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Background T cell-mediated rejection (TCMR) remains a challenge in kidney transplantation. Based on a histopathological biopsy examination, patients can be classified into groups such as no rejection (NR), borderline rejection (BR; Banff category 3), and acute rejection (AR; Banff category 4). Yet, this classification is not sufficient, since for the borderline cases a number of patients may require a clinical intervention. Thus, a robust classification by biopsy proteome profiling may provide a solution. Methods In this work, kidney tissue from patients classified into NR, BR, and AR were subjected to MS-based proteomic profiling. Subsequently, a panel of four proteins (GNB4, PDK1, AGXT, CD73) was selected for validation by immunohistochemistry (IHC). This retrospective study was approved by the Bioethics Committee of the Medical University of Gdańsk, no. NKBBN/201/2021. Results Proteomic analysis identified 2547 proteins whose abundance profiles demonstrated strong concordance between the BR and AR groups. In a quantitative comparison between the BR and AR groups, GNB4 and AGXT emerged as significantly differentiating. Moreover, AGXT was indicated as a potential biomarker following ROC analysis. PDK1 and CD73 were found to best classify the samples in a binary analysis. IHC confirmed only upregulation of GNB4 in immune cells and PDK1 in macrophages, with no significant changes in the tubular epithelium. Conclusions Thus, GNB4 and PDK1 in immune cells and macrophages have been identified as a potential target for further extensive studies. If their relevance were to be confirmed in a larger patient cohort, their IHC analysis could serve as an extension of established histopathological classification in the context of kidney transplant rejection.

Context.—Establishing adequate interobserver agreement is crucial not only for standardization of patient care but also to ensure validity of findings in multi-institutional trials. Objective.—To evaluate interobserver agreement in assessing chronic hepatitis C (HCV) and acute cellular rejection (ACR) among 17 hepatopathologists involved in the “Hepatitis C 3” trial. Design.—The trial is a randomized multicenter (17 institutions) study involving 312 patients undergoing transplantation for HCV. Patients are randomized to 3 treatment arms. For final data analysis, all biopsy specimens are reviewed by a central pathologist (G.J.N.). Recurrence of HCV is evaluated according to the Batts and Ludwig schema. The 1997 Banff schema is used to evaluate ACR. To assess interobserver agreement, hematoxylin-eosin–stained sections from 11 liver biopsy specimens (6 HCV and 5 ACR) were sent by the central pathologist to 16 local pathologists from 13 institutions. Statistical analysis was performed on raw ACR/HCV data as well as data grouped according to clinically significant primary endpoint cutoffs. Results.—Statistically significant agreement was found among all participating pathologists (P < .001). On κ analysis, the degree of agreement was rated “moderate” for HCV grade and stage and ACR global grading (κ = 0.30, 0.33, and 0.37, respectively). Interobserver agreement was weaker for rejection activity index scoring of ACR (κ = 0.15). A stronger degree of agreement was found when scores were grouped based on endpoint cutoffs (κ = 0.76 “almost perfect” for HCV and 0.62 “substantial” for ACR). Conclusions.—An overall statistically significant interobserver agreement was found among 17 pathologists using the 1997 Banff schema and the Batts and Ludwig schema.

In this study, DNA microarrays were used to examine gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. Subtypes of acute rejection, indistinguishable by light microscopy, could be distinguished by differences in immune activation and cellular proliferation. Dense CD20+ B-cell infiltrates were significantly associated with clinical glucocorticoid resistance and graft loss. DNA microarrays show subtypes of acute rejection. Acute rejection is a complex process of injury to the allograft caused by infiltrating cells of the host immune system. It leads to multiple responses within the graft and is a major risk factor for chronic rejection and loss of the graft. 1 – 3 Acute rejection typically develops soon after transplantation and is thought to be secondary to cell-mediated immune responses involving delayed mechanisms of hypersensitivity and cytotoxicity. Despite efforts at systematization, 4 , 5 clinical and pathological diagnosis and classification of acute rejection remain unreliable in predicting responses to therapy and graft outcomes. 6 – 10 Thus, there is a great need to improve . . .

Background: This study evaluated the impact of surgery in the incidence of lymphocele after kidney transplantation (KTx). Methods: A prospective randomized study was conducted during a 6-year period on a group of patients undergoing KTx and operated on by the same surgeon (CVS). A total of 280 patients undergoing KTx were randomly allocated into two groups: (1) group C (control group) was 140 patients who were submitted to KTx with standard technique: implantation of the kidney in the controlateral iliac fossa with vascular anastomoses on the external iliac vessels; and (2) group M (modified technique group) was 140 patients who underwent a modified technique with a cephalad implantation of the graft in the ipsilateral iliac fossa and vascular anastomoses in the common iliac vessels. Both groups were comparable for age, cold ischemia time, incidence of rejection episodes, presence of adult polycystic kidney disease, and source of donor graft. Results: Group M showed an incidence of lymphocele production (3 patients, 2.1%) significantly lower than group C (12 patients, 8.5%). Eight patients (1 in group M and 7 in group C) required surgical treatment by peritoneal fenestration. No allograft or recipient was lost as a result of fluid collection but the hospitalization was shorter in group M than in group C. Conclusions: A cephalad implantation of the renal graft in the ipsilateral iliac fossa has been associated with a lower incidence of lymphocele, probably because vascular anastomoses on the common iliac vessels cause less lymphatic derangement than those performed on the external iliac vessels.

Background Biomarker panels derived separately from genomic and proteomic data and with a variety of computational methods have demonstrated promising classification performance in various diseases. An open question is how to create effective proteo-genomic panels. The framework of ensemble classifiers has been applied successfully in various analytical domains to combine classifiers so that the performance of the ensemble exceeds the performance of individual classifiers. Using blood-based diagnosis of acute renal allograft rejection as a case study, we address the following question in this paper: Can acute rejection classification performance be improved by combining individual genomic and proteomic classifiers in an ensemble? Results The first part of the paper presents a computational biomarker development pipeline for genomic and proteomic data. The pipeline begins with data acquisition (e.g., from bio-samples to microarray data), quality control, statistical analysis and mining of the data, and finally various forms of validation. The pipeline ensures that the various classifiers to be combined later in an ensemble are diverse and adequate for clinical use. Five mRNA genomic and five proteomic classifiers were developed independently using single time-point blood samples from 11 acute-rejection and 22 non-rejection renal transplant patients. The second part of the paper examines five ensembles ranging in size from two to 10 individual classifiers. Performance of ensembles is characterized by area under the curve (AUC), sensitivity, and specificity, as derived from the probability of acute rejection for individual classifiers in the ensemble in combination with one of two aggregation methods: (1) Average Probability or (2) Vote Threshold. One ensemble demonstrated superior performance and was able to improve sensitivity and AUC beyond the best values observed for any of the individual classifiers in the ensemble, while staying within the range of observed specificity. The Vote Threshold aggregation method achieved improved sensitivity for all 5 ensembles, but typically at the cost of decreased specificity. Conclusion Proteo-genomic biomarker ensemble classifiers show promise in the diagnosis of acute renal allograft rejection and can improve classification performance beyond that of individual genomic or proteomic classifiers alone. Validation of our results in an international multicenter study is currently underway.

Since the acceptance of the detection of C4d in allografts as a reliable tool to mark a humoral alloresponse, de novo antibody-induced graft injury has attracted much attention. Antibodies and B cells are the new frontier in transplantation. At this juncture carefully designed studies are critical in order to gain solid diagnostic, therapeutic, and prognostic knowledge about the role of antibodies in graft injury and to avoid any confusion and misconception. One prerequisite is the strict adherence to refined classification systems of renal transplant rejection that carefully split and categorize different phenotypes of humoral mediated graft damage and ideally also include information on anti-donor antibody specificity and titers. Sun and colleagues follow this concept and provide evidence that mixed cellular and antibody-mediated graft rejection can respond favorably to intensified immunosuppression with tacrolimus and mycophenolate mofetil. What will the future bring to treat rejection episodes with a dominant, co-dominant, or minor antibody reponse?

In Japan, ABO-incompatible kidney transplantation has been performed in more than 1000 patients since 1989, and recently accounts for about 18% of all living donor kidney transplants. As for outcomes, since 2001 the 1-year and 3-year graft survival rates have increased to 96% and 94%, respectively, which are similar to those in ABO-compatible transplantation. These improved outcomes are attributed to a clearer understanding of the mechanisms underlying accommodation and acute antibody-mediated rejection, permitting the development of new therapeutic strategies. This review classifies and discusses the clinical significance of acute antibody-mediated rejection due to ABO-blood-group-related antigens during the critical period preceding the establishment of accommodation.

Kidney transplantation has become increasingly common in major health centres, making renal allograft evaluation through biopsy a common procedure. Early allograft dysfunction occurs in 30–50% of all transplants, while chronic graft failure is almost uniform at a rate of 2–4% a year. Allograft biopsy remains the gold standard for the diagnosis of graft dysfunction. Rejection, albeit the most important, is only one of many causes of allograft dysfunction. The widely accepted Banff classification has set criteria for the diagnosis of acute and chronic rejection. The major differential diagnoses are acute ischaemic injury, calcineurin inhibitor toxicity (acute and chronic), infections, including pyelonephritis and polyomavirus nephropathy, chronic obstruction/reflux, hypertension, and recurrent and de novo disease. In this review, there is an outline of the Banff criteria and their implications, the various causes of graft dysfunction, and a discussion on morphological guidelines towards the various diagnoses.

Acute renal allograft rejection with intimal arteritis: Histologic predictors of response to therapy and graft survival. Acute renal allograft rejection with intimal arteritis is designated by the widely used Banff 97 classification as type 2A or 2B depending on the extent of arteritis, without regard to interstitial inflammation or tubulitis. We examined whether the distinction between type 2A and 2B is relevant to short- and long-term clinical outcomes, and if outcomes in this subset of acute rejection also are affected by tubulitis, interstitial inflammation, and several additional histologic and clinical parameters. Pathology records were searched to identify cases of acute renal allograft rejection with intimal arteritis diagnosed between January 1985 and September 2000. For each case, the patient's chart was reviewed to determine the response of the rejection episode to therapy, type(s) of therapy given, and length of graft survival. All biopsies were reviewed and Banff acute and chronic indices recorded by a pathologist blinded to these data. Biopsies not showing type 2A or 2B rejection were excluded, as were repeat biopsies from the same patient and cases with recurrent glomerular disease, viral infection, donor-specific antibodies, or more than mild chronic change. The initial response to anti-rejection therapy was significantly worse in patients with type 2B acute rejection (N = 29) than in those with type 2A (N = 102) by univariate and multivariate analyses, despite more aggressive treatment of type 2B rejection. In a Cox proportional hazards model the hazard ratio for graft failure for 2B versus 2A was 1.9 (P = 0.05), but this was not significant when adjusted for the initial response to therapy. Cases with minimal or mild tubulitis responded better to therapy than those with moderate or severe tubulitis, although graft survival was not significantly affected by the tubulitis score. The distinction between types 2A and 2B acute rejection in the Banff 97 classification has significant prognostic value with regard to both short- and long-term clinical outcomes, although the difference in long-term graft survival is mainly related to the initial response to therapy. Reports of biopsies showing type 2A or 2B rejection also should specify the degree of tubulitis present, as the latter may significantly influence the initial response to therapy.

A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross-reacted with unknown pathogens on the skin and contributed to inflammation.