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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. [ABSTRACT FROM AUTHOR]

Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin (N = 8) or placebo (N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years (P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group (n = 7) than in the placebo (n = 3) group (P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT (P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Standards of immunosuppression in renal transplantation have changed dynamically in recent years. We here provide a refined advanced pharmacoeconomic model which uses state-of-the-art methods including a mixed treatment comparison (MTC) analysis. The aim was to assess the cost-effectiveness of current immunosuppressive therapy regimens (TR): 'sirolimus + early withdrawal of cyclosporine + steroids' (TR1), 'sirolimus-early transition' (TR2), 'everolimus-early transition' (TR3) and 'tacrolimus low dose + mycophenolate mofetil (MMF) + steroids' (TR4). Methods: An up-to-date Markov model with current source data was employed to assess the cost-effectiveness of modern immunosuppressive regimens over 12-month and 10-year time periods. Transition probabilities for the occurrence of events for the first year were based on an MTC analysis. The robustness of the model was tested in extensive sensitivity analyses. Results: Within the 12-month time period TR2 yields the highest life years (0.987 LY), generating costs of 17,500 €. In terms of years with functioning graft (FG), TR4 yields the best efficacy over the 12-month model duration (0.970 years with FG). For the 10-year time period, TR2 yields the lowest costs (107,246 €) and dominates both TR3 and TR1, as it is simultaneously more effective. Within the 10-year model duration, TR4 reaches slightly higher effects compared with TR2 (6.493 vs. 6.474 LY) resulting in an incremental cost-effectiveness ratio of 387,684 € per LY gained. Conclusions: The early transition to sirolimus provides long-term efficiency results comparable with a tacrolimus-based regimen, which represents a common treatment standard after kidney transplantation. Both are superior to other investigated immunosuppressive regimens. [ABSTRACT FROM AUTHOR]

Obese transplant recipients (BMI ≥ 30 kg/m2) 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/m2 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/m2 benefit from a protocol that incorporates RDP. [ABSTRACT FROM AUTHOR]