Impact of early corticosteroid withdrawal on simultaneous pancreas-kidney transplant long-term outcomes: Single center experience and comparison to the International Pancreas Transplant Registry.

BACKGROUND: There remains a paucity of modern data comparing early steroid withdrawal (ESW) versus chronic corticosteroid (CCS) immunosuppression in simultaneous pancreas kidney (SPK) transplant recipients with long-term follow-up. Therefore, the purpose of this study is to assess the effectiveness and tolerability of ESW compared to CCS post-SPK. METHODS: This was a retrospective single-center matched comparison with the International Pancreas Transplant Registry (IPTR). Patients from University of Illinois Hospital (UIH) represented the ESW group and were compared to those matched CCS patients from the IPTR. Included patients were adult recipients of a primary SPK transplant between 2003 and 2018 within the US receiving rabbit anti-thymocyte globulin induction. Patients were excluded if they had early technical failures, missing IPTR data, graft thrombosis, re-transplant, or positive crossmatch SPK. RESULTS: A total of 156 patients were matched and included in the analysis. Patients were predominantly African American (46.15%) males (64.1%) with Type 1 diabetes etiology (92.31%). Overall pancreas allograft survival (hazard ratio [HR] = .89, 95% confidence interval [CI] .34-2.30, p = .81) and kidney allograft survival (HR = .80, 95%CI .32-2.03, p = .64) were similar between the two groups. Immunologic pancreas allograft loss was statistically similar at 1-year (ESW 1.3% vs. CCS 0%, p = .16), 5-year (ESW 1.3% vs. CCS 7.7%, p = .16), and 10-year (ESW 11.0% vs. CCS 7.7%, p = .99). The 1-year (ESW 2.6% vs. CCS 0%, p > .05), 5-year (ESW 8.3% vs. CCS 7.0%, p > .05), and 10-year (ESW 22.7% vs. CCS 9.9%, p = .2575) immunologic kidney allograft loss were also statistically similar. There was no difference in 10-year overall patient survival (ESW 76.2% vs. CCS 65.6%, p = .63). CONCLUSIONS: No differences were found between allograft or patient survival post-SPK when comparing an ESW or CCS protocol. Future assessment is needed to determine differences in metabolic outcomes.

A systematic review of opioid use and multimodal strategies in solid organ transplant recipients and living donors.

The opioid epidemic has impacted analgesia in the postoperative period for solid organ transplant (SOT) donors and recipients. However, optimal pain management and opioid stewardship strategies have not been identified across this unique population. The purpose of this systematic review was to evaluate the impact of perioperative opioid use and to describe multimodal analgesic strategies to reduce opiate use in SOT recipients and living donors. A systematic review was conducted. Electronic searches were performed in Medline, Embase, Google Scholar, and Web of Science through December 31, 2021. Title and abstracts were screened. Relevant articles underwent full-text review. Literature was separated into effects of opioid exposure on post-transplant outcomes, recipient pain management strategies, and living donor pain management strategies. Search yielded 25,190 records, and 63 were ultimately included. The impact of opioid use on post-transplant outcomes was assessed in 19 publications. The risk of graft loss in pretransplant opioid users was assessed in six reports and was found to be higher in the majority (66%) of publications. Opioid minimization strategies were reported in 20 studies in transplant recipients. Twenty-four studies evaluated pain management strategies in living donors. Both populations used a combination of multimodal strategies to minimize opioid use throughout the hospitalization and on discharge. Opioids are associated with select negative outcomes in post-transplant recipients. To minimize their use while also maintaining appropriate analgesia, multimodal pain regimens should be considered in SOT recipients and donors.

Pain Interference in End Stage Kidney Disease is Associated with Changes in Gut Microbiome Features Before and After Kidney Transplantation.

BACKGROUND: Pain, a common debilitating symptom among kidney transplant recipients (KTRs), is among the most common and undertreated symptoms after kidney transplantation. AIMS: Characterize associations between gut microbiome features and pain interference before and after kidney transplantation. DESIGN: Longitudinal, repeated measures study, collecting fecal specimens and pain interference data pretransplant and 3 months posttransplant. SETTING: Participants were recruited at the kidney transplant clinic at the University of Illinois Hospital & Health Sciences System. PARTICIPANTS/SUBJECTS: 19 living donor kidney transplant recipients. METHODS: We assessed fecal microbial community structure with shotgun metagenomic sequencing; we used pain interference scores derived from the Patient-Reported Outcomes Measurement Information System-57. RESULTS: We measured a reduction in the Shannon diversity index in both groups after transplantation but observed no significant differences between groups at either time point. We did observe significant differences in fecal microbial Bray-Curtis similarity index among those reporting pain interference pre- transplant versus no pain interference at 3-months posttransplant (R = .306, p = .022), and between pain interference groups at posttransplant (R = .249, p = .041). Pairwise models showed significant differences between groups posttransplant in relative abundances of several taxa, including a 5-fold reduction.ßin Akkermansia among those with pain interference and a higher relative abundance of taxa associated with chronic inflammation in those with pain interference posttransplant. Functional gene analysis identified two features that were significantly enriched in those with pain interference, including a peptide transport system gene. CONCLUSIONS: Gut microbiota community structure differs between groups with and without pain interference at 3 months after kidney transplantation. Several taxa involved in intestinal barrier integrity and chronic inflammation were associated with posttransplant pain.

Clinical Implications of Tacrolimus Time in Therapeutic Range and Intrapatient Variability in Urban Renal Transplant Recipients Undergoing Early Corticosteroid Withdrawal.

Tacrolimus demonstrates wide intrapatient and interpatient variability requiring therapeutic drug monitoring. The utility of tacrolimus time in therapeutic range (TTR) after renal transplantation (RT) under an early corticosteroid withdrawal (ECSWD) protocol is unknown. The purpose of this study is to assess the impact of tacrolimus TTR in an ECSWD RT population. MATERIALS: A retrospective analysis of adult RT recipients maintained on tacrolimus was conducted. Patients were excluded if they were on nonstandard protocol immunosuppression agents <12 months post-RT. Tacrolimus TTR was calculated using the Rosendaal method. Patients were divided into high (TTR-H) and low (TTR-L) TTR groups based on cohort median. The primary outcome was to compare the incidence of acute rejection 12 months post-RT. Secondary outcomes included comparing rejection subtypes, incidence of donor-specific antibody (DSA) and de novo DSA (dnDSA), risk factors for acute rejection and dnDSA development, and allograft function (serum creatinine and estimated glomerular filtration rate). RESULTS: A total of 193 patients were analyzed (TTR-H = 98 and TTR-L = 95). There was no difference in the incidence of acute rejection (TTR-H 20.4% versus TTR-L 20.0%; P = 0.944). Positive DSA posttransplant (odds ratio [OR], 3.62; 95% confidence interval [CI], 1.41-9.26; P = 0.007) was associated with a higher acute rejection at 12 months posttransplant. Mycophenolate dose reduction (OR, 2.82; 95% CI, 1.13-6.97; P = 0.025) and acute rejection (OR, 2.99; 95% CI, 1.09-8.18; P = 0.032) were associated with dnDSA formation. No difference in serum creatinine or estimated glomerular filtration rate was observed (P > 0.05). CONCLUSIONS: Tacrolimus TTR was not significantly different with regards to acute rejection in an ECSWD population. Future studies are still needed to determine tacrolimus TTR thresholds post-RT and identify populations that may benefit from this intrapatient variability monitoring parameter.

Use of direct-acting oral anticoagulants in solid organ transplantation: A systematic review.

The use of direct-acting oral anticoagulants (DOACs) has increased secondary to the mounting evidence for comparable efficacy and potentially superior safety to vitamin K antagonists (VKAs) in the general population. However, insufficient data regarding DOAC use in solid organ transplant (SOT) recipients and numerous pharmacokinetic and pharmacodynamic considerations limit their use in this highly selected patient population. A systematic review of recent clinical evidence on the safety and efficacy of DOACs compared to VKAs in SOT recipients was conducted. Additional considerations including transplant-specific strategies for DOAC reversal and common pharmacokinetic/pharmacodynamic concerns were also reviewed. Although current evidence is limited to single-center retrospective analyses, DOACs, especially apixaban, appear to be a safe and effective alternative to VKAs for SOT recipients with stable graft function and without drug-drug interactions. Reliable data on DOAC reversal at the time of transplant surgery are lacking, and clinicians should consider idarucizumab, andexanet alfa, and other non-specific reversal agents on an individual patient basis. There is no evidence supporting deviations from the Food and Drug Administration labeling recommendations for DOAC dosing in the setting of drug-drug interactions, obesity, and renal function, especially in patients on hemodialysis.

Factors Influencing Emergency Department Utilization and Hospital Re-Admissions in a Predominantly Obese, Racially Diverse Urban Renal Transplant Population.

INTRODUCTION: Early emergency department and hospital re-admissions are common in renal transplant recipients, but data are lacking in unique populations. Study Aim: The purpose of this study was to identify patient risk factors for multiple acute care utilization events within the first year of renal transplantation. DESIGN: This was a single-center, retrospective cohort study of adult renal transplant recipients between 9/2013-9/2016. Patients were compared across number of emergency department visits and by hospital re-admissions. Diagnoses were categorized. Univariate and multivariate logistic regression was used to assess risk for multiple acute care utilization events within the first 12 months post-transplant. RESULTS: A total of 216 patients were analyzed and were on average 50.5 (SD 13.9) years old, redominantly Black (49.77%) with an average body mass index of 33.33 (9.8) and were recipients of deceased donor renal transplants (61.11%). A total of 105 (48.6%) patients visited the emergency epartment and 119 (55.1%) patients had a hospital readmission. Patients having a body mass index >35 kg/m2 did not differ across emergency department visit or hospitalization groups. Delayed graft function (OR 2.86, 95% CI 1.07-7.65) and previous renal transplant (OR 2.77, 95% CI 1.04-7.39) were significantly associated with multiple acute care utilizations. DISCUSSION: Acute care utilization following renal transplantation was similar to previously reported experiences. Obesity did not impact use of acute care resources or patient outcomes. Strategies addressing potential preventable emergency visits and hospital re-dmissions should be promoted.

Utilization of direct-acting oral anticoagulation in solid organ transplant patients: A national survey of institutional practices.

The safety and efficacy of direct-acting oral anticoagulants (DOACs) and reversal strategies are not well established in the solid organ transplant population. This was a survey of pharmacists to assess DOAC and urgent reversal practices among adult transplant programs in the United States. A 27-question survey was distributed to members of transplant pharmacy organization listservs between 5/28/19 and 6/30/19. A total of 115 responses were received from kidney (43.5%), heart (20.0%), lung (18.3%), liver (13.9%), and pancreas (4.4%) transplant programs. DOAC use prior to transplant was mostly prohibited in thoracic programs (77.3%) but more permissive in kidney transplant programs (64.0%). If permitted, apixaban (57.8%) was most preferred. At transplant surgery, reversal of DOAC was performed "as needed" (20.9%) or was not routine (18.3%). DOAC use post-transplant was more permissive (94.3%). A majority of responders follow FDA recommended dosing in the setting of drug-drug interactions (51.1%). Major factors influencing DOAC prescribing decisions included renal function, drug-drug interactions, and insurance. High clinical practice variability exists regarding DOAC utilization and urgent reversal strategies in pre-, peri-, and post-transplant stages. While more research is needed to refine the clinical landscape, many institutions are using DOAC therapy under the perception that they pose a similar risk of bleeding compared to a non-transplant population.

Reducing Donor-specific Antibody During Acute Rejection Diminishes Long-term Renal Allograft Loss: Comparison of Early and Late Rejection.

BACKGROUND: Reduction in donor-specific antibody (DSA) has been associated with improved renal allograft survival after antibody-mediated rejection (AMR). These observations have not been separately analyzed for early and late AMR and mixed acute rejection (MAR). The purpose of this study was to evaluate long-term responses to proteasome inhibitor-based therapy for 4 rejection phenotypes and to determine factors that predict allograft survival. METHODS: Retrospective cohort study evaluating renal transplant recipients with first AMR episodes treated with proteasome inhibitor-based therapy from January 2005 to July 2015. RESULTS: A total of 108 patients were included in the analysis. Immunodominant DSA reduction at 14 days differed significantly (early AMR 79.6%, early MAR 54.7%, late AMR 23.4%, late MAR 21.1%, P < 0.001). Death-censored graft survival (DCGS) differed at 3 years postrejection (early AMR 88.3% versus early MAR 77.8% versus late AMR 56.7% versus late MAR 54.9%, P = 0.02). Multivariate analysis revealed that immunodominant DSA reduction > 50% at 14 days was associated with improved DCGS (odds ratio, 0.12, 95% CI, 0.02-0.52, P = 0.01). CONCLUSIONS: In summary, significant differences exist across rejection phenotypes with respect to histological and DSA responses. The data suggest that DSA reduction may be associated with improved DCGS in both early and late AMR.

Detrimental Association of Hypogammaglobulinemia With Chronic Lung Allograft Dysfunction and Death Is Not Mitigated by On-Demand Immunoglobulin G Replacement After Lung Transplantation.

BACKGROUND:: Hypogammaglobulinemia (HGG), immunoglobulin G (IgG) <700 mg/dL, is associated with infections, chronic lung allograft dysfunction, and death following lung transplantation. This study evaluates the use of on-demand intravenous IgG in lung transplant recipients with HGG. MATERIALS AND METHODS:: This single-center retrospective cohort study of adult lung recipients evaluated 3 groups, no, untreated (u), or treated (t) HGG at first IgG administration or a matched time posttransplant. Primary outcome was freedom from allograft dysfunction. Secondary outcomes included development of advanced dysfunction, rejection, infection burden, and mortality. RESULTS:: Recipients included 484 (no HGG: 76, uHGG: 192, tHGG: 216). Freedom from chronic allograph dysfunction was highest in the non-HGG group 2 years post-enrollment (no HGG 77.9% vs uHGG 56.4% vs tHGG 52.5%; P = .002). Freedom from advanced dysfunction was significantly different 2 years post-enrollment (no HGG 90.5% vs uHGG 84.7% vs tHGG 75.4%; P = .017). Patients without HGG and those with uHGG had less mortality at 2 years post-enrollment (no HGG 84.2% vs uHGG 81.3% vs tHGG 64.8%; P < .001). Gram-negative pneumonias occurred more often in the tHGG group ( P = .02). CONCLUSIONS:: Development of chronic lung allograft dysfunction, patient survival, rejection burden, and key infectious outcomes in lung transplant recipients were still problematic in the context of on-demand IgG therapy. Prospective studies are warranted.

Pharmacokinetic and pharmacogenetic analysis of immunosuppressive agents after laparoscopic sleeve gastrectomy.

BACKGROUND: Severe obesity has been shown to limit access to renal transplantation in patients with end-stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence of tacrolimus products and immunosuppression pharmacokinetics. METHODS: This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended-release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. RESULTS: Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI; 89.6%-119.6%) for AUC0-24 and 92.5% (90% CI; 80.4%-106.4%) for Cmax . PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (P=.004) and Cmax (P=.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (P=.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values vs those with CYP3A5*3/*3 (IR-TACP<.001; ER-TACP=.008). Genotype did not impact MPA PK. CONCLUSION: Dose modification of immunosuppressants post-LSG may not be necessary aside from standard therapeutic drug monitoring.

Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation.

Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post-lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0-6) and freedom from ≥A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline >10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan-Meier method with log rank conversion was used to assess freedom from events. Fifty-seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42-1403) days. CRSS declined significantly (3 vs 0.67, P<0.001) after rescue. Freedom from ≥A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline >10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2-3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab.

Evaluation of Direct Oral Anticoagulation Therapy in Heart and Lung Transplant Recipients.

CONTEXT: Anticoagulation therapy is common in thoracic transplant recipients. Direct oral anticoagulants (DOACs) are alternatives to warfarin therapy, but characterization of their use in solid organ transplant is absent. OBJECTIVE: The primary objective of this study was to describe a thoracic transplant patient population initiated on DOAC therapy. Secondary objectives were to assess adverse reactions, venous thromboembolism (VTE) recurrence, and drug-drug interactions during DOAC therapy. STUDY DESIGN: Single-center retrospective cohort study. SETTING: A tertiary care medical center including inpatient hospitalization and outpatient transplant clinic visits. PATIENTS: Thoracic transplant recipients who were initiated on DOACs between May 1, 2011, and March 1, 2015, at the University of Pittsburgh Medical Center were included. RESULTS: A total of 37 patients were included in the analysis. A majority of the patients were lung transplant recipients (86.4%) with a median age of 60.7 years. Twenty-eight patients had a history of VTE. The primary indication for DOAC initiation was VTE (86.5%). Rivaroxaban (78.4%) was the most commonly utilized agent. Dose reductions for major drug interactions (37.8%), renal insufficiency (10.8%), or both (8.1%) occurred within the study. Two patients had breakthrough VTE during DOAC therapy. Eight bleeding events were reported in the cohort, one of which was considered a major bleed. There was no difference in the incidence of bleeding in patients with drug-drug interactions and without drug-drug interactions during DOAC therapy (26.0% vs 7.1%, P = .154). CONCLUSION: Direct oral anticoagulant therapy was well tolerated by thoracic transplant recipients. Drug interactions and renal dose adjustments were common.

Extrapyramidal symptoms following administration of oral perphenazine 4 or 8 mg: an 11-year retrospective analysis.

BACKGROUND: Perphenazine is a treatment option in postoperative nausea and vomiting (PONV) prophylaxis. Chronic administration and high dose are known to cause extrapyramidal system (EPS) dysfunction at a frequency of 8%, but the incidence of acute EPS after a single 4 or 8 mg dose is unknown. OBJECTIVE: A retrospective analysis of patient medication billing data and departmental quality records was performed (January 2001 to 10 July 2012) to identify patients who experienced EPS dysfunction after oral perphenazine. DESIGN: A retrospective analysis. SETTING: Surgical outpatients presenting to any one of 10 hospitals in the area of Pittsburgh, Pennsylvania, USA. PATIENTS: Overall, 45 766 patients received 4 or 8 mg of perphenazine before same-day surgery. MAIN OUTCOME MEASURES: EPS dysfunction was defined as acute dystonia, akathisia or pseudoparkinsonism. Records were reviewed to determine the likely number of reactions to perphenazine, the nature of these reactions and impact on patient care. RESULTS: There were four 'likely' cases of EPS dysfunction, and two 'possible' cases. Five reported events were consistent with akathisia, with the sixth being a dystonic reaction. All six patients had resolution of symptoms, with five receiving intravenous diphenhydramine for treatment. The incidence of EPS dysfunction was 1.3 events per 10 000 patients (95% confidence interval (CI) 0.4 to 3.0, based on six events). All patients who experienced reactions pre-operatively were able to proceed to surgery without complications or delay. One patient required unplanned admission and 3-h observation owing to sedation from diphenhydramine. The incidence of EPS dysfunction after oral perphenazine is low. Reactions that did occur were mild and easily treated. CONCLUSION: Given the infrequent side effects, this single, low dose of perphenazine should be encouraged as a low-risk adjunct to any multimodal PONV prophylaxis regimen, based on the selection criteria described.