Abstract and Introduction
Abstract
Objective: To investigate the association between 25-hydroxyvitamin D [25(OH)D] levels prior to liver transplantation (LT) and the development of acute cellular rejection (ACR) within the first year post LT.
Methods: This retrospective study included 275 consecutive LTs performed in 262 patients at Mayo Clinic in Jacksonville, Florida over 13 months. A total of 149 patients met the inclusion criteria. The correlations between 25(OH)D levels and the development, severity, and number of biopsy-proven ACR episodes were assessed.
Results: The prevalence of 25(OH)D levels <30 ng/mL was 92%. No association was found between pre LT 25(OH)D levels and the diagnosis of ACR (P = .61). Mean ± SD pre LT 25(OH)D levels were 16.1 ± 6.8 ng/mL for 48 subjects with no rejection, 16.1 ± 8.2 ng/mL for those with a mild first episode of ACR (n = 58), and 18.4 ± 12.4 ng/mL for those who experienced a moderate/severe first ACR (n = 39). However, in a subgroup analysis of patients with 25(OH)D levels <30 ng/mL, there was a statistically significant negative correlation (P = .0252) between 25(OH) D level and the ACR rate.
Conclusion: Vitamin D insufficiency and deficiency prior to LT was prevalent in our cohort. There was no statistically significant association between low 25(OH)D levels and the diagnosis or severity of ACR or the number of rejection episodes within the first year post LT. However, there was a negative correlation between 25(OH)D levels below 30 ng/mL and the rate of ACR within 1 year post LT
Introduction
In liver transplantation (LT), acute cellular rejection (ACR) may occur in up to 80% of liver allografts during the first postoperative year. Risk factors that have been independently associated with an increased risk of developing ACR include lower recipient age, acute kidney injury, elevated preoperative liver transaminases, older donor age, and certain types of liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and chronic hepatitis C virus infection.
After LT, ACR is triggered primarily by direct alloantigenic stimulation of recipient donor dendritic cells and Kupffer cells residing within portal tracts and hepatic sinusoids, respectively. Subsequently, recipient T lymphocytes form clusters with the donor dendritic cells; the recipient T cells undergo activation, secrete cytokines, and begin to divide. There is a predominance of CD8+ lymphocytes with an enhanced production of interleukin (IL)-2 early in ACR, whereas IL-5 appears later in the process. Other chemokines, such as vascular cell adhesion molecule (VCAM)-1 and macrophage inflammatory protein (MIP)-1α, enhance leukocyte migration into the liver and modulate various phases of the immune response.
There is a growing body of literature in organ transplantation and autoimmune disease that supports a role for vitamin D in immune regulation through effects on cytokine production and secretion. In vitro, 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D, inhibited T cell proliferation, primarily through inhibition of IL-2 production. Vitamin D receptor (VDR) ligands were shown to induce dendritic cells to acquire tolerogenic properties favoring the induction of regulatory T cells, which mediate transplantation tolerance (10–13). Adorini et al.found that short treatment with 1,25(OH)2D3 induced tolerance to fully mismatched mouse islet allografts that were stable to challenge with donor-type spleen cells and allowed acceptance of donor-type vascularized heart grafts. When 1,25(OH)2D3 was given as monotherapy, it significantly prolonged allograft survival and preserved renal function in a rat model of chronic allograft nephropathy, the leading cause of late allograft loss in kidney transplantation. Furthermore, the vitamin D analog MC1288 given in combination with a suboptimal dose of cyclosporine effectively reduced the number of acute rejections and the clinical and histologic signs of chronic rejection in rats after heterotopic renal transplantation. Vitamin D has also been shown to prevent Th1-mediated autoimmune diseases in animal models for systemic lupus erythematosus and experimental allergic encephalomyelitis, suggesting that 1,25(OH)2D3 may also affect T cell development. In addition, it may play a role in liver regeneration. Ethier et al found that vitamin D depletion was accompanied by hyporesponsiveness when liver DNA synthesis was challenged by a dietary protocol known to prime the liver for growth-inducing stimuli in an animal model.