Obesity is associated with a higher incidence of rejection in patients on belatacept: A pooled analysis from the BENEFIT/BENEFIT-EXT clinical trials.

Though belatacept is administered with a weight-based dosing schema, there has been higher clearance reported in obese patients. Therefore, we evaluated the association between body mass index (BMI) and transplant outcomes in kidney transplant recipients who were randomized to cyclosporine- or belatacept-based immunosuppression in the BENEFIT and BENEFIT-EXT randomized clinical trials. A total of 666 and 543 patients underwent randomization and transplantation in BENEFIT and BENEFIT-EXT, respectively, of which 1056 had complete data and were included in this analysis. Patients were grouped categorically according to BMI: <25, 25 to <30, and ≥30 kg/m2. BMI did influence both the incidence and severity of acute rejection. Obese patients with BMI >30 kg/m2 in the low intensity belatacept group experienced significantly more rejection at 12 months than did patients with BMI <25 kg/m2 or BMI 25 to <30 kg/m2. In both the moderate intensity belatacept and low intensity belatacept groups, obese patients with BMI >30 kg/m2 experienced significantly more severe acute rejection than did patients with BMI < 25 kg/m2 or BMI 25 to <30 kg/m2. These results suggest that obese kidney transplant recipients are at an increased risk for acute rejection when under belatacept-based immunosuppression when compared to nonobese patients.

UNOS Decisions Impact Data Integrity of the OPTN Data Registry.

BACKGROUND: The Organ Procurement Transplant Network (OPTN)/United Network for Organ Sharing (UNOS) registry is an important national registry in the field of solid organ transplantation. Data collected are mission critical, given its role in organ allocation prioritization, program performance monitoring by both the OPTN and the Centers for Medicare & Medicaid Services, and countless observational analyses that helped to move the field forward. Despite the multifaceted importance of the OPTN/UNOS database, there are clear indications that investments in the database to ensure the quality and reliability of the data have been lacking. METHODS: This analysis outlines 2 examples: (1) primary diagnosis for patients who are receiving a second transplant and (2) reporting peripheral vascular disease in kidney transplantation to illustrate the extensive challenges facing the veracity and integrity of the OPTN/UNOS database today. RESULTS: Despite guidance that repeat kidney transplant patients should be coded as "retransplant/graft failure" rather than their native kidney disease, only 59% of new incident patients are coded in this manner. Peripheral vascular disease prevalence more than doubled in a 20-y span when the variable became associated with risk adjustment. CONCLUSIONS: This article summarizes critical gaps in the OPTN/UNOS database, and we bring forward ideas and proposals for consideration as a path toward improvement.

Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort.

BACKGROUND: Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells. METHODS: In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes. RESULTS: Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P = 0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P = 0.0232), and T cell-mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell-mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P = 0.0052) and T cell-mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P = 0.0016). CONCLUSIONS: The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation.

Home Care Delivery and Remote Patient Monitoring of Kidney Transplant Recipients During COVID-19 Pandemic.

Telehealth plays a critical role in the response of healthcare organizations during the COVID-19 pandemic. While telemedicine offers a real-time patient-provider encounter, the inability to obtain vital signs during virtual visits is a potential limitation. Remote patient monitoring (RPM) uses portable devices in the patient's home to collect and electronically transmit physiological data to clinicians. Two kidney transplant recipients were enrolled in RPM in their immediate post-transplant period. Real-time monitoring of their physiological data at home through the RPM in combination with the ability to titrate medications resulted in normalization of the blood pressure and blood glucose measurements by six weeks. Our initial experience demonstrates that RPM is feasible and effective in the post-transplant period and can expand care opportunities on the remote care model. This is more relevant than ever as remote monitoring can facilitate the care of COVID-19-positive transplant patients who require close monitoring while isolated at home.

Outcomes of COVID-19 in solid organ transplant recipients: A matched cohort study.

Whether solid organ transplant (SOT) recipients are at increased risk of poor outcomes due to COVID-19 in comparison to the general population remains uncertain. In this study, we compared outcomes of SOT recipients and non-SOT patients hospitalized with COVID-19 in a propensity score matched analysis based on age, race, ethnicity, BMI, diabetes, and hypertension. After propensity matching, 117 SOT recipients and 350 non-SOT patients were evaluated. The median age of SOT recipients was 61 years, with a median time from transplant of 5.68 years. The most common transplanted organs were kidney (48%), followed by lung (21%), heart (19%), and liver (10%). Overall, SOT recipients were more likely to receive COVID-19 specific therapies and to require ICU admission. However, mortality (23.08% in SOT recipients vs. 23.14% in controls, P = .21) and highest level of supplemental oxygen (P = .32) required during hospitalization did not significantly differ between groups. In this propensity matched cohort study, SOT recipients hospitalized with COVID-19 had similar overall outcomes as non-SOT recipients, suggesting that chronic immunosuppression may not be an independent risk factor for poor outcomes in COVID-19.

Prevalence and predictors of SARS-CoV-2 antibodies among solid organ transplant recipients with confirmed infection.

It remains uncertain whether immunocompromised patients including solid organ transplant (SOT) recipients will have a robust antibody response to SARS-CoV-2 infection. We enrolled all adult SOT recipients at our center with confirmed SARS-CoV-2 infection who underwent antibody testing with a single commercially available anti-nucleocapsid antibody test at least 7 days after diagnosis in a retrospective cohort. Seventy SOT recipients were studied (56% kidney, 19% lung, 14% liver ± kidney, and 11% heart ± kidney recipients). Thirty-six (51%) had positive anti-nucleocapsid antibody testing, and 34 (49%) were negative. Recipients of a kidney allograft were less likely to have positive antibody testing compared to those who did not receive a kidney (p = .04). In the final multivariable model, the years from transplant to diagnosis (OR 1.26, p = .002) and baseline immunosuppression with more than two agents (OR 0.26, p = .03) were significantly associated with the antibody test result, controlling for kidney transplantation. In conclusion, among SOT recipients with confirmed infection, only 51% of patients had detectable anti-nucleocapsid antibodies, and transplant-related variables including the level and nature of immunosuppression were important predictors. These findings raise the concern that SOT recipients with COVID-19 may be less likely to form SARS-CoV-2 antibodies.

Tocilizumab for severe COVID-19 in solid organ transplant recipients: a matched cohort study.

The safety and efficacy of tocilizumab for the treatment of severe respiratory symptoms due to COVID-19 remain uncertain, in particular among solid organ transplant (SOT) recipients. Thus, we evaluated the clinical characteristics and outcomes of 29 hospitalized SOT recipients who received tocilizumab for severe COVID-19, compared to a matched control group who did not. Among a total of 117 total SOT recipients hospitalized with COVID-19, 29 (24.8%) received tocilizumab. The 90-day mortality was significantly higher among patients who received tocilizumab (41%) compared to those who did not (20%, P = .03). When compared to control patients matched by age, hypertension, chronic kidney disease, and administration of high dose corticosteroids, there was no significant difference in mortality (41% vs 28%, P = .27), hospital discharge (52% vs 72%, P = .26), or secondary infections (34% vs 24%, P = .55). Among patients who received tocilizumab, there was also no difference in mortality based on the level of oxygen support (intubated vs not intubated) at the time of tocilizumab initiation. In this matched cohort study, tocilizumab appeared to be safe but was not associated with decreased 90-day mortality. Larger randomized studies are needed to identify whether there are subsets of SOT recipients who may benefit from tocilizumab for treatment of COVID-19.

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

Solid organ transplant recipients may be at a high risk for SARS-CoV-2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty-six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty-two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non-rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID-19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID-19 has the potential to severely impact solid organ transplant recipients.

Using technology to enhance medication regimen education after solid organ transplantation.

PURPOSE: The design and implementation of a tool that combines clinical teaching with cutting-edge, simplified technology for providing medication education to solid organ transplant (SOT) recipients are described. METHODS: In a retrospective study of adults who received kidney transplants from February 2015 through May 2017, patients were educated about their medications using a tablet computer application, Medication Regimen Education (MRxEd), that presented concise videos describing the name, indication, dose, adverse effects, and associated interactions of all medications received, as well as special considerations applicable to each agent. Assessment questions were used to reinforce key concepts and identify knowledge gaps. RESULTS: The digital educational intervention was provided to 282 kidney transplant recipients. Patients were predominantly white (48%) and/or male (63%), with a median age of 51 years (interquartile range, 37-61 years). Patients came from a variety of education backgrounds. Most patients (81%) were educated on dual maintenance immunosuppression (with tacrolimus and mycophenolate) and 3 infection prophylaxis agents (nystatin, sulfamethoxazole-trimethoprim, and valganciclovir). Most patients (90%) correctly answered questions related to medication indications, dosing, and special rules, but many (61%) had difficulty correctly answering questions about adverse effects. CONCLUSION: An innovative approach for interactive and engaging medication teaching with the MRxEd application enhanced the education process for SOT recipients.

Association between the "Timed Up and Go Test" at transplant evaluation and outcomes after kidney transplantation.

BACKGROUND: Studies have demonstrated the Timed Up and Go Test's (TUGT) ability to forecast postoperative outcomes for several surgical specialties. Evaluations of the TUGT for waitlist and posttransplant outcomes have yet to be examined in kidney transplantation. OBJECTIVE: To assess the prognostic utility of the TUGT and its associations with waitlist and posttransplant outcomes for kidney transplant candidates. DESIGN AND METHODS: Single-center, prospective study of 518 patients who performed TUGT during their transplant evaluation between 9/1/2013-11/30/2014. TUGT times were evaluated as a continuous variable or 3-level discrete categorical variable with TUGT times categorized as long (>9 seconds), average (8-9 seconds), or short (5-8 seconds). RESULTS: Transplanted individuals had shorter TUGT times than those who remained on the waitlist (8.99 vs 9.79 seconds, P < 0.001). Bivariable and multivariable logistic regression showed that after adjusting for age, there was no association between TUGT times and probability of waitlist removal (OR 0.997 [0.814-1.221]), prolonged length of stay posttransplant (OR 1.113 [0.958-1.306] for deceased donor, OR 0.983 [0.757-1.277] for living donor), and 30-day readmissions (OR 0.984 [0.845-1.146] for deceased donor, OR 1.254 [0.976-1.613] for living donor). CONCLUSIONS: The TUGT was not associated with waitlist removal or prolonged hospitalization for kidney transplant candidates. Alternative assessments of global health, such as functional status or frailty, should be considered for evaluation of potential kidney transplant candidates.

Dynamic Interplay of Pharmacy Learners During a Solid Organ Transplantation Learning Experience.

Institutions with established clinical pharmacy services have the ability to offer focused patient care learning experiences, often led by a clinical specialist, for pharmacy residents and pharmacy students. Since all parties are continually involved in professional development and lifelong learning, the aforementioned groups can all be considered "pharmacy learners." By utilizing the dynamic interplay and collaboration between pharmacy learners through direct and nondirect patient care activities, experiential and educational opportunities may be improved and enhanced for each learner. A tiered learning approach engages individuals in areas such as direct patient care, patient education, presentations, research projects, career development, and the feedback process. We describe our experience during a solid organ transplantation learning experience using a layered learning practice model that included a clinical pharmacy specialist, a postgraduate year 2 specialty pharmacy resident, a postgraduate year 1 pharmacy resident, and a pharmacy student.

Using known drug interactions to manage supratherapeutic calcineurin inhibitor concentrations.

OBJECTIVES: To summarize the available body of evidence guiding the management of supratherapeutic concentrations of calcineurin inhibitors (CNI) using cytochrome P450 (CYP450) enzyme inducers. METHODS: A nondate restricted literature search within MEDLINE, Embase, and Scopus was performed using the terms "cyclosporine," "tacrolimus," "calcineurin inhibitor," "toxicity," "pharmacokinetics," "carbamazepine," "rifampin," "phenytoin," and "phenobarbital." Additional references were identified from a review of all included citations. All English-language reports that describe the management of supratherapeutic CNI concentrations with interventions targeting metabolic induction using CYP450 enzyme inducers were evaluated. RESULTS: A total of 10 publications were identified in which a CYP450 enzyme inducer was utilized intentionally to enhance CNI clearance in the setting of supratherapeutic concentrations; 7 case reports describe the use of phenytoin and 3 case reports describe the use of phenobarbital. Patient demographics, dosing strategies employed, and reported efficacy across this series of publications are heterogeneous; however, both agents appear to be well-tolerated when used in this setting. CONCLUSIONS: There is a paucity of published data on the use of CYP450 enzyme inducers for the management of supratherapeutic CNI concentrations. While routine use of this approach cannot be recommended, thorough risk-benefit analyses should be performed in the management of each such clinical scenario.

Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents.

BACKGROUND: Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. METHODS: We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. RESULTS: Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). CONCLUSIONS: Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant.

Acyclovir versus valganciclovir for preventing cytomegalovirus infection in intermediate-risk liver transplant recipients.

CONTEXT: Cytomegalovirus (CMV) is an opportunistic infection that causes profound morbidity and mortality after orthotopic liver transplant (OLT). The CMV immunoglobulin G serostatuses of donors and recipients are the main factors influencing risk for development of CMV infection after transplant. OBJECTIVE: To compare acyclovir and valganciclovir for preventing CMV infection after OLT. DESIGN, SETTING, AND PATIENTS: Retrospective assessment of adult OLT recipients at intermediate risk for CMV infection at New York Presbyterian Hospital. INTERVENTION: All patients received ganciclovir 5 mg/kg intravenously every 12 hours or valganciclovir 900 mg orally every 12 hours for 7 days after transplant. On postoperative day 8, patients received antiviral prophylaxis according to risk stratification: acyclovir 800 mg orally 3 times daily in donor seronegative/recipient seropositive (D-/R+) patients or valganciclovir 900 mg orally once daily in donor seropositive/recipient seropositive (D+/R+) patients. MAIN OUTCOME MEASURE: Composite incidence of CMV infection, syndrome, or tissue-invasive disease. RESULTS: Of 275 OLT recipients, 89 were at intermediate risk for CMV infection (29 D-/R+, 60 D+/R+). CMV infection, syndrome, or tissue-invasive disease occurred in 1 patient (3%) in the D-/R+ group and 5 patients (8%) in the D+/R+ group (P=.66). One patient (3%) in the D-/R+ group had a CMV infection develop. Five D+/R+ recipients (8%) had CMV infection; 3 of them had CMV syndrome (5%), 1 had CMV hepatitis (1.6%), and the other had CMV esophagitis (1.6%); all events occurred after prophylaxis was discontinued. The rates of CMV infection were similar in D-/R+ patients treated with acyclovir and D+/R+ patients receiving valganciclovir. This risk-stratified approach to viral prophylaxis after OLT resulted in an acceptable rate of CMV infection in D-/R+ recipients and may avoid the costs and adverse effects associated with valganciclovir therapy.

Clostridium difficile infection, a descriptive analysis of solid organ transplant recipients at a single center.

Clostridium difficile is a bacterial enteric pathogen, which causes clinical disease among solid organ transplant (SOT) recipients. This large, single-center, retrospective study describes incidence, demographics, and impact of C. difficile infection (CDI) among adult SOT recipients, cardiac (n=5), lung (n=14), liver (n=9), renal (n=26), and multiorgan (n=9) patients transplanted and diagnosed with CDI (geneB PCR) between 9/2009 and 12/2012. The overall incidence of CDI in our population during the 40-month period of study was 4%. CDI incidence among cardiac, lung, liver, and renal transplant recipients was 1.9%, 7%, 2.7%, and 3.2%, respectively (P=0.03 between organ-types). Median time from transplant to CDI for all was 51 (14-249) days, with liver recipients having the shortest time to infection, median 36 (15-101) days, and lung recipients having a longer time to infection, median 136 (29-611) days. Antibiotic exposure within 3 months of CDI was evident in 45 of the 63 (71%) patients in this study, 80%, 79%, 100%, 58%, and 67% of cardiac, lung, liver, renal, and multiorgan transplant recipients, respectively. Most patients (83%) were hospitalized within the 3 months preceding CDI. Recipients were followed for a median time of 23 (16-31) months; at the time of last follow-up, 83% of allografts were functioning, and 86% of patients were alive. One death and 1 graft failure were causally related to CDI. CDI had an overall incidence of 4%; clinicians should have heightened awareness for CDI, especially among patients receiving antibiotics, with increased monitoring and aggressive management of CDI.

Preformed donor-specific antibodies and risk of antibody-mediated rejection in repeat renal transplantation.

BACKGROUND: Allograft outcomes in patients undergoing repeat renal transplantation are inferior compared to first-time transplant recipient outcomes. Donor-specific antibodies detected by solid-phase assays (DSA-SPA) may contribute to the worse prognosis. The influence of DSA-SPA on repeat renal transplantation outcomes has not been previously studied in detail. DESIGN: This study reports the findings in 174 patients who underwent repeat renal transplantation between years 2007 and 2012. These included 62 patients with preformed DSA-SPA detected by Luminex at the time of transplantation. Patients received standard and consistent immunosuppression and were monitored closely for evidence of rejection. Recipients who underwent desensitization were excluded from this analysis. Endpoints included development of biopsy-proven acute rejection and analysis of graft survival and function. RESULTS: Patients in the DSA-SPA-positive and DSA-SPA-negative groups received similar immunosuppression, and a similar proportion of recipients had a peak panel reactive antibody greater than 20%; the two groups differed with respect to human leukocyte antigen mismatches (4.7 ± 1.1 vs. 4.1 ± 1.7, P=0.024). Recipients with preformed DSA-SPA had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001). Recipients who were DSA-SPA-positive and flow cytometry crossmatch (FCXM)-positive had a higher incidence of both AMR (OR 4.6, P=0.009) and of acute rejection (OR 3.57, P=0.02) as compared to those who were DSA-SPA-positive and FCXM-negative. Overall allograft survival was similar in the DSA-SPA-positive and DSA-SPA-negative groups (log-rank test=0.63, P=0.428). Differences in allograft function were detectable after 2 years (32.8 ± 13.1 vs. 47 ± 20.2 mL/min/1.73 m(2), P=0.023) and may be reflective of more AMR among DSA-SPA-positive patients. CONCLUSIONS: This analysis suggests that DSA-SPA increases the overall risk of acute rejection but does not appear to adversely impact allograft survival during the early follow-up period. Close monitoring of renal function and early biopsy for AMR detection appear to allow for satisfactory short-term allograft outcomes in repeat transplant recipients.