Rejection Episodes In Transplant Recipients Research Articles

Evaluation of the Infection Risk in Dialysis and Chronic Kidney Disease Patients Using an ATP Monitoring Assay

The ATP monitoring assay is a useful biomarker for risk monitoring to detect infection and rejection episodes in transplant recipients. Hemodialysis patients have a higher rate of infectious mortality. Infections in hemodialysis patients are mainly caused by venous catheters, uremia, malnutrition and inflammation. However, the risk of infection episodes has not been evaluated using a lymphocyte ATP monitoring assay in hemodialysis and chronic kidney disease (CKD) patients. We measured the ATP amounts in the peripheral CD4+ cells of CKD (N=85) and dialysis patients (N=17) using an "Immuknow" assay kit. These CKD patients were divided, according to kidney disease stage, into G3a, G3b, G4, and G5 groups. The ATP amounts in CD4+ cells of the dialysis patients and each of the CKD groups were compared with healthy subjects. In both the dialysis and CKD patients, the ATP amounts in CD4+ cells were lower than in healthy subjects. Furthermore, there were significant differences in the ATP amounts between healthy subjects and each of the CKD-G3a, CKD-G3b, and CKD-G4 groups (P<0.05). Patients with CKD-G3a, CKD-G3b and CKD-G4 were evaluated as being at high risk for infection according to the lymphocyte ATP monitoring assay. However, the ATP amounts in the dialysis and CKD-G5 patients did not differ from those in healthy subjects to a statistically significant extent. These results suggest that the ATP amount in the CD4+ cells of these patients with serve renal failure are influenced by dialysis treatment, uremia and/or oxidative stress.

Action profiles of statins and calcineurin inhibitors during human mixed lymphocyte reaction

The cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1 and CD40 on monocytes and their ligands such as lymphocyte function-associated antigen (LFA)-1 and CD40 ligand (CD40L) on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1 and CD40 on monocytes, the production of interferon (IFN)-γ and IL-12 and the proliferation of T-cells during the human mixed lymphocyte reaction (MLR). In addition to the cholesterol lowering effect, statins improve patient survival and decrease rejection episodes in transplant recipients. In the present study, we investigated the difference of effect of statins and calcineurin inhibitors during MLR. 3-Hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, fluvastatin and pravastatin and statin-derived LFA-1 inhibitors, LFA703 and LFA878, which did not inhibit HMG-CoA reductase, suppressed the production of IFN-γ and IL-12 and the lymphocyte proliferation as well as the expression of ICAM-1 and CD40 on monocytes regardless of the presence of IL-18. However, the calcineurin inhibitors, tacrolimus and cyclosporine A (CsA), inhibited the IL-18-enhanced cytokine production and lymphocyte proliferation without any effect on the adhesion molecule expression. Thus, the action mechanism of stain is different from that of calcineurin inhibitors.

Review: metabolism of immunosuppressant drugs.

Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients-is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval. In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly. Because of the critical-dose nature of most of the recent generation of immunosuppressive agents, therapeutic drug monitoring is becoming increasingly important in the selection of doses and treatment regimens.