The clinical and molecular epidemiology of pre‐transplant vancomycin‐resistant enterococci colonization among liver transplant recipients

Vancomycin‐resistant enterococci (VRE) infections cause significant morbidity in liver transplant recipients. The epidemiology and impact of pre‐transplant colonization with VRE among patients who undergo liver transplantation are poorly understood. We conducted an observational cohort study to identify risk factors and outcomes associated with pre‐transplant VRE colonization and described the molecular diversity among VRE strains colonizing patients who undergo liver transplantation. Perirectal VRE surveillance cultures were performed prior to transplantation. Repetitive sequence‐based polymerase chain reaction (rep‐PCR) testing was used to identify clonality among VRE isolates. Of 61 patients who underwent pre‐transplant VRE surveillance and subsequent liver transplantation, 27 (44%) were colonized with VRE. In multivariate analysis, pre‐transplant VRE colonization was associated with central venous catheterization (OR 9.4, 95% confidence interval [CI]= 1.3–70.2, p = 0.03) and rifaximin use (OR 15.4, 95% CI 1.5–159.7, p = 0.02). Pre‐transplant VRE colonization was associated with more hospital days post‐transplant (26.6 vs. 16.1 d, p = 0.04). Of VRE‐colonized patients analyzed with rep‐PCR, 68% were colonized with the same strain as another patient in the cohort. Active surveillance identifies VRE‐colonized patients who may benefit from targeted antimicrobial prophylaxis and enhanced infection prevention measures to prevent VRE spread. The relationship between rifaximin receipt and VRE colonization warrants further study. The identification of similar VRE isolates may suggest linked transmission during pre‐transplant hospitalizations, which should be further investigated in prospective studies.     

Associations between pre‐kidney‐transplant risk factors and post‐transplant cardiovascular events and death

The prevalence of cardiovascular risk factors in renal transplant candidates is high. A better understanding of the relation between these risk factors and cardiovascular morbidity and mortality is mandatory to improve transplantation outcome. In this retrospective cohort study 2187 adult patients who received a first kidney transplant between 1984 and 1997 were included. We analyzed the incidence of post‐transplant cardiovascular events and tried to identify independent pretransplant risk factors for post‐transplant cardiovascular events and all‐cause mortality. The cumulative incidence of post‐transplant cardiovascular events was 40%. The incidence was highest in the first 3 months after transplantation. Independent pretransplant risk factors for a post‐transplant cardiovascular event were diabetic nephropathy [Hazard ratio (HR) 3.02; 95% CI 2.85–3.98], claudication [HR 2.17 (1.42–3.31)], cardiac event [HR 1.76 (1.32–2.33)], cerebrovascular accident HR 1.53 (1.03–2.28), time‐on‐dialysis [HR 1.06 (1.02–1.11)], recipient age [HR 1.04 (1.04–1.05)], and body mass index [HR 1.03 (1.00–1.05)]. Diabetic nephropathy and cardiovascular disease were also important predictors for all‐cause mortality. Diabetic nephropathy and cardiovascular disease were the most important predictors for cardiovascular events and all‐cause mortality after renal transplantation. Early treatment of cardiovascular risk factors and pretransplant cardiovascular evaluation might improve transplantation outcome.     

Early clinical experience using donor‐derived cell‐free DNA to detect rejection in kidney transplant recipients

Donor‐derived cell‐free DNA (dd‐cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd‐cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor–specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd‐cfDNA was higher among patients with antibody–mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%‐1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%‐1.10%; P < .001) and cell–mediated rejection (CMR; median: 0.27%, IQR: 0.19%‐1.30%; P = .01). The dd‐cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17‐0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71‐0.93) and a dd‐cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd‐cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.     

Systematic review and meta‐analysis of post‐transplant lymphoproliferative disorder in lung transplant recipients

A systematic review of papers in English on post‐transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random‐effects model, and heterogeneity among studies was quantitated using I² values. Fourteen studies published from 2005 to 2015 were included in the meta‐analysis. One hundred and sixty‐four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67‐fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98‐29.70; P = .003). pOR of death for early onset PTLD (<1 year post‐LT) vs late onset (> 1 year post‐LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20‐1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI ?0.48‐0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08‐2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31‐3.52, P = .94). This meta‐analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.     

Forty‐eight hour kidney transplant admissions

Forty‐eight hour kidney transplantation admissions are a feasible option in selected recipients of live‐donor allografts through the use of standardized post‐operative protocols, multidisciplinary team patient care, and intensive follow‐up at outpatient centers. Age, gender, and pre‐transplant dialysis status did not impact the ability to achieve 48‐hour admissions. We did not identify any other pre‐operative risk factors that contributed to increased length of stay. Although ABO and highly sensitized recipients had longer lengths of stay, the subgroup was too small to achieve statistical significance. We did not encounter any readmissions within the first seven post‐operative days. Further improvements in clinical management will enhance the potential to shorten the length of hospital stay for all kidney transplant recipients.     

Pre‐transplant shedding of BK virus in urine is unrelated to post‐transplant viruria and viremia in kidney transplant recipients

BK virus‐(BKV) associated nephropathy (BKVN) is a major cause of allograft injury in kidney transplant recipients. In such patients, subclinical reactivation of latent BKV infection can occur in the pre‐transplant period. The purpose of this study was to determine whether urinary BKV shedding in the immediate pre‐transplant period is associated with a higher incidence of viruria and viremia during the first year after kidney transplantation. We examined urine samples from 34 kidney transplant recipients, using real‐time quantitative polymerase chain reaction to detect BKV. Urine samples were obtained in the immediate pre‐transplant period and during the first year after transplant on a monthly basis. If BKV viruria was detected, blood samples were collected and screened for BKV viremia. In the immediate pre‐transplant period, we detected BKV viruria in 11 (32.3%) of the 34 recipients. During the first year after transplantation, we detected BKV viruria in all 34 patients and viremia in eight (23.5%). We found no correlation between pre‐transplant viruria and post‐transplant viruria or viremia (p = 0.2). Although reactivation of latent BKV infection in the pre‐transplant period is fairly common among kidney transplant recipients, it is not a risk factor for post‐transplant BKV viruria or viremia.     

Medication understanding,non‐adherence,and clinical outcomes among adult kidney transplant recipients

We sought to evaluate the prevalence of medication understanding and non‐adherence of entire drug regimens among kidney transplantation (KT) recipients and to examine associations of these exposures with clinical outcomes. Structured, in‐person interviews were conducted with 99 adult KT recipients between 2011 and 2012 at two transplant centers in Chicago, IL; and Atlanta, GA. Nearly, one‐quarter (24%) of participants had limited literacy as measured by the Rapid Estimate of Adult Literacy in Medicine test; patients took a mean of 10 (SD=4) medications and 32% had a medication change within the last month. On average, patients knew what 91% of their medications were for (self‐report) and demonstrated proper dosing (via observed demonstration) for 83% of medications. Overall, 35% were non‐adherent based on either self‐report or tacrolimus level. In multivariable analyses, fewer months since transplant and limited literacy were associated with non‐adherence (all P<.05). Patients with minority race, a higher number of medications, and mild cognitive impairment had significantly lower treatment knowledge scores. Non‐white race and lower income were associated with higher rates of hospitalization within a year following the interview. The identification of factors that predispose KT recipients to medication misunderstanding, non‐adherence, and hospitalization could help target appropriate self‐care interventions.     

Post‐transplant lymphoproliferative disorders with naso‐ and oropharyngeal manifestation

The nasopharyngeal/oropharyngeal lymphatic tissues represent the anatomical site of Epstein–Barr virus (EBV) entry. Post‐transplant lymphoproliferative disorders (PTLD) are often associated with EBV, but little is known about the characteristics of nasopharyngeal/oropharyngeal mass‐forming PTLD. Retrospective evaluation of our own PTLD database (n = 79) and the PubMed^® database (n = 61) has been performed. Sinonasal/oro‐/nasopharyngeal lymphatic masses were early lesions (n = 54/140, 38.5%), polymorphic PTLD (n = 32/140, 23%), monomorphic B‐PTLD (n = 47/140, 33.5%) and T‐PTLD (n = 7/140, 5%). One‐fourth of lesions manifested as masses in the Waldeyer's ring, and in two‐thirds of cases, swelling of tonsils was related to manifestation of benign early lesions. Tonsil infiltration by polymorphic PTLD and monomorphic PTLD was present in one‐third of cases. Extratonsillar masses were mainly monomorphic PTLD. Meta‐analysis of our data in combination with previously published data revealed that lung transplantation and young patients are at a higher risk for earlier manifestation of monomorphic PTLD. Therapy is similar to PTLD therapy strategies, in general reduced immunosuppression and chemotherapy for polymorphic and monomorphic PTLD, and diagnostic and therapeutic surgical gross tumour resection of tonsillar/adenoid lesions. In summary, it is relevant for the clinical differential diagnosis that oro‐/nasopharyngeal aggressive PTLD manifested in ~30% as tonsillar masses and >90% at extratonsillar sites.     

Clopidogrel reduces post‐transplant obliterative bronchiolitis

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2^b) donor tracheas were orthotopically transplanted into CBA.J(H2^k). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real‐time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration [34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05]. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL‐12, IL‐4, IL‐6, TNF‐α, TGF‐β, PDGFβ, MCP1, P‐/E‐selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor‐specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.     

COVID‐19 in kidney transplant recipients

There is minimal information on coronavirus disease 2019 (COVID‐19) in immunocompromised individuals. We have studied 10 patients treated at 12 adult care hospitals. Ten kidney transplant recipients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by polymerase chain reaction, and 9 were admitted. The median age was 57 (interquartile range [IQR] 47‐67), 60% were male, 40% Caucasian, and 30% Black/African American. Median time from transplant to COVID‐19 testing was 2822 days (IQR 1272‐4592). The most common symptom was fever, followed by cough, myalgia, chills, and fatigue. The most common chest X‐ray and computed tomography abnormality was multifocal patchy opacities. Three patients had no abnormal findings. Leukopenia was seen in 20% of patients, and allograft function was stable in 50% of patients. Nine patients were on tacrolimus and a mycophenolic antimetabolite, and 70% were on prednisone. Hospitalized patients had their antimetabolite agent stopped. All hospitalized patients received hydroxychloroquine and azithromycin. Three patients died (30%), and 5 (50%) developed acute kidney injury. Kidney transplant recipients infected with COVID‐19 should be monitored closely in the setting of lowered immunosuppression. Most individuals required hospitalization and presenting symptoms were similar to those of nontransplant individuals.