Renal transplant patient compliance with free immunosuppressive medications.

BACKGROUND: Noncompliance with immunosuppressive medications after renal transplantation is believed to be a major cause of allograft rejection and graft loss, with the impressive costs of these agents considered a significant reason for noncompliance. Our purpose was to determine the compliance rates of renal transplant patients who received their immunosuppressant therapy free of charge and evaluate their patterns of compliance. METHODS: All patients who received a renal transplant and received their immunosuppressant medications at our institution for their first year posttransplant were included in the study. Compliance rate was calculated and serum immunosuppressant concentrations were obtained to validate compliance assessments. RESULTS: Eighteen patients were included in the study. Approximately 48% of noncompliant patients were found to have subtarget drug concentrations, although only 14% of compliant patients had subtarget levels (chi2=12.9, P<0.001). At 5 months posttransplant, 95% of the patients remained compliant; however, by 12 months posttransplant, only 48% of the patients remained compliant. The mean time to the first noncompliant month was 9.8 months (95% confidence intervals=8.60-11.0). CONCLUSIONS: Patients who received their immunosuppressants free of charge were generally compliant within their first year of transplantation, however, compliance tended to decrease over time. This suggests that drug cost alone does not explain noncompliant behavior. Intensive efforts to increase medication compliance before month 8 posttransplantation should be implemented.

Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. The U.S. Simulect Renal Transplant Study Group.

BACKGROUND: Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. METHODS: Serial blood samples (8.2+/-1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 microg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. RESULTS: Basiliximab clearance was 36.7+/-15.2 ml/hr, distribution volume 8.0+/-2.4 L, and half life 7.4+/-3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed < or =6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36+/-14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 microg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33+/-13 days vs. 37+/-14 days for rejection-free patients, P=0.162). CONCLUSIONS: There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years.

BACKGROUND: A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years. METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years. RESULTS: The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF. CONCLUSIONS: All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation.

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.

BACKGROUND: Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS: Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS: A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION: Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Cyclosporine, but not FK506, selectively induces renal and coronary artery smooth muscle contraction.

BACKGROUND: Cyclosporine immunosuppression for organ transplantation is associated with hypertension and nephrotoxicity. Because the effects of cyclosporine as an immunosuppressant are mediated by the effect of cyclosporine as a phosphatase inhibitor, and phosphatase inhibitors are potent vascular smooth muscle contractile agents, we hypothesized that cyclosporine might induce contraction of the renal artery vascular smooth muscle directly. METHODS: Strips of bovine renal, carotid, superior mesenteric, or coronary arteries were obtained fresh from an abattoir. The strips were equilibrated in a muscle bath, and the contractile responses to cyclosporine and FK506 were determined. RESULTS: Cyclosporine (50 to 5000 micrograms/ml), but not FK506, induced rapidly developing, sustained contractions of renal and coronary artery smooth muscle. The magnitude of the cyclosporine-induced contractions of carotid and superior mesenteric artery smooth muscles was significantly less. The magnitude of renal artery smooth muscle contractions induced by cyclosporine was enhanced in the presence of an intact endothelium. CONCLUSIONS: Although these effects occurred in vitro to relatively high doses of cyclosporine, these data suggest that cyclosporine may selectively induce renal artery smooth muscle contraction through activation of the Ca(2+)-dependent phosphatase (calcineurin) in the smooth muscle, and these contractions may be enhanced by the release of endothelial-derived contracting factors.

Living-related kidney donation.

Living renal donation is an effective means to expand the organ donor pool and allow more transplants to be performed at greater convenience for the recipient and with greater long-term success. Risks to the recipient appear to be minimal as long as careful donor screening is employed. Living donation has been implemented in extra-renal transplantation more recently. While the experience is limited so far, living donation is likely to remain an important option for liver and lung recipients.

Hypercalcemia due to hard water used for home hemodialysis.

We have described two patients from the same rural community in Georgia who had hypercalcemia during home hemodialysis. In the first patient the diagnosis was not considered until after the patient complained of the poor taste of her home tap water and of the white residue it left on her cooking utensils; other causes of hypercalcemia had been ruled out. The diagnosis was confirmed when samples of tap water that had passed through the in-line deionizer showed low to high calcium concentrations. Calcium concentrations were high after the deionizer filters had been in place for some time but within the acceptable guidelines for the type of filters used. The second patient, seen shortly after the first, had also received dialysis with hard water and also had hypercalcemia despite the use of an in-line deionizer. These cases suggest that dialysis-induced hypercalcemia can occur during home hemodialysis despite seemingly adequate pretreatment of the water source.

Polymicrobial bacteremia during long-term hemodialysis.

A review of hospital epidemiologic data disclosed five cases of polymicrobial bacteremia on a nephrology inpatient service over a period of 30 months. All five cases occurred in patients receiving long-term hemodialysis; four of them had indwelling silicone rubber vascular access devices. Although all patients had risk factors other than uremia and dialysis predisposing to an increased likelihood of infection, no patient had either obvious skin infection at the site of the vascular access or documented visceral infection. One patient died, and the other four recovered after removal of the vascular access device and appropriate antibiotic therapy. The increased risk of polymicrobial bacteremia associated with long-term hemodialysis should be taken into account when empiric antibiotic therapy is undertaken.

Impact of clinical pharmacy services on renal transplant patients' compliance with immunosuppressive medications.

BACKGROUND: Non-compliance with immunosuppressive medications may result in allograft rejection and is regarded as an important impediment to post-transplant care. This randomized, controlled trial evaluates the impact of clinical pharmacy services on renal transplant patients' compliance with immunosuppressive agents. METHODS: Patients who received a renal transplant at the Medical College of Georgia from February 1997 through January 1999 were randomized in the intervention or control group provided they met study criteria. In addition to routine clinic services at each clinic visit, patients in the intervention group received clinical pharmacy services, which included medication histories and review of patients' medications with an emphasis on optimizing medication therapy to achieve desired outcomes and minimizing adverse medication events. The clinical pharmacist also provided recommendations to the nephrologists with the goal of achieving desired outcomes. To promote medication compliance by using compliance enhancement strategies, the clinical pharmacist counseled patients concerning their medication therapy and instructed them how to properly take their medications. Patients in the control group received the same routine clinic services as the intervention group except that they did not have any clinical pharmacist interaction. Compliance rate (CR) was calculated and patient's compliance status was determined from the CR. The CR, the fraction of patients remaining compliant for each month, and the mean time patients were compliant were compared between groups. Whether there was a difference in the frequency of patients achieving 'target' immunosuppressive levels in the control and study groups was evaluated. RESULTS: The mean CR for patients who had clinical pharmacist intervention (n=12) was statistically higher than the control group's (n=12) mean CR (p<0.001). During the 12-month post-transplant study period, patients in the intervention group had a longer duration of compliance than patients in the control group (p<0.05). Additionally, patients who had clinical pharmacy services had a greater achievement of 'target' levels than patients who did not receive these services (p<0.05). CONCLUSIONS: Patients who received clinical pharmacy services with traditional patient care services had better compliance with immunosuppressants than patients who only received traditional patient care services. Results of this study suggest a multidisciplinary team that includes a clinical pharmacist as part of the care for post-transplant patients is beneficial for enhancing medication compliance.

Cost-benefit analysis of a clinical pharmacist-managed medication assistance program in a renal transplant clinic.

UNLABELLED: Medicare pays for 80% of the cost of immunosuppressant agents needed within the first 3 years of solid organ transplantation; however, many patients cannot afford the remaining 20%. Furthermore, many patients who are beyond 3 years post-transplantation and have prescription coverage cannot afford the co-payment for these medications. Other patients may not be able to afford their medications due to limited or no insurance coverage. The Medical College of Georgia (MCG) has been giving immunosuppressant medications to renal transplant patients if they cannot afford to pay for them. To assist MCG with drug cost for medications and maintain quality care for renal transplant patients, a clinical pharmacist-managed medication assistance program was implemented to procure immunosuppressants from pharmaceutical manufacturers. METHODS: All patients enrolled in medication assistance programs from 1 January 1998 through 31 December 1998 were included in this analysis. Medication acquisition costs with and without Medicare reimbursement and the cost of implementing the clinical pharmacist-managed medication assistance program were used to determine the value of implementing this service. RESULTS: Sixty-one patients were enrolled in manufacturers' assistance programs and a net cost avoidance of $124,793 was realized for the year of the program (benefit-to-cost ratio of 7.5:1). Assuming that the hospital collected the maximum amount allowed for patients receiving Medicare benefits, a cost avoidance of $69,233 was calculated (benefit-to-cost ratio of 4.16:1). CONCLUSIONS: A clinical pharmacist-managed medication assistance program in a renal transplant clinic produced substantial cost savings over this 1-year study period. For each dollar spent in pharmacist's time, a minimum of $4 was returned to the institution.

The impact of pre-transplant obesity on renal transplant outcomes.

The impact of obesity on graft survival after renal transplantation continues to be controversial. We have reviewed our experiences with living donor and cadaver transplantation in the current decade, focusing specifically on the impact of obesity on transplant outcome. Preoperative body mass index (BMI, kg/m2) was calculated for all adult renal transplant recipients between January 1990 and December 1995 and was used to classify patients as non-obese, moderately obese or morbidly obese. The effect of the degree of obesity on early and late outcomes after renal transplantation was examined. Three hundred and thirty-three recipients had pre-transplant BMI < 30 (normal or mild obesity), 68 BMI 30-40 (moderate obesity), and 7 BMI over 40 (morbid obesity). There was no correlation between obesity and other demographic factors. Wound infections and delayed graft function occurred more commonly in moderately and morbidly obese than in other cadaver donor recipients. Obese patients gained more weight after surgery and were given lower doses per kilogram of cyclosporine. There was, however, no significant correlation between obesity and graft survival for either cadaver or living donor transplants. Although obese patients have an increased risk of delayed graft function with cadaver donor transplantation, obesity has no discernible impact on either immunologic or overall graft survival with cadaver or living donor transplantation. The impact of moderate obesity on transplant outcome is modest and should not prevent these patients from receiving a transplant.