A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine.

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 +/- 21 mL/min in group A vs 56 +/- 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 +/- 91 vs 251 +/- 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients.

BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Role of platelet activating factor in hemodialysis.

A complex array of inflammatory mediators are generated as a consequence of blood contact with hemodialysis (HD) membranes. Beside complement activation, other mediators are involved in cell activation, and are thought possibly to be responsible for early and long-term multiple changes in immunity infection, hypercatabolism, beta 2-microglobulin generation and hemostatic mechanisms. Previous studies from our laboratories have established platelet activating factor (PAF) as one of the mediators generated by complement-dependent or independent mechanisms of cell interaction with hemodialysis membranes. Recent studies on the production of PAF from endotoxin-primed polymorphonuclear neutrophils in a closed miniaturized circuit, and on the effect of PAF in mediating endotoxin- and cytokine-induced leukocyte adherence to HD membranes, highlight so far undescribed new roles of this mediator in biocompatibility.

Production of platelet activating factor by human neutrophils after backfiltration of endotoxin contaminated dialysate.

Lipopolysaccharide (LPS) from gram negative bacteria has been shown to prime human polymorphonuclear neutrophil (PMN) production of platelet activating factor (PAF). PAF is a lipid mediator of inflammation and endotoxic shock and is also involved in leukocyte activation occurring during hemodialysis; PAF induces leukopenia, degranulation of lysosomal granules, and adherence to hemodialysis membranes. Transmembrane passage of LPS has also been shown to occur. To evaluate the relevance of transmembrane passage of LPS on the priming of PMN derived production of PAF, we designed in vitro studies using an experimental circuit equipped with different membranes (Cuprophan, polysulfone, polymethylmethacrylate, polyamide) and recirculation of purified human PMNs. At different time intervals, PMNs were stimulated with FMLP (10 microM) after back-filtration of sterile and LPS contaminated dialysate. The results of these studies suggest that priming of PMN derived production of PAF was related to the percent of backfiltered LPS, and they emphasize the need for careful assessment of microbiologic quality to improve biocompatibility.

Predilution hemofiltration. Clinical experience and removal of small molecular weight solutes.

Over 1500 treatments of hemofiltration with on-line preparation of substitution fluid were performed in 16 patients. Two patients were treated for over 40 months. On-line preparation of the solution allowed use of bicarbonate as a buffer. 73-74 L/session were infused in pre-dilution modality, at a rate of about 370 ml/min, and the treatment length was above 4 hrs. The good quality of on-line prepared solution was confirmed by the negativity of microbiological tests and by the absence of clinical or sub-clinical reactions in patients. Urea clearance was calculated by equations considering either plasma flow or whole blood flow. Results were 196-197 ml/min and 186-183 ml/min, respectively. The latter was nearer to the value of directly measured clearance (182-173 ml/min). Kt/V urea was about 1 per session and PCR ranged between 1.3 and 1.4 g/kg/day. A high vascular stability was also observed. Since sodium balance may, at least in part, account for better vascular stability, sodium sieving coefficient was measured during the treatment. The sodium-retaining effect of the increase of protein concentration within the filter, due to the ultrafiltration, was less relevant in pre-dilution hemofiltration if compared to post-dilution hemofiltration. It has been calculated that to obtain a sodium balance similar to that of the hemodialysis (HD), the sodium concentration of infusion solution should be about 2 mEq/L higher than HD dialysis solution. However, difficulty in performing accurate balance studies prevents a general agreement on these conclusions.