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Kidney transplantation is a highly effective treatment for end‐stage kidney disease. However, allograft rejection remains a significant clinical challenge in kidney transplant patients. Although kidney allograft biopsy is the gold‐standard diagnostic method, it is an invasive procedure. Since the current monitoring methods, including screening of serum creatinine and urinary protein, are not of sufficient sensitivity, there is a need for effective post‐transplant monitoring to detect allograft rejection at an early stage. Extracellular vesicles are vesicles with a lipid bilayer that originate from different cell types in pathological and physiological conditions. The content of extracellular vesicles reflects the status of cells at the time of their production. This review comprehensively summarizes clinical, in vivo, and in vitro reports that highlight the potential of extracellular vesicles as diagnostic biomarkers for kidney allograft rejection. Clarification would facilitate differentiation between rejection and non‐rejection and identification of the mechanisms involved in the allograft rejection. Despite increasing evidence, further research is necessary to establish the clinical utility of extracellular vesicles in the diagnosis and monitoring of allograft rejection in kidney transplant recipients. Using extracellular vesicles as non‐invasive biomarkers for diagnosis of kidney allograft rejection could have tremendous benefits in improving patient outcomes and reduce the need for invasive procedures. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 4 (IRF4) is expressed in immune cells and is a member of the interferon regulatory factor family. Recently, it has been found that IRF4 plays important roles in the acute kidney injury (AKI)-chronic kidney disease (CKD) transition, glomerular diseases and kidney allograft rejection. In particular, the relationship between IRF4 and the AKI-CKD transition has attracted widespread attention. Furthermore, it was also found that the deficiency of IRF4 hindered the transition from AKI to CKD through the suppression of macrophage-to-fibroblast conversion, inhibition of M1-m2 macrophage polarization, and reduction in neutrophil inward flow. Additionally, an examination of the crucial role of IRF4 in glomerular disease was conducted. It was reported that inhibiting IRF4 could alleviate the progression of glomerular disease, and potential physiopathology mechanisms associated with IRF4 were postulated. Lastly, IRF4 was found to have detrimental effects on the development of antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TC MR). [ABSTRACT FROM AUTHOR]

No consensus has been reached regarding the association beween the -308A/G single nucleotide polymorphism (SNP) in the tumor necrosis factor-α gene (TNFA) and kidney allograft rejection (KAR). Our retrospective casecontrol study aimed to assess the association of the SNP with KAR in Algerian patients who underwent kidney transplantation. The study enrolled 313 Algerian patients: 58 kidney-transplant recipients without rejection events (PWoR); 58 kidney-transplant recipients with at least one rejection event, with or without graft loss (PWR); and 197 healthy individuals (HI). The TNFA -308A/G SNP was genotyped using a real-time polymerase chain reaction. The results demonstrated that, the frequencies of TNFA -308A allele and AA genotype were higher in the PWR than in the III groups (p=0.001, OR=2.26, C.I=1.33-3.77 and p = 0.0004. OR=5.53, CI-1.89-16.6, respectively). Furthermore, the frequencies were higher among the PWR than among the PWoR groups (p=0.001, OR=3.29, Cl 1.56-7.21 and p = 0.0006, OR = 28.26, CI=1.62-493.2, respectively), particularly among PWR patients with de novo anti-human leukocyte antigens (HLA) antibodies (PG-a-HLA-Ab). However, the frequency of TNFA -308G allele was lower in the PWR group than in the PWoR group (p=0.001, OR = 0.3, CI = 0.1-0.64) and the HI group (p = 0.001, OR=0.44, CI=0.27-0.44). Our results suggest an association of the TNFA -308A/G alleles with KAR in Algerian patients who underwent kidney transplantation. Carriers of TNFA -308A allele who have PG-a-HLA-Ab might have a higher risk, whereas TNFA -308G allele carriers could have a lower risk of KAR. Titus, therapeutic strategies can be adapted to minimize KAR risk in patients who have a genetic proclivity for increased pro-inflammatory TNF-u activity. [ABSTRACT FROM AUTHOR]

BACKGROUND:The management of malignancy post kidney transplantation includes reduction in immunosuppression and referral to an oncologist management of their malignancy. Recent advances in oncology have resulted in the approval of several classes of drugs with immune-modulatory activity. However, activation of the immune system against malignant cells may precipitate allograft rejection in solid organ transplant recipients. CASE PRESENTATION:Herein we present a case of acute kidney allograft rejection in a 50 year old man following administration of the novel immune-modulatory agent nivolumab for the treatment of metastatic squamous cell carcinoma. CONCLUSION:The management of malignancy in solid organ transplant recipients requires a heightened awareness of the potential for allograft rejection in this new era of cancer therapeutics.

Extracellular vesicle‐bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer‐unrelated research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well‐characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. The SEC‐based method enriched pure EVs from urine of kidney transplant recipients, regardless of the allograft injury. Urinary evDNA represented up to 29.2 ± 8% (mean ± SD) of cell‐free DNA (cfDNA) and correlated with cfDNA in several characteristics but was less fragmented (P < 0.001). Importantly, using DNase treatment and immunogold labelling TEM, we demonstrated that evDNA was bound to the surface of urinary EVs. Normalised evDNA yield (P = 0.042) and evDNA copy number (P = 0.027) significantly differed between patients with normal histology, rejection injury and non‐rejection injury, the later groups having significantly larger uEVs (mean diameter, P = 0.045) and more DNA bound per uEV. ddDNA is detectable in uEV samples of kidney allograft recipients, but its quantity is highly variable. In a proof‐of‐principle study, several evDNA characteristics correlated with clinical and histological parameters (P = 0.040), supporting that the potential of evDNA as a biomarker for kidney allograft injury should be further investigated. [ABSTRACT FROM AUTHOR]

Abstract Extracellular vesicle‐bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer‐unrelated research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well‐characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. The SEC‐based method enriched pure EVs from urine of kidney transplant recipients, regardless of the allograft injury. Urinary evDNA represented up to 29.2 ± 8% (mean ± SD) of cell‐free DNA (cfDNA) and correlated with cfDNA in several characteristics but was less fragmented (P

African American (AA) kidney recipients have a higher risk of allograft rejection and failure compared to non-AAs, but to what extent these outcomes are due to genetic versus environmental effects is currently unknown. Herein, we tested the effects of recipient self-reported race versus genetic proportion of African ancestry (pAFR), and neighborhood socioeconomic status (SES) on kidney allograft outcomes in multiethnic kidney transplant recipients from Columbia University (N = 1083) and the University of Pennsylvania (N = 738). All participants were genotyped with SNP arrays to estimate genetic admixture proportions. US census tract variables were used to analyze the effect of neighborhood factors. In both cohorts, self-reported recipient AA race and pAFR were individually associated with increased risk of rejection and failure after adjustment for known clinical risk factors and neighborhood SES factors. Joint analysis confirmed that self-reported recipient AA race and pAFR were both associated with a higher risk of allograft rejection (AA: HR 1.61 (1.31-1.96), P = 4.05E-06; pAFR: HR 1.90 (1.46-2.48), P = 2.40E-06) and allograft failure (AA: HR 1.52 (1.18-1.97), P = .001; pAFR: HR 1.70 (1.22-2.35), P = .002). Further research is needed to disentangle the role of genetics versus environmental, social, and structural factors contributing to poor transplantation outcomes in kidney recipients of African ancestry., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Francesca Zanoni was supported by a research fellowship from UnitedHealthcare. Sumit Mohan reports personal fees outside of this work from HSAG, Kidney International Reports, and Sanofi and grant support from the Kidney Transplant Collaborative. Krzysztof Kiryluk reports consulting fees outside of this work from Kidney International, HiBio, and Travere Therapeutics, and research funding from Vanda, Visterra, and AstraZeneca. Y. Dana Neugut, Joy E. Obayemi, Lili Liu, Jun Y. Zhang, Lloyd E. Ratner, David J. Cohen, Ali G. Gharavi, and Brendan Keating report no conflicts of interest., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Abstract Background The management of malignancy post kidney transplantation includes reduction in immunosuppression and referral to an oncologist management of their malignancy. Recent advances in oncology have resulted in the approval of several classes of drugs with immune-modulatory activity. However, activation of the immune system against malignant cells may precipitate allograft rejection in solid organ transplant recipients. Case presentation Herein we present a case of acute kidney allograft rejection in a 50 year old man following administration of the novel immune-modulatory agent nivolumab for the treatment of metastatic squamous cell carcinoma. Conclusion The management of malignancy in solid organ transplant recipients requires a heightened awareness of the potential for allograft rejection in this new era of cancer therapeutics.

Background: Human natural killer (NK) cells are key functional players in kidney transplant rejection. However, the respective contributions of the two functionally distinct human NK cell subsets (CD56bright cytokine-producing vs. CD56dim cytotoxic effector) in episodes of allograft rejection remain uncertain, with current immunohistochemical methods unable to differentiate these discrete populations. We report the outcomes of an innovative multi-color flow cytometric-based approach to unequivocally define and evaluate NK cell subsets in human kidney allograft rejection.Methods: We extracted renal lymphocytes from human kidney transplant biopsies. NK cell subsets were identified, enumerated, and phenotyped by multi-color flow cytometry. Dissociation supernatants were harvested and levels of soluble proteins were determined using a multiplex bead-based assay. Results were correlated with the histopathological patterns in biopsies—no rejection, borderline cellular rejection, T cell-mediated rejection (TCMR), and antibody-mediated rejection (AMR).Results: Absolute numbers of only CD56bright NK cells were significantly elevated in TCMR biopsies. In contrast, both CD56bright and CD56dim NK cell numbers were significantly increased in biopsies with histopathological evidence of AMR. Notably, expression of the activation marker CD69 was only significantly elevated on CD56dim NK cells in AMR biopsies compared with no rejection biopsies, indicative of a pathogenic phenotype for this cytotoxic NK cell subset. In line with this, we detected significantly elevated levels of cytotoxic effector molecules (perforin, granzyme A, and granulysin) in the dissociation supernatants of biopsies with a histopathological pattern of AMR.Conclusions: Our results indicate that human NK cell subsets are differentially recruited and activated during distinct types of rejection, suggestive of specialized functional roles.

Background: Human natural killer (NK) cells are key functional players in kidney transplant rejection. However, the respective contributions of the two functionally distinct human NK cell subsets (CD56bright cytokine-producing vs. CD56dim cytotoxic effector) in episodes of allograft rejection remain uncertain, with current immunohistochemical methods unable to differentiate these discrete populations. We report the outcomes of an innovative multi-color flow cytometric-based approach to unequivocally define and evaluate NK cell subsets in human kidney allograft rejection. Methods: We extracted renal lymphocytes from human kidney transplant biopsies. NK cell subsets were identified, enumerated, and phenotyped by multi-color flow cytometry. Dissociation supernatants were harvested and levels of soluble proteins were determined using a multiplex bead-based assay. Results were correlated with the histopathological patterns in biopsies—no rejection, borderline cellular rejection, T cell-mediated rejection (TCMR), and antibody-mediated rejection (AMR). Results: Absolute numbers of only CD56bright NK cells were significantly elevated in TCMR biopsies. In contrast, both CD56bright and CD56dim NK cell numbers were significantly increased in biopsies with histopathological evidence of AMR. Notably, expression of the activation marker CD69 was only significantly elevated on CD56dim NK cells in AMR biopsies compared with no rejection biopsies, indicative of a pathogenic phenotype for this cytotoxic NK cell subset. In line with this, we detected significantly elevated levels of cytotoxic effector molecules (perforin, granzyme A, and granulysin) in the dissociation supernatants of biopsies with a histopathological pattern of AMR. Conclusions: Our results indicate that human NK cell subsets are differentially recruited and activated during distinct types of rejection, suggestive of specialized functional roles. [ABSTRACT FROM AUTHOR]

Circulating cell-free DNA (cf-DNA) is released from dead and/or apoptotic leukocytes and due to neutrophil extracellular traps contributing to an inflammatory response. Previous clinical studies have reported that the peak concentrations and dynamic changes of cf-DNA may be used as a noninvasive biomarker of worsening kidney function as well as a guide to the management of kidney allograft rejection. We hypothesized that the pattern and dynamic changes of cf-DNA might be a plausible predictive biomarker for patients at risk of chronic kidney disease (CKD), including individuals with type 2 diabetes mellitus, heart failure, cardiovascular disease and established CKD. Along with it, pre- and posthemodialysis levels of serum cf-DNA appear to be a independent predictor for all-cause mortality in patients with end-stage kidney disease.

Purpose: To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients.Procedures: The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10-26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05.Results: At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20-24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25-97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44).Conclusion: After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 4 (IRF4) is expressed in immune cells and is a member of the interferon regulatory factor family. Recently, it has been found that IRF4 plays important roles in the acute kidney injury (AKI)-chronic kidney disease (CKD) transition, glomerular diseases and kidney allograft rejection. In particular, the relationship between IRF4 and the AKI-CKD transition has attracted widespread attention. Furthermore, it was also found that the deficiency of IRF4 hindered the transition from AKI to CKD through the suppression of macrophage-to-fibroblast conversion, inhibition of M1-M2 macrophage polarization, and reduction in neutrophil inward flow. Additionally, an examination of the crucial role of IRF4 in glomerular disease was conducted. It was reported that inhibiting IRF4 could alleviate the progression of glomerular disease, and potential physiopathology mechanisms associated with IRF4 were postulated. Lastly, IRF4 was found to have detrimental effects on the development of antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR).

We used new micro-ELISA test with sequence-specific antibody for every day monitoring of serum amyloid A protein (SAA) in 20 patients with kidney allografts in order to facilitate an early diagnosis of rejection. Altogether 44 SAA peaks were observed (beside those caused by surgery) and 22 of them were caused by allograft rejections. When allograft rejection occurred in postsurgical period (first 4 days), SAA levels rose to mean 706 ± 161 mg/l while initial SAA peaks (caused by surgical trauma) reached the mean value 306 ± 55 mg/l. The statistical significance was very high, <0.0001. In all nine rejection episodes in this period SAA peaks were higher than 400 mg/l, so we chose this level as a reference limit for this period. SAA peaks caused by allograft rejection in later period were also markedly higher (mean 461 ± 176 mg/l) than those caused by infections or other complications (mean l33±82mg/l, <0.0001). Baseline mean level was 9±5 mg/l. In all 13 rejection episodes in this period SAA peaks were higher than 200 mg/l, so we chose this level as a reference limit for this period. In 20 of 22 rejection episodes (91%) SAA elevation predicted rejection and usually started to rise sharply 2 days before it. An excellent correlation between kidney allograft rejection and SAA reaction was found in this study (better than with CRP reaction) so we recommend everyday monitoring of SAA concentrations in patients with kidney allograft as a valuable aid in the early diagnosis and prediction of acute allograft rejection. [ABSTRACT FROM PUBLISHER]

We set up a laser nephelometric assay for the quantitation of serum amyloid A (SAA) in human plasma. Therefore monospecific antibodies were raised in sheep and used in parallel to measure SAA concentrations by nephelometry and also by radial immunodiffusion, an assay usually applied for determination of SAA. The nephelometric method is precise, simple and unlike radial immunodiffusion results are obtained within an hour. The antigen concentrations determined both by laser nephelometry and radial immunodiffusion correlated highly (r=0.98). As plasma SAA concentrations were reported to be a possible marker of kidney allograft rejection, the assay was applied to measure SAA concentrations in patients after kidney transplantation. Data were compared with clinical and other biochemical parameters. The period after kidney transplantation is reported for two cases, where SAA plasma concentrations were helpful in diagnosing allograft rejection. The rapid availability of the SAA plasma concentrations by nephelometry makes them a possible additional tool to decide quickly upon antirejection therapy. [ABSTRACT FROM AUTHOR]

Introduction: Biopsy of the allograft is the gold standard for assessing kidney allograft dysfunction. The aim of our pilot study was to identify serum biomarkers that could obviate the need for biopsy., Materials and Methods: We conducted a study to identify the biomarkers in the serum from different groups of chronic kidney disease (CKD) patients and kidney transplanted patients vs. healthy individuals. The four groups (n=25 in each group) were as follows: 1) Patients with unstable kidney allograft transplants requiring biopsy for cause, 2) Patients with stable kidney allograft transplants, 3) Patients with CKD not on immunosuppressive therapy and, 4) healthy subjects. We measured the activity and level of serum alkaline phosphatase (ALP) and other liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) as potential serum biomarkers in acute allograft dysfunction., Results: We found that ALP correlated with allograft biopsy findings, liver function, and clinical outcomes and possibly graft survival. Additionally, AST and ALT were higher in patients with graft rejection compared to non-rejected and stable kidney transplants. Moreover, the low Pearson correlations (r- values) between ALP level with age (r=0.179), gender, body mass index (r=0.236), creatinine (r=0.044) or estimated glomerular filtration rate (r=0.048) suggest that ALP may be an independent biomarker which is relatively unaffected by other individual-level variables., Conclusion: ALP may be a putative biomarker to predict kidney allograft function and rejection. Data also indicated that liver function plays an important role for the overall success of kidney transplantation.

Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)