Prospective Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. Sep 6, 2016; 5(5): 471-481
Published online Sep 6, 2016. doi: 10.5527/wjn.v5.i5.471
What is the optimal level of vitamin D in non-dialysis chronic kidney disease population?
Pablo Molina, José L Górriz, Mariola D Molina, Sandra Beltrán, Belén Vizcaíno, Verónica Escudero, Julia Kanter, Ana I Ávila, Jordi Bover, Elvira Fernández, Javier Nieto, Secundino Cigarrán, Enrique Gruss, Gema Fernández-Juárez, Alberto Martínez-Castelao, Juan F Navarro-González, Ramón Romero, Luis M Pallardó
Pablo Molina, Sandra Beltrán, Belén Vizcaíno, Verónica Escudero, Julia Kanter, Ana I Ávila, José L Górriz, Luis M Pallardó, Department of Nephrology, Dr Peset University Hospital, 46017 Valencia, Spain
José L Górriz, Luis M Pallardó, Department of Medicine, Universitat de València, 46005 Valencia, Spain
Mariola D Molina, Department of Mathematics, Universidad de Alicante, San Vicente del Raspeig, 03690 Alicante, Spain
Jordi Bover, Department of Nephrology, Fundació Puigvert, 080348 Barcelona, Spain
Elvira Fernández, Department of Nephrology, Hospital Universitari de Lleida, IRBlleida (Institut de Reserca Biomèdica de Lleida), 25198 Lleida, Spain
Javier Nieto, Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain
Secundino Cigarrán, Department of Nephrology, Hospital da Costa Burela, 7880 Lugo, Spain
Enrique Gruss, Gema Fernández-Juárez, Department of Nephrology, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain
Alberto Martínez-Castelao, Department of Nephrology, Hospital Universitario de Beellvitge, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain
Juan F Navarro-González, Research Unit and Department of Nephrology, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
Ramón Romero, Department of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
Author contributions: Molina P, Górriz JL and Pallardó LM drafted the manuscript, designed the research and supervised the study; Molina P and Molina MD performed statistical analysis; Beltrán S, Vizcaíno B, Escudero V, Kanter J, Ávila AI, Bover J, Fernández E, Nieto J, Cigarrán S, Gruss E, Fernández-Juárez G, Martínez-Castelao A and Navarro-González JF were involved with data collection, and assisted with data analysis; all authors read and approved the final manuscript.
Supported by Abbott and the Spanish Society of Nephrology.
Institutional review board statement: The study was reviewed and approved by the Dr Peset Hospital Research Ethics Committee.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Molina P, Górriz JL and Martínez-Castelao A have received honoraria for giving lectures and for consulting on advisory boards for Abbott. The others authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Pablo Molina, MD, PhD, Department of Nephrology, Dr Peset University Hospital, Avda. Gaspar Aguilar, 90, 46017 Valencia, Spain. molina_pab@gva.es
Telephone: +34-9-61622462 Fax: +34-9-61622462
Received: May 9, 2016
Peer-review started: May 11, 2016
First decision: June 14, 2016
Revised: June 22, 2016
Accepted: August 11, 2016
Article in press: August 13, 2016
Published online: September 6, 2016

Abstract
AIM

To evaluate thresholds for serum 25(OH)D concentrations in relation to death, kidney progression and hospitalization in non-dialysis chronic kidney disease (CKD) population.

METHODS

Four hundred and seventy non-dialysis 3-5 stage CKD patients participating in OSERCE-2 study, a prospective, multicenter, cohort study, were prospectively evaluated and categorized into 3 groups according to 25(OH)D levels at enrollment (less than 20 ng/mL, between 20 and 29 ng/mL, and at or above 30 ng/mL), considering 25(OH)D between 20 and 29 ng/mL as reference group. Association between 25(OH)D levels and death (primary outcome), and time to first hospitalization and renal progression (secondary outcomes) over a 3-year follow-up, were assessed by Kaplan-Meier survival curves and Cox-proportional hazard models. To identify 25(OH)D levels at highest risk for outcomes, receiver operating characteristic (ROC) curves were performed.

RESULTS

Over 29 ± 12 mo of follow-up, 46 (10%) patients dead, 156 (33%) showed kidney progression, and 126 (27%) were hospitalized. After multivariate adjustment, 25(OH)D < 20 ng/mL was an independent predictor of all-cause mortality (HR = 2.33; 95%CI: 1.10-4.91; P = 0.027) and kidney progression (HR = 2.46; 95%CI: 1.63-3.71; P < 0.001), whereas the group with 25(OH)D at or above 30 ng/mL did not have a different hazard for outcomes from the reference group. Hospitalization outcomes were predicted by 25(OH) levels (HR = 0.98; 95%CI: 0.96-1.00; P = 0.027) in the unadjusted Cox proportional hazards model, but not after multivariate adjusting. ROC curves identified 25(OH)D levels at highest risk for death, kidney progression, and hospitalization, at 17.4 ng/mL [area under the curve (AUC) = 0.60; 95%CI: 0.52-0.69; P = 0.027], 18.6 ng/mL (AUC = 0.65; 95%CI: 0.60-0.71; P < 0.001), and 19.0 ng/mL (AUC = 0.56; 95%CI: 0.50-0.62; P = 0.048), respectively.

CONCLUSION

25(OH)D < 20 ng/mL was an independent predictor of death and progression in patients with stage 3-5 CKD, with no additional benefits when patients reached the levels at or above 30 ng/mL suggested as optimal by CKD guidelines.

Key Words: Vitamin D, Chronic kidney disease, Mortality, Renal progression, Hospitalization

Core tip: This study examines the prognosis value of 25(OH)D levels on death, chronic kidney disease (CKD) progression, and hospitalization in a cohort of 3-5 stage CKD subjects not on dialysis. The main findings were the predictor value of vitamin D deficiency (< 20 ng/mL), but not insufficiency (< 30 ng/mL), for the 3-year incidence of death and CKD progression, which remained significant after multivariate adjustments. These results could highlight the need for a revision of the current guidelines, which have defined optimal vitamin D status at ≥ 30 ng/mL based on levels required to suppress parathyroid hormone, as opposed to our study, which evaluates thresholds for serum 25(OH)D concentrations in relation to “hard” endpoints.


Citation: Molina P, Górriz JL, Molina MD, Beltrán S, Vizcaíno B, Escudero V, Kanter J, Ávila AI, Bover J, Fernández E, Nieto J, Cigarrán S, Gruss E, Fernández-Juárez G, Martínez-Castelao A, Navarro-González JF, Romero R, Pallardó LM. What is the optimal level of vitamin D in non-dialysis chronic kidney disease population? World J Nephrol 2016; 5(5): 471-481
INTRODUCTION

There is a high prevalence of vitamin D (VD) deficiency in all stages of chronic kidney disease (CKD)[1-5]. Observational studies in this population have shown that VD levels correlated with cardiovascular disease and markers of renal injury, including albuminuria[1,6], renal progression[4,6-8], vascular calcification[9,10], left ventricular hypertrophy[9] and mortality[8,11-13]. Moreover, growing evidence supports a potential role for VD receptor activation in suppressing the renin-angiotensin system, reducing proteinuria and ameliorating kidney dysfunction[14-16], showing 25-hydroxyvitamin D [25(OH)D] as an attractive, cheap and feasible treatment target[17]. As a result of these findings, current guidelines have suggested VD supplementation in CKD patients[18-21], increasing VD supplementation rates among this population[22].

Nevertheless, these recommendations are opinion based and the optimal VD levels as well as the upper safe limit of VD intakes remains controversial[23,24]. Based on the inverse relationship between serum concentrations of 25(OH)D and parathyroid hormone (PTH), most current guidelines have defined VD deficiency and insufficiency, as a serum 25(OH)D level of < 20 ng/mL (50 nmol/L) and 20-29 ng/mL (52-72 nmol/L) respectively[18,19], suggesting a serum concentration of 25(OH)D above 30-40 ng/mL (75-100 nmol/L) to be desirable, levels at which PTH is suppressed to a minimum in its relation to 25(OH)D[25,26]. By contrast, the Institute of Medicine advocates VD repletion as a level of 20 ng/mL [27]. Determining the 25(OH)D target level for optimal health is especially important in CKD population, where overuse of VD leads to hypercalcemia, hypercalciuria and hyperphosphatemia, which could predispose to vascular calcification, nephrolithiasis and reduced glomerular filtration rate[28-30]. All these data suggest an optimal level of VD exists that is neither too high nor too low[31].

Aware of the lack of evidence behind guidelines recommendations, and our concerns about VD over-supplementation, encouraged us to investigate the optimal VD status in non-dialysis CKD patients. The aim of our study was to evaluate thresholds for serum 25(OH)D concentrations in relation to hard end-points such as death, kidney progression and hospitalization in this population.

MATERIALS AND METHODS
Study design and patient selection

OSERCE-2 was a 3-year follow-up prospective, observational, study which enrolled 742 adults with 3 to 5-stage CKD not on dialysis subjects attending 39 centres in Spain, to evaluate the effects of vascular calcifications and CKD-mineral bone disorders on mortality, hospitalization and kidney progression[32]. Inclusion criteria were age ≥ 18 years and CKD Stages 3-5. Exclusion criteria were acute kidney injury, transplantation, hospitalization in the month previous to the enrollment, and severe comorbidity. In this post-hoc analysis of the OSERCE-2 study, patients on current treatment with active VD (calcitriol, α-calcidol or paricalcitol) were also excluded, so 25(OH)D levels reflected the effect of the exposure to VD.

The study was reviewed and approved by the Dr Peset Hospital Research Ethics Committee. All study participants provided informed written consent prior to study enrollment.

Study protocol and baseline data

The study protocol of the OSERCE-2 study has been previously reported[32]. All patients were assessed at baseline for blood pressure measurement, lateral lumbar, pelvis and hands X-ray, an ankle brachial pressure index (ABPI) determination and laboratory blood sampling. All blood samples were analyzed in a central laboratory, including 25(OH)D, 1,25(OH)2 vitamin D, creatinine, calcium, phosphorus, intact PTH, albumin, and high-sensitive C-reactive protein. 25(OH)D levels were assessed by radioimmunoassay (Biosource), which were transformed to the usual method of reference (DiaSorin Liaison chemiluminescent radioimmunoassay) for improving the comparability of the results, as previously described[32]. To study the renal progression, blood samples for determination of serum creatinine levels were obtained every 12 mo. Estimated glomerular filtration rate (eGFR) was calculated using the modification of diet in renal disease (MDRD) formula[33].

Outcomes

Deaths episodes (primary outcome), time to first hospital admission and the appearance of a combined renal end-point, defined as a drop > 30% in eGFR, or beginning of renal replacement therapy (secondary outcomes), were prospectively gathered over a 3-year period[32].

Statistics analysis

Summary statistics were reported as frequencies or percentages, and as mean ± SD, for categorical and quantitative variables, respectively. Skewed quantitative variables were expressed as geometric mean (95%CI), after log transformation. Presence or absence of prominent calcification for Adragao (AS) and Kauppila scores (KS) was reported as AS ≥ 3 and KS > 6, respectively.

Patients were classified further into 3 groups by 25(OH)D level: < 20 ng/mL (deficiency), 20-29 ng/mL (insufficiency) and ≥ 30 ng/mL. Comparison of baseline characteristics in these 3 groups was assessed using one-way analysis of variance (ANOVA) for continuous variables, and χ2 test for trend, for categorical variables. Analysis of variables independently related to 25(OH)D levels was assessed by lineal regression model. To assess the relationship between the odds of VD deficiency and clinical and laboratory baseline characteristics, a stepwise binary logistic regression was performed between 25(OH)D level < 20 or ≥ 20 ng/mL as dependent variables. PTH and 1,25(OH)D levels were considered as posterior variables to 25(OH)D levels and then they were not introduced in the models, to avoid an overadjustment bias. Twenty-four hours urine proteinuria was not included either because it was available in only 50% of the patients.

Kaplan-Meier analysis and log-rank tests were used to estimate the effects of VD status on all-cause mortality, appearance of the composite renal endpoint, and hospitalizations. We then used univariate and multivariate Cox proportional hazard regression models to determine the association of VD levels with various pre-specified outcomes. Patients with 25(OH)D levels between 20 to 29 ng/mL were considered as reference group. Covariates significantly associated in the univariate analysis were entered (forward selection: Likelihood ratio) into the models. The relatively small number of deaths limited the list of adjustment variables that were included in the regression analyses. To identify VD levels at highest risk for outcomes, we performed a receiver operating characteristic (ROC) curve. The value associated with the highest accuracy was considered as the cut-off point for defining an increased risk of death, appearance of the composite renal endpoint, and hospitalization.

The literature indicates that annual mortality in patients with stage 3 to 5 CKD (not on dialysis), is between 3% and 9%. Previous studies have shown a 35% prevalence of VD deficiency in this population[3]. Compared with the group with VD deficiency, the group with VD insufficiency shows a 57% decrease in mortality[8]. With 470 patients included, a minimum follow-up of three years, and considering an error of alfa = 0.05, the power estimation of the study is 0.754. The statistical methods of this study were reviewed by MD Molina, from the Department of Mathematics, Universidad de Alicante, Spain, who was included as a co-author. All data analyses were conducted using SPSS, version 15.0 (SPSS Inc., Chicago, IL). A P-value < 0.05 was considered statistically significant.

RESULTS
Baseline data

From the 742 subjects enrolled at OSERCE-2 Study, 252 were excluded and 20 were lost to follow-up, leaving 470 patients in the final analysis (Figure 1). Tables 1 and 2 show the patient characteristics and laboratory values, respectively, as a function of vitamin D status. According to 25(OH)D levels, the proportion of patients with deficiency or insufficiency was 53% and 33%, respectively. At baseline, the proportion of patients with 5-stage CKD, diabetes mellitus, diabetic nephropathy and chronic heart failure was higher in the group with less 25(OH)D levels. ABPI, eGFR, PTH, 1,25(OH)2 vitamin D and albumin levels were increased in groups with better VD status, which showed lower degree of proteinuria. The group with 25(OH)D less than 20 ng/mL was prescribed more frequently treatment with diuretics and erythropoietin-stimulating agents, with a lower proportion of patients under native VD treatment.

Table 1 Baseline patient characteristics (n = 470), as a function of vitamin D status.
All25(OH)D < 20 ng/mL25(OH)D 20-29 ng/mL25(OH)D ≥ 30 ng/mLP
n470252 (53%)154 (33%)64 (14%)
Age (yr)66.1 ± 12.965.8 ± 13.165.9 ± 11.968.1 ± 12.10.421
Male sex (%)309 (66%)162 (64%)101 (66%)46 (72%)0.303
High blood pressure (%)444 (95%)242 (96%)144 (94%)58 (91%)0.072
Dyslipidemia (%)311 (66%)168 (68%)101 (66%)42 (66%)0.646
Diabetes mellitus (%)183 (39%)114 (45%)53 (34%)16 (25%)0.001
Ischemic heart disease (%)104 (22%)60 (24%)33 (22%)11 (17%)0.224
Chronic heart failure (%)43 (9%)33 (13%)7 (5%)3 (5%)0.005
Stroke (%)52 (11%)30 (12%)15 (10%)7 (11%)0.668
Peripheral arterial disease (%)93 (20%)59 (24%)22 (14%)12 (19%)0.117
Stage of CKD (%)
3 (eGFR = 30-59 mL/min per 1.73 m2)221 (47%)103 (41%)84 (54%)34 (53%)0.002
4 (eGFR = 15-29 mL/min per 1.73 m2)205 (44%)105 (46%)64 (42%)26 (41%)
5 (eGFR < 15 mL/min per 1.73 m2)44 (9%)34 (13%)6 (4%)4 (6%)
Etiology of CKD (%)
Hypertension108 (23%)54 (21%)40 (26%)14 (22%)0.039
Diabetes mellitus108 (23%)72 (29%)29 (19%)7 (11%)
Tubulointerstitial disease65 (14%)24 (10%)25 (16%)16 (25%)
Glomerulonephritis47 (10%)26 (10%)15 (10%)6 (10%)
Unknown/others142 (30%)75 (30%)44 (29%)20 (32%)
Smoking (%)1
Never231 (53%)124 (52%)82 (58%)25 (44%)0.494
Ex-smoker144 (33%)81 (34%)44 (31%)19 (33%)
Active64 (14%)35 (14%)16 (11%)13 (23%)
Blood pressure (kPa)
Systolic19.0 ± 2.919.3 ± 2.918.6 ± 2.819.0 ± 3.10.085
Diastolic10.2 ± 1.510.2 ± 1.610.1 ± 1.410.3 ± 1.70.617
Pulse pressure (kPa)8.8 ± 2.59.1 ± 2.58.5 ± 2.58.7 ± 2.50.098
Body mass index (kg/m2)28.6 ± 5.128.8 ± 5.528.6 ± 4.627.7 ± 4.40.294
Underweight ( ≤ 18.5)6 (1%)4 (2%)1 (1%)1 (2%)0.353
Normal (18.6-24.9)96 (20%)50 (20%)30 (19%)16 (25%)
Overweight (25.0-29.9)210 (45%)111 (44%)68 (44%)31 (48%)
Obesity (> 29.9)158 (34%)87 (34%)55 (36%)16 (25%)
Waist (cm)
Males102.2 ± 12.0102.1 ± 13.0102.2 ± 10.6102.4 ± 11.50.989
Females97.8 ± 13.598.3 ± 14.797.7 ± 12.295.7 ± 11.40.760
ABPI1.01 ± 0.210.98 ± 0.201.04 ± 0.211.05 ± 0.220.013
Abnormal ABPI2194 (41%)100 (41%)66 (44%)28 (44%)0.539
Abnormal Kauppila score3107 (29%)52 (27%)35 (29%)20 (36%)0.183
Abnormal Adragao score4121 (32%)66 (33%)38 (30%)17 (29%)0.474
Vitamin D supplementation (%)43 (9%)16 (6%)17 (11%)10 (16%)0.012
Use of phosphate binders (%)72 (15%)47 (19%)16 (11%)9 (14%)0.105
Use of ACEI/ARB (%)365 (78%)196 (79%)121 (82%)48 (76%)0.947
Use of diuretic (%)287 (61%)173 (70%)88 (58%)26 (42%)< 0.001
Use of ESA (%)124 (26%)77 (31%)31 (20%)16 (25%)0.015
Figure 1
Figure 1 Flow diagram of patient selection for analysis. CKD: Chronic kidney disease; 25(OH)D: 25-hydroxivitamin D.
Table 2 Baseline laboratory values, as a function of vitamin D status.
All (n = 470)25(OH)D < 20 ng/mL (n = 252)25(OH)D 20-29 ng/mL (n = 154)25(OH)D ≥ 30 ng/mL (n = 64)P
25-hydroxivitamin D (nmol/L)52 ± 2136 ± 961 ± 790 ± 16< 0.001
1,25(OH)2 vitamin D (pmol/L)103 ± 2897 ± 27111 ± 28107 ± 23< 0.001
Caalb (mmol/L)2.40 ± 0.202.40 ± 0.152.42 ± 0.232.45 ± 0.230.163
P (mmol/L)1.10 ± 0.261.10 ± 0.261.10 ± 0.261.07 ± 0.260.517
iPTH (ng/L)191 (85-97)106 (96-116)81 (73-91)64 (55-74)< 0.001
Creatinine (μmol/L)221 ± 97239 ± 106212 ± 88212 ± 880.017
eGFR (MDRD, mL/min per 1.73 m2)29.4 ± 11.528.1 ± 11.930.8 ± 10.830.5 ± 11.10.049
Urine protein excretion (g/24 h)120.592 (0.502-0.697)0.699 (0.573-0.853)0.448 (0.321-0.626)0.448 (0.271-0.742)0.034
hsCRP (nmol/L)136.2 (29.5-39.1)37.1 (33.3-41.0)36.2 (31.4-41.0)32.4 (26.7-39.1)0.506
Albumin (g/L)40 ± 539 ± 541 ± 540 ± 50.011
Total proteins (g/L)77 ± 1277 ± 1177 ± 1376 ± 140.877
Total cholesterol (mmol/L)4.7 ± 1.14.7 ± 1.14.7 ± 1.04.8 ± 1.10.603
HDL cholesterol (mmol/L)1.3 ± 0.41.3 ± 0.31.3 ± 0.41.3 ± 0.40.973
LDL cholesterol (mmol/L)2.7 ± 0.92.7 ± 0.92.7 ± 0.92.9 ± 0.80.344
Hemoglobin (g/L)130 ± 16129 ± 16132 ± 16132 ± 180.058
Ferritin (pmol/L)1225 (207-245)227 (202-252)216 (187-252)247 (191-319)0.635
Transferrin (μmol/L)3.0 ± 1.22.9 ± 1.23.0 ± 1.23.1 ± 1.30.289
Glucose (mmol/L)6.3 ± 2.26.3 ± 2.36.4 ± 2.45.9 ± 1.50.241
Relationship between 25(OH)D levels and baseline characteristics

Linear correlation analysis showed significant correlation between 25(OH)D levels and eGFR (R = 0.10; P = 0.027), body mass index (R = -0.10; P = 0.046), serum levels of albumin (R = 0.10; P = 0.027), calcium (R = 0.12; P = 0.013), 1,25(OH)2 vitamin D (R = 0.20; P < 0.001), PTH (R = -0.26; P < 0.001), and hemoglobin (R = 0.13; P = 0.005), proteinuria (log transformed, R = -0.19; P = 0.004) and ABPI (R = 0.15; P = 0.002). Multivariate binary logistic regression analysis showed as independent predictors of 25(OH) < 20 ng/mL the albumin levels (OR = 0.61; 95%CI: 0.40-0.92; P = 0.018), the ABPI (OR = 0.28; 95%CI: 0.11-0.73; P = 0.010), and treatment with native VD (OR = 0.35; 95%CI: 0.17-0.73; P = 0.005), and diuretics (OR = 2.03; 95%CI: 1.35-3.06; P = 0.001).

Mortality

Forty-six (10%) patients died after a mean follow-up of 29 ± 12 mo. Cardiovascular disease (n = 16, 35%) and infections (n = 8, 17%) were the most common causes of death. Tumors and others accounted for 11% (n = 5) and 13% (n = 6) of deaths, respectively. In 11 cases (24%) the cause of death was not identified. The Kaplan-Meier survival analysis (Figure 2A) suggested that patients with 25(OH)D less than 20 ng/mL had significantly higher mortality than the other two groups (log rank test, P = 0.031). Univariate Cox regression found a more than twice higher risk of death in the group with the 25(OH)D level less than 20 ng/mL compared with the reference group (HR = 2.47; 95%CI: 1.18-5.18; P = 0.017), whereas the group with 25(OH)D at or above 30 ng/mL was not significantly different from that with the 25(OH)D between 20 to 29 ng/mL (HR = 0.78; 95%CI: 0.26-2.32; P = 0.650). Multivariate analysis showed the predictive value of 25(OH)D levels as a continuous variable for preventing death when adjusted for multiple covariates in different models (Table 3). Adjusted for age, comorbidity, diabetes mellitus, eGFR and phosphorous and albumin levels, the HR for all-cause mortality for 25(OH)D < 20 vs 20-29 was 2.33 (95%CI: 1.10-4.91; P = 0.027; Figure 3). The 25(OH)D ≥ 30 group did not have a significantly different mortality hazard from the reference group (HR = 1.19; 95%CI: 0.37-3.81; P = 0.775).

Figure 2
Figure 2 Kaplan-Meier survival (A), and appearance of the composite renal endpoint (B) and the hospitalization (C) curves as a function of 25-hydroxyvitamin D levels (< 20 ng/mL, 20-29 ng/mL and ≥ 30 ng/mL).
Table 3 Adjusted Cox proportional hazards models of patient survival (events = 46).
ModelCovariates controlled forAdjusted HR (95%CI)P
0 (Unadjusted)25-hydroxivitamin D levels (mg/dL)0.95 (0.91-0.99)0.009
125-hydroxivitamin D levels (mg/dL) + age0.95 (0.91-0.99)0.009
2Model 1 + diabetes mellitus, ischemic heart disease, chronic heart failure0.96 (0.92-0.99)0.028
3Model 1 + peripheral arterial disease, abnormal ABPI1, phosphorous (mg/dL)0.95 (0.92-0.99)0.023
4Model 1 + DBP (mm Hg), 1,25(OH)2 vitamin D (pg/mL), estimated GFR (mL/min per 1.73 m2)0.96 (0.92-0.99)0.020
5Model 1 + vascular calcification [Kauppila score (log), Adragao score (log)], CKD stage 50.95 (0.91-1.00)0.050
6Model 1 + obesity, hemoglobin (g/L), albumin (g/dL)0.95 (0.92-0.99)0.019
Figure 3
Figure 3 Proportion of patients with different 25-hydroxyvitamin D levels and hazard ratio (95%CI) for mortality after adjustment by age, comorbidity, diabetes mellitus, estimated glomerular filtration rate and albumin levels. 25(OH)D: 25-hydroxivitamin D.
Progression of CKD and renal replacement therapy initiation

During the follow-up, 81 (17%) patients started renal replacement therapy and 156 (33%) patients showed the composite renal end-point. Kaplan-Meier analysis (Figure 2B) showed that the 25(OH)D < 20 group had significantly more risk than the other two groups (log rank test, P < 0.001). Univariate Cox regression found again higher risk of the renal end-point with 25(OH)D level less than 20 ng/mL compared with 20 to 29 ng/mL (HR = 2.78; 95%CI: 1.84-4.16; P < 0.001), whereas the group with 25(OH)D above 30 ng/mL did not show different risk from reference group (HR = 1.13; 95%CI: 0.59-2.13; P = 0.717). Multivariate analysis showed the predictive value of VD levels as a continuous variable for preventing appearance of renal end point when adjusted for multiple covariates (Table 4). Adjusted for age, gender, diabetes mellitus, eGFR, and phosphorous levels, the HR for the composite renal end-point for the 25(OH)D < 20 group compared to the reference group was 2.46 (95%CI: 1.63-3.71; P < 0.001; Figure 4). The 25(OH)D ≥ 30 group did not have a significantly different hazard for kidney progression from the reference group (HR = 1.20; 95%CI: 0.62-2.32; P = 0.581).

Table 4 Multivariate Cox regression analysis in relation to renal end point (events = 156).
HR (95%CI)P value
25-hydroxivitamin D (ng/mL)0.97 (0.95-0.99)0.004
Age (yr)0.99 (0.97-1.00)0.044
Male sex2.20 (1.47-3.30)< 0.001
Estimated GFR (mL/min per 1.73 m2)0.93 (0.91-0.95)< 0.001
ABPI (mmHg)0.23 (0.10-0.53)0.001
Hemoglobin (g/L)0.84 (0.78-0.94)0.001
Figure 4
Figure 4 Proportion of patients with different 25-hydroxyvitamin D levels and hazard ratio (95%CI) for composite renal end-point after adjustment by age, sex, diabetes mellitus, estimated glomerular filtration rate and albumin levels. 25(OH)D: 25-hydroxivitamin D.
Hospitalization

During the follow-up, 126 (27%) patients were admitted for hospitalization, cardiovascular (49%) and infections (20%) being the most common causes. Kaplan-Meier analysis (Figure 2C) indicated that crude hospitalization event-free period was different between the VD groups (log rank test, P = 0.039). Univariate Cox regression found a shorter hospitalization event-free period in patients with 25(OH)D level less than 20 ng/mL compared with 20-29 ng/mL (HR = 1.58; 95%CI: 1.05-2.36; P = 0.027), with no difference between the 25(OH)D ≥ 30 and the reference groups (P = 0.861). Hospitalization outcomes were predicted by 25(OH) levels (HR = 0.98; 95%CI: 0.96-1.00; P = 0.027) in the unadjusted Cox proportional hazards model, but not after adjusting for age, eGFR, diabetes and comorbidity.

Cutoff points to define VD sufficiency based on hard endpoints

ROC curves identified VD levels at highest risk for death, the composite renal endpoint, and hospitalization, at 17.4 ng/mL [area under the curve (AUC) = 0.60; 95%CI: 0.52-0.69; P = 0.027], 18.6 (AUC = 0.65; 95%CI: 0.60-0.71; P < 0.001), and 19.0 (AUC = 0.56; 95%CI: 0.50-0.62; P = 0.048), respectively.

DISCUSSION

One of the main limitations for the development of evidence-based clinical recommendations for VD supplementation lies in the discrepancies in the criteria for defining VD deficiency and insufficiency, which can explain conflicting results from meta-analysis addressing vitamin D levels and outcomes[24,34]. These criteria vary among authors and societies, including 25(OH)D levels below which osteomalacia [10 ng/mL (25 nmol/L)] or secondary hyperparathyroidism [20-30 ng/mL (50 to 75 nmol/L)] may appear[18-20,35,36]. Being aware of their potential clinical significance, the present study examines the prognosis value of 25(OH)D levels in a cohort of 3-5 stage CKD subjects not on dialysis, trying to identify cut-off points for serum 25(OH)D levels to define VD sufficiency. These cut-offs were not based on biological abnormalities as classically noted[25,26], but on VD levels at highest risk for death, CKD progression and all-cause hospitalization.

Although randomized clinical trials are the best way for generating a high evidence for treatment decisions, trials are rare and suboptimal in nephrology[37]. Therefore, observational studies have an important role, particularly when the intervention, in this case vitamin D supplementation, is inexpensive and potentially effective. Although there are previous prospective observational studies which examined the prognosis value of 25(OH)D levels in CKD subjects not on dialysis[8,12], this is the first one, to our knowledge, in which 25OH(D) levels unequivocally reflect exposure to VD, given that patients on treatment with active VD were excluded, as well as including the biggest cohort of non-dialysis CKD subjects with data regarding emerging cardiovascular risk factors as vascular calcification scores and ABPI. In the main analysis of the OSERCE-2 study, low VD levels were associated to worse survival and CKD progression only in the univariate analysis[32]. However, 26% of patients of the study received activated VD, which may confer a protective effect and therefore may decrease any negative effect of VD levels observed, as it has been stated on dialysis population[38]. In this context, we conducted this post-hoc analysis of the OSERCE-2 dataset in patients without active VD treatment. In this selected cohort, the main findings were the independent predictor value of VD deficiency, but not insufficiency, for the 3-year incidence of death and CKD progression, which remained significant after multivariate adjustments, as previously published[8,12]. In a prospective study involving 94 CKD patients, those with 25(OH)D levels less than 16.7 ng/mL had a higher mortality rate[12]. 25(OH)D was confirmed as an independent inverse predictor of death in a 6-year follow-up study which included 168 CKD subjects[8]. In that study patients with ≥ 15 ng/mL of 25(OH)D showed a reduction in mortality by 33% to 60% in the different models, compared to patients with 25(OH)D < 15 ng/mL. Less CKD progression to end-stage renal disease was also reported in the groups of patients with better VD status. All these data are in agreement with our results, which show how low 25(OH)D levels predicted mortality and CKD progression independently of such traditional and non-traditional risk factors, as vascular calcification or inflammation. In this context, it is noteworthy that the lack of association between 25(OH)D levels and vascular calcification observed in our study, is in agreement with some[12], but not all[9,10], previously published data. These findings indicate that 25(OH)D may impact on CKD outcomes by additional mechanisms including the suppression of the renin-angiotensin system, albuminuria reduction or amelioration of left ventricular hypertrophy[6,9,16,31,39]. Of note, we have detected ABPI as an independent predictor of VD deficiency, which could contribute to vascular stiffness and high cardiovascular risk for this population.

More interestingly, our study, as the first prospective which analyzed the upper level associated to better improvement in survival and CKD progression on CKD patients, did not demonstrate additional benefits on these hard outcomes when patients reached the optimal target levels for VD suggested by current guidelines (≥ 30 ng/mL). It is noteworthy that all three cut-off points for serum 25(OH)D levels at highest risk for death, CKD progression and all-cause hospitalization were between 17 ng/mL and 19, which reinforces the threshold value for abnormally reduced 25(OH)D in 20 ng/mL. These findings confirm the data reported in the biggest retrospective observational study analyzing VD and mortality in CKD patients. Navaneethan et al[40] studied 12763 patients with 3-4 stage CKD, showing 25(OH)D level ≤ 15 ng/mL to be associated independently with a 33% increased risk of all-cause mortality, whereas the group with 25(OH)D levels of 15-29 ng/mL did not show a significantly increased risk of mortality compared with patients with 25(OH)D levels ≥ 30 ng/mL.

Taking all these data together, we agree with the Institute of Medicine recommendation to consider sufficient 25(OH)D levels of at least 20 ng/mL, given that serum 25(OH)D concentrations above 30 ng/mL are not consistently associated with increased benefit[27,40]. In addition, most clinical trials have only confirmed the neutral effect of VD supplementation on hard outcomes[41], whereas some controlled studies have shown positive results in spite of the mean VD concentration not reaching the optimal recommended levels of ≥ 30 ng/mL[16]. Moreover, VD might not be safe in all settings, and supplementing could cause harm in people with CKD, who have a high prevalence of vascular calcification, and a decreasing ability for renal excretion of calcium and phosphorous[32,42]. Excessive VD supplementation may be particularly harmful in those high risk individuals with serum 25(OH)D levels above 20 ng/mL which are classified as insufficient according to current guidelines, and who then are treated with high-dose supplements of VD containing many times the levels of intake recommended for adults (600-800 UI/d)[18,27,43]. Although some experts suggest that it is safe to carry higher vitamin D levels (40-70 ng/mL), this recommendation is based on acute and not long-term observations[44].

Lastly, our study confirmed the high prevalence of low VD status on CKD patients[1-5]. There are many factors which could contribute to the deficiency that are not related to GFR, including limited exposure to the sun, reduced dietary intake and urinary loss of 25(OH)D and VD-binding protein in proteinuric nephropathies[24,44,45]. The present study, as others[8,12,38], has shown significant correlation between 25(OH)D levels and body mass index and albumin, which emphasizes the relationship between nutritional status, VD levels and survival in chronic illness as CKD. Of note, the independent relationship observed, even after adjustment for chronic heart failure, between VD deficiency and diuretic use. VD deficiency is highly prevalent in heart failure patients, being a significant predictor of reduced survival. In addition, loop diuretics treatment may worsen osteoporosis on general population, but no data are available in CKD patients[46,47].

Strengths and limitations

The strong points of the study include the relatively high number of patients included and the 3-year follow-up, which strengthens the study’s power. To minimize the inter-method and seasonal variability in VD and PTH measurements, blood samples were analyzed by a central laboratory, and patients’ recruitment was done in a short period of time (April-May)[32]. In contrast, there are several limitations to be commented. As a longitudinal study, it is still insufficient to determine whether the association between low 25(OH)D levels and worse CKD outcomes is causal and reversible, which should be tested in future randomized clinical trials. The results may not be valid to non-Caucasian populations living at other latitudes, or to patients on active VD treatment. The multivariate analysis of cardiovascular deaths was limited due to its low incidence. Lastly, it would be interesting to study other relevant bone-related clinical outcomes, such as bone-density changes or fracture risk.

In conclusion, in accordance with previously published data, the present study confirms: (1) a high prevalence of 25(OH)D deficiency and insufficiency in non-dialysis CKD patients; and (2) an independent association between serum 25(OH)D levels and worse clinical outcomes, such as death and CKD progression. The results of this study add to the knowledge of optimal VD status in non-dialysis CKD patients, identifying the threshold value for abnormally reduced 25(OH)D in 20 ng/mL, which is in agreement with the Institute of Medicine recommendations. Whereas high doses of VD supplementation on this population can lead to a calcium and phosphate overload, promoting vascular calcification and CKD progression, our results suggest that, with the limitations inherent to the observational studies, 25(OH)D levels between 20 to 30 ng/mL could be sufficient for CKD patients. Randomized clinical trials are warranted to know the most favorable 25(OH)D level for CKD patients.

ACKNOWLEDGMENTS

The authors gratefully acknowledge their co-investigators in the OSERCE-2 Study. The authors thank to Jacqueline Clarke, B.Ed (Hons) for her collaboration in translating this text. For the figure editing, the authors thank to David Almenar, PhD. Portions of this work were presented and published in thesis form in fulfillment of the requirements for the PhD for Student Pablo Molina from University Autonoma of Barcelona.

COMMENTS
Background

Although knowledge of the skeletal and non-skeletal effects of nutritional vitamin D (VD) has expanded, no consensus currently exists within the medical community regarding the criteria for defining thresholds for VD supplementation in chronic kidney disease (CKD) patients.

Research frontiers

Based on levels of 25(OH)D required to suppress parathyroid hormone (PTH), clinical guidelines most commonly recommend a serum concentration of 25(OH)D above 30-40 ng/mL (75-100 nmol/L), levels at which PTH is suppressed to a minimum in its relation to 25(OH)D. However, there is a lack of evidence regarding this target recommendation, and overuse of VD supplementation on this population can lead to a calcium and phosphate overload, promoting vascular calcification and CKD progression.

Innovations and breakthroughs

Being aware of both the therapeutic and iatrogenic power of VD supplementation, the present study examines the prognosis value of 25(OH)D levels in a cohort of 3-5 stage CKD subjects not on dialysis, trying to identify cut-off points for serum 25(OH)D levels to define VD sufficiency. These cut-offs were not based on biochemical abnormalities as classically noted, but on VD levels at highest risk for death, CKD progression and all-cause hospitalization. The results of this study add to the knowledge of optimal VD status in non-dialysis CKD patients, identifying the threshold value for abnormally reduced 25(OH)D in 20 ng/mL.

Applications

The data in this study suggested that the optimal VD level might be lower than is currently recommended, advocating that 25(OH)D levels at or above 20 ng/mL could be sufficient for CKD patients. The authors recommend caution when nutritional VD is prescribed.

Terminology

25(OH)D, also known as calcifediol, is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol). Serum 25(OH)D levels are considered the best indicator of VD status.

Peer-review

The paper with the title: “What is the optimal level of vitamin D in non-dialysis CKD population?” is an interesting well written article and the authors claim that their study as the first prospective which analyzed the upper level of VD associated to better improvement in survival and CKD progression on CKD patients, did not demonstrate additional benefits on these hard outcomes when patients reached the optimal target levels for VD suggested by current guidelines (≥ 30 ng/mL).So with this study, despite the limitations, the authors provide a new option in this so controversial field of VD treatment in CKD patients.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Urology and nephrology

Country of origin: Spain

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Eirini G, Pontremoli R S- Editor: Qiu S L- Editor: A E- Editor: Lu YJ

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