Immunoglobulin A vasculitis with periorbital edema and severe renal involvement: A case report.

Immunoglobulin A (IgA) vasculitis, or Henoch-Schonlein purpura, is the most common systemic vasculitis in children, clinically presenting as palpable purpura in combination with arthritis, gastrointestinal involvement, or kidney injury. Subcutaneous edema is reported in patients with IgA vasculitis, and it commonly affects the lower extremities, especially around joints. Here, we report a case of IgA vasculitis with a rare presentation of edema isolated to the periorbital area in a 7-year-old boy, who subsequently developed crescentic glomerulonephritis with nephrotic range proteinuria. Isolated periorbital edema is an uncommon cutaneous feature of IgA vasculitis.

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.

An Integrated Transcriptomic Approach to Identify Molecular Markers of Calcineurin Inhibitor Nephrotoxicity in Pediatric Kidney Transplant Recipients.

Calcineurin inhibitors are highly efficacious immunosuppressive agents used in pediatric kidney transplantation. However, calcineurin inhibitor nephrotoxicity (CNIT) has been associated with the development of chronic renal allograft dysfunction and decreased graft survival. This study evaluated 37 formalin-fixed paraffin-embedded biopsies from pediatric kidney transplant recipients using gene expression profiling. Normal allograft samples (n = 12) served as negative controls and were compared to biopsies exhibiting CNIT (n = 11). The remaining samples served as positive controls to validate CNIT marker specificity and were characterized by other common causes of graft failure such as acute rejection (n = 7) and interstitial fibrosis/tubular atrophy (n = 7). MiRNA profiles served as the platform for data integration. Oxidative phosphorylation and mitochondrial dysfunction were the top molecular pathways associated with overexpressed genes in CNIT samples. Decreased ATP synthesis was identified as a significant biological function in CNIT, while key toxicology pathways included NRF2-mediated oxidative stress response and increased permeability transition of mitochondria. An integrative analysis demonstrated a panel of 13 significant miRNAs and their 33 CNIT-specific gene targets involved with mitochondrial activity and function. We also identified a candidate panel of miRNAs/genes, which may serve as future molecular markers for CNIT diagnosis as well as potential therapeutic targets.

Resolution of IgA and C3 immune deposits in Staphylococcus infection-associated glomerulonephritis in a kidney transplant recipient
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Staphylococcus infection-associated glomerulonephritis (SAGN) is characterized by the presence of IgA and C3 as the predominant components present in the glomerular immune deposits. Glomerulonephritis frequently resolves after effective treatment of the staphylococcal infection. However, there have been few studies of repeat kidney biopsy after resolution of glomerulonephritis. We present a combined kidney-pancreas transplant patient who developed SAGN due to Staphylococcus aureus bacteremia from an old infected arteriovenous (AV) graft, which occurred after a long period of stable allograft function. Clinical improvement occurred following surgical debridement and appropriate antibiotics with subsequent clearance of bacteremia. However, 3 weeks later he presented with severe acute kidney injury related to rapidly progressive glomerulonephritis. Renal allograft biopsy revealed immune complex glomerulonephritis with predominance of IgA and C3 in subendothelial and mesangial deposits, consistent with SAGN. There was no evidence for recurrent staphylococcal infection. High-dose steroid therapy was followed by resolution of hematuria and improvement in allograft function with gradual return of serum creatinine concentration to near baseline levels. However, 1 year after the diagnosis of SAGN, he developed gradually worsening allograft function with persistent proteinuria. Repeat allograft biopsy showed sclerosing glomerular changes and extensive interstitial fibrosis and tubular atrophy. There was complete resolution of proliferative changes, and IgA and C3 deposits were no longer detectable. Despite transient allograft function stabilization, the patient progressed to end-stage renal disease (ESRD), and maintenance hemodialysis was reinitiated 2.5 years after the diagnosis of SAGN. Pancreatic allograft function remained normal.

Resolution of syphilis-related rapidly progressive glomerulonephritis with penicillin therapy: Case report
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Renal manifestations of syphilis are variable, with membranous nephropathy being the most commonly described lesion. Rapidly progressive glomerulonephritis (RPGN) is rare and there is only one case report in the literature describing syphilis-associated crescentic glomerulonephritis. We report a rare case of RPGN secondary to latent syphilis, which resolved with penicillin treatment in the absence of immunosuppressive therapy. A 28-year-old Black male with a history of HIV was evaluated for severe acute kidney injury, nephrotic-range proteinuria, and active urine sediment. Serologies for glomerulonephritis were negative. Rapid plasma reagin and treponema pallidum particle agglutination assay were reactive, confirming syphilis diagnosis. Kidney biopsy revealed focal and segmental necrotizing and crescentic lesion. Patient received weekly benzathine penicillin (PCN) for 3 weeks, and renal function improved to baseline. This dramatic improvement happened with PCN alone, a finding which has not been previously reported. We recommend that syphilis be considered in the differential diagnosis of all patients with proteinuria or suspected glomerulonephritis.

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.

Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.

Renal pathologists and nephrologists met on February 20, 2015 to establish an etiology/pathogenesis-based system for classification and diagnosis of GN, with a major aim of standardizing the kidney biopsy report of GN. On the basis of etiology/pathogenesis, GN is classified into the following five pathogenic types, each with specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular basement membrane GN, monoclonal Ig GN, and C3 glomerulopathy. The pathogenesis-based classification forms the basis of the kidney biopsy report. To standardize the report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The primary diagnosis should include the disease entity/pathogenic type (if disease entity is not known) followed in order by pattern of injury (mixed patterns may be present); score/grade/class for disease entities, such as IgA nephropathy, lupus nephritis, and ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. Guidelines for the report format, light microscopy, immunofluorescence microscopy, electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and provides guidelines for the standardized reporting of GN.

Update on endocarditis-associated glomerulonephritis.

Glomerulonephritis (GN) due to infective endocarditis (IE) is well documented, but most available data are based on old autopsy series. To update information, we now present the largest biopsy-based clinicopathologic series on IE-associated GN. The study group included 49 patients (male-to-female ratio of 3.5:1) with a mean age of 48 years. The most common presenting feature was acute kidney injury. Over half of the patients had no known prior cardiac abnormality. However, the most common comorbidities were cardiac valve disease (30%), intravenous drug use (29%), hepatitis C (20%), and diabetes (18%). The cardiac valve infected was tricuspid in 43%, mitral in 33%, and aortic in 29% of patients. The two most common infective bacteria were Staphylococcus (53%) and Streptococcus (23%). Hypocomplementemia was found in 56% of patients tested and ANCA antibody in 28%. The most common biopsy finding was necrotizing and crescentic GN (53%), followed by endocapillary proliferative GN (37%). C3 deposition was prominent in all cases, whereas IgG deposition was seen in <30% of cases. Most patients had immune deposits detectable by electron microscopy. Thus, IE-associated GN most commonly presents with AKI and complicates staphylococcal tricuspid valve infection. Contrary to infection-associated glomerulonephritis in general, the most common pattern of glomerular injury in IE-associated glomerulonephritis was necrotizing and crescentic glomerulonephritis.

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.

Clinical, morphologic, and genetic features of renal leukocyte chemotactic factor 2 amyloidosis.

Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is a recently described form of amyloidosis that most frequently manifests clinically with progressive renal failure. In a series of 414 cases of amyloidosis, there were 40 cases of ALECT2: the second most common type of renal amyloidosis in this series. This was particularly common in Hispanic patients in the Southwest United States, where more than half of amyloidosis cases were ALECT2. It is possible that this represents a familial amyloidosis as there were two brothers with ALECT2 in our study. Morphologically, there was consistent amyloid deposition in the renal cortex with medullary involvement in only about a third of cases. There were no mutations detected in the LECT2 gene, although all patients tested were homozygous for the G nucleotide in a non-synonymous SNP at position 172. Most patients presented with chronic kidney disease and, on follow-up, showed progression with an average deterioration in renal function of 0.5 ml/min/1.73 m(2) per month. Unfortunately, the etiology of ALECT2 is currently unknown and there is currently no efficacious treatment of the 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.

Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy.

Collapsing glomerulopathy is a devastating renal disease that primarily affects African Americans and associates with numerous etiologies, such as HIV and autoimmune disease. The presence of APOL1 risk alleles associates with HIV-associated collapsing glomerulopathy, but it is unknown whether these risk alleles also associate with systemic lupus erythematosus (SLE) -associated collapsing glomerulopathy. Here, re-examination of 546 renal biopsies from African-American patients with SLE identified 26 cases of collapsing glomerulopathy, which we genotyped for APOL1 risk alleles using DNA extracted from archived biopsy tissue. APOL1 strongly associated with SLE-associated collapsing glomerulopathy (P<0.001). In a recessive model, two APOL1 risk alleles conferred 5.4-fold (95% CI=2.4 to 12.1) higher odds of developing SLE-associated collapsing glomerulopathy (P<0.001). In conclusion, APOL1 genotyping of African-American patients with SLE might help identify patients at risk for collapsing glomerulopathy, an entity with a poor prognosis that is often resistant to treatment.

Successful use of rituximab in fibrillary glomerulopathy.

Fibrillary glomerulopathy (FG) can occur either alone or co-existing with other proteinuric glomerular disorders. FG has been associated with poor renal outcomes leading to End Stage Renal Disease (ESRD). Since FG is a relatively rare disorder, limited information is available concerning treatment protocols. We present two patients with FG who were treated with rituximab after they had already progressed to stage 3 chronic kidney disease (CKD) with worsening proteinuria. Rituximab therapy resulted in long-term stabilization of renal function.

Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis.

Rationale & Objective: Few data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics and correlates of histological disease severity in adults with FSGS who underwent a clinical kidney biopsy. Study Design: Real-world cohort study with data derived from health records. Setting & Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories from January 1, 2016 to May 31, 2020. Exposure: Race, chronic kidney disease stage, nephrotic proteinuria, age, sex, and hypertension. Outcomes: Severe histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical Approach: Demographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed using multiple logistic regression. Results: Among 2,011 patients with FSGS, 40.6% were White, and 23.6% Black. White patients were older (52.8 vs 45.5 years, P < 0.001) with a higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 vs 43.1 mL/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% vs 14.6%, P < 0.001) or IFTA >50% (34.6% vs 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (OR, 2.46; 95% CI, 1.59-3.79; P < 0.001). A higher proportion of patients with nephrotic than nonnephrotic proteinuria exhibited diffuse foot process effacement. Limitations: Unequal representation across United States regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. Conclusions: Black patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications. Plain-Language Summary: Focal segmental glomerulosclerosis (FSGS) accounts for around one-quarter of diagnoses derived from clinical kidney biopsies in the United States. Limited data are available regarding the classes and distribution of histological features at FSGS diagnosis among diverse real-world populations. Analyzing data from US patients who underwent kidney biopsy and were diagnosed with FSGS, we showed that up to half of patients had features of severe histological disease. Of this overall population, Black patients were more frequently diagnosed at a younger age but with more severe histological disease than White patients. The work highlights the need for timelier diagnosis of FSGS to enable intervention at an earlier disease stage.

Development and Use of Human Recombinant 64Cu-rHCF as a Kidney Glomerulus-Targeted Contrast Agent for Positron Emission Tomography.

In this work, we develop recombinant human cationic ferritin (rHCF) as a contrast agent to detect glomeruli in the kidney using positron emission tomography (PET). We first expressed recombinant human ferritin (rHF) in E. coli and then functionalized and radiolabeled it with Copper-64 (64Cu) to form 64Cu-rHCF. Intravenously injected 64Cu-rHCF bound to kidney glomeruli and was detected by PET. A subchronic toxicity study after an intravenous injection of rHCF revealed no significant toxicity. The development of rHCF is an important step toward the potential clinical translation of CF to detect the nephron number in humans.