We analyzed the Scientific Registry of Transplant Recipients (2004-2022) for primary kidney transplant 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.

Valid measures of side effects are important to inform clinical use of calcineurin inhibitors (CNIs). This study developed and established the content validity of a patient-reported outcome (PRO) measure to capture side effects among kidney transplant recipients taking CNIs.

Qualitative interviews for concept elicitation and cognitive debriefing.

Participants enrolled in the qualitative study were adults who had received a kidney transplant≤5 years earlier and were currently taking a CNI for immunosuppression.

Concept elicitation interview data were analyzed by developing a codebook from a list of symptoms described by participants that they attributed to CNIs or their immunosuppression regimen and by applying the constant comparative approach separately by 2 coders. The most bothersome and important side effects reported by participants were used to select existing PRO items. Cognitive debriefing examined item comprehensibility, comprehensiveness, and relevance.

Among 24 participating patients, 12 underwent concept elicitation interviews. Most participants (n=10) reported neurological or cognitive CNI side effects, and a majority of those (n=6) reported the neurological and cognitive side effects were the most bothersome adverse consequences of therapy. Based on these findings, 16 items were either selected from the Functional Assessment for Chronic Illness Therapy (FACIT) PRO item library or were newly written. These items were refined and reduced to 13 for cognitive debriefing, which was completed by 18 participants. These items were organized into 2 scales: Tremors and Cognitive Side Effects.

Though a diverse set of patients participated, they were not representative of all recipients of kidney transplants. The PRO measure's reliability, convergent and known-groups validity, and responsiveness to change were not evaluated. Symptoms could not be definitively attributed to CNIs.

A newly developed PRO measure, the Functional Assessment of Chronic Illness Therapy-Calcineurin Inhibitor-Neurotoxicity (FACIT-CNI-Ntx), captures important side effects among patients receiving CNIs.

People undergoing kidney transplantation require a lifelong regimen of immunosuppressing medications, including calcineurin inhibitors. Calcineurin inhibitors have side effects that may negatively impact transplant recipients' lives, sometimes interfering with important daily activities. We created a new survey for kidney transplant recipients to report on their experiences with calcineurin inhibitor side effects that we named the Functional Assessment of Chronic Illness Therapy-Calcineurin Inhibitor-Neurotoxicity (FACIT-CNI-Ntx) and that captures important side effects among patients receiving CNIs.

Background: This study aimed to assess the diagnostic accuracy of combining donor-derived cell-free DNA (dd-cfDNA) fraction and absolute quantification in detecting kidney allograft rejection. Methods: A prospective study was conducted from December 2019 to April 2021 at the First Affiliated Hospital of Sun Yat-sen University. Kidney transplant recipients who underwent biopsy, including cases of T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), and borderline rejection, were included. dd-cfDNA fraction and absolute concentrations were measured, and diagnostic efficacy was evaluated using receiver operating characteristic (ROC) analysis. The double-positive and double-negative methods were applied to assess performance. Results: A total of 50 kidney transplant recipients were included. The dd-cfDNA fraction cutoff of 1.08% achieved 93.33% sensitivity and 91.43% specificity (AUC = 0.95), with an NPV of 96.97% and a PPV of 82.35%. The absolute dd-cfDNA threshold of 32 cp/mL yielded 80.00% sensitivity and 71.43% specificity (AUC = 0.78), with an NPV of 89.29% and a PPV of 54.55%. The double-positive method provided superior accuracy, with a PPV of 91.67% and an NPV of 89.47%, demonstrating 73.33% sensitivity and 97.14% specificity. The double-negative method achieved 100% NPV and 100% sensitivity. Conclusions: Combining dd-cfDNA fraction and absolute quantification improves diagnostic accuracy for kidney transplant rejection, especially ABMR. The double-positive and double-negative approaches show high predictive value, offering potential clinical value for monitoring kidney transplant recipients.

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover its mechanism. Mice were divided into a TAC group and a control group (n = 5 per group). The TAC group received TAC subcutaneously (1 mg/kg/day for 28 days), while the control group received normal saline instead. After the administration period, whole blood was collected and metabolomic analysis was performed, revealing significant changes in 56 metabolites. The major metabolic changes were related to uremic toxins, vascular damage, and NAD+. NAD+ levels were significantly lower in the TAC group, and ADP-ribose, nicotinamide, and nicotinamide N-oxide, which are degradation products of NAD+, were significantly higher, suggesting impairment of the NAD+ salvage pathway. NAD+ deficiency suggests cellular aging and mitochondrial dysfunction, which may induce vascular damage and chronic kidney disease. Our study demonstrated a correlation between low NAD+ levels and the pathophysiology of TAC nephrotoxicity.

Long-term systemic immunosuppression is needed for vascularized composite allotransplantation (VCA). The high rate of acute rejection episodes in the first posttransplant year, the development of chronic rejection, and the adverse effects that come along with this treatment, currently prevent a wider clinical application of VCA. Opportunistic infections and metabolic disturbances are among the most observed side effects in VCA recipients. To overcome these challenges, local immunosuppression using biomaterial-based drug delivery systems (DDS) have been developed. The aim of these systems is to provide high local concentrations of immunosuppressive drugs while reducing their systemic load. This review provides a summary of recently investigated local DDS with different mechanisms of action such as on-demand, ultrasound-sensitive, or continuous drug delivery. In preclinical models, ranging from rodent to porcine and nonhuman primate models, this approach has been shown to reduce systemic tacrolimus (TAC) load and adverse effects, while prolonging graft survival. Localized immunosuppression using biomaterial-based DDS represents an encouraging approach to enhance graft survival and reduce toxic side effects of immunosuppressive drugs in VCA patients. Preclinical models using TAC-releasing DDS have demonstrated high local immunosuppressive effects with a low systemic burden. However, to reduce acute rejection events in translational animal models or in the clinical reality, the use of additional low-dose systemic TAC treatment may be envisaged. Patients may benefit through efficient graft immunosuppression and survival with negligible systemic adverse effects, resulting in better compliance and quality of life.

Alemtuzumab induction with belatacept/rapamycin-based maintenance immunotherapy (ABR) prevents kidney allograft rejection and specifically limits early costimulation blockade-resistant rejection (CoBRR). To evaluate the mechanisms by which this regimen alters CoBRR, we characterized the phenotype and functional response of preexisting memory cells to allogeneic endothelial cells using intracellular cytokine staining and flow cytometry. IL-7-induced lymphocyte proliferation in the presence or absence of rapamycin was assessed to characterize the phenotype of proliferating cells. Lymphocytes from 40 recipients who underwent transplant using the ABR regimen were studied longitudinally. The rapid immunoresponses of preexisting alloreactive cells to allogeneic endothelial cells were predominantly CD8+TNF-α+/IFN-γ+ cells. These cells were effector memory (TEM) and terminally differentiated effector memory cells lacking CD28 expression, and most were CD57+PD1-. Neither rapamycin nor belatacept directly inhibited these cells. IL-7, a cytokine induced during lymphopenia postdepletion, provoked dramatic CD8+ TEM cell proliferation and a low level of CD8+CD57+PD1- cell expansion in vitro. The IL-7 stimulation induced CD8+ cell mTOR phosphorylation, and rapamycin treatment markedly inhibited IL-7-induced TEM and CD57+PD1- cell expansion. This effect was evident in patients receiving the ABR in that the repopulation of CD8+CD57+PD1- TEM cells was substantially suppressed for at least 36 mo after transplant. These findings help define one mechanism by which a costimulation blockade/rapamycin-based therapy following alemtuzumab induction minimizes CoBRR, namely that in the presence of rapamycin, costimulation-resistant alloreactive cells are disproportionately ineffective at repopulating following post-transplant T cell depletion.

In kidney transplant (KT) recipients diabetes mellitus (DM) are associated with an increased mortality and a poorer graft survival. Glucagon-like peptide 1 receptor agonists (GLP1-RA) have demonstrated cardiovascular and renal benefits in the general population. However, there is lacking evidence in KT recipients.

To analyze the efficacy and safety of glucagon-like peptide 1 receptor GLP1-RA in a cohort of KT recipients.

Multicenter retrospective cohort study of KT patients with DM who started subcutaneous GLP1-RA in 3 hospitals in the province of Cádiz between February 2016 and July 2022. Estimated glomerular filtration rate (eGFR), proteinuria, and weight at baseline and after 6 and 12 months were collected. We analyzed glycemic control, blood pressure, lipid profile, and doses and trough levels of tacrolimus. We document episodes of acute rejection (AR), de novo donor-specific antibodies (dnDSA), and adverse effects.

During this period, 96 KT with DM started treatment with GLP1-RA, of which 84 had a minimum follow-up of 6 months and 61 were followed for 12 months. A significant reduction was observed in proteinuria (-19.1 mg/g, p = 0.000; -46.6 mg/g, p = 0.000), weight (-3.6 kg, p = 0.000; -3.6 kg, p = 0.000), glycosylated hemoglobin (-0.7%, p = 0.000; -0.9%, p = 0.000), systolic blood pressure (-7.5 mmHg, p = 0.013; -7.3 mmHg, p = 0.004), total cholesterol (-11.5 mg/dL, p = 0.001; -15.6 mg/dl, p = 0.002) and LDL cholesterol (-9.2 mg/dl, p = 0.002; -16.8 mg/dl, p = 0.000) at 6 months and 1 year of follow-up. The eGFR remained stable and the dose and trough levels of tacrolimus did not change. No episodes of AR or development of dnDSA were observed during follow-up.

GLP1-RA in KT patients can be a safe and effective option for the management of DM in KT.

Despite many people awaiting kidney transplant, kidney allografts from acute kidney injury (AKI) donors continue to be underutilized. We aimed to cluster kidney transplant recipients of AKI kidney allografts using an unsupervised machine learning (ML) approach.

Using Organ Procurement and Transplantation Network-United Network for Organ Sharing (OPTN/UNOS) data, a consensus clustering cohort analysis was performed in 12 356 deceased donor kidney transplant recipients between 2015 and 2019 in whom donors had a terminal serum creatinine ≥1.5 mg/dL. Significant cluster characteristics were determined, and outcomes were compared.

The median donor terminal creatinine was 2.2 (interquartile range [IQR] 1.7-3.3) mg/dL. Cluster analysis was performed on 12 356 AKI kidney recipients, and three clinically distinct clusters were identified. Young, sensitized kidney re-transplant patients characterized Cluster 1. Cluster 2 was characterized by first-time kidney transplant patients with hypertensive and diabetic kidney diseases. Older diabetic recipients characterized Cluster 3. Clusters 1 and 2 donors were young and met standard kidney donor profile index (KDPI) criteria; Cluster 3 donors were older, more likely to have hypertension or diabetes, and meet high KDPI criteria. Cluster 1 had a higher risk of acute rejection, 3-year patient death, and graft failure. Cluster 3 had a higher risk of death-censored graft failure, patient death, and graft failure at 1 and 3 years. Cluster 2 had the best patient-, graft-, and death-censored graft survival at 1 and 3 years. Compared to non-AKI kidney recipients, the AKI clusters showed a higher incidence of delayed graft function (DGF, AKI: 43.2%, 41.7%, 45.3% vs. non-AKI: 25.5%); however, there were comparable long-term outcomes specific to death-censored graft survival (AKI: 93.6%, 93.4%, 90.4% vs. non-AKI: 92.3%), patient survival (AKI: 89.1%, 93.2%, 84.2% vs. non-AKI: 91.2%), and overall graft survival (AKI: 84.7%, 88.2%, 79.0% vs. non-AKI: 86.0%).

In this unsupervised ML approach study, AKI recipient clusters demonstrated differing, but good clinical outcomes, suggesting opportunities for transplant centers to incrementally increase kidney utilization from AKI donors.

The metabolism- and transporter-based drug-drug interactions (DDIs) between mycophenolate mofetil (MMF) and co-administered medications may be key factors for the high individual variability in MMF exposure. This study systematically assessed the influence of co-medications on the mycophenolic acid (MPA) pharmacokinetic (PK) process in vitro, particularly to provide mechanistic evidence of the metabolic interaction among steroids, cyclosporine (CsA), and MMF.

Based on a previous study, we hypothesized that there are three main DDI pathways affecting MMF PK in vivo. A human hepatocyte induction study, transporter substrate/inhibition study using human embryonic kidney 293 cells, and multidrug resistance-associated protein 2 (MRP2) substrate/inhibition study using vesicle membrane were conducted to assess the mechanistic evidence of the metabolic interaction in triple therapies. The potential DDI risks associated with seven medications commonly co-administered with MMF in clinical practice were further evaluated.

The in vitro results suggested that prednisolone, the active metabolite of prednisone, induces the enzymatic activity of uridine 5'-diphospho-glucuronosyltransferase (UGT), particularly the UGT1A9 and UGT2B7 isoforms, resulting in increased metabolism of MPA to MPA glucuronide (MPAG). This induction potential was not observed in CsA-treated human hepatocytes. CsA inhibits organic anion-transporting polypeptide (OATP) 1B1- and OATP1B3-mediated MPAG. Prednisolone and CsA showed no inhibitory effect on MRP2-mediated MPAG efflux. Salvia miltiorrhiza significantly inhibited organic anion-transporting polypeptide and OAT 3 activities, suggesting that it affects the hepatic uptake and renal excretion of MPAG, causing increased MPAG exposure in vivo.

These identified factors may contribute to the high inter-individual variability in MMF exposure and facilitate further development of mechanistic MMF PK models and individualized therapies.

Quality indicators in kidney transplants are needed to identify care gaps and improve access to transplants. We used linked administrative health care databases to examine multiple ways of defining pre-emptive living donor kidney transplants, including different patient cohorts and censoring definitions. We included adults from Ontario, Canada with advanced chronic kidney disease between January 1, 2013, to December 31, 2018. We created 4 unique incident patient cohorts, varying the eligibility by the risk of progression to kidney failure and whether individuals had a recorded contraindication to kidney transplant (eg, home oxygen use). We explored the effect of 4 censoring event definitions. Across the 4 cohorts, size varied substantially from 20 663 to 9598 patients, with the largest reduction (a 43% reduction) occurring when we excluded patients with ≥1 recorded contraindication to kidney transplantation. The incidence rate (per 100 person-years) of pre-emptive living donor kidney transplant varied across cohorts from 1.02 (95% CI: 0.91-1.14) for our most inclusive cohort to 2.21 (95% CI: 1.96-2.49) for the most restrictive cohort. Our methods can serve as a framework for developing other quality indicators in kidney transplantation and monitoring and improving access to pre-emptive living donor kidney transplants in health care systems.

Remote ischemic conditioning (RIC) has shown great advantages in protecting organs from ischemia-reperfusion loss and applied research on RIC continues to increase. We performed a systematic review and meta-analysis to comprehensively investigate the value of RIC for different organ transplantation.

We searched PubMed, EMBASE, and the Cochrane Library from inception to November 1, 2023, for randomized controlled trials investigating whether RIC has an advantage in organ transplantation (including heart, lung, liver, and kidney) compared with controls. The primary outcomes varied according to the transplanted organ, including liver transplantation (graft loss, early allograft dysfunction, acute kidney injury, days in hospital, and mortality); kidney transplantation (delayed graft function, acute rejection (AR), graft loss, 50% decrease in serum creatinine, glomerular filtration rate, days in hospital, and mortality); heart and lung transplantation (AR, mortality). Two investigators independently selected suitable trials, assessed trial quality, and extracted the data.

A total of 11 randomized controlled trials were included in this study, including six kidney transplants, three liver transplants, and one heart and lung transplant each, with 561 RIC cases and 564 controls, and a total of 1125 patients. The results showed that RIC did not reduce mortality in transplant patients compared with controls (liver transplant: RR0.9, 95% confidence interval [0.31-2.66]; kidney transplant: RR 0.76, 95% confidence interval [0.17-3.33]), graft failure rate (liver transplantation: RR 0.3, 95% confidence interval [0.07, 1.19]; kidney transplantation: RR 0.89, 95% confidence interval [0.35, 2.27]), length of hospital stay (liver transplantation: standard mean difference [SMD] 0.14, 95% confidence interval [-0.15, 0.42]; kidney transplantation: SMD -0.1, 95% confidence interval [-0.3, 0.11]). In addition, RIC did not improve early liver function after liver transplantation (RR 0.97, 95% confidence interval [0.55,1.7]), acute kidney injury after liver transplantation (RR 1.17 95% confidence interval [0.9, 1.54]), delayed functional recovery after renal transplantation (RR 0.84, 95% confidence interval [0.62, 1.15]), AR rate (RR 1.04, 95% confidence interval [0.72, 1.49]), 50% serum creatinine decline rate (RR 1.1, 95% confidence interval [0.88, 1.37]), glomerular filtration rate 3 months after surgery (SMD 0.13, 95% confidence interval [-0.05, 0.31]) and postoperative 12 months glomerular filtration rate (SMD 0.13, 95% confidence interval [-0.06, 0.31]).

Remote ischemic modulation does not improve clinical outcomes in patients undergoing organ transplantation (heart, lung, liver, and kidney).

Immunosuppressive regimens are imperative for improving patient and graft survival following kidney transplantation in patients with kidney failure. However, real-world evidence regarding treatments and outcomes in these patients is scarce. We sought to describe the treatment switches (assessed by line of treatment [LOT]), patterns, and outcomes in patients who underwent kidney transplantation in the United States.

This retrospective cohort study used claims data from the Optum Research Database in the United States. Adult and pediatric patients undergoing a kidney transplantation between January 1, 2000, and June 30, 2019, who had ≥1 year of baseline and follow-up visits and continuous enrollment in the Optum Research Database, were included.

Data from 7159 patients (6833, adult; 326, pediatric) were included. The mean age for adult and pediatric patients was 51.4 ± 12.8 years and 10.4 ± 5.1 years, respectively. The mean number of LOTs in patients with ≥1 LOT (n = 7004) was 4.1 ± 2.6 LOTs. Tacrolimus, antiproliferative agents, and prednisone were the most frequently prescribed immunosuppressants. No strong correlations were identified between switching from LOT1 to LOT2 and potential predictors of treatment switches. The proportion of patients who did not experience graft loss gradually decreased between month 3 and month 120 (72%-36%), driven by return to dialysis (66%-18%). A slower decrease was observed for graft rejection (98%-84%), retransplantation (98%-93%), and graft removal (98%-92%).

We described treatment switches, patterns, and outcomes in patients who underwent kidney transplantation in the United States. Future analytical studies are needed to test hypotheses derived from these observations.

Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk.

We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation.

We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309).

NCT05148715.

There is limited data in the literature about pediatric kidney transplant (KT) following gut transplant (GT). The purpose of this study is to highlight the technical challenges and outcomes of KT in pediatric gut recipients who developed kidney failure (KF).

A retrospective single-center study of pediatric GT recipients from January 2000 to December 2019 was performed. In total, 14 (7%) out of 206 pediatric GT recipients developed KF and were listed for KT. Ten patients underwent kidney after gut transplant (KAGT), three patients underwent simultaneous kidney and re-do gut transplant (SKAGT), and one patient died on the KT waitlist.

1-, 5-, and 10-year kidney graft survival was 100%, 91%, and 78%, respectively. 1-, 5-, and 10-year GT graft survival was 100%, 77%, and 77%, respectively. 1-, 5-, and 10-year patient survival was 100%, 91%, and 91%, respectively.

Despite the technical complexity, KAGT and SKAGT for pediatric GT recipients that develop KF can be performed with favorable outcomes.

The study aim was to analyze the presentation, management, and follow-up of renal transplant patients developing bladder calculi.

Patients who underwent renal transplant with postoperative follow-up at our institution were retrospectively analyzed (1984-2023) to assess for the development of posttransplant bladder stones. All bladder stones were identified by computerized tomography imaging and stone size was measured using this imaging modality.

The prevalence of bladder calculi post-renal transplantation during the study window was 0.22% (N = 20/8,835) with a median time to bladder stone diagnosis of 13 years posttransplant. Of all bladder stone patients, 6 (30%) received deceased donor and 14 (70%) living donor transplants. There were 11 patients with known bladder stone composition available; the most common being calcium oxalate (N = 6). Eleven (55%) patients had clinical signs or symptoms (most commonly microhematuria). Fourteen of the bladder stone cohort patients (70%) underwent treatment including cystolitholapaxy in 12 subjects. Of these 14 patients, 9 (64%) were found to have nonabsorbable suture used for their ureteroneocystostomy closure.

The prevalence of bladder stones post-renal transplant is low. The utilization of nonabsorbable suture for ureteral implantation was the main risk factor identified in our series. This technique is no longer used at our institution. Other factors contributing to bladder stone formation in this population warrant identification.

Antibody-mediated rejection (ABMR) is a major cause of late kidney allograft failure, but its economic and humanistic impacts have not been well-characterized in the literature.

We reviewed available literature on economic burden (costs and healthcare resource use) and humanistic burden (health-related quality of life impacts [HRQOL] and utility estimates) in patients diagnosed with kidney transplant rejection; ABMR-specific studies were of particular interest. In total, 21 publications reporting economic and humanistic burden were included in the review; 9 of these reported ABMR-specific outcomes. The reviewed studies consistently showed a greater burden associated with ABMR-related transplant rejection than with non-ABMR transplant rejection.

Evidence suggests greater economic burden and increased HRQOL impairment with ABMR-related kidney transplant rejection relative to non-ABMR, although small sample sizes and missing definitions for ABMR make meaningful comparisons between studies challenging. Because no International Classification of Diseases (ICD)-10 codes currently describe the etiologies of transplant rejection, it is difficult to characterize the burden of distinct types of transplant rejection. The paucity of high-quality data on the burden of ABMR in kidney transplant rejection demonstrates the need for more etiology-centric ICD-10 codes.

Kidney transplantation stands out as the most effective renal replacement therapy for patients grappling with end-stage renal disease. However, post-transplant renal fibrosis is a prevalent and irreversible consequence, imposing a substantial clinical burden. Unfortunately, the clinical landscape remains devoid of reliable biological markers for diagnosing post-transplant renal interstitial fibrosis.

We obtained transcriptome and single-cell sequencing datasets of patients with renal fibrosis from NCBI Gene Expression Omnibus (GEO). Subsequently, we employed Weighted Gene Co-Expression Network Analysis (WGCNA) to identify potential genes by integrating core modules and differential genes. Functional enrichment analysis was conducted to unveil the involvement of potential pathways. To identify key biomarkers for renal fibrosis, we utilized logistic analysis, a LASSO-based tenfold cross-validation approach, and gene topological analysis within Cytoscape. Furthermore, histological staining, Western blotting (WB), and quantitative PCR (qPCR) experiments were performed in a murine model of renal fibrosis to verify the identified hub genes. Moreover, molecular docking and molecular dynamics simulations were conducted to explore possible effective drugs.

Through WGCNA, the intersection of core modules and differential genes yielded a compendium of 92 potential genes. Logistic analysis, LASSO-based tenfold cross-validation, and gene topological analysis within Cytoscape identified four core genes (CD3G, CORO1A, FCGR2A, and GZMH) associated with renal fibrosis. The expression of these core genes was confirmed through single-cell data analysis and validated using various machine learning methods. Wet experiments also verified the upregulation of these core genes in the murine model of renal fibrosis. A positive correlation was observed between the core genes and immune cells, suggesting their potential role in bolstering immune system activity. Moreover, four potentially effective small molecules (ZINC000003830276-Tessalon, ZINC000003944422-Norvir, ZINC000008214629-Nonoxynol-9, and ZINC000085537014-Cobicistat) were identified through molecular docking and molecular dynamics simulations.

Four potential hub biomarkers most associated with post-transplant renal fibrosis, as well as four potentially effective small molecules, were identified, providing valuable insights for studying the molecular mechanisms underlying post-transplant renal fibrosis and exploring new targets.

In the evolving landscape of nephrology and kidney transplants, assessing renal functional reserve (RFR) in living kidney donors is essential for ensuring donor safety and successful transplantation. This study explores the use of the Intra-Parenchymal Renal Resistive Index Variation (IRRIV) test, a novel non-invasive method, to measure RFR in living donors. Our observational study included 11 participants undergoing living kidney donations, evaluated using the IRRIV-based Renal Stress Test (RST) before and 12 months post-nephrectomy. The study demonstrated significant changes in creatinine and eGFR CKD-EPI levels post-donation, with an average creatinine rise from 69 to 97 µmol/L and a reduction in eGFR from 104 to 66 mL/min/1.73 m2. These variations align with the expected halving of nephron mass post-nephrectomy and the consequent recruitment of RFR and hyperfiltration in the remaining nephrons. This pilot study suggests that the IRRIV-based RST is a practical, safe, and reproducible tool, potentially revolutionizing the assessment of RFR in living kidney donors, with implications for broader clinical practice in donor eligibility evaluation, even in borderline renal cases. Furthermore, it confirms the feasibility of RST in living kidney donors and allows us to assess the sample size in 48 donors for a future study.

In this comprehensive meta-analysis, our objective was to evaluate the diagnostic utility of graft-derived cell-free DNA (GcfDNA) in kidney allograft rejection and explore associated factors. We conducted a thorough search of PubMed, Embase, and the Cochrane Library databases, spanning from their inception to September 2022. Statistical analysis was executed utilizing Stata 15, Meta-DiSc 1.4, and Review Manager 5.4 software. The combined pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristics (SROC) curve from the synthesis of findings across ten studies were as follows: 0.75 (0.67-0.81), 0.78 (0.72-0.83), 3.36 (2.89-4.35), 0.32 (0.24-0.44), 8.77 (4.34-17.74), and 0.83 (0.80-0.86), respectively. Among the ten studies primarily focused on GcfDNA's diagnostic potential for antibody-mediated rejection (ABMR), the optimal cut-off threshold demonstrated substantial diagnostic efficacy, with pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, DOR, and area under the summary receiver operating characteristics curve values of 0.83 (0.74-0.89), 0.75 (0.70-0.80), 3.37 (2.64-4.30), 0.23 (0.15-0.36), 14.65 (7.94-27.03), and 0.85 (0.82-0.88), respectively. These results underscore the high diagnostic accuracy of GcfDNA in detecting rejection. Furthermore, the optimal cut-off threshold proves effective in diagnosing ABMR, while a 1% threshold remains a robust diagnostic criterion for rejection. Notably, for ABMR diagnosis, droplet digital PCR digital droplet polymerase chain reaction emerges as a superior method in terms of accuracy when compared to other techniques. Nonetheless, further research is warranted to substantiate these findings.

Highly sensitized patients face many barriers to kidney transplantation, including higher rates of antibody-mediated rejection after HLA-incompatible transplant. IdeS, an endopeptidase that cleaves IgG nonspecifically, has been trialed as desensitization prior to kidney transplant, and successfully cleaves donor-specific antibody (DSA), albeit with rebound.

IdeS was generated and tested (2 mg/kg, IV) in two naïve and four allosensitized nonhuman primates (NHP). Peripheral blood samples were collected at regular intervals following IdeS administration. Total IgG, total IgM, and anti-CMV antibodies were quantified with ELISA, and donor-specific antibody (DSA) and anti-pig antibodies were evaluated using flow cytometric crossmatch. B cell populations were assessed using flow cytometry.

IdeS successfully cleaved rhesus IgG in vitro. In allosensitized NHP, robust reduction of total, DSA, anti-pig, and anti-CMV IgG was observed within one day following IdeS administration. Rapid rebound of all IgG antibody populations was observed, with antibody levels returning to baseline around day 14 post-infusion. Total IgM level was not affected by IdeS. Interestingly, a comparable reduction in antibody populations was observed after the second dose of IdeS. However, we have not observed any significant modulation of B cell subpopulations after IdeS.

This study evaluated efficacy of IdeS in the allosensitized NHP in IgG with various specificities, mirroring antibody kinetics in human patients. The efficacy of IdeS on preexisting anti-pig antibodies may be useful in clinical xenotransplantation. However, given the limitation of IdeS on its durability as a monotherapy, optimization of IdeS with other agents targeting the humoral response is further needed.

Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation.

This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established.

Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P  = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P  = 0.039) were observed in the study cohort.

A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).

Purpose: Further elucidate the potential drug interaction between tacrolimus and carbapenems in order to appropriately maintain the balance between infection treatment and therapeutic immunosuppression. Methods: This study was a retrospective evaluation of solid organ transplant recipients on a stable dose of tacrolimus who received either ertapenem or meropenem. Patients were excluded if they had acute kidney injury, acute liver failure, concomitant initiation of medications that interact with tacrolimus, or were pregnant. The primary endpoint was the change in the median daily tacrolimus dose after meropenem or ertapenem administration. The secondary endpoint was the change in serum tacrolimus levels after meropenem or ertapenem administration. Results: A total of 28 patients on tacrolimus were included in the study, 12 received ertapenem and 16 received meropenem. The median daily tacrolimus dose was 4.5 mg [IQR 3.0 mg - 8.8 mg] prior to and 3.4 mg [IQR 2.3 mg - 8.8 mg] after ertapenem administration. The median daily tacrolimus dose was 3.0 mg [IQR 1.6 mg - 5.5 mg] before and 3.0 mg [IQR 1.6 mg - 5.5 mg] after meropenem administration. No statistically significant difference in regard to the change in the median daily tacrolimus dose after ertapenem (P =.173) or meropenem administration (P =.755) was observed. There was no statistically significant difference found after ertapenem (P =.583) or meropenem (P =.317) administration when comparing pre- and post-administration median serum tacrolimus levels. Conclusion: The administration of ertapenem or meropenem did not affect serum tacrolimus levels or daily tacrolimus dose suggesting against empiric dose adjustments with co-administration.

Kidney transplantation causes large perturbations of the immune system. While many studies focus on the allograft, insights into systemic effects are largely missing. Here, we analyzed the systemic immune response in 3 cohorts of kidney transplanted patients. Using serum proteomics, laboratory values, mass cytometry, histological and clinical parameters, inter-patient heterogeneity was leveraged for multi-omic co-variation analysis. We identified circulating immune modules (CIM) that describe extra-renal signatures of co-regulated plasma proteins. CIM are present in nontransplanted controls, in transplant conditions and during rejection. They are enriched in pathways linked to kidney function, extracellular matrix, signaling, and cellular activation. A complex leukocyte response in the blood during allograft quiescence and rejection is associated with CIM activity and CIM-specific cytokines. CIM activity correlates with kidney function including a 2-month prediction. Together, the data suggest a systemic and multi-layered response of transplant immunity that might be insightful for understanding allograft dysfunction and developing translational biomarkers.

Patients with diabetes mellitus (DM) have worse graft and overall survival, but recent evidence suggests that the difference is no longer significant.

To compare the outcomes between patients with end-stage kidney disease due to DM (ESKD-DM) and ESKD due to nondiabetic etiology (ESKD-non-DM) who underwent kidney transplantation (KT) up to 10 years of follow-up.

Survival analysis of a retrospective cohort.

All patients who underwent KT at the Hospital Universitario San Ignacio, Colombia, between 2004 and 2022.

Overall and graft survival in ESKD-DM and ESKD-non-DM who received KT. Patients who died with functional graft were censored for the calculation of kidney graft survival.

Log-rank test, Cox proportional hazards model, and competing risk analysis were used to compare overall and graft survival in patients with ESKD-DM and ESKD-non-DM who underwent KT.

A total of 375 patients were included: 60 (16%) with ESKD-DM and 315 (84%) with ESKD-non-DM. Median follow-up was 83.3 months. Overall survival was lower in patients with ESKD-DM at 5 (75.0% vs 90.8%, P < .001) and 10 years (55.0% vs 86.7%, P < .001). Cardiovascular death was higher in patients with diabetes (27.3% vs 8.2%, P = .021). Death-censored graft survival was similar in both groups (96.7% vs 93.3% at 5 years, P = .324). On multivariate analysis, the factors associated with global survival were DM (hazard ratio [HR] = 2.11, 95% confidence interval [CI] = 1.23-3.60, P = .006), recipient age (HR = 1.05, 95% CI = 1.02-1.08, P < .001), delayed graft function (HR = 2.07, 95% CI = 1.24-3.46, P = .005), and donor age (HR = 1.03, 95% CI = 1.01-1.05, P = .002). In the competing risk analysis, DM was associated with mortality only in the cardiovascular death group (sub-hazard ratio [SHR] = 6.06, 95% CI = 1.01-36.4, P = .049).

Change in diabetes treatment received over time and adherence to glycemic targets were not considered. The sample size is relatively small, which limits the precision of our estimates. The Kidney Donor Profile Index and the occurrence of treated acute rejection were not included in the regression models.

Overall survival is lower in patients with diabetes, possibly due to older age and cardiovascular comorbidities. Therefore, patients with diabetes should be followed more closely to control cardiovascular risk factors. However, there is no difference in graft survival.

Ambient air pollution has become 1 of the most important public health issues worldwide. In particular, particulate matter with an aerodynamic diameter <2.5 μm (PM2.5) is a fatal component of air pollution. We aimed to analyze whether perioperative exposure to PM2.5 is associated with the deterioration of renal function in living kidney donors.

This study was conducted on 232 kidney donors with postoperative 2-year glomerular filtration rate (GFR). The GFR was determined by serum creatinine-based method using the Modification of Diet in Renal Disease equation and radionuclide-based method using 99mTc-DTPA renal scintigraphy. Perioperative exposure to PM2.5 was calculated using data from the AIRKOREA System. Multiple linear and logistic regression analyses were performed to estimate the associations between mean PM2.5 concentration and postoperative 2-year GFR.

Postoperative Modification of Diet in Renal Disease-estimated GFRs of kidney donors with low PM2.5 concentrations were significantly higher than those of those with high PM2.5 concentrations. A 1-μg/m3 increase in mean PM2.5 concentration was associated with decreased GFR by 0.20 mL/min/1.73 m2. In addition, a 1-μg/m3 increase in mean PM2.5 concentration was associated with an 11% increased risk of chronic kidney disease stage ≥3 at 2 years after donor nephrectomy.

In patients who underwent donor nephrectomy, exposure to PM2.5 negatively affects renal function and is positively associated with the prevalence of chronic kidney disease.

Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus.

In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure.

Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood.

Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.

Advances in immunosuppression have been relatively stagnant over the past 2 decades, and transplant recipients continue to experience long-term morbidity associated with immunosuppression regimens. Strategies to reduce or eliminate the dosage of immunosuppression medications are needed. We discovered a novel administration strategy using the classic adjuvant alum to condition murine islet transplant recipients, known as adjuvant conditioning (AC), to expand both polymorphonuclear and monocytic myeloid-derived suppressive cells (MDSCs) in vivo. These AC MDSCs potently suppress T cell proliferation when cultured together in vitro. AC MDSCs also facilitate naïve CD4+ T cells to differentiate into regulatory T cells. In addition, we were able to demonstrate a significant delay in alloislet rejection compared with that by saline-treated control following adjuvant treatment in a MDSC-dependent manner. Furthermore, AC MDSCs produce significantly more interleukin (IL)-10 than saline-treated controls, which we demonstrated to be critical for the increased T cell suppressor function of AC MDSCs as well as the observed protective effect of AC against alloislet rejection. Our data suggest that adjuvant-related therapeutics designed to expand MDSCs could be a useful strategy to prevent transplant rejection and curb the use of toxic immunosuppressive regimens currently used in transplant patients.

Kidney transplantation is the treatment of choice for all patients with end-stage kidney disease, including pediatric patients. Graft survival in pediatrics was lagging behind adults, but now is comparable with the adult cohort. Although many of the protocols have been adopted from adults, there are issues unique to pediatrics that one should be aware of to take care of this population. These issues include recipient size consideration, increased incidence of viral infections, problems related to growth, common occurrence of underlying urological issues, and psychosocial issues. This article addresses the similarities and differences in renal transplantation, from preparing a patient for transplant, the transplant process, to post-transplant complications.

The prevalence of end-stage renal disease has raised the need for renal replacement therapy over recent decades. Even though a kidney transplant offers an improved quality of life and lower cost of care than dialysis, graft failure is possible after transplantation. Hence, this study aimed to predict the risk of graft failure among post-transplant recipients in Ethiopia using the selected machine learning prediction models.

The data was extracted from the retrospective cohort of kidney transplant recipients at the Ethiopian National Kidney Transplantation Center from September 2015 to February 2022. In response to the imbalanced nature of the data, we performed hyperparameter tuning, probability threshold moving, tree-based ensemble learning, stacking ensemble learning, and probability calibrations to improve the prediction results. Merit-based selected probabilistic (logistic regression, naive Bayes, and artificial neural network) and tree-based ensemble (random forest, bagged tree, and stochastic gradient boosting) models were applied. Model comparison was performed in terms of discrimination and calibration performance. The best-performing model was then used to predict the risk of graft failure.

A total of 278 completed cases were analyzed, with 21 graft failures and 3 events per predictor. Of these, 74.8% are male, and 25.2% are female, with a median age of 37. From the comparison of models at the individual level, the bagged tree and random forest have top and equal discrimination performance (AUC-ROC = 0.84). In contrast, the random forest has the best calibration performance (brier score = 0.045). Under testing the individual model as a meta-learner for stacking ensemble learning, the result of stochastic gradient boosting as a meta-learner has the top discrimination (AUC-ROC = 0.88) and calibration (brier score = 0.048) performance. Regarding feature importance, chronic rejection, blood urea nitrogen, number of post-transplant admissions, phosphorus level, acute rejection, and urological complications are the top predictors of graft failure.

Bagging, boosting, and stacking, with probability calibration, are good choices for clinical risk predictions working on imbalanced data. The data-driven probability threshold is more beneficial than the natural threshold of 0.5 to improve the prediction result from imbalanced data. Integrating various techniques in a systematic framework is a smart strategy to improve prediction results from imbalanced data. It is recommended for clinical experts in kidney transplantation to use the final calibrated model as a decision support system to predict the risk of graft failure for individual patients.

With the rapid aging of the global population posing a serious problem, frailty, a non-specific state that reflects physiological senescence rather than aging in time, has become more widely addressed by researchers in various medical fields. A high prevalence of frailty is found among kidney transplant (KT) candidates and recipients. Therefore, their frailty has become a research hotspot in the field of transplantation. However, current studies mainly focus on the cross-sectional survey of the incidence of frailty among KT candidates and recipients and the relationship between frailty and transplantation. Research on the pathogenesis and intervention is scattered, and relevant review literature is scarce. Exploring the pathogenesis of frailty in KT candidates and recipients and determining effective intervention measures may reduce waiting list mortality and improve the long-term quality of life of KT recipients. Therefore, this review explains the pathogenesis and intervention measures for frailty in KT candidates and recipients to provide a reference for the formulation of effective intervention strategies.

LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring.

This was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele).

In this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race.

CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers.

Recent years have seen major advancements in xenotransplantation: the first pig-to-human heart transplant, the development of a brain-dead recipient model for kidney xenotransplantation, and the registration of the first xenokidney clinical trial. The attitudes of patients with kidney disease or transplants on xenotransplantation and an assessment of their reservations and considerations regarding the technology are crucial to successful clinical translation and eventual widespread implementation.

This systematic review was registered through PROSPERO (CRD42022344581) prior to initiation of the study and reported using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. We included studies that evaluated attitudes towards and willingness to undergo xenotransplantation in patients with end-stage renal disease (ESRD), including those who had already undergone transplantation. MEDLINE (via Ovid), Embase (via Elsevier), and Web of Science (via Clarivate) were searched from database inception to July 15, 2022 by an experienced medical librarian for studies on xenotransplantation and attitudes. Abstracts and full text were screened using Covidence software and data items regarding study methodology, patient demographics, and attitudes regarding xenotransplantation were extracted using Microsoft Excel. Risk of bias assessments were performed using the Critical Appraisal Skills Programmed and National Institute of Health study quality assessment tools.

Of 1992 studies identified, 14 studies met the inclusion criteria. These studies were conducted across eight countries, four in the United States, for a total of 3114 patients on the kidney waitlist or with a kidney transplant. All patients were over 17 years old and 58% were male. Acceptance of a xenotransplant was assessed using surveys in 12 studies. Sixty-three percent (n = 1354) of kidney patients reported that they would accept a xenotransplant with function comparable to that of an allotransplant. Acceptance of xenografts with inferior function to allografts (15%) or as bridge organs (35%) to allotransplantation was lower. Specific concerns expressed by patients included graft function, infection, social stigma, and animal rights. Subgroup analyses showed higher acceptance in already transplanted compared to waitlist patients and white compared to Black Americans.

An understanding of patient attitudes and reservations is key to the successful execution of the first xenotransplantation clinical trials. This study compiles important factors to consider, such as patient concerns, attitudes regarding practical clinical scenarios for the use of xenotransplantation, and the impact of demographic factors on acceptance of this emerging technology.

Although prolonged-release tacrolimus (PR-T) is widely approved for posttransplantation immunosuppression in kidney recipients, large-scale studies are required to assess long-term outcomes. We present follow-up data from the Advagraf-based Immunosuppression Regimen Examining New Onset Diabetes Mellitus in Kidney Transplant Recipients (ADVANCE) trial, in which kidney transplant patients (KTPs) received corticosteroid minimization with PR-T.

ADVANCE was a 24-wk, randomized, open-label, phase-4 study. De novo KTPs received PR-T with basiliximab and mycophenolate mofetil and were randomized to receive an intraoperative corticosteroid bolus plus tapered corticosteroids until day 10 (arm 1) or an intraoperative corticosteroid bolus (arm 2). In this 5-y, noninterventional follow-up, patients received maintenance immunosuppression according to standard practice. The primary endpoint was graft survival (Kaplan-Meier). Secondary endpoints included patient survival, biopsy-confirmed acute rejection-free survival, and estimated glomerular filtration rate (4-variable modification of diet in renal disease).

Follow-up study included 1125 patients. Overall graft survival at 1 and 5 y posttransplantation was 93.8% and 88.1%, respectively, and was similar between treatment arms. At 1 and 5 y, patient survival was 97.8% and 94.4%, respectively. Five-year graft and patient survival rates in KTPs who remained on PR-T were 91.5% and 98.2%, respectively. Cox proportional hazards analysis demonstrated similar risk of graft loss and death between treatment arms. Five-year biopsy-confirmed acute rejection-free survival was 84.1%. Mean ± standard deviation values of estimated glomerular filtration rate were 52.7 ± 19.5 and 51.1 ± 22.4 mL/min/1.73 m² at 1 and 5 y, respectively. Fifty adverse drug reactions were recorded, probably tacrolimus-related in 12 patients (1.5%).

Graft survival and patient survival (overall and for KTPs who remained on PR-T) were numerically high and similar between treatment arms at 5 y posttransplantation.

Rising incidence and prevalence of end-stage renal disease is a worldwide concern for sustainability of healthcare systems and societies. Living donor renal transplant [LDRT] provides highest health achievements and cost containment than any alternative form of renal replacement therapy. Nonetheless, about 25% of potential LDRTs are missed for causes directly related with inadequate timing in donor assessment. Our quality improvement (QI) project implement process control tools and strategy aiming at reducing total evaluation time for donor candidates and minimizing dialysis exposure for intended recipients, which are the two main determinants of clinical outcomes and costs.

The study includes patients who underwent donor nephrectomy between January 1, 2017 and December 31, 2021. Six Sigma DMAIC approach was adopted to assess Base Case performance (Jan2017-Jun2019) and to design and implement our QI project. Study of current state analysis focused on distribution of time intervals within the assessment process, analysis of roles and impacts of involved healthcare providers and identification of targets of improvement. Improved Scenario (Jul2019-Dec2021) was assessed in terms of total lead time reduction, total pre-transplantation dialysis exposure and costs reduction, and increase in pre-emptive transplantations. The study was reported following SQUIRE 2.0 Guidelines for QI projects.

Study population includes 63 patients, 37 in Base Case and 26 in Improved Scenario. Total lead time reduced from a median of 293 to 166 days and this in turn reduced pre-transplantation dialysis exposure and costs by 45%. Rate of potential pre-emptive donors' loss changes from 44% to 27%.

Lean methodology is an effective tool to improve quality and efficiency of healthcare processes, in the interest of patients, healthcare professionals and payers.

Vitamin D deficiency (VDD) or vitamin D insufficiency is common in kidney transplant recipients (KTRs). The impact of VDD on clinical outcomes in KTRs remain poorly defined and the most suitable marker for assessing vitamin D nutritional status in KTRs is unknown so far.

We conducted a prospective study including 600 stable KTRs (367 men, 233 women) and a meta-analysis to pool existing evidence to determine whether 25(OH)D or 1,25(OH)₂D predicted graft failure and all-cause mortality in stable KTRs.

Compared with a higher 25(OH)D concentration, a low concentration of 25(OH)D was a risk factor for graft failure (HR 0.946, 95% CI 0.912-0.981, p = 0.003), whereas 1,25 (OH)₂D was not associated with the study end-point graft loss (HR 0.993, 95% CI 0.977-1.009, p = 0.402). No association was found between either 25(OH)D or 1,25 (OH)₂D and all-cause mortality. We furthermore conducted a meta-analysis including 8 studies regarding the association between 25(OH)D or 1,25(OH)₂D and graft failure or mortality, including our study. The meta-analysis results were consistent with our study in finding that lower 25(OH)D levels were significantly associated with the risk of graft failure (OR = 1.04, 95% CI: 1.01-1.07), but not associated with mortality (OR = 1.00, 95% CI: 0.98-1.03). Lower 1,25(OH)₂D levels were not associated with the risk of graft failure (OR = 1.01, 95% CI: 0.99-1.02) and mortality (OR = 1.01, 95% CI: 0.99-1.02).

Baseline 25(OH)D concentrations but not 1,25(OH)₂D concentrations were independently and inversely associated with graft loss in adult KTRs.

Currently, there is a significant shortage of transplantable organs for patients in need. Interspecies chimerism and blastocyst complementation are alternatives for generating transplantable human organs in host animals such as pigs to meet this shortage. While successful interspecies chimerism and organ generation have been observed between evolutionarily close species such as rat and mouse, barriers still exist for more distant species pairs such as human-mouse, marmoset-mouse, human-pig, and others. One of the proposed barriers to chimerism is the difference in developmental stages between the donor cells and the host embryo at the time the cells are introduced into the host embryo. Hence, there is a logical effort to stage-match the donor cells with the host embryos for enhancing interspecies chimerism. In this study, we used an in silico approach to simultaneously stage-match the early developing embryos of four species, including human, marmoset, mouse, and pig based on transcriptome similarities. We used an unsupervised clustering algorithm to simultaneously stage-match all four species as well as Spearman's correlation analyses to stage-match pairs of donor-host species. From our stage-matching analyses, we found that the four stages that best matched with each other are the human blastocyst (E6/E7), the gastrulating mouse embryo (E6-E6.75), the marmoset late inner cell mass, and the pig late blastocyst. We further demonstrated that human pluripotent stem cells best matched with the mouse post-implantation stages. We also performed ontology analysis of the genes upregulated and commonly expressed between donor-host species pairs at their best matched stages. The stage-matching results predicted by this study will inform in vivo and in vitro interspecies chimerism and blastocyst complementation studies and can be used to match donor cells with host embryos between multiple species pairs to enhance chimerism for organogenesis.

The national kidney allocation system (KAS) implemented in December 2014 in the United States redefined the start of waiting time from the time of waitlisting to the time of kidney failure. Waitlisting has declined post-KAS, but it is unknown if this is due to transplant center practices or changes in dialysis facility referral and evaluation. The purpose of this study was to assess the impact of the 2014 KAS policy change on referral and evaluation for transplantation among a population of incident and prevalent patients with kidney failure.

Cohort study.

37,676 incident (2012-2016) patients in Georgia, North Carolina, and South Carolina identified within the US Renal Data System at 9 transplant centers and followed through December 2017. A prevalent population of 6,079 patients from the same centers receiving maintenance dialysis in 2012 but not referred for transplantation in 2012.

KAS era (pre-KAS vs post-KAS).

Referral for transplantation, start of transplant evaluation, and waitlisting.

Multivariable time-dependent Cox models for the incident and prevalent population.

Among incident patients, KAS was associated with increased referrals (adjusted HR, 1.16 [95% CI, 1.12-1.20]) and evaluation starts among those referred (adjusted HR, 1.16 [95% CI, 1.10-1.21]), decreased overall waitlisting (adjusted HR, 0.70 [95% CI, 0.65-0.76]), and lower rates of active waitlisting among those evaluated compared to the pre-KAS era (adjusted HR, 0.81 [95% CI, 0.74-0.90]). Among the prevalent population, KAS was associated with increases in overall waitlisting (adjusted HR, 1.74 [95% CI, 1.15-2.63]) and active waitlisting among those evaluated (adjusted HR, 2.01 [95% CI, 1.16-3.49]), but had no significant impact on referral or evaluation starts among those referred.

Limited to 3 states, residual confounding.

In the southeastern United States, the impact of KAS on steps to transplantation was different among incident and prevalent patients with kidney failure. Dialysis facilities referred more incident patients and transplant centers evaluated more incident patients after implementation of KAS, but fewer evaluated patients were placed onto the waitlist. Changes in dialysis facility and transplant center behaviors after KAS implementation may have influenced the observed changes in access to transplantation.