (23.4–39.9) Deficient (<30) 45.3 (2013) Clayton etal. [13] Australia cross-sectional HD (120) 29.5 (11.6–53.1) 64.1 (53.1–74.7) 20.0 (12.7–26.0) HD deficient (<20) 49 (2009) PD (31) 20.6 (10.5–43.8) 68.6 (58.1–72.1) 13.6 (8.4–15.0) HD insufficient (20–30) 33 PD deficient 77 PD insufficient 19 Iguaceletal. [11] Spain cross-sectional OL-HDF (33) 27.5 (12.0–70.5) 60.0±16.0 19 (13–27) Deficient (5–15) 51.0 (2010) HD (61) PD (21) 11 (6–16) 9 (6–12) Insufficient (16–30) 42.0 Hannaetal. [10] Australia cross-sectional HD (26) 22 (2–166) 63.6±15.1 21.5 (4.1–50.4) HD deficient (<10) 3.8 (2014) PD (30) 17 (1–70) 56.9±16.2 13.2 (5.0–33.2) HD insufficient (10–20) 30.8 PD deficient 33.3 Eyaletal. [15] Israel cross-sectional HD (50) 90.4±74.6 56.2±15.4 30.3±19.1 HD deficient (<15) 10 (2013) 23.5 ± 9.9 HD insufficient (16–30) 52 KT (103) KT deficient 22.3 KT insufficient 52.4 The present Thailand cross-sectional, OL-HDF (32) 72.6±57.4 55.5+16.8 17.7±8.5 OL-HDF deficient (<15) 50 study 44 retrospective, OL-HDF insufficient (15-30) single-center PD (37) 10.5±5.9 PD deficient 82 PD insufficient 18 KT (42) 15.4 ± 6.1 PD deficient 82 PD insufficient 18 KT insufficient 45
However, to our knowledge there are no available studies that compare simultaneously the prevalence of 25(OH)D deficiency among adult patients receiving various modalities of RRT. 25(OH)D deficiency can cause detrimental effects in patients receiving dialysis including increased all-cause mortality [20,21], long-term cardiovascular mortality because of atherosclerosis and endothelial dysfunction [22, 23], and a higher rate of hospitalization [24]. Similarly, KT recipient patients and low [25(OH) D] had higher rate of all-cause mortality, annual renal function decline, and development of acute cellular rejection [25,26,27].
The aims of the present study were to examine the impact of three different RRT modalities on serum [25(OH)D] in Thai patients simultaneously, and to assess factors that might affect vitamin D status.
The present study was a retrospective, observational, single tertiary center, cross-sectional study performed during June to July 2014 and was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No. 449/57). The study included data from 111 consecutive adult Thai patients who received either HD, PD, or KT at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, located at a latitude of just 13°43′N (suggesting strong exposure to sunlight). Demographic data including age, sex, comorbidity, dialysis vintage, and post-transplantation time were abstracted from a retrospective review of electronic medical records. No participants ever received oral ergocalciferol or cholecalciferol supplements.
Blood samples had been drawn midweek to obtain predialysis serum [25(OH)D], complete blood count, and calcium, phosphate, intact parathyroid hormone (iPTH), alkaline phosphatase, blood urea nitrogen (BUN), creatinine, uric acid, and albumin levels, lipid profile, and iron studies. Samples were immediately analyzed using standard automated methods. Serum [25(OH)D] was determined using a commercially available chemiluminescent immunoassay (DiaSorin Liaison, Stillwater, MN, USA). Interassay coefficient of variation (functional sensitivity) was 20% and the limit of detection was <4 ng/mL. According to the NKF/K/DOQI guidelines 25(OH)D deficiency is defined as <15 ng/mL, and insufficiency as 15–30 ng/mL, and sufficiency as >30 ng/mL. Total calcium (Ca) level was corrected using the equation: total Ca = serum Ca + [(4.0 – serum albumin) × 0.8]. Adequacy of dialysis was determined by using a urea kinetic model to achieve delivered Kt/V for HD patients. Total (renal and peritoneal) weekly Kt/V and total weekly creatinine clearance were assessed in patients receiving PD. Normalized protein nitrogen appearance (nPNA), representing daily protein intake, was derived from calculation of Kt/V, 24 h dialysate, and 24 h urine collection during a steady state. The renal dietitian routinely followed and monitored dialysis and KT recipients for body weight, height, body mass index (BMI) in conjunction with nutritional status assessment by the Malnutrition Inflammation Score.
All data are expressed as mean ± standard deviation (SD) while non-normally distributed variables are expressed as median with interquartile range (IQR). The statistical analysis was performed using SPSS Statistics for Windows, version 17.0 (SPSS Inc, Chicago, IL, USA). Differences between variables were compared using a one-way analysis of variance (ANOVA) and unpaired Student
We analyzed data from 111 patients who received on-line hemodiafiltration (OL-HDF, n = 32), PD (n = 37; continuous ambulatory PD, CAPD =13 and automated PD, APD = 24) and KT (n = 42; KT deceased donor, DDKT = 23 and KT living, related donor, LRKT = 19).
Baseline characteristics of patients whose data were included in the studyVariable OL-HDF (n = 32) PD (n = 37) KT (n = 42) P Age (y) 54.3±14.2 64.7±19.5 48.3±11.7 Male sex, n (%) 11 (34.4) 15 (40.5) 20 (47.6) 0.51 Body weight (kg) 52.0 (18) 53.3 (11) 60.3 (21) 0.32 Body mass index (kg/m2) 20.5 (8) 21.0 (5) 22.3 (6) 0.47 RRT duration (years) 5.6 (6.7) 3.5 (2.9) 4.7 (8.6) Presence of diabetes, n (%) 12 (37.5) 18 (48.6) 7 (16.7) RAS blockade (%) 40.6 48.6 26.2 0.11 Erythropoietin (units/kg) 209.8±206.3 150.7±133.3 73.2±44.8 0.14 Diabetic nephropathy 9 (28.1%) 17 (45.9%) 5 (11.9%) Glomerulonephritis 6 (18.7%) 6 (16.2%) 18 (42.9%) Obstruction 2 (6.3%) 2 (5.4%) 2 (4.8%) 0.96 Polycystic kidney disease 1 (3.1%) 1 (2.7%) 3 (7.1%) 0.58 Hypertension 10 (31.3%) 5 (13.5%) 1 (2.1%) Unknown 4 (12.5%) 6 (16.2%) 13 (31.0%) 0.11 25(OH)D (ng/mL) 17.7±8.5 10.5±5.9 15.4±6.1 Hemoglobin (g/dL) 10.9 (1.2) 11.0 (1.6) 11.9 (2.4) Blood urea nitrogen (mg/dL) 72.6±24.0 52.7±22.7 24.5±17.5 Creatinine (mg/dL) 10.3 (3.2) 8.0 (6.3) 1.2 (0.9) Uric acid (mg/dL) 7.6 ± 1.5 5.9±1.3 6.9 ± 2.3 Bicarbonate (mEq/L) 24.1 ± 2.3 26.2 ± 3.0 23.7 ± 3.4 Corrected calcium (mg/dL) 9.5 (1.2) 9.5 (0.9) 9.6 (1.0) 0.68 Phosphate (mg/dL) 4.9 (1.4) 4.2 (1.4) 3.3 (0.8) Total cholesterol (mg/dL) 157.9 ± 30.9 175.3 ± 45.5 195.4±43.5 Triglyceride (mg/dL) 98 (71.5) 127.0 (149) 117.5 (66.3) 0.21 Low density lipoprotein (mg/dL) 88.0 (30.3) 84 (31.5) 112.5 (55) High density lipoprotein (mg/dL) 48.7±14.5 42.9±18.8 63.8 ± 21.7 Intact parathyroid hormone (pg/mL) 534.4 (496.8) 288.8 (339.0) 106.2 (231.4) Albumin (g/dL) 4.1 (0.8) 3.6 (0.8) 4.2 (0.5) Kt/V 2.4 ± 0.4 2.2±0.5 NA 0.07 nPNA (g of N/kg/day) 1.1 (0.4) 1.0 (0.3) 1.0 (0.4) 0.10
Patients in the PD group had a significantly lower level of serum 25(OH)D than those in the OL-HDF and KT groups. All patients with severe vitamin D deficiency, that is, serum [25(OH)D] –5 ng/mL, were maintained on PD. Patients receiving PD were significantly older and had less dialysis vintage (years of treatment) than patients in the OL-HDF and KT groups. In the PD group, there were no significant differences in age, sex, history of diabetes, BMI, adequacy of dialysis, or serum albumin, calcium, or phosphate between those with CAPD and APD. Patients with APD tended to have a lower mean serum [25(OH)D] than those with CAPD, but the difference was not quite significant.
Vitamin D-deficient (<15 ng/mL) OL-HDF patients had significantly lower vascular access flow, lower hemoglobin levels, and significantly higher BMI than OL-HDF patients with 25(OH)D ≥15 ng/mL
Laboratory variables in patients receiving dialysis Deficiency Insufficiency weekly Kt/V for patients receiving PD; 25(OH)D, 25-hydroxyvitamin D (calcifediol); APD, ambulatory PD; CAPD, continuous ambulatory PD; RAS, renin–angiotensin system; CCl, Creatinine clearance; hs-CRP, high sensitive C-reactive protein; NA, not applicable; iPTH, intact parathyroid hormone; RAS, renin–angiotensin system; URR, urea reduction ratio; nPNA, normalized protein nitrogen;Variable OL-HDF PD 25(OH)D <15 ng/mL 25(OH)D ≥15 ng/mL P APD (n = 24) CAPD (n = 13) P Age (years) 51.4±14.3 57.1 ± 13.9 0.26 64.3 ± 20.0 65.5 ± 19.3 0.87 Male sex, n (%) 4 (25.0) 7 (43.8) 0.26 10 (41.7) 5 (38.5) 0.85 Dialysis duration (years) 7.6 ± 5.9 6.4 ± 4.8 0.54 4.3 ± 2.2 3.6±1.7 0.32 Diabetes, n (%) 7 (43.8) 5 (31.3) 0.46 13 (54.2) 5 (38.5) 0.36 Treatment with RAS blockade, n (%) 9 (56.3) 4 (25.0) 13 (54.2) 5 (38.5) 0.36 History of peritonitis (%) NA NA NA 11 (45.8) 1 (7.7) 25(OH)D (ng/mL) 11.4 ± 2.4 23.9 ± 7.7 9.3 ± 5.1 12.7 ± 6.7 0.09 Kt/V 2.4 ± 0.5 2.3 ± 0.3 0.73 2.2 ± 0.5 2.1 ± 0.4 0.41 URR (%) 84.6 ± 6.6 85.8 ± 3.2 0.52 NA NA NA Access blood flow (mL/min) 832.9 ± 364.9 1,238.9 ± 384.9 NA NA NA Weekly CCl (mL/min) NA NA NA 61.3 ± 32.3 64.1±20.1 0.78 Body mass index (kg/m2) 25.4 ± 7.7 20.3±2.9 21.8 ± 3.6 22.1 ± 3.7 0.81 nPNA (g of N/kg/day) 1.1 ± 0.3 1.2 ± 0.5 0.34 1.05±0.3 1.07 ± 0.3 0.84 Serum albumin (g/dL) 4.0 ± 0.4 4.1 ± 0.5 0.45 3.3 ± 0.5 3.6 ± 0.7 0.21 Protein loss via dialysate (g/day) NA NA NA 4.7 ± 3.2 5.1 ± 1.6 0.66 Hemoglobin (g/dL) 10.2±1.1 11.3 ± 1.3 11.2 ± 1.3 10.7 ± 2.1 0.38 Uric acid (mg/dL) 7.4±1.4 7.7±1.6 0.64 6.0±1.6 5.9 ± 0.7 0.72 Corrected calcium (mg/dL) 9.5 ± 0.9 9.5 ± 0.7 0.93 9.6 ± 0.9 9.5 ± 0.8 0.76 Phosphate (mg/dL) 4.7±1.5 5.0±1.1 0.53 4.4±1.5 4.6±1.3 0.68 iPTH (pg/mL) 743.8 ± 505.0 454.9 ± 248.1 0.09 518.5±601.9 521.9 ± 615.2 0.98 hs-CRP (mg/L) 6.6 ± 9.8 4.9 ± 4.5 0.55 6.3 ± 6.8 6.7 ± 7.8 0.88
DDKT recipients had significantly lower mean [25(OH)D] than patients with LRKT
Laboratory variables in kidney transplant (KT) recipientsVariable KT deceased donor (n=23) KT living, related donor (n=19) P 25(OH)D (ng/mL) 13.7 ± 6.0 17.5 ± 5.7 Age (years) 48.5±10.5 48.1 ± 13.3 0.91 Male sex, n (%) 12 (52.2) 8 (42.1) 0.52 Post transplantation time (years) 7.6 ± 5.7 6.5 ± 5.4 0.51 Treatment with RAS blockade, n (%) 7 (30.4) 4 (21.1) 0.49 Diabetes, n (%) 5 (21.7) 2 (10.5) 0.33 Prednisolone use, n (%) 12 (52.2) 14 (73.7) 0.15 Tacrolimus-based, n (%) 8 (34.8) 9 (47.4) 0.41 Blood urea nitrogen (mg/dL) 27.4±15.3 21.1±19.6 0.25 Creatinine (mg/dL) 1.9±2.2 1.5±1.5 0.45 24-Hour urine protein (g/day) 1.7±2.8 0.4±0.3 Body mass index (kg/m2) 23.1±4.2 23.2±4.4 0.97 Albumin (g/dL) 3.9±0.5 4.3±0.4 nPNA (g of N/kg/day) 1.1±0.3 0.9±0.2 Hemoglobin (g/dL) 11.8±1.7 12.1±1.6 0.55 Fasting blood sugar (mg/dL) 93.9±18.5 109.9±57.3 0.21 Uric acid (mg/dL) 6.9±2.5 6.8±2.1 0.79 Corrected calcium (mg/dL) 9.7±0.8 9.6±0.6 0.58 Phosphate (mg/dL) 3.3±1.0 3.4±0.7 0.77 iPTH (pg/mL) 267.0±297.3 144.8±145.3 0.13
Notably, LRKT recipients had significantly higher serum albumin and lower 24-hour urine protein loss than those in the DDKT group. There was no significant difference in age, renal function, BMI, immunosuppressive regimen, or prednisolone dose between KT recipient subgroups.
There were no significant differences in serum [25(OH)D] between patients of either sex, with or without diabetes, or high or low BMI (data not shown). Multiple logistic regression analysis showed treatment with renin angiotensin system (RAS) blockade, serum triglyceride, and iPTH were significantly associated with 25(OH)D deficiency in patients receiving RRT, and that serum uric acid and phosphate had a significant inverse association with vitamin D deficiency
Multiple logistic regression analysis of 25-hydroxyvitamin D (calcifediol) deficiency (<15 ng/mL) in 111 patients with renal replacement therapy OR per 10 mg/dL increase in serum triglyceride OR per 10 pg/mL increase in serum iPTH OR per 0.1 g/dL increase in serum albuminDeterminants Unadjusted OR 95% CI P Adjusted OR 95% CI P Treatment with RAS blockade 5.15 2.01, 13.16 7.45 2.17, 25.62 Triglyceride (mg/dL) 1.08 1.02, 1.14 1.08 1.01, 1.16 Uric acid (g/dL) 0.75 0.59, 0.94 0.72 0.52, 0.99 iPTH (pg/mL) 1.01 1.00, 1.02 1.02 1.00, 1.04 Phosphate (mg/dL) 0.95 0.71, 1.26 0.72 0.57 0.36, 0.90 Calcium (mg/dL) 0.89 0.55, 1.43 0.62 0.61 0.30, 1.23 0.17 Albumin (g/dL) 0.94 0.88, 1.01 0.08 0.93 0.85, 1.02 0.11 Female gender 1.76 0.81, 3.84 0.16 2.42 0.86, 6.82 0.10
Serum calcium, albumin, and female sex were not found significantly associated with serum 25(OH)D deficiency by multivariate analysis. Among patients receiving dialysis, treatment with RAS blockade and serum triglyceride level were significantly associated with 25(OH)D deficiency. In KT recipients, treatment with RAS blockade and older age were significantly associated with 25(OH)D deficiency after adjustment for confounding factors (data not shown).
The present study demonstrates that low vitamin D status (25(OH)D insufficiency or deficiency) was observed in 100% of patients receiving PD or with KT, and 94% of patients receiving OL-HDF. Patients receiving PD had the lowest [25(OH)D] among patients with the 3 different types of RRT, while the levels were comparable between the OL-HDF and KT group.
In the present study, patients receiving PD were the oldest and had significantly lower serum albumin levels than OL-HDF and KT recipient patients
As seen in
Calcineurin inhibitors can suppress vitamin D receptor expression, and corticosteroids can enhance catabolism of vitamin D [34]. Nevertheless, no significant differences for immunosuppressive regimen and corticosteroid dose were observed between DDKT recipients who had significantly lower serum [25(OH)D] than LRKT recipients
Earlier studies found that factors associated with 25(OH)D deficiency in patients receiving maintenance dialysis were female sex, diabetes mellitus, BMI, serum albumin, presence of residual renal function, and average sun exposure time [9,10,11,12,13]. Among post KT recipients, serum 25(OH)D concentration positively correlated with age, type of immuno-suppressive agent, use of corticosteroid, time from transplantation, and the presence of metabolic syndrome [15,18], while BMI and treatment by RAS blockade were inversely correlated with 25(OH)D deficiency [16, 17]. In the present study, multivariate regression analysis
The present study had some limitations. The number of patients in the present study was small. Because we included data only from patients with preexisting serum [25(OH)D] measurements, there might be a selection bias. In an attempt to circumvent this problem, we adjusted for confounding factors in the statistical analysis. The factors associated with [25(OH)D] do not provide proof of a causal relationship. There was no consideration of the effect of [25(OH)D] fluctuation because of dietary vitamin D supplementation in the present study, because the patients who previously consumed supplemental ergocalciferol or cholecalciferol were not included. Further studies are required to determine whether native vitamin D supplementation will improve clinical or laboratory variables in patients receiving RRT. In conclusion, the present study emphasizes that the prevalence of vitamin D deficiency and insufficiency is high among patients receiving RRT, and modality of RRT may be a factor related to vitamin D deficiency.