Search Results (109)

Background: While dehydration is associated with pediatric renal impairment, the regulation of hydration status can be affected by sleep. However, the interaction of hydration and sleep on kidney health remains unclear. Methods: We conducted a cohort study among 1914 healthy primary school children from October 2018 to November 2019 in Beijing, China. Four-wave urinary β₂-microglobulin and microalbumin excretion were assayed to assess transient renal tubular and glomerular impairment, and specific gravity was measured to determine hydration status with contemporaneous assessment of sleep duration, other anthropometric, and lifestyle covariates. We used generalized linear mixed-effects models to assess longitudinal associations of sleep duration and hydration status with renal impairment. Results: We observed 1378 children with optimal sleep (9–<11 h/d, 72.0%), 472 with short sleep (<9 h/d), and 64 with long sleep (≥11 h/d, 3.3%). Over half (55.4%) of events determined across 6968 person-visits were transient dehydration, 19.4% were tubular, and 4.9% were glomerular impairment events. Taking optimal sleep + euhydration as the reference, the results of generalized linear mixed-effects models showed that children with long sleep + dehydration (odds ratio [OR]: 3.87 for tubular impairment [tubules] and 3.47 for glomerular impairment [glomerulus]), long sleep + euhydration (OR: 2.43 for tubules), optimal sleep + dehydration (OR: 2.35 for tubules and 3.00 for glomerulus), short sleep + dehydration (OR: 2.07 for tubules and 2.69 for glomerulus), or short sleep + euhydration (OR: 1.29 for tubules) were more likely to present transient renal impairment, adjusting for sex, age, body mass index z-score, systolic blood pressure z-score, screen time, physical activity, and Mediterranean diet adherence. Conclusions: Dehydration and suboptimal sleep aggravate transient renal impairment in children, suggesting its role in maintaining pediatric kidney health. Full article

Background/Objectives: Phosphate is a macro-element involved in all cellular energetic processes. As about 90% of the phosphate filtered by the glomerulus is excreted by kidneys, the impairment of renal function and the consequent over-secretion of parathyroid hormone and fibroblast growth factor 23 results in the increase in the serum phosphate levels. The association between phosphate and hemoglobin is controversial, as both direct and indirect relationships have been reported. The present study aims to investigate the relationship between phosphate and hemoglobin in a large prospective, longitudinal cohort including dialysis patients from the Sicilian Registry of Nephrology, Dialysis, and Transplantation. Methods: In this prospective cohort study, we included 6263 hemodialysis patients to achieve a total of 120,462 repeated measurements of serum phosphate and hemoglobin over time. The longitudinal association between phosphate and hemoglobin was analyzed by univariate and multivariate Linear Mixed Models. Results: The mean age was 66 ± 16 years and the median dialysis vintage was 5 months [IQR: 2–16]. Mean and median values of hemoglobin and phosphate were 10.7 g/dL (SD 1.3 g/dL) and 4.6 mg/dL [IQR 3.9–5.5 mg/dL], respectively. The multivariate model, adjusted for potential confounders, confirmed the positive association between serum phosphate and hemoglobin [adjβ = 0.13, 95%CI 0.03–0.23, p = 0.01)]. These results were confirmed in analyses stratified for the use of phosphate binders. Conclusions: In our large cohort of dialysis patients, we found a linear, direct relationship between phosphate and hemoglobin levels. As a reduction in phosphate is associated with a parallel reduction in hemoglobin levels, hypophosphatemia can accentuate anemia in dialysis patients. Our results generate the hypothesis that monitoring serum phosphate in clinical practice might provide a better management of anemia. Full article

In the human body, the vascular system plays an indispensable role in maintaining homeostasis by supplying oxygen and nutrients to cells and organs and facilitating the removal of metabolic waste and toxins. Blood vessels—the key constituents of the vascular system—are composed of a layer of endothelial cells on their luminal surface. In most organs, tightly packed endothelial cells serve as a barrier separating blood and lymph from surrounding tissues. Intriguingly, endothelial cells in some tissues and organs (e.g., choroid plexus, liver sinusoids, small intestines, and kidney glomerulus) form transcellular pores called fenestrations that facilitate molecular and ionic transport across the vasculature and mediate immune responses through leukocyte transmigration. However, the development and unique functions of endothelial cell fenestrations across organs are yet to be fully uncovered. This review article provides an overview of fenestrated endothelial cells in multiple organs. We describe their development and organ-specific roles, with expanded discussions on their contributions to glomerular health and disease. We extend these discussions to highlight the dynamic changes in endothelial cell fenestrations in diabetic nephropathy, focal segmental glomerulosclerosis, Alport syndrome, and preeclampsia, and how these unique cellular features could be targeted for therapeutic development. Finally, we discuss emerging technologies for in vitro modeling of biological systems, and their relevance for advancing the current understanding of endothelial cell fenestrations in health and disease. Full article

Mitochondria are crucial for cellular ATP production. They are highly dynamic organelles, whose morphology and function are controlled through mitochondrial fusion and fission. The specific roles of mitochondria in podocytes, the highly specialized cells of the kidney glomerulus, remain less understood. Given the significant structural, functional, and molecular similarities between mammalian podocytes and Drosophila nephrocytes, we employed fly nephrocytes to explore the roles of mitochondria in cellular function. Our study revealed that alterations in the Pink1–Park (mammalian PINK1–PRKN) pathway can disrupt mitochondrial dynamics in Drosophila nephrocytes. This disruption led to either fragmented or enlarged mitochondria, both of which impaired mitochondrial function. The mitochondrial dysfunction subsequently triggered defective intracellular endocytosis, protein aggregation, and cellular damage. These findings underscore the critical roles of mitochondria in nephrocyte functionality. Full article

Primary focal segmental glomerulosclerosis (FSGS) is a disease of the podocytes and glomerulus, leading to nephrotic syndrome and progressive loss of renal function. One of the most serious aspects is its recurrence of disease in over 30% of patients following allogeneic kidney transplantation, leading to early graft loss. This research investigates the individual genetic predispositions and differences in the immune responses leading to recurrence of FSGS after transplantation. We performed exome sequencing on six patients with recurrent FSGS to identify variants in fifty-one genes and found significant variations in the alpha-2-macroglobulin (A2M). Immunoblotting was used to investigate effects of specific gene variants at the protein level. Further expression analysis identified A2M, exophilin 5 (EXPH5) and plectin (PLEC) as specific proteins linked to podocytes, endothelial cells, and the glomerulus. Subsequent protein array screening revealed the presence of non-HLA-specific antibodies, including TRIM21, after transplantation. Using Metascape for pathway and process enrichment analysis, we focused on the IL-17 signaling and chemotaxis pathways. ELISA measurements showed significantly elevated IL-17 levels in patients with recurrent FSGS (32.30 ± 9.12 pg/mL) compared to individuals with other glomerular diseases (23.16 ± 2.49 pg/mL; p < 0.01) and healthy subjects (22.28 ± 0.94 pg/mL; p < 0.01), with no significant difference in plasma CCL2/MCP-1 levels between groups. This study explores the molecular dynamics underlying recurrence of FSGS after transplantation, offering insights into potential biomarkers and therapeutic targets for the future development of individualized treatments for transplant patients. Full article

It is acknowledged that conventional renal cell carcinoma (cRCC), which makes up 85% of renal malignancies, is a highly vascular tumor. Humanized monoclonal antibodies were developed to inhibit tumor neo-angiogenesis, which is driven by VEGFA/KDR signaling. The results largely met our expectations, and in several cases, adverse events occurred. Our study aimed to analyze the expression of VEGFA and its receptor KDR by immunohistochemistry in tissue multi-array containing 811 cRCC and find a correlation between VEGFA/KDR signaling and new vessel formation. None of the 811 cRCC displayed VEGFA-positive immunostaining. However, each glomerulus in normal kidney showed VEGFA-positive endothelial cells. KDR expression in endothelial meshwork was found in only 9% of cRCC, whereas 2% of the cRCC displayed positive KDR reaction in the cytoplasm of tumor cells. Our results disclose the involvement of VEGFA/KDR signaling in the neo-vascularization of cRCC and explain the frequent resistance to drugs targeting the VEGFA/KDR signaling and the high frequency of adverse events. Full article

Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD⁺-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD⁺, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries. Full article

Carbon dioxide (CO₂) released by plants can serve as a cue for regulating insect behaviors. Hyphantria cunea is a widely distributed forestry pest that may use CO₂ as a cue for foraging and oviposition. However, the molecular mechanism underlying its ability to sense CO₂ has not been elucidated. Our initial study showed that CO₂ is significantly attractive to H. cunea adults. Subsequently, 44 H. cunea gustatory receptors (GRs) were identified using transcriptome data, and 3 candidate CO₂ receptors that are specifically expressed in the labial palps were identified. In vivo electrophysiological assays revealed that the labial palp is the primary organ for CO₂ perception in H. cunea, which is similar to findings in other lepidopteran species. By using the Xenopus oocyte expression system, we showed that the HcunGR1 and HcunGR3 co-expressions produced a robust response to CO₂, but HcunGR2 had an inhibitory effect on CO₂ perception. Finally, immunohistochemical staining revealed sexual dimorphism in the CO₂-sensitive labial pit organ glomerulus (LPOG). Taken together, our results clarified the mechanism by which H. cunea sense CO₂, laying the foundation for further investigations into the role of CO₂ in the rapid spread of H. cunea. Full article

Chronic kidney disease (CKD) affects more than 10% of the global population, and its incidence is increasing, partially due to an increase in the prevalence of disease risk factors. Acute kidney injury (AKI) is an independent risk factor for CKD and end-stage renal disease (ESRD). The pathogenic mechanisms of CKD provide several potential targets for its treatment. However, due to off-target effects, conventional drugs for CKD typically require high doses to achieve adequate therapeutic effects, leading to long-term organ toxicity. Therefore, ideal treatments that completely cure the different types of kidney disease are rarely available. Several approaches for the drug targeting of the kidneys have been explored in drug delivery system research. Nanotechnology-based drug delivery systems have multiple merits, including good biocompatibility, suitable degradability, the ability to target lesion sites, and fewer non-specific systemic effects. In this review, the development, potential, and limitations of low-molecular-weight protein–lysozymes, polymer nanomaterials, and lipid-based nanocarriers as drug delivery platforms for treating AKI and CKD are summarized. Full article

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy. Full article

Following recent advancements in medical laboratory technology, the analysis of high-resolution renal pathological images has become increasingly important in the diagnosis and prognosis prediction of chronic nephritis. In particular, deep learning has been widely applied to computer-aided diagnosis, with an increasing number of models being used for the analysis of renal pathological images. The diversity of renal pathological images and the imbalance between data acquisition and annotation have placed a significant burden on pathologists trying to perform reliable and timely analysis. Transfer learning based on contrastive pretraining is emerging as a viable solution to this dilemma. By incorporating unlabeled positive pretraining images and a small number of labeled target images, a transfer learning model is proposed for high-accuracy renal pathological image classification tasks. The pretraining dataset used in this study includes 5000 mouse kidney pathological images from the Open TG-GATEs pathological image dataset (produced by the Toxicogenomics Informatics Project of the National Institutes of Biomedical Innovation, Health, and Nutrition in Japan). The transfer training dataset comprises 313 human immunoglobulin A (IgA) chronic nephritis images collected at Fukushima Medical University Hospital. The self-supervised contrastive learning algorithm “Bootstrap Your Own Latent” was adopted for pretraining a residual-network (ResNet)-50 backbone network to extract glomerulus feature expressions from the mouse kidney pathological images. The self-supervised pretrained weights were then used for transfer training on the labeled images of human IgA chronic nephritis pathology, culminating in a binary classification model for supervised learning. In four cross-validation experiments, the proposed model achieved an average classification accuracy of 92.2%, surpassing the 86.8% accuracy of the original RenNet-50 model. In conclusion, this approach successfully applied transfer learning through mouse renal pathological images to achieve high classification performance with human IgA renal pathological images. Full article

The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS), along with intracellular RIG-like receptors (RLRs) and toll-like receptors (TLRs), are potent inducers of type I interferon (IFN-I) expression. These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as one cause of renal disease not attributed to viral infections. Instead, this pathway can recognize and signal in response to host-derived nucleic acids, which are also recognized by RLRs and TLRs. It is still unclear, however, whether the development of renal diseases depends on subsequent IFN-I induction or other processes involved. This review aims to explore the main endogenous inducers of IFN-I in glomerular cells, to discuss what effects autocrine and paracrine signaling have on IFN-I induction, and to identify the pathways that are implicated in the development of glomerular damage. Full article

Immunoglobulin A nephropathy (IgAN) remains the leading cause of primary glomerular disease worldwide. Outcomes are poor with high rates of progressive chronic kidney disease and kidney failure, which contributes to global healthcare costs. Although this disease entity has been described, there were no disease-specific treatments until recently, with the current standard of care focusing on optimal supportive measures including lifestyle modifications and optimization of the renin-angiotensin-aldosterone blockade. However, with significant advances in the understanding of the pathogenesis of IgAN in the past decade, and the acceptance of surrogate outcomes for accelerated drug approval, there have been many new investigational agents tested to target this disease. As these agents become available, we envision a multi-pronged treatment strategy that simultaneously targets the consequences of ongoing nephron loss, stopping any glomerular inflammation, inhibiting pro-fibrotic signals in the glomerulus and tubulo-interstitium, and inhibiting the production of pathogenic IgA molecules. This review is an update on a previous review published in 2021, and we aim to summarize the developments and updates in therapeutic strategies in IgAN and highlight the promising discoveries that are likely to add to our armamentarium. Full article

The purpose of blood purification therapy is to remove uremic toxins, and middle molecules (MMs) are a specific target. An MM is defined as a solute that passes through the glomerulus with a molecular weight in the range of 0.5–58 kDa, and new classifications of “small-middle 0.5–15 kDa,” “medium-middle 15–25 kDa,” and “large-middle 25–58 kDa” were proposed. In Japan, the removal of α1-microglobulin (αMG) in the large-middle range has been the focus, but a new theory of removal has been developed, emphasizing the antioxidant effect of αMG as a physiological function. Clinical proof of this mechanism will lead to further development of blood purification therapies. Full article

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown that fibrosis can be linked to oxidative stress and mitochondrial dysfunction in CKD. In this review, we will focus on three pathways that link oxidative stress and kidney fibrosis, namely: (i) hyperglycemia and mitochondrial energy imbalance, (ii) the mineralocorticoid signaling pathway, and (iii) the hypoxia-inducible factor (HIF) pathway. We selected these pathways because they are targeted by available medications capable of reducing kidney fibrosis, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1alpha-prolyl hydroxylase inhibitors. These drugs have shown a reduction in oxidative stress in the kidney and a reduced collagen deposition across different CKD subtypes. However, there is still a long and winding road to a clear understanding of the anti-fibrotic effects of these compounds in humans, due to the inherent practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers measurable in easily accessible matrices like urine. In this narrative review, we will describe these three pathways, their interconnections, and their link to and activity in oxidative stress and kidney fibrosis. Full article