Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with vasculitis. Current therapy involves administration of toxic therapy that is not optimally effective. The review will summarize evidence for the pathogenicity of ANCA, which will suggest possible strategies for improving treatment

Phenotypic heterogeneity in females with X-linked Alport syndrome

Aims: X-linked Alport syndrome (AS) is a monogenic inherited disorder of type IV collagen, a structural protein in the kidney and cochlea. Males typically exhibit a severe phenotype with end-stage renal disease (ESRD) and/or deafness by early adulthood. Because of the presence of two X chromosomes, females often have a less severe phenotype and hence the diagnosis of AS is often not considered. Herein, we present a case of an adolescent girl with proteinuria and hematuria in the setting of a strong family history of AL. Case report: The mother and maternal aunt of the proband had both presented with dipstick positive hematuria and proteinuria at age 8 years. These girls were not evaluated by nephrology until mid-adolescence when they had worsening creatinine levels. Kidney biopsy in the younger sister demonstrated segmental glomerulosclerosis with segmental thinning and lamination of the glomerular basement membrane, consistent with AS. Kidney biopsy in the older sister was performed just prior to the need for renal replacement therapy and showed only global glomerulosclerosis. Both sisters were transplanted by the age of 20 years. Their mother subsequently developed ESRD at age 53 years. With the advent of genetic testing, the proband and her family were brought in for evaluation. It had been assumed this family of AS had autosomal dominant transmission, however, genetic testing of the proband was positive for a splice site mutation of COL4A5 located on the X-chromosome. Sequencing of genes COL4A3, COL4A4, and COL4A6 were negative for mutation. Conclusions: The current case report demonstrates the importance of considering skewed X-inactivation in females who exhibit signs or symptoms of X-linked disorders

Diagnostic Significance of Peritubular Capillary Basement Membrane Multilaminations in Kidney Allografts: Old Concepts Revisited

Injury to peritubular capillaries and capillary basement membrane multilamination (PTCL) is a hallmark of antibody-mediated chronic renal allograft rejection. However, the predictive diagnostic value of PTCL is incompletely studied

Treatment with Glucocorticoids or Calcineurin Inhibitors in Primary FSGS

In primary FSGS, calcineurin inhibitors have primarily been studied in patients deemed resistant to glucocorticoid therapy. Few data are available about their use early in the treatment of FSGS. We sought to estimate the association between choice of therapy and ESRD in primary FSGS

The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies.

BACKGROUND: In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment. DESIGN: We reviewed 277 biopsies from the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository, enumerating 9,379 glomeruli by means of whole slide imaging. Glomerular number and the percentage of globally sclerotic glomeruli are values routinely recorded in the official renal biopsy pathology report from the 25 participating centers. Two general trends in reporting were noted: total number per biopsy or average number per level/section. Both of these approaches were assessed for their accuracy in comparison to the analogous numbers of annotated glomeruli on WSI. RESULTS: The number of glomeruli annotated was consistently higher than those reported (p CONCLUSIONS: Although glass slides were not available for direct comparison to whole slide image annotation, this study indicates that routine manual light microscopy assessment of number of glomeruli is inaccurate, and the magnitude of this error is proportional to the total number of glomeruli

The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies

In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment

Palladin is Upregulated in Kidney Disease and Contributes to Epithelial Cell Migration After Injury

Recovery from acute kidney injury involving tubular epithelial cells requires proliferation and migration of healthy cells to the area of injury. In this study, we show that palladin, a previously characterized cytoskeletal protein, is upregulated in injured tubules and suggest that one of its functions during repair is to facilitate migration of remaining cells to the affected site. In a mouse model of anti-neutrophilic cytoplasmic antibody involving both tubular and glomerular disease, palladin is upregulated in injured tubular cells, crescents and capillary cells with angiitis. In human biopsies of kidneys from patients with other kidney diseases, palladin is also upregulated in crescents and injured tubules. In LLC-PK1 cells, a porcine proximal tubule cell line, stress induced by transforming growth factor-β1 (TGF-β1) leads to palladin upregulation. Knockdown of palladin in LLC-PK1 does not disrupt cell morphology but does lead to a defect in cell migration. Furthermore, TGF-β1 induced increase in the 75 kDa palladin isoform occurs in both the nucleus and the cytoplasm. These data suggest that palladin expression is induced in injured cells and contributes to proper migration of cells in proximal tubules, possibly by regulation of gene expression as part of the healing process after acute injury

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

About one third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below normal transforming growth factor (TGF) β1 expression ameliorates the nephropathy and decreased glomerular filtration rate resulting from long-standing type 1 diabetes, while above normal TGFβ1 expression makes both worse. Reducing TGFβ1 expression in the glomerulus is more important in avoiding the decrease in glomerular filtration rate than altering expression in the tubule, while expression in the tubule is more important in controlling interstitial fibrosis and albuminuria. Suppressing TGFβ1 action in the kidney as a whole, or specifically in podocytes, could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes

Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images

The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen’s kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40<kappa ≤0.60) for 17 and good (0.60<kappa ≤0.80) for 8, for 52% with moderate or better kappas. Clustering of glomerular descriptors based on similar pathologic features improved concordance. Concordance was independent of years of experience, and increased with webinar cross-training. Excellent concordance was achieved for interstitial fibrosis and tubular atrophy. Moderate-to-excellent concordance was achieved for all ultrastructural podocyte descriptors, with good-to-excellent concordance for descriptors commonly used in clinical practice, foot process effacement, and microvillous transformation. NEPTUNE digital pathology scoring system enables novel morphologic profiling of renal structures. For all histologic and ultrastructural descriptors tested with sufficient observations, moderate-to-excellent concordance was seen for 31/54 (57%). Descriptors not sufficiently represented will require further testing. This study proffers the NEPTUNE digital pathology scoring system as a model for standardization of renal biopsy interpretation extendable outside the NEPTUNE consortium, enabling international collaborations