Abstract
Key Points
Vitamin D insufficiency is associated with higher risk of death-censored graft failure and infection-related mortality after kidney transplantation.
Vitamin D insufficiency is associated with a faster decline of graft function after kidney transplantation.
Background
Vitamin D inadequacy at or shortly after kidney transplantation is associated with poor outcomes. Circulating 25-hydroxyvitamin D [25(OH)D] levels generally increase over time after transplantation, but inadequacy remains common. Few studies have examined associations of later circulating 25(OH)D levels and long-term outcomes.
Methods
We analyzed data from the Wisconsin Allograft Recipient Database to assess the association of post-transplant 25(OH)D with overall graft failure, death-censored graft failure (DCGF), death with a functioning graft, cause-specific mortality, and eGFR trajectory over the next 4 years.
Results
A total of 2504 recipients who maintained a functioning graft for at least 13 months were included in our analysis. A total of 867 overall graft failures occurred during a median follow-up of 6.8 years. Vitamin D deficiency (≤20 ng/ml) was associated with a 43% higher hazard of overall graft failure (95% confidence interval [CI], 1.16 to 1.78), a 2.24-fold higher hazard of DCGF (95% CI, 1.60 to 3.12), and a 2.10-fold higher hazard (95% CI, 1.37 to 3.21) of infection-related mortality compared with sufficiency. It also was associated with a 1.38 ml/min per 1.73 m2 per year faster (95% CI, −1.97 to −0.79) annual eGFR decline compared with sufficiency. No association was detected for death with a functioning graft or other cause-specific mortality.
Conclusions
In conclusion, post-transplant vitamin D deficiency is associated with a higher risk of DCGF, infection-related mortality, and a faster decline of graft function in kidney transplant recipients.
Keywords: chronic allograft failure, survival, vitamin D
Visual Abstract
Introduction
Short-term survival after kidney transplantation has substantially improved over recent decades, with more than 95% of kidney transplant recipients (KTRs) surviving the first year with a functioning graft.1 Long-term graft survival, however, remains suboptimal, with approximately 13% of living donor grafts and 25% of deceased donor grafts lost within 5 years after transplantation.1 There is a growing need to identify modifiable post-transplant risk factors to maintain graft function and extend patient survival.
There is growing interest in the extraskeletal effects of vitamin D, especially its immunoregulatory properties. Extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D], the biologically active metabolite of vitamin D, has been well-recognized. Immune cells widely express 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D receptors.2–6 Laboratory studies have revealed the effect of 1,25(OH)2D in favor of tolerogenic adaptive immunity and anti-inflammation.7–11
Vitamin D inadequacy is common among KTRs at the time of transplantation12,13 and in the early post-transplant period.14–19 Serum 25-hydroxyvitamin D [25(OH)D] levels generally increase over time after transplantation, but many recipients remain insufficient or deficient even several years after transplantation,13,16,19–21 at least in part due to long-term exposure to immunosuppression and recommended limited sunshine exposure to reduce skin cancer risk. Multiple studies have investigated associations of circulating 25(OH)D levels measured at or shortly after transplantation with various outcomes. These studies have found associations of low 25(OH)D levels with post-transplant diabetes mellitus,22 infections,16,23 and graft and patient survival.14,15,17,24,25 Few studies, however, have examined associations of longer-term 25(OH)D levels and subsequent outcomes or examined the relationship between circulating 25(OH)D and subsequent changes in graft function.
Methods
Study Population
We used data from the Wisconsin Allograft Recipient Database, which longitudinally collected information on all solid-organ transplants performed at the University of Wisconsin (UW).26 Adult (18 years or older) kidney-only transplant recipients at UW from January 1, 2005, to December 31, 2020, who survived with a functioning graft at least 13 months after transplantation were eligible for this study. Only the most recent transplant for each recipient within the study period was included. Recipients with at least one serum 25(OH)D measurement from 5 to 13 months post-transplant (baseline window) were included in this study. Recipients who did not have any measurement of serum albumin, serum creatinine, or urine protein-creatinine ratio (UPCR) or had an eGFR <15 ml/min per 1.73 m2 during the baseline window were excluded. This study was approved by the UW Health Sciences Institutional Review Board and adhered to the Declaration of Helsinki. The clinical and research activities reported were consistent with the Principles of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism. Owing to the nature of this study, informed consent specific to this research was not obtained.
Post-Transplant Circulating 25(OH)D
Recipients at our center received 2000 IU/day of vitamin D supplement since the time of transplantation. Measurement of serum 25(OH)D levels was scheduled at 6 months post-transplant and then yearly as needed. All serum 25(OH)D measurements beyond 5 months post-transplant of eligible recipients were collected from the UW Hospital and Clinics Clinical Laboratory and other qualified laboratories, where serum 25(OH)D was measured by Liquid Chromatography-Tandem Mass Spectrometry. Levels of serum 25(OH)D lower than the detectable threshold (i.e., 5 ng/ml) were treated as missing. Post-transplant vitamin D status was defined in accordance with the Endocrine Society Guideline27: deficiency, ≤20 ng/ml (50 nmol/L); insufficiency, 21–29 ng/ml (52.5–72.5 nmol/L); and sufficiency, ≥30 ng/ml (75 nmol/L). Season of serum 25(OH)D measurement was categorized into winter (December–February), spring (March–May), summer (June–August), or fall (September–November).
Other Measurements
We collected demographics and clinical characteristics of eligible recipients at the time of transplantation, including age, sex, race, body mass index (BMI), cause of ESKD, donor type, donor age, previous kidney transplant, human leukocyte antigens mismatch, and calendar year of transplantation. Other post-transplant characteristics collected included the occurrence of delayed graft function (i.e., the need for dialysis within the first week after transplantation), induction and maintenance immunosuppression, and history of acute rejection within 13 months after transplantation. In addition, baseline serum albumin, serum creatinine, and UPCR were defined as the average of all levels in the baseline window. GFR was estimated based on serum creatinine using the race-neutral CKD-Epidemiology Collaboration Creatinine Equation (2021).28
Long-Term Survival
Eligible recipients were followed from 13 months after transplantation until graft failure (including death), loss to follow-up, or the end of the study (i.e., August 25, 2023), whichever came first. The outcomes of interest included overall graft failure (i.e., a composite end point of graft loss and death), death-censored graft failure (DCGF), death with a functioning graft (DWFG), and cause-specific mortality, namely, infection-related, cardiovascular disease (CVD)–related, and cancer-related mortality. Cause-specific mortality was ascertained through United Network for Organ Sharing primary cause of death.
Trajectory of eGFR
Longitudinal data on eGFR beyond 13 months post-transplant among eligible recipients mentioned above were collected. Repeated measurements of eGFR during follow-up were centered at 6-month intervals (e.g., eGFR at 18 months was calculated as the average of all levels from 15 to 21 months). eGFR measurements for the next 4 years were used to depict the post-transplant trajectory to ensure a sufficient period to detect a declining trajectory and preclude the potential bias due to missing data in a longer period of follow-up.
Statistical Analysis
Baseline characteristics were compared across post-transplant vitamin D status at baseline using a chi-squired test or ANOVA, as appropriate. The incidence rates of outcomes were calculated separately and compared across vitamin D statuses. Cumulative graft survival (i.e., surviving with a functioning graft) was depicted through Kaplan-Meier method. Cumulative incidence of clinical end points of interest was calculated separately. Survival analysis was conducted using cause-specific Cox proportional hazards models for different outcomes of interest. The proportional hazards assumption was tested through scaled Schoenfeld residuals.
Serum 25(OH)D level was fitted as a continuous variable and categorical variable as defined above. Other clinical characteristics involved in multivariate models as potential confounders included recipient age at transplant, recipient sex, recipient race, recipient BMI at transplant, cause of ESKD, donor type, donor age, delayed graft function, prior kidney transplant, human leukocyte antigen mismatch, induction and maintenance immunosuppression, history of acute rejection within 13 months after transplant, calendar year of transplantation, season of serum 25(OH)D measurement, serum albumin, UPCR, and eGFR. Potential nonlinear association between 25(OH)D and outcomes was evaluated, where 25(OH)D level was fitted using natural cubic spline with knots at 10, 50, and 90 percentiles.
Primary analyses used baseline 25(OH)D level (i.e., the first 25(OH)D level from 5 to 13 months post-transplant) as the exposure of interest. Sensitivity analysis was conducted using all subsequent 25(OH)D levels fitted as a time-varying variable, where only events occurring 30–365 days after each 25(OH)D measurement were analyzed to minimize the potential for reverse causality and ensure adequate length of follow-up. Updated eGFR and UPCR values were adjusted in multivariate models.
In addition, we performed longitudinal analysis of subsequent eGFR trajectories. We used linear mixed models with random intercepts and random slopes to account for the correlation of measurements within participants and the differing number of repeated measurements per participant.29 Other covariates mentioned above were included as potential confounders. The kidney donor profile index was further adjusted for. We further accounted for informative censoring due to graft failure or death through joint modeling of longitudinal and time-to-event data with a shared random effect in sensitivity analysis.30
Results
A total of 3899 adult KTRs survived at least 13 months after transplantation with a functioning graft in the study period. Among them, a total of 2504 recipients had at least one serum 25(OH)D measurement during the baseline window (i.e., 5–13 months post-transplant) and were included in our analysis (Figure 1). Few significant differences in baseline characteristics between the study population and excluded recipients were found, with the exception that recipients who received a transplant after 2010 were more likely to be included, and the study population was older and had a higher BMI at transplant than those excluded (Supplemental Table 1).
Figure 1.
Study design. Diagram of eligibility criteria of the study population and statistical analyses. KTR, kidney transplant recipients; UPCR, urine protein-creatinine ratio; 25(OH)D, 25-hydroxyvitamin D.
Recipients were followed for a median of 6.8 years after transplantation (interquartile range [IQR], 4.2–9.9). About 7% of them (n=178) were lost to follow-up primarily due to transferring to other providers. Most recipients had only one measurement of serum 25(OH)D in the baseline window and had their first serum 25(OH)D measurement from 6 to 9 months post-transplant (Table 1). Approximately 24% of them had vitamin D insufficiency (21–29 ng/ml) and 11% had vitamin D deficiency (≤20 ng/ml) on the basis of their first 25(OH)D level in the baseline window. The prevalence of vitamin D insufficiency was higher among recipients who were younger, had a higher BMI at transplant, had diabetes as the cause of ESKD, and received a graft from a deceased donor. The history of kidney transplant, delayed graft function, and previous acute rejection were associated with a lower level of 25(OH)D. Serum 25(OH)D level was higher in summer and lower in winter, as expected. The prevalence of vitamin D inadequacy was lower in those who received transplant in recent years. It was observed that serum 25(OH)D level was positively correlated with serum albumin level and negatively related with UPCR and eGFR.
Table 1.
Baseline characteristics of eligible kidney transplant recipients
| Characteristics | Serum 25(OH)Da | P Value | ||||
|---|---|---|---|---|---|---|
| Totalb | ≤ 20 ng/mlc | 21–29 ng/mlc | ≥ 30 ng/mlc | |||
| No. of KTRs, % | N=2504 | N=267 (10.6) | N=600 (24.0) | N=1637 (65.4) | ||
| Recipient age at transplant, yr | 52.9 (12.9) | 49.3 (13.6) | 51.9 (13.1) | 53.9 (12.5) | <0.01 | |
| Recipient male, % | 1544 (61.7) | 148 (9.6) | 373 (24.2) | 1026 (66.5) | 0.08 | |
| Recipient race, % | <0.01 | |||||
| Black | 300 (12.0) | 45 (15.0) | 90 (30.0) | 165 (55.0) | ||
| Othersd | 244 (9.7) | 29 (11.8) | 69 (28.3) | 146 (59.9) | ||
| White | 1960 (78.3) | 193 (9.8) | 441 (22.5) | 1326 (67.7) | ||
| BMI at transplant, kg/m2 | 28.5 (5.3) | 27.7 (5.3) | 29.2 (5.3) | 28.0 (5.3) | <0.01 | |
| Cause of ESKD, % | < 0.01 | |||||
| Diabetes | 622 (24.8) | 84 (13.5) | 199 (32.0) | 339 (54.5) | ||
| Hypertension | 330 (13.2) | 40 (12.1) | 68 (20.6) | 222 (67.3) | ||
| GN | 628 (25.1) | 60 (9.6) | 135 (21.5) | 433 (68.9) | ||
| PKD | 358 (14.3) | 22 (6.1) | 59 (16.5) | 277 (77.4) | ||
| Other | 566 (22.6) | 61 (10.8) | 139 (24.6) | 366 (64.7) | ||
| Living donor, % | 944 (37.7) | 70 (7.4) | 189 (20.0) | 685 (72.6) | <0.01 | |
| Donor age, yr | 43.9 (14.6) | 42.6 (14.2) | 43.6 (14.5) | 44.3 (14.6) | 0.18 | |
| Prior kidney transplant, % | 505 (20.2) | 67 (13.3) | 138 (27.3) | 300 (59.4) | <0.01 | |
| HLA antigen mismatch, % | 0.95 | |||||
| 0–2 | 462 (18.5) | 50 (10.8) | 110 (23.8) | 302 (65.4) | ||
| 3–4 | 1092 (43.6) | 116 (10.5) | 254 (23.3) | 722 (66.1) | ||
| 5–6 | 950 (37.9) | 101 (10.6) | 236 (24.8) | 613 (64.5) | ||
| Delayed allograft function, % | 488 (19.5) | 82 (16.8) | 148 (30.3) | 258 (52.9) | <0.01 | |
| Induction immunosuppression, % | <0.01 | |||||
| Basiliximab | 1397 (55.8) | 125 (8.9) | 342 (24.5) | 930 (66.6) | ||
| Alemtuzumab | 243 (9.7) | 35 (14.4) | 46 (18.9) | 162 (66.7) | ||
| Antithymocyte globulin | 825 (32.9) | 102 (12.4) | 210 (25.5) | 513 (62.2) | ||
| Other | 39 (1.6) | 5 (12.8) | 2 (5.1) | 32 (82.1) | ||
| Maintenance tacrolimus, % | 2409 (96.2) | 255 (10.6) | 576 (23.0) | 1578 (65.5) | 0.03 | |
| Acute rejection,e % | 357 (14.3) | 56 (15.7) | 95 (26.6) | 206 (57.7) | <0.01 | |
| Transplant yr, % | 0.02 | |||||
| 2005–2009 | 431 (17.2) | 41 (9.5) | 102 (23.7) | 288 (66.8) | ||
| 2010–2014 | 960 (38.3) | 101 (10.5) | 262 (27.3) | 597 (62.2) | ||
| 2015–2020 | 1113 (44.4) | 125 (11.2) | 236 (21.2) | 752 (67.6) | ||
| Serum 25(OH)D measurement time, mo after transplantf | 7.3 (6.3, 9.1) | 7.5 (6.4, 9.5) | 7.2 (6.3, 8.8) | 7.3 (6.3, 9.1) | 0.39 | |
| Season of 25(OH)D measurement, % | < 0.01 | |||||
| Winter | 694 (27.7) | 91 (13.1) | 189 (27.2) | 414 (59.7) | ||
| Spring | 665 (26.6) | 80 (12.0) | 146 (22.0) | 439 (66.0) | ||
| Summer | 571 (22.8) | 34 (5.9) | 134 (23.5) | 403 (70.6) | ||
| Fall | 574 (22.9) | 62 (10.8) | 131 (22.8) | 381 (66.4) | ||
| Serum albumin, g/dl d | 3.8 (3.6, 4.1) | 3.8 (3.5, 4.1) | 3.8 (3.5, 4.0) | 3.8 (3.6, 4.1) | <0.01 | |
| UPCR, mg/mg | 0.19 (0.12, 0.32) | 0.22 (0.14, 0.53) | 0.20 (0.13, 0.34) | 0.18 (0.12, 0.30) | 0.07 | |
| eGFR,g % | 0.04 | |||||
| ≥ 60 ml/min per 1.73 m2 | 1000 (39.9) | 128 (12.8) | 246 (24.6) | 626 (62.6) | ||
| 45–59 ml/min per 1.73 m2 | 889 (35.5) | 91 (10.2) | 205 (23.1) | 593 (66.7) | ||
| 30–44 ml/min per 1.73 m2 | 504 (20.1) | 36 (7.1) | 121 (24.0) | 347 (68.8) | ||
| <30 ml/min per 1.73 m2 | 111 (4.4) | 12 (10.8) | 28 (25.3) | 71 (64.0) | ||
Continuous variables were presented as mean (SD) or median (interquartile range). Categorical variables were presented as count (percentage). BMI, body mass index; HLA, human leukocyte antigens; KTR, kidney transplant recipients; PKD, polycystic kidney disease; UPCR, urine protein-creatinine ratio; 25(OH)D, 25-hydroxyvitamin D.
The earliest serum 25-hydroxyvitamin D measurement 5–13 months after transplantation.
Percentage in column.
Percentage in row.
Included American Indian, Alaska Natives, Asian, and Pacific Islander.
History of acute rejection within the first year after transplantation.
Measurement time of serum 25-hydroxyvitamin D was counted as months after transplantation and presented as median (interquartile range).
GFR was estimated based in serum creatinine using race-neutral CKD-Epidemiology Collaboration Creatinine Equation (2021).
Graft Failure
A total of 867 overall graft failures, including 303 DCGF occurred among the 2504 KTRs, included in this study. Recipients with vitamin D deficiency at baseline had a 50% higher incidence of overall graft failure and 2.5-fold higher incidence of DCGF compared with those with vitamin D sufficiency (Figure 2, A and B, and Table 2). These associations remained statistically significant after adjustment for covariates in Table 1. Vitamin D deficiency was associated with a 43% higher adjusted hazard of overall graft failure (adjusted hazard ratio [aHR]=1.43; 95% confidence interval [CI], 1.16 to 1.78; P < 0.01) and a 2.24-fold higher adjusted hazard of DCGF (aHR=2.24; 95% CI, 1.60 to 3.12; P < 0.01). Each 5 ng/ml lower 25(OH)D level was associated with a 10% higher hazard of DCGF (aHR=1.10; 95% CI, 1.04 to 1.17; P < 0.01) after adjustment. The association was approximately linear until the 25(OH)D level reached 40 ng/ml (Figure 3, A and B).
Figure 2.
Kaplan-Meier curve of long-term survival by post-transplant vitamin D status. (A) Graft survival; (B) incidence of DCGF; (C) incidence of DWFG. Vitamin D deficiency: ≤20 ng/ml (50 nmol/L); vitamin D insufficiency: 21–29 ng/ml (52.5–72.5 nmol/L); vitamin D sufficiency: ≥30 ng/ml (75 nmol/L). Graft survival was defined as surviving with a functioning graft. DCGF, death-censored graft failure; DWFG, death with a functioning graft.
Table 2.
Association of post-transplant circulating 25-hydroxyvitamin D and graft failure
| Outcomes | Baseline Serum 25(OH)Da | |||
|---|---|---|---|---|
| ≤20 ng/ml | 21–29 ng/ml | ≥30 ng/ml | Per 5 ng/ml Lower | |
| Overall graft failure (867 events) | ||||
| No. of events | 111 | 238 | 518 | |
| IR, per 100 person-yr (95% CI)b | 7.6 (6.3 to 9.1) | 6.3 (5.6 to 7.2) | 5.0 (4.6 to 5.4) | |
| Unadjusted HR (95% CI) | 1.59 (1.30 to 1.96) | 1.27 (1.09 to 1.48) | Reference | 1.05 (1.02 to 1.09) |
| P value (unadjusted) | <0.01 | <0.01 | <0.01 | |
| aHR (95% CI) | 1.43 (1.16 to 1.78) | 1.09 (0.93 to 1.28) | Reference | 1.03 (0.99 to 1.06) |
| P value (adjusted) | <0.01 | 0.29 | 0.09 | |
| DCGF (303 events) | ||||
| No. of events | 56 | 92 | 155 | |
| IR, per 100 person-yr (95% CI)b | 3.8 (2.9 to 5.0) | 2.4 (2.0 to 3.0) | 1.5 (1.3 to 1.7) | |
| Unadjusted HR (95% CI) | 2.69 (1.98 to 3.67) | 1.63 (1.26 to 2.11) | Reference | 1.17 (1.11 to 1.23) |
| P value (unadjusted) | <0.01 | <0.01 | <0.01 | |
| aHR (95% CI) | 2.24 (1.60 to 3.12) | 1.13 (0.86 to 1.49) | Reference | 1.10 (1.04 to 1.17) |
| P value (adjusted) | <0.01 | 0.36 | <0.01 | |
Cox proportional model using baseline serum 25-hydroxyvitamin D was fitted. Models adjusted for recipient age at transplant, sex, race, body mass index at transplant, cause of ESKD, donor type, donor age, delayed graft function, prior kidney transplant, human leukocyte antigens mismatch, induction and maintenance immunosuppression, acute rejection within 13 months post-transplant, transplant year, season of 25-hydroxyvitamin D measurement, baseline urine protein-creatinine ratio, serum albumin, and eGFR. aHR, adjusted hazard ratio; CI, confidence interval; DCGF, death censored graft failure; HR, hazard ratio; IR, incidence rate; 25(OH)D, 25-hydroxyvitamin D.
First serum 25-hydroxyvitamin D measurement from 5 to 13 months post-transplant.
Recipients were followed from 13 months post-transplant until allograft failure (including death) or the end of the study (i.e., August 25, 2023), whichever came first.
Figure 3.
aHR of long-term survival by post-transplant circulating 25(OH)D level. (A) Overall graft failure; (B) DCGF; (C) DWFG. HR was centered at a 25(OH)D level of 30 ng/ml. aHR, adjusted hazard ratio; HR, hazard ratio.
Patient Mortality
A total of 564 DWFG occurred, with an incidence of 3.6 events per 100 person-years. Infection was the leading cause of death (n=179), followed by cancer (n=95) and CVD (n=83). The incidence of DWFG was similar across vitamin D status (Figure 2C), Similarly, we did not detect any association between serum 25(OH)D level with DWFG (Figure 3C), cancer-related, or CVD-related mortality after adjustment (Table 3). Vitamin D deficiency, however, was associated with more than a doubling in the risk of infection-related mortality (aHR=2.10; 95% CI, 1.37 to 3.21; P < 0.01).
Table 3.
Association of post-transplant circulating 25-hydroxyvitamin D and patient mortality
| Outcomes | Baseline serum 25(OH)Da | |||
|---|---|---|---|---|
| ≤20 ng/ml | 21–29 ng/ml | ≥30 ng/ml | Per 5 ng/ml Lower | |
| DWFG (564 events) | ||||
| No. of events | 55 | 146 | 363 | |
| IR, per 100 person-yr (95% CI)b | 3.8 (2.9 to 4.9) | 3.9 (3.3 to 4.6) | 3.5 (3.1 to 3.9) | |
| Unadjusted HR (95% CI) | 1.12 (0.85 to 1.49) | 1.11 (0.92 to 1.35) | Reference | 1.01 (0.97 to 1.04) |
| P value (unadjusted) | 0.42 | 0.28 | 0.75 | |
| aHR (95% CI) | 1.09 (0.82 to 1.47) | 1.05 (0.86 to 1.28) | Reference | 0.99 (0.95 to 1.03) |
| P value (adjusted) | 0.53 | 0.65 | 0.68 | |
| Infection-related mortality (179 events) | ||||
| No. of events | 31 | 44 | 104 | |
| IR to per 100 person-yr (95% CI)b | 2.1 (1.5 to 3.1) | 1.2 (0.9 to 1.6) | 1.0 (0.8 to 1.2) | |
| Unadjusted HR (95% CI) | 2.28 (1.53 to 3.42) | 1.18 (0.83 to 1.68) | Reference | 1.06 (0.99 to 1.13) |
| P value (unadjusted) | <0.01 | 0.36 | 0.08 | |
| aHR (95% CI) | 2.10 (1.37 to 3.21) | 1.05 (0.73 to 1.51) | Reference | 1.04 (0.97 to 1.11) |
| P value (adjusted) | <0.01 | 0.80 | 0.25 | |
| Cancer-related mortality (95 events) | ||||
| No. of events | 6 | 21 | 68 | |
| IR, per 100 person-yr (95% CI)b | 0.4 (0.2 to 0.9) | 0.6 (0.4 to 0.8) | 0.6 (0.5 to 0.8) | |
| Unadjusted HR (95% CI) | 0.62 (0.27 to 1.44) | 0.86 (0.52 to 1.40) | Reference | 0.96 (0.89 to 1.04) |
| P value (unadjusted) | 0.27 | 0.53 | 0.32 | |
| aHR (95% CI) | 0.85 (0.36 to 2.01) | 1.04 (0.63 to 1.73) | Reference | 1.00 (0.92 to 1.09) |
| P value (adjusted) | 0.72 | 0.87 | 0.99 | |
| CVD-related mortality (83 events) | ||||
| No. of events | 9 | 22 | 52 | |
| IR, per 100 person-yr (95% CI)b | 0.6 (0.3 to 1.2) | 0.6 (0.4 to 0.9) | 0.5 (0.4 to 0.6) | |
| Unadjusted HR (95% CI) | 1.31 (0.65 to 2.67) | 1.17 (0.71 to 1.92) | Reference | 1.03 (0.94 to 1.12) |
| P value (unadjusted) | 0.45 | 0.55 | 0.58 | |
| aHR (95% CI) | 1.14 (0.55 to 2.39) | 1.01 (0.60 to 1.72) | Reference | 0.99 (0.90 to 1.09) |
| P value (adjusted) | 0.72 | 0.96 | 0.85 | |
Cox proportional model using baseline serum 25-hydroxyvitamin D was fitted. Models adjusted for recipient age at transplant, sex, race, body mass index at transplant, cause of ESKD, donor type, donor age, delayed graft function, prior kidney transplant, human leukocyte antigens mismatch, induction and maintenance immunosuppression, acute rejection within 13 months post-transplant, transplant year, season of 25-hydroxyvitamin D measurement, baseline urine protein-creatinine ratio, serum albumin, and eGFR. aHR, adjusted hazard ratio; CI, confidence interval, CVD, cardiovascular disease; DWFG, death with a functioning graft; HR, hazard ratio; IR, incidence rate; 25(OH)D, 25-hydroxyvitamin D.
First serum 25-hydroxyvitamin D measurement from 5 to 13 months post-transplant.
Recipients were followed from 13 months post-transplant until allograft failure (including death) or the end of the study (i.e., August 25, 2023), whichever came first.
Trajectory of eGFR
All eligible recipients (N=2504) had at least one measurement of eGFR beyond 13 months post-transplant. Over half of them had complete data at 6-month intervals over the next 4 years (IQR, 7–9). A total of 371 recipients were censored due to graft failure (including death). The trajectory of eGFR by vitamin D status at baseline is shown in Figure 4. Recipients with vitamin D sufficiency had a median eGFR of 55 ml/min per 1.73 m2 (IQR, 45–67) and a median of 60 ml/min per 1.73 m2 (IQR, 47–73) at 13 months and 5 years post-transplant, respectively, with an estimated increase rate of 0.23 ml/min per 1.73 m2 per year (coefficient=0.23; 95% CI, 0.03 to 0.43; P = 0.02). Recipients with vitamin D insufficiency had a median eGFR of 55 ml/min per 1.73 m2 (IQR, 45–69) and a median of 59 ml/min per 1.73 m2 (IQR, 43–74) at 13 months and 5 years post-transplant, respectively, with an estimated decline rate of 0.74 ml/min per 1.73 m2 per year (coefficient=−0.74; 95% CI, −1.10 to −0.37; P < 0.01). A decrease of eGFR from a median of 60 ml/min per 1.73 m2 (IQR, 49–74) at 13 months to 55 ml/min per 1.73 m2 (IQR, 38–77) at 5 years post-transplant was observed among those with vitamin D deficiency, with an estimated decline rate of 1.68 ml/min per 1.73 m2 per year (coefficient=−1.68; 95% CI, −2.38 to −0.98; P < 0.01). Vitamin D deficiency and insufficiency were associated with a 1.38 ml/min per 1.73 m2 per year faster (coefficient=−1.38; 95% CI, −1.97 to −0.79; P < 0.01) and a 0.65 ml/min per 1.73 m2 per year faster (coefficient=−0.65; 95% CI, −1.06 to −0.22; P < 0.01) annual decline rate of eGFR, respectively, compared with vitamin D sufficiency after adjusting for relevant confounders. Each 5 ng/ml lower 25(OH)D level was associated with a 0.14 ml/min per 1.73 m2 per year faster annual decline rate of eGFR (coefficient=−0.14; 95% CI, −0.21 to −0.07; P < 0.01) after adjustment (Table 4).
Figure 4.
Trajectory of eGFR over 5 years after transplantation by vitamin D status. The trajectory of median eGFR by vitamin D status was depicted through a magenta solid line with triangles for deficiency, a blue short dash line with circles for insufficiency, and a green dash line with diamonds for vitamin D sufficiency. The interquartile ranges of eGFR for recipients with vitamin D deficiency, insufficiency, and sufficiency were shown as green, blue, and magenta bars, respectively. Vitamin D status was defined as deficiency: ≤20 ng/ml (50 nmol/L), insufficiency: 21–29 ng/ml (52.5–72.5 nmol/L), and sufficiency: ≥30 ng/ml (75 nmol/L).
Table 4.
Association of post-transplant circulating 25-hydroxyvitamin D and eGFR trajectory over the next 4 years
| Model | Difference in Slope | Serum 25(OH)Da | |||
|---|---|---|---|---|---|
| ≤20 ng/ml | 21–29 ng/ml | ≥30 ng/ml | Per 5 ng/ml lower | ||
| Univariate | Coefficient (95% CI) | −1.83 (−2.42 to −1.25) | −0.96 (−1.37 to −0.55) | Reference | −0.21 (−0.27 to −0.14) |
| P value | <0.01 | <0.01 | <0.01 | ||
| Multivariate | Coefficient (95% CI) | −1.38 (−1.97 to −0.79) | −0.65 (−1.06 to −0.22) | Reference | −0.14 (−0.21 to −0.07) |
| P value | <0.01 | <0.01 | <0.01 | ||
Linear mixed models involving a random intercept and a random slope were fitted. Multivariate models included time, baseline 25-hydroxyvitamin D categories, the interaction between time and 25-hydroxyvitamin D categories, and the interaction between time and other potential confounders (recipient age at transplant, sex, race, recipient body mass index at transplant, cause of ESKD, donor type, donor age, kidney donor profile index, delayed graft function, prior kidney transplant, human leukocyte antigens mismatch, induction and maintenance immunosuppression, acute rejection within 13 months post-transplant, transplant year, season of 25-hydroxyvitamin D measurement, baseline urine protein-creatinine ratio, and serum albumin). CI, confidence interval; 25(OH)D, 25-hydroxyvitamin D.
First serum 25-hydroxyvitamin D measured 5–13 months post-transplant.
Sensitivity Analyses
A median of five post-transplant serum 25(OH)D levels (IQR, 3–8) for each recipient were used in time-varying analysis. A total of 446 overall graft failures, including 170 DCGF and 276 DWFG, were identified 30–365 days after a 25(OH)D measurement. Stronger associations for overall graft failure and DCGF were observed than in the primary analysis using only the baseline 25(OH)D level. Each 5 ng/ml lower 25(OH)D level was associated with an 8% higher risk of overall graft failure and a 12% higher risk of DCGF (Supplemental Table 2). Vitamin D deficiency and insufficiency were associated with a 2.08-fold higher (aHR=2.08; 95% CI, 1.55 to 2.79; P < 0.01) and a 48% higher hazard of overall graft failure (aHR=1.48; 95% CI, 1.18 to 1.86; P < 0.01), respectively, compared with sufficiency. Vitamin D deficiency and insufficiency were associated with a 2.68-fold higher (aHR=2.68; 95% CI, 1.78 to 4.02; P < 0.01) and a 72% higher hazard of DCGF (aHR=1.72; 95% CI, 1.19 to 2.48; P < 0.01), respectively, compared with sufficiency. No significant association was observed for DWFG. Sensitivity analysis was infeasible for cause-specific mortality due to limited sample size.
A stronger association of post-transplant 25(OH)D levels and eGFR trajectory was observed in sensitivity analysis, where informative censoring was accounted for through joint modeling of longitudinal data of eGFR and time-to-event data. Vitamin D deficiency and insufficiency were associated with a 1.56 ml/min per 1.73 m2 per year faster (coefficient=−1.56; 95% CI, −2.18 to −0.94; P < 0.01) and a 0.83 ml/min per 1.73 m2 per year faster (coefficient=−0.83; 95% CI, −1.27 to −0.39; P < 0.01) annual decline rate of eGFR, respectively, compared with sufficiency after adjusting for potential confounders. Each 5 ng/ml lower 25(OH)D level was associated with a 0.17 ml/min per 1.73 m2 per year faster annual decline rate of eGFR (coefficient=−0.17; 95% CI, −0.24 to −0.10; P < 0.01) after adjustment (Supplemental Table 3).
Discussion
We found that a lower circulating 25(OH)D level, measured 5–13 months post-transplant, is independently associated with a higher hazard of overall graft failure and DCGF among stable KTRs who survived at least 13 months with a functioning graft. The association is approximately linear at 25(OH)D levels up to 40 ng/ml. Vitamin D deficiency is associated with a 43% higher hazard of overall graft failure and 2.24-fold higher hazard of DCGF. Furthermore, longitudinal analysis revealed that vitamin D deficiency and insufficiency are associated with a 1.38 ml/min per 1.73 m2 per year faster and a 0.65 ml/min per 1.73 m2 per year faster annual decline rate of eGFR, respectively, compared with vitamin D sufficiency. These results highlight the potential of vitamin D as a modifiable risk factor for outcomes among stable KTRs. We also found that vitamin D deficiency was associated with a 2.10-fold higher hazard of infection-related mortality. This finding indicates the potential role of vitamin D in infection-related outcomes among stable KTRs.
There is limited evidence of the effect of vitamin D on survival in KTRs, and the results are not consistent across studies with different designs. Researchers have primarily focused on early post-transplant 25(OH)D levels. Bienaimé et al.14 found that low 25(OH)D level at 3 months post-transplant was associated with lower GFR at 12 months and higher risk of interstitial fibrosis and tubular atrophy, but not associated with death or graft loss among 634 KTRs followed for a median of 4 years. They also found that levels of calcium, phosphorus, 1,25(OH)2D, parathyroid hormone, or fibroblast growth factor-23 were not associated with graft outcomes. Obi et al.31 found a significant association between lower 25(OH)D measured before 10 years after transplantation and subsequent rapid decline in graft function, but no association was found for 25(OH)D measured after 10 years. An analysis of a national registry involving 762 KTRs found that lower serum 25(OH)D measured 10 weeks post-transplant is associated with poorer graft and patient survival.17 These studies suggest that vitamin D is a risk factor for long-term survival among KTRs. Unfortunately, the interpretation of these results is limited by using a single 25(OH)D measurement in an early period after transplantation, ignoring the recovery of vitamin D metabolism in the early phase post-transplant as shown by Fernández-Ruiz et al.16 and others.13,19 Our results are consistent with the findings of Keyzer et al.32 who found that lower 25(OH)D level is associated with all-cause mortality and very low levels of 25(OH)D (<12 ng/ml) are associated with a stronger annual decline in eGFR in a cohort of stable KTRs over 1 year after transplantation. Nevertheless, only one single-point measurement of 25(OH)D was used, and it remains unclear when it was measured.
Several studies have been conducted to investigate the association of vitamin D and specific post-transplant complications that might contribute to graft failure. Lee et al.15 analyzed 351 KTRs with serum levels of 25(OH)D measured within the first 30 days of transplantation. They found that vitamin D deficiency was an independent risk factor for acute rejection, but not for graft function at 1 year. Previous studies also revealed that low circulating 25(OH)D level is associated with higher risk of GN recurrence33 and post-transplant diabetes mellitus.22
A nationwide randomized controlled trial25 was conducted to evaluate the effect of high doses of cholecalciferol (100,000 IU monthly) compared with low doses (12,000 IU monthly) in stable KTRs who survived at least 12 months after transplantation with 25(OH)D levels of <30 ng/ml. Serum 25(OH)D level increased to an average of 43 and 25 ng/ml in the high-dose and low-dose groups, respectively. No significant difference was found for major cardiovascular events, cancer, change in eGFR, acute rejection, infection, or death within 2 years of follow-up. Similarly, no association between post-transplant 25(OH)D with DWFG, CVD-related, or cancer-related mortality was detected among stable KTRs in our study. By contrast, we did find a significant association with overall graft failure, DCGF, and infection-related mortality. There are several possible explanations of the discrepancy between results from observational studies and the clinical trial, despite potential bias of observational design. Only 3 deaths and two graft failures were observed among 538 stable KTRs within 2-year follow-up in the trial, which limited the statistical power to detect potential associations. In addition, the control group also was treated with vitamin D supplementation rather than a placebo. The effect size of high-dose versus low-dose vitamin D supplementation may be too small to be detected.
There are potential mechanisms underlying the association between 25(OH)D and graft survival. Alloimmune processes remain the major contributor to kidney graft loss,34–37 regardless of a reduced rate of acute rejection within the first year after transplantation. The immunoregulatory effect of 1,25(OH)2D toward immunotolerance has been well-studied. It could be attributable to the inhibition of maturation of dendritic cells,7 suppression of T-cell proliferation,38 limitation of Type 1 T helper cell response,11,39 enhanced T-cell differentiation toward regulatory T-cells,8 and suppressed B-cell proliferation and Ig production.9,40 Additional evidence of immunosuppressive and an anti-inflammatory effect of vitamin D comes from studies of autoimmune diseases.41–45 Recent clinical trials have shown a beneficial effect of vitamin D supplementation on the prevention of autoimmune diseases.46,47 Moreover, vitamin D might facilitate maintaining a functioning graft through local renal protective mechanisms. Both experimental and clinical studies have revealed that 1,25(OH)2D can attenuate glomerular and tubulointerstitial injury through the suppression the renin-angiotensin system,48,49 inhibition of local inflammation,50,51 and interstitial fibrosis.52,53
We found a significant association of post-transplant circulating 25(OH)D and infection-related mortality. Anti-infection properties of vitamin D have been recognized through in vitro and in vivo studies involving both innate and adaptive immunity.54–58 There is accumulating evidence of the preventive effect of vitamin D supplements on various infectious diseases in the general population.59–61 Moreover, evidence of the association between circulating 25(OH)D level and the risk of post-transplant infection is mounting. Kalluri et al.62 found that adequate levels of vitamin D in KTRs were associated with lower infection risk in the first year and at any time post-transplantation. Fernández-Ruiz et al.16 conducted a prospective cohort study and found that vitamin D deficiency (25(OH)D <12 ng/ml) at month 1 was an independent risk factor for overall and opportunistic infection. Specifically, we and others have found a significant association between circulating 25(OH)D level and post-transplant cytomegalovirus infection.23,63 More studies are needed to further investigate the role of vitamin D in different types of infection after transplantation.
Our study has some limitations. Our findings should be interpreted with caution due to the observational study design. The observed association does not necessarily indicate a causal relationship. It is susceptible to potential residual confounding, although most measured baseline characteristics were comparable and adjusted. We used 25(OH)D levels measured 5–13 months post-transplant, which precludes any analysis of how levels changed from the time of transplant. We used available measurements of 25(OH)D without information on indications for measurement and details of vitamin D supplementation among recipients. We have potentially limited generalizability based on a local cohort of KTRs at a high latitude. The results of cause-specific mortality require cautious interpretation with limited statistical power due to small number of events.
Our study also has significant strengths. Specifically, it benefits from a large cohort of KTRs with excellent retention, long follow-up, and close clinical management. We used both fixed 25(OH)D levels and time-varying 25(OH)D levels during follow-up. We defined the baseline window as 5–13 months post-transplant to allow for fluctuation of 25(OH)D levels within the first 6 months. We analyzed clinical end points happening at different periods after transplantation to account for the unknow latent period of effect, namely, graft failures (including death) until the end of follow-up in the primary analysis, those occurring 30–365 days after each 25(OH)D measurement in sensitivity analysis, and the trajectory of eGFR over the next 4 years. Consistent results across these analyses in our study indicate that the observed associations are less likely to result from bias.
In conclusion, post-transplant circulating 25(OH)D levels are significantly associated with long-term graft failure and a faster rate of graft function decline among KTRs. No association was observed for DWFG or cause-specific mortality, except for infection-related mortality. Further large-scale randomized controlled trials are needed to determine whether a causal relationship exists.
Supplementary Material
Acknowledgment
The authors appreciate all patients, clinicians, nurses, and data analysts who contribute to the Wisconsin Allograft Recipient Database.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B205.
Author Contributions
Conceptualization: Brad C. Astor, Michal L. Melamed, Zhongyu Yuan.
Data curation: Brad C. Astor, Zhongyu Yuan.
Formal analysis: Zhongyu Yuan.
Funding acquisition: Brad C. Astor.
Investigation: Brad C. Astor, Zhongyu Yuan.
Methodology: Brad C. Astor, Zhongyu Yuan.
Resources: Brad C. Astor, Didier Mandelbrot, Sandesh Parajuli.
Software: Zhongyu Yuan.
Supervision: Brad C. Astor.
Validation: Brad C. Astor, Zhongyu Yuan.
Visualization: Brad C. Astor, Zhongyu Yuan.
Writing – original draft: Zhongyu Yuan.
Writing – review & editing: Brad C. Astor, Didier Mandelbrot, Michal L. Melamed, Sandesh Parajuli.
Funding
B.C. Astor: Department of Medicine, School of Medicine and Public Health, UW-Madison (AAM7147 ASTOR DOM GENERAL PILOT).
Declarative Statements
This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. The need to obtain informed patient consent was waived. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.
Data Availability Statements
Partial restrictions to the data and/or materials apply. The University of Wisconsin Health Sciences Institutional Review Board restricts sharing of clinical data. A request for access to the data used in this study should be sent to the corresponding author, WI.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/KN9/B206.
Supplemental Table 1. Characteristics of study population and KTRs excluded.
Supplemental Table 2. Association of post-transplant circulating 25(OH)D and long-term survival in sensitivity analysis.
Supplemental Table 3. Association of post-transplant circulating 25(OH)D and eGFR trajectory over the next 4 years using joint modeling.
References
- 1.Johansen KL Chertow GM Gilbertson DT, et al. US renal data system 2022 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2023;81(3 suppl1):A8–A11. doi: 10.1053/j.ajkd.2022.12.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983;57(6):1308–1310. doi: 10.1210/JCEM-57-6-1308 [DOI] [PubMed] [Google Scholar]
- 3.Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221(4616):1181–1183. doi: 10.1126/SCIENCE.6310748 [DOI] [PubMed] [Google Scholar]
- 4.Adams JS, Gacad MA. Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med. 1985;161(4):755–765. doi: 10.1084/jem.161.4.755 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hewison M Burke F Evans KN, et al. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol. 2007;103(3–5):316–321. doi: 10.1016/j.jsbmb.2006.12.078 [DOI] [PubMed] [Google Scholar]
- 6.Cantorna MT, Arora J. Two lineages of immune cells that differentially express the vitamin D receptor. J Steroid Biochem Mol Biol. 2023;228:106253. doi: 10.1016/j.jsbmb.2023.106253 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Griffin MD, Lutz WH, Phan VA, Bachman LA, McKean DJ, Kumar R. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophysical Res Commun. 2000;270(3):701–708. doi: 10.1006/bbrc.2000.2490 [DOI] [PubMed] [Google Scholar]
- 8.Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001;167(4):1945–1953. doi: 10.4049/jimmunol.167.4.1945 [DOI] [PubMed] [Google Scholar]
- 9.Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179(3):1634–1647. doi: 10.4049/jimmunol.179.3.1634 [DOI] [PubMed] [Google Scholar]
- 10.Chen J, Bruce D, Cantorna MT. Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol. 2014;15(1):6. doi: 10.1186/1471-2172-15-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Chauss D Freiwald T McGregor R, et al. Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells. Nat Immunol. 2022;23(1):62–74. doi: 10.1038/s41590-021-01080-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Wissing KM, Broeders N, Moreno-Reyes R, Gervy C, Stallenberg B, Abramowicz D. A controlled study of vitamin D3 to prevent bone loss in renal-transplant patients receiving low doses of steroids. Transplantation. 2005;79(1):108–115. doi: 10.1097/01.TP.0000149322.70295.A5 [DOI] [PubMed] [Google Scholar]
- 13.Evenepoel P. Recovery versus persistence of disordered mineral metabolism in kidney transplant recipients. Semin Nephrol. 2013;33(2):191–203. doi: 10.1016/J.SEMNEPHROL.2012.12.019 [DOI] [PubMed] [Google Scholar]
- 14.Bienaimé F Girard D Anglicheau D, et al. Vitamin D status and outcomes after renal transplantation. J Am Soc Nephrol. 2013;24(5):831–841. doi: 10.1681/ASN.2012060614 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lee JR, Dadhania D, August P, Lee JB, Suthanthiran M, Muthukumar T. Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients. Transplantation. 2014;98(3):292–299. doi: 10.1097/TP.0000000000000055 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Fernández-Ruiz M Corbella L Morales-Cartagena A, et al. Vitamin D deficiency and infection risk in kidney transplant recipients: a single-center cohort study. Transpl Infect Dis. 2018;20(6):e12988. doi: 10.1111/tid.12988. [DOI] [PubMed] [Google Scholar]
- 17.Thorsen IS Bleskestad IH Åsberg A, et al. Vitamin D as a risk factor for patient survival after kidney transplantation: a prospective observational cohort study. Clin Transplant. 2019;33(5):e13517. doi: 10.1111/ctr.13517 [DOI] [PubMed] [Google Scholar]
- 18.Alfieri C Vettoretti S Ruzhytska O, et al. Vitamin D and subclinical cardiac damage in a cohort of kidney transplanted patients: a retrospective observational study. Sci Rep. 2020;10(1):19160. doi: 10.1038/s41598-020-76261-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Thorsen IS Bleskestad IH Åsberg A, et al. Klotho and fibroblast growth factor 23 are independent of vitamin D, and unlike vitamin D, are not associated with Graft- and patient survival after kidney transplantation. Transplant Direct. 2023;9(9):e1522. doi: 10.1097/TXD.0000000000001522 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Evenepoel P Meijers BKI de Jong H, et al. Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol. 2008;3(6):1829–1836. doi: 10.2215/CJN.01310308 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Molinari P Alfieri CM Mattinzoli D, et al. Bone and mineral disorder in renal transplant patients: overview of pathology, clinical, and therapeutic aspects. Front Med (Lausanne). 2022;9:821884. doi: 10.3389/fmed.2022.821884 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Le Fur A Fournier MC Gillaizeau F, et al. Vitamin D deficiency is an independent risk factor for PTDM after kidney transplantation. Transpl Int. 2016;29(2):207–215. doi: 10.1111/TRI.12697 [DOI] [PubMed] [Google Scholar]
- 23.Fernández-Ruiz M Rodríguez-Goncer I Ruiz-Merlo T, et al. Low 25-hydroxyvitamin D levels and the risk of late CMV infection after kidney transplantation: role for CMV-Specific mediated immunity. Transplantation. 2019;103(8):E216–E217. doi: 10.1097/TP.0000000000002770 [DOI] [PubMed] [Google Scholar]
- 24.Van Ballegooijen AJ Beulens JWJ Keyzer CA, et al. Joint association of vitamins D and K status with long-term outcomes in stable kidney transplant recipients. Nephrol Dial Transplant. 2020;35(4):706–714. doi: 10.1093/NDT/GFY399 [DOI] [PubMed] [Google Scholar]
- 25.Courbebaisse M Bourmaud A Souberbielle JC, et al. Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial. Am J Transplant. 2023;23(3):366–376. doi: 10.1016/j.ajt.2022.12.007 [DOI] [PubMed] [Google Scholar]
- 26.The Wisconsin Allograft Recipient Database (WisARD). Population Health Sciences, 2025. Accessed June 14, 2024. https://pophealth.wisc.edu/research/the-wisconsin-allograft-recipient-database-wisard/ [Google Scholar]
- 27.Holick MF Binkley NC Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930. doi: 10.1210/JC.2011-0385 [DOI] [PubMed] [Google Scholar]
- 28.Inker LA Eneanya ND Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737–1749. doi: 10.1056/NEJMoa2102953 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Leffondre K, Boucquemont J, Tripepi G, Stel VS, Heinze G, Dunkler D. Analysis of risk factors associated with renal function trajectory over time: a comparison of different statistical approaches. Nephrol Dial Transplant. 2015;30(8):1237–1243. doi: 10.1093/ndt/gfu320 [DOI] [PubMed] [Google Scholar]
- 30.Rizopoulos D. JM: anrpackage for the joint modelling of longitudinal and time-to-event data. J Stat Softw. 2010;35(9):1–33. doi: 10.18637/jss.v035.i0921603108 [DOI] [Google Scholar]
- 31.Obi Y Hamano T Ichimaru N, et al. Vitamin D deficiency predicts decline in kidney allograft function: a prospective cohort study. J Clin Endocrinol Metab. 2014;99(2):527–535. doi: 10.1210/jc.2013-2421 [DOI] [PubMed] [Google Scholar]
- 32.Keyzer CA Riphagen IJ Joosten MM, et al. Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients. J Clin Endocrinol Metab. 2015;100(1):81–89. doi: 10.1210/jc.2014-3012 [DOI] [PubMed] [Google Scholar]
- 33.Yuan Z Melamed ML Singh T, et al. Association of circulating 25-Hydroxyvitamin D and recurrence of glomerulonephritis in kidney transplant recipients: the Wisconsin allograft recipient database (WisARD). Transplant Direct. 2024;10(4):e1600. doi: 10.1097/TXD.0000000000001600 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.El-Zoghby ZM Stegall MD Lager DJ, et al. Identifying specific causes of kidney allograft loss. Am J Transplant. 2009;9(3):527–535. doi: 10.1111/j.1600-6143.2008.02519.x. [DOI] [PubMed] [Google Scholar]
- 35.Sellarés J de Freitas DG Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12(2):388–399. doi: 10.1111/j.1600-6143.2011.03840.x [DOI] [PubMed] [Google Scholar]
- 36.Naesens M Kuypers DRJ De Vusser K, et al. The histology of kidney transplant failure: a long-term follow-up study. Transplantation. 2014;98(4):427–435. doi: 10.1097/TP.0000000000000183 [DOI] [PubMed] [Google Scholar]
- 37.Van Loon E, Bernards J, Van Craenenbroeck AH, Naesens M. The causes of kidney allograft failure: more than alloimmunity. A viewpoint article. Transplantation. 2020;104(2):e46–e56. doi: 10.1097/TP.0000000000003012 [DOI] [PubMed] [Google Scholar]
- 38.Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest. 1984;74(4):1451–1455. doi: 10.1172/JCI111557 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Penna G Amuchastegui S Giarratana N, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol. 2007;178(1):145–153. doi: 10.4049/jimmunol.178.1.145 [DOI] [PubMed] [Google Scholar]
- 40.Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest. 1984;74(2):657–661. doi: 10.1172/JCI111465 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Tang J Zhou R Luger D, et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol. 2009;182(8):4624–4632. doi: 10.4049/jimmunol.0801543 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Jeffery LE, Raza K, Hewison M. Vitamin D in rheumatoid arthritis-towards clinical application. Nat Rev Rheumatol. 2016;12(4):201–210. doi: 10.1038/nrrheum.2015.140 [DOI] [PubMed] [Google Scholar]
- 43.Fletcher J, Cooper SC, Ghosh S, Hewison M. The role of vitamin D in inflammatory bowel disease: mechanism to management. Nutrients. 2019;11(5):1019. doi: 10.3390/nu11051019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Infante M Ricordi C Sanchez J, et al. Influence of vitamin D on islet autoimmunity and beta-cell function in type 1 diabetes. Nutrients. 2019;11(9):2185. doi: 10.3390/nu11092185 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Carlberg C, Mycko MP. Linking mechanisms of vitamin D signaling with multiple sclerosis. Cells. 2023;12(19):2391. doi: 10.3390/cells12192391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Hahn J Cook NR Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452. doi: 10.1136/BMJ-2021-066452 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Thouvenot E Laplaud D Lebrun-Frenay C, et al. High-dose vitamin D in clinically isolated syndrome typical of multiple sclerosis: the D-Lay MS randomized clinical trial. JAMA. 2025;333(16):1413–1422. doi: 10.1001/jama.2025.1604 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Yuan W Pan W Kong J, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 2007;282(41):29821–29830. doi: 10.1074/jbc.M705495200 [DOI] [PubMed] [Google Scholar]
- 49.Li YC. Vitamin D regulation of the renin–angiotensin system. J Cell Biochem. 2003;88(2):327–331. doi: 10.1002/jcb.10343 [DOI] [PubMed] [Google Scholar]
- 50.Zehnder D Quinkler M Eardley KS, et al. Reduction of the vitamin D hormonal system in kidney disease is associated with increased renal inflammation. Kidney Int. 2008;74(10):1343–1353. doi: 10.1038/ki.2008.453 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Sun J Kong J Duan Y, et al. Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor. Am J Physiol Endocrinol Metab. 2006;291(2):E315–E322. doi: 10.1152/ajpendo.00590.2005 [DOI] [PubMed] [Google Scholar]
- 52.Martínez-Arias L Panizo S Alonso-Montes C, et al. Effects of calcitriol and paricalcitol on renal fibrosis in CKD. Nephrol Dial Transplant. 2021;36(5):793–803. doi: 10.1093/ndt/gfaa373 [DOI] [PubMed] [Google Scholar]
- 53.Dos Santos MS Canale D Bernardo DRD, et al. The restoration of vitamin D levels slows the progression of renal ischemic injury in rats previously deficient in vitamin D. Front Med (Lausanne). 2021;8:625647. doi: 10.3389/fmed.2021.625647 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Liu PT Stenger S Li H, et al. Toll-like receptor triggering of a vitamin D-Mediated human antimicrobial response. Science. 2006;311(5768):1770–1773. doi: 10.1126/science.1123933 [DOI] [PubMed] [Google Scholar]
- 55.Hewison M. Antibacterial effects of vitamin D. Nat Rev Endocrinol. 2011;7(6):337–345. doi: 10.1038/nrendo.2010.226 [DOI] [PubMed] [Google Scholar]
- 56.Koivisto O, Hanel A, Carlberg C. Key vitamin D target genes with functions in the immune system. Nutrients. 2020;12(4):1140. doi: 10.3390/nu12041140 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.L Bishop E, Ismailova A, Dimeloe S, Hewison M, White JH. Vitamin D and immune regulation: antibacterial, antiviral, anti-inflammatory. JBMR Plus. 2021;5(1):e10405. doi: 10.1002/jbm4.10405 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.White JH. Emerging roles of vitamin D-Induced antimicrobial peptides in antiviral innate immunity. Nutrients. 2022;14(2):284. doi: 10.3390/nu14020284 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Jolliffe DA Camargo CA Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9(5):276–292. doi: 10.1016/S2213-8587(21)00051-6 [DOI] [PubMed] [Google Scholar]
- 60.Ganmaa D Uyanga B Zhou X, et al. Vitamin D supplements for prevention of tuberculosis infection and disease. New Engl J Med. 2020;383(4):359–368. doi: 10.1056/NEJMoa1915176 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Grant WB Lahore H McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12(4):988. doi: 10.3390/nu12040988 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Kalluri HV Sacha LM Ingemi AI, et al. Low vitamin D exposure is associated with higher risk of infection in renal transplant recipients. Clin Transplant. 2017;31(5):e12955. doi: 10.1111/ctr.12955 [DOI] [PubMed] [Google Scholar]
- 63.Astor BC, Djamali A, Mandelbrot DA, Parajuli S, Melamed ML. The association of 25-Hydroxyvitamin D levels with late cytomegalovirus infection in kidney transplant recipients: the Wisconsin allograft recipient database. Transplantation. 2019;103(8):1683–1688. doi: 10.1097/TP.0000000000002672 [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Data Availability Statement
Partial restrictions to the data and/or materials apply. The University of Wisconsin Health Sciences Institutional Review Board restricts sharing of clinical data. A request for access to the data used in this study should be sent to the corresponding author, WI.