Background Rosai-Dorfman disease (RDD) is a rare histiocytosis which involves principally lymph nodes. Thyroid involvement in RDD is a very rare situation, and lung involvement is even rarer. Case presentation We report the case of a 46-year-old woman presenting a painless mass in the right side of the neck and subacute dyspnoea. Computerised tomography (CT) scans of the neck and thorax showed a large thyroid mass causing tracheal stenosis and multiple cystic lesions in both lungs. Subtotal thyroidectomy with a tracheal segment resection and histological analysis confirmed the diagnosis of nodal and extranodal (thyroid, tracheal and probably lung) Rosai-Dorfman disease (RDD) with the presence of increased numbers of IgG4-bearing plasma cells. Clinical, functional and radiological follow up 4 years after surgery without medical treatment did not show any disease progression. Conclusions This case report indicates a benign course of nodal RDD with thyroid and tracheal infiltration following surgical resection, association of typical histological signs of RDD (emperipolesis) with IgG4-related disease features, and that lung cysts might be a manifestation of RDD.

Background Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxiainducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)-dependent sodium transport. Methods We investigated HIF's effect on ENaC expression in mpkCCDcl4 cells (a model of collecting duct principal cells) using real-time PCR and Western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule-specific Hif1α knockout mice. Results In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of βENaC and γENaC, as well as of Na,K-ATPase. HIF1α silencing increased βENaC and γENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γENaC abundance under high sodium intake. Conclusions This study reveals that γENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.

The cellular mechanisms of kidney tubule repair are poorly characterized in human. Here, we applied single-nucleus RNA sequencing to analyze the kidney in the first days after acute injury in 5 critically ill patients with COVID-19. We identified abnormal proximal tubule cell states associated with injury, characterized by altered functional and metabolic profiles and by pro-fibrotic properties. Tubule repair involved the plasticity of mature tubule cells in a process of cell de-differentiation and re-differentiation, which displayed substantial similarities between mouse and man. In addition, in man we identified a peculiar tubule reparative response determining the expansion of progenitor-like cells marked by PROM1 and following a differentiation program characterized by the sequential activation of the WNT, NOTCH and HIPPO signaling pathways. Taken together, our analyses reveal cell state transitions and fundamental cellular hierarchies underlying kidney injury and repair in critically ill patients.

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Phosphoenolpyruvate Carboxykinase 1 (PCK1, PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis and cataplerosis in the liver. Kidney proximal tubule cells display a high expression of this enzyme, which importance is currently not well defined. We generated PCK1 kidney specific knock-out and knock-in mice under the tubular cell specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal condition and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1 deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigating PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid base control, mitochondrial function and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.

Background The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases; while prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase Factor Inhibiting HIF inhibiting (FIH). Methods We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models, we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-CT imaging. We analyzed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies from various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach, to assess its relevance in CKD. Results In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with a reduced development of fibrosis. Conclusions The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seem promising in proteinuric kidney disease.

Background: Mechanisms and causes of death in older patients with SARS-CoV-2 infection are still poorly understood. Methods: We conducted in a retrospective monocentric study, a clinical chart review and post-mortem examination of patients aged 75 years and older hospitalized in acute care and positive for SARS-CoV-2. Full body autopsy and correlation with clinical findings and suspected causes of death were done. Results: Autopsies were performed in 12 patients (median age 85 years; median of 4 comorbidities, mainly hypertension and cardiovascular disease). All cases showed exudative or proliferative phases of alveolar damage and/or a pattern of organizing pneumonia. Causes of death were concordant in 6 cases (50%), and undetected diagnoses were found in 6. Five patients died from hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19), five had another associated diagnosis and two died from alternative causes. Deaths that occurred in the second week were related to SARS-CoV-2 pneumonia whereas those occurring earlier were related mainly to heart failure and those occurring later to complications. Conclusions: Although COVID-19 hypoxemic respiratory failure was the most common cause of death, post-mortem pathological examination revealed that acute decompensation from chronic comorbidities during the first week of COVID-19 and complications in the third week contributed to mortality.

"Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) is a recent reclassification of the encapsulated follicular variant of papillary thyroid carcinoma, which is supposed to reflect its indolent clinical behavior and to prevent overtreatment of patients with this neoplasm. The diagnosis of NIFTP can only be made histologically on the surgical specimen according to specific inclusion and exclusion criteria, which requires the examination of the whole nodule and its capsule. Spindle cell proliferations, especially of follicular cell origin, arising within thyroid follicular neoplasms are very rare and may cause diagnostic difficulties. Few reports described spindle cell proliferations arising in follicular thyroid adenoma and papillary thyroid carcinoma. To the best of our knowledge, only one case has been reported in NIFTP so far. In this article, we report a unique case of NIFTP associated with a spindle cell proliferation that was characterized immunohistochemically. Specific issues related to this case are discussed.