Pulsed oral sirolimus in advanced autosomal-dominant polycystic kidney disease (Vienna RAP Study) : study protocol for a randomized controlled trial

Background Autosomal-dominant polycystic kidney disease (ADPKD) is a hereditary illness that causes renal tubular epithelial cells to form cysts that proliferate and destroy renal tissue. This usually leads to a decline in renal function, and often to terminal kidney failure, with need for renal replacement therapy. There is currently no causative therapy. The mammalian target of rapamycin (mTOR) inhibitor sirolimus (SIR) is an immunosuppressant with strong antiproliferative effects, and is potentially able to stop or reduce cyst growth and preserve renal function in ADPKD. Continuous mTOR exposure results in a loss of its antiproliferative effects on renal tubular cells. With a half-life of roughly 60 hours, pulsed (weekly) administration of SIR may be an effective way to reduce cyst growth and preserve excretory renal function in ADPKD. Methods/Design The Vienna RAP Study is a randomized, double-blind, placebo-controlled trial, funded by the Anniversary Fund of the Oesterreichische Nationalbank. We will investigate the effects of a weekly dose of 3 mg SIR on kidney function in 34 patients with advanced ADPKD, compared to a placebo equivalent in 34 patients with advanced ADPKD, over 24 months. The primary endpoint is creatinine level (less or equal than 1.5-fold increase in serum creatinine without initiation of dialysis over two years) and dialysis, renal transplantation, or death. The secondary endpoints are safety, change in proteinuria (as indicated by albumin/creatinine- and protein/creatinine ratio, respectively), and creatinine clearance. Discussions The Vienna RAP Study is, to the best of our knowledge, the first study to investigate the effects of a pulsed (weekly) dose of SIR on renal function in ADPKD.(VLID)486735

PLOS One / Late Conversion of Kidney Transplant Recipients from Ciclosporin to Tacrolimus Improves Graft Function : Results from a Randomized Controlled Trial

Background Tacrolimus (TAC) to ciclosporin A (CSA) conversion studies in stable kidney transplant recipients have reported varying effects on graft function. Here we study graft function (eGFR) trajectories using linear mixed models, which provide effect estimates on both slope and baseline level of GFR and offer increased statistical power. Methods Secondary analysis of a randomized controlled trial of CSA treated kidney transplant recipients with stable graft function assigned to receive 0.1 mg/kg/day TAC (target 58 ng/ml) or to continue CSA based immunosuppression (target 70150 ng/ml) at a 2:1 ratio. Renal graft function was estimated via the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) formulas. Results Forty-five patients continued CSA and 96 patients were converted to TAC with a median follow up of 24 months. Baseline demographics (except for recipient age) including native kidney disease, transplant characteristics, kidney graft function, medication use and comorbid conditions did not differ between groups. In respect to long-term renal graft function, linear mixed models showed significantly improved eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001) in the TAC versus CSA group over 24 months of follow up. Estimated eGFRCKD-EPI group differences between TAC and CSA were 3.49 (p = 0.019) at 3 months, 5.50 (p<0.001) at 12 months, and 4.48 ml/min/1.73m2 (p = 0.003) at 24 months of follow up. Baseline eGFR was a significant predictor of eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001). Significant effects for randomization group were evident despite short-term trough levels in the supratherapeutic range (27% (n = 26) of TAC patients at week one). Median TAC trough levels were within target range at week 4 after conversion. Conclusion Conversion of CSA treated kidney transplant recipients with stable graft function to TAC (target 58 ng/ml) showed significantly improved long-term eGFR trajectories when compared to CSA maintenance (target 70150 ng/ml).(VLID)492411

Randomized, Single Blind, Controlled Trial to Evaluate the Prime-Boost Strategy for Pneumococcal Vaccination in Renal Transplant Recipients

<div><h3></h3><p>Renal transplant recipients are at increased risk of developing invasive pneumococcal diseases but may have poor response to the 23-valent pneumococcal polysaccharide vaccine (PPV). It may be possible to enhance immunogenicity by priming with 7-valent pneumococcal conjugate vaccine (7vPnC) and boosting with PPV 1 year later. In a randomized single-blind, controlled study, adult recipients of renal transplants received either 7nPVC or PPV followed by PPV 1 year later. The vaccine response was defined as 2-fold increase in antibody concentration from baseline and an absolute post-vaccination values ≥1 µg/ml. The primary endpoint was vaccine response of the primed group (7vPnC/PPV) compared with single PPV vaccination. Antibody concentrations for 10 serotypes were measured at baseline, 8 weeks after first vaccination, before second vaccination, and 8 weeks after second vaccination. Of 320 screened patients, 80 patients were randomized and 62 completed the study. Revaccination with PPV achieved no significant increase of immune response in the 7vPnC/PPV group compared with the single PPV recipients A response to at least 1 serotype was seen in 77.1% of patients who received 7vPnC and 93.1% of patients who received PPV (<em>P</em> = 0.046). After second vaccination response to at least 1 serotype was seen in 87.5% patients of 7vPnC/PPV group and 87.1% patients of PPV group (non significant p). The median number of serotypes eliciting a response was 3.5 (95% CI 2.5–4.5) in the 7vPnC/PPV group versus 5 (95% CI 3.9–6.1) in the PPV group (non-significant p). Immunogenicity of pneumococcal vaccination was not enhanced by the prime–boost strategy compared with vaccination with PPV alone. Administration of a single dose of PPV should continue to be the standard of care for adult recipients of renal transplants.</p> <h3>Trial Registration</h3><p>EudraCT 2007-004590-25.</p> </div

A non-randomized trial of conversion from ciclosporin and tacrolimus to tacrolimus MR4 in stable long-term kidney transplant recipients: Graft function and influences of ABCB1 genotypes.

TRIAL REGISTRATION:PEP Study: Ethics committee N° 393/2004, EudraCT 2004-004209-98. PEP-X Study: Ethics committee amendment application N° 154/01/2008. ClinicalTrials.gov NCT03751332

Geometric mean concentrations (95% CI), expressed as µg/mL, of serotype-specific anti-pneumococcal IgG serum antibody at baseline, 8 weeks, and 1 year after vaccination with 7vPnC and PPV, and 8 weeks after revaccination with PPV.

<p>Serotypes 1, 5, and 7F are not included in the 7vPnC vaccine.</p>a<p>P<0.001 for fold increase at weeks 8 weeks, vs. 7vPNC vaccine (Mann–Whitney U Test).</p>b<p>P<0.01 for fold increase at weeks 8 weeks, vs. 7vPNC vaccine (Mann–Whitney U Test).</p>c<p>P<0.001 for fold increase at weeks 8 weeks, vs. 7vPNC vaccine (Mann–Whitney U Test.</p>d<p>P = 0.049 for fold increase at weeks 8 weeks, vs 7vPNC vaccine (Mann–Whitney U Test).</p>e<p>P = 0.004 for fold increase at weeks 8 weeks, vs 7vPNC vaccine (Mann–Whitney U Test).</p

Consort flow diagram.

<p>Consort flow diagram.</p

TAC group eGFR and trough level fluctuations.

<p>Mean eGFR_CKD-EPI (solid line) and trough levels (dashed line) for the TAC study group at baseline, weeks 1, 2, 4, 8, and 3, 12 and 24 months after conversion.</p

Baseline Demographics for Patients Randomized to CSA and TAC.

<p>Baseline Demographics for Patients Randomized to CSA and TAC.</p