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  • Ultrasound-guided subcostal transversus abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic hand-assisted donor nephrectomy: a prospective randomised observer-blinded study
    Anaesthesia. 2016;[record in progress]

    Study Details

    Aims: To compare the effect of subcostal transversus abdominis plane (TAP) blocks using liposomal bupivacaine with TAP blocks using non-liposomal bupivacaine on postoperative maximal pain scores in patients undergoing donor nephrectomy.
    Interventions: Participants were randomized to undergo TAP block with either 1.3% liposomal bupivacaine with normal saline, versus non-liposomal 0.25% bupivacaine with adrenaline 1:200,000.
    Participants: 60 donor nephrectomy patients.
    Outcomes: The primary outcome measured was maximal pain score. Other outcomes measured included opioid and ketorolac use, minimum pain scores, nausea and vomiting, and length of stay.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This RCT compares transversus abdominis plane (TAP) blocks using liposomal bupivacaine versus non-liposomal bupivacaine with adrenaline in patients undergoing donor nephrectomy. The study was partly blinded as staff performing the block were not blinded but patients and outcome assessors were blinded to the intervention. The sample size calculation showed that 30 patients per arm were needed to achieve a power of 80% taking into account loss to follow, conversion to open surgery or change in surgical site, or noncompliance. 59 out of 60 randomised patients were analysed and provided pain scores up to 72 hours postoperatively. The liposomal bupivacaine group had lower median maximum pain scores between 24-72 hrs postoperatively and lower opoid use between 48-72 hrs postoperatively. There was no difference in ketorolac use between groups. Nausea and vomiting were reported less frequently and the median length of hospital stay was significantly shorter for the liposomal bupivacaine group.

    Expert Review

    Reviewer: Dr Cristiano Amarelli, Monaldi, Azienda dei Colli, Naples, Italy.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★☆ (4 of 5)
    This carefully designed trial demonstrates with a sufficient statistical power (80%), the superiority of ultrasound-guided liposomal Bupivacaine as anesthetic for transversus abdominis plane (TAP) blocks in 59 nephrectomies for kidney's living donation. Being an RCT on a surgical procedure the lack of surgical details dampened its generalizability. No data are recorded regarding clinical and/or echographic incidence of ematomas, bleedings and other surgical variables that could have led to increased pain in the control arm, then biasing the results. If an equal surgical trauma could have been demonstrated, the RCT's impact on clinical practice could have been greater thus favouring the adoption of liposomal Bupivacain as first choice drug for TAP also for similar surgical procedures. Next trials should better address surgical variables that may impact the result of an anesthetic policy over another.

    Abstract

    We compared the effect of subcostal transversus abdominis plane (TAP) block with liposomal bupivacaine to TAP block with non-liposomal bupivacaine on postoperative maximal pain scores in patients undergoing donor nephrectomy. Sixty patients were prospectively randomly assigned to receive ultrasound-guided bilateral TAPs with either 1.3% liposomal bupivacaine and normal saline or 0.25% non-liposomal bupivacaine with adrenaline. There was a significant decrease in maximal pain scores in the liposomal bupivacaine TAP group when compared with the non-liposomal bupivacaine group median (IQR [range]), 24-48 h after injection, 5 (3.0-5.2 [0-10]) vs. 6 (4.5-7.0 [1--9]) p = 0.009; 48-72 h after injection, 3 (2.0-5.0 [0-8]) vs. 5 (3.0-7.0 [0-10]) p = 0.02; and in opioid use 48-72 h after injection, mean (SD) mug equivalents of fentanyl 105 (97) vs. 182 (162) p = 0.03. Liposomal bupivacaine via subcostal TAP infiltration provided superior analgesia up to 72 h after injection when compared with non-liposomal bupivacaine.
  • Early conversion to prednisolone/everolimus as an alternative weaning regimen associates with beneficial renal transplant histology and function: the randomized-controlled MECANO trial
    American Journal of Transplantation. 2016;[record in progress]

    Study Details

    Aims: To determine whether minimizing exposure to calcineurin inhibitors and total amount of immunosuppression by switching to a non-nephrotoxic double drug regimen early after transplantation would maintain efficacy in renal transplant recipients.
    Interventions: Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS) and CsA. At 6 months, patients without rejection were randomized to receive one of three treatment arms; P/CsA, P/MPS, or P/everolimus.
    Participants: 224 patients aged 18-70 years receiving a first or second renal transplant from a deceased or living donor.
    Outcomes: The primary measured outcome was the development of interstitial fibrosis at the 24-month protocol biopsy. Secondary outcomes included the estimated glomerular filtration rate, incidence of acute rejection, and drug-related adverse events.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This report details a well conducted randomised controlled trial. Renal transplant recipients were randomised to conversion from maintenance immune suppression to either prednisolone and cyclosporine or prednisolone and everolimus. There was also a third arm (prednisolone and mycophenolate) that was terminated early due to poor results. At 24 months a protocol biopsy was taken and these showed significantly less fibrosis with everolimus than cyclosporine. Everolimus also showed a better renal function with about 5ml/min better eGFR over several months than cyclosporine. There was no significant difference in rates of clinical rejection over the same time period, development of DSA, patient or graft survival. Importantly there were significantly more serious adverse events with everolimus than cyclosporine, with much higher rates of change in regimen and cardiovascular events. This is of concern given the proven increased risk of hypercholesterolaemia with everolimus.

    Expert Review

    Reviewer: Professor Edward Cole, University Health Network, University of Toronto.
    Conflicts of interest: No
    Clinical Impact Rating : ★★☆☆☆ (2 of 5)
    This randomised controlled trial shows less interstitial fibrosis and better renal function at 24 months in patients randomised to prednisone/everolimus vs prednisone/cyclosporine. While well done, the impact of these results on clinical practice, in my opinion, is tempered by the following. Twenty-four per cent of patients withdrew before randomization. This seems, at least in part to relate to difficulties with the intense monitoring used. The dosing of both cyclosporine and everolimus was by multiple timed samples and AUC. This is inconsistent with routine clinical practice. Some patients were on 10 mg daily of prednisone, much higher than the dose in some constituencies. The use of cyclosporine as opposed to tacrolimus does not conform to the preferred calcineurin inhibitor in many centres. The incidence of serious adverse events was about twice as high in everolimus treated patients. Forty percent of everolimus vs 18% of cyclosporine treated patients switched immunosuppression during the study. The impact of cyclosporine nephrotoxicity on graft failure is controversial. In this study, while everolimus patients had better graft function at 2 years, the lines look parallel. Thus it is unclear whether the functional difference will lead to substantial difference in long term graft survival. There were 4 deaths in the everolimus arm vs 1 in the other arm. While not significant, there is another systematic review*, in addition to the one quoted by the authors, that shows a higher death rate in transplant recipients treated with TOR inhibitors despite a lower cumulative incidence in that group. *Knoll GA, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014 Nov 24;349.

    Abstract

    In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS) and CsA. At 6 months immunosuppression was tapered to P/CsA, P/MPS or P/EVL Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (P = 0.08). A post hoc analysis of HLA and Donor Specific Antibodies at one year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI-elimination to dual therapy with everolimus associated with decreased allograft fibrosis, preserved allograft function and good efficacy, but also with more SAEs and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity. This article is protected by copyright. All rights reserved.
  • Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial
    American Journal of Kidney Diseases. 2016;[record in progress]

    Study Details

    Aims: To summarise outcomes, specifically the safety and tolerability of belatacept at 36 months post randomization of kidney transplant recipients with low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept.
    Interventions: Participants were randomized to either switch to a belatacept-based immunosuppression (5 mg/kg of belatacept intravenous on days 1, 15, 29, 43, and 57 and every 28 days thereafter) or continue with CNI-based therapy.
    Participants: 173 adult stable kidney transplant recipients who were receiving CNI based maintenance immunosuppression.
    Outcomes: The primary outcome measured was safety, specifically adverse events (AEs) and serious AEs. Secondary outcomes measured were estimated glomerular filtration rate, acute rejection, transplant loss, and death.

    CET Conclusion

    Reviewer: Centre for Evidence in Transplantation
    This manuscript reports the 36-month extension from a phase 2 study randomising stable kidney transplant recipients (6-36 months post-transplant) to either continue CNI or switch to Belatacept. The renal function benefit seen at earlier time-points appears to be maintained, with an acceptable safety profile in both arms. Hazard for acute rejection is increased with Belatacept (HR 2.50), but this does not reach significance due to the small size of the study. In all, these data suggest that a switch to belatacept is safe and may result in small improvements in renal function compared to CNI-based therapy. The results are made difficult to interpret as patients/investigators were given the option to switch to belatacept at month 24. 16 patients (around 18%) in the CNI arm chose to switch, which may lead to an underestimation of any efficacy benefit or additional risk posed by the use of belatacept.

    Expert Review

    Reviewer: Dr Claudio Ponticelli, Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★★ (5 of 5)
    In this multicenter controlled trial, 173 CNI-treated adult kidney transplant recipients with stable graft function were randomly assigned to continue therapy with CNI (89 patients) or to be converted to belatacept (84 patients) at 6-36 months after transplantation. Belatacept-treated patients showed a significantly greater increase in GFR compared to CNI (+1.9 vs 0.07 ml/min). No difference between the two arms was seen in death, graft loss, acute rejection, serious adverse events, serious infection or malignancy. However, viral infection occurred more frequently in belatacept-treated patients. This study confirms that switching patients with stable renal graft function from CNI to belatacept is safe. The fact that the mean GFR at 36 months is better in belatacept-treated patients may represent an important result. However, it is also comforting to note that no attrition of renal function was seen in patients who continued CNI up to 3 years. Of note, the concern that belatacept might increase the risk of posttransplant lymphoproliferative disorder (PTLD) seems to be limited to EBV negative patients. Indeed, no case of PTLD was observed in this trial. In conclusion, the results of this study reinforce the idea that different but equally effective treatments are now available for kidney transplant recipients and that switching from a treatment to another one seems to be feasible and relatively safe, at least in patients with stable renal graft function.

    Abstract

    BACKGROUND In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. STUDY DESIGN 36-month follow-up of the intention-to-treat population. SETTING & PARTICIPANTS CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2). INTERVENTIONS At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). OUTCOMES Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. MEASUREMENTS Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. RESULTS Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). LIMITATIONS Exploratory post hoc analysis with a small sample size. CONCLUSIONS Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.
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