Cyclosporine In Recipients Research Articles

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Three-Year Outcomes From BENEFIT-EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Prospective Comparison of the Use of Sirolimus and Cyclosporine in Recipients of a Kidney From an Expanded Criteria Donor

A 6-month, open-label, multicenter prospective pilot study was conducted to evaluate the effects of sirolimus (SRL) versus cyclosporine (CsA) in recipients of kidneys from expanded criteria donors. All patients also received antithymocyte globulins induction, mycophenolate mofetil, and steroids. Sixty-nine patients (33 SRL, 36 CsA) were randomized. More patient were withdrawn in the SRL group (16 vs. 6, P<0.01), because of delayed graft function and surgical complications. Delayed graft function tended to be more frequent with SRL than with CsA (45.4% vs. 30.6%, P=0.22). Graft survival was numerically lower in the SRL group (87.5% vs. 97%, P=0.19). At 6 months, there were no significant differences in biopsy-proven acute rejection or calculated creatinine clearance (SRL 12.1% vs. CsA 8.3%; P=0.7 and 44.7+/-16.6 vs. 41.9+/-15.2 mL/min; P=0.54 respectively). These results do not support the use of SRL immediately after transplantation in expanded criteria donor recipients.

Pharmacokinetics of cyclosporine in recipients of marginal versus standard liver transplants

In the field of transplants, the practice of using marginal donor livers has become widely accepted, yielding good clinical results. This study investigated and compared the pharmacokinetics of cyclosporine in marginal and standard liver transplant recipients. Twenty-four de novo liver transplant patients, 12 with marginal and 12 with standard (normal) grafts, were treated with a microemulsion formulation of cyclosporine (capsules 100 mg) as immunosuppressive therapy. Blood concentration profiles were measured, and pharmacokinetic calculations performed at days 3 and 10 after transplantation. Different sampling strategies to predict drug exposure (AUC 0–12 h ) were compared, and the best limited-sampling strategies to monitor the desired blood levels were determined. Marginal and standard patients showed a significant difference in blood concentration and pharmacokinetic profiles of cyclosporine at the day 10 post-transplantation. Blood concentration at 4 h ( C 4 h ) was the single best timepoint to estimate AUC 0–12 h in marginal liver transplant ( r 2 = 0.700), while C 2 h was confirmed to be the optimal choice with standard graft ( r 2 = 0.720). Two blood samples at 2 and 6 h significantly improved the prediction model in both groups ( r 2 = 0.920). Our data suggest that patients receiving a marginal liver transplant present a different pharmacokinetic profile of cyclosporine from those receiving standard graft, which should be taken into account in dosing the patient to avoid subtherapeutic blood concentrations or toxic effects.

Comparison of Sequential Protocol using Basiliximab versus Antithymocyte Globulin with High-Dose Mycophenolate Mofetil in Recipients of a Kidney Graft from an Expanded-Criteria Donor

This retrospective pilot study investigated use of high-dose mycophenolate mofetil with biological induction and sequential introduction of low-dose cyclosporine in recipients of expanded criteria donor (ECD) kidneys. Fifty-four patients received mycophenolate mofetil 3 g/day for 45 days, cyclosporine 4 mg/kg/day, prednisolone, and rabbit antithymocyte globulin (rATG, n=14) or basiliximab (n=40). Acute rejection incidence was 11.3% (7.1% with rATG, 12.6% with basiliximab). Delayed graft function was observed in 31 patients (54%). At one year, measured glomerular filtration rate was 54+/-4 ml/min, with no significant differences between induction therapies. Thirty patients (55%) required > or =1 MMF dose reduction within month 1 due to adverse events (gastrointestinal symptoms, 67%; leucopenia 33%). Leucopenia was more frequent with rATG, while gastrointestinal symptoms were more frequent with basiliximab. Cytomegalovirus replication occurred in three patients (23%) with rATG and 3 (8%) with basiliximab. In conclusion, high-dose MMF, corticosteroids, delayed low-dose cyclosporine and induction therapy offers an excellent risk-to-benefit ratio in patients receiving an ECD allograft.

The Area Under the Concentration-Time Curve Versus Trough and Peak Blood Level Monitoring in Renal Transplant Recipients on Cyclosporine

Objective The area under the concentration-time curve of cyclosporine microemulsion is the best measure of the absorption and beneficial effects in renal transplant recipients. We sought to determine the best method of monitoring cyclosporine levels in these patients. Methods Prospective evaluation of peak cyclosporine blood levels and area under the curve monitoring were performed for 1 year in 65 renal transplant recipients (study group). Cyclosporine trough levels and peak cyclosporine blood levels were correlated with the calculated area under the curve. Cyclosporine trough levels were monitored in equal numbers of matched controls. Results There were no significant differences in the incidence of acute rejection, cyclosporine nephrotoxicity, proteinuria, serum creatinine levels, or graft and patient outcomes between the groups ( P = .1). Peak cyclosporine blood levels guided by calculating the area under the curve were found to be 27% to 32% lower than previously reported. The correlation coefficient was <70% for cyclosporine trough levels ( P < .02) and >90% for peak cyclosporine blood levels ( P < .001) when related to the calculated area under the curve. The calculated area under the curve was approximately 6000 ng/mL/h following transplantation, gradually decreasing to approximately 3000 ng/mL/h at 1 year. Both appeared to the acceptable therapeutic values. Conclusion Calculating the area under the curve using trough and peak blood levels versus using isolated readings for either of these levels alone is the most effective method of monitoring cyclosporine in recipients undergoing renal transplant.

Cyclosporine plasma unbound fraction in heart and lung transplantation recipients.

To investigate the variability in the unbound fraction (fu) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fu was determined ex vivo in plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. The unbound fraction (x100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53%+/-0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold interpatient variation. In heart transplant recipients (66 patients), the values of fu were significantly lower (p < 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade la rejections. The value of fu did not vary with organ transplanted (p = 0.35) or etiology of organ failure (p = 0.32). Cyclosporine fu was negatively correlated with the age of the patient (r = -0.18, p < 0.05). Correlations were not observed between fu and blood biochemical and cytologic indices. However, fu was significantly lower (p < 0.01) in hypercholesterolemic transplant recipients (1.37+/-0.52%) than in normocholesterolemic patients (1.60+/-0.63%). Administration of simvastatin resulted in a significant increase in the mean fu from 1.40+/-0.09%) to 1.82+/-0.13% (paired t test, n = 13; p < 0.01). In patients who received ketoconazole, fu was not different from controls. These findings suggest that the level of cyclosporine fu may be an important determinant of immunosuppressive activity of cyclosporine. Moreover, the variation in fu could be strongly related to the concentration of serum lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.

The Specificity of Monoclonal Fluorescence Polarization Immunoassay for Cyclosporine in Recipients of Simultaneous Pancreas-Kidney Transplants

Simultaneous kidney-pancreas transplant (SPK) recipients have a higher rate of acute organ rejection than do recipients of a kidney-alone transplant. The etiology of this increased number of rejection episodes is unknown. Cyclosporine (CsA) monitoring in SPK recipients is an important tool in the care of these patients. Many centers use the monoclonal fluorescence polarization immunoassay (mFPIA) to monitor CsA levels in this group of organ recipients. The reported specificity of the mFPIA for the CsA parent compound has varied in several studies but has not been systematically studied in recipients of an SPK transplant. Twelve recipients of an SPK transplant from 1 month to 3 months after surgery had serial simultaneous whole blood high-performance liquid chromatography (HPLC) and mFPIA CsA concentrations evaluated. A control group of 15 nondiabetic kidney-alone recipients underwent a similar evaluation. The average mFPIA/HPLC ratio in recipients of an SPK was 1.71 +/- 0.05 (r = 0.94), whereas it was 1.56 +/- 0.03 (r = 0.98) in the kidney-alone group (p > 0.01). Interpatient variability (range, 1.41 to 2.13) was very high in the SPK group, whereas intrapatient variability was lower. Seven patients had AUC profiles. The average AUC mFPIA/HPLC ratio was not significantly different from each patient's respective trough ratios. Our study suggests that the mFPIA overestimates CsA parent compound to a greater extent in SPK recipients than in kidney-alone recipients. In addition, the large interpatient variability in the specificity of the mFPIA makes assessing individual patient's levels problematic.