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Microvascular inflammation (MVI) in kidney transplant biopsies is mainly associated with antibody-mediated rejection (AMR), sparking debate within the Banff Classification of Renal Allograft Pathology regarding its exclusivity. This study reviewed the literature on MVI in T cell-mediated rejection (TCMR) and analyzed MVI in our transplant population. We searched English publications in MEDLINE, Embase, Web of Science, Cochrane, and Google Scholar until June 2024, focusing on glomerulitis (g), peritubular capillaritis (ptc), or MVI in kidney transplant biopsies classified as TCMR. Additionally, we examined g, ptc, and MVI in 69 patients with AMR, TCMR, and no rejection. Our search yielded 541 citations, with 10 studies included, covering 810 TCMR and 156 AMR biopsies. The studies showed g, ptc, and MVI were present in TCMR but were less prevalent and severe than in AMR. In our cohort, AMR had significantly higher g, ptc, and MVI scores compared to aTCMR and ATN, however, aTCMR also displayed MVI. These findings confirm that MVI occurs in aTCMR and should not be exclusively linked to AMR. These findings highlight the need to further explore MVI's significance in TCMR and investigate the inflammatory composition. This could refine the Banff Classification, improving Classification accuracy of kidney transplant pathology assessments. [ABSTRACT FROM AUTHOR]

Background/Objectives: Chemical fumigation can effectively inhibit the occurrence of soil-borne diseases; however, this approach can negatively affect the structure of the soil microbial community. The combination of soil fumigant and organic fertilizer application thus represents a widely adopted strategy in agricultural practice. Traditional Chinese medicine residue (TCMR) is a high-quality organic fertilizer; however, the impact of post-fumigation TCMR application on keystone taxa and their functional traits remains uncertain. Methods: This study examined the effects of five fertilization treatments on the diversity, key species, and related functional genes of microbial communities in rhizosphere soil of continuous cropping pepper. Results: Chemical fumigation followed by TCMR application markedly enhanced soil nutrient content in the rhizosphere and significantly influenced microbial community composition as well as functional gene patterns associated with microbial nitrogen cycling. It was also strongly correlated with soil bioavailable nitrogen content. The abundance of keystone bacterial species (Pseudomonadota, Actinomycetota, and Bacillota) substantially increased following TCMR application, alongside a notable rise in Ascomycota abundance within the fungal community. This shift contributed to an increase in beneficial bacterial abundance while reducing that of harmful bacteria. Additionally, TCMR addition affected the abundance of denitrification and DNRA genes involved in nitrogen cycling; specifically, nirB and nirK were strongly associated with soil organic nitrogen content. Conclusions: The combined application of chemical fumigants and TCMR modified the composition of keystone microbial community species by influencing rhizosphere soil TN and other nutrients, and these alterations were linked to multiple nitrogen-cycling functional genes. [ABSTRACT FROM AUTHOR]

The KDIGO guideline for acute rejection treatment recommends use of corticosteroids and suggests using lymphocyte-depleting agents as second line treatment. Aim of the study was to determine the current practices of detection and treatment of TCMR of kidney allografts amongst European kidney transplant centres. An invitation was sent through ESOT/EKITA newsletters and through social media to transplant professionals in Europe for taking part in the survey. A total of 129 transplant professionals responded to the survey. There was equal representation of small and large sized transplant centres. The majority of centres treat borderline changes (BL) and TCMR (Grade IA-B, IIA-B) in indication biopsies and protocol biopsies with corticosteroids as first line treatment. Thymoglobulin is used mainly as second line treatment for TCMR Grade IA-B (80%) and TCMR IIA-B (85%). Treatment success is most often evaluated within one month of therapy. There were no differences observed between the large and small centres for the management of TCMR. This survey highlights the common practices and diversity in clinics for the management of TCMR in Europe. Testing new therapies for TCMR should be in comparison to the current standard of care in Europe. Better consensus on treatment success is crucial for robust study designs. [ABSTRACT FROM AUTHOR]

Abstract Background T cell-mediated rejection is an important factor affecting early transplant kidney survival. Ferroptosis has been shown to play a pathogenic role in a variety of diseases, which was not reported in TCMR. Here we developed a model for assessing activation of ferroptosis-related genes in TCMR to find a better screening method and explore the contribution of ferroptosis in TCMR. Methods We performed unsupervised consensus clustering according to expression of ferroptosis-related genes based on RNA-seq data from kidney transplant biopsies, and developed an assessment model characterized by ferroptosis gene expression through PCA, which was evaluated in multiple external datasets as well as blood and urine samples. Pathway enrichment and immune cell infiltration analysis were used to explore the possible targets and pathways involved in ferroptosis and TCMR. Results A ferroptosis gene expression scoring model was established. The diagnostic specificity and sensitivity of TCMR in renal biopsy samples were both over 80%, AUC = 0.843, and AUC was around 0.8 in multi-dataset validation, and was also close to 0.7 in blood and urine samples, while in predicting of graft survival at 3 years, scoring model had a good prognostic effect as well. Pathway enrichment and PPI network speculated that TLR4, CD44, IFNG, etc. may be the key genes of ferroptosis in TCMR. Conclusions Ferroptosis scoring model could better diagnose TCMR and predict graft loss, and could be used as a potential screening method in blood and urine samples. We speculate that ferroptosis plays an important role in TCMR.

Background: T cell-mediated rejection is an important factor affecting early transplant kidney survival. Ferroptosis has been shown to play a pathogenic role in a variety of diseases, which was not reported in TCMR. Here we developed a model for assessing activation of ferroptosis-related genes in TCMR to find a better screening method and explore the contribution of ferroptosis in TCMR. Methods: We performed unsupervised consensus clustering according to expression of ferroptosis-related genes based on RNA-seq data from kidney transplant biopsies, and developed an assessment model characterized by ferroptosis gene expression through PCA, which was evaluated in multiple external datasets as well as blood and urine samples. Pathway enrichment and immune cell infiltration analysis were used to explore the possible targets and pathways involved in ferroptosis and TCMR. Results: A ferroptosis gene expression scoring model was established. The diagnostic specificity and sensitivity of TCMR in renal biopsy samples were both over 80%, AUC = 0.843, and AUC was around 0.8 in multi-dataset validation, and was also close to 0.7 in blood and urine samples, while in predicting of graft survival at 3 years, scoring model had a good prognostic effect as well. Pathway enrichment and PPI network speculated that TLR4, CD44, IFNG, etc. may be the key genes of ferroptosis in TCMR. Conclusions: Ferroptosis scoring model could better diagnose TCMR and predict graft loss, and could be used as a potential screening method in blood and urine samples. We speculate that ferroptosis plays an important role in TCMR. [ABSTRACT FROM AUTHOR]

Kidney transplant recipients (KTRs) with ultralong-term survival represent a growing, yet insufficiently studied patient cohort. In this single-center retrospective study, we analyzed 248 ultralong-term survivors (≥20 years). KTRs were classified into those with superior graft function (defined as eGFR ≥45 ml/min + proteinuria ≤300 mg/day + eGFR-slope ≤ 2 ml/min/1.73m2/year) and inferior graft function regarding the risk of CKD progression. 20 years post-transplant, median eGFR was 54 ml/min (11-114), proteinuria 200 mg/24 h (0-7,620), eGFR decline 0.45 ml/min/1.73m2/year (11.7 6.5) and DSA had been detected in 19.7% of KTRs. We identified 96 KTRs (38.7%) with superior (group 1) and 152 KTRs (61.3%) with inferior graft function (group 2). Donation after cardiac death, female sex, glomerulonephritis as primary disease, and early TCMR were independently associated with inferior graft function. Graft survival was significantly better in group 1 compared to group 2 (LogRank, p < 0.001). Besides group affiliation (HR 20.515, p = 0.003), multivariable analysis identified DSA development (HR 3.081, p = 0.023) and donor age (HR 1.032, p = 0.024) as independent factors. Interestingly, there was no significant difference in patient survival (LogRank, p = 0.350). In ultralong-term survivors, excellent graft function refers to superior graft survival but does not extend ultimate patient survival. DSA-formation should be taken seriously even in the ultralongterm. [ABSTRACT FROM AUTHOR]

Background: Indication biopsies for deterioration of kidney allograft function often require follow-up biopsies to assess treatment response or lack of improvement. Immune-mediated injury, namely borderline rejection (BLR), T-cell mediated rejection (TCMR), or antibody-mediated rejection (ABMR), results from preformed or de novo alloreactivity due to donor and recipient HLA-mismatches. The impact of HLA-mismatches on alloreactivity is determined by highly immunogenic HLA-epitopes. Methods: We analyzed 123 kidney transplant recipients (KTRs) from 2009 to 2019 who underwent a first indication and a follow-up biopsy. KTRs were divided into three groups according to the first biopsy: No rejection (NR)/BLR (n=68); TCMR (n=21); ABMR (n=34). The HLA-derived epitope-mismatches were calculated using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm. Results: Group NR/BLR: KTRs with higher total PIRCHE-II scores were more likely to develop TCMR in the follow-up biopsy (p=0.031). Interestingly, these differences were significant for both HLA-class I- (p=0.017) and HLA-class IIderived (p=0.017) PIRCHE-II scores. Group TCMR: KTRs with ongoing TCMR in the follow-up biopsy were more likely to show higher total PIRCHE-II scores (median 101.50 vs. 74.00). Group ABMR: KTRs with higher total PIRCHE-II scores were more likely to show an increase in the microvascular inflammation score in the follow-up biopsy. This difference was more pronounced for the HLA-class II-derived PIRCHE-II scores (median 70.00 vs. 31.76; p=0.086). Conclusions: PIRCHE-II scores may prove useful as a biomarker to predict the histopathological changes of immune-related injury from a first indication to a follow-up biopsy. This immunological risk stratification may contribute to individualized treatment strategies. [ABSTRACT FROM AUTHOR]

BackgroundIndication biopsies for deterioration of kidney allograft function often require follow-up biopsies to assess treatment response or lack of improvement. Immune-mediated injury, namely borderline rejection (BLR), T-cell mediated rejection (TCMR), or antibody-mediated rejection (ABMR), results from preformed or de novo alloreactivity due to donor and recipient HLA-mismatches. The impact of HLA-mismatches on alloreactivity is determined by highly immunogenic HLA-epitopes.MethodsWe analyzed 123 kidney transplant recipients (KTRs) from 2009 to 2019 who underwent a first indication and a follow-up biopsy. KTRs were divided into three groups according to the first biopsy: No rejection (NR)/BLR (n=68); TCMR (n=21); ABMR (n=34). The HLA-derived epitope-mismatches were calculated using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm.ResultsGroup NR/BLR: KTRs with higher total PIRCHE-II scores were more likely to develop TCMR in the follow-up biopsy (p=0.031). Interestingly, these differences were significant for both HLA-class I- (p=0.017) and HLA-class II-derived (p=0.017) PIRCHE-II scores. Group TCMR: KTRs with ongoing TCMR in the follow-up biopsy were more likely to show higher total PIRCHE-II scores (median 101.50 vs. 74.00). Group ABMR: KTRs with higher total PIRCHE-II scores were more likely to show an increase in the microvascular inflammation score in the follow-up biopsy. This difference was more pronounced for the HLA-class II-derived PIRCHE-II scores (median 70.00 vs. 31.76; p=0.086).ConclusionsPIRCHE-II scores may prove useful as a biomarker to predict the histopathological changes of immune-related injury from a first indication to a follow-up biopsy. This immunological risk stratification may contribute to individualized treatment strategies.

BackgroundBiopsy-proven causes of graft loss many years after kidney transplantation are scarcely documented.MethodsPatients transplanted between 1995 and 2005 (n = 737) in a single center were followed on a regular basis until 2021. The recipients were divided according to age at transplantation into 3 groups; 18–39 years (young), 40–55 years (middle age), and older than 55 years (elderly). For cause biopsies of renal transplants were clustered into the categories, rejection, IFTA, return original disease, and diagnosis of de novo kidney disease.ResultsRejection was the main cause of graft failure censored for death at every time period after transplantation. The incidence of T cell-mediated rejection (TCMR) became rare 6 years after transplantation while the cumulative incidence of antibody-mediated rejection (ABMR) increased over time (1.1% per year). ABMR was not diagnosed anymore beyond 15 years of follow-up in recipients without pre-transplant donor-specific antibodies (DSA). An episode of TCMR was associated with an increased incidence of ABMR diagnosis in the short-term but did not increase the overall incidence of AMBR not in the long-term. Death as a cause of graft failure was an important competitive risk factor long after transplantation and resulted in a significantly lower frequency of rejection-related graft loss in the elderly group (11 vs. 23% in the young group at 15 year follow-up).ConclusionRejection is a major cause of graft loss but recipient’s age, time after transplantation, and the presence of DSA before transplantation determine the relative contribution to overall graft loss and the type of rejection involved.

Background: Glycosylation is a complex and fundamental metabolic biosynthetic process orchestrated by multiple glycosyltransferases (GT) and glycosidases enzymes. Functions of GT have been extensively examined in multiple human diseases. Our study investigated the potential role of GT genes in T-cell mediated rejection (TCMR) and possible prediction of graft loss of kidney transplantation., Methods: We downloaded the microarray datasets and GT genes from the GEO and the HUGO Gene Nomenclature Committee (HGNC) databases, respectively. Differentially expressed GT genes (DE-GTGs) were obtained by differential expression and Venn analysis. A TCMR diagnostic model was developed based on the hub DE-GTGs using LASSO regression and XGboost machine learning algorithms. In addition, a predictive model for graft survival was constructed by univariate Cox and LASSO Cox regression analysis., Results: We have obtained 15 DE-GTGs. Both GO and KEGG analyses showed that the DE-GTGs were mainly involved in the glycoprotein biosynthetic process. The TCMR diagnostic model exhibited high diagnostic potential with generally highly correlated accuracies [aera under the curve (AUC) of 0.83]. The immune characteristics analysis revealed that higher levels of immune cell infiltration and immune responses were observed in the high-risk group than in the low-risk group. In particular, the Kaplan-Meier survival analysis revealed that renal grafts in the high-risk group have poor prognostic outcomes than the low-risk group. The predictive AUC values of 1-, 2- and 3-year graft survival were 0.76, 0.81, and 0.70, respectively., Conclusion: Our results indicated that GT genes could be used for diagnosis of TCMR and prediction of graft loss in kidney transplantation. These results provide new perspectives and tools for diagnosing, treating and predicting kidney transplant-related diseases., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024. Published by Elsevier B.V.)

BackgroundThe diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury.MethodsWe identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes.ResultsTotal PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003).ConclusionsHigh PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.

Background: The diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury. Methods: We identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes. Results: Total PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003). Conclusions: High PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies. [ABSTRACT FROM AUTHOR]

Recently machine learning applications have been widely used in oil and gas industry. Artificial intelligence applications in petrophysics are used for predicting some petrophysical parameters such as porosity and permeability. In this paper we are calculating petrophysical parameters in some field in the Middle East Gulf area and use these calculated parameters applying machine learning KNearest Neighbor (KNN) regression method to predict these parameters in some other portions of the field. The data used in this study were Nuclear Magnetic Resonance (NMR) logs. The constructed prediction models estimate porosity and permeability logs using a mathematical model of machine learning (KNN) method followed by preprocessing data analysis as importing libraries, datasets, processing dummy variables and feature scaling. NMR porosity and permeability logs were taken as dependent variables (Y) depending on independent input variables (X) such as T2 distribution and T2LM that resulted in essential prediction of porosity and permeability at a certain depth interval of interest. The used KNN regression models showed a valid accuracy of the numerically predicted logs. [ABSTRACT FROM AUTHOR]

Immune cell infiltration plays an important role in the pathophysiology of kidney grafts, but the composition of immune cells is ill-defined. Here, we aimed at evaluating the levels and composition of infiltrating immune cells in kidney grafts. We used CIBERSORT, an established algorithm, to estimate the proportions of 22 immune cell types based on gene expression profiles. We found that non-rejecting kidney grafts were characteristic with high rates of M2 macrophages and resting mast cells. The proportion of M1 macrophages and activated NK cells were increased in antibody-mediated rejection (ABMR). In T cell-mediated rejection (TCMR), a significant increase in CD8 T cell and γδT cell infiltration was observed. CD8 positive T cells were dramatically increased in mixed-ABMR/TCMR. Then, the function of ABMR and TCMR prognostic molecular biomarkers were identified. Finally, we described the gene expression of molecular markers for ABMR diagnosis was elevated and related to the ratio of monocytes and M1 macrophages in ABMR biopsies, while the expression of TCMR diagnosis markers was increased too and positively correlated with γδT cells and activated CD4 memory T cells in TCMR biopsies. Our data suggest that CIBERSORT's deconvolution analysis of gene expression data provides valuable information on the composition of immune cells in renal allografts. [ABSTRACT FROM AUTHOR]

Background Long-term outcomes of the Eurotransplant Senior Program (ESP) are urgently needed to improve selection criteria and allocation policies in the elderly. Methods We analysed patient and allograft outcomes of 244 ESP-kidney transplant recipients (KTRs) between 1999 and 2019 and assessed quality of living compared with 82 ESP-waitlisted dialysis patients using standardized short form-8. Results We observed 1-, 5- and 10-year patient survival of 91.7, 66.3 and 38.0%, respectively. Mortality risk factors included male gender (P = 0.006) and T-cell-mediated rejection (P < 0.001). Median patient survival of male ESP-KTRs was 80 versus 131 months for female ESP-KTRs (P = 0.006). 1-, 5- and 10-year death-censored allograft survival was 93.3, 82.6 and 70.4%. Risk factors included high body mass index (P < 0.001) and T-cell-mediated rejection (P < 0.001). After re-initiation of dialysis median patient survival was 58 months. Change of estimated glomerular filtration rate showed a mean decline of 2.3 and 6.8 mL/min at 5 and 10 years. Median physical and mental component scores of ESP-KTRs were 40.2 and 48.3, significantly higher compared with dialysis patients (P < 0.05). Of ESP-KTRs, 97.5% who underwent transplantation would again do so. Conclusions Long-term outcomes of ESP-KTRs ultimately support the effectiveness of an age-matched allocation system. Our data suggest that the survival advantage of women is maintained after kidney transplantation and calls for gender-specific care. [ABSTRACT FROM AUTHOR]

Abstract: Steroid withdrawal following renal transplantation is challenging and widely debated. This retrospective study aimed at investigating the frequency and determinants of successful steroid withdrawal guided by surveillance biopsies. We analyzed 156 pretransplant DSA‐negative renal transplants receiving basiliximab induction and maintenance immunosuppression with tacrolimus‐mycophenolate‐steroids. The absence of rejection in surveillance biopsies at 3 or 6 months post‐transplant initiated steroid withdrawal, which was monitored by subsequent indication and/or surveillance biopsies. The primary outcome was the frequency of successful (i.e., rejection‐free) steroid withdrawal at 1 year post‐transplant. In the whole study population, successful steroid withdrawal was achieved in 73 of 156 patients (47%). Steroid withdrawal was initiated in 98 of 156 patients (63%) and successful in 73 of 98 patients (74%). Subsequent clinical rejection occurred in only one of 98 patients (1%), whereas 24 of 98 patients (24%) experienced subclinical rejection. Steroid withdrawal was not initiated in 58 of 156 patients (37%) mainly due to current or prior severe (Banff TCMR ≥IA) subclinical rejection. Prediction of successful steroid withdrawal by pretransplant or early post‐transplant parameters was poor. In conclusion, (sub)clinical rejection‐free steroid withdrawal can be expected in about half of pretransplant DSA‐negative patients. As successful steroid withdrawal cannot be well predicted by pre‐ and early post‐transplant parameters, guidance by surveillance biopsies is an attractive strategy. [ABSTRACT FROM AUTHOR]

In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P F Halloran reports financial support was provided by Thermo Fisher Scientific. P F Halloran reports financial support was provided by Natera Inc. P F Halloran reports a relationship with Natera, Inc. that includes: consulting or advisory. Disclosure P F Halloran holds shares in Transcriptome Sciences Inc (TSI), a University of Alberta research company dedicated to developing molecular diagnostics, supported in part by a licensing agreement between TSI and Thermo Fisher Scientific, and by a research grant from Natera Inc. P.F. Halloran is a consultant to Natera Inc. The other authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Among kidney transplant recipients, the treatment of choice for acute T cell mediated rejection (TCMR) with pulse steroids or antibody protocols has variable outcomes. Some rejection episodes are resistant to an initial steroid pulse, but respond to subsequent antibody protocols. The biological mechanisms causing the different therapeutic responses are not currently understood. Histological examination of the renal allograft is considered the gold standard in the diagnosis of acute rejection. The Banff Classification System was established to standardize the histopathological diagnosis and to direct therapy. Although widely used, it shows variability among pathologists and lacks criteria to guide precision individualized therapy. The analysis of the transcriptome in allograft biopsies, which we analyzed in this study, provides a strategy to develop molecular diagnoses that would have increased diagnostic precision and assist the development of individualized treatment. Our hypothesis is that the histological classification of TCMR contains multiple subtypes of rejection. Using R language algorithms to determine statistical significance, multidimensional scaling and hierarchical we analyzed differential gene expression based on microarray data from biopsies classified as TCMR. Next, we identified KEGG functions, protein-protein interaction networks, gene regulatory networks and predicted therapeutic targets using the integrated database ConsesnsusPathDB. Based on our analysis 2 distinct clusters of biopsies termed TCMR01 and TCMR02 were identified. Despite having the same Banff classification, we identified 1933 differentially expressed genes between the 2 clusters. These genes were further divided into three major groups: a core group contained within both the TCMR01 and TCMR02 subtypes, as well as genes unique to TCMR01 or TCMR02. The subtypes of TCMR utilized different biological pathways, different regulatory networks and were predicted to respond to different therapeutic agents. Our results suggest approaches to identify more precise molecular diagnoses of TCMR which could form the basis for personalized treatments.

Histopathology is still an indispensable tool for the diagnosis of kidney transplant dysfunction in adult and pediatric patients. This review presents consolidated knowledge, recent developments and future prospects on the biopsy procedure, the diagnostic work-up, classification schemes, the histopathology of rejection, including antibody-mediated forms, ABO-incompatible transplants, protocol biopsies, recurrent and de novo disease, post-transplant lymphoproliferative disorder, infectious complications and drug-induced toxicity. It is acknowledged that frequently the correct diagnosis can only be reached in consensus with clinical, serological, immunogenetical, bacteriological and virological findings. This review shall enhance the understanding of the pediatric nephrologist for the thought processes of nephropathologists with the aim to facilitate teamwork between these specialist groups for the benefit of the patient. [ABSTRACT FROM AUTHOR]

Among kidney transplant recipients, the treatment of choice for acute T cell-mediated rejection (TCMR) with pulse steroids or antibody protocols has variable outcomes. Some rejection episodes are resistant to an initial steroid pulse, but respond to subsequent antibody protocols. The biological mechanisms causing the different therapeutic responses are not currently understood. Histological examination of the renal allograft is considered the gold standard in the diagnosis of acute rejection. The Banff Classification System was established to standardize the histopathological diagnosis and to direct therapy. Although widely used, it shows variability among pathologists and lacks criteria to guide precision individualized therapy. The analysis of the transcriptome in allograft biopsies, which we analyzed in this study, provides a strategy to develop molecular diagnoses that would have increased diagnostic precision and assist the development of individualized treatment. Our hypothesis is that the histological classification of TCMR contains multiple subtypes of rejection. Using R language algorithms to determine statistical significance, multidimensional scaling, and hierarchical, we analyzed differential gene expression based on microarray data from biopsies classified as TCMR. Next, we identified KEGG functions, protein-protein interaction networks, gene regulatory networks, and predicted therapeutic targets using the integrated database Consesnsus- PathDB (CPDB). Based on our analysis, two distinct clusters of biopsies termed TCMR01 and TCMR02 were identified. Despite having the same Banff classification, we identified 1933 differentially expressed genes between the two clusters. These genes were further divided into three major groups: a core group contained within both the TCMR01 and TCMR02 subtypes, as well as genes unique to TCMR01 or TCMR02. The subtypes of TCMR utilized different biological pathways, different regulatory networks and were predicted to respond to different therapeutic agents. Our results suggest approaches to identify more precise molecular diagnoses of TCMR, which could form the basis for personalized treatments. [ABSTRACT FROM AUTHOR]

Allograft rejection after renal transplantation remains a challenge to overcome. Interleukin (IL)-21, a cytokine with pleiotropic effects, maintains immune homeostasis post-transplantation. Here, we report higher levels of IL-21 in kidney transplant recipients with non-rejection (NR) than in recipients with T cell-mediated rejection (TCMR, P < 0.001) and antibody-mediated rejection (ABMR, P = 0.005). We observed a negative correlation between IL-21 and creatinine (Cr) levels ( P = 0.016). The receiving operating characteristic (ROC) curve showed a promising diagnostic value of IL-21 to identify acute rejection with an area under the curve (AUC) of 0.822 ( P < 0.001). In contrast, exogenous administration of IL-21 accelerated acute rejection in a comparative translational kidney transplant (KT) mouse model. Reduced IL-21 levels in the peripheral blood were observed in KT mice after IL-21 injection. Further analysis revealed that increased IL-21 levels in the spleen induced proliferation of CD4+ T cells and CD19+ B cells after IL-21 treatment. Our findings suggest a critical function of IL-21 in kidney transplantation and the potential involvement of the IL-21/IL-21R pathway in acute rejection management.