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Introduction: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA)., Methods: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework., Results: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab., Conclusion: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

While kidney transplantation (KTx) has traditionally required lifelong immunosuppression, an investigational stem cell therapy, FCR001, has been demonstrated to induce tolerance and eliminate the need for immunosuppression through the establishment of persistent mixed chimerism in a phase 2 clinical study. Real-world evidence (RWE) methods were employed to compare the safety and efficacy of non-myeloablative conditioning with FCR001 with standard of care [SOC] immunosuppression in a retrospective single-center analysis of outcomes among propensity score matched living-donor KTx receiving SOC (n = 144) or FCR001 (n = 36). Among the FCR001 recipients, 26 (72%) developed persistent chimerism allowing durable elimination of all immunosuppression. There was no significant difference in the composite primary endpoint (biopsy-proven acute rejection [BPAR], graft loss, or death) at 60 months (FCR001 27.8%, n = 10 and SOC 28.5%, n = 41; p = .9). FCR001 recipients demonstrated superior kidney function at 5 years (estimated glomerular filtration rate [eGFR] [mean ± standard deviation]: 64.1 ± 15.3) compared to SOC (51.7 ± 18.8; p = .02). At 5 years, FCR001 recipients experienced fewer complications including new-onset diabetes post-transplant, although two patients developed graft versus host disease. In conclusion, RWE demonstrated that KTx combined with non-myeloablative conditioning and FCR001 resulting in superior kidney function without increasing the risk of rejection, graft loss, or death among patients off immunosuppression., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2023 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Objectives: We provide a contemporary consideration of long-term outcomes and trends of induction therapy use following lung transplantation in the United States., Methods: We reviewed the United Network for Organ Sharing registry from 2006 to 2018 for first-time, adult, lung-only transplant recipients. Long-term survival was compared between induction classes (Interleukin-2 inhibitors, monoclonal or polyclonal cell-depleting agents, and no induction therapy). A 1:1 propensity score match was performed, pairing patients who received basiliximab with similar risk recipients who did not receive induction therapy. Outcomes in matched populations were compared using Cox, Kaplan-Meier and Logistic regression modeling., Measurements and Main Results: 22 025 recipients were identified; 8003 (36.34%) were treated with no induction therapy, 11 045 (50.15%) with basiliximab, 1556 (7.06%) with alemtuzumab and 1421 (6.45%) with anti-thymocyte globulin. Compared with those who received no induction, patients receiving basiliximab, alemtuzumab or anti-thymocyte globulin were found on multivariable Cox-regression analyses to have lower long-term mortality (all p < .05). Following propensity score matching of basiliximab and no induction populations, analyses demonstrated a statistically significant association between basiliximab use and long- term survival (p < .001). Basiliximab was also associated with a lower risk of acute rejection (p < .001) and renal failure (p = .002)., Conclusion: Induction therapy for lung transplant recipients-specifically basiliximab-is associated with improved long-term survival and a lower risk of renal failure or acute rejection., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Complement inhibition offers a novel treatment approach for antibody-mediated rejection (AMR). We examined patients with hemodynamic compromise AMR 2010-2020, comparing eight patients supplemented with eculizumab to 10 patients without; administration was at the treating physician's discretion. There were no significant differences between groups though eculizumab patients had a non-significantly higher inotrope score (208.8 mcg/kg/min vs. 2.6 mcg/kg/min; P = .22), more extracorporeal membrane oxygenation (ECMO) (62.5% vs. 20%; P = .066), and worse 1-year survival (37.5% vs. 60%; P = .63). The role of eculizumab is uncertain in AMR; multicenter collaborative studies are essential to better define its role., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost-containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher-quality evidence for high single-dose rATG, and dose-rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target-attainment or on ideal-body-weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost-saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high-cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost-burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient-specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost-saving initiatives in the transplant population., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic has negatively impacted organ donation and transplantation across the globe., Methods: This study analyzed transplant outcomes during the pre-pandemic [PPE, 1/2019-2/2020] and pandemic era [PE, 3/2020-8/2020] based on changes in induction immunosuppression. During PPE, high immunological risk patients received 4-6 mg/kg, moderate risk 2-4 mg/kg, and low risk 1-2 mg/kg of ATG. During PE, ATG doses were reduced to 3-4 mg/kg for high risk, 1-2 mg/kg for moderate, and low changed to basiliximab. Primary outcomes are as follows: biopsy-proven rejection [BPAR], de-novo donor-specific antibody [DSA], delayed graft function [DGF], infection rates, graft loss, and all-cause of mortality., Results: During PPE, 224 kidney transplants [KTx] and 14 kidney/pancreas transplants [KP] were included, while 180 KTx and 5 KP were included for PE. Basiliximab use increased by 30% in the PE. The odds of DGF were statistically significant between PE vs PPE, OR 1.7 [1.05, 2.8, p-value = .042]. The odds of developing DSAs and BPAR during the PE vs. PPE were 0.34 [0.16, 0.71, p-value = .004] and OR 0.34 (0.1 to 1.1, p-value, .104)], respectively. Cytomegalovirus [19% in PE, 37% in PPE] and BK virus [5.4% PE vs. 16% PPE] incidence reduced during PE vs. PPE. COVID-19, graft loss, and mortality were comparable between groups., Conclusion: KTx and KP transplants were performed safely during the COVID-19 pandemic with a reduction of induction immunosuppression., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This is a descriptive study reviewing the outcomes of mammalian target of rapamycin inhibitors (mTORs) in intestinal (IT) and multivisceral transplantation (MVT). This study included 22 patients, 20 adults, and two children, and an overall mean age of 46 years old at the time of transplantation. Twelve patients (54.5%) received IT, and the remainder (45.5%) MVT. The mean time between transplantation and mTORs initiation was 24 months. The indication was worsening renal function in 13 patients (59%), with 9/13 (69.2%) noted to have an increase in glomerular filtration rate of at least 10 ml/min/1.73m 2 . The indication for four patients (18.2%) was a history of neuroendocrine tumor. After mTOR initiation, 50% of patients were reduced or weaned off tacrolimus and 13.7% off prednisone. mTORs were discontinued in 11/22 patients. Six patients (54.5%) stopped due to side effects, two (18.1%) for surgery, and one (9%) for acute cellular rejection. Side effects were edema (33.3%), headaches (33.3%), diarrhea (16.7%), and oral ulcers (16.7%). The average duration of mTORs prior to discontinuation due to side effects was 7 months. mTORs may function in their own niche of patients due to the potential renal safety profile, but use is most limited by tolerance to side effects., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Reducing immunosuppression can effectively treat BK viremia (BKV) and BK nephropathy, but has been associated with increased risks for acute rejection and development of donor-specific antibodies (DSA). To date there have been no systematic evaluations of re-escalating immunosuppression in transplant patients with resolving BKV. Importantly, the safety of this approach and impact on graft survival is unclear., Methods: We performed a single-center retrospective review of kidney transplant recipients between July 2011 and June 2013 who had immunosuppression reduction after developing BKV (plasma PCR ≥ 1000 copies/ml). Changes in immunosuppression and patient outcomes were tracked until occurrence of a complication event: biopsy-proven acute rejection (BPAR), detection of de novo DSA, or recurrent BKV. Patients were grouped according to whether or not net immunosuppression was eventually increased., Results: Out of 88 patients with BKV, 44 (50%) had net immunosuppression increased while the other 44 did not. Duration of viremia, peak viremia, induction, and sensitization status were similar between the two groups. In a Kaplan-Meier analysis, increasing immunosuppression was associated with less BPAR (P = .001) and a trend toward less de novo DSA development (P = .06). Death-censored graft survival (P = .27) was not different between the two groups. In the net immunosuppression increase group, recurrent BKV occurred in 22.7% without any BKV-related graft losses., Conclusion: These findings support potential benefits of increasing immunosuppression in patients with low-level or resolved BKV, but prospective trials are needed to better understand such an approach., (© 2020 Wiley Periodicals LLC.)

Background: Currently, there is limited literature evaluating rATG induction dosing and incidence of opportunistic viral infections when using steroid-free maintenance immunosuppression., Methods: This single-center, retrospective, study compared high rATG (>4.5 mg/kg) versus low (<4.5 mg/kg) induction dosing and the overall incidence of early opportunistic viral infection at 180 days in the setting of maintenance immunosuppression consisting of tacrolimus, mycophenolate, rapid steroid withdrawal, and a tiered antiviral prevention strategy based on donor-recipient Cytomegalovirus (CMV) serostatus., Results: A total of 209 patients were included; 76 patients received low-dose and 133 patients received high-dose rATG. Incidence of overall opportunistic viral infection occurred more frequently in patients who received high compared to low dose (29.8% vs 25% p = .030). Incidence of CMV infection was also significantly increased in the high-dose group (31.6% vs 18.4% p = .039). In a multivariable model, rATG dose, as a continuous variable, remained a significant independent predictor of infection along with CMV risk (OR 1.46, 95% CI 1.02-2.09) controlling for age and CMV risk. There were no differences in graft-related outcomes at 180 days., Conclusion: Higher cumulative rATG induction dose was associated with increased incidence of opportunistic viral infections, in the setting of a steroid-free maintenance immunosuppression in the early post-transplant period., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Obese transplant recipients (BMI ≥ 30 kg/m 2 ) have decreased posttransplant patient and graft survival compared with their nonobese counterparts. At the same time, many prednisone-related side effects (eg, new-onset diabetes) are similar to those associated with obesity. Using SRTR data, we studied outcomes associated with prednisone-free maintenance immunosuppression (rapid discontinuation of prednisone-RDP). Between January 1, 2000, and December 31, 2014, 44 635 first transplant recipients with BMI ≥ 30 kg/m 2 had a first kidney transplant (28 176 DD; 16 459, LD); 12,994 (29%) were discharged from the hospital on a prednisone-free protocol. We compared outcomes to those discharged on a protocol incorporating maintenance prednisone (intention-to-treat analysis). RDP-treated obese first DD recipients had significantly better patient survival (HR, 0.88; CI, 0.81-0.96) and graft survival (HR, 0.93; CI, 0.88-0.99) compared with their counterparts on maintenance immunosuppression. Although not statistically significant, the same trends were seen for LD recipients. For both DD and LD recipients, there was no difference between groups for death-censored graft survival, suggesting that the benefit of RDP was due to improved patient survival. Our findings suggest that kidney transplant recipients with BMI ≥ 30 kg/m 2 benefit from a protocol that incorporates RDP., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rejection rates in HIV-infected kidney transplant (KTx) recipients are higher than HIV-negative recipients. Immunosuppression and highly active antiretroviral therapy (HAART) protocols vary with potentially significant drug-drug interactions, likely influencing outcomes. This is an IRB-approved, single-center, retrospective study of adult HIV-infected KTx patients between 5/2009 and 12/2014 with 3-year follow-up, excluding antibody-depleting induction. A total of 42 patients were included; median age was 52 years, 81% male, 50% African American, 29% Hispanic, 17% Caucasian. The most common renal failure etiology was hypertensive nephrosclerosis (50%) with 5.8 median years of pre-transplant dialysis. All patients received IL-2 receptor antagonist, were maintained on tacrolimus (76%) or cyclosporine (17%), and 40% received ritonavir-boosted PI-based HAART (rtv+) regimen. Patient and graft survival at 3 years were 93% and 90%. At 1-, 2-, and 3-year time points, median serum creatinine was 1.49, 1.35, and 1.67; treated biopsy-proven rejection was 38%, 38%, and 40.5%; and 92% of episodes were acute rejection. At these time points, rejection rates were significantly higher with boosted PI HAART regimens compared to other HAART regimens, 59% vs 24% (P = 0.029), 59% vs 24% (P = 0.029), and 68% vs 24% (P = 0.01). Despite higher rejection rates, HIV-infected KTx recipients have reasonable outcomes. Given significantly higher rejection rates using rtv+ regimens, alternative HAART regimens should be considered prior to transplantation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires retransplantation. This study evaluates the incidence and outcome of the patients with CR at a large living donor liver transplant (LDLT) center., Methods: Data of patients with CR were retrospectively analyzed in 1232 adult (age >18 years) LDLT on tacrolimus (mainly)-based immunosuppression. Sirolimus/everolimus (mammalian target of rapamycin [mTOR] inhibitors) was added to baseline immunosuppression as rescue therapy in patients with CR. Data are shown as median (interquartile range [IQR])., Results: Twenty-three patients (22 males), aged 42 (IQR 45-56) years, had biopsy-proven chronic rejection at 21 (8-44) months after liver transplantation. The incidence of chronic rejection was 1.9% in this cohort. The patients with CR (n = 23) had a significantly higher incidence of cytomegalovirus (CMV) viremia, acute cellular rejection, and history of anastomotic biliary strictures as compared to patients without CR. Five patients were noncompliant with immunosuppression before the diagnosis of CR. Twelve patients (52%) responded to addition of mTOR inhibitors, whereas 11 did not respond and had poor outcome., Conclusion: The incidence of chronic rejection is low in LDLT. Treatment with mTOR inhibitors can reverse graft dysfunction in approximately half of the patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Trichodysplasia spinulosa (TS) is a rare dermatologic complication associated with the immunosuppressive therapy used in solid organ transplantation. The distinctive clinical manifestation of this condition is spiny follicular papules on the face, ears, extremities, and trunk. Histopathologically, abnormally maturing hair follicles with hyperkeratotic material are noted. The condition is produced by the trichodysplasia spinulosa-associated polyomavirus. Treatment of this condition in the past has entailed a reduction in immunosuppression, topical agents such as cidofovir or retinoids, or oral valganciclovir. Herein, we report a case of generalized TS treated successfully with leflunomide., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)