Raymond Dandavino

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

BACKGROUNDnThe 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.nnnMETHODSnBetween 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.nnnRESULTSnThe 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).nnnCONCLUSIONSnMeCsA 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.

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.

BACKGROUNDnThere has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events.nnnMETHODSnThe 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.nnnRESULTSnNo 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).nnnCONCLUSIONSnTolerance 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.

Hepatitis C Virus Genotype 7, a New Genotype Originating from Central Africa

ABSTRACT We report a new hepatitis C virus (HCV) genotype identified in patients originating from the Democratic Republic of Congo. The prototype QC69 virus is shown to be a new lineage distinct from genotypes 1 to 6. Three additional patients were also found to be infected by a virus from this lineage, confirming its circulation in humans. We propose that these viruses be classified into HCV genotype 7.

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.

Brain death diagnoses and evaluation of the number of potential organ donors in Québec hospitals

PurposeFaced with our inability to respond to the growing number of Quebec patients waiting for organ transplants, we sought to determine the number of potential organ donors (OD) in acute care hospitals.MethodsA retrospective chart review of all acute care, inhospital deaths in Quebec in the year 2000 was undertaken. Hospital record librarians provided statistics and completed questionnaires on each chart after applying exclusion and inclusion criteria.ResultsThere were 24,702 acute care in-hospital deaths reported by 83 hospitals participating in the study on a voluntary basis. Analyzing 2,067 files meeting inclusion criteria, we identified 348 potential OD (1.4% of deaths). In hospitals not providing tertiary adult trauma care, the potential donor rate was 0.99% of all deaths. There were 4.5 times more potential donors in tertiary care adult trauma centers. Brain death was formally diagnosed in 268/348 patients, and organ donation discussed as an option with 230/268 families. Consent for donation was given in 70% of cases, although not all these patients proved to be suitable after evaluation. There were 125 actual donors in Quebec in the year 2000 (18 per million population).ConclusionsThe gap between used and potential donors can be explained by several factors including failure to approach families for organ donation, family refusal, incomplete neurological assessment of patients, and medical unsuitability of some consented donors. There is room for improvement in the identification of potential donors and in the presentation of organ donation as an end of life option to families.RésuméObjectifDevant l’incapacité de répondre au nombre croissant de patients du Québec qui attendent une transplantation d’organe, nous avons cherché à déterminer le nombre de donneurs d’organes (DO) potentiels dans les hôpitaux de soins actifs.MéthodeUne étude rétrospective de tous les patients décédés à l’hôpital de soins actifs au Québec en 2000 a été entreprise. Les archivistes des hôpitaux ont fourni les statistiques et rempli les questionnaires sur chaque dossier après avoir appliqué les critères d’inclusion et d’exclusion.RésultatsIl y a eu 24 702 décès parmi les 83 hôpitaux de soins actifs participants à l’étude. Ľanalyse de 2 067 fiches répondant aux critères d’inclusion a permis de recenser 348 DO potentiels (1,4 % des décès). Dans les hôpitaux qui n’offrent pas de soins tertiaires pour traumas chez les adultes, le taux de donneur potentiel était de 0,99 % de tous les décès. Il y avait 4,5 fois plus de donneurs potentiels dans les centres de soins tertiaires pour polytraumatisés adultes. La mort neurologique a été formellement diagnostiquée chez 268/348 patients et l’option du don d’organe discutée avec 230/268 familles. Il y a eu consentement pour un don dans 70 % des cas, mais après l’évaluation, il n’y a eu en fait que 125 donneurs au Québec en 2000 (18 par million de population).ConclusionLa différence entre les donneurs potentiels et réels peut s’expliquer par certains facteurs dont le défaut de parler aux familles du don d’organes, le refus de la famille, l’évaluation neurologique incomplète des patients et l’inaptitude médicale de certains donneurs consentants. Il y a matière à amélioration dans la façon d’identifier les donneurs et dans la présentation aux familles du don d’organes comme choix de fin de vie.

The role of proton pump inhibitors on early mycophenolic acid exposure in kidney transplantation: evidence from the CLEAR study.

Introduction: Proton pump inhibitors (PPIs) are often prescribed posttransplantation to prevent gastrointestinal complications. A series of recent studies have reported a relationship between PPI comedication and decreased mycophenolic acid (MPA) exposure. The objective of this subanalysis of the CLEAR data set was to determine the impact of PPI therapy on full MPA area under the curve exposures at Day 5 post kidney transplant. Material and Methods: Patients were randomized to receive either intensified dosing of mycophenolate mofetil (1.5 g twice daily on Days 1-5, then 1.0 g twice daily, n = 68) or standard dosing (1.0 g twice daily, n = 67). All recipients received tacrolimus and prednisone. Results: In the modified intention-to-treat population, 57.9% of patients (73 of 126) received PPI therapy. The most frequently administered therapies were pantoprazole and omeprazole. There was no significant difference in mean MPA area under the curve at Day 5 for patients receiving PPI therapy as compared with those not receiving PPI therapy (51.3 versus 55.8 mg.h/L, P = 0.265). However, the MPA concentration-time curve analysis demonstrated a significant decrease in MPA concentrations at 2 hours and 12 hours postdose in patients receiving PPI therapy (P = 0.0009 and P = 0.034). No significant differences were identified in the 3-g arm specifically. In the multivariate model, only serum creatinine and albumin significantly predicted MPA area under the curve less than 30 mg.h/L at Day 5. Discussion and Conclusion: PPI therapy in combination with mycophenolate mofetil does not appear to have a significant impact on full MPA exposure. Because MPA pharmacokinetics were not significantly impacted when a 3-g, 5-day loading dose of mycophenolate mofetil was used in combination with PPI therapy, this strategy may be required for adequate MPA exposure whether or not a patient receives PPI comedication.

The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients

Conversion from a calcineurin‐inhibitor‐based immunosuppression to a rapamycin‐based immunosuppression may preserve kidney graft function. The side effects of rapamycin can limit its usefulness, but their management and evolution are rarely reported in clinical trials. We performed a retrospective cohort study in patients transplanted before December 31, 2008 and who received rapamycin to replace calcineurin inhibitors. In 219 patients studied, 98% presented ≥1 side effects after starting rapamycin. Side effects occurring in ≥10% of patients were dyslipidemia (52%, 95% confidence interval (CI): 45–59%), peripheral edema (37%, 95%CI: 31–43%), cytopenia (36%, 95% CI: 30–42%), acne (29%, 95% CI: 23–35%), proteinuria (23%, 95% CI: 17–29%), and oral ulcers 14% (95% CI: 10–18%). Proteinuria, ulcers, and edema were difficult to manage and were more likely to cause cessation of rapamycin. Rapamycin was discontinued in 46% of patients (95% CI: 40–52%). Age (odds ratio [OR] per 10‐yr increase: 1.29, 95% CI: 1.05–1.59) and obesity (OR: 2.57, 95% CI: 1.10–6.01) were independently associated with cessation of rapamycin. We conclude that successful control of dyslipidemia and cytopenia can be achieved without discontinuing rapamycin. Most other side effects are harder to manage. Leaner and younger patients are less likely to discontinue rapamycin due to side effects.

Sirolimus Immunoprophylaxis and Renal Histological Changes in Long-Term Cardiac Transplant Recipients A Pilot Study

Background: The effects of sirolimus (SIR), as a substitution for calcineurin inhibitor (CNI) immunoprophylaxis, on renal function in very-long-term cardiac transplant recipients have been a matter of controversy. Objective: To assess the impacts of SIR as a substitution for CNI on renal function up to 24 months in long-term cardiac recipients as well as the renal histological changes in patients with suspected CNI-induced nephrotoxicity. Methods: A total of 23 cardiac transplant recipients aged 57.7 ± 11.2 years, 91 months post–cardiac transplantation were recruited; 15 patients were randomized to CNI-free immune suppression with SIR, and 8 patients were allocated to continue their CNI regimens. Serum creatinine and calculated serum creatinine clearance were measured at prespecified time points up to 24 months. Renal structure and function were assessed by renal biopsies, renal ultrasound, and magnetic resonance imaging at baseline. Results: There were no significant changes in creatinine clearance during the course of the study in patients treated with SIR. However, SIR-treated patients exhibited a significant decrease in 24-hours and nighttime systolic and diastolic blood pressures. Typical findings of significant hypertensive renal disease were detected in 9 of the 11 (82%) patients. Features of chronic CNI toxicity were detected in 6 (55%) patients. Conclusions: There is a very high rate of hypertensive renal disease concomitantly with some degree of CNI toxicity in long-term cardiac transplant recipients with renal dysfunction. This very high rate of hypertension-related disease may limit the impact of SIR on improving renal function long term following cardiac transplantation.

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

BACKGROUNDnReplacing 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.nnnMATERIALS AND METHODSnWe 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.nnnRESULTSnThe 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.nnnCONCLUSIONnConversion 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.

Risk-benefit of OKT3 prophylaxis in immunologic high-risk cadaver kidney transplant recipients

Study sample 100 patients were recruited into the study of whom 26 entered the high-risk group (receiving the OKT3 prophylaxis) and 74 the low-risk group. Since the patients entered these groups on the basis of their immunological risk status, no randomisation was performed. No power calculations were undertaken and there is no evidence that the samples were of adequate size to demonstrate statistically significant differences. It is not stated whether any patients refused to participate nor whether any patients were excluded from the initial samples.