Carbapenem-resistant Enterobacterales (CRE) are an important threat to the health of solid organ transplant recipients (SOTr); data comparing outcomes of SOTr with CRE to non-SOTr with CRE are lacking. A matched cohort study was performed within two prospective, multicenter, cohort studies (CRACKLE, CRACKLE-2). The epidemiology, desirability of outcome rankings (DOOR) outcomes, and mortality of SOTr and non-SOTr hospitalized in the United States (December 2011 - August 2017) with clinical isolates with Centers for Disease Control and Prevention-defined CRE were compared. In total, 121 SOTr and 242 matched non-SOTr were included. Fifty one percent of isolates met infection criteria. SOTr were younger (p<0.001), less acutely ill (p=0.029), less often had a malignancy history (p=0.006), and more often were admitted from home (p<0.001) than non-SOTr. SOTr had more favorable adjusted DOOR outcomes; a randomly selected SOTr had a 58% (95% CI 53%-64%) probability of a better outcome as compared to a randomly selected non-SOTr. All-cause 30-day mortality was 14% (17/121) in SOTr vs. 25% (60/242) in non-SOTr, p=0.018. After stabilized inverse-probability weighted adjustment, SOTr had a 7% lower 30-d mortality risk than non-SOTr (95% CI -15%, 1%). SOTr with CRE do not have worse outcomes than matched patients without transplant history.

Developing real-world evidence from electronic health records (EHR) is vital to advance kidney transplantation (KT). We assessed the feasibility of studying KT using the Epic Cosmos aggregated EHR dataset, which includes 274 million unique individuals cared for in 238 U.S. health systems, by comparing it with the Scientific Registry of Transplant Recipients (SRTR). We identified 69,418 KT recipients transplanted between January 2014 and December 2022 in Cosmos (39.4% of all US KT transplants during this period). Demographics and clinical characteristics of recipients captured in Cosmos were consistent with the overall SRTR cohort. Survival estimates were generally comparable, although there were some differences in long-term survival. At 7 years post-transplant, patient survival was 80.4% in Cosmos and 77.8% in SRTR. Multivariable Cox regression showed consistent associations between clinical factors and mortality in both cohorts, with minor discrepancies in the associations between death and both age and race. In summary, Cosmos provides a reliable platform for KT research, allowing EHR-level clinical granularity not available with either the transplant registry or healthcare claims. Consequently, Cosmos will enable novel analyses to improve our understanding of KT management on a national scale.

The manufacturing process of Regulatory T (Treg) cells for clinical application begins with the positive selection of CD25 cells using superparamagnetic iron-oxide nanoparticle (SPION)-conjugated anti-CD25 antibodies (spCD25) and immunomagnetic cell separation technology. Our findings revealed that the interaction of spCD25 with its cell target induced the internalization of the complex spCD25-Interleukin-2 Receptor. Accumulation of intracellular spCD25 triggered oxidative stress, causing delayed Treg expansion and temporary reduction in suppressor activity. This activation delay hindered the efficient generation of clinically competent cells. During this early phase, Treg cells exhibited elevated mitochondrial superoxide and lipid peroxidation levels, with concomitant decrease on mitochondrial respiration rates. The results uncovered the increased mitochondrial unfolded protein response (mitoUPR). This protective, redox-sensitive activity is inherent of Tregs when contrasted with homologous, spCD25-treated, conventional T cells. While the temporary effects of spCD25 on clinically competent cells did not impede their use in a safety/feasibility pilot study with kidney transplant recipients*, it is reasonable to anticipate a potential reduction in their therapeutic efficacy. The mechanistic understanding of the adverse effects triggered by spCD25 is crucial for improving the manufacturing process of clinically competent Treg cells, a pivotal step in the successful implementation of immune cell therapy in transplantation. *Clinical trial registration number NCT03284242 at ClinicalTrials.gov.

Pediatric donors are underutilized for simultaneous pancreas-kidney transplantation (SPK) due to concern about technical complications and inadequate islet and/or renal mass. We analyzed our experience with simultaneous en-bloc kidney and pancreas transplantation (SEBKP) using pediatric donors on eight consecutive adult patients from 1997-2018. En-bloc kidney transplants were implanted intraperitoneally and contralaterally to right-sided pancreas grafts. All patients became insulin independent immediately; with one case of delayed kidney function and one case of insulin resistance; there were no graft thromboses. Donor age averaged 5.0±1.7 years and weight 19.8±4.8kg; recipients averaged 46.6±12.8 years and BMI 25.2±3.8kg/m. Postoperative creatinine, glucose and c-peptide reflected good graft function. SEBKP transplantation is a safe technique providing excellent long-term glycemic control and kidney function to adult recipients.

Kaposi sarcoma herpesvirus/human herpesvirus-8 (HHV-8) neoplastic and non-neoplastic disease in solid organ transplant (SOT) recipients can be life-threatening. We evaluated the seroprevalence of HHV-8 infection among donors (D) and recipients (R), the incidence of HHV-8 transmission/reactivation, and the clinical characteristics, management, and outcomes of HHV-8-related diseases, including Kaposi sarcoma herpesvirus-associated inflammatory cytokine syndrome (KICS), in consecutive SOT patients from 2011 to 2023. HHV-8 seroprevalence was 3.3% in 1349 donors and 8.4% in 1856 recipients screened (p<0.0001). Among the D+/R- group (n=49), 13 patients developed HHV-8-related diseases: 7 liver recipients had KICS, and 1 lung recipient had Kaposi sarcoma (KS) with subsequent KICS. Four KICS patients treated with rituximab survived, while the 3 patients not treated with rituximab died. Within the D-/R- group, out of 5 (0.3%) patients with non-donor-derived primary HHV-8 infection, 3 liver recipients developed KICS. In the R+ patients (n=155), 3 developed KS. In our cohort, 25/944 (2.6%) liver transplant recipients had a primary HHV-8 infection, and 10 of them (40%) developed KICS; 40% (4/10) of HHV-8 seropositive heart transplant recipients developed reactivation and 2 of them (50%) had fatal KS. Serologic screening and molecular surveillance of D+/R- patient groups facilitate early recognition and effective therapy of KICS.

We report a case of a 55-year-old male with intrahepatic cholangiocarcinoma (iCCA) who underwent living donor liver transplantation (LDLT) after complete radiographic response on second line pemigatinib. LDLT for iCCA is controversial, but recent reports have cited the potential benefit for patients with unresectable disease, especially those with disease stability after 6 months of systemic therapy. Concomitantly, genomic profiling has identified potentially treatable oncologic targets in iCCA. This patient's tumor genomic profile revealed a FGFR2 rearrangement and was treated with pemigatinib, a competitive inhibitor for FGFR1/2/3. This resulted in complete radiographic and metabolic response after two months of treatment. He was considered eligible for LDLT after 6 months of observation on treatment with sustained response. He underwent an uncomplicated LDLT (including an uncomplicated donor surgery) and at one year follow-up is without evidence of disease recurrence. We believe this is the first report of LDLT for this indication.

In this study using a discordant, xenogeneic, transplant model we demonstrate functionality and safety of the first stent-based bioartificial pancreas device implanted endovascularly into an artery, harnessing the high oxygen content in blood to support islet viability. The device is a self-expanding nitinol stent that is coated with a bilayer of polytetrafluorethylene (PTFE) that forms channels to hold islets embedded in hydrogel. We completed a one-month study in the non-diabetic swine model (N=3) to test the safety of the device and to assess islet functionality after device retrieval. The luminal diameter of the devices from three animals on day 0 and day 30 was 10.01 ± 0.408 mm and 10.05 ± 0.25 mm, respectively. The stimulation index of the control and eBAP devices explanted at day 30 were 3.35 ± 0.97 and 4.83 ±1.20, respectively, and the islets stained positively for insulin and glucagon after 30 days in-vivo. This pilot study shows that BAP implantation into a peripheral artery is safe and supports islet functionality over 30 days, providing groundwork for future work assessing in-vivo function of the device in diabetic swine.

Induction immunosuppression in solid organ transplantation involves a short course of potent immunosuppression in the perioperative period, with the goal of preventing early acute rejection and delaying initiation or reducing the dose of calcineurin inhibitors to minimize kidney injury. The use of induction immunosuppression in lung transplantation has increased over time, with over 80% of adult lung transplant recipients receiving some form of induction therapy. Currently, more than 70% of lung transplant recipients receive induction with an IL-2 receptor antagonist, and basiliximab is the most used agent. Despite this now common practice, the evidence to support and guide induction immunosuppression following lung transplantation is limited, making the use of induction somewhat controversial. Here, we review the available literature addressing the use of induction immunosuppression in lung transplant recipients.

The implications of a lung malignancy in a lung transplant recipient are poorly understood. Here, we linked national transplant and cancer databases to determine how lung cancer impacted prognosis in lung transplant recipients with incidentally explanted lung cancers (IELCs). Records from the Scientific Registry of Transplant Recipients and National Cancer Database were linked to identify 186 patients who received a lung transplant and were subsequently diagnosed with lung cancer. These patients were determined to have IELC and were compared to control patients who received a lung transplant but were not diagnosed with IELC. Of the 186 patients, 144 had non-small cell lung cancer (NSCLC), 6 had small cell lung cancer, and 36 had a neuroendocrine cancer. Patients with stage I/II NSCLC or any stage neuroendocrine cancer had comparable overall survival and rates of cancer-related mortality compared to controls. Conversely, patients with stage III/IV NSCLC had worse overall survival, higher rates of cancer-related mortality, and infrequently received cancer-specific non-operative treatment. Taken together, stage I/II NSCLC and neuroendocrine cancers should be reconsidered as an absolute contraindication to transplant. Conversely, patients with stage III/IV NSCLC had worse outcomes, and strategies are needed to increase the use of adjuvant therapy.

The microbiota composition is known to influence the kinetics of graft rejection, but many questions remain as to whether/how microbiota-derived metabolites affect graft outcome. We investigated the effects of the short-chain fatty acid butyrate, a product of dietary fiber fermentation. Sustained intragastric administration of a micelle-based formulation of butyrate (ButM) that releases its cargo in the lower gastrointestinal (GI) tract elevated cecal butyrate content and significantly prolonged minor- and major-mismatched skin allograft survival in mice. While ButM did not influence Tregs or the adaptive alloimmune responses we tested, it modulated the myeloid cell compartment. At steady-state, ButM treatment reduced the number of circulating Ly6CCD11b monocytes and other myeloid cells in secondary lymphoid organs and skin, altered their expression of genes involved in mitochondrial metabolism and key inflammatory processes, and reduced their ability to produce TNFα, likely via an indirect mechanism. ButM treatment also reduced numbers of graft-infiltrating monocytes but not T cells. Consistent with its critical effect on myeloid cells, ButM's extension of graft survival depended on the presence of CCR2 cells. These findings imply that cecal ButM improves distal allograft outcomes by quantitatively and qualitatively modulating myeloid cells, thereby inhibiting the innate immune cell-mediated effector phase of alloimmunity.

Kidney Transplant is the preferred treatment for end-stage renal disease (ESRD) patients. However, a subset of otherwise eligible patients have severe iliac artery calcification that preclude them from receiving a kidney transplant. This report highlights the application of a physician-modified external iliac artery stent graft with a side branch extension (SBE) to facilitate successful kidney transplantation in a 69-year-old African American female who was otherwise ineligible for kidney transplant due to the presence of severe circumferential bilateral iliac artery calcification. Four months later, the patient received a kidney transplant and recovered without complications. Her duplex ultrasound (DUS) revealed patent vasculature to the kidney graft, she produced adequate urine output, and creatinine and glomerular filtration rate (GFR) normalized by discharge. This underscores the potential for stent graft with SBE as an option for patients who were traditionally ineligible for kidney transplantation due to the presence of severe aortoiliac calcification.

Severe ischemia-reperfusion injury (IRI) causes acute and chronic kidney allograft damage. As therapeutic interventions to reduce damage are limited yet, research on how to promote kidney repair has gained significant interest. To address this question, we performed genome-wide transcriptome and epigenome profiling in progenitor cells isolated from urine of deceased (severe IRI) and living (mild IRI) donor human kidney transplants and identified LIM homebox-1 (LHX1) as an epigenetically regulated gene whose expression depends on the IRI severity. Using a mice model of IRI, we observed a relationship between IRI severity, LHX1 promoter hypermethylation and LHX1 gene expression. By functional studies we confirmed that LHX1 expression is involved in proliferation of epithelial tubular cells and podocyte differentiation from kidney progenitor cells. Our results provide evidence that severe IRI may reduce intrinsic mechanisms of kidney repair through epigenetic signaling.

Cancer and its treatment may lead to kidney injury and need for kidney replacement therapy (KRT). We identified 287 pediatric KRT patients with a malignancy history from the ESPN/ERA Registry. Of these, 197 had cancer as a primary cause of KRT (group 1) and 90 had a malignancy diagnosis before KRT (group 2). Two matched controls without malignancy were randomly selected for each patient. Data were complemented with a questionnaire. Median time to kidney transplantation (KT) from KRT initiation was 2.4 (IQR: 1.5-4.7), 1.5 (IQR: 0.4-3.3), 3.6 (IQR: 1.3-Q3 not reached), and 1.1 (IQR: 0.3-3.6) years for group 1, their controls, group 2 and their controls, respectively. Overall 10-year mortality on KRT was higher among cancer patients vs. controls in group 1: 16% vs. 9% (aHR 2.02, 95% CI: 1.21-3.37) and in group 2: 23% vs. 14% (aHR 2.32, 95% CI: 1.11-4.85). In contrast, 10-year patient survival after first KT was comparable to controls (93% vs. 96%; 100% vs. 94%, in groups 1 and 2, respectively). In summary, childhood cancer survivors' KT was delayed, their overall mortality on KRT was increased, but once transplanted, their long-term outcome was similar to other KT recipients.

We analyzed the Scientific Registry of Transplant Recipients (2004-2022) for primary kidney recipients with HIV who had average immunologic risk and were discharged on tacrolimus/mycophenolate mofetil (with or without corticosteroids). Recipients were grouped by induction type: rabbit antithymocyte globulin (r-ATG, n=688) and human interleukin-2 receptor antagonist (IL2Ra, n=467). Kaplan-Meier curves were generated to examine recipient and graft survival by induction type. We used mixed Cox proportional hazard models to determine associations between induction type and outcomes of interest, with adjustments for recipient and donor factors and transplant center as a random effect. Regression with propensity score weighting reduced selection bias from nonrandom induction allocation. The unadjusted 10-year survival rate was 57% for those receiving r-ATG and 64% for those receiving IL2Ra (P<.001). Adjusted risk of death was significantly lower for IL2Ra induction than r-ATG induction with Cox multivariable (hazard ratio, 0.65; 95% CI, 0.47-0.91; P=.01) and inverse probability treatment weighting (hazard ratio, 0.38; 95% CI, 0.29-0.50; P<.01) models. Death-censored kidney graft survival did not differ by induction type in either model. The 1-year rejection rate was 10.1% and 11.6% for r-ATG and IL2Ra recipients, respectively (P=.52). Overall, IL2Ra conferred better long-term survival than r-ATG without increased risk of graft loss.

Complications like acute cellular rejection (ACR) and infection are known risk factors for the development of chronic lung allograft dysfunction (CLAD), impacting long-term patient and graft survival after lung transplantation (LTx). Differentiating between complications remains challenging and time-sensitive, highlighting the need for accurate and rapid diagnostic modalities. We assessed the ability of exhaled breath analysis using an electronic nose (eNose) to distinguish between ACR, infection and mechanical complications in LTx recipients (LTR) presenting with suspected complications. LTR with suspected complications and subsequently proven diagnosis underwent exhaled breath analysis using an eNose. Supervised machine learning was used to assess the eNose's ability to discriminate between complications. Next we determined the added value of the eNose measurement on top of standard clinical parameters. In 90 LTR, 161 measurements were performed during suspected complications, with 84 proven diagnoses. The eNose could distinguish between ACR, infection and mechanical complications with 74% accuracy, and ACR and infection with 82% accuracy. Combining eNose measurements with standard clinical parameters improved diagnostic accuracy to 88% (p=0.0139), with 94% sensitivity and 80% specificity. Exhaled breath analysis using eNose technology is a promising, non-invasive, diagnostic modality for distinguishing LTx complications, enabling timely diagnosis and interventions.