Hepatitis C virus genotype 7, a new genotype originating from central Africa.

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.

Conversion from twice-daily to once-daily extended-release tacrolimus in renal transplant recipients: 2-year results and review of the literature.

OBJECTIVES: Tacrolimus extended-release formulation has been approved for use in Canada since October 2008. In initial studies, efficacy and safety profile were demonstrated as similar for both formulations (twice-daily tacrolimus and extended-release formula tacrolimus). To validate the safety and efficacy of extended-release formula tacrolimus, we conducted a prospective observational study. MATERIALS AND METHODS: At our institution, between January 2009 and January 2010, the switch from tacrolimus to extended-release formula tacrolimus was done in 130 stable kidney recipients. Clinical data were accessed at baseline (data before conversion), 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and 24 months after conversion. RESULTS: One hundred thirty renal transplant recipients were included in the current study. During the observation period, we saw no acute rejection and no change in graft function (mean serum creatinine levels remained stable). However, compared with baseline, mean tacrolimus trough levels were significantly reduced at 1 to 2 weeks, at 1 month, 6 months, 12 months, and at 24 months after conversion. Regarding the safety profile, no significant changes were noted in blood glucose, potassium, and magnesium. Approximately 35% of recipients preferred the extended-release formula tacrolimus to twice-daily tacrolimus. CONCLUSIONS: Conversion from twice-daily tacrolimus to extended-release once-daily tacrolimus appears to be safe and convenient up to 2 years after conversion in some recipients.

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.

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.

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 CLEAR study: a 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.

BACKGROUND AND OBJECTIVES: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg.h/L) by day 5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points. RESULTS: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels<30 mg.h/L compared with those >or=30 mg.h/L at day 5. No significant differences were seen in common adverse events. CONCLUSIONS: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.

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

PURPOSE: Faced 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. METHODS: A retrospective chart review of all acute care, in-hospital 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. RESULTS: There 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). CONCLUSIONS: The 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.

Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion.

BACKGROUND: MO2ART (monitoring of 2-hr absorption in renal transplantation) is the first prospective, multicenter trial of cyclosporine (CsA) blood level 2 hr postdose (C2) monitoring in de novo kidney recipients receiving CsA microemulsion (ME) (Neoral; Novartis, Basel, Switzerland). Efficacy and safety results from the first 3 months are presented here. METHODS: MO2ART is a 12-month, open-label, randomized study involving 296 patients. In all patients, the dose of CsA-ME was adjusted to achieve protocol-defined C2 targets of 1.6 to 2.0 microg/mL for the first month, with subsequent tapering. Randomization into two target groups occurred at 3 months. All patients received steroids and mycophenolate mofetil (89%) or azathioprine. For patients with delayed graft function, the protocol permitted reduced C2 targets and prophylactic administration of antibodies. RESULTS: At 3 months, overall incidence of biopsy-proven acute rejection was 11.5%. Median serum creatinine was 132 micromol/L. Patient and graft survival were 96.6% and 91.2%, respectively. C2 levels greater than 1.6 microg/mL were achieved within 5 days by 60.6% of patients with immediate graft function and 19.5% of patients with delayed graft function. Prophylactic antibodies were used in 15% of the total population. Twenty-four patients (8.1%) experienced serious adverse events with a suspected relation to CsA, and 26 patients (8.8%) discontinued the study because of adverse events (n=15) or after a switch in immunosuppression after rejection episodes (n=11). CONCLUSIONS: Patient management by C2 monitoring resulted in a low incidence of biopsy-proven acute rejection in standard risk de novo kidney recipients, 85% of whom did not receive prophylactic antibodies. CsA-ME with C2 monitoring provides excellent short-term efficacy and safety among de novo renal transplant patients.