Deciphering the True Immunologic Risk in Renal Transplantation in Patients With HIV.

Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P = .045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated.

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.

A Number of Modifiable and Nonmodifiable Factors Increase the Risk for Elbow Medial Ulnar Collateral Ligament Injury in Baseball Players: A Systematic Review.

PURPOSE: To analyze the current literature regarding risk factors associated with medial ulnar collateral ligament (MUCL) injury in baseball players and to serve as a robust source for identifying modifiable risk factors that once optimized, have the potential to reduce injury risk. METHODS: Comprehensive search of the available literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Studies were included if they evaluated risk factors for MUCL injuries in the elbow of baseball players. Risk of bias assessment was performed via Methodological Index for Non-randomized Studies (MINORS) scoring system. The Oxford Centre for Evidence-Based Medicine was used to determine level of evidence. Variables of interest; player age, position, shoulder motion, humeral retrotorsion, joint laxity, strength, balance, geography, velocity, pitch count, pitch types, throwing volumes, and throwing mechanics were recorded. RESULTS: Twenty-one studies were included in this systematic review. MINORS scores ranged from 75 to 87%, and variables demonstrated significant heterogeneity. Performance-based risk factors for MUCL injury included: increased pitch count (both annual and per game), higher percentage of fastballs thrown, smaller pitch repertoire, and/or a loss of pitching velocity. Biomechanical studies demonstrated the relationship between decreased shoulder range of motion (total ROM, ER, IR, and abduction), increased humeral retrotorsion, increased elbow valgus opening in the throwing arm, lower Y-Balance score, and increased lateral release position to increased MUCL injury. CONCLUSIONS: Risk factors for MUCL injury can generally be categorized into 4 primary groups: 1) various player demographics and characteristics, 2) throwing too hard (high velocity), 3) throwing too much (pitch count/volume), and 4) throwing with poor mechanics. In this systematic review, the most significant nonmodifiable risk factors for MUCL injuries included: increased glenohumeral retrotorsion and elbow valgus opening. The most consistent modifiable risk factors included: total shoulder range of motion, pitch count, pitch selection, Y balance score, and lateral release position. Pitch velocity was inconsistent in literature, but most studies found this as a risk for injury. These risk factors may serve as appropriate targets for future evidence-based injury mitigation strategies. LEVEL OF EVIDENCE: Level IV, systematic review of Level II-IV studies.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype.

BACKGROUND: Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requi rements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting. AIM: To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype. METHODS: Single-arm, prospective, single-center, open-label, observational study (ClinicalTrials.gov: NCT037 13645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion. RESULTS: Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients. CONCLUSION: Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacro limus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Individualizing the Throwing Progression Following Injury in Baseball Pitchers: the Past, Present, and Future.

PURPOSE OF REVIEW: A critical component of any rehabilitation program following injury is a graduated exposure of pathologic or vulnerable tissue to sport-specific stressors. A foundational aspect in the return to sport process following an injury in baseball athletes is the development of an interval throwing program. A shift has occurred in recent years from generic programs to individualized progressions. The current review explores the evolution of interval throwing program construction and discusses the possibilities of the future with advancements in technology and understanding. RECENT FINDINGS: Early interval throwing programs relied primarily on pre-determined throwing distance and volume to estimate total training load while following a fixed throwing schedule. Currently, clinicians have begun to utilize available technology in attempts to determine training prescription and obtain more accurate estimates of stresses placed upon the body. Thus, interval throwing programs have become more individualized and flexible to account for each athlete's individual differences and biological response to training. Future development may be able to predict specific internal response to stressors and proactively adjust training load to maximize positive adaptations while minimizing any maladaptive events. As with all concepts and principles within the realm of athlete rehabilitation, clinicians must continue to adapt how they conceptualize and develop individualized interval throwing programs for the overhead throwing athlete. We will continue to see a shift away from a responsive approach to a proactive one, where clinicians can utilize modern technologies to precisely prescribe a throwing dosage based upon expected tissue response within the athlete.

The use of non-transplant biologics in solid organ transplant recipients: A practical review for the frontline clinician.

Biologics have become the forefront of medicine for management of autoimmune conditions, leading to improved quality of life. Many autoimmune conditions occur in solid organ transplant (SOT) recipients and persist following transplant. However, the use of biologics in this patient population is not well studied, and questions arise related to risk of infection and adjustments to induction and maintenance immunosuppression. Guidelines have been published highlighting management strategies of biologics around the time of elective surgical procedures, but this is not always feasible in urgent situations, especially with deceased donor transplantation. The aim of this review is to summarize the current literature regarding the use of these agents in solid organ transplant recipients, and specifically address induction and maintenance immunosuppression, as well as the need for alternative infective prevention strategies to create a practical reference for the frontline clinician, when faced with this complex clinical scenario.

Correlation of Rehabilitation and Throwing Program Milestones With Outcomes After Ulnar Collateral Ligament Reconstruction: An Analysis of 717 Professional Baseball Pitchers.

BACKGROUND: There remains room for improvement in surgical outcomes after medial ulnar collateral ligament reconstruction (MUCLR) in professional pitchers. The role and influence of postoperative rehabilitation on the outcomes of MUCLR are unknown. There is a paucity of clinical data in the current literature comparing the success of various postsurgical rehabilitation protocols after MUCLR. PURPOSE: To summarize the current rehabilitation process for professional pitchers recovering from MUCLR, evaluates what player and surgical factors correlate with outcomes, and determines whether rehabilitation timing and milestones correlate with successful outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: 717 professional baseball pitchers who underwent MUCLR between 2010 and 2016 were identified and included in the analysis. Player characteristics evaluated included age at the time of surgery, throwing side dominance, primary pitching role (starter vs reliever), and level of play (MLB, AAA, AA, A). Surgical factors studied included date of surgery, graft type (palmaris longus autograft vs gracilis autograft), and surgical technique (figure of 8 vs docking vs other). The rehabilitation and throwing progression details were as follows: initiation date; first throw date; dates to start throwing from various distances; longest distance thrown; first flat ground throw date; first mound throw date; and first live batting practice (BP) date. The primary outcomes of interest were the ability to return to play at any level (RTP), the ability to return to the same level (RSL), and the time to RTP/RSL. RESULTS: On average, pitchers threw a baseball for the first time 4.9 months after surgery, with a broad range (2.8-14.9 months). For the 675 (94%) pitchers who were able to progress to mound throwing, the first throws off a mound occurred at a mean of 9.4 months after surgery. Before progressing to the mound, the mean longest long-toss distance reached was 137.5 feet, with a broad range (105-300 feet). A high variation in the time to RTP (7.6-53.9 months) and RSL (8.6-60.7 months) was noted. A total of 599 (84%) pitchers were able to RTP at a mean time of 14.9 ± 4.9 months after surgery (range, 7.6-53.9 months). Also, 528 (74%) pitchers were able to RSL after MUCLR at a mean of 17.4 ± 7 months (range, 8.6-60.7 months) postoperatively. Age was the most significant predictor of RTP (hazard ratio [HR], 1.03 [95% CI, 1.01-1.05]; P = .01) and RSL (HR, 0.96 [95% CI, 0.93-0.99]; P < .01). For every 1-year increase in age, there was a 3% increase in the chance of RTP. Conversely, for every 1-year decrease in age, there was a 4% increase in the chance of RSL. MLB players were more likely to RTP (HR, 1.39 [95% CI, 1.18-1.63]; P < .01) but not necessarily to RSL (HR, 0.90 [95% CI, 0.75-1.08]; P = .24). The time from surgery to any of the rehabilitation milestones of interest (first throw, first flat ground pitching, first mound throwing, and first live BP) did not correlate with RTP or RSL (all, P >.05). The same was true for the greatest long-toss distance thrown before transitioning to the mound. CONCLUSION: Significant variability in the postoperative rehabilitation protocols after MUCLR was observed in 717 professional baseball pitchers. The timing of achievement of throwing progression and rehabilitation milestones postoperatively varied widely but did not correlate with outcomes. Player characteristics-except for player age and professional pitching level-did not correlate with RTP and RSL outcomes. Older pitchers and MLB pitchers were more likely to RTP, but younger players were more likely to RSL. Surgical factors did not correlate with rehabilitation outcomes.

Characterization of Kidney Retransplantation Following Graft Failure Due to BK Virus Nephropathy.

INTRODUCTION: Immunosuppression following kidney transplantation increases risk of BK polyomavirus reactivation, a common cause of graft dysfunction and failure. Subsequent retransplantation is a viable option that has not been extensively studied. This study further characterizes BK Virus Nephropathy (BKVN) and retransplantation in the most expansive population to date, geographically, temporally, and in magnitude. MATERIALS AND METHODS: The OPTN/UNOS database was used to identify patients who received kidney or kidney-pancreas transplantation between 1987 and 2018 that resulted in BKVN-attributed failure (n = 1587). This population was divided into those who underwent retransplantation (n = 495) and those who did not (n = 1092). RESULTS: The retransplanted cohort was younger (45 vs. 53 yr; P<0.0001) and had fewer prior kidney transplants (P<0.003), lower expected post-transplant survival (P<0.001), lower rates of delayed graft function (DGF) (14.1% vs. 22.2%; P=0.0008), a greater proportion of white patients (55.4% vs. 43.2%; P=0.0002), a greater proportion of living donors (35.8% vs. 23.0%; P<0.0001), and longer allograft lifespan (2.95 vs. 2.41 yr; P<0.0001), compared to those not retransplanted. Among retransplants, DGF and high kidney donor profile index (KDPI) were associated with decreased allograft lifespan (P=0.001, P=0.0005, respectively). Steroid induction had no effect on allograft lifespan when compared to steroid-free regimens (P=0.915). Retransplanted allografts lasted longer than previous BKVN-failed grafts (10.44 and 3.70 years, respectively; P<0.0001). CONCLUSIONS: Retransplantation following BKVN-associated graft failure has been associated with favorable outcomes. To maximize allograft lifespan in retransplantation, clinicians may consider selection of low KDPI donors, prevention of delayed graft function, and tailored immunosuppressive regimens that minimize steroids.

Guiding therapeutic plasma exchange for antibody-mediated rejection treatment in lung transplant recipients - a retrospective study.

Antibody-Mediated Rejection (AMR) due to donor-specific antibodies (DSA) is associated with poor outcomes after lung transplantation. Currently, there are no guidelines regarding the selection of treatment protocols. We studied how DSA characteristics including titers, C1q, and mean fluorescence intensity (MFI) values in undiluted and diluted sera may predict a response to therapeutic plasma exchange (TPE) and inform patient prognosis after treatment. Among 357 patients consecutively transplanted without detectable pre-existing DSAs between 01/01/16 and 12/31/18, 10 patients were treated with a standardized protocol of five TPE sessions with IVIG. Based on DSA characteristics after treatment, all patients were divided into three groups as responders, partial responders, and nonresponders. Kaplan-Meier Survival analyses showed a statistically significant difference in patient survival between those groups (P = 0.0104). Statistical analyses showed that MFI in pre-TPE 1:16 diluted sera was predictive of a response to standardized protocol (R2  = 0.9182) and patient survival (P = 0.0098). Patients predicted to be nonresponders who underwent treatment with a more aggressive protocol of eight TPE sessions with IVIG and bortezomib showed improvements in treatment response (P = 0.0074) and patient survival (P = 0.0253). Dilutions may guide clinicians as to which patients would be expected to respond to a standards protocol or require more aggressive treatment.