Cardio Iq Vitamin D
Are low levels of 25-hydroxyvitamin D a risk factor for cardiovascular diseases or malignancies in renal transplantation?
Roberto Marcén, Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on: Department of Nephrology , Hospital Ramón y Cajal , Madrid 28034 , Spain Search for other works by this author on:
Accepted:
28 September 2012
Published:
01 December 2012
Abstract
Background
Observational studies in healthy people suggest an inverse relationship between 25-hydroxy-vitamin D (25(OH)D levels) and cardiovascular diseases and malignancies. We performed an observational prospective study in renal transplant recipients to investigate the effects of vitamin D deficiency on cardiovascular and malignancy risks.
Methods
From 389 renal transplant recipients, 331 with a functioning graft at 12 months were included in the study. Mineral metabolism parameters were measured at 1, 3, 4 and 12 months. Information regarding the cardiovascular events and malignancies were collected from an electronic database.
Results
According to the 1-year mean of 25(OH)D levels, 75 recipients (22.7%) had a normal vitamin D status, 161 (48.6%) had insufficiency and 95 (28.7%) had deficiency in vitamin D levels. During the follow-up, 80 recipients presented at least one cardiovascular event. The total cardiovascular diseases included: 27 patients with coronary diseases, 25 with cardiac failure, 18 with arrhythmia, 11 with acute cerebrovascular events and 19 with peripheral vascular disease. Cardiovascular events were not associated with 25(OH)D levels or vitamin D status, and the 10-year cumulative incidence was 29.3% for normal vitamin D status and 31.6% for insufficiency and 51.9% for deficiency (P = 0.216). Furthermore, Cox univariate analysis showed no association between cardiovascular events and vitamin D levels or vitamin D status. In addition, 53 recipients presented at least one malignancy: 33 non-melanoma skin malignancies and 20 non-skin malignancies (5 prostate, 3 kidney and urinary tract, 2 colon, 2 lung, 2 lymphoma, 2 breast and 4 from other locations). The cumulative incidence of malignancies was 21.3% for normal vitamin D status, 22.7% for insufficiency and 16.7% for deficiency (P = 0.818).
Conclusions
Our data suggested that low vitamin D levels were not associated with an increased risk of cardiovascular diseases or malignancies. However, due to the small number of patients and events, the results should not be considered as definitive. Additional studies with a higher number of patients are required to elucidate the true impact of vitamin D status on cardiovascular and malignancy risks.
Introduction
Vitamin D, a steroid molecule produced in the skin, regulates the expression of a large number of genes. Vitamin D deficiency is very common in the general population and is considered a pandemia [1]. Most authors agree that a 25-hydroxy-vitamin D (25(OH)D, calcidiol) concentration of >30 ng/mL is considered sufficient. This is based on the observation that calcium absorption in the intestine is maximized and parathyroid hormone (PTH) concentrations reach their nadir at 30–40 ng/mL [1, 2]. Although the best-characterized sequelae of vitamin D deficiency involve the musculoskeletal system, it has been associated in recent years with the risk factors of cardiovascular diseases, cancer and overall mortality [3–7]. Furthermore, vitamin D deficiency is also very common in patients with chronic renal failure [8, 9] and it was associated with mortality in some studies [9]. A functioning kidney transplant does not improve the vitamin D status, and between 70% and 90% of renal transplant recipients have vitamin D insufficiency or deficiency due to the avoidance of sun exposure and to the use of protective creams [10–12]. Moreover, renal transplant recipients have a higher risk of cardiovascular diseases and mortality and of malignancies than the general population [13, 14]. So, we hypothesized a link between vitamin D deficiency and cardiovascular diseases and malignancies in this population. No studies are available in the English medical literature in which the possible association between the vitamin D status and cardiovascular events has been investigated. In fact, there is only one report where the association between the vitamin D status before transplant and malignancies was assessed [15]. In this study, low pre-transplant and 1-year vitamin D levels were associated with a higher incidence of malignancies.
The purpose of the present study was to investigate the possible association of vitamin D insufficiency/deficiency and the occurrence of cardiovascular events or malignancies in a population of renal transplant recipients.
Materials and methods
Study design
This is an observational prospective cohort study, designed to assess the effect of vitamin D status and vitamin D levels in the first year after transplantation on cardiovascular and malignancy risks in renal transplant recipients followed for at least 3 years.
Patients
All adult (≥18 years) renal transplant recipients who were transplanted between January 2000 and June 2008 were screened for inclusion in this study. Patients were excluded if they had lost the graft before 12 months. The study subjects were identified using the electronic medical records. Recipient variables (age, gender, time on dialysis, body mass index at transplant, primary renal disease and cardiovascular disease), donor variables (age, gender and cause of death), graft variables (HLA mismatches, delayed graft function, acute rejection and immunosuppression) and the time of presentation and the characteristics of post-transplant cardiovascular diseases (ischaemic heart disease, congestive heart failure, arrhythmias, cerebrovascular diseases, peripheral vascular diseases) and of malignancies were systematically collected at the time of the transplant and when an event occurred.
Definitions
Ischaemic heart disease was defined as angina and a positive stress test, myocardial infarction (defined as the presence of chest pain accompanied by characteristic electrocardiogram changes of infarction) or revascularization (coronary bypass grafting or percutaneous transluminal angioplasty). Congestive heart failure was defined as dyspnea plus two of the following: raised jugular venous pressure, bibasilar crackles and chest X-ray. The diagnosis was performed by one of the three doctors of the transplant unit who cared for the patients during the whole study. Cerebrovascular disease was defined as stroke or documented transient ischemic attack. Peripheral vascular disease was defined as claudication with documented vascular insufficiency, revascularization procedure or amputation. Cardiovascular death was considered when it was recorded within 30 days of a cardiovascular event. Patients with pre-transplant cardiovascular disease were considered to have post-transplant cardiovascular disease if they presented a new event.
Methods
Blood and morning urine samples were obtained after overnight fasting to measure graft function and mineral metabolism parameters that included serum creatinine, serum calcium, serum phosphate, tubular phosphate reabsorption, intact parathyroid hormone (iPTH), 25(OH)D and 1,25-dihydroxy-vitamin D (1,25(OH)D) at discharge, 3, 6 and 12 months after transplantation. Serum iPTH was determined by an immunocheminometric assay (Elecsys, Roche Diagnostics Gmbh, Mannheim, Germany)]. 25(OH)D was measured using the enzyme-linked immunsorbent assay (IDS systems; Boldon, UK) and 1,25(OH)D was determined by radioimmunoassay (Biosource Europe, Nivelles, Belgium). Tubular reabsorption of phosphate (TRP) was calculated by the following equation: urinary phosphate × serum creatinine/serum phosphate × urinary creatinine, and expressed as percentage. Bone metabolism markers were measured at the times previously described according to our protocol of follow-up. All biochemical data were systematically recorded in the patient electronic database. Vitamin D status was defined as normal when serum calcidiol was ≥30 ng/mL, insufficient when serum calcidiol was <30 ng/mL and ≥16 ng/mL and deficient when serum calcidiol was <16 ng/mL. We classified the patients according to the calcidiol levels at 12 months and to the mean of all values obtained in the first year because of seasonal changes in vitamin D levels.
Statistical analysis
The numerical data were expressed as mean ± standard deviation and the categorical data as percentage. The Student's t-test and one-way analysis of variance were used to compare numerical variables and the chi-squared test was used to compare categorical data. The cumulative incidence of cardiovascular diseases and malignancies was determined by the Kaplan–Meier analysis. The log-rank test was used to compare the cumulative incidence of cardiovascular diseases or malignancies according to the vitamin D status. Cox univariate and multivariate analyses were used to determine the variables associated with cardiovascular diseases, mortality and malignancies. Variables included in the multivariate model were those statistically significant in the univariate analysis. Only the first cardiovascular or malignancy event was used in the analysis.
Results
From 389 recipients, 331 were included in the study. The demographic characteristics are displayed in Table1. At the time of hospital discharge, the serum creatinine level was 2.0 ± 1.02 mg/dL, iPTH 265 ± 263 pg/mL, serum 25(OH)D 21.2 ± ng/mL and serum 1,25(OH)D 19.0 ± pg/mL. Patients were classified according to the vitamin D status using the mean of the serum 25(OH)D determinations during the first year: 75 recipients (22.7%) had normal vitamin D status, 161 recipients (48.6%) had insufficiency and 95 recipients (28.7%) had deficiency. Demographic parameters, graft function, iPTH, 25(OH)D and 1,25(OH)D levels and some cardiovascular risk factors according to the vitamin D status are shown in Table2. There were no differences in blood pressure, body weight and treatment with angiotensin receptor antagonists (ARA) or statin therapy. More patients with normal or insufficient vitamin D were on treatment with vitamin D (calcitriol) at 12 months compared with deficient recipients (P = 0.021). Since 2007, a total of 104 recipients were treated with cholecalciferol 400–800 IU/day for at least 6 months according to the criteria of the physicians treating the patients. A total of 40 recipients (12.1%) had a previous history of cardiovascular disease: 17 ischaemic heart disease (9 with a revascularization procedure), 11 cerebrovascular accident, 7 arrhythmia and 5 peripheral vascular disease.
Table 1.
Demographic characteristics
| Variable | |
|---|---|
| Age at transplant (years) | 52.2 ± 14.1 |
| Recipient gender (male/female) | 204/127 |
| Time on dialysis (months) | 28.8 ± 28.0 |
| Primary renal disease | |
| Chronic glomerulonephritis | 56 (16.9%) |
| Interstitial nephritis | 61 (18.4%) |
| Adult polycystic disease | 61 (18.4%) |
| Nephroangiosclerosis | 21 (6.3%) |
| Diabetic nephropathy | 27 (8.2%) |
| Unknown | 67 (20.2%) |
| Other | 38 (11.5%) |
| Donor age (years) | 49.7 ± 16.8 |
| Initial immunosuppression: | |
| Tacrolimus-based | 264 |
| Cyclosporine-based | 60 |
| No calcineurin inhibitors | 7 |
| Delayed graft function (no/yes) | 214/117 |
| Acute rejection (no/yes) | 294/37 |
| Length of follow-up (months) | 84.6 ± 31.8 |
| Variable | |
|---|---|
| Age at transplant (years) | 52.2 ± 14.1 |
| Recipient gender (male/female) | 204/127 |
| Time on dialysis (months) | 28.8 ± 28.0 |
| Primary renal disease | |
| Chronic glomerulonephritis | 56 (16.9%) |
| Interstitial nephritis | 61 (18.4%) |
| Adult polycystic disease | 61 (18.4%) |
| Nephroangiosclerosis | 21 (6.3%) |
| Diabetic nephropathy | 27 (8.2%) |
| Unknown | 67 (20.2%) |
| Other | 38 (11.5%) |
| Donor age (years) | 49.7 ± 16.8 |
| Initial immunosuppression: | |
| Tacrolimus-based | 264 |
| Cyclosporine-based | 60 |
| No calcineurin inhibitors | 7 |
| Delayed graft function (no/yes) | 214/117 |
| Acute rejection (no/yes) | 294/37 |
| Length of follow-up (months) | 84.6 ± 31.8 |
Table 1.
Demographic characteristics
| Variable | |
|---|---|
| Age at transplant (years) | 52.2 ± 14.1 |
| Recipient gender (male/female) | 204/127 |
| Time on dialysis (months) | 28.8 ± 28.0 |
| Primary renal disease | |
| Chronic glomerulonephritis | 56 (16.9%) |
| Interstitial nephritis | 61 (18.4%) |
| Adult polycystic disease | 61 (18.4%) |
| Nephroangiosclerosis | 21 (6.3%) |
| Diabetic nephropathy | 27 (8.2%) |
| Unknown | 67 (20.2%) |
| Other | 38 (11.5%) |
| Donor age (years) | 49.7 ± 16.8 |
| Initial immunosuppression: | |
| Tacrolimus-based | 264 |
| Cyclosporine-based | 60 |
| No calcineurin inhibitors | 7 |
| Delayed graft function (no/yes) | 214/117 |
| Acute rejection (no/yes) | 294/37 |
| Length of follow-up (months) | 84.6 ± 31.8 |
| Variable | |
|---|---|
| Age at transplant (years) | 52.2 ± 14.1 |
| Recipient gender (male/female) | 204/127 |
| Time on dialysis (months) | 28.8 ± 28.0 |
| Primary renal disease | |
| Chronic glomerulonephritis | 56 (16.9%) |
| Interstitial nephritis | 61 (18.4%) |
| Adult polycystic disease | 61 (18.4%) |
| Nephroangiosclerosis | 21 (6.3%) |
| Diabetic nephropathy | 27 (8.2%) |
| Unknown | 67 (20.2%) |
| Other | 38 (11.5%) |
| Donor age (years) | 49.7 ± 16.8 |
| Initial immunosuppression: | |
| Tacrolimus-based | 264 |
| Cyclosporine-based | 60 |
| No calcineurin inhibitors | 7 |
| Delayed graft function (no/yes) | 214/117 |
| Acute rejection (no/yes) | 294/37 |
| Length of follow-up (months) | 84.6 ± 31.8 |
Table 2.
Patient characteristics according to the vitamin D status
| Normal | Insufficiency | Deficiency | P | |
|---|---|---|---|---|
| N | 75 (22.7%) | 161 (48.6%) | 95 (28.7%) | |
| Age at transplant (years) | 48.8 ± 14.7* | 52.2 ± 14.2 | 54.7 ± 12.8 | 0.025 |
| Recipient gender (male/female) | 52/23 | 101/60 | 51/44 | 0.105 |
| Time on dialysis (months) | 21.4 ± 17.6+ | 29.7 ± 30.5 | 30.3 ± 25.2 | 0.053 |
| Cardiovascular disease before transplant (no/yes) | 69/6 | 136/25 | 81/14 | 0.771 |
| Donor age (years) | 44.5 ± 17.1 | 49.1 ± 16.5 | 54.4 ± 15.9 | 0.009 |
| iPTH at discharge (pg/mL) | 207 ± 196** | 252 ± 243* | 332 ± 322 | 0.005 |
| iPTH at 6 months (pg/mL) | 156 ± 115* | 162 ± 134* | 229 ± 283 | 0.013 |
| iPTH at 12 months (pg/mL) | 154 ± 132 | 155 ± 133* | 194 ± 132 | 0.051 |
| 25(OH)D at discharge (ng/mL) | 39.4 ± 19.2**,++ | 18.9 ± 8.9** | 12.3 ± 4.8 | 0.000 |
| 25(OH)D at 6 months (ng/mL) | 38.9 ± 18.3**,++ | 24.5 ± 10.6** | 13.4 ± 5.9 | 0.000 |
| 25(OH)D at 12 months (ng/mL) | 36.8 ± 20.1**,++ | 24.1 ± 10.7** | 13.1 ± 6.0 | 0.000 |
| 1,25(OH)D at discharge (pg/mL) | 20.9 ± 20.7 | 17.9 ± 19.2 | 19.7 ± 23.6 | 0.654 |
| 1,25(OH)D at 6 months (pg/mL) | 26.5 ± 19.6 | 34.1 ± 23.2 | 31.9 ± 24.2 | 0.104 |
| 1,25(OH)D at 12 months (p/mL) | 32.8 ± 23.5 | 37.9 ± 29.7 | 42.2 ± 36.7 | 0.165 |
| Serum calcium at 12 months (mg/dL) | 9.4 ± 0.6 | 9.6 ± 0.6 | 9.8 ± 0.7 | 0.161 |
| Serum phosphate at 12 months (mg/dL) | 3.0 ± 0.5 | 3.0 ± 0.6 | 3.1 ± 0.7 | 0.516 |
| TRP at 12 months (%) | 59.2 ± 16.3*,++ | 64.8 ± 14.4 | 64.9 ± 12 | 0.014 |
| Body weight at 12 months (kg) | 73.5 ± 12.0 | 73.2 ± 13.4 | 71.7 ± 16.2 | 0.652 |
| Systolic blood pressure at 12 months (mmHg) | 141 ± 18 | 142 ± 21 | 146 ± 24 | 0.284 |
| Diastolic blood pressure at 12 months (mmHg) | 78 ± 8 | 80 ± 12 | 79 ± 11 | 0.510 |
| Serum creatinine at 12 months (mg/dL) | 1.6 ± 0.5 | 1.5 ± 0.5 | 1.6 ± 0.6 | 0.408 |
| Serum haemoglobin at 12 months (g/dL) | 13.8 ± 1.9 | 13.9 ± 1.8* | 13.3 ± 1.7 | 0.056 |
| Serum albumin at 12 months (g/dL) | 4.7 ± 0.3 | 4.7 ± 0.3 | 4.7 ± 0.2 | 0.458 |
| Treatment with ARAs at 12 months (no/yes) | 66/9 | 137/24 | 75/20 | 0.241 |
| Treatment with ACEIs at 12 months (no/yes) | 74/1 | 152/9 | 85/10 | 0.042 |
| Treatment with statins at 12 months (no/yes | 54/21 | 105/56 | 58/37 | 0.326 |
| Treatment with vitamin D at 12 months (no/yes) | 40/35 | 100/61 | 70/25 | 0.021 |
| Length of follow-up (months) | 101 ± 28**,++ | 83 ± 31** | 72 ± 30 | 0.000 |
| Treatment with nutritional vitamin D (no/yes) | 59/16 | 110/51 | 58/37 | 0.049 |
| Normal | Insufficiency | Deficiency | P | |
|---|---|---|---|---|
| N | 75 (22.7%) | 161 (48.6%) | 95 (28.7%) | |
| Age at transplant (years) | 48.8 ± 14.7* | 52.2 ± 14.2 | 54.7 ± 12.8 | 0.025 |
| Recipient gender (male/female) | 52/23 | 101/60 | 51/44 | 0.105 |
| Time on dialysis (months) | 21.4 ± 17.6+ | 29.7 ± 30.5 | 30.3 ± 25.2 | 0.053 |
| Cardiovascular disease before transplant (no/yes) | 69/6 | 136/25 | 81/14 | 0.771 |
| Donor age (years) | 44.5 ± 17.1 | 49.1 ± 16.5 | 54.4 ± 15.9 | 0.009 |
| iPTH at discharge (pg/mL) | 207 ± 196** | 252 ± 243* | 332 ± 322 | 0.005 |
| iPTH at 6 months (pg/mL) | 156 ± 115* | 162 ± 134* | 229 ± 283 | 0.013 |
| iPTH at 12 months (pg/mL) | 154 ± 132 | 155 ± 133* | 194 ± 132 | 0.051 |
| 25(OH)D at discharge (ng/mL) | 39.4 ± 19.2**,++ | 18.9 ± 8.9** | 12.3 ± 4.8 | 0.000 |
| 25(OH)D at 6 months (ng/mL) | 38.9 ± 18.3**,++ | 24.5 ± 10.6** | 13.4 ± 5.9 | 0.000 |
| 25(OH)D at 12 months (ng/mL) | 36.8 ± 20.1**,++ | 24.1 ± 10.7** | 13.1 ± 6.0 | 0.000 |
| 1,25(OH)D at discharge (pg/mL) | 20.9 ± 20.7 | 17.9 ± 19.2 | 19.7 ± 23.6 | 0.654 |
| 1,25(OH)D at 6 months (pg/mL) | 26.5 ± 19.6 | 34.1 ± 23.2 | 31.9 ± 24.2 | 0.104 |
| 1,25(OH)D at 12 months (p/mL) | 32.8 ± 23.5 | 37.9 ± 29.7 | 42.2 ± 36.7 | 0.165 |
| Serum calcium at 12 months (mg/dL) | 9.4 ± 0.6 | 9.6 ± 0.6 | 9.8 ± 0.7 | 0.161 |
| Serum phosphate at 12 months (mg/dL) | 3.0 ± 0.5 | 3.0 ± 0.6 | 3.1 ± 0.7 | 0.516 |
| TRP at 12 months (%) | 59.2 ± 16.3*,++ | 64.8 ± 14.4 | 64.9 ± 12 | 0.014 |
| Body weight at 12 months (kg) | 73.5 ± 12.0 | 73.2 ± 13.4 | 71.7 ± 16.2 | 0.652 |
| Systolic blood pressure at 12 months (mmHg) | 141 ± 18 | 142 ± 21 | 146 ± 24 | 0.284 |
| Diastolic blood pressure at 12 months (mmHg) | 78 ± 8 | 80 ± 12 | 79 ± 11 | 0.510 |
| Serum creatinine at 12 months (mg/dL) | 1.6 ± 0.5 | 1.5 ± 0.5 | 1.6 ± 0.6 | 0.408 |
| Serum haemoglobin at 12 months (g/dL) | 13.8 ± 1.9 | 13.9 ± 1.8* | 13.3 ± 1.7 | 0.056 |
| Serum albumin at 12 months (g/dL) | 4.7 ± 0.3 | 4.7 ± 0.3 | 4.7 ± 0.2 | 0.458 |
| Treatment with ARAs at 12 months (no/yes) | 66/9 | 137/24 | 75/20 | 0.241 |
| Treatment with ACEIs at 12 months (no/yes) | 74/1 | 152/9 | 85/10 | 0.042 |
| Treatment with statins at 12 months (no/yes | 54/21 | 105/56 | 58/37 | 0.326 |
| Treatment with vitamin D at 12 months (no/yes) | 40/35 | 100/61 | 70/25 | 0.021 |
| Length of follow-up (months) | 101 ± 28**,++ | 83 ± 31** | 72 ± 30 | 0.000 |
| Treatment with nutritional vitamin D (no/yes) | 59/16 | 110/51 | 58/37 | 0.049 |
ACEI, angiotensin-converting enzyme inhibitors; ARA, angiotensin receptor antagonist; TRP, tubular reabsorption of phosphate.
*P < 0.05 versus deficiency.
**P < 0.01 versus deficiency.
+P < 0.05 versus insufficiency.
++P < 0.01 versus insufficiency.
Table 2.
Patient characteristics according to the vitamin D status
| Normal | Insufficiency | Deficiency | P | |
|---|---|---|---|---|
| N | 75 (22.7%) | 161 (48.6%) | 95 (28.7%) | |
| Age at transplant (years) | 48.8 ± 14.7* | 52.2 ± 14.2 | 54.7 ± 12.8 | 0.025 |
| Recipient gender (male/female) | 52/23 | 101/60 | 51/44 | 0.105 |
| Time on dialysis (months) | 21.4 ± 17.6+ | 29.7 ± 30.5 | 30.3 ± 25.2 | 0.053 |
| Cardiovascular disease before transplant (no/yes) | 69/6 | 136/25 | 81/14 | 0.771 |
| Donor age (years) | 44.5 ± 17.1 | 49.1 ± 16.5 | 54.4 ± 15.9 | 0.009 |
| iPTH at discharge (pg/mL) | 207 ± 196** | 252 ± 243* | 332 ± 322 | 0.005 |
| iPTH at 6 months (pg/mL) | 156 ± 115* | 162 ± 134* | 229 ± 283 | 0.013 |
| iPTH at 12 months (pg/mL) | 154 ± 132 | 155 ± 133* | 194 ± 132 | 0.051 |
| 25(OH)D at discharge (ng/mL) | 39.4 ± 19.2**,++ | 18.9 ± 8.9** | 12.3 ± 4.8 | 0.000 |
| 25(OH)D at 6 months (ng/mL) | 38.9 ± 18.3**,++ | 24.5 ± 10.6** | 13.4 ± 5.9 | 0.000 |
| 25(OH)D at 12 months (ng/mL) | 36.8 ± 20.1**,++ | 24.1 ± 10.7** | 13.1 ± 6.0 | 0.000 |
| 1,25(OH)D at discharge (pg/mL) | 20.9 ± 20.7 | 17.9 ± 19.2 | 19.7 ± 23.6 | 0.654 |
| 1,25(OH)D at 6 months (pg/mL) | 26.5 ± 19.6 | 34.1 ± 23.2 | 31.9 ± 24.2 | 0.104 |
| 1,25(OH)D at 12 months (p/mL) | 32.8 ± 23.5 | 37.9 ± 29.7 | 42.2 ± 36.7 | 0.165 |
| Serum calcium at 12 months (mg/dL) | 9.4 ± 0.6 | 9.6 ± 0.6 | 9.8 ± 0.7 | 0.161 |
| Serum phosphate at 12 months (mg/dL) | 3.0 ± 0.5 | 3.0 ± 0.6 | 3.1 ± 0.7 | 0.516 |
| TRP at 12 months (%) | 59.2 ± 16.3*,++ | 64.8 ± 14.4 | 64.9 ± 12 | 0.014 |
| Body weight at 12 months (kg) | 73.5 ± 12.0 | 73.2 ± 13.4 | 71.7 ± 16.2 | 0.652 |
| Systolic blood pressure at 12 months (mmHg) | 141 ± 18 | 142 ± 21 | 146 ± 24 | 0.284 |
| Diastolic blood pressure at 12 months (mmHg) | 78 ± 8 | 80 ± 12 | 79 ± 11 | 0.510 |
| Serum creatinine at 12 months (mg/dL) | 1.6 ± 0.5 | 1.5 ± 0.5 | 1.6 ± 0.6 | 0.408 |
| Serum haemoglobin at 12 months (g/dL) | 13.8 ± 1.9 | 13.9 ± 1.8* | 13.3 ± 1.7 | 0.056 |
| Serum albumin at 12 months (g/dL) | 4.7 ± 0.3 | 4.7 ± 0.3 | 4.7 ± 0.2 | 0.458 |
| Treatment with ARAs at 12 months (no/yes) | 66/9 | 137/24 | 75/20 | 0.241 |
| Treatment with ACEIs at 12 months (no/yes) | 74/1 | 152/9 | 85/10 | 0.042 |
| Treatment with statins at 12 months (no/yes | 54/21 | 105/56 | 58/37 | 0.326 |
| Treatment with vitamin D at 12 months (no/yes) | 40/35 | 100/61 | 70/25 | 0.021 |
| Length of follow-up (months) | 101 ± 28**,++ | 83 ± 31** | 72 ± 30 | 0.000 |
| Treatment with nutritional vitamin D (no/yes) | 59/16 | 110/51 | 58/37 | 0.049 |
| Normal | Insufficiency | Deficiency | P | |
|---|---|---|---|---|
| N | 75 (22.7%) | 161 (48.6%) | 95 (28.7%) | |
| Age at transplant (years) | 48.8 ± 14.7* | 52.2 ± 14.2 | 54.7 ± 12.8 | 0.025 |
| Recipient gender (male/female) | 52/23 | 101/60 | 51/44 | 0.105 |
| Time on dialysis (months) | 21.4 ± 17.6+ | 29.7 ± 30.5 | 30.3 ± 25.2 | 0.053 |
| Cardiovascular disease before transplant (no/yes) | 69/6 | 136/25 | 81/14 | 0.771 |
| Donor age (years) | 44.5 ± 17.1 | 49.1 ± 16.5 | 54.4 ± 15.9 | 0.009 |
| iPTH at discharge (pg/mL) | 207 ± 196** | 252 ± 243* | 332 ± 322 | 0.005 |
| iPTH at 6 months (pg/mL) | 156 ± 115* | 162 ± 134* | 229 ± 283 | 0.013 |
| iPTH at 12 months (pg/mL) | 154 ± 132 | 155 ± 133* | 194 ± 132 | 0.051 |
| 25(OH)D at discharge (ng/mL) | 39.4 ± 19.2**,++ | 18.9 ± 8.9** | 12.3 ± 4.8 | 0.000 |
| 25(OH)D at 6 months (ng/mL) | 38.9 ± 18.3**,++ | 24.5 ± 10.6** | 13.4 ± 5.9 | 0.000 |
| 25(OH)D at 12 months (ng/mL) | 36.8 ± 20.1**,++ | 24.1 ± 10.7** | 13.1 ± 6.0 | 0.000 |
| 1,25(OH)D at discharge (pg/mL) | 20.9 ± 20.7 | 17.9 ± 19.2 | 19.7 ± 23.6 | 0.654 |
| 1,25(OH)D at 6 months (pg/mL) | 26.5 ± 19.6 | 34.1 ± 23.2 | 31.9 ± 24.2 | 0.104 |
| 1,25(OH)D at 12 months (p/mL) | 32.8 ± 23.5 | 37.9 ± 29.7 | 42.2 ± 36.7 | 0.165 |
| Serum calcium at 12 months (mg/dL) | 9.4 ± 0.6 | 9.6 ± 0.6 | 9.8 ± 0.7 | 0.161 |
| Serum phosphate at 12 months (mg/dL) | 3.0 ± 0.5 | 3.0 ± 0.6 | 3.1 ± 0.7 | 0.516 |
| TRP at 12 months (%) | 59.2 ± 16.3*,++ | 64.8 ± 14.4 | 64.9 ± 12 | 0.014 |
| Body weight at 12 months (kg) | 73.5 ± 12.0 | 73.2 ± 13.4 | 71.7 ± 16.2 | 0.652 |
| Systolic blood pressure at 12 months (mmHg) | 141 ± 18 | 142 ± 21 | 146 ± 24 | 0.284 |
| Diastolic blood pressure at 12 months (mmHg) | 78 ± 8 | 80 ± 12 | 79 ± 11 | 0.510 |
| Serum creatinine at 12 months (mg/dL) | 1.6 ± 0.5 | 1.5 ± 0.5 | 1.6 ± 0.6 | 0.408 |
| Serum haemoglobin at 12 months (g/dL) | 13.8 ± 1.9 | 13.9 ± 1.8* | 13.3 ± 1.7 | 0.056 |
| Serum albumin at 12 months (g/dL) | 4.7 ± 0.3 | 4.7 ± 0.3 | 4.7 ± 0.2 | 0.458 |
| Treatment with ARAs at 12 months (no/yes) | 66/9 | 137/24 | 75/20 | 0.241 |
| Treatment with ACEIs at 12 months (no/yes) | 74/1 | 152/9 | 85/10 | 0.042 |
| Treatment with statins at 12 months (no/yes | 54/21 | 105/56 | 58/37 | 0.326 |
| Treatment with vitamin D at 12 months (no/yes) | 40/35 | 100/61 | 70/25 | 0.021 |
| Length of follow-up (months) | 101 ± 28**,++ | 83 ± 31** | 72 ± 30 | 0.000 |
| Treatment with nutritional vitamin D (no/yes) | 59/16 | 110/51 | 58/37 | 0.049 |
ACEI, angiotensin-converting enzyme inhibitors; ARA, angiotensin receptor antagonist; TRP, tubular reabsorption of phosphate.
*P < 0.05 versus deficiency.
**P < 0.01 versus deficiency.
+P < 0.05 versus insufficiency.
++P < 0.01 versus insufficiency.
During the follow-up, 80 recipients presented at least one new cardiovascular event, and the cumulative incidence was 34.7% at 10 years. The total cardiovascular diseases included 27 patients with ischaemic heart disease, 25 with congestive heart failure, 18 with arrhythmia, 11 with cerebrovascular disease and 19 with peripheral vascular disease. A total of 14 patients presented the first cardiovascular event in the first year. The cumulative incidence of cardiovascular disease was similar in the three groups of patients at 5 and 8 years (Figure1), but it was 29.3% for normal, 31.6% for insufficiency and increased to 51.9% for deficiency at 10 years (P = 0.216). Despite the important differences in the cumulative incidence of cardiovascular disease between normal, insufficiency and deficiency at 10 years, they did not reach statistical significance probably due to the small number of recipients with deficiency at 10-year follow-up. Cox univariate analysis showed that cardiovascular events were associated with age at transplant, cardiovascular disease before transplant, serum creatinine at 12 months, serum haemoglobin at 12 months and serum albumin at 12 months. There was no association between cardiovascular disease and vitamin D levels or vitamin D status in the Cox univariate analysis. The variables remaining in the multivariate analysis were age at transplant (HR = 1.06, 95% CI 1.04–1.09, P = 0.000), cardiovascular disease before transplant (HR = 2.41, 95% CI 1.06–43.92, P = 0.000) and serum creatinine at 3 months (HR = 1.59, 95% CI 1.06–2.39, P = 0.025). There were no statistical differences in the percentage of patients with or without cardiovascular disease treated with nutritional vitamin D (23.7% versus 33.8, P = 0.119). When patients with a cardiovascular event during the first year were censored, the vitamin D levels and vitamin D status were not associated with cardiovascular disease (Cox analysis). Thirty patients died during the follow-up. The causes of death were cardiovascular in 10 cases (33.3%), infection in 9 cases (30.0%), malignancies in 7 cases (23.3%) and others in 4 cases (13.3%). Patient mortality was associated with age of the recipient, male gender, months on dialysis and inversely with serum hemoglobin at 12 months.
Fig. 1.
Cardiovascular disease-free survival according to the mean of 25(OH)D levels during the first year (P = 0.216). Normal (-), insufficiency (–), deficiency (…).
Fig. 1.
Cardiovascular disease-free survival according to the mean of 25(OH)D levels during the first year (P = 0.216). Normal (-), insufficiency (–), deficiency (…).
In addition, 53 recipients presented at least one malignancy, and the cumulative incidence at 10 years was 21.1%. There were 33 patients with non-melanoma skin malignancies and 20 with non-skin malignancies. The sites of non-skin malignancies were five prostate, three kidney and urinary tract, two colon, two lung, two lymphoma, two breast, one pancreas, one tongue, one metastatic melanoma and 1 biliary duct. One patient had skin and non-skin malignancies (bladder). No differences in the cumulative incidence of cancer at 10 years were observed in patients with low levels of vitamin D (Figure2). The cumulative incidence at 10 years was 21.3% for normal, 22.7% for insufficiency and 16.7% for deficiency (P = 0.818). Malignancies were associated with age at transplant (HR = 1.06, 95% CI 1.04–1.09, P = 0.000) and male gender (HR = 2.00, 95% CI 1.02–3.44, P = 0.029) in the multivariate analysis. As in the case of cardiovascular diseases, there were no statistical differences in the percentage of patients with or without malignancies treated with nutritional vitamin D (33.9% versus 30.9; P = 0.784) (Figure2).
Fig. 2.
Malignancy-free survival according to the mean of 25(OH)D levels during the first year (P = 0.818). Normal (-), insufficiency (–), deficiency (…).
Fig. 2.
Malignancy-free survival according to the mean of 25(OH)D levels during the first year (P = 0.818). Normal (-), insufficiency (–), deficiency (…).
Discussion
This is the first study in the English medical literature in which the possible association between post-transplant levels of vitamin D and cardiovascular diseases has been investigated. We did not find any association of the vitamin D levels measured during the first year after transplantation with cardiovascular diseases and recipient mortality. Several cross-sectional and prospective studies have confirmed that the low levels of vitamin D resulted in a higher risk of myocardial infarction, stroke and congestive heart failure as well as with all-cause and cardiovascular mortality in the general population [5, 16, 17]. A meta-analysis suggests a nonlinear effect of circulating calcidiol on mortality, with an increased risk at low and high concentrations [18]. The low levels of vitamin D were also a predictor of death in patients with stage 2–5 chronic kidney disease in some studies [9, 19] but not in others [8]. The association between cardiovascular diseases and mortality and low levels of vitamin D could be due to the effects of vitamin D on traditional or nontraditional cardiovascular risk factors as well as due to direct effects on cardiac or vascular cells [4, 20]. Alternatively, low vitamin D levels could be the consequence of underlying diseases or high-risk conditions which cause vitamin D deficiency. Cardiovascular risk factors such as body weight, blood pressure, serum haemoglobin, graft function and treatment with statins showed no or little differences between the three categories of vitamin D status in our patients. Ours findings were in agreement with those reported by Lee et al. [21]. They have investigated the effects of vitamin D status on cardiovascular parameters in 95 renal transplant recipients: arterial stiffness, endothelial dysfunction and carotid intima-media thickness were not different between patients with normal or vitamin D insufficiency. These results are different from those reported in the general population and in chronic kidney disease patients. Data from the NHANES III, which is a national survey designed to estimate the prevalence of common chronic conditions and associated risk factors for disease control and prevention, showed that serum 25(OH)D levels were associated with important cardiovascular disease risk factors (obesity, hypertension and diabetes) in US adults [4]. Furthermore, in patients with chronic kidney disease, groups with lower vitamin D levels showed an increased cardiovascular risk profile [8].
We observed a 21.1% cumulative incidence of malignancies at 10 years and no relationship in the univariate and multivariate analyses was found between vitamin D levels after transplantation and cancer. In prospective case–control studies in the general population, patients with the highest levels of vitamin D have a reduced risk of some kinds of cancer such as colon, breast, prostate and ovary. Moreover, treatment with vitamin D supplements resulted in a decreased risk of cancer. In a 4-year double-blind randomized placebo-control trial including 1180 postmenopausal women, there was a reduction in the risk of cancer in the group receiving calcium and vitamin D supplements [22]. However, a recent meta-analysis, in which 19 trials and 28 observational studies were systematically reviewed, concluded that the evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer [23]. There is only one study in renal transplant recipients in which the relationship between the vitamin D status and cancer was investigated. Doucloux et al. [15] evaluated the predictive value of pre- and post-transplant serum levels of vitamin D for the development of cancer in 363 patients. Pre-transplant vitamin D was a risk factor in the multivariate analysis and when it was replaced by 12-month post-transplant vitamin D in the model, it still remained a significant risk for cancer. Our study did not confirm these findings, the number of patients and demographic characteristics were quite similar in both the studies but the levels of vitamin D were lower than those observed in our patients at 12 months after transplant. Furthermore, our patients were followed for a longer period of time, 5 versus 10 years.
The prevalence of vitamin D deficiency/insufficiency in our recipients was lower than that reported in cross-sectional studies from the Northern European countries [10, 11, 15] and the findings are consistent with a higher sun exposure. As in other previous studies, vitamin D deficiency was associated with higher levels of iPTH and there were no differences in serum calcium and 1,25OHD levels [10, 11]. Due to the lower levels of vitamin D being associated with various diseases and mortality, the Kidney Disease: Improving Global Outcomes clinical practice guidelines recommend correction of vitamin D deficiency and insufficiency using similar strategies in renal transplant patients as in the general population [24]. In the general population, treatment with nutritional vitamin D compounds such as ergocalciferol and cholecalciferol in variable doses (300– 2000 IU/day) seems to decrease total mortality for any cause [25]. However, in patients with chronic renal failure, the administration of nutritional vitamin D compounds increases 25(OH)D and 1,25(OH)D levels and reduces PTH levels. But, there are no data showing that the repletion of vitamin D to a specific 25(OH)D level reduces mortality or other complications [26]. Moreover, the safe concentrations of vitamin D to be reached or whether similar vitamin levels prevent cardiovascular diseases and cancer are not known. Some authors suggest that the relationship between vitamin D levels and cancer can vary across different populations and for different types of cancer [23]. We have treated 104 recipients with cholecalciferol for at least 6 months, but as the treatment was started at different lengths of follow-up and without uniform criteria we cannot evaluate its utility.
The present study has several weaknesses. The number of patients studied and the number of complications, cardiovascular diseases and malignancies are small. Due to this, our findings cannot be considered as definitive. The strength of our results lays in the fact that the data of the patients were systematically collected: the pre-transplant and transplant data at the time of transplantation, the biochemical parameters at each clinical visit and the cardiovascular events and malignancies at the time of diagnosis.
In conclusion, our data suggest no association between the low levels of vitamin D and the incidence of cardiovascular diseases and cancer. However, due to the paramount importance for decreasing morbidity and mortality, it should be firmly established whether vitamin D deficiency or insufficiency is a risk factor for cardiovascular disease and cancer, as well as the strategies required to achieve adequate vitamin D levels in a population such as renal transplant recipients with a high risk for both complications.
Acknowledgements
We thank Mary Harper for her help in preparing the English version of the manuscript.
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