Endothelial Dysfunction in Renal Transplant Recipients: Role of Vitamin D and Fibroblast Growth Factor-23 T. Yildirim*, R. Yilmaz, M. Altindal, E. Turkmen, M. Arici, B. Altun, and Y. Erdem Hacettepe University Medical Faculty Nephrology Department, Ankara, Turkey
ABSTRACT Background. Endothelial dysfunction can be detected at early stages of chronic kidney disease. Although endothelial functions improve after successful renal transplantation, renal transplant recipients have still worse endothelial functions compared to healthy subjects. Vitamin D deficiency and high fibroblast growth factor23 (FGF-23) levels may have a role on endothelial dysfunction in chronic kidney disease patients. The aim of this study is to investigate the association between endothelial functions, vitamin D, and FGF-23 levels in renal transplant recipients. Methods. One hundred nine renal transplant recipients (71 male, 38 female) underwent brachial flow-mediated dilatation (FMD), serum 25-OH vitamin D, and FGF-23 level measurements. Vitamin D and FGF-23 levels were compared between patients with normal and abnormal endothelial functions. Correlations between FMD, vitamin D, and FGF-23 were also investigated. Results. Endothelial functions were abnormal in 72.5% of the patients. Prevalence of vitamin D deficiency was 80.7%. Vitamin D levels were significantly lower in patients with endothelial dysfunction compared to patients with normal endothelial functions (12.6 6.6 mg/L vs 17.3 10.0 mg/L respectively, P ¼ .02). FGF-23 levels were not different between the two groups. 25-OH vitamin D levels had a significant positive correlation with amount of FMD (r ¼ 0.218 and P ¼ .02) and were an independent predictor of FMD after adjusting for potential confounding factors including age, transplantation duration, body mass index, mean blood pressure, glomerular filtration rate, proteinuria, hemoglobin, and FGF-23 in multivariate regression analysis (beta ¼ 0.194, P ¼ .04). FGF-23 levels were not predictive of FMD in this model (beta: 0.125, P ¼ .197) Conclusion. Vitamin D deficiency is associated with endothelial dysfunction in renal transplant recipients. Further clinical and experimental studies are necessary to define a causal relationship between the parameters, discover the potential mechanisms, and observe the effect of vitamin D replacement on endothelial functions in renal transplant recipients.
C
ARDIOVASCULAR diseases are the most common cause of mortality in patients with chronic kidney disease (CKD) [1]. Endothelial dysfunction, which plays a pathogenic role in the atherosclerotic process, can be detected at early stages of CKD and contributes to a high cardiovascular mortality rate in this population [2]. Although endothelial functions improve after successful renal transplantation [3,4], renal transplant recipients have still worse endothelial functions compared to healthy subjects [5e7]. ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 343e347 (2015)
This may be related to pretransplantation prevalent traditional and nontraditional cardiovascular risk factors that can be aggravated by the effects of immunosuppressive drugs. Recent studies showed that vitamin D deficiency, which is very prevalent in the transplantation population [8,9], may *Address correspondence to Tolga Yildirim, MD, Hacettepe Üniversitesi Tıp Fakültesi Hastanesi Nefroloji Bilim Dali Sıhhiye, Ankara, Turkey. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.12.023
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have a role in endothelial dysfunction in patients with CKD besides its well-known effects on calcium and phosphorus metabolism [10,11]. On the other hand, fibroblast growth factor23 (FGF-23) is a marker that is closely related to vitamin D and is another regulator of phosphorus metabolism. It reduces vitamin D synthesis by inhibiting 1-alpha hydroxylase activity, which thereby increases the parathyroid hormone (PTH) and has a phosphaturic effect [12]. FGF-23 levels markedly increase in CKD patients and decrease after 1 year of renal transplantation if renal functions are normal [13]. High FGF-23 levels are also strongly associated with endothelial dysfunction and cardiovascular events in CKD patients [14,15]. The relationship of vitamin D and FGF-23 with endothelial functions was not extensively investigated in renal transplant recipients. In the most remarkable study on this subject, it was recently shown that endothelial functions improve after renal transplantation, which is in parallel to a decrease in FGF-23 levels and an increase in 25-OHvitamin D levels [16]. The aim of the present study was to investigate the association between endothelial dysfunction, vitamin D, and FGF-23 in renal transplant recipients, including patients with excellent graft function and also patients with low glomerular filtration rate (GFR). METHODS Study Population Adult renal transplant recipients regularly followed in Hacettepe University Medical Faculty Nephrology Department were included in this study. Patients
ABSTRACT Background. Endothelial dysfunction can be detected at early stages of chronic kidney disease. Although endothelial functions improve after successful renal transplantation, renal transplant recipients have still worse endothelial functions compared to healthy subjects. Vitamin D deficiency and high fibroblast growth factor23 (FGF-23) levels may have a role on endothelial dysfunction in chronic kidney disease patients. The aim of this study is to investigate the association between endothelial functions, vitamin D, and FGF-23 levels in renal transplant recipients. Methods. One hundred nine renal transplant recipients (71 male, 38 female) underwent brachial flow-mediated dilatation (FMD), serum 25-OH vitamin D, and FGF-23 level measurements. Vitamin D and FGF-23 levels were compared between patients with normal and abnormal endothelial functions. Correlations between FMD, vitamin D, and FGF-23 were also investigated. Results. Endothelial functions were abnormal in 72.5% of the patients. Prevalence of vitamin D deficiency was 80.7%. Vitamin D levels were significantly lower in patients with endothelial dysfunction compared to patients with normal endothelial functions (12.6 6.6 mg/L vs 17.3 10.0 mg/L respectively, P ¼ .02). FGF-23 levels were not different between the two groups. 25-OH vitamin D levels had a significant positive correlation with amount of FMD (r ¼ 0.218 and P ¼ .02) and were an independent predictor of FMD after adjusting for potential confounding factors including age, transplantation duration, body mass index, mean blood pressure, glomerular filtration rate, proteinuria, hemoglobin, and FGF-23 in multivariate regression analysis (beta ¼ 0.194, P ¼ .04). FGF-23 levels were not predictive of FMD in this model (beta: 0.125, P ¼ .197) Conclusion. Vitamin D deficiency is associated with endothelial dysfunction in renal transplant recipients. Further clinical and experimental studies are necessary to define a causal relationship between the parameters, discover the potential mechanisms, and observe the effect of vitamin D replacement on endothelial functions in renal transplant recipients.
C
ARDIOVASCULAR diseases are the most common cause of mortality in patients with chronic kidney disease (CKD) [1]. Endothelial dysfunction, which plays a pathogenic role in the atherosclerotic process, can be detected at early stages of CKD and contributes to a high cardiovascular mortality rate in this population [2]. Although endothelial functions improve after successful renal transplantation [3,4], renal transplant recipients have still worse endothelial functions compared to healthy subjects [5e7]. ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 343e347 (2015)
This may be related to pretransplantation prevalent traditional and nontraditional cardiovascular risk factors that can be aggravated by the effects of immunosuppressive drugs. Recent studies showed that vitamin D deficiency, which is very prevalent in the transplantation population [8,9], may *Address correspondence to Tolga Yildirim, MD, Hacettepe Üniversitesi Tıp Fakültesi Hastanesi Nefroloji Bilim Dali Sıhhiye, Ankara, Turkey. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.12.023
343
344
have a role in endothelial dysfunction in patients with CKD besides its well-known effects on calcium and phosphorus metabolism [10,11]. On the other hand, fibroblast growth factor23 (FGF-23) is a marker that is closely related to vitamin D and is another regulator of phosphorus metabolism. It reduces vitamin D synthesis by inhibiting 1-alpha hydroxylase activity, which thereby increases the parathyroid hormone (PTH) and has a phosphaturic effect [12]. FGF-23 levels markedly increase in CKD patients and decrease after 1 year of renal transplantation if renal functions are normal [13]. High FGF-23 levels are also strongly associated with endothelial dysfunction and cardiovascular events in CKD patients [14,15]. The relationship of vitamin D and FGF-23 with endothelial functions was not extensively investigated in renal transplant recipients. In the most remarkable study on this subject, it was recently shown that endothelial functions improve after renal transplantation, which is in parallel to a decrease in FGF-23 levels and an increase in 25-OHvitamin D levels [16]. The aim of the present study was to investigate the association between endothelial dysfunction, vitamin D, and FGF-23 in renal transplant recipients, including patients with excellent graft function and also patients with low glomerular filtration rate (GFR). METHODS Study Population Adult renal transplant recipients regularly followed in Hacettepe University Medical Faculty Nephrology Department were included in this study. Patients
