Rejection is one of the major factors affecting the long-term prognosis of kidney transplantation, and timely recognition and aggressive treatment of rejection is essential to prevent disease progression. RBPs are proteins that bind to RNA to form ribonucleoprotein complexes, thereby affecting RNA stability, processing, splicing, localization, transport, and translation, which play a key role in post-transcriptional gene regulation. However, their role in renal transplant rejection and long-term graft survival is unclear. The aim of this study was to comprehensively analyze the expression of RPBs in renal rejection and use it to construct a robust prediction strategy for long-term graft survival. The microarray expression profiles used in this study were obtained from GEO database. In this study, a total of eight hub RBPs were identified, all of which were upregulated in renal rejection samples. Based on these RBPs, the renal rejection samples could be categorized into two different clusters (cluster A and cluster B). Inflammatory activation in cluster B and functional enrichment analysis showed a strong association with rejection-related pathways. The diagnostic prediction model had a high diagnostic accuracy for T cell mediated rejection (TCMR) in renal grafts (area under the curve = 0.86). The prognostic prediction model effectively predicts the prognosis and survival of renal grafts (p < .001) and applies to both rejection and non-rejection situations. Finally, we validated the expression of hub genes, and patient prognosis in clinical samples, respectively, and the results were consistent with the above analysis.

UNASSIGNED: Antibody-mediated rejection (ABMR) significantly affects transplanted kidney survival, yet the macrophage phenotype, ontogeny, and mechanisms in ABMR remain unclear.
UNASSIGNED: We analyzed post-transplant sequencing and clinical data from GEO and ArrayExpress. Using dimensionality reduction and clustering on scRNA-seq data, we identified macrophage subpopulations and compared their infiltration in ABMR and non-rejection cases. Cibersort quantified these subpopulations in bulk samples. Cellchat, SCENIC, monocle2, and monocle3 helped explore intercellular interactions, predict transcription factors, and simulate differentiation of cell subsets. The Scissor method linked macrophage subgroups with transplant prognosis. Furthermore, hdWGCNA, nichnet, and lasso regression identified key genes associated with core transcription factors in selected macrophages, validated by external datasets.
UNASSIGNED: Six macrophage subgroups were identified in five post-transplant kidney biopsies. M1-like infiltrating macrophages, prevalent in ABMR, correlated with pathological injury severity. MIF acted as a primary intercellular signal in these macrophages. STAT1 regulated monocyte-to-M1-like phenotype transformation, impacting transplant prognosis via the IFNγ pathway. The prognostic models built on the upstream and downstream genes of STAT1 effectively predicted transplant survival. The TLR4-STAT1-PARP9 axis may regulate the pro-inflammatory phenotype of M1-like infiltrating macrophages, identifying PARP9 as a potential target for mitigating ABMR inflammation.
UNASSIGNED: Our study delineates the macrophage landscape in ABMR post-kidney transplantation, underscoring the detrimental impact of M1-like infiltrating macrophages on ABMR pathology and prognosis.

The routine use of donor-derived cell-free DNA (dd-cfDNA) assays to monitor graft damage in patients after kidney transplantation is being implemented in many transplant centers worldwide. The interpretation of the results can be complicated in the setting of multiple sequential kidney transplantations where accurate donor assignment of the detected dd-cfDNA can be methodologically challenging.
We investigated the ability of a new next-generation sequencing (NGS)-based dd-cfDNA assay to accurately identify the source of the detected dd-cfDNA in artificially generated samples as well as clinical samples from 31 patients who had undergone two sequential kidney transplantations.
The assay showed a high accuracy in quantifying and correctly assigning dd-cfDNA in our artificially generated chimeric sample experiments over a clinically meaningful quantitative range. In our clinical samples, we were able to detect dd-cfDNA from the first transplanted (nonfunctioning) graft in 20% of the analyzed patients. The amount of dd-cfDNA detected from the first graft was consistently in the range of 0.1%-0.6% and showed a fluctuation over time in patients where we analyzed sequential samples.
This is the first report on the use of a dd-cfDNA assay to detect dd-cfDNA from multiple kidney transplants. Our data show that a clinically relevant fraction of the transplanted patients have detectable dd-cfDNA from the first donor graft and that the amount of detected dd-cfDNA is in a range where it could influence clinical decision-making.

Living donor (LD) kidney transplantation in the setting of ABO blood group incompatibility (ABOi) has been previously reported to be associated with increased risk for antibody-mediated rejection (ABMR). It is however unclear if the presence of pre-transplant donor specific antibodies (DSA) works as an additive risk factor in the setting of ABOi and if DSA positive ABOi transplants have a significantly worse long-term outcome as compared with ABO compatible (ABOc) DSA positive transplants.
We investigated the effect of pre-transplant DSA in the ABOi and ABOc setting on the risk of antibody-mediated rejection (ABMR) and graft loss in a cohort of 952 LD kidney transplants.
We found a higher incidence of ABMR in ABOi transplants as compared to ABOc transplants but this did not significantly affect graft survival or overall survival which was similar in both groups. The presence of pre-transplant DSA was associated with a significantly increased risk of ABMR and graft loss both in the ABOi and ABOc setting. We could not detect an additional risk of DSA in the ABOi setting and outcomes were comparable between DSA positive ABOi and ABOc recipients. Furthermore, a combination of DSA directed at both Class I and Class II, as well as DSA with a high mean fluorescence intensity (MFI) showed the strongest relation to ABMR development and graft loss.
The presence of pre-transplant DSA was associated with a significantly worse long-term outcome in both ABOi and ABOc LD kidney transplants and our results suggests that the risk associated with pre-transplant DSA is perhaps not augmented in the ABOi setting. Our study is the first to investigate the long-term effects of DSA in the ABOi setting and argues that pre-transplant DSA risk could potentially be evaluated similarly regardless of ABO compatibility status.

Infection with BK polyomavirus (BKPyV) is a common opportunistic infection after kidney transplantation (KT) and may affect graft function. We aimed to determine the incidence, risk factors, and clinical outcomes of BKPyV DNAemia in a prospective cohort of 601 KT recipients transplanted from 2012 to 2020. BKPyV PCR on plasma was performed at days 60, 90, 180, 270, and 360 post-KT. Any BKPyV DNAemia was defined as a single BKPyV DNA of ≥1000 copies/mL. Severe BKPyV DNAemia was defined as two consecutive BKPyV DNA of ≥10,000 copies/mL. Cumulative incidences were investigated using the Aalen-Johansen estimator, and the risk factors were investigated in Cox proportional hazard models. The incidence of any BKPyV DNAemia and severe BKPyV DNAemia was 21% (18-25) and 13% (10-16) at one year post-KT, respectively. Recipient age > 50 years (aHR, 1.72; 95% CI 1.00-2.94; p = 0.049), male sex (aHR, 1.96; 95% CI 1.17-3.29; p = 0.011), living donors (aHR, 1.65; 95% CI 1.03-2.74; p = 0.045), and >3 HLA-ABDR mismatches (aHR, 1.72; 95% CI 1.01-2.94; p = 0.046) increased the risk of severe BKPyV DNAemia. Any BKPyV DNAemia was associated with an increased risk of graft function decline (aHR, 2.26; 95% CI 1.00-5.12; p = 0.049), and severe BKPyV DNAemia was associated with an increased risk of graft loss (aHR, 3.18; 95% CI 1.06-9.58; p = 0.039). These findings highlight the importance of BKPyV monitoring post-KT.

UNASSIGNED: Immunoglobulin A nephropathy (IgAN) is the most frequent recurrent disease in kidney transplant recipients and its recurrence contributes to reducing graft survival. Several variables at the time of recurrence have been associated with a higher risk of graft loss. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with recurrent IgAN.
UNASSIGNED: We performed a multicentre retrospective study including kidney transplant recipients with biopsy-proven recurrence of IgAN in which Banff and Oxford classification scores were available. \'Tubulo-interstitial inflammation\' (TII) was defined when \'t\' or \'i\' were ≥2. The main endpoint was progression to chronic kidney disease (CKD) stage 5 or to death censored-graft loss (CKD5/DCGL).
UNASSIGNED: A total of 119 kidney transplant recipients with IgAN recurrence were included and 23 of them showed TII. Median follow-up was 102.9 months and 39 (32.8%) patients reached CKD5/DCGL. TII related to a higher risk of CKD5/DCGL (3 years 18.0% vs 45.3%, log-rank 7.588, P = .006). After multivariate analysis, TII remained related to the risk of CKD5/DCGL (HR 2.344, 95% CI 1.119-4.910, P = .024) independently of other histologic and clinical variables.
UNASSIGNED: In kidney transplant recipients with IgAN recurrence, TII contributes to increasing the risk of CKD5/DCGL independently of previously well-known variables. We suggest adding TII along with the Oxford classification to the clinical variables to identify recurrent IgAN patients at increased risk of graft loss who might benefit from intensified immunosuppression or specific IgAN therapies.

UNASSIGNED: This study aimed to analyze risk factors and develop a predictive model for early allograft loss due to early graft dysfunction (EGD) in adult live-donor liver transplantation (LDLT).
UNASSIGNED: Data of patients who underwent LDLT from 2011 to 2019 were reviewed for EGD, associated factors, and outcomes. A homogeneous group of 387 patients was analyzed: random cohort A (n = 274) for primary analysis and random cohort B (n = 113) for validation.
UNASSIGNED: Of 274 recipients, 92 (33.6%) developed EGD. The risk of graft loss within 90 days was 29.3% and 7.1% in those with and without EGD, respectively (P < 0.001). Multivariate logistic regression analysis determined donor age (P = 0.045), estimated (e) graft weight (P = 0.001), and the model for end-stage liver disease (MELD) score (0.001) as independent predictors of early graft loss due to EGD. Regression coefficients of these factors were employed to formulate the risk model: Predicted (P) early graft loss risk (e-GLR) score = 10 × [(donor age × 0.052) + (e-Graft weight × 1.681) + (MELD × 0.145)] - 8.606 (e-Graft weight = 0, if e-Graft weight ≥640 g and e-Graft weight = 1, and if e-Graft weight < 640 g). Internal cross-validation revealed a high predictive value (C-statistic = 0.858).
UNASSIGNED: Our novel risk score can efficiently predict early allograft loss following graft dysfunction, which enables donor-recipient matching, evaluation, and prognostication simply and reliably in adult LDLT.

BACKGROUND: Operational tolerance as the ability to accept the liver transplant without pharmacological immunosuppression is a common phenomenon in the long-term course. However, it is currently underutilized due to a lack of simple diagnostic support and fear of rejection despite its recognized benefits. In the present work, we present a simple score based on clinical parameters to estimate the probability of tolerance.
METHODS: In order to estimate the probability of tolerance, clinical parameters from 82 patients after LT who underwent weaning from the IS for various reasons at our transplant center were extracted from a prospectively organized database and analyzed retrospectively. Univariate testing as well as multivariable logistic regression analysis were performed to assess the association of clinical variables with tolerance in the real-world setting.
RESULTS: The most important factors associated with tolerance after multivariable logistic regression were IS monotherapy, male sex, history of hepatocellular carcinoma pretransplant, time since LT, and lack of rejection. These five predictors were retained in an approximate model that could be presented as a simple scoring system to estimate the clinical probability of tolerance or IS dispensability with good predictive performance (AUC = 0.89).
CONCLUSIONS: In parallel with the existence of a tremendous need for further research on tolerance mechanisms, the presented score, after validation in a larger collective preferably in a multicenter setting, could be easily and safely applied in the real world and already now address all three levels of prevention in LT patients over the long-term course.

Early graft loss following kidney transplantation is mainly a result of acute rejection or surgical complications, while long-term kidney allograft loss is more complex. We examined the association between systemic inflammation early after kidney transplantation and long-term graft loss, as well as correlations between systemic inflammation scores and inflammatory findings in biopsies 6 weeks and 1 year after kidney transplantation.
We measured 21 inflammatory biomarkers 10 weeks after transplantation in 699 patients who were transplanted between 2009 and 2012 at Oslo University Hospital, Rikshospitalet, Norway. Low-grade inflammation was assessed with predefined inflammation scores based on specific biomarkers: one overall inflammation score and five pathway-specific scores. Surveillance or indication biopsies were performed in all patients 6 weeks after transplantation. The scores were tested in Cox regression models.
Median follow-up time was 9.1 years (interquartile range 7.6-10.7 years). During the study period, there were 84 (12.2%) death-censored graft losses. The overall inflammation score was associated with long-term kidney graft loss both when assessed as a continuous variable (hazard ratio 1.03, 95% CI 1.01-1.06, P = 0.005) and as a categorical variable (4th quartile: hazard ratio 3.19, 95% CI 1.43-7.10, P = 0.005). In the pathway-specific analyses, fibrogenesis activity and vascular inflammation stood out. The vascular inflammation score was associated with inflammation in biopsies 6 weeks and 1 year after transplantation, while the fibrinogenesis score was associated with interstitial fibrosis and tubular atrophy.
In conclusion, a systemic inflammatory environment early after kidney transplantation was associated with biopsy-confirmed kidney graft pathology and long-term kidney graft loss. The systemic vascular inflammation score correlated with inflammatory findings in biopsies 6 weeks and 1 year after transplantation.

BACKGROUND: Growing interest has been recently reported in the potential detrimental role of donor gamma-glutamyl transferase (GGT) peak at the time of organ procurement regarding the risk of poor outcomes after liver transplantation (LT). However, the literature on this topic is scarce and controversial data exist on the mechanisms justifying such a correlation. This study aims to demonstrate the adverse effect of donor GGT in a large European LT cohort regarding 90-day post-transplant graft loss.
METHODS: This is a retrospective international study investigating 1335 adult patients receiving a first LT from January 2004 to September 2018 in four collaborative European centers.
RESULTS: Two different multivariable logistic regression models were constructed to evaluate the risk factors for 90-day post-transplant graft loss, introducing donor GGT as a continuous or dichotomous variable. In both models, donor GGT showed an independent role as a predictor of graft loss. In detail, the log-transformed continuous donor GGT value showed an odds ratio of 1.46 (95% CI = 1.03-2.07; p = 0.03). When the donor GGT peak value was dichotomized using a cut-off of 160 IU/L, the odds ratio was 1.90 (95% CI = 1.20-3.02; p = 0.006). When the graft-loss rates were investigated, significantly higher rates were reported in LT cases with donor GGT ≥160 IU/L. In detail, 90-day graft-loss rates were 23.2% vs. 13.9% in patients with high vs. low donor GGT, respectively (log-rank p = 0.004). Donor GGT was also added to scores conventionally used to predict outcomes (i.e., MELD, D-MELD, DRI, and BAR scores). In all cases, when the score was combined with the donor GGT, an improvement in the model accuracy was observed.
CONCLUSIONS: Donor GGT could represent a valuable marker for evaluating graft quality at transplantation. Donor GGT should be implemented in scores aimed at predicting post-transplant clinical outcomes. The exact mechanisms correlating GGT and poor LT outcomes should be better clarified and need prospective studies focused on this topic.