Allograft Outcomes Research Articles

Successful lung transplantation using an allograft from a COVID-19–recovered donor: a potential role for subgenomic RNA to guide organ utilization

Although the risk of SARS-CoV-2 transmission through lung transplantation from acutely infected donors is high, the risks of virus transmission and long-term lung allograft outcomes are not as well described when using pulmonary organs from COVID-19–recovered donors. We describe successful lung transplantation for a COVID-19–related lung injury using lungs from a COVID-19–recovered donor who was retrospectively found to have detectable genomic SARS-CoV-2 RNA in the lung tissue by multiple highly sensitive assays. However, SARS-CoV-2 subgenomic RNA (sgRNA), a marker of viral replication, was not detectable in the donor respiratory tissues. One year after lung transplantation, the recipient has a good functional status, walking 1 mile several times per week without the need for supplemental oxygen and without any evidence of donor-derived SARS-CoV-2 transmission. Our findings highlight the limitations of current clinical laboratory diagnostic assays in detecting the persistence of SARS-CoV-2 RNA in the lung tissue. The persistence of SARS-CoV-2 RNA in the donor tissue did not appear to represent active viral replication via sgRNA testing and, most importantly, did not negatively impact the allograft outcome in the first year after lung transplantation. sgRNA is easily performed and may be a useful assay for assessing viral infectivity in organs from donors with a recent infection.

Comparison of Autografts vs Allografts for Anterior Cruciate Ligament Reconstruction: A Meta-Analysis of Current Perspective

Objective: To describe the outcomes of autografts and allografts in anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstruction with respect to instrumented laxity measurements, patient-reported outcome scores, complications, and graft failure risk. Methods: We searched PubMed, Cochrane Library, and EMBASE for published randomized controlled trials (RCT) and case controlled trials (CCTs) to compare the outcomes of the autografts versus allografts after cruciate ligament reconstruction. Data analyses were performed using Cochrane Collaboration RevMan 5.0. Results: Nine studies were identified from the literature review. Of these studies, three studies compared the results of bone–patellar tendon–bone (BPTB) and ligament augmentation and reconstruction system (LARS), while six studies compared the results of four-strand hamstring tendon graft (4SHG) and LARS. The comparative study showed no difference in Lysholm score and failure risk between autografts and synthetics. Discussion: The combined results of the meta-analysis indicated that there was a significantly lower rate of side-to-side difference > 3 mm (Odds Ratio [OR] 2.46, 95% confidence intervals [CI] 1.44–4.22, P = 0.001), overall IKDC (OR 0.40, 95% CI 0.19–0.83, P = 0.01), complications (OR 2.54, 95% CI 1.26–5.14, P = 0.009), and Tegner score (OR −0.31, 95% CI −0.52–0.10, P = 0.004) in the allografts group than in the autografts group. Conclusion: This systematic review comparing long-term outcomes after cruciate ligament reconstruction with either autograft or allografts suggests no significant differences in failure risk. Autografts were inferior to allografts with respect to restoring knee joint stability and patient-reported outcome scores, and were also associated with more postoperative complications.

Sex-specific differences in the epidemiology, progression, and outcomes of chronic kidney disease

Higher prevalence of chronic kidney disease (CKD) in women than in men was reported all over the world. This difference could be partly explained by longer life expectancy and slower CKD progression rate in women. Potential factors associated with sex differences in CKD progression are as follows: difference in glomerular hemodynamic and the response to angiotensin II; sex hormones ? estrogen has protective and testosterone deleterious effects on CKD progression; lifestyle. In most countries, the percentage of men is higher than that of women among incident and prevalent patients on hemodialysis (HD). In HD patients, the Kt/V index overestimates HD adequacy, secondary hyperparathyroidism is more common in women, and women require higher doses of erythropoiesis-stimulating agents for achieving and maintaining the hemoglobin target level. The survival of HD patients is equal for both sexes. In earlier years, an equal percentage of women and men started peritoneal dialysis, but in recent years, a higher percentage of women, especially at younger ages, start peritoneal dialysis. Initial peritoneal transport properties differ between men and women. A smaller percentage of women than men receive deceased donor kidneys, but women are more likely to be living kidney donors. Kidney allograft outcome depends on the sex and age of both the recipient and the donor. Cardiovascular diseases are the most common cause of death for renal replacement therapy patients of both sexes. Although sex-specific differences have been described in CKD patients, the inequality of patients in access to medical care has not been found in most regions of the world.

Is Lysate-based Human Leukocyte Antigen Crossmatch a Reliable Method to Contraindicate a Transplant?

The presence of preformed cytotoxic donor-specific antibodies (DSAs) has been associated with inferior allograft outcomes in the immediate posttransplant period. Since the 1970s, the primary method for determining the presence of DSAs has been the complement-dependent cytotoxicity crossmatch. Solid phase assays on the Luminex platform were introduced in India in 2010 in the form of human leukocyte antigen antibody screening, single antigen bead (SAB) assay and lysate-based crossmatch (LumXM) to identify low titer antibodies, which are deleterious to allograft. Instead of SAB, LumXM has been popularly used in India to identify DSAs and also called DSA crossmatch, which is not recommended or validated in International literature for denying or accepting to transplant a patient due to its fallacies. We are reporting three cases which showcase the flawed nature of this test and the implications of this test on day to day practice in transplantation.

Associations of Perioperative Red Blood Cell Transfusion With Outcomes of Kidney Transplantation in Korea Over a 16-Year Period.

This study investigated the associations between transfusion of different types of red blood cell (RBC) preparations and kidney allograft outcomes after kidney transplantation (KT) over a 16-year period in Korea using a nationwide population-based cohort. We investigated the reported use of RBCs during hospitalization for KT surgery, rejection, and graft failure status using nationwide data from the National Health Information Database (2002-2017). The associations between the type of perioperative RBC product and transplant outcomes were evaluated among four predefined groups: no RBC transfusion, filtered RBCs, washed RBCs, and packed RBCs (pRBCs). A total of 17,754 KT patients was included, among which 8,530 (48.0%) received some type of RBC transfusion. Of the patients who received RBC transfusion, 74.9%, 19.7%, and 5.4% received filtered RBCs, pRBCs, or washed RBCs, respectively. Regardless of the type of RBC products, the proportions of acute rejection and graft failure was significantly greater in patients receiving transfusion (P < 0.001). Cox proportional hazards regression analyses showed that the filtered RBC and pRBC groups were significantly associated with both rejection and graft failure. The washed RBC group also had hazard ratios greater than 1.0 for rejection and graft failure, but the association was not significant. Rejection-free survival of the pRBC group was significantly lower than that of the other groups (P < 0.001, log-rank test), and graft survival for the no RBC transfusion group was significantly greater than in the other groups (P < 0.001, log-rank test). Perioperative RBC transfusion was associated with poor graft outcomes. Notably, transfusion of pRBCs significantly increased transplant rejection. Therefore, careful consideration of indications for RBC transfusion and selection of the appropriate type of RBCs is necessary, especially for patients at high risk of rejection or graft failure.

The effect of sex inequality on solid organ transplantation: A systematic review and meta-analysis

BackgroundSex disparities are related to biological differences, which may have significant impact on patient and allograft outcomes. The aim was to investigate the impact of sex on clinical and safety outcomes after solid organ transplantation (SOT). MethodsA systematic review and meta-analysis was performed. Observational studies comparing females vs. males after SOT were considered for inclusion after a systematic search of the Pubmed, Cochrane Library, and Web of Science databases conducted from 2016 to 2021. Primary outcome was mortality. PROSPERO register number: CRD42021282615. ResultsAfter retrieving 1103 studies, 22 observational studies (1,045,380 subjects) were finally deemed eligible for inclusion. Females accounted 36.3% of SOT recipients, but presented significantly lower mortality (odds ratio (OR): 0.87, 95% confidence interval (CI): 0.83–0.92, I2=78%). In subgroup analyses, mortality was significantly lower in females undergoing liver (OR: 0.89 95%CI: 0.86–0.92, I2=0%) or kidney transplantation (OR: 0.82 95%CI: 0.76–0.89, I2=72%). Male sex was consistently reported as a protective factor against hospital readmission. Among the outcomes, allograft dysfunction was influenced by a combination of donor-recipient sex and age. Data on overall infections were inconclusive. Several reports suggest a higher risk of malignancy among males. ConclusionsFemales represent one-third of SOT recipients but have higher survival rates than males after liver and kidney transplantation. The impact on graft dysfunction was heterogeneous. While further research is warranted, our findings should encourage clinicians and researchers to consider sex as a factor when taking decisions regarding SOT management.

Machine learning does not outperform traditional statistical modelling for kidney allograft failure prediction

Machine learning (ML) models have recently shown potential for predicting kidney allograft outcomes. However, their ability to outperform traditional approaches remains poorly investigated. Therefore, using large cohorts of kidney transplant recipients from 14 centers worldwide, we developed ML-based prediction models for kidney allograft survival and compared their prediction performances to those achieved by a validated Cox-Based Prognostication System (CBPS). In a French derivation cohort of 4000 patients, candidate determinants of allograft failure including donor, recipient and transplant-related parameters were used as predictors to develop tree-based models (RSF, RSF-ERT, CIF), Support Vector Machine models (LK-SVM, AK-SVM) and a gradient boosting model (XGBoost). Models were externally validated with cohorts of 2214 patients from Europe, 1537 from North America, and 671 from South America. Among these 8422 kidney transplant recipients, 1081 (12.84%) lost their grafts after a median post-transplant follow-up time of 6.25 years (Inter Quartile Range 4.33-8.73). At seven years post-risk evaluation, the ML models achieved a C-index of 0.788 (95% bootstrap percentile confidence interval 0.736-0.833), 0.779 (0.724-0.825), 0.786 (0.735-0.832), 0.527 (0.456-0.602), 0.704 (0.648-0.759) and 0.767 (0.711-0.815) for RSF, RSF-ERT, CIF, LK-SVM, AK-SVM and XGBoost respectively, compared with 0.808 (0.792-0.829) for the CBPS. In validation cohorts, ML models' discrimination performances were in a similar range of those of the CBPS. Calibrations of the ML models were similar or less accurate than those of the CBPS. Thus, when using a transparent methodological pipeline in validated international cohorts, ML models, despite overall good performances, do not outperform a traditional CBPS in predicting kidney allograft failure. Hence, our current study supports the continued use of traditional statistical approaches for kidney graft prognostication.

Uncontrolled donation after cardiac death kidney transplantation: Opportunity to expand the donor pool?

BackgroundCompared to controlled donation after cardiac death (cDCD), uncontrolled DCD (uDCD) kidney transplantation remains an underutilized resource in the United States. However, it is unclear whether long-term allograft outcomes following uDCD are inferior to that of cDCD kidney transplantation. MethodsFrom January 1995 to January 2018, the OPTN/UNOS database was queried to discover all reported cases of uDCD and cDCD kidney transplantation. Primary non-function, delayed graft function, ten-year graft and patient survival were compared among uDCD and cDCD patients. ResultsRates of primary non-function (4.0% [uDCD] vs. 1.8% [cDCD], P < 0.001) and delayed graft function (51.1% [uDCD] vs. 41.7% [cDCD], P < 0.001) were higher following uDCD transplant. However, ten-year graft survival (47.5% [uDCD] vs. 48.4% [cDCD], P = 0.21) and patient survival were similar to cDCD transplantation (59.4% [uDCD] vs. 59.2% [cDCD], P = 0.32). ConclusionAlthough initial allograft outcomes are inferior following uDCD, long-term durability of uDCD kidney allografts is on par to cDCD transplantation. Kidney allografts derived by uDCD may be a viable and durable option to increase the donor pool.

2105. Early-onset and Late-onset BK Polyomavirus-associated Nephropathy: A 10-year Retrospective Analysis

Abstract Background Polyomavirus-associated nephropathy (BKVAN) is one of the serious causes of allograft dysfunction and allograft loss in kidney transplant (KT) patients. Most of the patients were diagnosed with BKVAN within the first year after transplantation but some more cases of BKVAN occur later. A study focused on the differentiation between early and late-onset BKVAN is needed. Methods We conducted a retrospective cohort study among KT recipients at Ramathibodi Hospital between January 2010 – December 2020. The incidence of early-onset (diagnosed within 1 year) and late-onset (diagnosed after 1 year) BKVAN, as well as composite kidney allograft outcomes, were compared. Results From 1032 KT recipients, 645 (62.5%) were screened for BK viral infection. BKVAN was diagnosed in 83 (12.8%) patients. Of those, 46 (55.4%) and 37 (44.6%) were diagnosed with early-onset and late-onset BKVAN, respectively. Composite kidney allograft outcomes of GFR decline≥ 40% from baseline, graft loss or death were greater in early-onset BKVAN compared to late-onset BKVAN (7.5 vs 5.52 per 1000 person-months; hazard ratio 0.47; 95%CI, 0.23-0.95; P=0.037). In multivariate analysis, female gender and living-related kidney transplantation (LRKT) were independently associated with late-onset BKVAN compared to early-onset BKVAN. The more advanced the BKVAN diagnosis, the worse the allograft outcome occurs, even with optimizing immunosuppressive drugs and adjunctive therapy. Conclusion BKVAN could occur later after one-year post-transplantation, although relatively better composite kidney outcomes were observed compared to early-onset BKVAN. Female individuals who underwent living-related KT should be considered for BK virus preemptive monitoring beyond one year to detect this late-onset BK virus infection. Disclosures All Authors: No reported disclosures.

Effect of intraoperative support mode on circulating inflammatory biomarkers after lung transplantation surgery.

Processes that activate the immune system during lung transplantation can lead to primary graft dysfunction (PGD) or allograft rejection. We analyzed cytokine expression profiles after reperfusion and allograft outcomes in a cohort of patients (n=59) who underwent lung transplantation off-pump (n=26), with cardiopulmonary bypass (CPB; n=18), or with extracorporeal membrane oxygenation (ECMO; n=15). Peripheral blood was collected from patients at baseline and at 6 and 72h after reperfusion. To adjust for clinical differences between groups, we utilized a linear mixed model with overlap weighting. PGD3 was present at 48 or 72h after reperfusion in 7.7% (2/26) of off-pump cases, 20.0% (3/15) of ECMO cases, and 38.9% (7/18) of CPB cases (p=0.04). The ECMO and CPB groups had greater reperfusion-induced increases in MIP-1B, IL-6, IL-8, IL-9, IL1-ra, TNF-alpha, RANTES, eotaxin, IP-10, and MCP-1 levels than the off-pump group. Cytokine expression profiles after reperfusion were not significantly different between ECMO and CPB groups. Our data suggest that, compared with an off-pump approach, the intraoperative use of ECMO or CPB during lung transplantation is associated with greater reperfusion-induced cytokine release and graft injury.

Fibroblastic reticular cells orchestrate long-term graft survival following recipient treatment with CD40 ligand-targeted costimulatory blockade.

Fibroblastic reticular cells (FRCs) maintain the architecture of secondary lymphoid organs, which optimize interactions between antigen-presenting dendritic cells and reactive naive T cells. In this issue of the JCI, Zhao, Jung, and colleagues investigated CD4+FoxP3+ regulatory T cell development and long-term heart allograft survival in recipients treated with peritransplant costimulatory blockade to inhibit CD40/CD40 ligand (CD40L) signaling. Treatment with an anti-CD40L monoclonal antibody (mAb) increased the lymph node (LN) population of Madcam1+ FRCs and altered their transcription profile to express immunoregulatory mediators. Administration of nanoparticles, containing the anti-CD40L mAb and a targeting antibody against high endothelial venules, delivered the treatment into LNs of allograft recipients. Direct LN delivery of the costimulatory blockade allowed decreased dosing and increased the efficacy in extending graft survival. The results provide insights into mechanisms by which FRCs can promote donor-reactive tolerance, and establish a strategy for administering costimulation-blocking reagents that circumvent systemic effects and improve allograft outcomes.

Clinical outcomes of posttransplantation diabetes mellitus in kidney transplantation recipients: a nationwide population-based cohort study in Korea

Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after KT that causes graft failure and cardiovascular complications in kidney transplantation (KT) recipients. Using the national claim data of South Korea, 7612 KT recipients between 2009 and 2017 were analyzed. PTDM was defined as a consecutive 30-day prescription history of antidiabetic medication after KT. Among these patients, 24.7% were diagnosed with PTDM, and 51.9% were diagnosed within 6 months after KT. Compared to patients without PTDM, those with PTDM were older, more likely to be men, more likely to be diagnosed with hypertension and cardio-cerebrovascular disease, and experienced more rejection episodes requiring high-dose steroid treatment after KT. During the follow-up, 607 DCGFs, 230 DWGFs, 244 MACEs, and 260 all-cause mortality events occurred. Patients with PTDM showed a higher risk of DCGF (adjusted hazard ratio [aHR] 1.49; 95% confidence interval [CI] 1.22–1.82; P < 0.001) and MACEs (aHR 1.76; 95% CI 1.33–2.31; P < 0.001) than patients without PTDM. The risks for all clinical outcomes were higher in the insulin group than in the non-use insulin group. PTDM in KT recipients resulted in both worse allograft and patient outcomes represented by DCGF and MACE, especially in patients needing insulin treatment.

Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection.

To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes

Of all kidney transplants, half are still lost in the first decade after transplantation. Here, using genetics, we probed whether interleukin 6 (IL-6) could be a target in kidney transplantation to improve graft survival. Additionally, we investigated if a genetic risk score (GRS) based on IL6 and IL10 variants could improve prognostication of graft loss. In a prospective cohort study, DNA of 1271 donor-recipient kidney transplant pairs was analyzed for the presence of IL6, IL6R, IL10, IL10RA, and IL10RB variants. These polymorphisms and their GRS were then associated with 15-year death-censored allograft survival. The C|C-genotype of the IL6 polymorphism in donor kidneys and the combined C|C-genotype in donor-recipient pairs were both associated with a reduced risk of graft loss (p=.043 and p=.042, respectively). Additionally, the GRS based on IL6, IL6R, IL10, IL10RA, and IL10RB variants was independently associated with the risk of graft loss (HR 1.53, 95%-CI [1.32-1.84]; p<.001). Notably, the GRS improved risk stratification and prediction of graft loss beyond the level of contemporary clinical markers. Our findings reveal the merits of a polygenic IL-6-based risk score strengthened with IL-10- polymorphisms for the prognostication and risk stratification of late graft failure in kidney transplantation.

Calcification of the visceral aorta and celiac trunk is associated with renal and allograft outcomes after deceased donor liver transplantation

PurposeAtherosclerosis affects clinical outcomes in the setting of major surgery. Here we aimed to investigate the prognostic role of visceral aortic (VAC), extended visceral aortic (VAC+), and celiac artery calcification (CAC) in the assessment of short- and long-term outcomes following deceased donor orthotopic liver transplantation (OLT) in a western European cohort.MethodsWe retrospectively analyzed the data of 281 consecutive recipients who underwent OLT at a German university medical center (05/2010–03/2020). The parameters VAC, VAC+, or CAC were evaluated by preoperative computed tomography-based calcium quantification according to the Agatston score.ResultsSignificant VAC or CAC were associated with impaired postoperative renal function (p = 0.0016; p = 0.0211). Patients with VAC suffered more frequently from early allograft dysfunction (EAD) (38 vs 26%, p = 0.031), while CAC was associated with higher estimated procedural costs (p = 0.049). In the multivariate logistic regression analysis, VAC was identified as an independent predictor of EAD (2.387 OR, 1.290–4.418 CI, p = 0.006). Concerning long-term graft and patient survival, no significant difference was found, even though patients with calcification showed a tendency towards lower 5-year survival compared to those without (VAC: 65 vs 73%, p = 0.217; CAC: 52 vs 72%, p = 0.105). VAC+ failed to provide an additional prognostic value compared to VAC.ConclusionThis is the first clinical report to show the prognostic role of VAC/CAC in the setting of deceased donor OLT with a particular value in the perioperative phase. Further studies are warranted to validate these findings.Graphical abstractCT computed tomography, OLT orthotopic liver transplantation

Transitional B cell cytokines risk stratify early borderline rejection after renal transplantation

Borderline rejection (BL) in renal transplantation is associated with decreased allograft survival, yet many patients with BL maintain stable graft function. Identifying patients with early BL at risk for shortened allograft survival would allow for timely targeted therapeutic intervention aimed at improving outcomes. 851/1187 patients transplanted between 2013-18 underwent early biopsy (0-4 mos). 217/851 (25%) had BL and were compared to 387/851 without significant inflammation (NI). Serial surveillance and for-cause biopsies and seven-year follow-up were used to evaluate histological and clinical progression. To identify high-risk patients, we examined clinical/histological parameters using regression and non-linear dimensionality reduction (tSNE) and a biomarker based on peripheral blood transitional-1 B cell (T1B) IL-10/TNFα ratio. Compared to NI, early BL was associated with increased progression to late acute rejection (AR; 5-12 mos), premature interstitial fibrosis and tubular atrophy (IFTA) and decreased seven-year graft survival. However, decreased graft survival was limited to BL patients who progressed to late AR or IFTA, and was not influenced by treatment. Although tSNE clustered patients into groups based on clinical factors, the ability of these factors to risk stratify BL patients was modest. In contrast, a low T1B IL-10/TNFα ratio at 3 months identified BL patients at high risk for progression to AR (ROC AUC 0.87) and poor 7-yr graft survival (52% vs. 92%, p=0.003), while BL patients with a high ratio had similar graft survival to patients with NI (91%, p=NS). Thus, progressive early allograft inflammation manifested as BL that progresses to late AR in the first post-transplant year represents a high-risk clinical state for poor allograft outcomes. Such high-risk status can be predicted by the T1B IL-10/TNFα ratio before irreversible scarring sets in, thus allowing timely risk stratification.

Bariatric Surgery in Kidney Transplant Candidates and Recipients: Experience at an Asian Center.

Kidney transplant (KT) candidates and recipients with obesity experience more frequent complications such as infection, poorer allograft outcomes, diabetes, and mortality, limiting their eligibility for transplantation. Bariatric surgery (BS) is not commonly performed among KT patients given concerns about immunosuppression absorption, wound healing, infections, and graft outcomes. Its role has not been described before in an Asian KT patient setting. A retrospective review of patients who underwent BS at the largest KT center in Singapore from 2008 to 2020 was conducted. Metabolic outcomes, immunosuppression doses, graft outcomes, and mortality were studied. Seven patients underwent BS and KT (4 underwent BS before KT, 3 underwent BS after KT; 4 underwent sleeve gastrectomy, 3 underwent gastric bypass). Mean total weight losses of 23.8% at 1 year and 18.6% at 5 years post-BS were achieved. Among the five patients with diabetes, glycemic control improved after BS. There were no deaths in the first 90 days or graft loss in the first year after KT and BS. Patients who underwent BS after KT had no significant changes in immunosuppression dose. BS can be safely performed in KT recipients and candidates and results in sustainable weight losses and improvements in metabolic comorbidities. Although no major complications were observed in our study, close monitoring of this complex group of patients is imperative.

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Outcome of keratolimbal allograft transplantation with deep anterior lamellar keratoplasty for bilateral limbal stem cell deficiency.

To evaluate and compare the outcome of keratolimbal allograft (KLAL) transplantation with or without deep anterior lamellar keratoplasty (DALK) for bilateral severe limbal stem cell deficiency (LSCD). This retrospective review included 49 eyes of 46 patients who underwent KLAL transplantation at the Department of Ophthalmology of Chinese PLA general hospital, 2009-2020, for bilateral severe LSCD were examined for corneal clarity and corneal scarring to determine whether to combine DALK with KLAL transplantation. Preoperative information, surgical decision tree, surgical procedures, and postoperative data were collected for each eye. All patients had preoperative severe or total LSCD. Twenty-four eyes underwent KLAL transplantation only, 25 KLAL transplantation plus DALK. The mean follow-up was 46.80 ± 31.22 months (18-158 months). Overall KLAL survival (with or without DALK) was 71.43% at the final follow-up (KLAL-only 66.67%, KLAL-DALK 76%). Kaplan-Meier survival analysis showed that the 3-year survival probability of all grafts was 70.53 ± 10.89% (KLAL-only 64.86 ± 10.11%, KLAL-DALK 75.79 ± 8.62%). The proportion of BCVA ≥ 20/200 eyes among all KLAL transplantations increased from 11 eyes (22.45%) preoperatively to 25 eyes (51.02%) after 1 year and 24 eyes (48.98%) at the last follow-up (P = 0.01). The proportion of BCVA ≥ 20/200 eyes in the KLAL-DALK group increased significantly (P = 0.04), from 16.0% at baseline to 48.0% after 1 year to 44.0% at the last follow-up. Seventeen eyes (34.69%) had postoperative complications. KLAL-DALK is an effective option to restore a stable ocular surface and visual acuity rapidly in patients with bilateral, late-stage, severe LSCD.

Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation

Donor age is a major risk factor for allograft outcome in kidney transplantation. The underlying cellular mechanisms and the recipient's immune response within an aged allograft have yet not been analyzed. A comprehensive immunophenotyping of naïve and transplanted young versus aged kidneys revealed that naïve aged murine kidneys harbor significantly higher frequencies of effector/memory T cells, whereas regulatory T cells were reduced. Aged kidney-derived CD8+ T cells produced more IFNγ than their young counterparts. Senescent renal CD8+ T and NK cells upregulated the cytotoxicity receptor NKG2D and the enrichment of memory-like CD49a+ CXCR6+ NK cells was documented in aged naïve kidneys. In the C57BL/6 to BALB/c kidney transplantation model, recipient-derived T cells infiltrating an aged graft produced significantly more IFNγ, granzyme B and perforin on day 7 post-transplantation, indicating an enhanced inflammatory, cytotoxic response towards the graft. Pre-treatment of aged kidney donors with the senolytic drug ABT-263 changed the recipient-derived effector molecule profile to significantly reduced levels of IFNγ and IL-10 compared to controls. Graft function after ABT-263 pre-treatment was significantly improved 28 days post kidney transplantation. In conclusion, renal senescence also occurs at the immunological level (inflamm-aging) and aged organs provoke an altered recipient-dominated immune response in the graft.