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Antibody-mediated rejection (AMR) is the major cause of graft loss in kidney transplant recipients. The Banff classification defines two classes of AMR, active and chronic active but over time this classification has become increasingly complex. To simplify the approach to AMR, we developed activity and chronicity indices based on kidney transplant biopsy findings and examined their association with graft survival in 147 patients with active or chronic active AMR, all of whom had donor-specific antibodies and were treated for AMR. The activity index was determined as the sum of Banff glomerulitis (g), peritubular capillaritis (ptc), arteritis (v) and C4d scores, with a maximum score of 12. The chronicity index was the sum of interstitial fibrosis (ci), tubular atrophy (ct), chronic vasculopathy (cv), and chronic glomerulopathy (cg) scores, the latter doubled, with a maximum score of 15. While the activity index was generally not associated with graft loss, the chronicity index was significantly associated with graft loss with an optimal threshold value of 4 or greater for predicting graft loss. The association of the chronicity index of 4 or greater with graft loss was independent of other parameters associated with graft loss, including the estimated glomerular filtration rate at the time of biopsy, chronic active (versus active) AMR, AMR with de novo (versus persistent/rebound) donor-specific antibodies, Banff (g+ptc) scores, concurrent T cell-mediated rejection and donor-specific antibody reduction post-biopsy. The association of the chronicity index of 4 or greater with graft loss was confirmed in an independent cohort of 61 patients from Necker Hospital, Paris. Thus, our findings suggest that the chronicity index may be valuable as a simplified approach to decision-making in patients with AMR.

BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown. METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'. RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN. CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.

Interleukin-6 (IL-6) is an important mediator of inflammation and activation of T cells, B cells, and plasma cells. Excessive IL-6 production is linked to human diseases characterized by unregulated antibody production, including alloimmunity, where persistence of donor-specific antibodies (DSAs), chronic active antibody-mediated rejection (cAMR), and graft loss are noted. Here, we report our experience investigating clazakizumab, a novel IL-6 inhibitor, in treating human leukocyte antigen (HLA)-sensitized patients with cAMR.Between February 2018 and January 2019, 10 adults with biopsy-proven cAMR were enrolled in a phase 2, single-center, open-label study. Patients received clazakizumab 25 mg subcutaneously (s.c.) monthly for 12 months, with a 6-month protocol biopsy. Primary end points included patient survival, graft survival, estimated glomerular filtration rate (eGFR), and safety. Secondary end points assessed immune markers (DSAs, IgG, T-regulatory [Treg] cells). At 12 months, stable patients entered a long-term extension (LTE).LTE patients received clazakizumab for2.5 years. Mean eGFRs showed significant declines from -24 months to study initiation (0 months) (52.8 ± 14.6 to 38.11 ± 12.23 ml/min per 1.73 mIn this small cohort of patients with cAMR, clazakizumab treatment showed a trend toward stabilization of eGFR and reductions in DSA and graft inflammation. No significant safety issues were observed. A randomized, placebo-controlled clinical trial (IMAGINE) of clazakizumab in cAMR treatment is underway (NCT03744910).

2021 marks the 30th anniversary of the original development of the Banff Classification of Kidney Allograft Pathology, when in August 1991 a group of pathologists and transplant clinicians led by Kim Solez and Lorraine Racusen met in Banff, Alberta, Canada, and established the first widely accepted criteria for the diagnosis of kidney transplant rejection and other lesions seen on kidney allograft biopsies. Since that time, Banff conferences have been held every 2 years at many sites around the world, resulting in several major revisions to the classification and expansion well beyond pure histopathology of kidney allografts to encompass other solid organ transplants, and with involvement of immunogeneticists, immunologists, other basic scientists, biostatisticians, and data scientists defining a very diverse and integrated Banff community. This approach with multidisciplinary international input, constantly incorporating new evidence from the scientific literature and from studies performed by Banff working groups while still maintaining the importance of a long-standing consensus process, has resulted in the Banff classification gaining overwhelming international acceptance as the main reference used for the scoring of kidney allograft biopsies in research studies, routine practice, and clinical trials. This review focuses on the major milestones in the development of the Banff classification of kidney allograft pathology and the evolution of the Banff process over the past 3 decades, with prospects for future advances and refinements.

Donor-derived cell-free DNA (dd-cfDNA) is a biomarker validated to detect rejection when measured to assess kidney allograft dysfunction. However, it remains unclear whether routine surveillance with dd-cfDNA provides additional information over standard monitoring of kidney allografts with creatinine and donor-specific antibodies (DSAs), particularly among those with little suspicion of rejection or injury. We investigated the value of measuring dd-cfDNA in patients with preserved allograft function and describe its association with future events.Three-hundred seventeen kidney transplant recipients with a creatinine ≤1.5 mg/dL, no current DSA, and no prior rejection were assessed with dd-cfDNA and categorized into low (dd-cfDNA0.5%; n = 239), moderate (dd-cfDNA 0.5% to1.0%; n = 43), and high (dd-cfDNA ≥1.0%; n = 35) groups. The occurrence of rejection, DSA, graft loss, and change in estimated glomerular filtration rate over time after dd-cfDNA assessment was compared.Over follow-up, rejections were more commonly found among patients with high vs low dd-cfDNA (17% versus 5%; P = 0.01); a similar nonsignificant trend was observed among patients with moderate compared to low dd-cfDNA (12% versus 5%; P = 0.13). DSA development was uncommon and not different between groups (low: 4%; moderate: 3%; high: 0%; P = 0.52). There was only 1 graft loss in a patient with low dd-cfDNA, and dd-cfDNA was not associated with graft dysfunction over time.Most patients with elevated dd-cfDNA in conjunction with preserved allograft function remained stable over follow-up without deterioration in function or graft loss. Studies are needed to differentiate patients with elevated dd-cfDNA who will develop adverse outcomes from those who will remain clinically stable.

The role of angiotensin II type 1 receptor antibodies (AT1R-Ab) in pediatric renal transplantation is unclear. Here, we evaluated pre-transplant AT1R-Ab on transplant outcomes in the first 5 years. Secondary analysis compared pre-transplant AT1R-Ab levels by age.Thirty-six patients, 2-20 years old, were divided into two groups: pre-transplant AT1R-Ab- (17 U/ml; n = 18) and pre-transplant AT1R-Ab+ (≥17 U/ml; n = 18). eGFR was determined at 6-month, 1-, 2-, and 4-year post-transplant. Allograft biopsies were performed in the setting of strong HLA-DSA (MFI 10 000), AT1R-Ab ≥17 U/ml, and/or elevated creatinine.Mean age in pre-transplant AT1R-Ab- was 13.3 years vs. 11.0 in pre-transplant AT1R-Ab+ (p = 0.16). At 6 months, mean eGFR was 111.3 ml/min/1.73 mIn our small cohort, pre-transplant AT1R-Ab ≥17 U/ml was not associated with reduced graft function or rejection. The pathogenicity of pre-transplant AT1R-Ab in pediatric kidney transplantation requires further investigation.

It has been suggested that the liver allograft can protect the kidney allograft from antibody mediated rejection in simultaneous liver/kidney transplant (SLK) recipients by reducing preexisting donor specific antibodies (DSA) via adsorption of DSA by the liver allograft. Recently, the SLK allocation system was altered to provide a kidney safety net to those who do not recover native kidney function after liver transplant. However, the kidney transplant under the safety net creates a theoretical challenge for sensitized patients as the liver graft may not be able to adsorb human leukocyte antigen (HLA) antibodies against the kidney under the safety net because the liver and kidney grafts are from different donors and may carry different HLA antigens. This prompts us to examine levels of non-donor specific HLA antibodies in SLK recipients in our hospital. We found that levels of both DSA and non-DSA decreased post SLK transplant. The presence of preexisting DSA was also not associated with kidney graft survival and antibody mediated rejection in SLK recipients. Our results indicate that the liver transplant can reduce non-DSA, which may increase the pool of compatible kidneys offered under the safety net program for sensitized patients.

Background: For the better part of the past 6 decades, transmission electron microscopy (EM), together with routine light microscopy and immunofluorescence and/or immunohistochemistry (IHC), has been an essential component of the diagnostic workup of medical renal biopsies, particularly native renal biopsies, with increasing frequency in renal allograft biopsies as well. Studies performed prior to the year 2000 have indeed shown that a substantial fraction of renal biopsies cannot be accurately diagnosed without EM. Still, EM remains costly and labor-intensive, and with increasing pressure to reduce healthcare costs, some centers are de-emphasizing diagnostic EM. This trend has been coupled with advances in IHC and other methods in renal biopsy diagnosis over the past 2–3 decades. Summary: Nonetheless, it has been our experience that the diagnostic value of EM in the comprehensive evaluation of renal biopsies remains similar to what it was 20–30 years ago. In this review, we provide several key examples from our practice where EM was essential in making the correct renal biopsy diagnosis, ranging from relatively common glomerular lesions to rare diseases. Key Messages: EM remains an important component of the diagnostic evaluation of medical renal biopsies. Failure to perform EM in certain cases will result in an incorrect diagnosis, with possible clinical consequences. We strongly recommend that tissue for EM be taken and stored in an appropriate fixative and ultrastructural studies be performed for all native renal biopsies, as well as appropriate renal allograft biopsies as recommended by the Banff consortium.

Treatment options for antibody-mediated rejection (AMR) are limited. Recent studies have shown that inhibition of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling can reduce inflammation and slow AMR progression.We report our experience using monthly tocilizumab (anti-IL6R) in 25 pediatric renal transplant recipients with AMR, refractory to IVIg/Rituximab. From January 2013 to June 2019, a median (IQR) of 12 (6.019.0) doses of tocilizumab were given per patient. Serial assessments of renal function, biopsy findings, and HLA DSA (by immunodominant HLA DSA [iDSA] and relative intensity score [RIS]) were performed.Median (IQR) time from transplant to AMR was 41.4 (24.367.7) months, and time from AMR to first tocilizumab was 10.6 (8.317.6) months. At median (IQR) follow up of 15.8 (8.435.7) months post-tocilizumab initiation, renal function was stable except for 1 allograft loss. There was no significant decrease in iDSA or RIS. Follow up biopsies showed reduction in peritubular capillaritis (p = .015) and C4d scoring (p = .009). The most frequent adverse events were cytopenias.Tocilizumab in pediatric patients with refractory AMR was well tolerated and appeared to stabilize renal function. The utility of tocilizumab in the treatment of AMR in this population should be further explored.

IgA nephropathy (IgAN) is a progressive disease with great variability in the clinical course. Among the clinical and pathologic features contributing to variable outcomes, the presence of crescents has attracted particular interest as a distinct pathological feature associated with severity. Several uncontrolled observations have led to the general thought that the presence and extent of crescents was a prognostic indicator associated with poor outcomes. However, KDIGO 2021 guidelines concluded that either the presence or the relative number of crescents should not be used to determine the progression of IgAN nor should they suggest the choice of immunosuppression. Our aim is to report and discuss recent data on the debated issue of the value of active (cellular and fibrocellular) crescents in the pathogenesis and clinical progression of IgAN, their predictive value, and the impact of immunosuppression on renal function. We conclude that the value of crescents should not be disregarded, although this feature does not have an independent predictive value for progression in IgAN, particularly when considering immunosuppressed patients. An integrated overall evaluation of crescents with other active MEST scores, clinical data, and novel biomarkers must be considered in achieving a personalized therapeutic approach to IgAN patients.

Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.

Measure effect of late-afternoon communication and patient planning (CAPP) rounds to increase early electronic discharge orders (EDO).We enrolled 4485 patients discharged from six subspecialty medical services. We implemented late-afternoon CAPP rounds to identify patients who could have morning discharge the subsequent day. After an initial successful implementation of the intervention, we identified lack of sustainability. We made changes with sustained implementation of the intervention. This is a before-after study of a quality improvement intervention.Primary measures of intervention effectiveness were percentage of patients who received EDO by 11 am and patients discharged by noon. Additional measure of effectiveness were percent of patients admitted to the correct ward, emergency department (ED)-to-ward transfer time compared between intervention and nonintervention periods. We compared the overall expected LOS and the average weekly discharges to assess for comparability across the control and intervention time periods. We used the readmission rate as balancing measure to ensure that the intervention was not have unintended negative patients consequences.Expected length of stay based upon discharge diagnosis/comorbidities and readmission rates were similar across the intervention and control time periods. The average weekly discharges were not statistically significant. Percentage of EDO by 11 am was higher in the first intervention period, second intervention period and combined intervention periods (28.9% vs. 21.8%,Afternoon CAPP rounds to identify early patient discharges the following day led to increase in EDO entered by 11 am and discharges by noon without an adverse change in readmission rates and LOS.

Detection of donor-derived cell-free DNA (dd-cfDNA) reliably identifies allograft rejection in pediatric and adult kidney transplant (KT) recipients. Here, we evaluate the utility of dd-cfDNA for monitoring response to treatment among pediatric renal transplant recipients suffering graft rejection.58 pediatric transplant recipients were enrolled between April 2018 and March 2020 and underwent initial dd-cfDNA testing to monitor for rejection. Allograft biopsy was performed for dd-cfDNA scores1.0%. Patients with histologically proven rejection formed the study cohort and underwent appropriate treatment. Results of dd-cfDNA, serum creatinine (SCr), biopsy findings, and treatment outcomes were evaluated. Standard statistical analyses were applied.Nineteen of 58 (31%) patients had dd-cfDNA score1.0%, of which 18 (94.7%) had biopsy-proven rejection. Median dd-cfDNA value was 1.90% (interquartile range 1.43%-3.23%), and biopsy results showed 11 patients (61.1%) with antibody-mediated rejection (AMR), 2 patients (11.1%) with T-cell mediated rejection (TCMR), and 5 patients (27.7%) with mixed AMR/TCMR. SCr at time of biopsy was 1.28 ± 1.09 mg/dl. Following treatment, dd-cfDNA scores decreased for all types of rejection but still remained1.0% in both AMR (1.50% [0.90%-3.10%]) and mixed (1.40% [0.95%-4.15%]) groups. Repeat dd-cfDNA values were1.0% for patients with TCMR (0.20%-0.28%). SCr showed minimal change from pre-treatment levels regardless of rejection subtype.Patients with TCMR may be reliably followed by dd-cfDNA; however, it remains unclear whether persistently elevated dd-cfDNA levels in AMR is a reflection of ongoing subclinical rejection or an inherent limitation of the assay's utility.

Alloantibodies are a significant barrier to successful transplantation. While desensitization has emerged, efficacy is limited. Interleukin-6 (IL-6) is an important mediator of inflammation and immune cell activation. Persistent IL-6 production increases the risk for alloantibody production. Here we report our experience with clazakizumab (anti-IL-6) for desensitization of highly HLA-sensitized patients (HS). From March 2018 to September 2020, 20 HS patients were enrolled in an open label pilot study to assess safety and limited efficacy of clazakizumab desensitization. Patients received PLEX, IVIg, and clazakizumab 25 mg monthly X6. If transplanted, graft function, pathology, HLA antibodies and regulatory immune cells were monitored. Transplanted patients received standard immunosuppression and clazakizumab 25 mg monthly posttransplant. Clazakizumab was well tolerated and associated with significant reductions in class I and class II antibodies allowing 18 of 20 patients to receive transplants with no DSA rebound in most. Significant increases in T

Chronic interstitial nephritis in agricultural communities (CINAC) is a progressive form of tubulointerstitial nephritis affecting agricultural workers in different parts of the world. Its underlying etiology is not known, although a study by Vervaet and coworkers in this issue of Kidney International provides strong evidence that CINAC is a lysosomal tubulopathy induced by toxin exposure. Key to this important discovery is a thorough morphologic analysis of kidney tissue, including ultrastructural as well as histopathologic examination.

Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression.A retrospective cohort study.In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year.Renal arteriolar microangiopathic lesions.Composite kidney end point event defined as a50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death.All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes.Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (all P0.001) than patients without microangiopathic lesions. After a median follow-up of 4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at the time of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P = 0.5).A single Chinese center's experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes).Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.

Donor-derived cell-free DNA (dd-cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd-cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor-specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd-cfDNA was higher among patients with antibody-mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%-1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%-1.10%; P < .001) and cell-mediated rejection (CMR; median: 0.27%, IQR: 0.19%-1.30%; P = .01). The dd-cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17-0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71-0.93) and a dd-cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd-cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.

Child sexual offenders convene in dark web spaces to exchange indecent imagery, advice and support. In response, law enforcement agencies deploy undercover agents to pose as offenders online to gather intelligence on these offending communities. Currently, however, little is known about how offenders interact online, which raises significant questions around how undercover officers should ‘authentically’ portray the persona of a child sexual offender. This article presents the first linguistic description of authentic offender–offender interactions taking place on a dark web image exchange chatroom. Using move analysis, we analyse chatroom users’ rhetorical strategies. We then model the move sequences of different users and user types using Markov chains, to make comparisons between their linguistic behaviours. We find the predominant moves characterising this chatroom are Offering Indecent Images, Greetings, Image Appreciation, General Rapport and Image Discussion, and that rhetorical strategies differ between users of different levels of offending and dark web image-sharing experience.

Purpose of review To review recent efforts to develop uniformity and precision in defining individual glomerular histologic and ultrastructural lesions and proposals for developing greater uniformity in reporting of glomerular diseases. Recent findings Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have several consortia for the study of glomerular diseases. However, one important limitation faced by renal pathologists and nephrologists has been a lack of uniformity and precision in defining the morphologic lesions seen by light and electron microscopy on which the scoring systems are based. In response to this, the Renal Pathology Society organized a working group that over 4 years arrived at consensus definitions for many such lesions. These definitions can be applied within the context of scoring systems for different glomerular diseases, and recently proposed reporting systems based on pathogenic categories and for defining the overall severity of chronic changes. Summary From extensive discussions a panel of 13 renal pathologists reached consensus in defining 47 individual glomerular lesions seen on light microscopy and 56 glomerular lesions and key normal structures seen by electron microscopy. Validation of the impact of these consensus definitions on interobserver agreement in lesion identification is currently underway.

Chronic active T cell–mediated rejection (CA TCMR) is a newly described variant of kidney allograft rejection associated with long-term graft loss. Whether this form of rejection is related to under immunosuppression is debated and the benefit of immunosuppressive therapy in CA TCMR is unknown. Here we investigate the amenability of CA TCMR to treatment and examine the impact of clinical, histologic, and molecular parameters on outcomes. In a retrospective single institution review, we identified 48 cases of isolated CA TCMR, of which 44 were treated with pulse steroids or anti-thymocyte globulin, or both. Defining treatment response as an at least 50% estimated glomerular filtration rate recovery, a response was achieved in 20% of cases at four weeks post initiation of immunosuppressive therapy. Treatment responsiveness did not reflect the presence of concomitant acute T cell–mediated rejection, and was not significantly different between cases with mild, moderate, and severe parenchymal scarring. Although not statistically significant, there was a trend toward greater treatment responsiveness in cases with moderate as opposed to severe tubulitis. By targeted transcriptional profiling, increased allograft mast cells and alterations in lipid metabolism were identified as possible features of treatment resistant CA TCMR. Thus, our study shows that although its prognosis is generally poor, CA TCMR is not a homogenous entity and in a subset of cases, improvement in kidney function can be achieved with immunosuppressive therapy.

Primary IgA nephropathy (IgAN) diagnosis is based on IgA-dominant glomerular deposits and histological scoring is done on formalin-fixed paraffin embedded tissue (FFPE) sections using the Oxford classification. Our aim was to use this underexploited resource to extract RNA and identify genes that characterize active (endocapillary–extracapillary proliferations) and chronic (tubulo-interstitial) renal lesions in total renal cortex. RNA was extracted from archival FFPE renal biopsies of 52 IgAN patients, 22 non-IgAN and normal renal tissue of 7 kidney living donors (KLD) as controls. Genome-wide gene expression profiles were obtained and biomarker identification was carried out comparing gene expression signatures a subset of IgAN patients with active (N = 8), and chronic (N = 12) renal lesions versus non-IgAN and KLD. Bioinformatic analysis identified transcripts for active (DEFA4,TNFAIP6,FAR2) and chronic (LTB,CXCL6, ITGAX) renal lesions that were validated by RT-PCR and IHC. Finally, two of them (TNFAIP6 for active and CXCL6 for chronic) were confirmed in the urine of an independent cohort of IgAN patients compared with non-IgAN patients and controls. We have integrated transcriptomics with histomorphological scores, identified specific gene expression changes using the invaluable repository of archival renal biopsies and discovered two urinary biomarkers that may be used for specific clinical decision making.

Supplemental Digital Content is available in the text., Background. Higher Banff inflammation and chronicity scores on kidney transplant biopsies are associated with poorer graft survival, although histology alone has limitations in predicting outcomes. We investigated if integrating donor-derived cell-free DNA (dd-cfDNA, Allosure; CareDx, Inc.) with Banff biopsy scores into a predictive model for estimated glomerular filtration rate over time can improve prognostic assessment versus histology alone. Methods. We identified 180 kidney transplant patients with dd-cfDNA assessed within 1 mo of biopsy. Using linear mixed–effects models, a prediction model of Banff histology scores and dd-cfDNA on estimated glomerular filtration rate over time was derived. Nested models were compared using the likelihood-ratio test, Akaike Information Criterion, and Bayesian Information Criterion to assess if inclusion of dd-cfDNA into a model consisting of Banff biopsy scores would improve model fit. Results. Univariate models identified significant covariate-by-time interactions for cg = 3 versus

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This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B‐HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data‐driven process distilled a gene list from peer‐reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B‐HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin‐fixed paraffin‐embedded samples. The B‐HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision‐making and clinical trials., This Banff meeting report summarizes the progress of the Banff Molecular Diagnostics Working Group, which generated consensus on a transplant‐specific discovery gene panel and a potential roadmap for its validation for diagnostic application.

ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:21 issue:5 pages:1689-1690 ispartof: location:United States status: published

IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.

The Banff working group on preimplantation biopsy was established to develop consensus criteria (best practice guidelines) for the interpretation of preimplantation kidney biopsies. Digitally scanned slides were used (i) to evaluate interobserver variability of histopathologic findings, comparing frozen sections with formalin-fixed, paraffin-embedded tissue of wedge and needle core biopsies, and (ii) to correlate consensus histopathologic findings with graft outcome in a cohort of biopsies from international medical centers. Intraclass correlations (ICCs) and univariable and multivariable statistical analyses were performed. Good to fair reproducibility was observed in semiquantitative scores for percentage of glomerulosclerosis, arterial intimal fibrosis and interstitial fibrosis on frozen wedge biopsies. Evaluation of frozen wedge and core biopsies was comparable for number of glomeruli, but needle biopsies showed worse ICCs for glomerulosclerosis, interstitial fibrosis and tubular atrophy. A consensus evaluation form is provided to help standardize the reporting of histopathologic lesions in donor biopsies. It should be recognized that histologic parameters may not correlate with graft outcome in studies based on organs deemed to be acceptable after careful clinical assessment. Significant limitations remain in the assessment of implantation biopsies.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Background Some renal biopsies cannot distinguish minimal change disease (MCD) from primary focal segmental glomerulosclerosis (FSGS) because of inadequate sampling and/or a lack of sampled glomeruli with segmental sclerosis. As protein excretion in MCD has been described as being albumin-selective, we examined whether the ratio of immunoglobulin G (IgG)/albumin staining in protein reabsorption droplets (tPRD) might help distinguish MCD from FSGS. Methods Frozen tissue from 144 native renal biopsies from patients with nephrotic syndrome and a diagnosis of MCD or FSGS [73 MCD, 30 FSGS tip variant (FSGS-tip), 38 FSGS-not otherwise specified (FSGS-NOS), 3 FSGS collapsing] was retrospectively stained by direct immunofluorescence for IgG and albumin; none of these samples showed diagnostic lesions of FSGS. IgG and albumin staining of tPRD were graded on a scale of 0 to 3+ based on the distribution and intensity of staining. Results Mean (standard deviation) IgG/albumin staining ratios were 0.186 ± 0.239 for MCD, 0.423 ± 0.334 for FSGS-tip (P = 0.0001 versus MCD) and 0.693 ± 0.297 for FSGS-NOS (P Conclusions In summary, IgG/albumin staining in tPRD was correlated with histologic diagnosis in renal biopsies with MCD and FSGS. A ratio of ≤0.33 was associated with MCD, whereas a ratio of 1.0 was most often seen with FSGS-NOS.

BACKGROUND: Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month post-transplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of Eculizumab as primary therapy for active AMR early post-transplant. METHODS: We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014 and January 31, 2018 and had AMR within the first 30 days post-transplant and treated with eculizumab ± plasmapheresis. RESULTS: Fifteen patients had early active AMR at a median [IQR] of 10 [7-11] days post-transplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven and 2 cases were presumed based on donor specific antibody trends and allograft function. Within 1 week of treatment the median estimated glomerular filtration rate (eGFR) increased from 21 mL/min to 34 mL/min (P = .001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4-6 months. No graft losses occurred and at last follow-up (median [IQR] of 13 [12-19] months) the median IQR eGFR increased to 52 (46-60) mL/min. CONCLUSIONS: Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.

Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA- at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA- patients.From January 2013 to October 2016, 90 HS patients (PRA80%, DSA+ = 50 versus DSA- = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant.Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/- (n=19), DSA-/+ (n=10), and DSA-/- (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/- (11%), and DSA-/- (10%) patients (P0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar.Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.

The 13th Banff Conference on Allograft Pathology was held in Vancouver, British Columbia, Canada from October 5 to 10, 2015. The cardiac session was devoted to current diagnostic issues in heart transplantation with a focus on antibody‐mediated rejection (AMR) and small vessel arteriopathy. Specific topics included the strengths and limitations of the current rejection grading system, the central role of microvascular injury in AMR and approaches to semiquantitative assessment of histopathologic and immunophenotypic indicators, the role of AMR in the development of cardiac allograft vasculopathy, the important role of serologic antibody detection in the management of transplant recipients, and the potential application of new molecular approaches to the elucidation of the pathophysiology of AMR and potential for improving the current diagnostic system. Herein we summarize the key points from the presentations, the comprehensive, open and wide‐ranging multidisciplinary discussion that was generated, and considerations for future endeavors., This article summarizes the Banff conference on heart transplantation with a focus on antibody‐mediated rejection, strengths and limitations of the current rejection grading system, the important role of serologic antibody detection and the potential application of new molecular approaches to the elucidation of the pathophysiology of antibody‐mediated rejection, and the potential for improving the current diagnostic system. See the companion report on page 28.

Among glomerular diseases, even the very uncommon ones, fibrillary GN (FGN) has always been among the most poorly understood. From an early description as “Congo red-negative amyloidosis-like glomerulopathy,”[1][1] its ultrastructural appearance has both captivated and confused renal

Large-scale, contemporary studies exploring glomerular disease epidemiology in the United States are lacking. We aimed to determine 30-year temporal and demographic trends in renal biopsy glomerular disease diagnosis frequencies in the southeastern United States.In this cross-sectional, observational study, we identified all patients with a native kidney biopsy specimen showing one of 18 widely recognized glomerular disease diagnoses referred to the University of North Carolina Chapel Hill Division of Nephropathology between 1986 and 2015. Biopsy era (1986-1995, 1996-2005, and 2006-2015) and demographics (age, sex, and race) were our primary and secondary predictors, respectively, and the relative frequency of each glomerular disease diagnosis was our primary outcome.Among 21,374 patients (mean age =48.3±18.3 years old; 50.8% men; 56.8% white; 38.3% black; 2.8% Latino; 1.4% Asian; 0.8% other), the frequency of diabetic glomerulosclerosis in renal biopsy specimens increased dramatically over the three decades (5.5%, 11.4%, and 19.1% of diagnoses, respectively;We identified significant changes in relative renal biopsy frequencies of many glomerular disease subtypes over three decades. Temporal trends were consistently observed within all major demographic groups, although relative predominance of individual glomerular disease subtypes differed according to patient age, sex, and race. We propose that exploration of behavioral and environmental exposures that likely underlie these findings should be the focus of future hypothesis-driven research.