Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury

During renal ischemia-reperfusion, local and distant tissue injury is caused by an influx of neutrophils into the affected tissues. Here we measured the kinetics of margination and transmigration of neutrophils in vivo in the kidney and lungs following renal ischemia-reperfusion. After bilateral renal injury, kidney neutrophil content increased threefold at 24 h. The neutrophils were found primarily in the interstitium and to a lesser degree marginated to the vascular endothelium. These interstitial neutrophils had significantly lower levels of intracellular IFN-γ, IL-4, IL-6, and IL-10 a tendency for decreased amounts of IL-4 and TNF-α compared to the marginated neutrophils. Localization of the neutrophils to the kidney interstitium was confirmed by high resolution microscopy and these sites of transmigration were directly associated with areas of increased vascular permeability. Activation of the adenosine 2A receptor significantly decreased both kidney neutrophil transmigration by about half and vascular permeability by about a third. After unilateral renal ischemia-reperfusion, the unclipped kidney and lungs did not accumulate interstitial neutrophils or have increased vascular permeability despite a marked increase of neutrophil margination in the lungs. Our findings suggest there is a sequential recruitment and transmigration of neutrophils from the vasculature into the kidney interstitium at the site of tissue injury following renal ischemia-reperfusion

DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and ‘hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study)

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types

Thrombotic Thrombocytopenia Purpura Complicated with ANCA Induced Vasculitis

Case Presentation: A 68-year-old woman with a past medical history of hypertension and relapsing thrombotic thrombocytopenic purpura (TTP) presented with acute kidney injury. The patient had been diagnosed with TTP 9 years previously and had three subsequent relapses. The last episode was seven years prior to the biopsy. During this period, she had received treatment with steroids, Rituximab, and plasmapheresis. Non-steroidal anti-inflammatory drugs had been taken for hip pain during the previous six months but had been discontinued approximately one month before presentation due to a slight increase in serum creatinine (Cr) from a baseline of 1.0 to 1.3. Despite this measure, renal function continued to deteriorate with Cr reaching 2.3. The patient reported no fevers, chills, sinus, or respiratory symptoms. There was no skin rash. A renal ultrasound showed no evidence of hydronephrosis. Urinalysis revealed nephrotic-range proteinuria and microscopic hematuria with no dysmorphic forms. Hematologic testing revealed normocytic anemia with a hemoglobin level of 9.2. Serology revealed positive perinuclear anti-neutrophil cytoplasmic antibody (P-ANCA) at 1:320, as well as positive antinuclear antigen (ANA), anti-Smith, Sjögren syndrome-related antigen A (SSA), ribonucleoprotein (RNP), and anti-chromatin B antibodies. Anti-ds DNA antibody, cytoplasmic ANCA, and anti-glomerular basement membrane antibodies were all negative. A kidney biopsy demonstrated necrotizing glomerulonephritis with scant immune complex formation, consistent with ANCA-associated glomerulonephritis. No evidence of TTP was found on the biopsy. The patient was admitted for emergent immunosuppression, including intravenous steroids and Rituximab, resulting in improved kidney function. Discussion: TTP is characterized by microangiopathy that leads to thrombocytopenia and hemolytic anemia. Clinical manifestations include fever, severe renal disease, and neurological symptoms such as headaches, confusion, and even transient ischemic attacks. Autoantibodies against disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) proteases are thought to be the most common cause of TTP. Several studies have shown an association between TTP and vasculitic disorders, including thromboangiitis obliterans, Behçet\u27s disease, and ANCA-associated vasculitis. ANCA-associated vasculitis divided into three main disorders. These disorders are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis. Renal-Limited Vasculitis (RLV) is pauci-immune necrotizing glomerulonephritis that is considered as part of GPA and MPA. Patients with RLV may subsequently develop extrarenal manifestations of GPA or MPA. We hypothesize that patients with TTP due to autoimmune antibodies are at risk for autoimmune vasculitis. These disorders are treated successfully with rituximab and steroids