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Clinical Chemistry 53: 1841-1846, 2007. First published August 23, 2007; 10.1373/clinchem.2006.084699
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(Clinical Chemistry. 2007;53:1841-1846.)
© 2007 American Association for Clinical Chemistry, Inc.

Nutrition

Decreased Serum Retinol Is Associated with Increased Mortality in Renal Transplant Recipients

Grainne M. Connolly1,a, Ronan Cunningham2, A. Peter Maxwell2 and Ian S. Young1

1 Department of Clinical Biochemistry, Royal Victoria Hospital, Belfast, Northern Ireland.
2 Department of Nephrology, Belfast City Hospital, Belfast, Northern Ireland.

aAddress correspondence to this author at: Department of Clinical Biochemistry, Royal Victoria Hospital, Grosvenor Rd., Belfast BT12 6BA, Northern Ireland. Fax 044-2890234029; e-mail Grainne.Connolly{at}bll.n-i.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Vitamin A plays a central role in epithelial integrity and immune function. Given the risk of infection after transplantation, adequate vitamin A concentrations may be important in patients with a transplant. We assessed whether there was an association between retinol concentration and all-cause mortality in renal transplant recipients.

Methods: We recruited 379 asymptomatic renal transplant recipients between June 2000 and December 2002. We measured serum retinol at baseline and collected prospective follow-up data at a median of 1739 days.

Results: Retinol was significantly decreased in those renal transplant recipients who had died at follow-up compared with those who were still alive at follow-up. Kaplan–Meier analysis showed that retinol concentration was a significant predictor of mortality. In multivariate Cox regression analysis, decreased retinol concentration remained a statistically significant predictor of all-cause mortality after adjustment for traditional cardiovascular risk factors, high-sensitivity C-reactive protein, and estimated glomerular filtration rate.

Conclusions: Serum retinol concentration is a significant independent predictor of all-cause mortality in renal transplantation patients. Higher retinol concentration might impart a survival advantage via an antiinflammatory or anti-infective mechanism.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The success of renal transplantation depends on a compromise between achieving sufficient immunosuppression to avoid rejection and maintaining a sufficient level of immune competence to protect the recipient from infection or development of cancer. Cardiovascular disease, infection, and cancer are the leading causes of morbidity and mortality after renal transplantation (1)(2)(3)(4).

Because these diseases are all associated with oxidative stress and inflammation, dietary antioxidants such as vitamin E, ß-carotene, and the carotenoids may protect against the main causes of morbidity and mortality in renal transplant recipients. Vitamin A is also a weak antioxidant, but it also plays a central role in epithelial integrity, immune function, and retinal physiology (5). Deficiency of vitamin A has been shown to impair innate immunity by impeding normal regeneration of mucosal barriers damaged by infection and by diminishing the function of neutrophils, macrophages, and natural killer cells(6). Children with mild vitamin A deficiency are at increased risk of infections and death(7)(8), and several large randomized control trials conducted in developing countries around the world have shown that vitamin A supplementation reduces child mortality by approximately one-third(7)(9)(10)(11)(12).

Vitamin A deficiency or marginal vitamin A status is often exacerbated by infectious disease, and conversely, poor vitamin A status may prolong or exacerbate the course of illness (12). Given the risk of infection following transplantation, adequate vitamin A levels may be of particular importance in patients who receive a renal transplant. Therefore, in this study, we assessed for the 1st time whether there is an association between the serum concentration of retinol or other dietary antioxidants and mortality in renal transplant recipients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients and methods
We studied a convenience sample of 379 patients from the renal transplant clinics at Belfast City Hospital and Antrim Area Hospital in Northern Ireland between June 2000 and December 2002. Ethics permission was obtained from the Queen’s University Belfast Research Ethics Committee, and fully informed written consent was obtained from each participant before enrollment. Patients were eligible for entry if they had a functioning renal transplant present for at least 3 months. Although no formal exclusion criteria were imposed, patients who were unwell or had signs of sepsis at initial assessment were deferred until a subsequent reassessment.

The 379 renal transplant recipients enrolled in this study represented 71.9% of patients with a functioning renal transplant in Northern Ireland at the end of 2002. The remaining patients with a functioning renal transplant not enrolled in this study represent patients who attended geographically more distant transplantation clinics at other hospitals in the Northern Ireland region.

From each participant, we obtained a fasting blood sample in a standard serum tube. Specimens were centrifuged at 4 °C, 800g for 10 min, separated into aliquots of serum, and frozen at –70 °C until biochemical analysis. At enrollment, patients completed a questionnaire with the assistance of a research nurse. This set of questions recorded age, sex, smoking history, presence of diabetes, and previous history of cardiovascular disease. The use of vitamin supplements was noted for each patient, but dietary intake and clinical assessment for nutritional deficiency were not assessed. Each patient’s weight and height were recorded using electronic scales (Seca 766) and a Seca 220 measuring rod. Blood pressure was recorded as the mean of the last 3 blood pressure measurements (Disytest sphygmomanometer; Welch-Allyn) recorded at the renal transplant clinic.

We measured serum concentrations of retinol, vitamin E ({alpha}-tocopherol and {gamma}-tocopherol), {alpha}-carotene, ß-carotene, lutein, ß-cryptoxanthine, and zeaxanthin by use of a modified version of the HPLC assay described by Craft (13).

An aliquot of serum or calibrator was pipetted into a labeled glass tube, and we added ethanol containing 0.25 g/L butylated hydroxytoluene, the internal standard {alpha}-tocopherol acetate, and heptane to each tube. Tubes were vortex-mixed vigorously and centrifuged. We retained the resulting heptane layer, and transferred it to an identically labeled glass tube, and performed a 2nd heptane extraction. The combined heptane layers were evaporated to dryness in a centrifugal evaporator under vacuum. We added 150 µL methanol to the calibrator and sample tubes, which were then vortex-mixed, and the solution was assayed using a Thermo Separation Products automated HPLC system with a diode array detector. We used Standard Reference Material 968c to assign a value to a serum pool, which was stored as aliquots at –80 °C and used as a secondary calibrator in each sample run. The reference interval for retinol, based on measurement of retinol using the methodology described in this report in 611 community living adults from the local population, was 0.77 to 4.81 µmol/L.

Because the plasma concentration of {alpha}-tocopherol varies with the amount of concurrent lipids, {alpha}-tocopherol concentration was adjusted for cholesterol: {alpha}-tocopherol ratio = {alpha}-tocopherol:total cholesterol (14). Analysis was performed within 3 years of sample collection. Retinol binding protein was not measured. We used VITROS slides and a VITROS 700 System (Ortho Clinical Diagnostics) to measure total cholesterol, HDL cholesterol, and serum creatinine.

We calculated estimated glomerular filtration rate (GFR) 1 for all patients using the Modification of Diet in Renal Disease Study equation (15): estimated GFR (mL/min/1.73 m2) = 186 x (serum creatinine/89)–1.154 x Age–0.203 x (0.742 if female) x (1.21 if African American). We used an immunoturbidimetric assay (Randox) to measure high-sensitivity C-reactive protein (hsCRP). Samples were analyzed using a Roche Cobas Fara (Roche).

prospective data collection
We completed the collection of prospective follow-up data in June 2006 at a mean of 1626 days and a median of 1739 days after enrollment. Mortality information, including date of death where applicable, was available for all participants. We obtained this information from the mortality data recorded on the Regional Nephrology Database at Belfast City Hospital and via letter and telephone contact with the primary care physicians of patients enrolled in the study.

statistical analysis
Data analysis was performed using SPSS (version 12.0). Kolmogorov-Smirnoff analysis was used to test for nongaussian distribution. Logarithmic transformation was performed for variables that did not conform to a gaussian distribution. For gaussian-distributed variables, data are expressed as arithmetic mean (SD). For those variables that were not gaussian distributed, data are expressed as median (interquartile range).

We assessed correlations between continuous variables using Pearson correlation coefficients for gaussian-distributed variables. We assessed the significance of differences between 2 groups using independent samples t-test for gaussian-distributed variables and Mann–Whitney U-test for non–gaussian-distributed variables. A 2-tailed P value <0.05 was considered to be statistically significant. Variables were banded into thirds, and Kaplan–Meier analysis with log-rank test was used for univariate survival analysis. We used a Cox regression model for cumulative survival analysis and analyzed retinol as a continuous variable and as a categorical variable by banding into tertiles. Because risk equations based on traditional risk factors (sex, age, smoking, blood pressure, body mass index, total cholesterol, HDL cholesterol, and the presence of diabetes) are used worldwide as a predictor of cardiovascular disease and mortality, and because renal function, as measured by estimated GFR, is an established determinant of outcome in patients with chronic kidney disease, we chose these variables as covariates to be included in the Cox regression model. In addition, because retinol is known to decrease as part of the acute-phase response, we included hsCRP as a covariate in the Cox regression model to reduce confounding from subclinical inflammation.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The biological characteristics of the participants at enrollment are shown in Table 1 : 243 participants (64%) were male, 72 (19%) were smokers, and 54 (14%) were diabetic. Serum retinol was <0.77 µmol/L in 7 renal transplant recipients. No participants were receiving vitamin or provitamin A supplements.


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  		Table 1. Biological characteristics of the study participants at enrollment.1

To achieve a gaussian distribution, retinol concentration was logarithmically transformed. There was no significant correlation between serum creatinine and retinol (r = 0.102, P = 0.052) or between estimated GFR and retinol (r = –0.089, P = 0.092). Retinol correlated negatively with hsCRP (r = –0.124, P = 0.019).

At follow-up, 317 participants were alive and 62 had died, 24 of a cardiovascular cause and 29 of a noncardiovascular cause; for 9 participants, cause of death could not be established. Patients were divided into 2 groups based on survival at follow-up. As shown in Table 2 , those who had died were older, more likely to be diabetic, had lower estimated GFR, had lower retinol and zeaxanthin concentrations, and had higher hsCRP than those who were alive at follow-up. Interestingly, there were no significant differences in the concentrations of {alpha}- or {gamma}-tocopherol or the other carotenoids in those who had died vs those who were still alive at follow-up (Table 2 ). There was no significant difference in retinol concentration in those renal transplant recipients who had died of a cardiovascular cause compared to those who had died of a noncardiovascular cause [2.07 (1.35–2.64) and 1.94 (1.22–3.72) respectively, P = 0.669].


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  		Table 2. Biological and biochemical differences in those who had died at follow-up compared with those who were still alive.1

In Kaplan–Meier analysis, retinol concentration divided into thirds was significantly associated with mortality (P = 0.0489) (Table 3 , Fig. 1 ). In contrast, {alpha}- and {gamma}-tocopherol, zeaxanthin, and the other carotenoids were not significantly associated with mortality (Table 3 ).


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  		Table 3. Kaplan–Meier analysis for vitamin A, vitamin E, vitamin E adjusted for cholesterol, and carotenoids banded into thirds.


Figure 1
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  		Figure 1. Kaplan–Meier survival curve for renal transplant recipients, stratified by retinol concentration (P = 0.0489).

After log transformation to achieve a gaussian distribution, retinol remained a statistically significant predictor of mortality in univariate Cox regression analysis when treated as a continuous variable (Table 4 ).


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  		Table 4. Cox regression survival analysis for retinol treated as a continuous variable.

Renal function is an important determinant of outcome in patients with chronic kidney disease. As shown in Tables 4Up and 5 , retinol remained a significant predictor of all-cause mortality in the renal transplant recipients enrolled in this study after adjustment for estimated GFR.


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  		Table 5. Kaplan–Meier and Cox regression survival analysis for retinol banded into thirds.

Interestingly, as shown in Tables 4Up and 5Up , retinol treated as both a continuous and a categorical variable remained a significant predictor of mortality after adjustment for traditional cardiovascular risk factors (sex, age, smoking, blood pressure, body mass index, total cholesterol, HDL cholesterol, and the presence of diabetes), hsCRP, and estimated GFR.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Vitamin A is essential for a variety of biological processes, but an association between vitamin A concentrations and outcome in renal transplant recipients has not previously been reported. The results of this study are the 1st to demonstrate that low serum retinol concentration is significantly associated with all-cause mortality in patients with a renal transplant.

Interestingly, {alpha}-tocopherol, {gamma}-tocopherol, and the other carotenoids were not significantly associated with mortality in this group of renal transplant recipients. The survival advantage seen in patients with higher retinol concentrations therefore appears to be unique to retinol and suggests a mechanism specific to retinol. Given that vitamin A has weaker antioxidant properties than vitamin E or ß-carotene (16)(17), the biological mechanisms contributing to the improved survival in renal transplant recipients with higher retinol concentrations are unlikely to be related to the antioxidant effects of vitamin A.

In 1929, Mellanby and Green (18) described increased infections in vitamin A–deficient rats, and this finding led them to dub vitamin A an "anti-infective agent". In 1968, Scrimshaw et al.(19) summarized that "no nutritional deficiency is more consistently synergistic with infectious disease than that of vitamin A".

Vitamin A is important in maintaining the normal morphology and function of epithelial cells in many organs (20)(21), and squamous metaplasia with loss of ciliary and goblet cells occurs in the epithelial tissues of vitamin A–deficient animals and humans(22). Vitamin A is also an important regulator of monocytic differentiation and function(21)(23)(24)(25) and can influence the secretion by macrophages of key cytokines, including tumor necrosis factor-{alpha}, interleukin (IL)-1, IL-6, and IL-12. In addition, natural killer cells, the first line of defense against tumors and viral infections, are reduced during experimental vitamin A deficiency in animals(26).

Vitamin A deficiency therefore compromises the physical and biological integrity of epithelial tissue, which is the 1st barrier to infection, and once the epithelial barriers have been breached, the body’s specific response to infection is depressed.

The results of this study demonstrated that those renal transplant recipients who had died at follow-up were significantly older and more likely to have diabetes and lower estimated GFR than those who were still alive at follow-up. Age (27)(28)(29), diabetes(30)(31), renal function(28)(30), and CRP(32) have been reported to be associated with increased risk of mortality in other renal transplant populations. Interestingly, however, the results of this study demonstrated that in multivariate survival analysis after adjustment for these covariates, low retinol remained significantly associated with increased all-cause mortality.

The results of this study also demonstrated a significant negative correlation between retinol concentration and hsCRP. Retinol was significantly lower and hsCRP significantly higher in those renal transplant recipients who had died at follow-up compared with those who were still alive.

Serum retinol concentration decreases during inflammation (33), and because nutritional deficiency results in a similar decrease in retinol concentration, interpretation of serum retinol concentration can be difficult in patients with increases of acute-phase reactants. It is therefore important, when addressing retinol concentration, to monitor inflammatory status, because otherwise a misclassification of nutritional status may occur(34)(35). Measurement of hsCRP facilitates recognition of data-confounding by subclinical inflammation and allows discrimination between deficiency and inflammation as causes for decreased concentrations of retinol(36).

Because the leading causes for death in renal transplant recipients are cardiovascular disease, infection, and malignancy (1)(2)(3)(4), all of which are associated with an inflammatory response, adjustment for confounding from inflammation is of particular importance when assessing the significance of retinol as a predictor of mortality in patients with a renal transplant. In the renal transplant recipients enrolled in this study, retinol remained a significant predictor of all-cause mortality in multivariate survival analysis after adjustment for hsCRP. Therefore, although vitamin A concentrations are known to decrease as part of the acute-phase response, the results of this study show that the association between retinol and mortality persisted after adjustment for the presence of subclinical inflammation. Therefore we suggest that in patients with a renal transplant, higher retinol concentration may impart a survival advantage via an antiinflammatory or anti-infective mechanism.

Whatever the mechanisms, the results of this study are the 1st to demonstrate that retinol is independently associated with all-cause mortality in renal transplant recipients. We acknowledge that, given the small number of deaths during follow-up, a limitation of this study may be overfitting of the Cox regression model. It has been suggested that there should be at least 10 events (deaths) for each variable modeled multivariately in Cox regression analysis (37). However, the covariates included in the Cox regression model analyzed in this study were chosen for the reasons discussed above and chosen at the time of the study design, before any analysis of the dataset, and without knowledge of the number of events in the period of follow-up. Nevertheless, it would be important to investigate these findings in prospective follow-up studies of other independent renal transplant populations.

The results of this study suggest that a retinol concentration within the lower normal reference interval is associated with increased mortality in patients with a renal transplant. It may be that retinol, like CRP, has more than 1 reference interval for interpretation. CRP, for example, has a cardiovascular disease interval and an acute infection interval—a given CRP concentration may be within the interval to exclude an acute infection but be at a level associated with increased risk of cardiovascular disease. Similarly, vitamin A may have a reference interval to define deficient and toxic concentrations and another associated with increased risk of disease or mortality.

Because vitamin A supplementation has been shown to reduce mortality in children with mild vitamin A deficiency (12), if our observation of higher mortality in renal transplant recipients with low vitamin A concentrations is confirmed and is independent of an acute-phase reaction, then a randomized trial of vitamin A supplementation in patients with a renal transplant may be appropriate.


   Acknowledgments
 
Grant/funding support: G.M.C. and R.C. were supported by the Northern Ireland Kidney Research Fellowship Fund. This was the only source of funding and the authors declare no conflict of interest.

Financial disclosures: None declared.

Acknowledgments: We thank the renal transplant recipients who participated in this study, the research nurses for help with patient recruitment, Dr. Chris Patterson for his statistical advice, and Dr. Peter McNamee, Colin Craig, and the primary care physicians for their assistance in the collection of prospective data.


   Footnotes
 
1 Nonstandard abbreviations: GFR, glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein; IL, interleukin.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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