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Gene expression profiling from formalin-fixed paraffin-embedded (FFPE) renal allograft biopsies is a promising approach for feasibly providing a molecular diagnosis of rejection. However, large-scale studies evaluating the performance of models using NanoString platform data to define molecular archetypes of rejection are lacking. We tested a diverse retrospective cohort of over 1400 FFPE biopsy specimens, rescored according to Banff 2019 criteria and representing 10 of 11 United Network of Organ Sharing regions, using the Banff Human Organ Transplant panel from NanoString and developed a multiclass model from the gene expression data to assign relative probabilities of 4 molecular archetypes: No Rejection, Antibody-Mediated Rejection, T Cell-Mediated Rejection, and Mixed Rejection. Using Least Absolute Shrinkage and Selection Operator regularized regression with 10-fold cross-validation fitted to 1050 biopsies in the discovery cohort and technically validated on an additional 345 biopsies, our model achieved overall accuracy of 85% in the discovery cohort and 80% in the validation cohort, with ≥75% positive predictive value for each class, except for the Mixed Rejection class in the validation cohort (positive predictive value, 53%). This study represents the technical validation of the first model built from a large and diverse sample of diagnostic FFPE biopsy specimens to define and classify molecular archetypes of histologically defined diagnoses as derived from Banff Human Organ Transplant panel gene expression profiling data., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Antibrush border antibody disease (ABBA) is an autoimmune tubulointerstitial kidney disease that primarily affects older individuals and results in progressive kidney failure. It is rare with only 20 reported cases. Here, we describe a case series to further define the clinicopathologic spectrum and natural history, and to inform management., Methods: We identified 67 patients with ABBA who underwent kidney biopsy, including 65 native and 2 transplants. Demographics, clinical findings, and laboratory data were obtained. Histopathologic data included light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2, CUBN, and AMN. Follow-up data, including treatment(s), laboratory values, and outcomes, were available from 51 patients., Results: Patients with ABBA were predominantly male with a median age of 72 years. Median serum creatinine was 2.7 mg/dl, proteinuria was 2.8 g/day, and hematuria was present in two-thirds of the patients. Tubular injury with LRP2-positive tubular basement membrane (TBM) deposits were seen in 94.2% of patients. Thirty-eight patients (56.7%) had a second kidney disease, commonly glomerular diseases with high-grade proteinuria. These diseases included podocytopathies, membranous nephropathy (MN), IgA nephropathy, diabetic glomerulopathy, lupus nephritis (LN), crescentic glomerulonephritis (GN), tubulointerstitial nephritis, and involvement by lymphoma. The majority of patients were treated with immunosuppression. Of those patients with follow-up, 29.4% achieved remission, 70.6% had no response, and 52.8% required dialysis or were deceased. Untreated patients were at the highest risk., Conclusion: ABBA is a rare autoimmune kidney disease that often occurs with other kidney diseases. Although the overall prognosis of ABBA is poor, there is potential benefit from immunosuppression., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy., Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed., Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria., Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery., Competing Interests: The authors declare that they have no relevant financial interests or conflicts of interest., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The Thrombotic Microangiopathy Banff Working Group (TMA-BWG) was formed in 2015 to survey current practices and develop minimum diagnostic criteria (MDC) for renal transplant TMA (Tx-TMA). To generate consensus among pathologists and nephrologists, the TMA BWG designed a 3-Phase study. Phase I of the study is presented here. Using the Delphi methodology, 23 panelists with >3 years of diagnostic experience with Tx-TMA pathology listed their MDC suggesting light, immunofluorescence, and electron microscopy lesions, clinical and laboratory information, and differential diagnoses. Nine rounds (R) of consensus resulted in MDC validated during two Rs using online evaluation of whole slide digital images of 37 biopsies (28 TMA, 9 non-TMA). Starting with 338 criteria the process resulted in 24 criteria and 8 differential diagnoses including 18 pathologic, 2 clinical, and 4 laboratory criteria. Results show that 3/4 of the panelists agreed on the diagnosis of 3/4 of cases. The process also allowed definition refinement for 4 light and 4 electron microscopy lesions. For the first time in Banff classification, the Delphi methodology was used to generate consensus. The study shows that Delphi is a democratic and cost-effective method allowing rapid consensus generation among numerous physicians dealing with large number of criteria in transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Afrouzian, Kozakowski, Liapis, Broecker, Truong, Avila-Casado, Regele, Seshan, Ambruzs, Farris, Buob, Chander, Cheraghvandi, Clahsen-van Groningen, de Almeida Araujo, Ertoy Baydar, Formby, Galesic Ljubanovic, Herrera Hernandez, Honsova, Mohamed, Ozluk, Rabant, Royal, Stevenson, Toniolo and Taheri.)

The Banff community summoned the TMA Banff Working Group to develop minimum diagnostic criteria (MDC) and recommendations for renal transplant TMA (Tx-TMA) diagnosis, which currently lacks standardized criteria. Using the Delphi method for consensus generation, 23 nephropathologists (panelists) with >3 years of diagnostic experience with Tx-TMA were asked to list light, immunofluorescence, and electron microscopic, clinical and laboratory criteria and differential diagnoses for Tx-TMA. Delphi was modified to include 2 validations rounds with histological evaluation of whole slide images of 37 transplant biopsies (28 TMA and 9 non-TMA). Starting with 338 criteria in R1, MDC were narrowed down to 24 in R8 generating 18 pathological, 2 clinical, 4 laboratory criteria, and 8 differential diagnoses. The panelists reached a good level of agreement (70%) on 76% of the validated cases. For the first time in Banff classification, Delphi was used to reach consensus on MDC for Tx-TMA. Phase I of the study (pathology phase) will be used as a model for Phase II (nephrology phase) for consensus regarding clinical and laboratory criteria. Eventually in Phase III (consensus of the consensus groups) and the final MDC for Tx-TMA will be reported to the transplantation community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Afrouzian, Kozakowski, Liapis, Broecker, Truong, Avila-Casado, Regele, Seshan, Ambruzs, Farris, Buob, Chander, Cheraghvandi, Clahsen-van Groningen, de Almeida Araujo, Ertoy Baydar, Formby, Galesic Ljubanovic, Herrera Hernandez, Honsova, Mohamed, Ozluk, Rabant, Royal, Stevenson, Toniolo and Taheri.)

Collapsing glomerulopathy (CG) is a form of podocytopathy that is challenging to manage. CG can be idiopathic or associated with other conditions including autoimmune connective tissue diseases. In the setting of autoimmune connective tissue diseases, there are no current guidelines to guide therapy. Here we report a unique and challenging case of CG with mixed connective tissue disease (MCTD) that responded to steroids followed by mycophenolate. In PubMed, we identified three previously reported cases of CG with MCTD in addition to other forms of autoimmune diseases, including Sjogren syndrome, adult-onset still's disease, and vasculitis, etc. We are providing a literature review of collapsing glomerulopathy cases in the setting of autoimmune connective tissue diseases and with MCTD. CG in the setting of autoimmune connective tissue diseases is more common in females and black patients. Response to therapy was inconsistent. Many patients progressed to dialysis despite use of various treatment modalities., Competing Interests: Declaration of Competing Interest The authors of this manuscript have nothing to disclose or conflict of interest., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Renal and urinary involvement has been reported to occur in 4% to 23% of inflammatory bowel disease (IBD) patients. Parenchymal renal disease is rare and most commonly affects glomerular and tubulointerstitial compartments. The most common findings on renal biopsy of IBD patients are IgA nephropathy and tubulointerstitial nephritis. Overall morbidity of IBD-related renal manifestations is significant, and there is often only a short window of injury reversibility. This, along with subtle clinical presentation, requires a high index of suspicion and routine monitoring of renal function. There are no established guidelines for the optimal screening and monitoring of renal function in IBD patients., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients., Methods: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment., Results: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P  < 0.001), more frequently white (89.7% vs. 78.9%, P  = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m 2 , P  < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P  < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P  < 0.001)., Conclusion: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

Primary renal tubulointerstitial disease resulting from proximal tubule antigen-specific antibodies and immune complex formation has not been well characterized in humans. We report a cohort of patients with a distinct, underappreciated kidney disease characterized by kidney antibrush border antibodies and renal failure (ABBA disease). We identified ten patients with ABBA disease who had a combination of proximal tubule damage, IgG-positive immune deposits in the tubular basement membrane, and circulating antibodies reactive with normal human kidney proximal tubular brush border. All but one of the patients also had segmental glomerular deposits on renal biopsy specimen. Patients with ABBA disease were elderly and presented with AKI and subnephrotic proteinuria. Serum from all patients but not controls recognized a high molecular weight protein in renal tubular protein extracts that we identified as LDL receptor-related protein 2 (LRP2), also known as megalin, by immunoprecipitation and mass spectrometry. Immunostaining revealed that LRP2 specifically colocalized with IgG in the tubular immune deposits on the ABBA biopsy specimen but not the control specimen analyzed. Finally, ABBA serum samples but not control samples showed reactivity against recombinantly expressed N-terminal LRP2 fragments on Western blots and immunoprecipitated the recombinantly expressed N-terminal region of LRP2. This case series details the clinicopathologic findings of patients with ABBA disease and shows that the antigenic target of these autoantibodies is LRP2. Future studies are needed to determine the disease prevalence, stimulus for ABBA, and optimal treatment., (Copyright © 2018 by the American Society of Nephrology.)

Objectives: To implement Lean principles to accommodate expanding volumes of gastrointestinal biopsies and to improve laboratory processes overall., Design: Our continuous improvement (kaizen) project analyzed the current state for gastrointestinal biopsy handling using value-stream mapping for specimens obtained at a 487-bed tertiary care pediatric hospital in Dallas, Texas. We identified non-value-added time within the workflow process, from receipt of the specimen in the histology laboratory to the delivery of slides and paperwork to the pathologist. To eliminate non-value-added steps, we implemented the changes depicted in a revised-state value-stream map., Results: Current-state value-stream mapping identified a total specimen processing time of 507 minutes, of which 358 minutes were non-value-added. This translated to a process cycle efficiency of 29%. Implementation of a revised-state value stream resulted in a total process time reduction to 238 minutes, of which 89 minutes were non-value-added, and an improved process cycle efficiency of 63%., Conclusions: Lean production principles of continuous improvement and waste elimination can be successfully implemented within the clinical laboratory.

Background: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma and is often difficult to diagnose. Early-stage disease is particularly challenging and requires clinical and histopathologic correlation to make an accurate diagnosis. In order to facilitate the diagnosis of early MF, an algorithm has been proposed by the International Society for Cutaneous Lymphomas (ISCL) whereby clinical and histopathologic characteristics as well as immunohistochemistry and T-cell receptor gene rearrangement studies may be applied to suspected cases of MF. The diagnostic utility of this algorithm has not yet been validated. We sought to determine the validity of the proposed algorithm via an investigator-blinded, retrospective, case-control study., Methods: A total of 34 cases were randomly selected from the database of a clinic for cutaneous T-cell lymphomas and included patients with MF and patients with clinicopathologic mimics. The proposed diagnostic algorithm was systematically applied to the entire cohort. Each case was assigned a composite score based on the parameters in the proposed algorithm., Results: Among the 24 cases of MF, 21 cases achieved four or more points through application of the algorithm. Among the 10 cases of MF mimics, only four achieved four or more points. This difference was significant (Fisher's exact test, p = 0.009). The sensitivity of the 4-point threshold for a diagnosis of MF was 87.5% and the specificity was 60%., Conclusions: The diagnostic algorithm proposed by the ISCL is a statistically valid method for defining cases of early MF and distinguishing these cases from other benign dermatoses. However, the clinical utility of the algorithm may be limited by its low specificity. Further refinement of the algorithm may improve its accuracy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The effects of nephropathy risk variants in the apolipoprotein L1 gene (APOL1) on renal histopathology in African Americans with arterionephrosclerosis or putative 'hypertension-associated' nephropathy are unknown. APOL1 genotype-phenotype correlations were performed in a blinded manner from renal biopsies in 196 self-reported African Americans with arterionephrosclerosis on kidney biopsy at a large national nephropathology practice. Subjects had chronic kidney disease without nephrotic syndrome. A discovery analysis compared histopathologic changes in the glomerular and tubulointerstitial compartments in 58 subjects with 2 versus 56 subjects with 0 APOL1 risk variants. Validation was performed in biopsies from 82 additional subjects with 0, 1, and 2 risk variants. Two risk variant versus zero risk variant group genotype associations and subphenotypes were assessed by χ(2) analyses. ANOVA compared means of continuous variables. In discovery analyses, significantly less obsolescent glomerulosclerosis, more (solidified and disappearing) glomerulosclerosis, more thyroidization-type tubular atrophy, and more microcystic tubular dilatation were seen in patients with two versus zero APOL1 risk alleles. Greater degrees of arteriosclerosis were present in those with zero risk alleles. Segmental glomerulosclerosis did not differ significantly between groups. Presence of two of the following discriminatory histopathologic findings from discovery, that is, <50% obsolescent glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilatation, was specific for the presence of two APOL1 risk alleles in the validation phase. African Americans with arterionephrosclerosis who possess two APOL1 risk variants more often lack obsolescent glomerulosclerosis and have greater degrees of (solidified and disappearing) glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilation than patients with fewer than two risk variants. These findings support involvement of multiple cell types in subnephrotic forms of APOL1-associated nephropathy, particularly renal tubule cells with resultant tubulointerstitial disease.

There have been recent reports and warnings of a thrombotic thrombocytopenic purpura-like illness associated with intravenous abuse of a prescription narcotic intended for oral use. Oral extended-release oxymorphone hydrochloride (Opana ER) is an opioid agonist that has undergone a tamper-resistant reformulation. However, instances of melting and dissolving tablets with subsequent injection continue to occur. We report 3 cases of hemolytic anemia and acute kidney injury associated with intravenous abuse of this reformulated drug. All 3 patients underwent native kidney biopsy that showed thrombotic microangiopathy characterized by severe arterial and arteriolar mucoid intimal edema with resultant glomerular and tubular ischemia. All 3 patients required hemodialysis and 2 also underwent therapeutic plasma exchange. Early follow-up suggests that kidney outcome is poor, with only partial recovery of function despite aggressive treatment. The specific component or components of this reformulated drug associated with endothelial injury is unknown. Most importantly, a high degree of clinical suspicion is needed when treating patients with a thrombotic thrombocytopenic purpura-like illness of unknown cause., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Kidney disease as a complication of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), has been the subject of case reports. However, no cases series examining IBD and kidney disease has been published to date. This study aimed to evaluate a large series of kidney biopsy specimens from patients with IBD to better define the spectrum and relative frequencies of IBD-associated kidney pathology., Design, Setting, Participants, & Measurements: A retrospective review of native kidney biopsy specimens obtained from March 2001 to June 2012 identified 83 patients with IBD. Standard processing of all biopsy specimens included light microscopy, immunofluorescence, and electron microscopy., Results: There were 45 cases of CD and 38 cases of UC represented. The most common indication for kidney biopsy was acute or chronic kidney failure (63% [52 of 83]) and nephrotic-range proteinuria (16% [13 of 83]). IgA nephropathy was the most common diagnosis (24% [20 of 83]), followed by interstitial nephritis (19% [16 of 83]), arterionephrosclerosis (12% [10 of 83]), acute tubular injury (8% [7 of 83]), proliferative GN (7% [6 of 83]), and minimal-change disease (5% [4 of 83]). When compared, the frequency of IgA nephropathy in IBD was significantly higher than in all other native renal biopsy specimens from the same time period (24% [20 of 83] versus 8% [2734 of 33,630]; P<0.001). Of the 16 cases of interstitial nephritis, 9 (56%) had current or recent past exposure to aminosalicylates, including all cases of granulomatous interstitial nephritis., Conclusions: IBD is associated with a spectrum of kidney diseases most commonly affecting the glomerular and tubulointerstitial compartments. IgA nephropathy is the most frequent kidney biopsy diagnosis in IBD and has a significantly higher diagnostic prevalence compared with all non-IBD kidney biopsy specimens. This may reflect a common pathogenic mechanism. Although many cases of tubulointerstitial nephritis are related to aminosalicylate exposure, the possibility of a direct relationship with IBD cannot be ruled out.