-
Frontiers in Pediatrics 2020The crucial point for prompt diagnostics, ideal therapeutic approach, and follow-up of hydronephrosis associated with UPJ anomalies in children is the severity of... (Review)
Review
The crucial point for prompt diagnostics, ideal therapeutic approach, and follow-up of hydronephrosis associated with UPJ anomalies in children is the severity of hydronephrosis. Such many hydronephrosis grading systems as AP diameter, SFU, radiology, UTD, and Onen have been developed to evaluate hydronephrosis severity in infants. Unfortunately, it is still an ongoing challenge and there is no consensus between different disciplines. AP diameter is a very dynamic parameter and is affected by many factors (hydration, bladder filling, position, respiration). More importantly, its measurement is very variable and misleading due to different renal pelvic configurations. The radiology grading system has the same grades 1, 2, and 3 as the SFU grading system with addition of the AP diameter for the first 3 grades. This grading system divides parenchymal loss into two different grades. Grade 4 represents mild parenchymal loss while grade 5 suggests severe parenchymal loss. However, it is operator dependent, is not decisive, and does not differentiate grades 4 and 5 clearly. All grades of SFU are very variable between operators and clinicians. UTD classification aims to put all significant abnormal urinary findings together including the kidney, ureter, and bladder and thus determines the risk level for infants with any urinary disease. Different renal deterioration risks occur depending on the mechanism of hydronephrosis. Therefore, SFU and UTD classification may result in significant confusion and misleading in determining the severity of hydronephrosis. SFU-4 and UTD-P3 represent a considerable range of severity of hydronephrosis. Both represent minimal thinning of the medullary parenchyma and severe thinning of the cortical parenchyma (cyst-like hydronephrotic kidneys) at the same grade. The wide definition of SFU-4 and UTD-P3 fails to indicate accurately the severity of hydronephrosis and thus significantly misleads from a prompt treatment. They do not suggest who need surgical treatment and who can safely be followed non-operatively. The anatomy and physiology of the 4 suborgans of the kidney (renal pelvis, calices, medulla, and cortex) are completely different from each other. Therefore, each part of the kidney affect and behave differently as a response to UPJ-type hydronephrosis (UPJHN) depending on the severity of hydronephrosis. The upgraded Onen hydronephrosis grading system has been developed based on this basic evidence both for prenatal and post-natal periods. The Onen grading system determines specific detailed findings of significant renal damage, which clearly show and suggest who can safely be followed conservatively from who will need surgical intervention for UPJHN. Neither AP diameter nor radiology, SFU, or UTD classification is the gold standard in determining the severity of hydronephrosis. All these grading systems are based on subjective parameters and are affected by many factors. They do not determine the exact severity of UPJHN and thus cause permanent renal damage due to a delay in surgical decision in some infants while they may cause an unnecessary surgery in others. The Onen grading system has resolved all disadvantages of other grading systems and promises a safer follow-up and a prompt treatment for UPJHN. It is an accurate and easily reproducible grading that has high sensitivity and specificity.
PubMed: 32984198
DOI: 10.3389/fped.2020.00458 -
JCI Insight Jun 2021Single-cell sequencing studies have characterized the transcriptomic signature of cell types within the kidney. However, the spatial distribution of acute kidney injury...
Single-cell sequencing studies have characterized the transcriptomic signature of cell types within the kidney. However, the spatial distribution of acute kidney injury (AKI) is regional and affects cells heterogeneously. We first optimized coordination of spatial transcriptomics and single-nuclear sequencing data sets, mapping 30 dominant cell types to a human nephrectomy. The predicted cell-type spots corresponded with the underlying histopathology. To study the implications of AKI on transcript expression, we then characterized the spatial transcriptomic signature of 2 murine AKI models: ischemia/reperfusion injury (IRI) and cecal ligation puncture (CLP). Localized regions of reduced overall expression were associated with injury pathways. Using single-cell sequencing, we deconvoluted the signature of each spatial transcriptomic spot, identifying patterns of colocalization between immune and epithelial cells. Neutrophils infiltrated the renal medulla in the ischemia model. Atf3 was identified as a chemotactic factor in S3 proximal tubules. In the CLP model, infiltrating macrophages dominated the outer cortical signature, and Mdk was identified as a corresponding chemotactic factor. The regional distribution of these immune cells was validated with multiplexed CO-Detection by indEXing (CODEX) immunofluorescence. Spatial transcriptomic sequencing complemented single-cell sequencing by uncovering mechanisms driving immune cell infiltration and detection of relevant cell subpopulations.
Topics: Acute Kidney Injury; Animals; Epithelial Cells; Female; Humans; Kidney; Mice; Middle Aged; Reperfusion Injury; Single-Cell Analysis; Transcriptome
PubMed: 34003797
DOI: 10.1172/jci.insight.147703 -
Nature Communications Dec 2023Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial...
Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
Topics: Humans; Ferroptosis; Kidney; Acute Kidney Injury; Autophagy; Reperfusion Injury; Ischemia
PubMed: 38110369
DOI: 10.1038/s41467-023-44228-5 -
Nature Reviews. Nephrology Jul 2021Complex multicellular life in mammals relies on functional cooperation of different organs for the survival of the whole organism. The kidneys play a critical part in... (Review)
Review
Complex multicellular life in mammals relies on functional cooperation of different organs for the survival of the whole organism. The kidneys play a critical part in this process through the maintenance of fluid volume and composition homeostasis, which enables other organs to fulfil their tasks. The renal endothelium exhibits phenotypic and molecular traits that distinguish it from endothelia of other organs. Moreover, the adult kidney vasculature comprises diverse populations of mostly quiescent, but not metabolically inactive, endothelial cells (ECs) that reside within the kidney glomeruli, cortex and medulla. Each of these populations supports specific functions, for example, in the filtration of blood plasma, the reabsorption and secretion of water and solutes, and the concentration of urine. Transcriptional profiling of these diverse EC populations suggests they have adapted to local microenvironmental conditions (hypoxia, shear stress, hyperosmolarity), enabling them to support kidney functions. Exposure of ECs to microenvironment-derived angiogenic factors affects their metabolism, and sustains kidney development and homeostasis, whereas EC-derived angiocrine factors preserve distinct microenvironment niches. In the context of kidney disease, renal ECs show alteration in their metabolism and phenotype in response to pathological changes in the local microenvironment, further promoting kidney dysfunction. Understanding the diversity and specialization of kidney ECs could provide new avenues for the treatment of kidney diseases and kidney regeneration.
Topics: Adaptation, Physiological; Endothelial Cells; Endothelium, Vascular; Humans; Kidney; Kidney Diseases; Oxygen; Phenotype; Stress, Mechanical
PubMed: 33767431
DOI: 10.1038/s41581-021-00411-9 -
Signal Transduction and Targeted Therapy May 2023Chronic kidney disease (CKD) and heart failure (HF) are highly prevalent, aggravate each other, and account for substantial mortality. However, the mechanisms underlying...
Chronic kidney disease (CKD) and heart failure (HF) are highly prevalent, aggravate each other, and account for substantial mortality. However, the mechanisms underlying cardiorenal interaction and the role of kidney afferent nerves and their precise central pathway remain limited. Here, we combined virus tracing techniques with optogenetic techniques to map a polysynaptic central pathway linking kidney afferent nerves to subfornical organ (SFO) and thereby to paraventricular nucleus (PVN) and rostral ventrolateral medulla that modulates sympathetic outflow. This kidney-brain neural circuit was overactivated in mouse models of CKD or HF and subsequently enhanced the sympathetic discharge to both the kidney and the heart in each model. Interruption of the pathway by kidney deafferentation, selective deletion of angiotensin II type 1a receptor (AT1a) in SFO, or optogenetic silence of the kidney-SFO or SFO-PVN projection decreased the sympathetic discharge and lessened structural damage and dysfunction of both kidney and heart in models of CKD and HF. Thus, kidney afferent nerves activate a kidney-brain neural circuit in CKD and HF that drives the sympathetic nervous system to accelerate disease progression in both organs. These results demonstrate the crucial role of kidney afferent nerves and their central connections in engaging cardiorenal interactions under both physiological and disease conditions. This suggests novel therapies for CKD or HF targeting this kidney-brain neural circuit.
Topics: Rats; Animals; Mice; Rats, Sprague-Dawley; Heart Failure; Kidney; Paraventricular Hypothalamic Nucleus; Renal Insufficiency, Chronic
PubMed: 37169751
DOI: 10.1038/s41392-023-01402-x -
Nature Communications Jul 2023Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal...
Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.
Topics: Humans; Kidney Medulla; Matrix Metalloproteinase 9; Matrix Metalloproteinase 7; Calcium Oxalate; Transcriptome; Kidney Calculi
PubMed: 37468493
DOI: 10.1038/s41467-023-38975-8 -
Pflugers Archiv : European Journal of... Dec 2019Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in... (Review)
Review
Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.
Topics: Animals; Apoptosis; Epithelial Cells; Humans; Membrane Transport Proteins; Urea; Urinary Bladder; Urea Transporters
PubMed: 31734718
DOI: 10.1007/s00424-019-02323-x