Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Chronically Immunosuppressed Adults Following Renal Transplant: A Phase 3, Randomized Clinical Trial.

BACKGROUND: The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy. METHODS: In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2. RESULTS: Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups. CONCLUSIONS: RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose. CLINICAL TRIALS REGISTRATION: NCT02058589.

DAMPAned Methotrexate: A Case Report and Review of the Management of Acute Methotrexate Toxicity.

RATIONALE: Consensus guidelines on the management of methotrexate-induced nephrotoxicity using glucarpidase (Voraxaze) may be relatively unfamiliar to the nephrology community. PRESENTING CONCERNS OF THE PATIENT: A 61-year-old man with intravascular large B-cell lymphoma was admitted for cycle #1 of high-dose methotrexate (HDMTX) following 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. On admission, he was clinically euvolemic and had a creatinine clearance of 98 mL/min. He received standard HDMTX toxicity prophylaxis with volume expansion, urinary alkalinization, and leucovorin rescue. DIAGNOSES: Despite prophylactic efforts, he developed a severe acute kidney injury, creatinine 63 to 226 µmol/L (2.56 mg/dL), following HDMTX, impaired methotrexate clearance, and neurotoxicity manifested by status epilepticus. INTERVENTIONS: He was given glucarpidase to convert extracellular methotrexate into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino-N 10-methylpteroic acid) at 52 hours post-HDMTX. Cross-reactivity between commercial methotrexate immunoassays with DAMPA led to falsely elevated methotrexate concentrations for much longer than expected based on the current guideline (5 days instead of <48 hours). This required ongoing monitoring of methotrexate concentration by mass spectrometry. OUTCOMES: The patient remained nonoliguric and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX. He ultimately had a full renal and neurologic recovery. LESSONS LEARNED: Glucarpidase is an effective option for nonrenal elimination of methotrexate-induced nephrotoxicity. Timing of methotrexate concentration monitoring to assess for toxicity, how to access the drug, and the need for ongoing monitoring by mass spectrometry beyond the guideline recommendation are highlighted for centers where HDMTX therapy may be used.

JUSTIFICATION: Les lignes directrices consensuelles sur la prise en charge de la néphrotoxicité induite par le méthotrexate par l'administration de glucarpidase (VoraxazeMD) sont possiblement mal connues en néphrologie. PRÉSENTATION DU CAS: Nous présentons le cas d'un patient de 61 ans atteint d'un lymphome intravasculaire à grandes cellules B qui avait été admis pour un cycle de traitement à dose élevée de méthotrexate (HDMTX) après deux cycles de chimiothérapie par R-CHOP. À l'admission, le patient était cliniquement euvolémique et présentait une clairance de la créatinine à 98 mL/min. Le patient a reçu la prophylaxie standard pour une toxicité à HDMTX avec expansion volumique, alcalinisation urinaire et sauvetage par leucovorine. DIAGNOSTIC: Malgré les mesures prophylactiques, l'état du patient a évolué vers une grave insuffisance rénale aigüe (créatinine initiale de 63 à 226 µmol/L [2,56 mg/dL]) après le traitement au HDMTX, de même qu'une altération de la clairance du méthotrexate et une neurotoxicité manifestée par un status epilepticus. INTERVENTIONS: Le patient a reçu du glucarpidase pour convertir le méthotrexate extracellulaire en ses métabolites inactifs, le glutamate et le DAMPA (acide 4-déoxy-4-amino-N 10-méthylptéroïque) 52 heures après le traitement au HDMTX. La réactivité croisée entre les immunoessais commerciaux au méthotrexate et le DAMPA a entraîné des concentrations faussement élevées de méthotrexate pour beaucoup plus longtemps que prévu selon la recommandation actuelle (5 jours plutôt que < 48 heures). Cette situation a nécessité une surveillance continue de la concentration du méthotrexate par spectrométrie de masse. RÉSULTATS: Le patient est demeuré non oligurique et n'a pas nécessité de dialyse. Le taux de créatinine sérique a culminé à 608 µmol/L (6,88 mg/dL) six jours après l'administration de HDMTX. Les fonctions rénale et neurologique du patient se sont finalement rétablies complètement. LEÇONS TIRÉES: La glucarpidase est une option efficace pour éliminer de façon non rénale la néphrotoxicité induite par le méthotrexate. Le moment de mesurer la concentration de méthotrexate pour évaluer la toxicité, la façon d'accéder au médicament et la nécessité d'une surveillance continue par spectrométrie de masse au-delà de la recommandation actuelle sont clarifiés pour les centres où un traitement par HDMTX pourrait être administré.

Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial.

IMPORTANCE: BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies. OBJECTIVE: To determine if levofloxacin can prevent BK viruria in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013. INTERVENTIONS: Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation. MAIN OUTCOMES AND MEASURES: The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival. RESULTS: The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95). CONCLUSIONS AND RELEVANCE: Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01353339.

Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial.

BACKGROUND: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. METHODS/DESIGN: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. DISCUSSION: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. TRIAL REGISTRATION: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).