The novel coronavirus SARS-CoV-2 (coronavirus disease 19, or COVID-19) primarily causes pulmonary injury, but has been implicated to cause hepatic injury, both by serum markers and histologic ...evaluation. The histologic pattern of injury has not been completely described. Studies quantifying viral load in the liver are lacking. Here we report the clinical and histologic findings related to the liver in 40 patients who died of complications of COVID-19. A subset of liver tissue blocks were subjected to polymerase chain reaction (PCR) for viral ribonucleic acid (RNA). Peak levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated; median ALT peak 68 U/l (normal up to 46 U/l) and median AST peak 102 U/l (normal up to 37 U/l). Macrovesicular steatosis was the most common finding, involving 30 patients (75%). Mild lobular necroinflammation and portal inflammation were present in 20 cases each (50%). Vascular pathology, including sinusoidal microthrombi, was infrequent, seen in six cases (15%). PCR of liver tissue was positive in 11 of 20 patients tested (55%). In conclusion, we found patients dying of COVID-19 had biochemical evidence of hepatitis (of variable severity) and demonstrated histologic findings of macrovesicular steatosis and mild acute hepatitis (lobular necroinflammation) and mild portal inflammation. We also identified viral RNA in a sizeable subset of liver tissue samples.
Transplantable kidneys are in very limited supply. Accurate viability assessment prior to transplantation could minimize organ discard. Rapid and accurate evaluation of intra-operative donor kidney ...biopsies is essential for determining which kidneys are eligible for transplantation. The criterion for accepting or rejecting donor kidneys relies heavily on pathologist determination of the percent of glomeruli (determined from a frozen section) that are normal and sclerotic. This percentage is a critical measurement that correlates with transplant outcome. Inter- and intra-observer variability in donor biopsy evaluation is, however, significant. An automated method for determination of percent global glomerulosclerosis could prove useful in decreasing evaluation variability, increasing throughput, and easing the burden on pathologists. Here, we describe the development of a deep learning model that identifies and classifies non-sclerosed and sclerosed glomeruli in whole-slide images of donor kidney frozen section biopsies. This model extends a convolutional neural network (CNN) pre-trained on a large database of digital images. The extended model, when trained on just 48 whole slide images, exhibits slide-level evaluation performance on par with expert renal pathologists. Encouragingly, the model's performance is robust to slide preparation artifacts associated with frozen section preparation. The model substantially outperforms a model trained on image patches of isolated glomeruli, in terms of both accuracy and speed. The methodology overcomes the technical challenge of applying a pretrained CNN bottleneck model to whole-slide image classification. The traditional patch-based approach, while exhibiting deceptively good performance classifying isolated patches, does not translate successfully to whole-slide image segmentation in this setting. As the first model reported that identifies and classifies normal and sclerotic glomeruli in frozen kidney sections, and thus the first model reported in the literature relevant to kidney transplantation, it may become an essential part of donor kidney biopsy evaluation in the clinical setting.
Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and ...outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs. 11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.
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ABSTRACT
Acute interstitial nephritis (AIN), defined by the presence of interstitial inflammation accompanied by tubulitis, is an often overlooked cause of acute kidney injury (AKI). It is now well ...established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause a wide variety of kidney injuries, most commonly acute tubular injury and collapsing glomerulopathy. In comparison, AIN is rarely documented in association with SARS-CoV-2 both anecdotally and in larger series of autopsy or biopsy studies. In this issue of the Journal, León-Román describe five cases of AIN in patients with a history of coronavirus disease 2019 (COVID-19) and highlight AIN as a possibly under-reported or ignored facet of renal disease associated with SARS-CoV-2. They describe three scenarios in which AIN can be seen: (i) SARS-CoV-2 infection after diagnosis of AIN, (ii) AIN followed by SARS-CoV-2 infection in the same admission and (iii) Severe SARS-CoV-2 and AIN possibly associated with SARS-CoV-2 itself. Overall, AIN remains rare in SARS-CoV-2 and causality is difficult to ascertain. Interestingly, AIN is not only seen in association with the disease itself but also with SARS-CoV-2 vaccination. This scenario is equally rare and causality is no less difficult to prove. A history of preceding SARS-CoV-2 infection and vaccination should be actively sought when patients present with otherwise unexplained AIN.
In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this ..."stand-alone" kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis.
Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed.
Five characteristic features of lupus nephritis were identified: "full-house" staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98.
In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis.
Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings ...in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment.
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Introduction: Immune checkpoint inhibitor (ICPI) therapy is used to treat various malignancies; however, it can be associated with off-target effects including kidney injury. Acute tubulointerstitial ...nephritis is the most commonly described renal pathology associated with ICPIs, although less frequently, glomerulopathies may be identified when a kidney biopsy is performed in the work-up of acute kidney injury (AKI). Case Presentation: Two patients with small cell carcinoma of the lung were treated with etoposide, carboplatin, and the ICPI atezolizumab. During 2 and 1.5 months of atezolizumab therapy, respectively, patients developed AKI, hematuria, and proteinuria, and kidney biopsies were performed. Both biopsies showed fibrillary glomerulonephritis with focal crescentic features. One patient died 5 days after the kidney biopsy, while the second showed improvement of renal function after discontinuation of atezolizumab and initiation of corticosteroid therapy. Discussion: We describe two cases of fibrillary glomerulonephritis with crescents after administration of atezolizumab. Development of impaired kidney function following initiation of ICPI therapy in both cases raises the possibility that ICPI therapy may potentiate the development of endocapillary proliferation and crescents (i.e., an “active” glomerulitis) via immune modulation. Thus, exacerbation of underlying glomerulonephritis should be kept in the differential diagnosis of patients who develop AKI, proteinuria, and hematuria following ICPI therapy.
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