A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

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The spectrum of tumors arising in the salivary glands is wide and has recently been shown to harbor a network of tumor-specific fusion genes. Acinic cell carcinoma (AciCC) is one of the more frequently encountered types of salivary gland carcinoma, but it has remained a genetic orphan until recently when a fusion between the HTN3 and MSANTD3 genes was described in one case. Neither of these 2 genes is known to be implicated in any other malignancy. This study was undertaken to investigate whether the HTN3-MSANTD3 fusion is a recurrent genetic event in AciCC and whether it is a characteristic of one of its histological variants. Of the 273 AciCCs screened, 9 cases showed rearrangement of MSANTD3 by break-apart fluorescence in situ hybridization, 2 had 1 to 2 extra signals, and 1 had gain, giving a total of 4.4% with MSANTD3 aberrations. In 6 of 7 available cases with MSANTD3 rearrangement, the HTN3-MSANTD3 fusion transcript was demonstrated with real-time polymerase chain reaction. Histologically, all fusion-positive cases were predominantly composed of serous tumor cells growing in solid sheets, with serous tumor cells expressing DOG-1 and the intercalated duct-like cell component being CK7 positive and S-100 positive in 6/9 cases. All but one case arose in the parotid gland, and none of the patients experienced a recurrence during follow-up. In contrast, the case with MSANTD3 gain metastasized to the cervical lymph nodes and lungs. In conclusion, we find the HTN3-MSANTD3 gene fusion to be a recurrent event in AciCC with prominent serous differentiation and an indolent clinical course.

Pathogenic gene fusions have been identified in several histologic types of salivary gland neoplasia, but not previously in acinic cell carcinoma (AcCC). To discover novel gene fusions, we performed whole-transcriptome sequencing surveys of three AcCC archival cases. In one specimen we identified a novel HTN3-MSANTD3 gene fusion, and in another a novel PRB3-ZNF217 gene fusion. The structure of both fusions was consistent with the promoter of the 5’ partner (HTN3 or PRB3), both highly expressed salivary gland genes, driving overexpression of full-length MSANTD3 or ZNF217. By fluorescence in situ hybridization of an expanded AcCC case series, we observed MSANTD3 rearrangements altogether in 3 of 20 evaluable cases (15%), but found no additional ZNF217 rearrangements. MSANTD3 encodes a previously uncharacterized Myb/SANT domain-containing protein. Immunohistochemical staining demonstrated diffuse nuclear MSANTD3 expression in 8 of 27 AcCC cases (30%), including the three cases with MSANTD3 rearrangement. MSANTD3 displayed heterogeneous expression in normal salivary ductal epithelium, as well as among other histologic types of salivary gland cancer though without evidence of translocation. In a broader survey, MSANTD3 showed variable expression across a wide range of normal and neoplastic human tissue specimens. In preliminary functional studies, engineered MSANTD3 overexpression in rodent salivary gland epithelial cells did not enhance cell proliferation, but led to significant upregulation of gene sets involved in protein synthesis. Our findings newly identify MSANTD3 rearrangement as a recurrent event in salivary gland AcCC, providing new insight into disease pathogenesis, and identifying a putative novel human oncogene.

recent WHO classification of primary sinonasal malignancies contains 44 distinct histopathologic entities [3]. Understandably, these cancers present a formidable challenge for both the surgeon and pathologist.In this article we present an unusual case of clear cell neoplasia of the paranasal sinuses found to be consistent with sinonasal renal cell-like adenocarcinoma (SNRCLA). The finding of clear cell neoplasia in a sinonasal specimen is rare but associated with a surprisingly wide differential diagnosis. When evaluating the differential diagnosis for a clear cell neoplasm of the sinonasal tract, an underlying renal cell carcinoma (RCC) must first be ruled out. RCC is the most common metastatic lesion to the nasal cavity and paranasal sinuses [4] and approximately 6-15% of patients with RCC will have metastatic deposits in the head and neck [5,6]. In addition to metastatic RCC, other diagnostic considerations for clear cell neoplasia in the paranasal sinuses include a clear cell variant of squamous cell carcinoma, melanoma, primary salivary clear cell carcinoma, metastatic clear cell thyroid carcinoma, clear cell predominant mucoepidermoid carcinoma, and SNRCLA. Case ReportAn 80 year old female presented to our otolaryngology clinic with an asymptomatic right sinonasal mass. She reported a history of left sided acinic cell carcinoma treated at an outside institution with endonasal resection and adjuvant radiotherapy approximately eight years prior. Diagnostic nasal endoscopy revealed a large friable soft tissue mass arising from the lateral nasal wall near the axilla of the right middle turbinate. Imaging revealed a 3 cm tumor centered at the right nasolacrimal sac with extension superiorly to involve the nasal septum and dura of the anterior Abstract The differential diagnosis for clear cell neoplasms of the sinonasal tract is wide but critical to understand. In this paper, we describe a case of renal cell-like adenocarcinoma (SNRCLA) presenting as a paranasal sinus mass with clear cell morphology. The relevant literature is reviewed and the workup for clear cell neoplasms described. SNRCLA is a rarely encountered low grade glandular malignancy of the paranasal sinuses. Despite its morphologic mimicry of renal cell carcinoma, SNRCLA demonstrates a seromucinous phenotype and is associated with a favorable prognosis and low recurrence rates after surgical resection.

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