Kidney international最新文献

Clonal monocytosis reflects a preneoplastic or neoplastic sustained increase in the absolute monocyte count in the absence of reactive causes. Causes of clonal monocytosis include clonal cytopenias with monocytosis and acute and chronic myeloid neoplasms. Chronic myelomonocytic leukemia is a prototypical myelodysplastic/myeloproliferative overlap neoplasm in adults, characterized by sustained peripheral blood monocytosis. Kidney abnormalities, including acute kidney injury and chronic kidney disease, are frequent in patients with chronic myelomonocytic leukemia and are predictors of worse outcomes. In addition, acute kidney injury/chronic kidney disease often limits eligibility for allogeneic stem cell transplantation or enrollment in clinical trials. In this review, we highlight clonal monocytosis-related etiologies that give rise to acute kidney injury and chronic kidney disease, with special emphasis on chronic myelomonocytic leukemia and lysozyme-induced nephropathy. Monocytes produce lysozyme, which, in excess, can accumulate in and damage the proximal renal tubular epithelium. Early identification of this etiology and a timely reduction in monocyte counts can salvage kidney function. Other etiologies of kidney injury associated with clonal monocytosis include direct renal infiltration by monocytes, renal extramedullary hematopoiesis, myeloproliferative neoplasm-associated glomerulopathy, autoimmune (membranous nephropathy, minimal change disease) and paraneoplastic manifestations, thrombotic microangiopathy, obstructive nephropathy due to myeloproliferation, and urate nephropathy due to tumor lysis syndrome. We propose to group these mechanistic etiologies of kidney injury as clonal monocytosis of renal significance and provide guidance on their diagnosis and management.

Human pluripotent stem cell-derived kidney organoids hold promise for future applications in regenerative medicine. However, significant biological hurdles need to be overcome to enable their use as a transplantable stem cell-derived therapeutic graft. Current kidney organoid protocols do not recapitulate a complete integrated developing kidney, but embryonic kidney transplantations have provided clues for advancing maturation and functionality of kidney organoids. Transplantation, subsequent vascularization and blood perfusion of kidney organoids improve nephron patterning and maturation, suggesting a role for angiocrine factors as well as metabolic wiring in these processes. Transplanted organoids exhibit filtration, but the resulting filtrate has no apparent exit path for excretion. Improved in vitro patterning of kidney organoids may be required such that a more structurally correct tissue is formed prior to transplant. Here we review current progress with kidney organoid transplantation, their engraftment and integration, and identify the key obstacles to therapeutic success and how these might be achieved.

Onset, progression and cardiovascular outcome of chronic kidney disease (CKD) are influenced by the concomitant sterile inflammation. The pro-inflammatory cytokine family interleukin (IL)-1 is crucial in CKD with the key alarmin IL-1 playing an additional role as an adhesion molecule that facilitates immune cell tissue infiltration and consequently inflammation. Here, we investigate calcium ion and reactive oxygen species (ROS)-dependent regulation of different aspects of IL-1-mediated inflammation. We show that human CKD monocytes exhibit altered purinergic calcium ion signatures. Monocyte IL-1 release was reduced when inhibiting P2X7, and to a lesser extent P2X4, two ATP-receptors that were found upregulated compared to monocytes from healthy people. In murine CKD models, deleting P2X7 (P2X7-/-) abolished IL-1 release but increased IL-1 surface presentation by bone marrow derived macrophages and impaired immune cell infiltration of the kidney without protecting kidney function. In contrast, immune cell infiltration into injured wild type and P2X7-/- hearts was comparable in a myocardial infarction model, independent of previous kidney injury. Both the chimeric mouse line harboring P2X7-/- immune cells in wild type recipient mice, and the inversely designed chimeric line showed less acute inflammation. However, only the chimera harboring P2X7-/- immune cells showed a striking resistance against injury-induced cardiac remodeling. Mechanistically, ROS measurements reveal P2X7-induced mitochondrial ROS as an essential factor for IL-1 release by monocytes. Our studies uncover a dual role of P2X7 in regulating IL-1 biogenesis with consequences for inflammation and inflammation-induced deleterious cardiac remodeling that may determine clinical outcomes in CKD therapies.

Idiopathic nephrotic syndrome (INS), the most common glomerular disorder in children, has long been considered an immune-mediated disease based on the efficacy of glucocorticoids at inducing remission. Nevertheless, the immune processes leading to podocytopathy have largely remained elusive. The success of B cell-depletion with rituximab, descriptions of B cell dysregulation during active disease, and the most recent discovery of autoantibodies targeting the major podocyte antigen Nephrin denote an autoimmune humoral etiology for INS. Research into the immune factors involved in INS pathogenesis have uncovered common features with other autoimmune disorders that will aid in prognostication and in guiding the expansion of our glucocorticoid-sparing therapeutic arsenal. In this review, we discuss the emerging autoimmune architecture of INS, with a specific focus on pediatric steroid-sensitive disease, including the podocyte-reactive B cell response that gives rise to anti-podocyte antibodies (APAs), the predisposing genetic factors that shape the podocyte-reactive immune landscape, and the immune triggers driving active disease.

Glomeruli filter blood through the coordination of podocytes, mesangial cells, fenestrated endothelial cells, and the glomerular basement membrane. Cellular changes, such as podocyte loss, are associated with pathologies like diabetic kidney disease. However, little is known regarding the in situ molecular profiles of specific cell types and how these profiles change with disease. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is well-suited for untargeted tissue mapping of a wide range of molecular classes. Importantly, additional imaging modalities can be integrated with MALDI IMS to associate these biomolecular distributions to specific cell types. Here, we integrated workflow combining MALDI IMS and multiplexed immunofluorescence (MxIF) microscopy. High spatial resolution MALDI IMS (5 μm) was used to determine lipid distributions within human glomeruli from a normal portion of fresh-frozen kidney cancer nephrectomy tissue revealing intra-glomerular lipid heterogeneity. Mass spectrometric data were linked to specific glomerular cell types and substructures through new methods that enable MxIF microscopy to be performed on the same tissue section following MALDI IMS, without sacrificing signal quality from either modality. Machine learning approaches were combined enabling cell type segmentation and identification based on MxIF data. This was followed by mining of cell type or cluster-associated MALDI IMS signatures using classification and interpretable machine learning. This allowed automated discovery of spatially specific molecular markers for glomerular cell types and substructures as well as lipids correlated to deep and superficial glomeruli. Overall, our work establishes a toolbox for probing molecular signatures of glomerular cell types and substructures within tissue microenvironments providing a framework applicable to other kidney tissue features and organ systems.

Can direct activation of soluble guanylyl cyclase (sGC) provide kidney-protection? To answer this, we tested the kidney-protective effects of a sGC activator, which functions independent of nitric oxide and with oxidized sGC, in an acute kidney injury (AKI) model with transition to chronic kidney disease (CKD). We hypothesize this treatment would provide protection of kidney microvasculature, kidney blood flow, fibrosis, inflammation, and kidney damage. Assessment took place on days three, seven, 14 (acute phase) and 84 (late phase) after unilateral ischemia reperfusion injury (IRI) in rats. Post-ischemia, animals received vehicle or the sGC activator BAY 60-2770 orally. In the vehicle group, medullary microvessels narrowed and cortical microvessels showed hypertrophic inward remodeling. The mRNA levels of acute injury markers (Kim-1, Ngal) were high in the acute phase but declined in the late phase. Kidney weight decreased after the acute phase, while fibrosis started after day seven. Abundance of fibrotic (Col1a, Tgf-β1) and inflammatory markers (Il-6, Tnf-α) remained elevated throughout, along with mononuclear cell invasion, with elevated plasma cystatin C and creatinine. BAY 60-2770 treatment increased tissue cGMP concentration, dilated kidney microvasculature, and enhanced blood flow and oxygenation. This intervention significantly attenuated kidney weight loss, cell damage, fibrosis, and inflammation. Plasma cystatin C and creatinine improved significantly with sGC activator treatment indicating functional recovery, though possible GFR increase above kidney reserve in uninjured kidneys could not be excluded. In cultured human tubular cells (HK-2 cells) exposed to hypoxia or profibrotic TGF-b, BAY 60-2770 improved abundance patterns of pathologically relevant genes. Overall, our results show that sGC activation may provide effective kidney-protection and attenuate the AKI-to-CKD transition.

Podocytes can undergo PANoptosis (apoptosis, pyroptosis, and necroptosis). Diabetic kidney disease (DKD) is the leading cause of kidney failure, and podocyte loss is a major event leading to the progression of DKD. Here, we compared single cell RNA sequencing (scRNA-seq) data between three normal and three DKD human kidney samples and found a significant increase of TNFSF10 and TNFRSF10B expression in podocytes of patients with DKD. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), coded by TNFSF10, belongs to the TNF superfamily members and TNFRSF10B codes for death receptor 5 (DR5). We confirmed that expression of TRAIL and DR5 increased in podocytes of patients with DKD and correlated with the severity of DKD. In vitro, TNF-α stimulated TRAIL and DR5 expression in cultured human podocytes. Silence of TRAIL or DR5 by small interfering RNA alleviated TNF-α-stimulated podocytes PANoptosis, while overexpression of TRAIL, treatment with recombinant human TRAIL (rh-TRAIL) or the DR5 activator (Bioymifi) enhanced podocytes PANoptosis. In vivo, podocyte-specific deletion of TNFSF10 or TNFRSF10B alleviated podocyte and glomerular injury in high fat diet and streptozotocin-induced obese diabetic mice and was associated with decreased podocyte PANoptosis. Conversely, the induction of TNFSF10 overexpression specifically in podocytes exacerbated albuminuria and kidney injury in diabetic mice with increased podocyte PANoptosis. Additionally, administration of soluble DR5-Fc, an inhibitor of DR5, resulted in a marked reduction in albuminuria and glomerular injury in BTBR ob/ob mice. Our findings suggest a critical autocrine role of TRAIL/DR5 in inducing podocyte injury in DKD via activation of PANoptosis.

Endoplasmic Reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.