Conversion from calcineurin inhibitors to sirolimus in kidney transplant recipients: a retrospective cohort study.

BACKGROUND: Replacing a calcineurin inhibitor (CNI) with sirolimus (SRL) may preserve kidney graft function. However, at the present time, only short follow-up after conversion is available. The aim of this study was to assess whether conversion from a CNI-based to an SRL-based maintenance regimen was safe and effective. MATERIALS AND METHODS: We performed a retrospective cohort study among kidney graft patients whose CNI was withdrawn to be replaced by SRL. Two-tailed paired t tests were used to compare glomerular filtration rates (GFRs) and proteinuria levels before and up to 2 years after conversion. We used linear regression to determine the factors associated with changes in renal function after conversion. RESULTS: The 193 study subjects had a mean GFR at conversion of 41 +/- 16 mL/min/1.73 m(2) a median proteinuria level of 0 g/L (interquartile range = 0-0.15). After conversion, the GFR was stable: at 1 year, the change was -0.34 mL/min/1.73 m(2) (95% confidence interval [CI] = -2.71, 2.03) and at 2 years, -0.96 mL/min/1.73 m(2) (95% CI = 4.26, 2.34). There was a small but significant increase in dipstick proteinuria at 1 year of +0.5 g/L, (95% CI = 0.20, 0.75). On multivariate analysis, proteinuria > or = 1 g/L at the time of conversion was the only predictor of deteriorating GFR at 1 year (beta: -7.91 mL/min/1.73 m(2); 95% CI = -14.10, -1.70). SRL had to be discontinued in 31% of patients. CONCLUSION: Conversion from CNI to SRL resulted in stable graft function at 2 years and in a slight increase in proteinuria. Despite the relatively high reconversion rate, this strategy offers a reasonable alternative to CNIs for most patients.

Cytomegalovirus infection in kidney transplant recipients: Evolution of approach through three eras.

Cytomegalovirus (CMV) prophylaxis is recommended for high-risk patients, while preemptive therapy is considered acceptable for patients at moderate/low risk. After reviewing kidney transplant patients from 1992-1995 and 1996-1999, we decided to replace prophylaxis by preemptive therapy. Herein we have presented our data. From 1996-1999 we treated 129 patients with ganciclovir prophylaxis for 3 months if D+/R- or if they received depleting antibodies. The incidence of CMV was 13.2% versus 3.7% in the 1992-1995 cohort. The increase was associated with mycophenolate mofetil (MMF) use (P = .002). Forty-two percent of the D+/R- developed an infection with 89% of bouts occurring in the first month after cessation of prophylaxis. From 2002-2004, we never gave prophylaxis to 129 patients except when they received thymoglobulin. High-risk D+/R- patients were monitored by polymerase chain reaction (PCR) CMV for 3 months. The incidence of CMV was 17.1% with 54% of the D+/R- developing CMV. CMV infection occurred mostly during the first trimester posttransplantation. Creatinine at 1 year posttransplantation was worse in the presence of CMV infection (154.3 mumol/L-1.75 mg % versus 130.2 mumol/L-1.47 mg %, P = .03). Time to cure CMV infection was longer when MMF was discontinued: 36.7 days versus 69.9 days (P = .026). Our results indicated that CMV incidence is increasing: 3.7% (1992-1995) --> 13.2% (1996-1999) -->17.1% (2002-2004) and that it impairs 1 year graft function. Recovery was faster among patients still receiving MMF compared with those discontinuing MMF. Although MMF inhibits synthesis of anti-CMV IgM, it increases the anti-herpes virus effect of ganciclovir and may protect against chronic allograft nephropathy. Based on our experience, we plan to reintroduce prophylaxis in high-risk patients and to continue MMF when treating CMV infection.

Trichosporon beigelii funguria in renal transplant recipients.

Trichosporon beigelii funguria in renal transplant recipients is usually benign and is seldom associated with invasive or deep-seated infections.

Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group.

BACKGROUND: There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events. METHODS: The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up. RESULTS: No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035). CONCLUSIONS: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Economic analysis of Neoral in de novo renal transplant patients in Canada.

This pilot economic evaluation was performed as part of the Canadian arm of an international randomized, controlled, double-blind safety and tolerability trial (OLM-105/NOF-2). The clinical study compared the safety and tolerability of a new microemulsion oral formulation of cyclosporine A (Neoral) with the oral cyclosporine. A preparation currently in use (Sandimmune SGC)/(SGC). To assess the economic impact of Neoral in newly grafted renal transplant patients, primary cost data were collected at the five participating Canadian centers and evaluated from the Ministry of Health (MOH) and hospital perspectives. The results of this cost analysis are presented in this paper. Since the new formulation has shown more consistent absorption and a more predictable pharmacokinetic profile, medical resource utilization and, consequently, cost of treatment could be expected to be lower for those renal transplant recipients treated with Neoral than for those receiving standard SGC. The findings of this study support this hypothesis. Robustness of the conclusion was confirmed with sensitivity analyses. Reduced health care costs for patients treated with Neoral were primarily a result of fewer hospitalization days and lower physician costs for inpatient and outpatient procedures.

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUND: The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. METHODS: Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. RESULTS: The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). CONCLUSIONS: MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Determinants of late allograft nephrectomy.

When loss of graft function occurs more than six months after transplantation, allograft nephrectomy is not routinely performed at the time of graft failure. It is usually performed only on those patients who subsequently develop specific complications. However, little is known about the characteristics that make patients more likely to require allograft nephrectomy. The purpose of our study was to identify risk factors for the subsequent need for allograft nephrectomy in patients with graft failure occurring more than 6 months after transplantation. Forty-one patients were studied. Inclusion criteria were: loss of graft function > or = 6 months after transplantation, resumption of dialysis and initiation of weaning from immunosuppression. Thirty patients were treated with cyclosporine + prednisone +/- azathioprine and 11 with azathioprine + prednisone. Mean follow-up time was 17.8 months, ranging from 6 months to 6.1 years. Recipient age, sex and race, original renal disease, donor, donor source (cadaveric vs living related), HLA compatibility, levels of panel reactive antibodies, occurrence of initial delayed graft function, causes of graft failure and tapering of immunosuppression were similar in patients with and without allograft nephrectomy. Using univariate analysis, allograft nephrectomy was found to be significantly more frequent in patients with a history of 2 or more episodes of acute rejection than in patients with no rejection episode: 83% vs 30% (p = 0.03). In addition, allograft nephrectomy was found to be significantly more frequent if the immunosuppressive regimen included cyclosporine (62% vs 27.3%; p = 0.04). Using multivariate analysis however, the number of previous episodes of rejection was found to be the only significant predictor for allograft nephrectomy. None of the other variables considered in the multivariate analysis, including the type of immunosuppressive therapy, was identified as a significant predictor for the need to perform allograft nephrectomy. In summary, the need for late allograft nephrectomy was correlated with the number of previous episodes of acute rejection. Patients with a history of numerous rejection episodes should thus be considered more likely to require allograft nephrectomy once immunosuppression is withdrawn. Possible interventions to reduce or prevent the need for nephrectomy include more gradual tapering of immunosuppression at the time of graft failure or indefinite low-dose immunosuppressive therapy.

[Development of organ transplantation in Quebec from 1985 to January 1990]. / Evolution de la transplantation d'organes au Québec de 1985 à janvier 1990.

In Québec, the first organ transplantations have been realized in 1958. Several kidney transplant programs started at that time. Cardiac, liver, pancreas and lungs programs followed and reached a full development in the eighties when Cyclosporin became available. Today, there are 4 university transplant programs in Québec (McGill, Montréal, Laval and Sherbrooke) with a total of 7 kidney, 4 liver, 4 heart, 2 pancreas and 2 lungs centers. More than 2,900 transplantations have been realized. Since 1970, organ procurement and distribution is organized by a central agency called Québec-Transplant (previously Métro-transplantation). Organ donation is done on a voluntary basis as every where in North America. More than 90% of the organs comes from cadaveric donors and more than 90% of the relatives accept organ donation. 50% of the donors have deceased from head trauma and 50% from cerebral hemorrhage. In 1989, multi-organ harvesting has been realized in 64% of the donors. Despite efforts and progresses, the number of patients awaiting an organ transplant is steadily growing and outlast the number of available organs. It is hoped that maximal utilisation of the donors and growing exchanges at a national and international level will help to solve this crucial problem.

A randomized study of cyclosporine with and without prednisone in renal allograft recipients. Canadian Transplant Group.

Sixty-nine patients receiving Cs after cadaveric or LRD renal transplants were randomly allocated to receive prednisone or no prednisone beginning on the day of transplant. There were 36 in the prednisone group and 33 in the group assigned to no prednisone. Of these latter, only seven (21%) never received prednisone and an additional four had one short course for rejection episodes (11%). Of the remaining 22 who were placed on continuous steroids, only 12 met rejection criteria and either some or all of the remainder probably had Cs nephrotoxicity. The patient and graft survival were better but not statistically so in the no-prednisone group (97% v 89%) and (88% v 78%), and the number of infections was only half that of the prednisone-treated group (22% v 42%). A policy of withholding steroids except for rejection episodes does not prejudice graft or patient survival in Cs-treated patients.