Dyslipidemia can reduce the immunosuppressive effects of cyclosporine.

AIMS: Dyslipidemia is a significant risk factor for the development of atherosclerotic disease and of chronic allograft rejection. Few data are available on the effects of dyslipidemia on the immunosuppressive action of immunosuppressive agents. We investigate the in vitro effects of lipids solution on the immunosuppressive action of cyclosporine (CsA). METHODS: Peripheral blood mononuclear cells (PBMC) were PHA or OKT3 activated in vitro with/without different concentrations of Intralipid solution (INT, range 0.5% to 15%). CsA inhibition of activation was measured after a 3 day incubation, by adding H3-thimidine. The intracellular concentration of CsA was measured by radioimmunoassay and related to the CsA inhibitory effects. RESULTS: Increasing INT concentration in the medium, CsA inhibition of PBMC activation by PHA or OKT3 was reduced from 72+/-13% to 8+/-2% and from 80+/-10% to 18+/-3%, respectively. A significant reduction of the intracellular CsA concentration was also evident with increasing INT concentrations and was related to the inhibitory activity of CsA. CONCLUSIONS: These results suggest that dyslipidemia may reduce the availability of intracellular CsA concentration to inhibit the immune activation process and may explain the relationship between dyslipidemia and chronic allograft loss.

Long-term predictive value of cyclosporine microemulsion C2 level for chronic renal allograft dysfunction.

This observational study was undertaken in maintenance renal transplant recipients to assess the relationship between cyclosporine C(2) and the long-term risk of chronic renal allograft dysfunction (CRAD). Pharmacokinetic profiling was undertaken twice yearly in 79 patients with stable graft function receiving cyclosporine microemulsion (Neoral) and steroids. Mean time since transplantation at study entry was 56 +/- 49 months posttransplant. At the end of the observational period (mean 43 +/- 14 months) 24 patients (30%) had developed CRAD, defined as proteinuria > 500 mg/24 hours associated with a rising serum creatinine and confirmed by graft biopsy. There were no significant differences at baseline between patients who did vs did not develop CRAD, except for reduced incidence of acute rejection in CRAD-free patients. The cyclosporine AUC was significantly higher among patients without CRAD (5707 ng. h/mL vs 3994 ng. h/mL, P =.0007). Mean C(2) was also significantly higher: 1001 ng/mL in the CRAD-free group versus 640 ng/mL in the CRAD group (P =.002). There was no significant difference in C(0). Regression analysis showed that the best predictors for the occurrence of CRAD were a low AUC (relative risk [RR] 1.54, P <.0001), a low C(2) (RR 1.30, P <.0001) and proteinuria (RR 4.95, P <.0001). Probability of freedom from CRAD was 90% for C(2) > 900 ng/mL. C(2) appears to be a superior strategy to C(0) monitoring of cyclosporine in stable renal transplant patients with regard to the risk of CRAD. C(2) values above 900 ng/mL are appropriate to minimize the risk of CRAD among patients receiving cyclosporine microemulsion and steroids.

Rapid conversion to sirolimus for chronic progressive deterioration of the renal function in kidney allograft recipients.

The aim of this study was to evaluate the safety of conversion to sirolimus (SRL) immunosuppression among 19 renal transplant recipients (KTX) with progressive chronic renal allograft dysfunction (CRAD). Conversion to SRL was performed with concomitant sharp withdrawal of the calcineurin inhibitor (CI). SRL was added at a starting dose of 3 mg, then adjusted to obtain SRL target trough blood levels of 8 to 10 ng/mL. CI were stopped the evening before starting SRL. All patients enrolled in the study have now completed 6 months of follow-up: all are alive without acute rejection or major infection following rapid conversion to SRL. No significant change in the 6 months postconversion hematologic and hepatic profile was observed compared with the preconversion values, while significant dyslipidemia was induced. After conversion to SRL, significant amelioration of the renal function was found in 36% of patients, stabilization in 21%, and continuous deterioration in 43%. Patients whose renal function improved were found to have been converted at a significantly lower creatinine: (pre 2.6 +/- 0.9 vs post 1.9 +/- 0.2; P =.038) with respect to those patients who had continuous renal deterioration. In KTX with CRAD, sharp withdrawal of CI with concomitant conversion to SRL is safe, avoiding major infections, acute rejections, and significant side effects. Short-term amelioration of the renal function is best obtained when early conversion is performed. Long-term follow-up will be necessary to confirm these preliminary data.

Plasma levels of transforming growth factor-beta1 in renal transplant recipients receiving different immunosuppressive regimens.

Experimental and clinical evidence support the role of transforming growth factor beta-1 (TGF-beta(1)), a cytokine with complex immune and nonimmune effects, on the development of chronic renal allograft nephropathy (CAN). We investigated the effects of different immunosuppressive regimens on circulating TGF-beta(1) plasma levels in stable kidney transplant (KTx) recipients. Two hundred ninety-nine TGF-beta(1) plasma levels were measured in 125 kidney transplant (KTX) recipients exhibiting stable renal function, immunosuppressed with cyclosporine (CsA), tacrolimus (TAC), or sirolimus (SIR), and in 18 normal healthy volunteers (C). Activated immunoreactive TGF-beta(1) was detected in platelet-depleted plasma by an enzyme-linked immunoadsorbent assay. Multivariate analyses correlated immunosuppressive regimens with TGF-beta(1) levels. KTX recipients displayed significantly higher TGF-beta(1) levels compared to C (P =.0005). Patients receiving CsA had significantly higher TGF-beta(1) plasma levels compared to those receiving TAC or SIR (P =.0384). Multivariate analyses showed no correlation between TGF-beta(1) levels and immunosuppressive drug trough blood levels or doses, but only correlations with the main immunosuppressive drug. These data show that: (1) TGF-beta(1) production is activated in kidney transplant recipients; (2) CsA patients display significantly higher plasma TGF-beta(1) levels. Follow-up studies seek to assess the possible relationship with clinical events.