Allograft Survival Research Articles

Sirolimus in combination with low-dose extended-release tacrolimus in kidney transplant recipients.

Many challenges remain for long-term survival of renal allografts. Once-daily sirolimus (SRL) combined with low-dose extended-release tacrolimus (LER-TAC) may improve medication adherence and reduce the potential nephrotoxicity of calcineurin inhibitors (CNI) compared with standard immunosuppression regimens, thus potentially improving long-term graft survival. This retrospective, observational, single-center, propensity score matching (PSM) study compared conversion to SRL combined with low-dose ER-TAC and mycophenolic acid (MPA) combined with standard-dose TAC in kidney transplant recipients. After PSM, there were 56 patients in each group. Efficacy, safety, and medication adherence were evaluated over 12 months. There was no significant difference between the two groups in terms of graft and recipient survival and incidence of biopsy-proven acute rejection (p = 1.000), and none of the recipients developed dnDSA after conversion. The mean eGFR improved in SRL + LER-TAC group after conversion compared to before conversion (51.12 ± 20.1 ml/min/1.73 m2 vs. 56.97 ± 19.23 ml/min/1.73 m2, p < 0.05). The medication adherence at 12 months after conversion was superior to before conversion (p = 0.002). Our findings suggest that an immunosuppressive regimen of SRL combined with low-dose ER-TAC is no less effective and safe than standard immunosuppressive regimens for renal transplant recipients and may improve graft renal function and medication adherence.

Retinoic acid-inducible gene-1 knockdown induces immature properties in dendritic cells and prolongs the survival time of allograft mice

BackgroundThe mature state of dendritic cells (DCs) determines their ability to regulate immune responses. Retinoic acid-inducible gene-1 (RIG-1) plays a critical role in DC activation and maturation. RIG-1 activation triggers mitogen-activated protein kinase and nuclear factor-kappa B signal transduction. In this study, we aimed to investigate the effects of inhibiting RIG-1 expression in DCs and its potential in inducing immune tolerance. MethodsDCs were transduced with the recombinant lentiviral vector (Lv) to inhibit RIG-1 expression. A murine islet and skin transplantation model were constructed to find out whether DC-DDX58-RNAi could prolong allograft survival. The phenotypes of DCs and T-cells were analyzed using flow cytometry. Cytokines in serum were detected by the enzyme-linked immunosorbent assay. Protein levels were determined by Western blot. ResultsRIG-1-deficient DCs had low expression of costimulatory molecules and major histocompatibility complex and a strong phagocytic ability. DC-DDX58-RNAi induced regulatory T cell differentiation in the transplant recipient spleens. The DC-DDX58-RNAi-treated recipients showed satisfactory islet allograft function and longer survival time. ConclusionInhibition of RIG-1 with DDX58-RNAi prevented the activation and maturation of the DCs, affected T cell differentiation, protected the biological function of the allograft, and prolonged graft survival. These findings may have important therapeutic implications for new immunomodulatory regimens.

Surgical site infections after kidney transplantation are independently associated with graft loss

Surgical site infections (SSIs) are common health care-associated infections. SSIs after kidney transplantation (K-Tx) can endanger patient and allograft survival. Multicenter studies on this early posttransplant complication are scarce. We analyzed consecutive adult K-Tx recipients enrolled in the Swiss Transplant Cohort Study who received a K-Tx between May 2008 and September 2020. All data were prospectively collected with the exception of the categorization of SSI which was performed retrospectively according to the Centers for Disease Control and Prevention criteria. A total of 58 out of 3059 (1.9%) K-Tx recipients were affected by SSIs. Deep incisional (15, 25.9%) and organ/space infections (34, 58.6%) predominated. In the majority of SSIs (52, 89.6%), bacteria were detected, most frequently Escherichia coli (15, 28.9%), Enterococcus spp. (14, 26.9%), and coagulase-negative staphylococci (13, 25.0%). A BMI ≥25 kg/m2 (multivariable OR 2.16, 95% CI 1.07-4.34, P = .023) and delayed graft function (multivariable OR 2.88, 95% CI 1.56-5.34, P = .001) were independent risk factors for SSI. In Cox proportional hazard models, SSI was independently associated with graft loss (multivariable HR 3.75, 95% CI 1.35-10.38, P = .011). In conclusion, SSI was a rare complication after K-Tx. BMI ≥25 kg/m2 and delayed graft function were independent risk factors. SSIs were independently associated with graft loss.

Blockade of Common Gamma Chain Cytokine Signaling with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, in Combination with Costimulatory Blockers Delayed Skin Graft Rejection in Mice

There is a current medical need to identify innovative maintenance therapies to prevent allograft rejection in solid organ transplantation. During transplant rejection, recipient immune cells identify a grafted organ as foreign and attack it: CD4 + T cells orchestrate transplant rejection by recruiting a range of effector cells responsible for the damage of rejection including CD8 + T cells, NK cells, B cells and macrophages. These pathogenic immune cell responses can be driven by cytokines of the common gamma chain (γ c) cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). γ c cytokines signal through their corresponding receptors, expressed primarily on immune cells, that share a common coreceptor, interleukin 2 receptor subunit gamma (IL2RG) that is required for signaling. To understand the role of γ c cytokines in driving transplant rejection, we generated REGN7257, a fully human IL2RG monoclonal antibody that inhibits γ c cytokine-induced signaling, and we tested its ability to suppress allogeneic immune cell responses in a mouse model of skin graft rejection when delivered as a monotherapy and in combination with mycophenolate mofetil (MMF) or T cell costimulatory pathway blockers. In this model, recipient B6/129 (mixed background) Il2rg hu/hu mice were transplanted with tail skin from BALB/cJ donor mice. Graft survival was analyzed using a log rank Mantel-Cox test to detect statistically significant differences across groups (*=p&amp;lt;0.033; **= p&amp;lt;0.002; ***=p&amp;lt;0.0002; ****=p&amp;lt;0.0001). In a mouse model of skin graft rejection, γ c cytokine signaling blockade with REGN7257 given as maintenance immunosuppression effectively improved overall graft survival (Median Survival Time [MST] IL2RG=13) compared to mice that received a control antibody (MST CTRL=9 [****vs IL2RG Ab]), and with similar efficacy to that observed with the calcineurin inhibitor tacrolimus (MST TAC=12.5 [**vs control, n.s. vs IL2RG Ab]). In treatment combination experiments, while monotherapy treatment with the antiproliferative agent MMF was not as efficient as REGN7257 at delaying skin graft rejection (MST MMF=10 [*vs control] and MST IL2RG=12 [*vs MMF]), simultaneous blockade of cell proliferation and γ c cytokine signaling conferred an advantage over monotherapies (MST MMF+IL2RG=15.5 [****vs control, **vs IL2RG Ab]). Similarly, induction therapy consisting of γ c cytokine signaling blockade followed by maintenance immunosuppression using the CTLA4-Ig fusion protein abatacept, significantly improved overall skin graft survival (MST IL2RG+CTLA4=19.5 [****vs control]) compared to REGN7257 induction only (MST IL2RG=11 [****vs control and combo]) or abatacept maintenance only (MST CTLA4=10 [*vs control, ****vs combo]). Finally, maintenance immunosuppression combining blocking of γc cytokine signaling together with blocking of both CD28 and CD40L costimulatory signals prolonged skin graft survival better than any combination therapies of only 2 pathway blockers (MST TRIPLE=26 [**vs control] and MST DOUBLE=16-21 [n.s.-** vs triple]). Overall, our study showed that γ c cytokine blockade could potentially be an alternative to calcineurin inhibitor-based regimens to prevent rejection by specifically targeting immune cells. Our data also highlighted the inherent complexity of effector mechanisms and pathways involved in allograft rejection and showed that prolonged allograft survival requires simultaneous blockade of multiple T cell activating signals, including inhibition of cytokine signaling and costimulatory signals. These data provide evidence of γ c cytokines as key drivers of allogeneic immune cell responses during acute transplant rejection, offering a potentially novel strategy for the management of transplant patients.

Treatment of Hypercalcemic Hyperparathyroidism After Kidney Transplantation Is Associated With Improved Allograft Survival.

Hyperparathyroidism (HPT) and malignancy are the most common causes of hypercalcemia. Among kidney transplant (KT) recipients, hypercalcemia is mostly caused by tertiary HPT. Persistent tertiary HPT after KT is associated with allograft failure. Previous studies on managing tHPT were subjected to survivor treatment selection bias; as such, the impact of tertiary HPT treatment on allograft function remained unclear. We aim to assess the association between hypercalcemic tertiary HPT treatment and kidney allograft survival. We identified 280 KT recipients (2015-2019) with elevated post-KT adjusted serum calcium and parathyroid hormone (PTH). KT recipients were characterized by treatment: cinacalcet, parathyroidectomy, or no treatment. Time-varying Cox regression with delayed entry at the time of first elevated post-KT calcium was conducted, and death-censored and all-cause allograft failure were compared by treatment groups. Of the 280 recipients with tHPT, 49 underwent PTx, and 98 received cinacalcet. The median time from KT to first elevated calcium was 1 month (IQR: 0-4). The median time from first elevated calcium to receiving cinacalcet and parathyroidectomy was 0(IQR: 0-3) and 13(IQR: 8-23) months, respectively. KT recipients with no treatment had shorter dialysis vintage (P = .017) and lower PTH at KT (P = .002), later onset of hypercalcemia post-KT (P < .001). Treatment with PTx (adjusted hazard ratio (aHR) = 0.18, 95%CI 0.04-0.76, P = .02) or cinacalcet (aHR = 0.14, 95%CI 0.004-0.47, P = .002) was associated with lower risk of death-censored allograft failure. Moreover, receipt of PTx (aHR = 0.28, 95%CI 0.12-0.66, P < .001) or cinacalcet (aHR = 0.38, 95%CI 0.22-0.66, P < .001) was associated with lower risk of all-cause allograft failure. This study demonstrates that treatment of hypercalcemic tertiary HPT post-KT is associated with improved allograft survival. Although these findings are not specific to hypercalcemia of malignancy, they do demonstrate the negative impact of hypercalcemic tertiary HPT on kidney function. Hypercalcemic HPT should be screened and aggressively treated post-KT.

Indoleamine 2, 3-dioxygenase-transfected bone marrow-derived mesenchymal stem cells promote corneal allograft survival by inhibiting T cell proliferation: A rat study

PurposeAllograft rejection is still the main cause of corneal transplantation failure. Therefore, we investigated the role of indoleamine 2,3-dioxygenase (IDO)-transfected bone marrow-derived mesenchymal stem cells (IDO-BMSCs) in corneal allograft rejection in rats. MethodsIDO-BMSCs were constructed and co-cultured with CD4+CD24− T cells to detect their effects on the proliferation of CD4+CD25−T cells in vitro. A corneal allograft rat model was used to confirm our in vitro and in vivo observations. Therefore, IDO-BMSCs were injected directly into the recipient's conjunctiva on the day of corneal transplantation and on day 5 after operation. Corneal graft rejection indices, including corneal neovascularization, opacity, and edema, were measured for up to 14 days after transplantation. The recipients' cervical lymph nodes and peripheral blood were collected to test the role of IDO-BMSCs in immune cells using flow cytometry. ResultsThe lentivirus-mediated IDO gene was successfully transfected into BMSCs, which stably secreted the IDO protein. The proliferation of CD4+CD25−T cells was significantly inhibited after their co-culture with IDO-BMSCs. Subconjunctival injection of IDO-BMSCs into corneal allografts of rats effectively reduced graft neovascularization, promoted allograft survival, and induced immune tolerance. Both CD4+ and CD8+ T cells in the local lymph nodes and peripheral blood, along with CD4+CD25−T cells in the local lymph nodes, were significantly reduced after transplantation. ConclusionOur results suggest that IDO-BMSC treatment enhances the direct immunomodulatory effect of corneal allograft transplants in rats, promoting corneal allograft survival by inhibiting the proliferation of CD4+, CD8+, and CD4+CD25−T cells. Therefore, modification of BMSCs by lentivirus-mediated IDO gene transfection may provide a novel strategy for controlling corneal allograft rejection.

Human mesenchymal stem cells derived from adipose tissue showed a more robust effect than those from the umbilical cord in promoting corneal graft survival by suppressing lymphangiogenesis

BackgroundMesenchymal stem cells (MSCs) have shown promising potential in allograft survival. However, few reports have focused on comparing the immunosuppressive capacity of MSCs from different sources and administered via different routes in inhibiting transplant rejection. Moreover, virtually nothing is known about the role of MSCs in the regulation of graft neovascularization and lymphangiogenesis. In this study, we compared the efficacy of human adipose MSCs (hAD-MSCs) and human umbilical cord MSCs (hUC-MSCs) in vitro and in corneal transplantation models to explore the underlying molecular mechanisms and provide a powerful strategy for future clinical applications.MethodshAD-MSCs and hUC-MSCs were generated, and their self-renewal and multi-differentiation abilities were evaluated. The inhibitory effect of human MSCs (hMSCs) was examined by T-cell proliferation assays with or without transwell in vitro. Two MSCs from different sources were separately adoptively transferred in mice corneal transplantation (5 × 105 or 1 × 106/mouse) via topical subconjunctival or intravenous (IV) routes. Allograft survival was evaluated every other day, and angiogenesis and lymphomagenesis were quantitatively analyzed by immunofluorescence staining. The RNA expression profiles of hMSCs were revealed by RNA sequencing (RNA-seq) and verified by quantitative real-time PCR (qRT‒PCR), western blotting or ELISA. The function of the differentially expressed gene FAS was verified by a T-cell apoptosis assay.ResultshAD-MSCs induced stronger immunosuppression in vitro than hUC-MSCs. The inhibitory effect of hUC-MSCs but not hAD-MSCs was mediated by cell–cell contact-dependent mechanisms. Systemic administration of a lower dose of hAD-MSCs showed better performance in prolonging corneal allograft survival than hUC-MSCs, while subconjunctival administration of hMSCs was safer and further prolonged corneal allograft survival. Both types of hMSCs could inhibit corneal neovascularization, while hAD-MSCs showed greater superiority in suppressing graft lymphangiogenesis. RNA-seq analysis and confirmation experiments revealed the superior performance of hAD-MSCs in allografts based on the lower expression of vascular endothelial growth factor C (VEGF-C) and higher expression of FAS.ConclusionsThe remarkable inhibitory effects on angiogenesis/lymphangiogenesis and immunological transplantation effects support the development of hAD-MSCs as a cell therapy against corneal transplant rejection. Topical administration of hMSCs was a safer and more effective route for application than systemic administration.

Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model.

Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model. Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo . Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4 , H2-Eb1 , TRAT1 , and CD74 ) and upregulated the expression of IL-10 and transforming growth factor (TGF)-β pathway-related genes and Treg signature genes ( CTLA4 , Foxp3 , CD74 , and ICOS ). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo , and it enhanced the inhibitory function of inducible Tregs. HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Circular RNA MAP2K2-modified immunosuppressive dendritic cells for preventing alloimmune rejection in organ transplantation.

Long-term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long-term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to prevent immune rejection. We hypothesized that knockdown of circMAP2K2 induces immunosuppressive DCs and that treatment with circMAP2K2 silenced-DCs can prevent alloimmune rejection. DCs were cultured and transfected with siRNA for circMAP2K2. circMAP2K2 levels were measured by qRT-PCR. DC's maturation and immune function were assessed by flow cytometry and mixed lymphocyte reactions. The function of circMAP2K2 was illustrated by a series of RIP and IP. The therapeutics of engineered DCs was tested in a mouse heart transplantation model. We found that circMAP2K2 was highly expressed in mature DCs. Knockdown of circMAP2K2 reduced expression of MHCII, CD40 and CD80, attenuated the ability of DCs to activate allogeneic naïve T cells, and enhanced CD4+CD25+FOXP3+ regulatory T cells (Treg). circMAP2K2-induced immunosuppressive DCs by interacting with SENP3. Treatment with circMAP2K2-knockdown DCs attenuated alloimmune rejection and prolonged allograft survival in a murine heart transplantation model. The immune suppression induced in vivo was donor-antigen specific. In conclusion, knockdown of circMAP2K2 can induce immunosuppressive DCs which are able to inhibit overactive immune response, highlighting a new promising therapeutic approach for immune disorder diseases.

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

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

The Impact of Subclinical T Cell-Mediated Rejection on Subsequent Rejections and Allograft Survival in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

The Impact of Subclinical T Cell-Mediated Rejection on Subsequent Rejections and Allograft Survival in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

Role of Urine Exosomal Proteome for Identifying Potential Biomarkers to Predict Renal Allograft Survival

Role of Urine Exosomal Proteome for Identifying Potential Biomarkers to Predict Renal Allograft Survival

Pretransplant HbA1C as a Predictor of Kidney and Pancreas Allograft Survival in Simultaneous Pancreas-Kidney Transplantation: A Retrospective Nationwide Study

Pretransplant HbA1C as a Predictor of Kidney and Pancreas Allograft Survival in Simultaneous Pancreas-Kidney Transplantation: A Retrospective Nationwide Study

The frequency of peripheral PD-1+ TCD4+ cells is reversely associated with serum creatinine levels in recipients of kidney allografts

The long-term survival of solid organ allografts remains a challenge for organ transplantation systems worldwide. T-cell exhaustion has been supposed to be associated with immunologic tolerance in transplantation and might reflect the immunologic status in recipients. The aim of the present study was to compare the TCD4+ cells of kidney transplant recipients with high and low serum creatinine levels for their expressions of PD-1 and TIGIT as two well-known exhaustion markers.Blood samples were taken from 20 kidney allograft recipients with serum creatinine levels above 2 mg/dL and 20 recipients with creatinine levels below 2 mg/dL. The percentages of PD-1+ CD4+ and TIGIT+ CD4+ cells were analyzed along with the evaluation of TNF-α, IFN-γ, and IL-10 release from peripheral blood mononuclear cells (PBMCs).The patients with serum creatinine levels below 2 mg/dL demonstrated a higher frequency of PD-1+ CD4+ T-cells (p = 0.003) along with lower TNF-α secretion from PBMCs (p = 0.028). The frequency of PD-1 + CD4+ T-cells was reversely correlated with the serum creatinine levels in recipients of kidney allografts (r = 0.59, p < 0.001). Besides, the MFI of TIGIT on TCD4+ cells demonstrated a trend for higher expression in patients with serum creatinine levels below 2 mg/dL (p = 0.070).The expression of PD-1+ on CD4+ T-cells demonstrated a potential for estimation of the immunologic status of the host in interaction with alloantigens. The exhaustion markers could be regarded as potential diagnostic indicators for the evaluation of immunologic tolerance in renal transplantation.

Asarinin inhibits immunological rejection via the Toll-like receptor-myeloid differentiation factor 88 signaling pathway in vitro

Asarinin has been found to prolong allograft survival and inhibit post-transplant immune rejection via the Toll-like receptor (TLR) signaling pathway. However, the underlying mechanism is not completely understood. Therefore, elucidating the possible pathophysiological role of asarinin in the TLR signaling pathway is essential. Here, dendritic cells were isolated from Sprague–Dawley® rats and cultured with splenocytes from Wistar rats treated with asarinin, lipopolysaccharide (LPS), and/or dimethyl sulfoxide. mRNA expression of TLR-2, TLR-4, myeloid differentiation factor 88 (MyD88), and nuclear factor kB (NF-kB) was determined using real-time polymerase chain reaction. Interleukin (IL)-6 and IL-12 levels were examined using an enzyme-linked immunosorbent assay. LPS resulted in an increase in the expression of TLR-2 rather than TLR-4 and MyD88. Furthermore, it inhibited the secretion of IL-6 and IL-12. MyD88 can be silenced after lentiviral transduction, and LPS can activate MyD88, whereas asarinin can inhibit this kind of activation. The effect of LPS and asarinin on TLR-4 could only be achieved when MyD88 was not silenced by lentivirus transduction. Therefore, asarinin might suppress TLR-4-mediated activation via the MyD88-dependent pathway. Overall, asarinin has a pre-application effect in inhibiting graft rejection.

Development and validation of a nomogram to predict allograft survival after pediatric liver transplantation.

Liver transplantation is the main treatment for cholestatic liver disease and some metabolic liver diseases in children. However, no accurate prediction model to determine the survival probability of grafts prior to surgery exists. This study aimed to develop an effective prognostic model for allograft survival after pediatric liver transplantation. This retrospective cohort study included 2032 patients who underwent pediatric liver transplantation between January 1, 2006, and January 1, 2020. A nomogram was developed using Cox regression and validated based on bootstrap sampling. Predictive and discriminatory accuracies were determined using the concordance index and visualized using calibration curves; net benefits were calculated for model comparison. An online Shiny application was developed for easy access to the model. Multivariable analysis demonstrated that preoperative diagnosis, recipient age, body weight, graft type, preoperative total bilirubin, interleukin-1β, portal venous blood flow direction, spleen thickness, and the presence of heart disease and cholangitis were independent factors for survival, all of which were selected in the nomogram. Calibration of the nomogram indicated that the 1-, 3-, and 5-year predicted survival rates agreed with the actual survival rate. The concordance indices for graft survival at 1, 3, and 5 years were 0.776, 0.757, and 0.753, respectively, which were significantly higher than those of the Pediatric End-Stage Liver Disease and Child-Pugh scoring systems. The allograft dysfunction risk of a recipient could be easily predicted using the following URL: https://aspelt.shinyapps.io/ASPELT/ / CONCLUSION: The allograft survival after pediatric liver transplantation (ASPELT) score model can effectively predict the graft survival rate after liver transplantation in children, providing a simple and convenient evaluation method for clinicians and patients.

Association of Implantation Biopsy Findings in Living Donor Kidneys With Donor and Recipient Outcomes

Some living donor kidneys are found to have biopsy evidence of chronic scarring and/or glomerular disease at implantation, but it is unclear if these biopsy findings help predict donor kidney recovery or allograft outcomes. Our objective was to identify the prevalence of chronic histological changes and glomerular disease in donor kidneys, and their association with donor and recipient outcomes. Retrospective cohort study. Single center, living donor kidney transplants from January 2010 to July2022. Chronic histological changes, glomerular disease in donor kidney implantation biopsies. For donors, single-kidney estimated glomerular filtration rate (eGFR) increase, percent total eGFR loss,≥40% eGFR decline from predonation baseline, and eGFR<60mL/min/1.73m2 at 6 months after donation; for recipients, death-censored allograft survival. Biopsies were classified as having possible glomerular disease by pathologist diagnosis or chronic changes based on the percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease. We used logistic regression to identify factors associated with the presence of chronic changes, linear regression to identify the association between chronic changes and single-kidney estimated glomerular filtration rate (eGFR) recovery, and time-to-event analyses to identify the relationship between abnormal biopsy findings and allograft outcomes. Among 1,104 living donor kidneys, 155 (14%) had advanced chronic changes on implantation biopsy, and 12 (1%) had findings suggestive of possible donor glomerular disease. Adjusted logistic regression showed that age (odds ratio [OR], 2.44 per 10 years [95% CI, 1.98-3.01), Hispanic ethnicity (OR, 1.87 [95% CI, 1.15-3.05), and hypertension (OR, 1.92 [95% CI, 1.01-3.64), were associated with higher odds of chronic changes on implantation biopsy. Adjusted linear regression showed no association of advanced chronic changes with single-kidney eGFR increase or relative risk of eGFR<60mL/min/1.73m2. There were no differences in time-to-death-censored allograft failure in unadjusted or adjusted Cox proportional hazards models when comparing kidneys with chronic changes to kidneys without histological abnormalities. Retrospective, absence of measured GFR. Approximately 1 in 7 living donor kidneys had chronic changes on implantation biopsy, primarily in the form of moderate vascular disease, and 1% had possible donor glomerular disease. Abnormal implantation biopsy findings were not significantly associated with 6-month donor eGFR outcomes or allograft survival. Kidney biopsies are the gold standard test to identify the presence or absence of kidney disease. However, kidneys donated by healthy living donors-who are extensively screened for any evidence of kidney disease before donation-occasionally show findings that might be considered "abnormal," including the presence of scarring in the kidney or findings suggestive of a primary kidney disease. We studied the frequency of abnormal kidney biopsy findings among living donors at our center. We found that about 14% of kidneys had chronic abnormalities and 1% had findings suggesting possible glomerular kidney disease, but the presence of abnormal biopsy findings was not associated with worse outcomes for the donors or their recipients.

Exosomal miR-181d-5p Derived from Rapamycin-Conditioned MDSC Alleviated Allograft Rejection by Targeting KLF6.

Immune rejection and side effects of long-term administration of immunosuppressants are the two major obstacles to allograft acceptance and tolerance. The immunosuppressive extracellular vesicles (EVs)-based approach has been proven to be effective in treating autoimmune/inflammatory disorders. Herein, the anti-rejection advantage of exosomes (Rapa-Exo) from rapamycin-conditioned myeloid-derived suppressor cells (MDSCs) over exosomes (Exo-Nor) from the untreated MDSCs is shown. The exosomal small RNA sequencing and loss-of-function assays reveal that the anti-rejection effect of Rapa-Exo functionally relies on miR-181d-5p. Through target prediction and double-luciferase reporter assay, Kruppel-like factor (KLF) 6 is identified as a direct target of miR-181d-5p. Finally, KLF6 knockdown markedly resolves inflammation and prolongs the survival of corneal allografts. Taken together, these findings support that Rapa-Exo executes an anti-rejection effect, highlighting the immunosuppressive EVs-based treatment as a promising approach in organ transplantation.

In vitro and in vivo immune assessments of genetically-engineered pig skin grafts in New World (squirrel) monkeys.

Half a million patients in the USA alone require treatment for burns annually. Following an extensive burn, it may not be possible to provide sufficient autografts in a single setting. Genetic manipulations (GM) of pigs offer the possibility of reducing primate humoral and cellular rejection of pig skin xenografts and thus extending graft survival. We compared the survival of skin grafts from pigs with 9-GM with that of autografts and allografts in squirrel monkeys. Monitoring for rejection was by (1) macroscopic examination, (2) histopathological examination of skin biopsies, and (3) measurement of anti-monkey and anti-pig IgM and IgG antibodies. Autografts (n = 5) survived throughout the 28 days of follow-up without histopathological features of rejection. Median survival of allografts (n = 6) was 14 days and of pig xenografts (n = 12) 21 days. Allotransplantation was associated with an increase in anti-monkey IgM, but the anticipated subsequent rise in IgG had not yet occurred at the time of euthanasia. Pig grafts were associated with increases in anti-pig IgM and IgG. In all cases, histopathologic features of rejection were similar. 9-GM pig skin xenografts survive at least as long as monkey skin allografts (and trended to survive longer), suggesting that they are a realistic clinical option for the temporary treatment of burns. Although monkeys with pig skin grafts developed anti-pig IgM and IgG antibodies, these did not cross-react with monkey antigens, indicating that a primary 9-GM pig skin graft would not be detrimental to a subsequent monkey skin allograft.

Delayed graft function post renal transplantation: a review on animal models and therapeutics.

The incidence of end-stage renal disease (ESRD) has been increasing worldwide. Its treatment involves renal replacement therapy, either by dialyses or renal transplantation from a living or deceased donor. Although the initial mortality rates for patients on dialysis are comparable with kidney transplant recipients, the quality of life and long-term prognosis are greatly improved in transplanted patients. However, there is a large gap between availability and need for donor kidneys. This has led to the increase in the use of expanded kidney donor criteria. Allograft dysfunction immediately after transplant sets it up for many complications, such as acute rejection and shorter allograft survival. Delayed graft function (DGF) is one of the immediate posttransplant insults to the kidney allograft, which is increasing in prevalence due to efforts to maximize the available donor pool for kidneys and use of expanded kidney donor criteria. In this review, we discuss the risk factors for DGF, its implications for long-term allograft survival, animal models of DGF, and the therapeutic options currently under evaluation for prevention and management of DGF.