Abstract
Background and objectives
Molecular evidence suggests that levels of vitamin D are associated with kidney function loss. Still, population-based studies are limited and few have considered the potential confounding effect of baseline kidney function. This study evaluated the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline, and incidence of CKD and albuminuria.
Design, setting, participants, & measurements
Baseline (2003–2006) and 5.5-year follow-up data from a Swiss adult general population were used to evaluate the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline (annual loss >3 ml/min per 1.73 m2), and incidence of CKD and albuminuria. Serum 25-hydroxyvitamin D was measured at baseline using liquid chromatography–tandem mass spectrometry. eGFR and albuminuria were collected at baseline and follow-up. Multivariate linear and logistic regression models were used considering potential confounding factors.
Results
Among the 4280 people included in the analysis, the mean±SD annual eGFR change was −0.57±1.78 ml/min per 1.73 m2, and 287 (6.7%) participants presented rapid eGFR decline. Before adjustment for baseline eGFR, baseline 25-hydroxyvitamin D level was associated with both mean annual eGFR change and risk of rapid eGFR decline, independently of baseline albuminuria. Once adjusted for baseline eGFR, associations were no longer significant. For every 10 ng/ml higher baseline 25-hydroxyvitamin D, the adjusted mean annual eGFR change was −0.005 ml/min per 1.73 m2 (95% confidence interval, −0.063 to 0.053; P=0.87) and the risk of rapid eGFR decline was null (odds ratio, 0.93; 95% confidence interval, 0.79 to 1.08; P=0.33). Baseline 25-hydroxyvitamin D level was not associated with incidence of CKD or albuminuria.
Conclusions
The association of 25-hydroxyvitamin D with eGFR decline is confounded by baseline eGFR. Sufficient 25-hydroxyvitamin D levels do not seem to protect from eGFR decline independently from baseline eGFR.
Keywords: renal function decline, vitamin D, chronic kidney disease, epidemiology and outcomes, glomerular filtration rate
Introduction
The kidney plays a key role in the metabolism of vitamin D, particularly by converting 25-hydroxyvitamin D (25[OH]D) into the biologically active 1,25-dihydroxyvitamin D (1,25[OH]2D). The decline in kidney function is associated with a progressive decrease in the ability of the kidney to produce 1,25(OH)2D (1). Deficiency in 1,25(OH)2D is therefore common in patients with impaired kidney function, as measured by the GFR, even in the early stages of impairment (2). By contrast, growing evidence suggests that sufficient 25(OH)D and 1,25(OH)2D levels could protect against kidney function loss (3).
An inverse association of 25(OH)D levels with proteinuria has been reported (4–6), but the associations of 25(OH)D levels with eGFR and CKD stages are less clear (2,7–10). Most studies conducted so far were cross-sectional and hence subject to temporality bias. In fact, the product of 25(OH)D metabolism (24,25[OH]D) seems to be decreased in CKD, leading to a stagnating metabolism of vitamin D (11). Thus, the level of 25(OH)D could paradoxically be higher among people with early stages of CKD than among those with adequate eGFR (11). The 1,25(OH)2D deficiency in CKD could be mediated via fibroblast growth factor-23 (FGF-23), a protein that is elevated in CKD and inhibits the conversions of 25(OH)D into 1,25(OH)2D and stimulates the catabolism of 1,25(OH)2D (12,13).
So far, three longitudinal studies have assessed the association of baseline circulating 25(OH)D with change in eGFR and incident CKD (9,14,15). The Cardiovascular Health Study showed lower levels of serum 25(OH)D were associated with both increased annual loss in eGFR and increased risk of rapid eGFR decline (9). However, the analyses were not adjusted for baseline eGFR. The Framingham Heart Study showed plasma 25(OH)D to be associated with neither incident CKD nor rapid decline in eGFR (14). In an Australian cohort, serum 25(OH)D levels <15 ng/ml were associated with a higher annual incidence of albuminuria but not with reduced eGFR (15).
Despite the high prevalence of 25(OH)D deficiency in the general adult population (16), the epidemiologic data remain scarce and conflicting. This study thus explores the association of serum 25(OH)D with change in eGFR, including rapid decline in eGFR, and with incidence of CKD and albuminuria after controlling for major factors known to influence 25(OH)D levels.
Materials and Methods
CoLaus Study
The primary aim of the CoLaus study was to assess the prevalence of cardiovascular risk factors in the population of Lausanne, Switzerland (17). The CoLaus study complied with the Declaration of Helsinki and was approved by the local institutional ethics committees. All participants gave written informed consent.
The sampling procedure of the CoLaus study has been described elsewhere (17). Briefly, the CoLaus study was population-based and included participants aged 35–75 years. Recruitment took place in Lausanne, Switzerland, a town of 117,161 inhabitants. A simple, nonstratified random sample of 35% of the overall population was drawn. Recruitment began in June 2003 and ended in May 2006. The sample of 8121 adults who agreed to participate represented 41% of the initially sampled population. Participants were asked to attend the outpatient clinic in the morning after an overnight fast. Between 2009 and 2012, all CoLaus participants (n=6184) were invited for a follow-up (CoLaus 2), of whom 4679 (75.7%) accepted. The follow-up included standardized questionnaires, medication, physical examination, and blood tests.
Personal and Clinical Data
Questionnaires recorded information on demographic data, socioeconomic status, and several lifestyle factors. A questionnaire focused on personal and family history of disease and cardiovascular risk factors. Self-reported prescription and self-prescribed drugs, vitamins, and mineral supplements were recorded. Use of oral contraception and hormonal replacement therapy was self-reported.
BP was measured thrice on the left arm after at least 10 minutes' rest in the seated position using a clinically validated oscillometric device (Omron HEM-907, Matsusaka, Japan) (18). The average of the last two BP readings was used for analyses. Hypertension was defined as mean systolic BP ≥140 mmHg or mean diastolic BP ≥90 mmHg or use of antihypertensive medication. Diabetes was defined as a fasting glucose level ≥7 mmol/L and/or presence of antidiabetic drug treatment (insulin or oral drugs). In addition, weight, height, and waist and hip circumferences were measured using standardized procedures. Body mass index was defined as weight in kg/height in m2 (19).
Biologic Data
Venous blood samples were drawn after an overnight fast. Glucose was measured by glucose dehydrogenase, and total serum cholesterol, HDL cholesterol, and serum triglycerides were measured by glycerol-3-phosphate oxidase–phenol aminophenazone. Total serum calcium was measured by O-cresolphthalein. Ultrasensitive C-reactive protein was measured by immunoassay and high-sensitivity latex assay.
A morning spot urine was collected for the assessment of creatinine and albumin. To estimate proteinuria, the urine albumin-to-creatinine ratio (ACR) was calculated and log-transformed for analysis. Albumin (serum and urine) was measured by bromocresol green (Wako and Roche Diagnostics; maximum inter- and intrabatch coefficient of variation, 2.5%–0.4%) and creatinine (serum and urine) was measured by isotope dilution mass spectrometry–traceable Jaffe kinetic compensated method (Roche Diagnostics CH; coefficient of variation, 2.9%–0.7%). Albuminuria was defined as urine ACR ≥30 mg/g. The eGFR was calculated using the CKD Epidemiology Collaboration (CKD-EPI) equation (20). CKD was defined as eGFR<60 ml/min per 1.73 m2.
Altitude and Hours of Sunshine
To account for the fact that most 25(OH)D is synthesized after exposure to sunshine, and in the absence of information on exposure to sunshine, studies generally adjust for month or season of blood sampling. We directly collected data on sunshine hours and altitude (see Supplemental Material). Because including altitude and sunshine in models have raised concerns about overadjustment and production of biased model coefficients, models adjusted for altitude and sunshine hours were considered as sensitivity analysis only.
25(OH)D
A fast, accurate, and reliable method to quantify the vitamin D metabolites—25-hydroxyvitamin D2, 25-hydroxyvitamin D3, and 3-epi-25hydroxyvitamin D3—in human serum samples was developed and validated for this project (21). An ultra–high-pressure liquid chromatography–tandem mass spectrometry system was developed.
Serum 25(OH)D was expressed in ng/ml (Conversion factor for 25[OH]D: 1 ng/ml=2.496 nmol/L). To describe the cohort, we used customary definitions of vitamin D status as sufficient, insufficient, and deficient for 25(OH)D corresponding to ≥30 ng/ml, 20–29.9 ng/ml, and <20 ng/ml, respectively (22–24).
Statistical Analyses
Statistical analyses were performed using Stata software, version 12.0 (Stata Corp., College Station, TX), and SAS software, version 9.3 (SAS Institute, Cary, NC). Descriptive results were expressed as mean±SD or as number of participants (percentage). Annual change in eGFR was defined as the difference between eGFR (estimated using the CKD-EPI equation) at follow-up and eGFR at baseline, standardized to 1 year. We also considered rapid eGFR decline, CKD incidence, and albuminuria incidence as dependent outcomes. Rapid eGFR decline was defined a priori an annual loss >3 ml/min per 1.73 m2 according to previous reports (9,25). Incident CKD was defined as an eGFR<60 ml/min per 1.73 m2 at follow-up among participants with eGFR≥60 ml/min per 1.73 m2 at baseline. Incident albuminuria was defined as albuminuria (i.e., ACR≥30 mg/g) at follow-up among participants without albuminuria (i.e., ACR<30 mg/g) at baseline.
To explore the associations of eGFR with vitamin D, we alternatively used (1) 25(OH)D serum concentrations as a continuous variable and (2) vitamin D status (sufficient, insufficient, deficient) as the independent variable of interest.
We first modeled the annual change in eGFR in ml/min per 1.73 m2 as a function of baseline 25(OH)D using linear regression models. Then, rapid eGFR decline, incidence of CKD, and incidence of albuminuria were modeled separately as a function of vitamin D at baseline using unconditional logistic regressions. Both eGFR and albuminuria have been previously associated with change in eGFR, rapid eGFR decline, and incident CKD (26,27). In the CoLaus study, the age- and sex-adjusted associations of baseline eGFR and albuminuria (independently of each other) with change in eGFR, rapid eGFR decline, and incident CKD were all highly significant (P<0.001); higher baseline eGFR was associated with greater eGFR loss, higher prevalence of rapid decline and lower CKD incidence; higher baseline albuminuria was associated with greater loss in eGFR, increased rapid decline, and greater CKD incidence. To take into account the effect of baseline albuminuria and eGFR on the association of 25(OH)D and kidney outcomes, models were further adjusted for baseline albuminuria and eGFR. Because it is not clear whether change in eGFR should be adjusted for baseline eGFR (28–30), models of change in eGFR without and with adjustment for the initial eGFR value are presented. De Boer and colleagues could not consider the effect of baseline albuminuria on the associations of 25(OH)D with change in eGFR (9). To fulfill this gap, we compared the association of 25(OH)D with change in eGFR with and without adjustment for baseline albuminuria. We also conducted stratified analyses by the presence or absence of albuminuria at baseline because we found a statistical interaction between 25(OH)D and albuminuria (P<0.05). To identify factors to be included in the initial multivariate models, bivariate associations between eGFR, 25(OH)D, and covariates of interest were tested.
Results
Participants Characteristics
A total of 4280 participants (corresponding to 91.5% of the cohort) were included in the analysis. The mean and median durations of follow-up were 5.5 years and 5.5±0.45 years (interquartile range, 5.4–5.7 years). The characteristics of the participants by vitamin D status are detailed in Table 1. The prevalence rates of vitamin D sufficiency, insufficiency, and deficiency were 13.1%, 33.1%, and 53.8%, respectively, with mean 25(OH)D levels of 35.5±, 24.5±2.8, and 13.1±4.2 ng/ml, respectively. The correlation between baseline eGFR and 25(OH)D was −0.19 (P<0.001), and the mean eGFRs were 80.2±14.8, 83.8±14.0, and 87.8±14.6 ml/min per 1.73 m2 in participants with vitamin D sufficiency, insufficiency, and deficiency, respectively. At baseline, 56.3% and 4.3% of patients had eGFR in the 60–89.9 and <60 ml/min per /1.73 m2 categories, respectively, and 5.4% presented with albuminuria (ACR≥30 mg/g). The three groups of vitamin D status statistically significantly differed by all characteristics apart from education, altitude, triglycerides, and albuminuria.
Table 1.
Baseline characteristics of the CoLaus participants, by vitamin D status (n=4280)
| Characteristic | All | Sufficient: 25(OH)D ≥30 ng/ml | Insufficient: 25(OH)D 20–29.9 ng/ml | Deficient: 25(OH)D <20 ng/ml | P Value |
|---|---|---|---|---|---|
| Patients, n (row %) | 4280 (100.0) | 559 (13.1) | 1416 (33.1) | 2305 (53.8) | |
| Age (yr) | 52.5±10.5 | 54.0±10.7 | 52.8±10.6 | 52.0±10.4 | <0.001 |
| Women, n (%) | 2320 (54.2) | 318 (56.9) | 796 (56.2) | 1206 (52.3) | 0.03 |
| Education, n (%) | 0.14 | ||||
| Low | 2324 (54.3) | 289 (51.7) | 745 (52.6) | 1290 (56.0) | |
| Middle | 1085 (25.4) | 156 (27.9) | 377 (26.6) | 552 (24.0) | |
| High | 871 (20.3) | 114 (20.4) | 294 (20.8) | 463 (20.0) | |
| Smoking status, n (%) | 0.02 | ||||
| Never smokers | 1735 (40.5) | 230 (41.1) | 592 (41.8) | 913 (39.6) | |
| Former smokers | 1455 (34.0) | 206 (36.8) | 489 (34.5) | 760 (33.0) | |
| Smokers | 1090 (25.5) | 123 (22.1) | 335 (23.7) | 632 (27.4) | |
| Physical activity, n (%) | <0.001 | ||||
| Never or no answer | 1392 (32.5) | 136 (24.3) | 371 (26.2) | 885 (38.4) | |
| Once/week | 406 (9.5) | 34 (6.1) | 120 (8.5) | 252 (10.9) | |
| Twice or more/week | 2482 (58.0) | 389 (69.6) | 925 (65.6) | 1168 (50.7) | |
| Hypertension, n (%) | 1421 (33.2) | 170 (30.4) | 417 (29.4) | 834 (36.2) | <0.001 |
| Diabetes, n (%) | 230 (5.4) | 13 (2.3) | 63 (4.4) | 154 (6.7) | <0.001 |
| Oral contraceptive (women, n=2320), n (%) | 197 (8.5) | 43 (13.5) | 59 (7.4) | 95 (7.9) | 0.002 |
| Waist circumference (cm) | 88.4±13.1 | 85.1±12.0 | 87.4±12.7 | 89.6±13.4 | <0.001 |
| Albumin-corrected calcium (mg/dl) | 8.84±0.36 | 8.92±0.36 | 8.84±0.32 | 8.80±0.32 | <0.001 |
| Vitamin D supplements or medication, n (%) | 180 (4.2) | 70 (12.5) | 74 (5.2) | 36 (1.6) | <0.001 |
| Altitude (m) | 534.6±91.3 | 526.6±83.3 | 535.8±91.7 | 535.9±92.9 | 0.08 |
| Mean monthly sunshine (hr) | 5.1±2.3 | 5.9±2.1 | 5.5±2.3 | 4.6±2.1 | <0.001 |
| hsCRP (mg/L) | 2.35±3.3 | 2.20±3.3 | 2.19±3.2 | 2.48±3.4 | 0.02 |
| Triglycerides (mg/dl) | 119.5±79.6 | 116.8±97.3 | 115.9±79.6 | 122.1±79.6 | 0.10 |
| HDL cholesterol (mg/dl) | 63.7±16.9 | 67.6±17.4 | 64.5±17.4 | 62.2±16.2 | <0.001 |
| eGFR and albuminuria | |||||
| eGFR (ml/min per 1.73 m2) | 85.5±14.8 | 80.2±14.0 | 83.8±14.6 | 87.8±14.7 | <0.001 |
| ACR (mg/g) | 12.4±48.6 | 10.5±34.5 | 11.1±36.6 | 13.7±57.2 | 0.17 |
| Albuminuria (ACR ≥30 mg/g), n (%) | 232±5.4 | 25±4.3 | 69±4.9 | 138±6.0 | 0.16 |
| eGFR categories, n (%) | <0.001 | ||||
| ≥90 ml/min per 1.73 m2 | 1687 (39.4) | 130 (23.3) | 484 (34.2) | 1073 (46.6) | |
| 60–89.9 ml/min per 1.73 m2 | 2411 (56.3) | 390 (69.8) | 865 (61.1) | 1156 (50.1) | |
| <60 ml/min per 1.73 m2 | 182 (4.3) | 39 (6.9) | 67 (4.7) | 76 (3.3) |
Results are expressed as mean±SD or number of participants (column percentage unless otherwise stated). hsCRP, highly sensitive C-reactive protein; ACR, urine albumin-to-creatinine ratio; 25(OH)D, 25-hydroxyvitamin D.
Follow-up
The mean annual eGFR change was −0.57±1.78 ml/min per 1.73 m2 (Table 2). The correlation between baseline 25(OH)D and annual eGFR change was 0.09 (P<0.001). Annual change in eGFR was −0.26±1.82, −0.46±1.70, and −0.71±1.80 ml/min per 1.73 m2 in participants with vitamin D sufficiency, insufficiency, and deficiency, respectively (P<0.001). Two hundred eighty-seven (6.7%) participants presented a rapid eGFR decline, as did 4.5%, 5.4%, and 8.1% of participants with vitamin D sufficiency, insufficiency, and deficiency, respectively (P<0.001). Among participants without CKD (eGFR≥60 ml/min per 1.73 m2) at baseline, 179 (4.4%) presented a new CKD at follow-up (eGFR<60 ml/min per 1.73 m2) (no difference across vitamin D status). Among participants without albuminuria (ACR<30 mg/g) at baseline, 166 (4.1%) presented albuminuria at follow-up (ACR≥30 mg/g) (no difference across vitamin D status).
Table 2.
Kidney phenotypes and outcomes, by vitamin D status (n=4280)
| Variable | All | Sufficient: 25(OH)D ≥30 ng/ml | Insufficient: 25(OH)D 20–29.9 ng/ml | Deficient: 25(OH)D <20 ng/ml | P Value |
|---|---|---|---|---|---|
| Mean annual change in eGFR±SD (ml/min per 1.73 m2) | −0.57±1.78 | −0.26±1.82 | −0.46±1.70 | −0.71±1.80 | <0.001 |
| Rapid eGFR decline (%) | 6.7 | 4.5 | 5.4 | 8.1 | <0.001 |
| Incident CKD (%) | 4.4 | 5.6 | 4.5 | 4.0 | 0.26 |
| Incident albuminuria (%) | 4.1 | 4.3 | 3.7 | 4.3 | 0.68 |
Rapid eGFR decline was defined a priori as an annual loss >3 ml/min per 1.73 m2. Incident CKD was defined as new CKD (i.e., eGFR<60 ml/min per 1.73 m2) at follow-up among participants without CKD (i.e., eGFR≥60 ml/min per 1.73 m2) at baseline. Incident albuminuria defined as new albuminuria (i.e., ACR≥30 mg/g) at follow-up among participants without albuminuria (i.e., ACR<30 mg/g) at baseline. 25(OH)D, 25-hydroxyvitamin D.
For every 10 ng/ml higher baseline 25(OH)D, the partially (model 2) adjusted mean annual eGFR decline was slower by 0.15 ml/min per 1.73 m2 (95% confidence interval [95% CI], 0.09 to 0.21; P<0.001) (Table 3). Further adjustment for baseline albuminuria did not attenuate the positive association (annual eGFR change, 0.14; 95% CI, 0.08 to 0.21; P<0.001), whereas further adjustment for baseline eGFR neutralized the association. After further adjustment for baseline eGFR, the adjusted mean annual eGFR change was −0.005 ml/min per 1.73 m2 (95% CI, −0.06 to 0.05 ml/min per 1.73 m2; P=0.87) for every 10 ng/ml higher baseline 25(OH)D. Associations among participants without albuminuria at baseline were similar to those observed in the entire sample (Table 3).
Table 3.
Associations of baseline 25-hydroxyvitamin D level with annual change in eGFR
| Variable | Baseline 25(OH)D (per 10 ng/ml unit) | ||
|---|---|---|---|
| Participants in Analysis (n) | Annual Change in eGFR (95% CI) (ml/min per 1.73 m2) | P Value | |
| All participants | 4280 | ||
| Model 1 unadjusted | 0.19 (0.13 to 0.25) | <0.001 | |
| Model 2a | 0.15 (0.09 to 0.21) | <0.001 | |
| Model 2a + adjusted for log ACR at baseline | 0.14 (0.08 to 0.21) | <0.001 | |
| Model 2a + adjusted for eGFR at baseline | −0.0007 (−0.05 to 0.06) | 0.98 | |
| Model 2a + adjusted for log ACR and eGFR at baseline | −0.005 (−0.06 to 0.05) | 0.87 | |
| Participants without albuminuria (ACR<30 mg/g) at baseline | 4048 | ||
| Model 1 unadjusted | 0.17 (0.11 to 0.23) | <0.001 | |
| Model 2a | 0.14 (0.08 to 0.20) | <0.001 | |
| Model 2a + adjusted for log ACR at baseline | 0.13 (0.07 to 0.20) | <0.001 | |
| Model 2a + adjusted for eGFR at baseline | −0.009 (−0.07 to 0.05) | 0.75 | |
| Model 2a + adjusted for log ACR and eGFR at baseline | −0.01 (−0.07 to 0.05) | 0.74 | |
| Participants with albuminuria (ACR≥30 mg/g) at baseline | 232 | ||
| Model 1 unadjusted | 0.42 (0.09 to 0.75) | 0.01 | |
| Model 2a | 0.32 (−0.03 to 0.66) | 0.07 | |
| Model 2a + adjusted for log ACR at baseline | 0.30 (−0.04 to 0.65) | 0.08 | |
| Model 2a + adjusted for eGFR at baseline | 0.12 (−0.21 to 0.45) | 0.49 | |
| Model 2a + adjusted for log ACR and eGFR at baseline | 0.09 (−0.24 to 0.42) | 0.58 | |
25(OH)D, 25-hydroxyvitamin D; ACR, urine albumin-to-creatinine ratio.
Model 2 is adjusted for age, sex, education, smoking status, physical activity, hypertension, diabetes, oral contraceptives (women), waist circumference, albumin-corrected calcium, vitamin D supplements or medications, high-sensitivity C-reactive protein, triglycerides, and HDL cholesterol.
Before adjustment for baseline eGFR, baseline 25(OH)D level was negatively associated with the risk of rapid eGFR decline. For every 10 ng/ml higher baseline 25(OH)D, the risk decreased by 19% (odds ratio, 0.81; 95% CI, 0.70 to 0.95; P=0.008) in the partially adjusted model (model 2) (Table 4). This negative association persisted upon adjustment for albuminuria at baseline but not for eGFR at baseline. After further adjustment for baseline eGFR, the odds ratio was 0.93 (95% CI, 0.79 to 1.08; P=0.33). Results were similar in analyses restricted to participants without albuminuria at baseline.
Table 4.
Associations of baseline 25-hydroxyvitamin D level with rapid loss in eGFR, incident CKD, and incident albuminuria
| Baseline 25(OH)D (per 10 ng/ml unit) | Rapid eGFR Decline | Incident CKD | Incident Albuminuria | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Participants in Analysis (n) | OR (95% CI) | P Value | Participants in Analysis (n) | OR (95% CI) | P Value | Participants in Analysis (n) | OR (95% CI) | P Value | |
| All participants | 4280 | 4098 | |||||||
| Model 1 unadjusted | 0.76 (0.66 to 0.88) | <0.001 | 1.10 (0.93 to 1.30) | 0.26 | |||||
| Model 2a | 0.81 (0.70 to 0.95) | 0.008 | 1.14 (0.95 to 1.38) | 0.16 | |||||
| Model 2a + adjusted for log ACR at baseline | 0.82 (0.71 to 0.96) | 0.01 | 1.17 (0.97 to 1.42) | 0.09 | |||||
| Model 2a + adjusted for eGFR at baseline | 0.92 (0.79 to 1.07) | 0.29 | 0.96 (0.79 to 1.17) | 0.69 | |||||
| Model 2a + adjusted for log ACR and eGFR at baseline | 0.93 (0.79 to 1.08) | 0.33 | 0.99 (0.81 to 1.21) | 0.91 | |||||
| Participants without albuminuria (ACR <30 mg/g) at baseline | 4048 | 3893 | 4048 | ||||||
| Model 1 unadjusted | 0.78 (0.67 to 0.90) | <0.001 | 1.14 (0.96 to 1.34) | 0.14 | 0.88 (0.73 to 1.05) | 0.16 | |||
| Model 2a | 0.81 (0.69 to 0.95) | 0.01 | 1.15 (0.94 to 1.40) | 0.18 | 0.98 (0.81 to 1.19) | 0.86 | |||
| Model 2a + adjusted for log ACR at baseline | 0.82 (0.70 to 0.96) | 0.01 | 1.16 (0.95 to 1.41) | 0.15 | 1.05 (0.86 to 1.29) | 0.61 | |||
| Model 2a + adjusted for eGFR at baseline | 0.93 (0.79 to 1.09) | 0.39 | 0.96 (0.78 to 1.18) | 0.69 | 0.97 (0.80 to 1.18) | 0.79 | |||
| Model 2a + adjusted for log ACR and eGFR at baseline | 0.93 (0.79 to 1.09) | 0.38 | 0.97 (0.78 to 1.20) | 0.78 | 1.03 (0.84 to 1.26) | 0.78 | |||
| Participants with albuminuria (ACR ≥30 mg/g) at baseline | 232 | 205 | |||||||
| Model 1 unadjusted | 0.69 (0.42 to 1.12) | 0.14 | 0.99 (0.60 to 1.63) | 0.98 | |||||
| Model 2a | 0.74 (0.42 to 1.30) | 0.29 | 1.20 (0.62 to 2.33) | 0.59 | |||||
| Model 2a + adjusted for log ACR at baseline | 0.74 (0.41 to 1.32) | 0.30 | 1.35 (0.66 to 2.75) | 0.41 | |||||
| Model 2a + adjusted for eGFR at baseline | 0.78 (0.44 to 1.40) | 0.40 | 1.03 (0.51 to 2.09) | 0.94 | |||||
| Model 2a + adjusted for log ACR and eGFR at baseline | 0.78 (0.43 to 1.42) | 0.42 | 1.21 (0.58 to 2.54) | 0.61 | |||||
Rapid eGFR decline was defined a priori as an annual loss >3 ml/min per 1.73 m2. Incident CKD was defined as new CKD (i.e., eGFR <60 ml/min per 1.73 m2) at follow-up among participants without CKD (i.e., eGFR ≥60 ml/min per 1.73 m2) at baseline. 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio; CI, confidence interval; ACR, urine albumin-to-creatinine ratio
Model 2 is adjusted for age, sex, education, smoking status, physical activity, hypertension, diabetes, oral contraceptives (women), waist circumference, albumin-corrected calcium, vitamin D supplements or medications, high-sensitivity C-reactive protein, triglycerides, and HDL cholesterol.
Baseline 25(OH)D level was associated with neither CKD nor albuminuria incidence (Table 4).
Compared with participants with vitamin D sufficiency at baseline, the difference in annual eGFR change adjusted for covariates in model 2 was −0.17 (95% CI, −0.34 to 0.007; P=0.06) and −0.38 (95% CI, −0.55 to −0.22; P<0.001) among participants with vitamin D insufficiency and deficiency, respectively. These associations remained upon adjustment for baseline albuminuria but not after further adjustment for baseline eGFR (fully adjusted difference in annual eGFR change, −0.01 [95% CI, −0.17 to 0.15; P=0.90] and −0.05 [95% CI, −0.20 to 0.11; P=0.56] among participants with vitamin D insufficiency and deficiency, respectively). Similar null associations after adjustment for baseline eGFR were found among participants without albuminuria at baseline (Supplemental Table 1).
Rapid eGFR decline was positively associated with vitamin D deficiency with (odds ratio, 1.65; 95% CI, 1.06 to 2.58; P=0.03) and without (odds ratio, 1.69; 95% CI, 1.08 to 2.64; P=0.02) further adjustment for baseline albuminuria. Rapid eGFR decline was not associated with vitamin D deficiency once further adjusted for baseline eGFR (odds ratio, 1.05; 95% CI, 0.65 to 1.69; P=0.85). Similar null associations after adjustment for baseline eGFR were found among participants without albuminuria at baseline (Supplemental Table 2). CKD incidence and albuminuria incidence were not associated with vitamin D deficiency with or without adjustment for baseline albuminuria and/or baseline eGFR.
Results were similar among participants without vitamin D supplements or therapy and after further adjustment for altitude and sun exposure with no evidence of overadjustment (data not shown).
Discussion
We showed that once adjusted for baseline eGFR, 25(OH)D is not independently associated with change and risk of rapid eGFR decline in adults with predominantly normal baseline kidney function.
Circulating 25(OH)D and 1,25(OH)2D have been associated with eGFR and proteinuria (1,31). This association is mediated by different mechanisms, including a decline in the 1-αhydroxylation of 25(OH)D to the metabolically active form of vitamin D (1,25[OH]2D) (32); an increased urinary loss of 25(OH)D and vitamin D–binding protein (33); and an increase in renin secretion and activity of the renin-angiotensin system (34). Kidney retention of phosphorus and increased FGF-23 in kidney failure may also contribute to 1,25(OH)2D deficiency (35). Compared with people without CKD, patients with CKD might also have decreased sunlight exposure and suboptimal dietary vitamin D intake (36). The relationship between vitamin D and kidney function seems to be bidirectional. Indeed, while kidney failure certainly disrupts 25(OH)D and 1,25(OH)2D metabolism and catabolism (12), recent evidence suggests that 25(OH)D and 1,25(OH)2D may influence kidney filtration rate and proteinuria (31,37,38). Animal studies suggested potential renoprotective mechanisms of 1,25(OH)2D or vitamin D analogues, including reduction of proteinuria and glomerulosclerosis and inhibition of inflammation and fibrosis (31,37,38). Among patients with CKD, 25(OH)D levels have been associated with kidney disease progression and death (31,38), probably via mechanisms involving proteinuria and inflammation (4,6). Data among patients without CKD are very limited, and longitudinal data may therefore contribute to disentangle this bidirectional relationship in the general population.
Using data on older adults, de Boer et al. recently reported lower level of serum 25(OH)D are associated with both increased loss in eGFR and increased risk of rapid eGFR decline (9). Their analyses were, however, not adjusted for baseline eGFR. While before adjustment for baseline eGFR, our results are in line with these findings, we show that the associations of 25(OH)D or vitamin D status with annual eGFR change or rapid eGFR decline did not resist further adjustment for baseline eGFR. This suggests that 25(OH)D is not associated with change or rapid eGFR decline independently from baseline eGFR. De Boer et al. did not explain why they did not adjust their models for baseline eGFR. It may be argued that this represents an overadjustment. Indeed, if 25(OH)D influences kidney function through mechanisms including glomerular filtration, baseline eGFR would lie in the causal pathway of the relation between 25(OH)D and rapid eGFR decline. Because of mathematical coupling and reversal paradox, experts have warned against adjusting for the initial value when modeling change in the value (28–30,39). Conversely, adjusting for baseline eGFR may better reflect the biology. In addition, not taking into account baseline GFR may lead to biased associations because regression to the mean cannot be excluded. As we consider that the rationale for adjusting, or not, for baseline eGFR is unsettled, we decided to present models sequentially adjusted for urine ACR at baseline and eGFR at baseline.
De Boer et al. lacked information on proteinuria and acknowledged this limitation and the associated risk of confounding. We used urinary ACR to account for the effect of albuminuria. After adjustment for baseline albuminuria but not baseline eGFR, we show that higher vitamin D is, in general, independently associated with slower decline in eGFR and less rapid decline.
Albuminuria is a strong predictor of change in eGFR and rapid decline (26). Yet, we found that higher 25(OH)D was associated with lower annual decline in eGFR and less rapid decline among participants without albuminuria at baseline even after adjustment for baseline albuminuria. While these findings expend the work by de Boer et al., it must be stressed that when models were adjusted for baseline eGFR (i.e., eGFR being considered as a confounder and not as a factor in the causal pathway) all associations disappeared.
No association was found between 25(OH)D at baseline and incidence of CKD, a finding already reported by O’Seaghdha et al. (14). We found no association of 25(OH)D levels or status with incident albuminuria. This is in line with a previous analysis from the Framingham Offspring Study (14), but in contrast with a more recent report from the AusDiab study (15). Of note, in the latter study and similarly to our results, vitamin D status was not independently associated with incident albuminuria. Thus, combining results from our study and the existing literature, there is currently no clear evidence that vitamin D predicts incident albuminuria in the general adult population.
This study has also some limitations. We do not have direct measures of GFR. Although the CKD-EPI equation is more accurate than other equations (e.g., Modification of Diet in Renal Disease), we cannot exclude the possibility that some of the observed associations result from the inaccuracy of the CKD-EPI method, in addition to the intra-individual and intra-assay variabilities. Several potential confounders, such as parathyroid hormone and FGF-23, were not available. All participants were white, and our findings may not be generalizable to nonwhite populations, in particular because vitamin D measurement and outcomes may vary by race (40). Finally, observational studies are prone to reverse causation and confounding. To determine whether this relationship is causal, randomized controlled trials must explore whether correcting vitamin D deficiency before the clinical emergence of a reduced eGFR slows down the age-related eGFR decline.
In conclusions, our results suggest that baseline eGFR confounds the association of vitamin D status with eGFR decline in adults.
Disclosures
None.
Supplementary Material
Acknowledgments
The CoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, Switzerland, and the Swiss National Science Foundation (grant no: 33CSCO-122661, 33CS30-139468 and 33CS30-148401). Vitamin D measures were supported by research grant from the Loterie Romande.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.04960514/-/DCSupplemental.
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