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  • The Appropriate Dose of Thymoglobulin Induction Therapy in Kidney Transplantation
    Clinical Transplantation. 2017;04:04

    Expert Review

    Reviewer: Professor Rita R. Alloway, Transplant Clinical Research, University of Cincinnati, College of Medicine, USA.
    Conflicts of interest: I am on the Sanofi/Genzyme speakers bureau and I served as a consultant on the Sanofi/Genzyme FDA submission.
    Clinical Impact Rating : ★☆☆☆☆ (1 of 5)
    This 90 patient randomized kidney transplant study by Nafar et al compared three different Thymoglobulin induction-dosing regimens of 4.5mg/kg over 3 days (Arm A), 4.5mg/kg as a single bolus, and 6mg/kg over 3 days (Arm C). The primary endpoint of incidence of rate and severity of biopsy proven acute rejection (BPAR) was low (2 per group) and not statistically different. Study results should be interpreted with caution due to 1) the sample size is inadequate to assess the endpoint, 2)16% and 10% of patients in Arm B and C respectively did not receive full randomized dose, and 3) the author acknowledged, the BPAR rate was limited by patients unwillingness to undergo biopsy. Recently Thymoglobulin was FDA approved for prophylaxis of acute rejection in patients receiving a kidney transplant at a dose of 1.5mg/kg administered daily for 4-7 days. This dose was based upon two historical randomized trials and extensive safety information. While this dose range is efficacious and safe, further refinements in Thymoglobulin dosing based upon 1) immunologic risk, 2) safety factors, 3) dosing factors (i.e. ideal body weight, actual body weight, dose maximum, etc.) and 4) concomitant immunosuppression, are desirable to individualize immunosuppression. While this study attempts to assess the impact of lower Thymoglobulin induction doses, these results are not generalizable. Appropriately, controlled and powered dose finding studies would be required.

    Abstract

    BACKGROUND Thymoglobulin is used effectively as an induction agent in kidney transplantation, but there is no consensus on the optimal dose. In order to delineate the safest effective dose an open-labeled randomized clinical trial was designed. METHODS In this study, 90 adult kidney transplant recipients (KTR) were randomized before transplantation in three groups to receive Thymoglobulin: Arm A (4.5 mg/kg in 3 days), Arm B (4.5 mg/kg single bolus dose), and Arm C (6 mg/kg in 3 days). Renal function, infections and rate of readmissions were evaluated during the first post transplantation year. RESULTS Ninety adult kidney recipients were enrolled (51% deceased donor) No significant statistical difference was found in acute rejection episodes or type of rejection between these groups, although patients in arm A showed more severe histopathologic changes according to Banff 2013 criteria, in renal biopsies(P = 0.03).At the first month after transplantation serum Cr was lower (P=0.001) and GFR was higher (P=0.04) in arm A, but there was no significant difference among the three groups at 3, 6 and 12 months post-transplant. CONCLUSION Although all regimens showed same efficacy regarding to the rate of rejection episodes, 3-day 4.5 mg/kg Thymoglobulin had significantly lower complications. This article is protected by copyright. All rights reserved. Copyright This article is protected by copyright. All rights reserved.
  • Treatment With Ledipasvir-Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial
    Annals of Internal Medicine. 2017;166(2):109-117

    Study Details

    Aims: To compare the efficacy and safety of 12 and 24 weeks of ledipasvir–sofosbuvir without ribavirin in kidney transplant patients with chronic hepatitis C virus (HCV) genotype 1 or 4 infection.
    Interventions: Participants were randomised to receive either 12 versus 24 weeks of treatment with a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg).
    Participants: 114 recipients of a kidney transplant ≥6 months before the baseline study visit, aged ≥18 years who had chronic HCV genotype 1 or 4 infection, with plasma HCV RNA levels ≥15 IU/mL.
    Outcomes: The primary outcomes measured were the percentage of patients with HCV RNA less than the lower limit of quantification (LLOQ) 12 weeks after stopping the study drug, and any adverse event leading to permanent discontinuation of the study drug.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This industry-sponsored study investigates the use of the combination of ledipasvir and sofosbuvir in stable renal transplant recipients with chronic hepatitis C. Patients were randomised to either 12 or 24 weeks of treatment, and both groups achieved sustained virological response at 12 weeks after the end of therapy of 100%. Treatment was well tolerated with only 3 serious adverse events reported to be due to the study medication. The SVR12 seen is impressive, and treatment appears much better tolerated in this population than standard treatment with interferon and ribavirin. The lack of a control arm on this standard therapy makes direct comparison impossible, however. The results do offer the possibility of opening up the HCV-positive donor pool to selected recipients, but this would warrant careful further investigation and consideration.

    Expert Review

    Reviewer: Dr Wilson Wong, King's College London, UK.
    Conflicts of interest: No
    Clinical Impact Rating : ★☆☆☆☆ (1 of 5)
    This study compares the use of combined Ledipasvir and Sofosbuvir treatment in kidney transplant recipients with chronic hepatitis C infection. They concluded that both 12 and 24 weeks of treatment were well tolerated and effective with significant reduction of viral load after treatment. This study has a number of significant limitations. It is unclear why the authors only included patients with genotype 1 and 4. Given that current guidelines already recommend treatment of 12 weeks, the rationale for performing this study is unclear, other than to see whether patients can tolerate 24 weeks of treatment. Whether 24 weeks of treatment would be more effective compared to 12 weeks would be a reason to perform such a study, but the way it was designed did not really allow the authors to examine this. In summary, the authors confirmed that current recommendations are well tolerated, but no conclusion can be drawn about its efficacy and whether longer duration of treatment is of benefit. Therefore, clinicians should continue to follow current guidelines.

    Abstract

    Background: Use of interferon and ribavirin to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients is limited because of the risk for allograft rejection and poor tolerability. Objective: To evaluate the safety and efficacy of the interferon- and ribavirin-free regimen ledipasvir-sofosbuvir in kidney transplant recipients with chronic genotype 1 or 4 HCV infection. Design: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT02251717). Setting: 5 sites in Europe. Patients: Treatment-naive or -experienced kidney transplant recipients with chronic genotype 1 or 4 HCV infection, with or without compensated cirrhosis, and with an estimated glomerular filtration rate (eGFR) of 40 mL/min or greater were randomly assigned 1:1 to receive ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 or 24 weeks. Measurements: The primary end point was sustained virologic response at 12 weeks after therapy ended (SVR12). Results: Among 114 patients, the median age was 53 years, 58% were male, 91% had genotype 1 infection, 69% were treatment naive, and 15% had compensated cirrhosis. The median eGFR was 56 mL/min (range, 35 to 135 mL/min). One hundred percent of patients (57 of 57) treated for 12 weeks (95% CI, 94% to 100%) and 100% of those (57 of 57) treated for 24 weeks (CI, 94% to 100%) achieved SVR12. Serious adverse events were reported in 13 patients (11%). Of these, 3 events-syncope, pulmonary embolism, and serum creatinine increase-in 3 patients were determined to be treatment related. One patient permanently discontinued treatment because of an adverse event (syncope). The most frequent adverse events overall were headache (n = 22 [19%]), asthenia (n = 16 [14%]), and fatigue (n = 11 [10%]). Limitations: The study was open label, no inferential statistics were planned, and only patients with genotype 1 or 4 infection were included. Few patients with HCV genotype 1a and cirrhosis were enrolled. Conclusion: Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks was well-tolerated and seemed to have an acceptable safety profile among kidney transplant recipients with HCV genotype 1 or 4 infection, all of whom achieved SVR12. Primary Funding Source: Gilead Sciences.
  • Prophylactic ureteric stents in renal transplant recipients: a multicentre randomised controlled trial of early versus late removal
    American Journal of Transplantation. 2017;11:11

    Study Details

    Aims: To determine the optimal duration for stent removal post renal transplantation.
    Interventions: Participants were randomised to either early stent removal (on day 5 without cystoscopy) versus late stent removal (6 weeks with cystoscopy).
    Participants: 227 patients aged 2-75 years scheduled for renal transplantation.
    Outcomes: The primary outcome measured was a composite of transplant ureteric stent complications defined as pain, urinary tract infection, haematuria, fragmentation and migration. Secondary outcomes measured included major urological complications, health status and patient acceptability.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This interesting study investigated the impact of early (day 5) versus late (week 6) ureteric stent removal in adult and paediatric renal transplant recipients. The authors report increased incidence of stent-related complications with late removal, mainly due to increased incidence of urinary tract infection, supporting the early removal of stents. It should be noted that there was a numerical (but not significant) increase in major and intermediate ureteric complications (stenosis, leak, temporary obstruction) in the early removal group. Whilst the results appear to support the early removal of stents, there are some limitations to note. Firstly, a number of randomised patients did not undergo early removal due to technical difficulties connecting the stent to the catheter. When analysed as intent-to-treat, the difference in stent-related complications did not quite reach significance. This may represent a technical learning curve and be improved with more experience. Secondly, whilst there was a protocol for urine sampling for infection and a clear definition provided, the number of samples analysed in each group is not reported. As the study is unblinded, it is possible that some measurement bias exists. Finally, longer-term follow-up for late ureteric stenoses will be important to ensure that there are no long-term effects of early removal.

    Expert Review

    Reviewer: Professor Riadh A. S. Fadhil, Qatar Organ Donation Center, Hamad Medical Corporation, Doha.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★☆☆ (3 of 5)
    This multicentre randomised controlled trial was designed to investigate two groups: early- removal of the stent with the attached urethral catheter (5 days without cystoscopy) versus late-removal of the stent (6 weeks with cystoscopy). The study demonstrated that the early group had a significantly lower stent related complications (mainly the UTI) than the late group with low incidence of stent symptoms. However, the stent placement technique in the early group needed special attention and training curve, 15 cases were moved from the early to the late group due to technical difficulties in attaching stent to catheter. Although not statistically significant, incidence of major urological complications in the early group is higher than the late group. Six cases (7.6 %) of the early group needed further surgical intervention such as open surgical revision, nephrostomy or temporary stenting and some of these complications could have been prevented by longer stenting time. The evidence provided by this trial is not enough to make prophylactic stent users change their practice to the described early removal technique. The evidence could have been improved if a third group were included where the stent is removed in 2-4 weeks time and a longer-term follow up of the early group.

    Abstract

    Prophylactic ureteric stenting in renal transplantation reduces major urological complications (MUCs). There is however morbidity related to the indwelling duration of a stent, we aimed to determine the optimal duration for stents in this clinical setting. Patients (aged 2-75 years) from 6 UK hospitals undergoing renal transplantation were recruited and randomly assigned, to either early stent removal at 5 days (without cystoscopy) or late at 6 weeks post-transplantation (with cystoscopy). The primary outcome was a composite of stent-related complications defined as pain, visible haematuria, migration, fragmentation, and urinary tract infections (UTIs) within 3 months of transplantation. Between May 2010 and Nov 2013, we randomly assigned 227 participants, with 205 included in the final analysis of the primary outcome. Stent-related complications were significantly higher in the late compared to the early stent removal group; (36/126, 28.6% vs 6/79, 7.6%; p<0.001). The majority of stent complications consisted of UTIs, with an incidence of 31/126 (24.6%) in the late group compared with 6/79 (7.6%) in the early group; (p=0.004). We found early stent removal on day 5 significantly reduces stent-related complications and improves quality of life in the first 3 months post-transplantation. (International Standard Randomised Controlled Trial Number, 09184595.) This article is protected by copyright. All rights reserved. Copyright This article is protected by copyright. All rights reserved.
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