Rat cytomegalovirus infection in kidney allograft recipients is associated with increased expression of intracellular adhesion molecule-1 vascular adhesion molecule-1, and their ligands leukocyte function antigen-1 and very late antigen-4 in the graft.

BACKGROUND: Cytomegalovirus (CMV) infection is suggested to be a risk factor for chronic rejection. We have recently shown that rat CMV (RCMV) increases the inflammatory response and accelerates chronic rejection in a model of rat kidney allograft. In this study, the early inflammatory response and time-related expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and their ligands, leukocyte function antigen-1 (LFA-1) and very late antigen-4 (VLA-4), in the grafts were investigated in RCMV-infected rats and compared to noninfected rats developing chronic rejection. METHODS: Transplantations were performed in a rat strain combination of DA (RT1a)->BN (RT1n) receiving triple drug immunosuppression. One group of rats was infected with RCMV, and the other was left uninfected. The grafts were harvested at different time points after transplantation. The adhesion molecules, their ligands and activation markers, MHC class II antigens and interleukin-2-receptors (IL-2-R), were demonstrated by monoclonal antibodies and immunoperoxidase staining from frozen sections of the grafts. Graft histology was evaluated according to the Banff criteria. RESULTS: RCMV caused a significant, prolonged increase of VCAM-1 and ICAM-1 expression in the vascular endothelium compared to the noninfected grafts. Also, the number of cells expressing activation markers, LFA-1 and VLA-4 was significantly enhanced in these animals. Significantly enhanced histological changes of chronic rejection were seen in the RCMV-infected group. CONCLUSIONS: Prolonged, increased expression of ICAM-1 and VCAM-1, and increased numbers of inflammatory cells expressing their ligands in the CMV infected grafts, were associated with accelerated chronic allograft nephropathy.

Sequential changes in vitamin D and calcium metabolism after successful renal transplantation.

A prospective study was made of sequential changes in the metabolism of vitamin D and calcium in 19 allograft recipient during the first year after successful renal transplantation. All but one of the patients received cyclosporine A combined with corticosteroids and azathioprine as immunosuppressive therapy. Shortly after transplantation most patients showed transient hypocalcemia and hypophosphatemia. At the time of transplantation 17 of 19 patients had an elevated plasma intact parathyroid hormone (PTH) level, and at the close of follow-up one in four patients. In six other patients intact PTH was within the reference range, but high in relation to simultaneously measured serum ionized calcium. According, one year after transplantation less than half of the patients showed complete resolution of hyperparathyroidism. The change towards normal in the metabolism of vitamin D began within the first post-transplantation week irrespective of the onset of diuresis. One to two weeks after transplantation 1,25(OH)2D3 and 24,25(OH)2D3 reached the lower limit of normal range. In these renal allograft recipients who received cyclosporine A the long-term values of serum 1,25(OH)2D3 did not differ from those of normal subjects.

Acute vascular rejection in renal transplantation--diagnosis and outcome.

Thirty episodes of histologically verified acute vascular rejection in kidney transplant recipients were studied. In 11 grafts the rejection was mainly vascular, whereas in 19 grafts a concomitant cellular rejection was seen. Histological features prognostic for bad outcome were glomerular necrosis and thrombi in the arteries and arterioles. Characteristic findings in transplant cytology, i.e., high number of monocytes and low number of lymphocytes and blast cells were noted prior to the onset of clinical signs of rejection, and this finding was also persisting throughout the rejection episode. The numbers of lymphocytes and blast cells were significantly lower in grafts with a pure vascular rejection than in grafts with a concomitant cellular rejection. Vascular rejection was reversible in 15 cases. As rescue therapy plasmapheresis and added immunosuppression were often successful.

Insulin resistance and insulin deficiency in the pathogenesis of posttransplantation diabetes in man.

Although steroids can induce insulin resistance, it is not known whether additional defects in insulin secretion are necessary for the development of diabetes. To address this question, we measured insulin sensitivity (euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) and insulin secretion (hyperglycemic clamp) in three groups of subjects: (1) 10 kidney transplant patients with normal oral glucose tolerance, (2) 14 patients who developed diabetes after kidney transplantation, and (3) 10 healthy controls. Glucose utilization, primarily storage of glucose as glycogen, was reduced by 34% in kidney transplant patients with normal glucose tolerance when compared with healthy control subjects (18.2 +/- 2.9 vs. 27.5 +/- 2.7 microM/L; P less than 0.05). Insulin secretion was normal in relation to the degree of insulin resistance in transplanted non-diabetic patients, thus maintaining a normal oral glucose tolerance. Development of transplantation diabetes was associated with only minor further deterioration of glucose storage (14.7 +/- 2.7 microM/L; P less than 0.001 vs. control subjects), whereas first-phase, second-phase, and glucagon-stimulated insulin secretion measured during hyperglycemic clamping (incremental area under the insulin curve 287 +/- 120, 1275 +/- 419, and 3515 +/- 922 pM) became impaired as compared with nondiabetic kidney transplant patients (769 +/- 216, 3084 +/- 545, and 6293 +/- 533 pM; P less than 0.05). We conclude that both insulin resistance and insulin deficiency are necessary for the development of diabetes in kidney transplant patients.