Impact Graft Survival Research Articles

Analysis of two reperfusion techniques in uterine transplantation in an experimental model.

Uterine transplantation was developed for the treatment of absolute uterine factor infertility. As it is a new modality of transplantation, there is still room for technical improvement. A factor that impacts graft survival in organ transplantation is the warm ischemia time. In uterine transplantation specifically, at least two vascular anastomoses are performed on each side of the uterus, and the graft revascularization takes place when the vascular clamps of the arteries and veins are released on both sides simultaneously. For this reason, the warm ischemia time in uterine transplant is expected to be considerably long. The purpose of this study was to compare the sequential technique of uterine graft revascularization, which aims to reduce the warm ischemia time of the procedure, with the simultaneous revascularization technique. For the procedure, the uterine auto-transplantation technique was performed using 10 non-pregnant adult ewes weighing about 45 kg, divided into two groups: simultaneous revascularization group (5 animals) and sequential revascularization group (5 animals). To evaluate the groups, we analyzed the procedure and warm ischemia times, graft macroscopy, hemodynamic, laboratory, and histological parameters of the uterus. The sequential revascularization technique group had similar surgical procedure times, and the warm ischemia time was significantly shorter with medians of 32 min in the sequential group versus 72 min in the simultaneous group (p < 0.008). The graft macroscopy and hemodynamic, laboratory, and histological parameters evaluated were similar between the groups. The sequential revascularization technique proved to reduce the warm ischemia time in the sheep uterine auto-transplantation model without compromising graft viability.

Multicenter, prospective, observational study for urinary exosomal biomarkers of kidney allograft fibrosis

Severity of deceased donor kidney fibrosis impacts graft survival in deceased-donor kidney transplantation. Our aim was to identify potential miRNA biomarkers in urinary exosomes that mirror interstitial fibrosis and tubular atrophy (IFTA) severity. Among 109 urine samples from deceased donors, 34 displayed no IFTA in the zero-day biopsy (No IFTA group), while the remaining 75 deceased donor kidneys exhibited an IFTA score ≥ 1 (IFTA group). After analyzing previous reports and electronic databases, six miRNAs (miR-19, miR-21, miR-29c, miR-150, miR-200b, and miR-205) were selected as potential IFTA biomarker candidates. MiR-21, miR-29c, miR-150, and miR-205 levels were significantly higher, while miR-19 expression was significantly lower in the IFTA group. MiR-21 (AUC = 0.762; P < 0.001) and miR-29c (AUC = 0.795; P < 0.001) showed good predictive accuracy for IFTA. In the No IFTA group, the eGFR level at 1 week after transplantation was significantly higher compared to the IFTA group (41.34 mL/min/1.73m2 vs. 28.65 mL/min/1.73m2, P = 0.012). These findings signify the potential of urinary exosomal miRNAs as valuable biomarker candidates for evaluating the severity of IFTA in deceased donor kidneys before they undergo recovery.

263.1: Advanced donor age does not impact graft survival in a large single centre lung transplant cohort.

263.1: Advanced donor age does not impact graft survival in a large single centre lung transplant cohort.

Effect of angiotensin II type 1 receptor antibodies on graft function and survival in paediatric kidney transplant recipients.

HLA donor specific antibodies (DSA) are implicated in antibody-mediated rejection (AMR), graft dysfunction and failure in kidney transplant (KT) recipients. Non-HLA antibodies including angiotensin II type 1 receptor (AT1R) may also play a role in AMR, impact graft function and survival. Data is limited in paediatric KT cohorts. We aimed to assess the prevalence and effect of pre-transplant AT1R antibodies on rejection, graft function and survival in paediatric KT recipients. This was a retrospective cohort study conducted across two paediatric centres including KT recipients with a pre-transplant AT1R antibody level. Outcomes included rejection, de novo DSA formation, graft function, failure, proteinuria and hypertension. Of 71 individuals, 72% recorded a positive pre-transplant AT1R Ab level (≥17 U/mL). Over a median follow-up of 4.7 years, AT1R Ab positivity demonstrated a trend towards increased risk of rejection however was not statistically significant (HR 3.45, 95% CI 0.97-12.35, p-value 0.06). Sensitivity analysis with AT1R Ab levels of ≥25 U/mL (HR 2.05 95% CI 0.78-5.39, p-value 0.14) and ≥40 U/mL (HR 1.32, CI 95% 0.55-3.17, p-value 0.53) validated this. De novo DSA formation occurred more frequently with AT1R Ab positivity (41% vs. 20%, p-value 0.9). AT1R Ab was not associated with hypertension, proteinuria, graft failure or dysfunction. In conclusion, this cohort study demonstrated a high prevalence of pre-transplant AT1R Ab positivity (72%). AT1R Ab positivity demonstrated a trend towards increased risk of rejection and de novo DSA formation however did not meet statistical significance. There was no association between AT1R Ab and hypertension, proteinuria, graft failure or dysfunction.

P.401: Plasma cell-rich rejection significantly impacts graft survival in paediatric liver transplantation recipients.

P.401: Plasma cell-rich rejection significantly impacts graft survival in paediatric liver transplantation recipients.

Multi-parametric MRI-based machine learning model for prediction of pathological grade of renal injury in a rat kidney cold ischemia-reperfusion injury model

BackgroundRenal cold ischemia-reperfusion injury (CIRI), a pathological process during kidney transplantation, may result in delayed graft function and negatively impact graft survival and function. There is a lack of an accurate and non-invasive tool for evaluating the degree of CIRI. Multi-parametric MRI has been widely used to detect and evaluate kidney injury. The machine learning algorithms introduced the opportunity to combine biomarkers from different MRI metrics into a single classifier.ObjectiveTo evaluate the performance of multi-parametric magnetic resonance imaging for grading renal injury in a rat model of renal cold ischemia-reperfusion injury using a machine learning approach.MethodsEighty male SD rats were selected to establish a renal cold ischemia -reperfusion model, and all performed multiparametric MRI scans (DWI, IVIM, DKI, BOLD, T1mapping and ASL), followed by pathological analysis. A total of 25 parameters of renal cortex and medulla were analyzed as features. The pathology scores were divided into 3 groups using K-means clustering method. Lasso regression was applied for the initial selecting of features. The optimal features and the best techniques for pathological grading were obtained. Multiple classifiers were used to construct models to evaluate the predictive value for pathology grading.ResultsAll rats were categorized into mild, moderate, and severe injury group according the pathologic scores. The 8 features that correlated better with the pathologic classification were medullary and cortical Dp, cortical T2*, cortical Fp, medullary T2*, ∆T1, cortical RBF, medullary T1. The accuracy(0.83, 0.850, 0.81, respectively) and AUC (0.95, 0.93, 0.90, respectively) for pathologic classification of the logistic regression, SVM, and RF are significantly higher than other classifiers. For the logistic model and combining logistic, RF and SVM model of different techniques for pathology grading, the stable and perform are both well. Based on logistic regression, IVIM has the highest AUC (0.93) for pathological grading, followed by BOLD(0.90).ConclusionThe multi-parametric MRI-based machine learning model could be valuable for noninvasive assessment of the degree of renal injury.

Socioeconomic deprivation is associated with worse patient and graft survival following adult liver transplantation.

The impact of social determinants of health (SDOH) on adult liver transplant recipient outcomes is not clear at a national level. Further understanding of the impact of SDOH on patient outcomes can inform effective equitable healthcare delivery. Unadjusted and multivariable models were used to analyze the Scientific Registry of Transplant Recipients to evaluate the association between the Social Deprivation Index (SDI) based on liver transplant recipient's residential location and patient and graft survival. We included adult recipients between 1/1/2008-12/1/2021. Patient and graft survival were lower in adults living in areas with deprivation scores above the median. Five-year patient and graft survival were 78.7% and 76.5% respectively in the cohort above median SDI compared to 80.5% and 78.3% below median SDI. Compared to the recipients in low deprivation residential areas, recipients residing in highest deprivation (SDI quintile=5) cohort had 6% higher adjusted risk of mortality (Adjusted Hazard Ratio [AHR]=1.06,95%C.I. 1.01-1.13) and 6% higher risk of graft failure (AHR=1.06,95% C.I. 1.001-1.11). The increased risks for recipients residing in more vulnerable residential areas were higher (AHR=1.11,95% CI 1.03-1.20 for both death and graft loss) following the first-year post-transplantation. Importantly, overall risk for graft loss associated with SDI was not linear but instead accelerated above the median level of deprivation. In the United States, SDOH, as reflected by residential distress, significantly impact 5-year patient and graft survival. The overall effect of residential deprivation are modest, but importantly, results illustrate they are more strongly associated with longer-term follow up and accelerate at higher deprivation levels. Further research is needed to evaluate effective interventions and policies to attenuate disparities in outcomes among recipients in highly disadvantaged areas.

Analysis of Graft Survival in Pediatric Patients Undergoing Kidney Transplantation

Introduction: Kidney transplantation is the gold standard therapy for end-stage chronic kidney disease (CKD). However, aspects related to the characteristics of the donor and the recipient, the surgical technique, the immunosuppression protocol and comorbidities can impact graft survival. Objectives: To evaluate factors associated with graft survival in pediatric patients undergoing kidney transplantation. Methods: Descriptive, retrospective cohort study, which included all patients aged 1 to 18 years who underwent kidney transplantation at Unidade Renal Pediátrica of Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil, from January 2017 to December 2021, with a minimum follow-up time of 10 months, totaling 51 patients. The IMIP ethics and research committee approved the study under CAAE: 52023921.1.0000.5201. Results: The median age of patients undergoing kidney transplantation was 12 years(9-13); 27 (52.9%) were male and eight (15.6%) were younger than 5 years of age. The main etiologies of CKD were congenital anomalies of the kidney and urinary tract (n = 25; 49%). As for kidney transplants, 49 (96.1%) were from a deceased donor and the median follow-up time was 32 (14-42) months. After transplantation, 58% of the population were hypertensive, while 80.4% had dyslipidemia. The 5-year graft and patient survival rates, assessed using the Kaplan Meier curve, were 86.3 and 90.2%, respectively. Seven (n = 5) patients lost the graft, the most common cause being renal vein thrombosis. Nonglomerular causes of CKD showed lower graft survival when compared to glomerular causes (log rank p = 0.035). Conclusion: Our sample’s graft and patient survival rates are similar to national and global data. The most frequent causes of graft loss were thromboembolic events. Furthermore, we observed a high prevalence of hypertension and dyslipidemia. These results direct us to establish strategies to improve survival in pediatric kidney transplants.

Leflunomide as adjunct therapy for BK viremia management in pediatric kidney transplant recipients.

BK viremia after kidney transplantation (KT) poses significant risk for BK virus-associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti-viral therapy with immunosuppressive properties such as leflunomide is an attractive option. We performed a multi-center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus-associated nephropathy in pediatric KT recipients. Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti-proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni- and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy.

The detrimental effect of donor-specific antibodies is irrespective of its level in highly-immunized living donor kidney transplant recipients: A case-control series.

The impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts. We have performed a retrospective analysis of all consecutive HLA-incompatible living donor kidney transplant recipients in our center between 2010-2019. Recipients who underwent plasmafiltration for a positive CDC-crossmatch were excluded. For each DSA+ recipient (DSA+), one immunized recipient without DSA (pPRA+) and two non-immunized recipients (pPRA-) were included. Patient and graft survival were analyzed and a subgroup analysis of DSA+ recipients was performed. For 63 DSA+ recipients, 63 PRA+ and 126 PRA- recipients were included. 26 (41%) had class I, 24 (38%) class II and 13 (21%) combined HLA class I and II DSA. Death-censored graft survival was inferior in DSA+ recipients compared to pPRA+ (HR 2.38 [95% CI 1.00-5.70]) as well as to pPRA- (HR 3.91 [1.86-8.22]). In multivariate analysis, DSA remained of negative influence on death-censored graft survival. Flowcytometric crossmatch, MFI value, HLA class and origin of DSA were not of significant impact. In our cohort of (highly-) immunized recipients, pretransplant DSA led to inferior death-censored graft survival. There were no "safe" DSA characteristics since only DSA per se impacted death-censored graft survival.

The Optimization of Renal Graft Preservation Temperature to Mitigate Cold Ischemia-Reperfusion Injury in Kidney Transplantation.

Renal transplantation is the preferred treatment for patients with end-stage renal disease. The current gold standard of kidney preservation for transplantation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal ischemia-reperfusion injury (IRI), a pathological process that negatively impacts graft survival and function. Recent efforts to mitigate cold renal IRI involve preserving renal grafts at higher or subnormothermic temperatures. These temperatures may be beneficial in reducing the risk of cold renal IRI, while also maintaining active biological processes such as increasing the expression of mitochondrial protective metabolites. In this review, we discuss different preservation temperatures for renal transplantation and pharmacological supplementation of kidney preservation solutions with hydrogen sulfide to determine an optimal preservation temperature to mitigate cold renal IRI and enhance renal graft function and recipient survival.

413.7: Normothermic Machine Perfusion Compared With Static Cold Storage of Liver Grafts for Late Liver Retransplantation: Results of the NAPLES Initiative

Introduction: The pool of donor organs available for patients undergoing liver retransplantation is small, due to the perceived need for an optimal graft. Strategies that can facilitate transplantation of suboptimal organs into retransplant candidates requires investigation. The aim of this study was to determine if patients undergoing liver retransplantation, can be safely transplanted with sub-optimal grafts following normothermic machine perfusion. Methods: Between November 2018 and November 2021, a prospectively enrolled group of retransplant candidates consented to receive livers with suboptimal features but preserved and viability tested with normothermic machine perfusion (NMP). Donor, graft and clinical outcomes were compared to a retrospective group that underwent retransplantation with a graft preserved via static cold storage (SCS) between January 2015 and November 2021. All recipients received grafts from deceased brain death donors. The primary outcome of this study was 6-month graft and patient survival. Results: During the study period, 37 patients underwent retransplantation with a NMP preserved graft. Three of these received two NMP preserved grafts. The CS control group comprised 54 patients, and two of these patients received two CS grafts. Therefore, the NMP and CS groups comprised 40 and 56 grafts respectively. Donor, graft, operative and outcome variables are displayed in table 1. The 6-month graft (90% v 86%. P=0.59) and patient (94% vs 93%, P=0.79) survival did not differ between groups (Table 1). This was despite the NMP group having significantly more steatotic grafts (Moderate steatosis; 30% vs 4%, P=<0.01), donors with transaminases >1000 IU/L (0% v 23%, P=<0.01), and grafts previously declined by at least one other transplant centre (78% v 26%, P=<0.01) (Table 1). The peak alanine transaminase in the initial post-operative 7 days was significantly lower (521 vs 796, P=0.02) in the NMP group, however the rate of early acute rejection was higher (50% vs 27%, P=0.02) but did not impact graft survival. Significantly higher rates of CVVH in the NMP group did not translate to a longer length of stay in ICU. Furthermore, longer term graft and patient survival did not differ between groups (Figure 1). Conclusion: This is the first study to demonstrate that NMP technology can be safely used for sub-optimal liver grafts, and these can be safely transplanted into patients that require retransplantation. This technology can therefore expand the graft options available to this high-risk group. Anne Fox Foundation, University Hospitals Birmingham Charity.

The effect of perichondrium on cartilage graft properties.

The role of perichondrium in cartilage graft survival has been long debated. Although the innate function of perichondrium in providing mechanical and regenerative support to cartilage in its native position is relatively undisputed, studies continue to vacillate over how the perichondrium effects cartilage grafts once transplanted. This review evaluates historical and recent experiments showing how perichondrium may or may not impact graft survival. Experimental studies in animal models have more recently evaluated macroscopic and microscopic properties of diced cartilage grafts with and without perichondrium, finding that in general grafted cartilage with perichondrial components retains greater weight and mechanical strength compared with cartilage without perichondrial components. However, these findings have not been replicated in humans. Solid pieces of rib cartilage have most recently been used without perichondrium to prevent warping, though no studies have evaluated whether retaining perichondrium with oblique and concentric cutting techniques may effect overall resorption. Although historical opinions and more recent animal studies suggest a role of perichondrium in cartilage graft survival, randomized controlled human studies are still lacking on whether retaining perichondrium truly effects graft survival and ultimate surgical outcomes.

Paper 39: Sex Mismatch Between Donor and Recipient is Associated with Decreased Graft Survivorship at 5-years After Osteochondral Allograft Transplantation

Objectives:Sex mismatch between donor and recipient has been considered a potential contributor to adverse outcomes following solid organ transplantation. However, the influence of sex mismatching in osteochondral allograft (OCA) transplantation is yet to be determined. Therefore, the objective of this study was to evaluate whether donor-recipient sex mismatching impacts graft survival after OCA transplantation.Methods:In this review of prospectively collected data, patients who underwent OCA transplantation between November 2013 and November 2017 by a single surgeon were analyzed. Cumulative survival was performed through the Kaplan–Meier method using log-rank tests to compare patients with similar donor groups. Multivariable Cox regression analysis adjusted for patient age, graft size and body mass index (BMI) were used to evaluate the influence of donor–recipient sex on graft survival.Results:A total of 154 patients were included, 102 (66.2%) who received OCAs from a same sex donor, and 52 (33.8%) from a different sex donor. At 5 years follow-up, a significantly lower graft survival rate was observed for different sex donor transplantation in comparison to same sex donor (63% versus 92%, p = 0.01). (Figure 1.) When correcting for age, graft size and BMI, donor-recipient sex mismatching demonstrated a 2.9 times greater likelihood to fail at 5 years compared to donor-recipient same sex (p = 0.03). A subgroup analysis showed no significant difference in graft survival between female-to-female and female-to-male groups (91% and 84%, respectively). (Figure 2.) Conversely, male-to-male demonstrated a significant higher cumulative 5-year survival (94%, p = 0.04), whereas a lower survival was found in the male-to-female group (64%, p = 0.04). Multivariable Cox regression indicated a 2.6 times higher likelihood of failure for male-to-female in comparison with other groups (p = 0.04). Male-to-male had a tendency toward decreased likelihood of OCA failure (0.33 hazard ratio), although without statistical significance.Conclusions:Mismatch between donor and recipient sex has a negative effect on OCA survival following transplantation, particularly in those cases when male donor tissue was transplanted into a female recipient.

Kidney transplant candidates' and recipients' perspectives on the decision-making process to accept or refuse a deceased donor kidney offer: Trust and graft survival matter.

The decision to accept a kidney from a deceased donor can be a difficult one. This study aims to capture the perspectives of transplant candidates (TCs) and kidney transplant recipients (KTRs) on the decision-making process when a deceased kidney is offered. We conducted six focus groups with KTRs and TCs. The content of the focus groups was analyzed using the qualitative thematic method. KTRs reported that the experience of being offered a kidney could be difficult because of the circumstances of the offer and unpreparedness to participate in the discussion. Both KTRs and TCs trusted the medical expertise. Age and having experience with dialysis could influence the decision to accept an offer. In order to engage in the discussion, patients wanted to obtain estimates of expected graft survival. Patients did not express interest for a web-based calculator for patient use, but expected transplant physicians to summarize and explain the information that would impact graft survival time. TCs and KTRs wanted to be involved in the decision to accept a deceased donor kidney. Tools that can help physicians communicate the risks and benefits of accepting an offer could improve patient participation in the decision-making process.

Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival.

The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient’s immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.

Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation.

BACKGROUNDIn a previous paper, we reported a high prevalence of donor-specific antibody (DSA) in pediatric patients with chronic rejection and expressed the need for confirmation of these findings in a larger cohort.AIMTo clarify the importance of DSAs on long-term graft survival in a larger cohort of pediatric patients.METHODSWe performed a retrospective analysis of 123 pediatric liver transplantation (LT) recipients who participated in yearly follow-ups including Luminex testing for DSA at our center. The cohort was split into two groups according to the DSA status (DSA-positive n = 54, DSA-negative n = 69). Groups were compared with regard to liver function, biopsy findings, graft survival, need for re-LT and immunosuppressive medication.RESULTSDSA-positive pediatric patients showed a higher prevalence of chronic rejection (P = 0.01), fibrosis (P < 0.001) and re-transplantation (P = 0.018) than DSA-negative patients. Class II DSAs particularly influenced graft survival. Alleles DQ2, DQ7, DQ8 and DQ9 might serve as indicators for the risk of chronic rejection and/or allograft fibrosis. Mean fluorescence intensity levels and DSA number did not impact graft survival. Previous episodes of chronic rejection might lead to DSA development.CONCLUSIONDSA prevalence significantly affected long-term liver allograft performance and liver allograft survival in our cohort of pediatric LT. Screening for class II DSAs in combination with assessment of protocol liver biopsies for chronic antibody-mediated rejection improved early identification of patients at risk of graft loss.

Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection.

The current transplant immunology dogma defends that allograft rejection is initiated by recipient's adaptive immune system. In this prevalent model, innate immune cells in general, and natural killer (NK) cells in particular, are merely considered as downstream effectors which participate in the destruction of the graft only upon recruitment by adaptive effectors: alloreactive T cells or donor-specific antibodies (DSA). Challenging this vision, recent data demonstrated that recipients' NK cells are capable of a form of allorecognition because they can sense the absence of self HLA class I molecules on the surface of graft endothelial cells. Missing-self triggers mTORC1-dependent activation of NK cells, which in turn promote the development of graft microvascular inflammation and detrimentally impact graft survival. The fact that some patients develop chronic vascular rejection in absence of DSA or genetically-predicted missing self suggests that other molecular mechanisms could underly NK cell allorecognition. This review provides an overview of these proven and putative molecular mechanisms and discusses future research directions in this emerging field in organ transplant immunology.

Correlation of Chronic Histologic Changes on Preimplantation Frozen Section Biopsy With Transplant Outcomes After Deceased Donor Kidney Transplantation.

It is unclear if preimplantation frozen section biopsy correlates with outcomes after deceased donor kidney transplantation. To assess if chronic histologic changes on the preimplant frozen section correlates with graft loss and estimated glomerular filtration rate independently of kidney donor profile index (KDPI). Seven hundred three preimplantation biopsies were reviewed and a Banff sum score was calculated using glomerular sclerosis, interstitial fibrosis, vascular intimal thickening, and arteriolar hyalinosis. The posttransplant outcomes were compared for preimplantation biopsy Banff sum 0-1, 2-3, and 4-9. The cohort was also stratified by KDPI 85 or less versus more than 85. For the entire biopsy cohort, graft survival, estimated glomerular filtration rate at 1 year, and chronic changes on a 1-year posttransplant biopsy were superior in the group with preimplantation Banff sum 0-1. After stratifying by KDPI, the Banff sum no longer correlated with graft survival. In a univariate mode, using the Banff sum score as a continuous variable, a higher Banff sum score was significantly associated with graft failure (P = .03); however, after adjusting the KDPI, the Banff sum score no longer correlated with graft failure (P = .45). The 1-year estimated glomerular filtration rate and 1-year biopsy changes were superior in the group with Banff sum 0-1 only in the cohort with KDPI 85 or less. In donor kidneys used for transplant, preimplantation biopsy chronic changes correlate with estimated glomerular filtration rate and biopsy findings at 1 year, but biopsies with mostly mild chronicity and Banff sum scores less than or equal to 5 did not impact graft survival beyond KDPI.

Evidence suggesting that deletion of expression of N-glycolylneuraminic acid (Neu5Gc) in the organ-source pig is associated with increased antibody-mediated rejection of kidney transplants in baboons.

Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs) and expressing "protective" human transgenes are likely sources of organs for transplantation into human recipients. Testing of human sera against red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs has revealed minimal evidence of natural antibody binding. However, unlike humans, baboons exhibit natural antibody binding to TKO pig cells. The xenoantigen specificities of these natural antibodies are postulated to be one or more carbohydrate moieties exposed when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival of renal grafts in baboons from pigs that either expressed Neu5Gc (GTKO pigs; Group1, n=5) or did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group2, n=5). An anti-CD40mAb-based immunosuppressive regimen was administered in both groups. Group1 kidneys functioned for 90-260days (median 237, mean 196days), with histopathological features of antibody-mediated rejection in two kidneys. Group2 kidneys functioned for 0-183days (median 35, mean 57), with all of the grafts exhibiting histologic features of antibody-mediated rejection. These findings suggest that the absence of expression of Neu5Gc on pig kidneys impacts graft survival in baboon recipients.