Renal Allograft Pathology Research Articles

Microvascular Inflammation of Kidney Allografts and Clinical Outcomes.

The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression. A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation. Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.).

Evaluation of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Renal Allograft Biopsies:- Comparison of Visual Analysis with Morphometric Quantification and its Correlation with Renal Function

ABSTRACT Introduction: With the increase in number of allografts being performed, the frequency of chronic allograft nephropathy (CAN) has also increased. It is characterized clinically by a progressive decline in glomerular filtration rate, and histologically, by a progressive interstitial fibrosis (IF) and tubular atrophy (TA) which can even be seen in recipients with good allograft function. Objectives: To compare visual analysis with morphometric quantification of interstitial fibrosis and tubular atrophy (IFTA) in renal allograft biopsies and its correlation with renal function. Materials and Methods: A total of 29 renal allograft biopsies were evaluated for fibrosis and tubular atrophy by light microscopy by visual method on Masson’s trichrome-stained and PAS-stained sections, respectively, as well as by computer-assisted morphometry. IFTA was graded as per Banff working classification of renal allograft pathology, which includes a four-point estimate of the prevalence of IF (ci score) and for tubular atrophy (ct score). The estimation of IF and TA by the two methods was correlated with the renal function state; the serum creatinine level. Result: The percentage of IFTA showed statistically significant correlation between manual and morphometric methods (P < 0.001). Each of the method was correlated with serum creatinine level. IF showed a good correlation with serum creatinine by both the methods; however, no correlation could be established between TA and serum creatinine by either method. Conclusion: When calculating scoring IFTA as per Banff criteria, by either the visual method or the morphometric method, there was a significant correlation between the two methods. However when expressed only as a percentage of total area, the visual method was associated with slight overestimation of both the parameters.

Unsatisfactory reproducibility of interstitial inflammation scoring in allograft kidney biopsy

Interstitial inflammation scoring is incorporated into the Banff Classification of Renal Allograft Pathology and is essential for the diagnosis of T-cell mediated rejection. However, its reproducibility, including inter-rater and intra-rater reliabilities, has not been carefully investigated. In this study, eight renal pathologists from different hospitals independently scored 45 kidney allograft biopsies with varying extents of interstitial inflammation. Inter-rater reliabilities and intra-rater reliabilities were investigated by kappa statistics and conditional agreement probabilities. Individual pathologists’ scoring patterns were examined by chi-squared tests and proportions tests. The mean pairwise kappa values for inter-rater reliability were 0.27, 0.30, and 0.26 for the Banff i score, ti score, and i-IFTA, respectively. No rater pair performed consistently better or worse than others on all three scorings. After dichotomizing the scores into two groups (none/mild and moderate/severe inflammation), the averaged conditional agreements ranged from 47.1% to 50.0%. The distributions of the scores differed, but some pathologists persistently scored higher or lower than others. Given the important role of interstitial inflammation scoring in the diagnosis of T-cell mediated rejection, transplant practitioners should be aware of the possible clinical implications of the far-from-optimal reproducibility.

Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection.

To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

Controlled Donation After Circulatory Death Using Normothermic Regional Perfusion Does Not Increase Graft Fibrosis in the First Year Posttransplant Surveillance Biopsy.

The number of kidney transplants obtained from controlled donations after circulatory death is increasing, with long-term outcomes similar to those obtained with donations after brain death. Extraction using normothermic regional perfusion can improve results with controlled donors after circulatory death; however, information on the histological impact and extraction procedure is scarce. We retrospectively investigated all kidney transplants performed from October 2014 to December 2019, in which a follow-up kidney biopsy had been performed at 1-year follow-up, comparing controlled procedures with donors after circulatory death and normothermic regional perfusion versus donors after brain death. Interstitial fibrosis/tubular atrophy was assessed by adding the values of interstitial fibrosis and tubular atrophy, according to the Banff classification of renal allograft pathology. When we compared histological data from 66 transplants with donations after brain death versus 24 transplants with donations after circulatory death and normothermic regional perfusion, no differences were found in the degree of fibrosis in the 1-year follow-up biopsy (1.7 ± 1.3 vs 1.7 ± 1.1; P = .971) or in the ratio of patients with increased fibrosis calculated as interstitial fibrosis/tubular atrophy >2 (18% vs 13%; P = .522). In our multivariate analysis, which included acute rejection, expanded criteria donation, and the type of donation, no variable was independently related to an increased risk of interstitial fibrosis/tubular atrophy >2. The outcomes of kidney grafts procured in our center using controlled procedures with donors after circulatory death and normothermic regional perfusion were indistinguishable from those obtained from donors after brain death, showing the same degree of fibrosis in the 1-year posttransplant surveillance biopsy. Our data support the conclusion that normothermic regional perfusion should be the method of choice for extraction in donors after circulatory death.

Evaluating tubulointerstitial compartments in renal biopsy specimens using a deep learning-based approach for classifying normal and abnormal tubules.

Renal pathology is essential for diagnosing and assessing the severity and prognosis of kidney diseases. Deep learning-based approaches have developed rapidly and have been applied in renal pathology. However, methods for the automated classification of normal and abnormal renal tubules remain scarce. Using a deep learning-based method, we aimed to classify normal and abnormal renal tubules, thereby assisting renal pathologists in the evaluation of renal biopsy specimens. Consequently, we developed a U-Net-based segmentation model using randomly selected regions obtained from 21 renal biopsy specimens. Further, we verified its performance in multiclass segmentation by calculating the Dice coefficients (DCs). We used 15 cases of tubulointerstitial nephritis to assess its applicability in aiding routine diagnoses conducted by renal pathologists and calculated the agreement ratio between diagnoses conducted by two renal pathologists and the time taken for evaluation. We also determined whether such diagnoses were improved when the output of segmentation was considered. The glomeruli and interstitium had the highest DCs, whereas the normal and abnormal renal tubules had intermediate DCs. Following the detailed evaluation of the tubulointerstitial compartments, the proximal, distal, atrophied, and degenerated tubules had intermediate DCs, whereas the arteries and inflamed tubules had low DCs. The annotation and output areas involving normal and abnormal tubules were strongly correlated in each class. The pathological concordance for the glomerular count, t, ct, and ci scores of the Banff classification of renal allograft pathology remained high with or without the segmented images. However, in terms of time consumption, the quantitative assessment of tubulitis, tubular atrophy, degenerated tubules, and the interstitium was improved significantly when renal pathologists considered the segmentation output. Deep learning algorithms can assist renal pathologists in the classification of normal and abnormal tubules in renal biopsy specimens, thereby facilitating the enhancement of renal pathology and ensuring appropriate clinical decisions.

Histopathologic findings on indication renal allograft biopsies after recovery from acute COVID-19.

Current knowledge on histopathological changes occurring after COVID‐19 in transplanted kidneys is limited. Herein, we present renal allograft pathology findings in patients recovered from COVID‐19.Six patients underwent indication biopsy, and one required allograft nephrectomy after acute COVID‐19. Demographic data, clinical characteristics, and laboratory findings were recorded. The histopathological analysis included light microscopy, immunostaining, and electron microscopy.Five patients were hospitalized for acute COVID‐19, and all were diagnosed with imaging‐confirmed pneumonia, one requiring mechanical ventilation, and two requiring dialysis. Two patients had mild form. Histopathologic examination of renal allograft specimens revealed collapsing, perihilar, tip‐lesion and secondary FSGS in one patient each. One patient had borderline acute cellular rejection, and two had chronic antibody‐mediated rejection. Histopathologic changes of glomerular tufts were accompanied by acute tubular injury in four patients. None of our patients had signs of viral inclusions in kidney cells.One patient died and one remained dialysis‐dependent after the good initial response to treatment. Patients with collapsing and perihilar FSGS had further progression of their chronic allograft nephropathy still without need for dialysis.In conclusion, diverse kidney pathology may be found in SARS‐CoV‐2–infected renal transplant patients. It seems that viral infection may affect the immune system with triggering of glomerular diseases, while the acute tubular injury is of multifactorial etiology. Direct viral effect is less likely.

Diffusion-Weighted Imaging and Mapping of T1 and T2 Relaxation Time for Evaluation of Chronic Renal Allograft Rejection in a Translational Mouse Model.

We hypothesized that multiparametric MRI is able to non-invasively assess, characterize and monitor renal allograft pathology in a translational mouse model of chronic allograft rejection. Chronic rejection was induced by allogenic kidney transplantation (ktx) of BALB/c-kidneys into C57BL/6-mice (n = 23). Animals after isogenic ktx (n = 18) and non-transplanted healthy animals (n = 22) served as controls. MRI sequences (7T) were acquired 3 and 6 weeks after ktx and quantitative T1, T2 and apparent diffusion coefficient (ADC) maps were calculated. In addition, in a subset of animals, histological changes after ktx were evaluated. Chronic rejection was associated with a significant prolongation of T1 time compared to isogenic ktx 3 (1965 ± 53 vs. 1457 ± 52 ms, p < 0.001) and 6 weeks after surgery (1899 ± 79 vs. 1393 ± 51 ms, p < 0.001). While mean T2 times and ADC were not significantly different between allogenic and isogenic kidney grafts, histogram-based analysis of ADC revealed significantly increased tissue heterogeneity in allografts at both time points (standard derivation/entropy/interquartile range, p < 0.05). Correspondingly, histological analysis showed severe inflammation, graft fibrosis and tissue heterogeneity in allogenic but not in isogenic kidney grafts. In conclusion, renal diffusion weighted imaging and mapping of T2 and T1 relaxation times enable detection of chronic renal allograft rejection in mice. The combined quantitative assessment of mean values and histograms provides non-invasive information of chronic changes in renal grafts and allows longitudinal monitoring.

Comparative Long-Term Renal Allograft Outcomes of Recurrent Immunoglobulin A with Severe Activity in Kidney Transplant Recipients with and without Rituximab: An Observational Cohort Study.

Recurrent IgA nephropathy (IgAN) remains an important cause of allograft loss in renal transplantation. Due to the limited efficacy of corticosteroid in the treatment of recurrent glomerulonephritis, rituximab was used in kidney transplant (KT) recipients with severe recurrent IgAN. A retrospective cohort study was conducted between January 2015 and December 2020. Accordingly, there were 64 KT recipients with biopsy-proven recurrent IgAN with similar baseline characteristics that were treated with the conventional standard therapy alone (controls, n = 43) or together with rituximab (cases, n = 21). All of the recipients had glomerular endocapillary hypercellularity and proteinuria (>1 g/d) with creatinine clearance (CrCl) > 30 mL/min/1.73 m2 and well-controlled blood pressure using renin–angiotensin–aldosterone blockers. The treatment outcomes were renal allograft survival rate, proteinuria, and post-treatment allograft pathology. During 3.8 years of follow-up, the rituximab-based regimen rapidly decreased proteinuria within 12 months after rituximab administration and maintained renal allograft function—the primary endpoint—for approximately 3 years. There were eight recipients in the case group (38%), and none in the control group reached a complete remission (proteinuria < 250 mg/d) at 12 months after treatment. Notably, renal allograft histopathology from patients with rituximab-based regimen showed the less severe endocapillary hypercellularity despite the remaining strong IgA deposition. In conclusion, adjunctive treatment with rituximab potentially demonstrated favorable outcomes for treatment of recurrent severe IgAN post-KT as demonstrated by proteinuria reduction and renal allograft function in our cohort. Further in-depth mechanistic studies with the longer follow-up periods are recommended.

MO065DIAGNOSTIC CRITERIA OF HUMORAL REJECTION IN RENAL TRANSPLANT RECIPIENTS WITH PRE-EXISTING ANTI-HLA ANTIBODIES BASED ON SENTINEL SKIN FLAP BIOPSY

Abstract Background and Aims Twenty years of transplantation of composite vascularised allografts have revealed the high immunogenicity of the constituent parts, especially the skin.Several researchers have proposed the use of vascular stalk flaps, which allow to performe skin biopsy and diagnose rejection without biopsy of the transplanted solid organ.Pre-existing anti-HLA antibodies represent a serious immunological barrier to successful kidney transplantation.We are not aware of any studies on the diagnosis of antibody-associated acute kidney allograft rejection from deceased donors in recipients with pre-existing antibodies, based on morphological examination of a sentinel skin flap on a vascular stalk. The Aim: To determine the morphological features of humoral rejection in renal transplant recipients with pre-existing anti-HLA antibodies based on sentinel skin flap biopsy. Method Three skin-kidney allografts recipients underwent skin flap biopsy on 2nd day after transplantation. A kidney allograft biopsy was performed on day 7, 30, 60, 90.The results of morphological studies are presented using the Banff classification of renal allograft and skin allograft pathology. All recipients were female; 35, 44, and 57 years old. Two patients were re-transplanted and the main cause of CKD was chronic glomerulonephritis. The third patient, with congenital abnormality of the urinary tract, received her first graft.Pre-existing anti-HLA antibody levels before transplantation were 50%, 60%, 80%, respectively. Results All recipients showed signs of humoral rejection of the skin flap with thrombosis of the feeding vascular bundle, phlebitis, predominantly intimal arteritis with median necrosis, detachment and areactive necrosis of epidermis and epithelium of skin appendages. Clinical rejection, similar to the algorithm proposed by Etra J.W. et al. to assess preclinical skin rejection in an animal model (2019), was interpreted as G2 in two cases and G3 in one case. The Banff classification of the skin flap offers a qualitative assessment of certain biopsy parameters, while the kidney graft has qualitative-quantitative criteria for assessing rejection. When comparing the two classifications, a quantitative gradation of pathological changes in the skin flap according to the parameter of intimal arteritis (v) and immunoreactivity of the C4d marker similar to renal rejection was possible. In histological examination of skin flap biopsies, the degree of vasculitis was assessed in a large feeding artery: in all three cases this parameter was equal to v3. C4d expression was analyzed in the endothelium of microcirculatory blood vessels of the dermis and hypodermis: C4d1 in one case and C4d3 in the other two. The analysis of renal allograft biopsies revealed signs of humoral rejection (v1) only at day 30 in two recipients whose C4d expression in the skin and hypodermis was strong (C4d3). Conclusion Antibody-mediated rejection of a vascularized sentinel skin flap in recipients with combined skin-kidney transplantation is characterized by vasculitis affecting a core vascular bundle in the form of endarteritis with necrosis of media,phlebitis and associated thrombosis.Further studies are required to determine the feasibility of using a vascular stalked skin flap in the diagnosis of humoral rejection after renal transplantation.

POS-699 BORDERLINE REJECTION AMONG KIDNEY TRANSPLANT RECIPIENTS: WHERE DOES THE TREATMENT STAND

Borderline rejection is a frequently encountered diagnosis in the post-transplant period. According to the Banff classification of renal allograft pathology, the category of borderline changes uses a lower diagnostic threshold that is insufficient to fulfill criteria for a diagnosis of acute T cell-mediated rejection. There is still controversy hovering around this diagnosis and speculating that it is more of a T cell acute rejection with incomplete criteria for the full diagnosis. The relationship between borderline changes and graft survival still remains unclear. Thus the therapeutic behavior differs from one department to another. Herein is a descriptive and analytic single-center study that was conducted in the department of clinical nephrology and transplantation at Fattouma Bourguiba university hospital in Monastir - Tunisia. 112 kidney transplant recipients were gathered between the years 2008 and 2018 .20 patients were identified to have a histological diagnosis of BORDERLINE changes on kidney biopsies that were performed in response to kidney allograft dysfunction. Mean age was 32 +/- 12 years (ranging from 20 to 46) for recipients and 39 +/- 16 years (range: 26-61) for donors. Males were predominant among recipients (60% vs. 40%) and females were predominant among donors (80% vs. 20%). The mean serum creatinine level after the immediate graft was 161 μmol / L (range 87-513 μmol. / L). These levels were achieved after a median of 20 days (interquartile range: 3-56). Biopsies exhibiting borderline infiltrates were performed at a median duration of 4.7 days (interquartile range: 2-18) and the mean serum creatinine at the time of the biopsy was 250 μmol / L (range: 163-883). The biopsies showed borderline cellular infiltrates (interstitial inflammation 1 [i1] and tubulitis [t1] lesions with no transmural arteritis (v = 0)). All recipients except one received anti-rejection treatment: either by increasing doses of corticosteroids to 0.5 mg / kg / day (n = 3) or by administering intra venous solumedrol boli during 3 days followed by full-dose corticosteroids( n = 17). 17 of the recipients responded well to treatment with a decline in serum creatinine toward the baseline, with a mean serum creatinine of 195.37 μmol / L (range: 116-448 μmol / L). Only one patient did not improve his graft function and 2 patients were still under evaluation. This response was obtained within a median duration of 26.6 days (range: 4-45 days) after the start of treatment. The borderline cellular infiltrates may impact the long-term outcomes in kidney transplant recipients exposing the patient to late rejections, nephron loss, and kidney failure. Accordingly, treatment is paramount, and intensification of immunosuppression may be required. Close monitoring after treatment is mandatory.

Artificial intelligence and algorithmic computational pathology: an introduction with renal allograft examples.

Whole slide imaging, which is an important technique in the field of digital pathology, has recently been the subject of increased interest and avenues for utilisation, and with more widespread whole slide image (WSI) utilisation, there will also be increased interest in and implementation of image analysis (IA) techniques. IA includes artificial intelligence (AI) and targeted or hypothesis-driven algorithms. In the overall pathology field, the number of citations related to these topics has increased in recent years. Renal pathology is one anatomical pathology subspecialty that has utilised WSIs and IA algorithms; it can be argued that renal transplant pathology could be particularly suited for whole slide imaging and IA, as renal transplant pathology is frequently classified by use of the semiquantitative Banff classification of renal allograft pathology. Hypothesis-driven/targeted algorithms have been used in the past for the assessment of a variety of features in the kidney (e.g. interstitial fibrosis, tubular atrophy, inflammation); in recent years, the amount of research has particularly increased in the area of AI/machine learning for the identification of glomeruli, for histological segmentation, and for other applications. Deep learning is the form of machine learning that is most often used for such AI approaches to the 'big data' of pathology WSIs, and deep learning methods such as artificial neural networks (ANNs)/convolutional neural networks (CNNs) are utilised. Unsupervised and supervised AI algorithms can be employed to accomplish image or semantic classification. In this review, AI and other IA algorithms applied to WSIs are discussed, and examples from renal pathology are covered, with an emphasis on renal transplant pathology.

Inflammation in areas of fibrosis: The DeKAF prospective cohort.

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsy specimens has been associated with decreased death-censored graft survival (DC-GS). Additionally, an i-IFTA score≥2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i-IFTA and t-IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90days posttransplant (n=598); mean (SD) 1.7±1.4years posttransplant. I-IFTA, present in 196 biopsy specimens, was strongly correlated with t-IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score=0. Unlike previous studies, i-IFTA=1 (vs 0) was associated with worse 3-year DC-GS: (i-IFTA=0, 81.7%, [95% CI 77.7 to 85.9%]); i-IFTA=1, 68.1%, [95% CI 59.7 to 77.6%]; i-IFTA=2, 56.1%, [95% CI 43.2 to 72.8%], i-IFTA=3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i-IFTA with decreased DC-GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T-IFTA was similarly associated with decreased DC-GS. Of these indication biopsies, those with i-IFTA≥2, without meeting other criteria for CA TCMR had similar postbiopsy DC-GS as those with CA TCMR. Those with i-IFTA=1 and t≥2, ti≥2 had postbiopsy DC-GS similar to CA TCMR. Biopsies with i-IFTA=1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i-IFTA and t-IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.

Defining housekeeping genes suitable for RNA-seq analysis of the human allograft kidney biopsy tissue

BackgroundRNA-seq is poised to play a major role in the management of kidney transplant patients. Rigorous definition of housekeeping genes (HKG) is essential for further progress in this field. Using single genes or a limited set HKG is inherently problematic since their expression might be altered by specific diseases in the patients being studied.MethodsTo generate a HKG set specific for kidney transplantation, we performed RNA-sequencing from renal allograft biopsies collected in a variety of clinical settings. Various normalization methods were applied to identify transcripts that had a coefficient of variation of expression that was below the 2nd percentile across all samples, and the corresponding genes were designated as housekeeping genes. Comparison with transcriptomic data from the Gene Expression Omnibus (GEO) database, pathway analysis and molecular biological functions were utilized to validate the housekeeping genes set.ResultsWe have developed a bioinformatics solution to this problem by using nine different normalization methods to derive large HKG gene sets from a RNA-seq data set of 47,611 transcripts derived from 30 biopsies. These biopsies were collected in a variety of clinical settings, including normal function, acute rejection, interstitial nephritis, interstitial fibrosis/tubular atrophy and polyomavirus nephropathy. Transcripts with coefficient of variation below the 2nd percentile were designated as HKG, and validated by showing their virtual absence in diseased allograft derived transcriptomic data sets available in the GEO. Pathway analysis indicated a role for these genes in maintenance of cell morphology, pyrimidine metabolism, and intracellular protein signaling.ConclusionsUtilization of these objectively defined HKG data sets will guard against errors resulting from focusing on individual genes like 18S RNA, actin & tubulin, which do not maintain constant expression across the known spectrum of renal allograft pathology.

Subclinical Inflammation in Renal Transplantation.

The standardization of renal allograft pathology began in 1991 at the first Banff Conference held in Banff, Alberta, Canada. The first task of transplant pathologists, clinicians, and surgeons was to establish diagnostic criteria for T-cell-mediated rejection (TCMR). The histological threshold for this diagnosis was arbitrarily set at "i2t2": a mononuclear interstitial cell infiltrate present in at least 25% of normal parenchyma and >4 mononuclear cells within the tubular basement membrane of nonatrophic tubules. TCMR was usually found in dysfunctional grafts with an elevation in the serum creatinine; however, our group and others found this extent of inflammation in "routine" or "protocol" biopsies of normally functioning grafts: "subclinical" TCMR. The prevalence of TCMR is higher in the early months posttransplant and has decreased with the increased potency of current immunosuppressive agents. However, the pathogenicity of lesser degrees of inflammation under modern immunosuppression and the relation between ongoing inflammation and development of donor-specific antibody has renewed our interest in subclinical alloreactivity. Finally, the advances in our understanding of pretransplant risk assessment, and our increasing ability to monitor patients less invasively posttransplant, promises to usher in the era of precision medicine.

Renal allograft dysfunction: An update on immunological graft injury

Renal transplantation is the treatment of choice in most patients with end-stage renal disease, especially with improvement in surgical techniques and immunosuppressive regimens; however, the long-term graft survival remains to be improved. Immunological graft injury leading to rejection plays a major role in long-term graft loss. With pretransplant immunological evaluation using various crossmatch tests, identification of donor-specific antibodies, a better understanding of renal allograft pathology and its standardization with the Banff classification having regular updates led to prevention, early and accurate diagnosis of rejection and its histological differentiation. Some newer biomarkers are in pipeline may enable early and accurate identification of graft pathology noninvasively.

The relationship between pathologic lesions of active and chronic antibody-mediated rejection in renal allografts.

The Banff classification of renal allograft pathology defines specific morphologic lesions that are used in the diagnosis of active (glomerulitis, peritubular capillaritis, endarteritis) and chronic (transplant glomerulopathy, peritubular capillary basement membrane multilayering, transplant arteriopathy) antibody-mediated rejection (ABMR). However, none of these individual lesions are specific for ABMR, and for this reason Banff requires 1 or more additional findings, including C4d deposition in peritubular capillaries, presence of circulating donor-specific antibodies (DSAs), and/or expression in the tissue of transcripts strongly associated with ABMR, for a definitive diagnosis of ABMR to be made. In addition, while animal studies examining serial biopsies have established the progression of morphologic lesions of active to chronic ABMR as well as intermediate forms (chronic active ABMR) exhibiting features of both, clear documentation that lesions of chronic ABMR require the earlier presence of corresponding active and intermediate lesions is less well established in human renal allografts. This review examines temporal relationships between key morphologic lesions of active and chronic ABMR in biopsies of human grafts, likely intermediate forms, and findings for and possibly against direct and potentially interruptible progression from active to chronic lesions.

Quality and Quantity in Kidney Cancer Surgery: The Role of Nonneoplastic Kidney and Kidney Volumetrics in Predicting Postoperative Renal Function.

To model renal function 2 years following radical nephrectomy with quantitative analyses using clinical, histopathologic, and renal composite cortical volumes (CCV). This retrospective study involved an assessment of the nonneoplastic kidney tissue by three blinded nephropathologists using modified Banff 1997 criteria for renal allograft pathology. Volumetric image acquisition was obtained by three independent radiologists using preoperative imaging. A 2-year estimated glomerular filtration (eGFR) calculator was created. Among the 126 patients, median age was 60 years; median CCV, 398.1 cm3; preoperative eGFR, 77 mL/min/1.73 m2; and 2-year postoperative eGFR, 54 mL/min/1.73 m2. Of the subjects, 64% had hypertension, 26% diabetes, and 37% were smokers. Increasing age, glomerulopathy/sclerosis, tubulointerstitial scarring, and arteriosclerosis were statistically significantly and adversely associated with eGFR. Conversely, increasing CCV was associated with a higher eGFR. Quantitative analysis of the nephrectomized kidney in conjunction with patient age can accurately predict renal function at 2 years.

Introduction.

We are pleased to bring you this supplement to Nephrology, which contains the proceedings of the 20th and 21st Japanese Clinicopathological Conference on Renal Allograft Pathology, held on 16 July 2016 in Tokyo and on 15 July 2017 in Nagoya, Japan, respectively. The conference is held annually, with clinical nephrologists, transplant surgeons, urologists and renal pathologists meeting to discuss the issues in cases and topics concerning renal transplantation. The conference has made a great contribution to the field of renal transplantation in Japan. Each year, we set several topics for detailed discussion at the conference. In 2016, the 20th conference consisted of one educational lecture, two special lectures, 18 oral presentations and 15 poster presentations, which focused on graft dysfunction in the chronic phase, recurrent kidney disease and infection. The educational lecture titled ‘Post-transplant immunoglobulin A deposition and nephropathy in allografts’ was presented by Dr. Tadashi Sofue and is published in this supplement. Mr. Shigeru Horita discussed ‘Usefulness of immunofluorescence technique in transplant kidney biopsy’ in one of the special lectures, and the other, ‘Essence of the Banff 2015 meeting’, was delivered by Dr. Sigeo Hara. In 2017, the 21st conference comprised two educational lectures, two special lectures, 15 oral presentations and eight poster presentations. An overview of the educational lecture ‘Recurrence of native kidney disease after kidney transplantation’, which was presented by Dr. Izumi Yamamoto, is published in this supplement. Also, Professor Ken Sakai spoke about ‘Protocol graft biopsy in kidney transplantation’. The special lecture titled ‘Viral infections directly involve in kidney allograft function’ was presented by Dr. Kosuke Masutani, and is published in this supplement as a mini review. In addition, Dr. Shigeo Hara discussed ‘Cell-mediated rejection revisited: past, current, and future direction’. We believe that the reports in this supplement address recent important issues in the field of renal transplantation. The guest editors thank all authors and participants for their contributions. Finally, we would like to express our sincere appreciation to Dr. Morozumi and Dr. Yamaguchi for their dedication to these conferences. The authors have no conflicts of interest to declare.

Is Banff 2013 Classification of Renal Allograft Pathology Superior to 2007 Banff in Detecting and Managing Cases of Antibody-Mediated Rejection?

Is Banff 2013 Classification of Renal Allograft Pathology Superior to 2007 Banff in Detecting and Managing Cases of Antibody-Mediated Rejection?