Treat the bones and get less rejection!

Abstract

Known since antiquity, rickets was a common disease until the beginning of the 20th century. It took many years and the collaborative effort of several laboratories to identify the compound present in cod liver oil responsible for the therapeutic effect against rickets. The vitamin D structure was finally described in 1936 by the German chemist Adolf Windaus (1876–1959). Since then, we have come to understand the synthesis of 1α,25(OH)2-vitamin D3 (calcitriol) and its mechanism of action through a nuclear receptor, VDR, to regulate calcium homeostasis and bone mineralization. VDR is expressed not only in intestinal cells and osteoblasts but also constitutively in monocytes and in activated macrophages, dendritic cells, natural killer cells, T and B cells, which suggests immunomodulatory functions for calcitriol. Calcitriol acts as an inhibitor of the adaptive immune system. It has inhibitory effects on macrophages and dendritic cells. Calcitriol enables dendritic cells with tolerogenic properties (1) and acts directly in Th cells to enhance the development of a Th2 phenotype (2). These features could be of benefit in the transplantation setting. In retrospective studies, the administration of calcitriol to kidney transplant recipients improved graft function, graft survival and decreased episodes of acute rejection (3–5). Similar results have been published for heart transplantation. Low post-operative calcitriol serum concentrations are independently associated with high 1-year mortality in cardiac transplant recipients (6). Patients receiving low-dose calcitriol after cardiac transplantation required substantially lower cumulative doses of cyclosporin for organ rejection without any detectable change in the episodes of rejection (7). What about liver transplantation and calcitriol? We investigated the effect of calcitriol as an immunosuppressive agent in an experimental model for liver transplantation (8). Calcitriol increased the survival of vascularized liver allografts in rats when compared with controls. Vitamin D reduced the concentration of interleukin (IL)-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity after transplantation was significantly lower in treated rats compared with vehicle-treated controls. In this issue of Liver International, Bitetto et al. (9) present a highly anticipated clinical study that investigates whether vitamin D has beneficial immune properties after liver transplantation. Based on a collection of 133 liver transplantation recipients, the authors report that a low pretransplant serum 25-OH vitamin D is independently associated with rejection episodes (Banff score ≥6) in the first 2 months following liver transplantation and that the introduction of vitamin D3 supplementation in the first month after liver transplantation is associated with a decreased risk for acute rejection (Banff score ≥3) in the following 3–8 months. These results are not surprising, but are important nonetheless. It is estimated that two-third of patients with cirrhosis and 96% of patients awaiting liver transplantation have low serum vitamin D levels (10) and the present study found optimal vitamin D levels (>30 ng/ml) in only 7.5% of the patients tested. Osteoporosis, which increases the risk of vertebral fractures, occurs in 12–55% of patients with cirrhosis (10). In the months following liver transplantation, further bone loss occurs in most liver recipients and exacerbates pre-existing osteopenia with a high incidence of fracturing (10). Patients listed for a liver transplantation should then receive vitamin D before and after transplantation. This supplementation is safe, well tolerated and appears to have additional non-negligible immune effects. Acute rejection is rarely a serious issue after liver transplantation today. Nevertheless, immunosuppressive drugs have side effects, which limit the long-term benefit of liver transplantation. Calcineurin inhibitors impair renal function and every large liver transplantation centre must provide dialysis for some of their transplant recipients and some even receive kidney transplantation. The hope that mTOR inhibitors could serve as renal protective immunosuppressors is vanishing. A retrospective, controlled study showed that the administration of sirolimus after orthotopic liver transplantation did not protect against renal dysfunction (11). Another case–control retrospective series suggested that the choice of sirolimus for liver transplant patients with chronic renal insufficiency is associated with the stabilization of renal function but conferred no additional benefit over low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of <30 ml/min (12). In this context, vitamin D as a calcineurin inhibitor sparing immunosuppressant in liver transplantation is an attractive option. The retrospective nature of the work of Bitetto is a disadvantage as are the arbitrarily chosen endpoints. It is imperative that prospective randomized studies be designed in the liver transplantation field to establish definitively the immunosuppressive role of vitamin D as it is already the case in the renal transplantation field (13). We should not miss the opportunity to treat the bones and get less rejection!