A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

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.

Hemolysis-associated hemoglobin cast nephropathy results from a range of clinicopathologic disorders.

Intravascular hemolysis is relatively rare but can lead to acute kidney injury (AKI), from increased destruction of erythrocytes and release of free hemoglobin. Since hemolysis and hemoglobinuria are known causes of acute kidney injury we sought to define clinicopathologic findings and outcomes of patients with hemolysis-associated hemoglobin cast nephropathy through a retrospective analysis of 27 cases. The mean patient age was 47 years (range 19-79) and the female-to-male ratio was 1.3:1. All patients presented with AKI with a mean serum creatinine of 8.0 (range 2.9-17.0) mg/dL. Etiologies included autoimmune hemolytic anemia (30%), medication (26%), paroxysmal nocturnal hemoglobinuria (7%), procedural/mechanical causes (7%), transfusion of incompatible blood (4%), toxin ingestion (4%), disseminated intravascular coagulation (4%), and hemoglobinopathy (4%). All biopsies showed acute tubular injury and pigmented, proteinaceous casts characterized by positive hemoglobin immunohistochemistry. After a mean follow-up of nine months (range 0.5-26), the mean serum creatinine was 1.3 (range 0.6-3.3) mg/dL, with 78% of patients returning to normal kidney function. Thus, based on our clinicopathologic case series, hemolysis-associated hemoglobin cast nephropathy is an important entity for clinicians and pathologists to recognize as treatment hinges upon elimination of the pathogenic driver of intravascular hemolysis.

LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease.

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.

Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits.

The diagnosis of membranoproliferative glomerulonephritis (MPGN) has recently undergone change from an electron microscopy-based classification scheme to one based largely on immunofluorescence findings. This change is due to the recognition that many of these cases are driven by abnormalities of the alternative complement cascade, resulting in the concept of C3 glomerulopathy. Here we reviewed our case files to identify those with an MPGN pattern that show false negative staining for monoclonal immunoglobulins by routine immunofluorescence. Monoclonal immunoglobulin deposits were unmasked by performing immunofluorescence on formalin-fixed paraffin embedded tissue after protease digestion. Clinico-pathological details of 16 such cases with a mean serum creatinine of 2.7 mg/dl and mean 24 h proteinuria of 7.1 g were then determined. Hypocomplementemia was present in two-thirds of patients. Fourteen patients had a paraprotein on serum immunofixation, all of which matched the biopsy immunofluorescence staining pattern. Bone marrow biopsy showed plasma cell dyscrasia or B-cell lymphoproliferative disorder in 13 patients. Ten of these patients had findings on biopsy most consistent with C3 glomerulonephritis prior to performing paraffin immunofluorescence. Thus a high index of suspicion is necessary to avoid misdiagnosis in these cases, as many would have been mistakenly diagnosed as C3 glomerulopathy or unclassified MPGN if paraffin immunofluorescence was not performed.

Paraffin immunofluorescence in the renal pathology laboratory: more than a salvage technique.

Immunofluorescence studies on paraffin-embedded tissue after Pronase digestion (paraffin immunofluorescence) is used as a salvage technique in renal pathology, when frozen tissue for routine immunofluorescence is inadequate. We have recently found that it is also useful in rare cases in which the immune deposits are 'masked' on routine immunofluorescence, giving false-negative staining by routine immunofluorescence and positive staining by paraffin immunofluorescence. This study aims to evaluate the role of paraffin immunofluorescence in clinical practice with emphasis on its utility to avoid misdiagnosis of cases with masked immune complex deposits. Paraffin immunofluorescence was used in 304 (6.1%) of 4969 native biopsies reviewed from our files. In 207 (68.1%) cases, paraffin immunofluorescence was used as a salvage technique. It was necessary for diagnosis in 24 (11.6%) and had a significant contribution in 63 (30.4%) of these cases. Paraffin immunofluorescence was used to evaluate masked deposits in 97 (31.9%) cases. In 61 (62.9%) of these cases it was used to evaluate masked immune complex glomerular deposits, and in 36 cases (37.1%) it was used to evaluate masked paraproteins. Of the cases where immune complex deposits were sought, paraffin immunofluorescence was necessary for diagnosis in 16 (26.2%) cases and had a significant contribution in 4 (6.6%) cases. Fourteen of the 20 cases with masked deposits had C3 dominant stain by routine immunofluorescence, which could have been misdiagnosed as C3 glomerulopathy. Overall, paraffin immunofluorescence was necessary or had a significant contribution to diagnosis in >1/3 of the cases and is a valuable technique in renal pathology.

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease.

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.

Membranous-like glomerulopathy with masked IgG kappa deposits.

The diagnostic classification of glomerulonephritis is determined by the interplay of changes seen using light, immunofluorescence, and electron microscopy of the renal biopsy. Routine direct immunofluorescence on fresh tissue is currently considered the gold standard for the detection and characterization of immune deposits. We recently found a peculiar form of glomerular immune complex deposition in which masked deposits required an antigen-retrieval step to be visualized. Over a 2-year period, 14 cases were characterized by numerous, large subepithelial deposits visualized by electron microscopy and C3-predominant staining by routine immunofluorescence on fresh tissue with weak to negative immunoglobulin staining. Repeat immunofluorescence after digestion of the formalin-fixed paraffin-embedded tissue with pronase elicited strong IgG-κ staining restricted within the deposits. The patients were often young with a mean age of 26 years and commonly had clinical evidence of vague autoimmune phenomenon. The clinicopathologic findings in this unusual form of glomerulopathy do not fit neatly into any currently existing diagnostic category. We have termed this unique form of glomerulopathy membranous-like glomerulopathy with masked IgG-κ deposits.

Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies.

Autoantibody formation directed against phospholipase A2 receptor (PLA2R)1 is the underlying etiology in most cases of primary membranous glomerulopathy. This new understanding of the pathogenesis of primary membranous is in the process of transforming the way the disease is diagnosed. We validated an indirect immunofluorescence assay to examine PLA2R1 in renal biopsies utilizing a commercially available antibody and standard indirect immunofluorescence. Using this assay, we examined a total of 165 cases of membranous glomerulopathy including 85 primary and 80 secondary. We found tissue staining for PLA2R1 to have a sensitivity of 75% (95% CI 65-84%) and a specificity of 83% (95% CI 72-90%) for primary membranous glomerulopathy. Hepatitis C virus was the secondary etiology with the most number of cases staining positive for PLA2R1 (7/11, 64%) followed by sarcoidosis (3/4, 75%) and neoplasm (3/12, 25%). Autoimmune etiologies showed rare PLA2R1-positive staining (1/46, 2%). All cases of secondary membranous glomerulopathy with positive PLA2R1 showed IgG4-predominant staining, which is typically associated with primary membranous glomerulopathy. This IgG4 predominance raises the possibility that these cases are more pathogenically related to primary membranous glomerulopathy than secondary. We present the largest case series to date examining PLA2R1 involvement in membranous glomerulopathy utilizing a technique that is readily adoptable by most renal pathology laboratories.

Identification of betaArrestin2 as a corepressor of androgen receptor signaling in prostate cancer.

Androgen receptor (AR) signaling regulates the development and homeostasis of male reproductive organs, including the prostate. Deregulation of AR and AR coregulators, expression, or activity is involved in the initiation of prostate cancer and contributes to the transition of the disease to hormone-refractory stage. The ubiquitous betaArrestin proteins are now recognized as bona fide adapters and signal transducers with target effectors found in both the cytosol and nucleus. Here, we provide evidence that betaArrestin2 forms a complex with AR and acts as an AR corepressor in androgen-dependent prostate cancer cells. Accordingly, the forced overexpression of betaArrestin2 diminishes, and knockdown of betaArrestin2 expression with RNAi increases the androgen-induced prostate-specific antigen (PSA) gene expression. betaArrestin2 serves as an adapter, bringing into close proximity the Mdm2 E3 ligase and AR, thereby promoting AR ubiquitylation and degradation. Human prostate tissues evidence an inverse relationship between the expression of betaArrestin2 and AR activity: glands that express high levels of betaArrestin2 exhibit low expression of PSA, and those glands that express low levels of betaArrestin2 evidence elevated PSA levels. We conclude that betaArrestin2 acts as a corepressor of AR by serving as a scaffold for Mdm2 leading to the AR ubiquitylation and degradation.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits triggered by COVID-19: a case report.

Acute kidney injury (AKI) frequently complicates corona virus disease 2019 (COVID-19) and is associated with significant mortality. Kidney disease in COVID-19 is usually due to acute tubular injury, but a variety of glomerular processes, especially collapsing glomerulopathy, have been increasingly described. Until recently, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) had not been reported in the setting of COVID-19. We present a case of dialysis-dependent AKI developing soon after symptomatic COVID-19 which, on kidney biopsy, was found to be due to PGNMID with IgG3 kappa deposits. As is typical of PGNMID, a search for evidence of extra-renal monoclonal immunoglobulin or clonal lymphocyte population was negative. However, the patient had a favorable response to anti-plasma cell therapy and was ultimately able to stop hemodialysis. Though monoclonal gammopathy of renal significance (MGRS) is usually not associated with infection, other cases of post-viral MGRS, including PGNMID, have been previously reported. PGNMID has recently been linked specifically to COVID-19, with this representing one of only four cases reported thus far. Though causality between the preceding viral infection and the subsequent glomerulonephritis cannot be proven in these reports, nephrologists should be aware that not all kidney disease occurring in the aftermath of COVID-19 is due to tubular injury or collapsing glomerulopathy. As such, kidney biopsy should be routinely considered in the setting of COVID-19-associated glomerular disease as findings may change management. In the case of COVID-19-associated PGNMID data to guide treatment are limited, but our report suggests that anti-plasma cell therapy may be effective.

The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation.

The renal diseases most frequently associated with myeloma include amyloidosis, monoclonal immunoglobulin deposition disease, and cast nephropathy. Less frequently reported is light chain proximal tubulopathy, a disease characterized by κ-restricted crystal deposits in the proximal tubule cytoplasm. Light chain proximal tubulopathy without crystal deposition is only loosely related to the typical light chain proximal tubulopathy, and little is known about this entity. A search was performed of the 10 081 native kidney biopsy samples processed by our laboratory over the past 2 years for cases that had light chain restriction limited to the proximal tubule cytoplasm. A total of 10 cases of light chain proximal tubulopathy without crystal deposition were found representing 3.1% of light chain-related diseases. Nine of these 10 showed λ-light chain restriction. Only three cases of light chain proximal tubulopathy with crystals were found accounting for 0.9% of light chain-related diseases. Two of these three were κ subtype. Plasma cell dyscrasia was unsuspected in seven of the 10 patients with light chain proximal tubulopathy without crystals at the time of renal biopsy. After the biopsy was reported, follow-up was available on 9/10 patients with 9/9 showing a plasma cell dyscrasia including 8/9 with multiple myeloma. We found that light chain proximal tubulopathy without crystal formation, despite being rarely described in the literature, is over three times more common than light chain proximal tubulopathy with crystal formation in our series. And given that it is often associated with previously unrecognized myeloma, it is a critically important diagnosis.

Interstitial cells of the white matter in the dorsolateral prefrontal cortex in deficit and nondeficit schizophrenia.

An increased density of neurons in the white matter of the neocortex has been found in schizophrenia, and the original reports suggested this abnormality was restricted to a subgroup of patients. In a study of the inferior parietal cortex, we found that deficit schizophrenia subjects, but not nondeficit subjects, had an increased density of ICWMs. We extended that finding by comparing the density of microtubule-associated protein 2-immunoreactive ICWMs in deficit schizophrenia (N = 3), nondeficit schizophrenia (N = 4), and control (N = 5) subjects, using postmortem tissue from the dorsolateral prefrontal cortex (Brodmann area 46). The deficit group differed significantly from the other two groups; the respective mean (SD) density values for the deficit, nondeficit, and control groups were 1.27 (.10),.53 (.39), and.76 (.20) cells per 10-6 cubic microns. These group differences provide further evidence that deficit and nondeficit schizophrenia differ in their pathophysiology.

Acute myeloid leukemia with t(8; 21)(q22; q22) preceded by breast granulocytic sarcoma / Leucemia mielóide aguda com t(8; 21)(q22; q22) precedido de sarcoma granulocítico na mama

Granulocytic sarcoma (GS) is a rare extramedullary tumor mass composed of immature cells derived from the hematopoietic myeloid series. It is usually associated with leukemia and other myeloproliferative disorders but can also occur without overt hematologic diseases. The breast has been reported to be an uncommon site of presentation. We report a case of acute myeloid leukemia preceded by GS of the breast. The immunohistochemistry revealed myeloperoxidase, CD68 and CD43 positivity, thus indicating a diagnosis of GS. Conventional cytogenetic analysis of peripheral blood cells showed t(8;21)(q22;22). Complete remission was achieved with Daunorubicin and Cytarabine induction therapy followed by three courses of high-dose Cytarabine consolidation. The patient remains in continuous complete remission at 27 months.

Sarcoma granulocítico (GS) é um raro tumor extramedular composto de células imaturas derivadas das linhagens hematopoiéticasmielóides. É geralmente associada à leucemia ou outras desordens mieloproliferativas, mas também pode ocorrer sem manifestação de doenças hematológicas. A mama tem sido relatada como local incomum de apresentação. Relatamos um caso de leucemia mielóide aguda precedida por GS da mama. A imunohistoquímica revelou mieloperoxidase, CD68 e CD43 positivos, indicando um diagnóstico da GS. A análise citogenética convencional de células de sangue periférico mostrou t(8; 21)(q22; 22). Remissão completa foi atingida com indução terapêutica com daunorubicina e citarabina, seguida de três ciclos de alta dose de citarabina. O paciente permanece em completa remissão há 27 meses.