Transplantation-steroid-impaired glucose metabolism: a hope for improvement?

Glucocorticoids (also called ‘corticosteroids’ or just ‘steroids’) have been used as immunosuppressive agents in kidney transplantation since the early 1950s. Although there were some concerns regarding their efficacy at the very beginning [1], this view has changed rapidly, and these drugs have become the cornerstone of immunosuppression now for more than half a century. Steroids show their immunosuppressive effects by interrupting multiple steps in immune activation. They block T-cell and APC-derived cytokine expression; inhibit transcription of cytokine genes and, subsequently, decrease serum levels of IL-1, IL-2, IL-3, IL-6, TNF-α and IFN-γ. As a result, a broad range of specific immune responses mediated by T cells and B cells, such as antigen presentation, cytokine production and proliferation of lymphocytes are inhibited. Steroids also show potent suppressive effects on the effector functions of phagocytes and cause lymphopenia [2]. Unlike several other immuno suppressants, steroids can be used in both induction and maintenance regimens; they are useful not only in preventing, but also treating on-going rejection episodes and, most importantly, they are very cheap. Considering all these advantages, steroids (which, in transplantation practice, are almost always prednisone or its metabolite prednisolone) have been widely used for many years. As a matter of fact, in the kidney disease: improving global outcomes transplant guideline, it has been underlined that ‘prednisone should be continued, rather than withdrawn, if it is being used beyond the first week after transplantation’ [3]. On the other hand, steroids may result in serious side effects in many organs and systems as well, which include, but are not limited to, gastrointestinal problems, infections, dyslipidaemia, weight gain and cushingoid appearance of the body, growth impairment in children, osteoporosis, osteonecrosis and impairment in glucose metabolism [4]. Glucocorticoids increase peripheral insulin resistance and hepatic glucose production, and also inhibit pancreatic insulin secretion [4]. Subsequent derangements in glucose metabolism may adversely affect not only the graft, but also patient survival in both previously diabetic and non-diabetic transplant recipients. ‘Previously, diabetic patients’ are more frequently complicated by delayed graft function [5], which is a risk factor for allograft failure and mortality in the post-transplant period [6]. These patients may also lose their grafts because of recurrence of diabetic lesions in the allograft, which is directly related to the extent of glycaemic control [7]. Interestingly, impaired glucose metabolism has also been associated with increased risk of rejections because hyperglycaemia may stimulate inflammation and immunity via exaggerated inflammatory response to ischaemia/ reperfusion, enhanced expression of allo-antigens and co-stimulatory molecules [8]. As a result, diabetic patients suffer from worse allograft [9] and patient [10] survivals when compared with their non-diabetic counterparts. ‘Post-transplant diabetes’ [or new onset diabetes after transplantation (NODAT)] is a serious problem in previously nondiabetic transplant recipients. Cumulative incidence of NODAT may reach even up to 30% by the end of the second year [11]. These patients suffer from increased risk of graft failure, cardiovascular problems and mortality when compared with the transplant recipients with normal glucose metabolism [12]. Prognostic significance of impaired glucose metabolism in ‘non-diabetic transplant recipients’ is not known. Communitybased studies have shown that minor increments in serum HbA1c levels predict cardiovascular disease and mortality in adults, unrelated to fasting glucose levels [13], which underlines the detrimental effects of impaired glucose metabolism, even if it is in the sub-diabetic range. Similar findings have also been noted in chronic peritoneal dialysis patients without diabetes mellitus [14]. Therefore, it is very probable that such associations exist in non-diabetic transplant recipients as well, who already have several risks for cardiovascular disease development. Interestingly, similar to the diabetic cases, increased glycaemia levels have been reported to be associated with more frequent rejection episodes in non-diabetic transplant patients as well [15]. IN F O C U S