Acute Rejection In Kidney Transplantation Research Articles

Multidrug resistant 1 (MDR1) C3435T and G2677T gene polymorphism: impact on the risk of acute rejection in pediatric kidney transplant recipients

BackgroundTacrolimus is the backbone drug in kidney transplantation. Single nucleotide polymorphism of Multidrug resistant 1 gene can affect tacrolimus metabolism consequently it can affect tacrolimus trough level and incidence of acute rejection. The aim of this study is to investigate the impact of Multidrug resistant 1 gene, C3435T and G2677T Single nucleotide polymorphisms on tacrolimus pharmacokinetics and on the risk of acute rejection in pediatric kidney transplant recipients.MethodsTyping of Multidrug resistant 1 gene, C3435T and G2677T gene polymorphism was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 83 pediatric kidney transplant recipients and 80 matched healthy controls.ResultsIn Multidrug resistant 1 gene (C3435T), CC, CT genotypes and C allele were significantly associated with risk of acute rejection when compared to none acute rejection group (P = 0.008, 0.001 and 0.01 respectively). The required tacrolimus doses to achieve trough level were significantly higher among CC than CT than TT genotypes through the 1st 6 months after kidney transplantation. While, in Multidrug resistant 1 gene (G2677T), GT, TT genotypes and T allele were associated with acute rejection when compared to none acute rejection (P = 0.023, 0.033 and 0.028 respectively). The required tacrolimus doses to achieve trough level were significantly higher among TT than GT than GG genotypes through the 1st 6 months after kidney transplantation.ConclusionThe C allele, CC and CT genotypes of Multidrug resistant 1 gene (C3435T) and the T allele, GT and TT genotypes of Multidrug resistant 1 gene (G2677T) gene polymorphism may be risk factors for acute rejection and this can be attributed to their effect on tacrolimus pharmacokinetics. Tacrolimus therapy may be tailored according to the recipient genotype for better outcome.

COVID-19 as a cause of acute kidney transplant rejection: clinical and morphological analysis of a fatal case report

COVID-19 against the background of the respiratory system damage often causes changes in the morpho-functional state of the kidneys, accelerates the progression and development of complications of chronic kidney disease, and is the cause of a high mortality rate in kidney transplant recipients. In the article, the authors conduct a detailed clinical and morphological analysis of a fatal case report of acute kidney transplant rejection of antibody-mediated and cell-mediated genesis, the development of which was determined by the presence of COVID-19 in the patient. The authors emphasize that the morphological study is crucial for the diagnosis of renal transplant rejection. This clinical and morphological analysis of a case report shows the need for an individual approach to this category of patients for the purpose of timely diagnosis, treatment and prevention of COVID-19.

401 Successful Treatment of Thrombotic Microangiopathy Due to Acute Antibody Mediated Rejection of Kidney Transplant

401 Successful Treatment of Thrombotic Microangiopathy Due to Acute Antibody Mediated Rejection of Kidney Transplant

Changes and Significance of Interleukin 17 Expression in Patients After Renal Transplantation

The purpose of this study was to investigate the expression and significance of interleukin (IL)-17 in acute rejection after renal transplantation. From September 2019 to December 2021, patients and healthy volunteers who underwent renal allograft transplantation and renal biopsy in our hospital were selected and divided into 4 groups: the stable group (stable) showed no obvious abnormality in renal transplantation pathology; the pathologic diagnosis of acute rejection was the rejection group; the pathologic diagnosis of renal transplantation was immunosuppressive poisoning in the drug group; and the normal group (control) was healthy volunteers. The expression of IL-17 was detected by reverse transcription-polymerase chain reaction, quantitative enzyme-linked immunosorbent assay, and immunohistochemistry. Analysis of the area under the curve and sensitivity and specificity of IL-17 for the diagnosis of acute rejection after raw transplantation was done using receiver operating characteristic curves. Compared with those in the normal group and the stable group, the expression of IL-17 DNA in the blood, the value of IL-17 in the blood, and the integrated optical density value of IL-17 in the transplanted kidney were significantly higher in the rejection group (P < .05). There were no statistically significant differences in the expression of blood IL-17 DNA, the value of blood IL-17, or the integrated optical density value of transplanted kidney IL-17 between the normal group and the stable group (P > .05). IL-17 is involved in acute rejection after renal transplantation. Increased expression of IL-17 is seen in the blood and kidneys of patients with acute rejection after renal transplantation. The detection of IL-17 may provide a theoretical basis for diagnosing and treating acute rejection in human kidney transplantation.

Role of Biomarkers in Detecting Acute Rejection in Kidney Transplantation

Medicine has evolved from the so-called experience-based medicine to evidence-based medicine, which is now evolving into precision-based medicine [...]

Identification of PDCD1 as a potential biomarker in acute rejection after kidney transplantation via comprehensive bioinformatic analysis.

Acute rejection is a determinant of prognosis following kidney transplantation. It is essential to search for novel noninvasive biomarkers for early diagnosis and prompt treatment. Gene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the intersected differentially expressed genes (DEGs) was calculated. We conducted the DEGs with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Distribution of immune cell infiltration was calculated by CIBERSORT. A hub gene marker was identified by intersecting the rejection-related genes from WGCNA and a selected KEGG pathway-T cell receptor signaling pathway (hsa04660), and building a protein-protein interaction network using the STRING database and Cytoscape software. We performed flow-cytometry analysis to validate the hub gene. A total of 1450 integrated DEGs were obtained from five datasets (GSE1563, GSE174020, GSE98320, GSE36059, GSE25902). The GO, KEGG and immune infiltration analysis results showed that AR was mainly associated with T cell activation and various T-cell related pathways. Other immune cells, such as B cells, Macrophage and Dendritic cells were also associated with the progress. After utilizing the WGCNA and PPI network, PDCD1 was identified as the hub gene. The flow-cytometry analysis demonstrated that both in CD4+ and CD8+ T cells, PD1+CD57-, an exhausted T cell phenotype, were downregulated in the acute rejection whole blood samples. Our study illustrated that PDCD1 may be a candidate diagnostic biomarker for acute kidney transplant rejection via integrative bioinformatic analysis.

Application of plasma donor-derived cell free DNA for lung allograft rejection diagnosis in lung transplant recipients

BackgroundDonor-derived cell-free DNA (dd-cfDNA) has been applied to monitor acute rejection (AR) in kidney and heart transplantation. This study was aimed to investigate the application of dd-cfDNA levels in the diagnosis of AR and chronic lung allograft dysfunction (CLAD) among the lung transplantation recipients (LTRs).MethodsOne hundred and seventy LTRs were enrolled at the First Affiliated Hospital of Guangzhou Medical University between 1 June 2015 and 30 March 2021. Patients were divided into 4 groups: stable group, AR group, infection group and CLAD group. The level of dd-cfDNA was analyzed using target region sequencing and the performance characteristics of dd-cfDNA for diagnosis of AR and CLAD were determined, respectively.ResultsKruskal–Wallis test showed that there were some significant differences in the level of dd-cfDNA (%) among the 4 groups, with p < 0.001. Among them, the level of dd-cfDNA (%) was highest (median 2.17, IQR [1.40–3.82]) in AR group, and higher in CLAD group (median 1.07, IQR [0.98–1.31]), but lower in infection group (median 0.71, IQR [0.57–1.07]) and lowest in stable group (median 0.71, IQR [0.61–0.84]). AUC-ROC curve analysis showed that the threshold of dd-cfDNA for AR was 1.17%, with sensitivity being 89.19% and specificity being 86.47%, and the optimal threshold of 0.89% was determined of CLAD, with sensitivity being 95.00% and specificity of 76.99%.ConclusionsPlasma dd-cfDNA could be a useful tool for the assessment of lung allograft rejection, including AR and CLAD, and holds promise as a noninvasive biomarker for “allograft injury” in both acute and chronic rejection following lung transplantation.

HLA-DPB1 molecular mismatches are risk factors for acute rejection and low 5-year graft function in first kidney transplants.

The study aimed to investigate the impact of HLA-DPB1 allelic and molecular mismatches on the occurrence of acute rejection (AR) and low 5-year graft function (5Y-GF) in first kidney transplant (KT) recipients. This is a single center retrospective study of 130 deceased donor KT recipients transplanted between 2014 and 2016. HLA-DPB1 allelic MM and the following molecular MM (mMM) were analyzed: expression MM with the high expression G allele in the donor; T cell epitope MM (TCE MM); epitope MM (EMM), considering all six hypervariable regions (EMM-ABCDEF HVR), or only ABEF regions (EMM-ABEF HVR); eplet MM (EpMM); antibody-verified eplet MM (AbVer EpMM); and solvent accessible amino acid MM (SAMM). There was no association of allelic MM with AR or 5Y-GF. The variables independently associated (Cox regression analyses) with AR were high donor final creatinine, nonpermissive TCE MM, ABCDEF EMM load ≥6, EpMM load ≥6; SAMM load ≥5, and AbVer EpMM load ≥3. No association between any HLA-DPB1 mMM and 5Y-GF was observed when all 130 transplant recipients were considered. However, when transplants from expanded criteria donors were excluded, independent associations were detected (logistic regression analyses) with AbVerEpMM load ≥2, SAMM load ≥7, cerebro-vascular death, donor age, and AR. To our knowledge, this is the first study that shows that some HLA-DPB1 mMM are associated with AR and low 5Y-GF in a population of exclusively first kidney transplant recipients.

Potential Utility of Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte, and Neutrophil, Lymphocyte, and Platelet Ratios in Differential Diagnosis of Kidney Transplant Acute Rejection: A Retrospective, Propensity Score Matched Analysis.

BACKGROUND Acute kidney transplant rejection can negatively affect long-term graft function. The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio have been proposed as non-invasive predictors of acute rejection in stable kidney transplant recipients. The aim of this study was to validate the predictive value of these ratios, as well as neutrophil, lymphocyte, and platelet ratios in the diagnosis of acute rejection during the early post-transplant period. MATERIAL AND METHODS After propensity score matching, we compared 71 kidney recipients with biopsy-proven acute rejection with 71 patients without rejection and also subjects with different histologic types of rejection. All 3 types of blood cell count-derived ratios were calculated 6 and 3 days prior to biopsy and on the day of biopsy. RESULTS There were 15 patients with T cell-mediated rejection, 33 with vascular rejection, and 23 with antibody-mediated rejection. The values of all examined ratios did not differ between subgroups with and without rejection. However, at all post-transplant study time-points, patients with antibody-mediated rejection had significantly higher values of all analyzed ratios than subjects with other types of rejection. In multivariate regression models, higher values of blood cell count-derived ratios were independently associated with the occurrence of antibody-mediated rejection. CONCLUSIONS In the early post-transplant period, the values of neutrophil-to-lymphocyte, platelet-to-lymphocyte, and neutrophil, lymphocyte, and platelet ratios were similar in patients with and without an acute rejection episode, but significantly higher values were found in subjects with antibody-mediated rejection as compared with other types of rejection and those without rejection. High values of analyzed ratios in patients with satisfactory early kidney graft function may be helpful in selecting subjects with increased risk of subclinical antibody-mediated rejection.

Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.

Transplant rejection is a major cause of graft loss and morbidity. Currently, no human models of antibody-mediated rejection (AMR) exist, limiting mechanistic investigation and organ-specific targeted therapy. Here, using 12 human kidneys and ex-vivo normothermic machine perfusion, we demonstrate phenotypes of AMR after addition of antibodies against either human HLA class I or blood group antigens (A, B), thus modelling clinical AMR that can follow HLA incompatible (HLAi) or blood group incompatible (ABOi) transplantation. Discarded human kidneys with wide ranging demographics and cold ischaemia times (11-54h) were perfused with red blood cells and fresh frozen plasma (FFP) as a source of complement/coagulation factors. For the HLAi model, 600μg of W6/32 anti-class 1 HLA antibody was added to the circuit (time '0'). For the ABOi model, high titre FFP of the relevant blood group antibody was added. Renal blood flow index (RBFi, mL/min/100 g), C3 desArg, prothrombin fragments 1+2 and histology were determined. Our endpoints included haemodynamic changes, thrombosis, and biopsy proven complement deposition. Compared to control kidneys perfused without anti-donor antibodies, both models demonstrated haemodynamic collapse after antibody perfusion with only the HLAi model showing glomerular C4d deposition. We show that a clinically relevant human kidney model of AMR is feasible, and anticipate that these models, with refinements, could provide a basis to test different strategies to prevent AMR. The Rosetrees and Stonygate Trust, The Royal College of Surgeons of England Fellowship Grant, NIHR Biomedical Research Centre/KCL Early Career Grant, Kidney Research U.K.

Perturbations of the T-cell immune repertoire in kidney transplant rejection.

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.

Association Between the Intracellular Tacrolimus Concentration in CD3 + T Lymphocytes and CD14 + Monocytes and Acute Kidney Transplant Rejection.

Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC [PBMC] ) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3 + T lymphocytes (TAC [CD3] ) and CD14 + monocytes (TAC [CD14] ) with acute rejection after kidney transplantation. From a total of 61 samples in this case-control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3 + T lymphocytes and CD14 + monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured. The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC [CD3] was significantly lower than TAC [CD14] (median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC [PBMC] (48.5 versus 44.4 pg/million cells; P = 0.82), TAC [CD3] (13.4 versus 12.5 pg/million cells; P = 0.28), and TAC [CD14] (90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC [PBMC] than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors. Differences in TAC [CD3] and TAC [CD14] between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC [PBMC] between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.

Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation

The genomic mismatch level between donor and recipient may be associated with the risk of rejection and graft survival. We determined the association of genome-level matching with acute rejection in deceased-donor kidney transplantation. The study cohort consists of 1025 recipient-donor pairs transplanted in a single center from 2007 to 2017 in Helsinki. The associations between the sums of whole-genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox model. In addition, we analyzed 40 deletion-tagging variants using Cox model. The association analysis between mismatch sums of kidney-related proteins and acute rejection resulted in an unadjusted hazard ratio (HR) of 1.15 (95% confidence interval [CI], 1.01-1.30; P= 0.029) and adjusted HR of 1.13 (95% CI, 0.99-1.28; P= 0.071). In deletion analysis, a mismatch in rs7542235 genotype GG tagging a homozygous deletion at the complement factor H-related (CFHR), proteins locus, predisposed to acute rejection with an unadjusted HR of 3.10 (95% CI, 1.53-6.29; P= 0.002) and adjusted HR of 2.97 (95% CI, 1.46-6.05; P= 0.003). In conclusion, analyses of genome-level mismatches may be useful tools in prediction of transplantation outcome. The relative importance differs between populations, because we found evidence for CFHR deletion but could not replicate the finding of previously reported LIMS1 deletion.

316.11: HLA-DPB1 Molecular Mismatches Are Associated With Acute Rejection and Long-term Graft Function in First Kidney Transplants

Introduction: It is generally accepted that HLA-DP mismatches (MM) do not impact the survival of first transplants but that they may exert a deleterious effect in retransplants. This study aimed to investigate the impact of HLA-DPB1 allele and molecular MM (mMM) on the occurrence of acute rejection (AR) and low 5-year graft function (5-yGF) in first kidney transplants (KT). Method: HLA-DPB1 allele and mMM were determined in 130 first KT from deceased donors, performed between 2014 and 2016. The following mMM models were investigated: expression MM, with the high expression G allele in the donor, T cell epitope (TCE) MM, classified as permissive and nonpermissive MM, epitope MM (EMM), considering all six HLA-DPB1 hypervariable regions (EMM-ABCDEF HVR) or only ABEF regions (EMM-ABEF HVR), Eplet MM (EpMM), considering all or only antibody-verified (AbVer) eplets, and solvent accessible amino acid MM (SAMM). EMM, EpletMM and SAMM loads were categorized using thresholds determined by ROC analysis for each outcome. The outcomes were AR and 5-yGF (estimated by CKD-EPI). Logistic and Cox regressions were used to investigate variables associated with 5-yGF and AR, respectively. Results: 119 (91.5%) KT were performed with one or two HLA-DPB1 allele MM. The overall incidence of AR was 17.7% and the median 5-yGF was 40.3 (27.0 - 51.7) mL/min/1.73m2. No association between HLA-DPB1 allele MM and 5-yGF or rejection was observed. Considering only recipients of standard criteria donor, five logistic models for 5-yGF were built including variables that reached a p-value <0.10 in the univariable analysis (age and donor sex, cause of brain death, ABDR MM and AR) and the mMM (TCE, SAMM, all and AbVer EpMM, EMM-ABCDEF and ABEF HVR). In the model 2, variables associated with 5-yGF≤ 40 were donor age (OR=1.08; CI95%=1.02-1.14; p=0.005) and SAMM≥7 (OR=4.40; CI95%=1.56-12.36, p<0.005), while in the model 4, donor age (OR= 1.09; CI95%=1.03-1.15; p=0.003) and EpMM(AbVer≥2 (OR=3.39; CI95%=1.2-9.45, p=0.02) were associated with low GF. The AUC-ROC for predicting 5-yGF was 0.83 (0.75-0.92) for the model 2, and 0.68 (0.57-0.79) for the model 4. Lastly, for the outcome AR in all recipients, beyond the final donor creatinine, the following mMM models were statistically significant: TCE (HR=3.01; CI95%=1.33-6.84; p=0.008), SAMM≥5 (HR=2.69; CI95%=1.10-6.56; p=0.03), AbVerEpMM ≥3 (HR=3.38; 95%CI=1.32-8.70; p=0.01), and EMM-ABCDEF HVR ≥ 6 (HR=5.08; 95%CI=2.19-11.82; p<0.001). Conclusion: To the best of our knowledge, this is the first study that shows that some mMM, in contrast to classical allele HLA-DPB1 MM, are associated with acute rejection and long-term graft function in a population of exclusively first kidney transplants.

235.4: Analyzing the Impact of T-Cell Receptor Diversity in Acute Kidney Transplant Rejection

Purpose: Recent developments in T-cell receptor (TCR) immunosequencing allow for analysis of alloreactive human T-cell populations both before and after engraftment. In this study, we mapped T-cell repertoire from transplant recipients and assessed the role of chronological changes in T-cell clonality, immune repertoire turnover, T-cell Fraction (TCFr), and tissue pathological score to acute rejection (AR) risk stratification and management. Methods: The study included 339 blood samples, collected before and after transplantation, from 200 kidney transplant recipients; 100 with biopsy confirmed acute rejection (AR), 100 with biopsy confirmed stable (STA) allograft histology. Immunosequencing of the CDR3 regions of human TCRβ locus was performed using the immune SEQ Assay. Sequences were collapsed and filtered in order to identify and quantitate the absolute abundance of each unique TCRβ CDR3 region for further analysis. Results: More diverse T-cell Repertoire at baseline was associated with AR post-transplant. When compared to STA patients, AR patients had lower (TCFr) before transplantation (p=0.01). After transplantation, patients who developed rejection had greater repertoire turnover (p=0.0024) and increased TCFr. Significant increase in T-cell fraction at late rejection and in ABMR was observed which was significant in late rejection cases >6 mo post-transplantation (p<0.001)(Fig1A). There was an increase in T-cell fraction in ABMR compared to non-ABMR samples (p=0.05)(Fig1B). There was an increased peripheral T-cell fraction among AR subjects compared to STA among AR samples collected at 6 mo post-transplantation (p=0.003)(Fig1C). TCFr also correlated with microcirculation inflammation. Conclusions: In conclusion, our study demonstrated that T-cell repertoire changes with post-transplant rejection episodes and suggested that the T-cell repertoire changes may provide pre-transplant and post-transplant predictors of rejection risk which in turn can support immunosuppression management decisions at and after transplantation.

MO994: Impact of Hla-A, B DR and DQ on renal transplant outcomes in the Tacrolimus/Mmf Era: An Artificial Intelligence Approach

Abstract BACKGROUND AND AIMS One of the biological barriers that can increase risk of acute rejection in kidney transplantation is HLA mismatch. Several immunotherapy protocols have been implemented to reduce the effect of HLA-mismatch and improve outcomes. The aim of our study is to assess the effect of HLA mismatches on acute rejection rates in the Tacrolimus era. METHOD All kidney transplant patients registered in UNOS database between 1 January 2005 and 1 December 2019 were retrospectively reviewed. Inclusion criteria: deceased donor transplants that were discharged on Tacrolimus/Mycophenolate Mofetil. Exclusion criteria: multiple organ transplants, previous kidney transplants, recipient age &amp;lt;18 years old, living donor transplants, patients not discharged on Tacrolimus/Mycophenolate Mofetil immunotherapy, missing HLA mismatch or ABO incompatible transplant. We used double-selection lasso (‘least absolute shrinkage and selection operator) logistic regression model to assess for the effect of HLA-A, B, DR and DQ on acute rejection rates at one-year post-transplant. We used square-root lassos for the variables of interest. Variables of interest were HLA-A, B, DR and DQ mismatch. Variables Lasso selected from were: recipient characteristics (age, sex, BMI, ethnicity, diabetes, recipient/donor CMV status, time on dialysis), donor characteristics (KDPI score) and transplant characteristics (type of induction therapy, steroid therapy at time of discharge, cold ischemia time, delayed graft function, PRA). For survival analysis, we fit a penalized Cox model to the entire set of data and obtained the estimated set of alphas. The variables included in the penalized cox model donor, recipient and transplant factors in addition to the HLA mismatches. Then we determined the set of alpha for evaluation using optimized cross-validated grid-search. Moreover, we visualized how the coefficients changed for varying α using ridge regression model. RESULTS About 73 910 were included in our study. Worse acute rejection rates at one-year post-transplant were noted with incremental increase in HLA-DQ (Two HLA-DQ: OR = 1.56, P = 0.005, 95%CI: 1.04–1.27; One HLA DQ: OR = 1.15, P = 0.01, 95%CI: 1.03–1.24), HLA-DR mismatches (two HLA-DR: HR = 1.46, P &amp;lt; 0.01, 95%CI: 1.31–1.62; One HLA-DR: OR = 1.29, P &amp;lt; 0.01, 95%CI: 1.16–1.43), and Two HLA-A (OR = 1.12, P = 0.049, 95%CI: 1.0006–1.26). However, the effect of different HLA-mismatches on death-censored graft survival were minimal (HLA-DQ coefficient: 0.003, HLA-DR coefficient: 0.05, HLA-A coefficient: 0.008 and HLA-B coefficient: 0.007). Mean follow-up time was 3.79 years. Figure 1 shows the visualisation of coefficients among different alphas for the ridge penalised cox regression model. CONCLUSION HLA-DQ, DR and A mismatches still play a vital role in the occurrence of acute rejection in the Tacrolimus/MMF era. However, the effect of HLA mismatches on the graft survival is minimal.

The role of the NGAL biomarker in the assessment of early and prediction of late graft function in kidney transplantation from a living related donor

The aim. To study the role of NGAL in assessing the recovery of early graft function (GF) and in predicting GF in the first year after kidney transplantation (KT) from a living-related donor (LRD). Materials and methods. For this aim, a total of 60 kidney recipients who underwent KT from LRDs were examined. To study the early GF, NGAL concentrations in urine samples were measured on days 1, 2, 3, 7 after KT. To study the late GF, the glomerular filtration rate (GFR) was calculated at 3, 6, 12 months after KT. To study the prognosis of GF during the first year after KT, the relationship between u-NGAL and GFR levels at 3, 6, 12 months after KT was analyzed. The incidence of acute kidney transplant rejection (AKTR), delay of graft function (DGF), primary non-function was recorded. Results. DGF was observed in 5 (8.33 %) recipients with statistically significantly increased mean NGAL levels (P &lt; 0.05) on days 1, 2, 3, 7 as compared to those in normal GF. AKTR was detected in 10 (16.67 %) recipients with statistically significantly increased mean NGAL levels (P &lt; 0.05) on days 1, 2, 3, 7 compared to those in normal GF. Primary allograft non-function was diagnosed in 8 (13.33 %) recipients with statistically significantly increased mean NGAL levels (P &lt; 0.05) on days 1, 2, 3, 7 compared to those in normal GF. Assessing the relationship between NGAL levels on days 1, 2, 3, 7 and GFR at 3, 6, 12 months after transplantation, it was found that GFR was higher in recipients with NGAL levels on days 1, 2, 3, 7 after transplantation within the reference values (&lt;131.7 ng/ml) than that in recipients with NGAL levels on days 1, 2, 3, 7 after transplantation above 131.7 ng/ml. Conclusions. Evaluation of NGAL after KT informs about the restoration of renal function (rapid decrease in NGAL) or the development of complications (DGF, primary allograft non-function, AKTR) with slow decrease or increase in NGAL levels. Thus, u-NGAL is an early, non-invasive and accurate predictor of the need for dialysis in the first week after KT and the restoration of GF within 12 months.

How Should Acute T-cell Mediated Rejection of Kidney Transplants Be Treated: Importance of Follow-up Biopsy.

Background.Limited published data exist to guide patient monitoring after the treatment of T-cell mediated rejection (TCMR) of kidney allografts.Methods.We reviewed the kidney function and histological outcomes after treatment of 163 first episodes of biopsy-proven TCMR between January 1‚ 2015‚ and July 31‚ 2020.Results.Of the 146 patients treated with steroid pulse alone, complete histological response was seen in 83% of patients with borderline rejection, 82.5% with grade 1A, 67% with grade 1B, and 50% with grade IIA. Of the 17 patients treated with steroids plus antithymocyte globulin, the complete histological response rate was 100% with grade 1A, 75% with grade 1B, 100% with grade IIA, and 57% with grade IIB. Among the patients with complete response as assessed by kidney function, 14% only had a partial or no response histologically. Among patients with no kidney function response, 68% had a complete response histologically.Conclusion.We thus find that responses based on kidney function alone do not correlate well with histological responses. If further treatment had been based solely on changes in estimated glomerular filtration rate, a significant number of patients would have been subsequently undertreated or overtreated. These results support the use of protocol follow-up biopsies after the treatment of TCMR.

A Novel Method of CD31-Combined ABO Carbohydrate Antigen Microarray Predicts Acute Antibody-Mediated Rejection in ABO-Incompatible Kidney Transplantation.

Isohemagglutinin assays employing red blood cells (RBCs) are the most common assays used to measure antibody titer in ABO-incompatible kidney transplantation (ABOi KTx). However, ABO antigens expressed on RBCs are not identical to those of kidney and antibody titers do not always correlate with clinical outcome. We previously reported that CD31 was the main protein linked to ABO antigens on kidney endothelial cells (KECs), which was different from those on RBCs. We developed a new method to measure antibody titer using a microarray of recombinant CD31 (rCD31) linked to ABO antigens (CD31-ABO microarray). Mass spectrometry analysis suggested that rCD31 and native CD31 purified from human kidney had similar ABO glycan. To confirm clinical use of CD31-ABO microarray, a total of 252 plasma samples including volunteers, hemodialysis patients, and transplant recipients were examined. In transplant recipients, any initial IgG or IgM antibody intensity >30,000 against the donor blood type in the CD31-ABO microarray showed higher sensitivity, specificity, positive predictive value, and negative predictive value of AABMR, compared to isohemagglutinin assays. Use of a CD31-ABO microarray to determine antibody titer specifically against ABO antigens expressed on KECs will contribute to precisely predicting AABMR or preventing over immunosuppression following ABOi KTx.

Clinical and Molecular Profiling to Develop a Potential Prediction Model for the Response to Alemtuzumab Therapy for Acute Kidney Transplant Rejection.

Alemtuzumab, a monoclonal antibody that depletes CD52‐bearing immune cells, is an effective drug for the treatment of severe or glucocorticoid‐resistant acute kidney transplant rejection (AR). Patient‐specific predictions on treatment response are, however, urgently needed, given the severe side effects of alemtuzumab. This study developed a multidimensional prediction model with the aim of generating clinically useful prognostic scores for the response to alemtuzumab. Clinical and histological characteristics were collected retrospectively from patients who were treated with alemtuzumab for AR. In addition, targeted gene expression profiling of AR biopsy tissues was performed. Least absolute shrinkage and selection operator (LASSO) logistic regression modeling was used to construct the ALEMtuzumab for Acute Rejection (ALEMAR) prognostic score. Response to alemtuzumab was defined as patient and allograft survival and at least once an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 during the first 6 months after treatment. One hundred fifteen patients were included, of which 84 (73%) had a response to alemtuzumab. The ALEMAR‐score accurately predicted the chance of response. Gene expression analysis identified 13 differentially expressed genes between responders and nonresponders. The combination of the ALEMAR‐score and selected genes resulted in improved predictions of treatment response. The present preliminary prediction model is potentially helpful for the development of stratified alemtuzumab treatment for acute kidney transplant rejection but requires validation.