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Frontiers in Medicine 2024Renal hypouricemia (RHUC) is a rare autosomal recessive disorder characterized by impaired renal tubular uric acid reabsorption and abnormally high uric acid clearance,...
Renal hypouricemia (RHUC) is a rare autosomal recessive disorder characterized by impaired renal tubular uric acid reabsorption and abnormally high uric acid clearance, which may be manifested by reduced serum uric acid (SUA) levels and elevated fractional excretion of uric acid (FE-UA >10%). Most RHUC patients are often asymptomatic or have accidentally decreased SUA levels during health examinations, while others develop kidney stones and exercise-induced acute kidney injury (EIAKI). We now report a case of RHUC complicated with an asymptomatic kidney stone, and we identified a heterozygous mutation of c.269G > A (p.R90H) and a novel heterozygous mutation of c.674C > G (p.T225R) in the gene in the patient through whole exon gene detection (NGS method). This case offers valuable insights into the mechanisms, clinical management, and prognosis of RHUC and its associated complications.
PubMed: 38384421
DOI: 10.3389/fmed.2024.1218232 -
Frontiers in Pediatrics 2024This study was designed to measure the concentration and activity of urinary proteases that activate renal epithelial sodium channel (ENaC) mediated Na transport in...
INTRODUCTION
This study was designed to measure the concentration and activity of urinary proteases that activate renal epithelial sodium channel (ENaC) mediated Na transport in infants with congenital heart disease, a potential mechanism for fluid retention.
METHODS
Urine samples from infants undergoing cardiac surgery were collected at three time points: T1) pre-operatively, T2) 6-8 h after surgery, and T3) 24 h after diuretics. Urine was collected from five heathy infant controls. The urine was tested for four proteases and whole-cell patch-clamp testing was conducted in renal collecting duct M-1 cells to test whether patient urine increased Na currents consistent with ENaC activation.
RESULTS
Heavy chain of plasminogen, furin, and prostasin were significantly higher in cardiac patients prior to surgery compared to controls. There was no difference in most proteases before and after surgery. Urine from cardiac patients produced a significantly greater increase in Na inward currents compared to healthy controls.
CONCLUSION
Urine from infants with congenital heart disease is richer in proteases and has the potential to increase activation of ENaC in the nephron to enhance Na reabsorption, which may lead to fluid retention in this population.
PubMed: 38379911
DOI: 10.3389/fped.2024.1338672 -
SAGE Open Medical Case Reports 2024Antenatal Bartter syndrome is a rare condition that affects approximately 1.2 individuals per million. It is caused by renal tubular dysfunction that impairs the...
Antenatal Bartter syndrome is a rare condition that affects approximately 1.2 individuals per million. It is caused by renal tubular dysfunction that impairs the reabsorption of sodium and chloride. This results in various symptoms such as polyuria, vomiting, dehydration, and failure to thrive. Because of its low prevalence, diagnosing this disorder can be challenging for medical professionals. In this report, we describe a rare case of a 3-month-old female infant who had symptoms of Bartter syndrome, such as severe hypotension, facial flattening, cough, and seizures. She also had the typical features of the condition, except for prematurity and hypercalciuria, which were not present. In this case, we highlight the importance of regular follow-ups and monitoring of patients with dehydration and electrolyte imbalances, as these can lead to complications in Bartter syndrome. Early intervention and close monitoring can enhance patient outcomes and avoid complications.
PubMed: 38379632
DOI: 10.1177/2050313X241233117 -
BioRxiv : the Preprint Server For... Feb 2024Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in...
UNLABELLED
Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments. EFA detects mitochondrial respiration and glycolysis by measuring oxygen consumption and extracellular acidification rates, respectively. We show that both measurements positively correlate with sample sizes of a few centimeter-length renal tubules. The thick ascending limbs (TALs) and distal convoluted tubules (DCTs) predominantly utilize glucose/pyruvate as energy substrates, whereas proximal tubules (PTs) are significantly much less so. Acute inhibition of TALs' transport activity by ouabain treatment reduces basal and ATP-linked mitochondrial respiration. Chronic inhibition of transport activity by 2-week furosemide treatment or deletion of with-no-lysine kinase 4 (Wnk4) decreases maximal mitochondrial capacity. In addition, chronic inhibition downregulates mitochondrial DNA mass and mitochondrial length/density in TALs and DCTs. Conversely, gain-of-function Wnk4 mutation increases maximal mitochondrial capacity and mitochondrial length/density without increasing mitochondrial DNA mass. In conclusion, EFA is a sensitive and reliable method to investigate mitochondrial functions in isolated renal tubules. Transport activity tightly regulates mitochondrial bioenergetics and biogenesis to meet the energy demand in renal tubules. The system allows future investigation into whether and how mitochondria contribute to tubular remodeling adapted to changes in transport activity.
KEY POINTS
A positive correlation between salt reabsorption and oxygen consumption in mammalian kidneys hints at a potential interaction between transport activity and mitochondrial respiration in renal tubules.Renal tubules are heterogeneous in transport activity and mitochondrial metabolism, and traditional assays using bulk kidney tissues cannot provide segment-specific information.Here, we applied an extracellular flux analysis to investigate mitochondrial respiration and energy metabolism in isolated renal tubules. This assay is sensitive in detecting oxygen consumption and acid production in centimeter-length renal tubules and reliably recapitulates segment-specific metabolic features.Acute inhibition of transport activity reduces basal and ATP-linked mitochondrial respirations without changing maximal mitochondrial respiratory capacity. Chronic alterations of transport activity further adjust maximal mitochondrial respiratory capacity via regulating mitochondrial biogenesis or non-transcriptional mechanisms.Our findings support the concept that renal tubular cells finely adjust mitochondrial bioenergetics and biogenesis to match the new steady state of transport activity.
PubMed: 38370657
DOI: 10.1101/2024.02.04.578838 -
BMC Pediatrics Feb 2024Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to...
BACKGROUND
Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to hypophosphataemia, rickets and bone pain. Here, we present a case of HHRH in a Chinese boy.
CASE PRESENTATION
We report a 11-year-old female proband, who was admitted to our hospital with bilateral genuvarum deformity and short stature. Computed Tomography (CT) showed kidney stones, blood tests showed hypophosphatemia, For a clear diagnosis, we employed high-throughput sequencing technology to screen for variants. Our gene sequencing approach encompassed whole exome sequencing, detection of exon and intron junction regions, and examination of a 20 bp region of adjacent introns. Flanking sequences are defined as ±50 bp upstream and downstream of the 5' and 3' ends of the coding region.The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039), and the pathogenic variant sites were annotated using Annovar. Subsequently, the suspected pathogenic variants were classified according to ACMG's gene variation classification system. Simultaneously, unreported or clinically ambiguous pathogenic variants were predicted and annotated based on population databases. Any suspected pathogenic variants identified through this analysis were then validated using Sanger sequencing technology. At last, the proband and her affected sister carried pathogenic homozygous variant in the geneSLC34A3(exon 13, c.1402C > T; p.R468W). Their parents were both heterozygous carriers of the variant. Genetic testing revealed that the patient has anLRP5(exon 18, c.3917C > T; p.A1306V) variant of Uncertain significance, which is a rare homozygous variant.
CONCLUSION
This case report aims to raise awareness of the presenting characteristics of HHRH. The paper describes a unique case involving variants in both theSLC34A3andLRP5genes, which are inherited in an autosomal recessive manner. This combination of gene variants has not been previously reported in the literature. It is uncertain whether the presence of these two mutated genes in the same individual will result in more severe clinical symptoms. This report shows that an accurate diagnosis is critical, and with early diagnosis and correct treatment, patients will have a better prognosis.
Topics: Child; Female; Humans; Familial Hypophosphatemic Rickets; Heterozygote; Hypercalciuria; Hypophosphatemia; Introns; Mutation; Phosphorus Metabolism Disorders
PubMed: 38355430
DOI: 10.1186/s12887-024-04589-2 -
Nefrologia 2024Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the... (Review)
Review
Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described.
Topics: Humans; Magnesium; Hypocalcemia; Nephrocalcinosis; Kidney Tubules; Protein Serine-Threonine Kinases; TRPM Cation Channels; Magnesium Deficiency
PubMed: 38350738
DOI: 10.1016/j.nefroe.2024.02.003 -
Annual Review of Physiology Feb 2024Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the... (Review)
Review
Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the maintenance of homeostatic energetics and, hence, supply should match demand by the consuming organs. In its journey through the body, glucose encounters cellular barriers for transit at the levels of the absorbing intestinal epithelial wall, the renal epithelium mediating glucose reabsorption, and the tight capillary endothelia (especially in the brain). Glucose transiting through these cellular barriers must escape degradation to ensure optimal glucose delivery to the bloodstream or tissues. The liver, which stores glycogen and generates glucose de novo, must similarly be able to release it intact to the circulation. We present the most up-to-date knowledge on glucose handling by the gut, liver, brain endothelium, and kidney, and discuss underlying molecular mechanisms and open questions. Diseases associated with defects in glucose delivery and homeostasis are also briefly addressed. We propose that the universal problem of sparing glucose from catabolism in favor of translocation across the barriers posed by epithelia and endothelia is resolved through common mechanisms involving glucose transfer to the endoplasmic reticulum, from where glucose exits the cells via unconventional cellular mechanisms.
Topics: Animals; Humans; Glucose; Epithelium; Brain; Biological Transport; Intestines; Mammals
PubMed: 38345907
DOI: 10.1146/annurev-physiol-042022-031657 -
Clinical Kidney Journal Feb 2024Familial renal glucosuria (FRG) is a hereditary disorder caused by variants in encoding sodium-glucose cotransporter 2 (SGLT2). In this study, we aimed to characterize...
BACKGROUND
Familial renal glucosuria (FRG) is a hereditary disorder caused by variants in encoding sodium-glucose cotransporter 2 (SGLT2). In this study, we aimed to characterize proximal tubule solute transport, glucagon secretion and the genotype-phenotype relationship in FRG patients.
METHODS
We sequenced and in 21 FRG patients and measured the renal threshold of glucose (RT) in 15 patients. We built an open-source online calculator of RT, evaluated the proximal tubule transport of amino acid, uric acid and phosphate, and explored glucagon secretion after glucose ingestion in FRG patients.
RESULTS
We identified 12 novel variants (G484D, R564W, A212S, c.574+1G>C, W649*, S592Cfs*6, Q579*, Y339*, V39F, G491E, A464E and G360D) in our cohort and yielded 111 variants from literature review. RT in our cohort ranged from 1.0 to 9.2 mmol/L. Patients with two variants had lower RT (3.9 vs 6.2 mmol/L) and higher 24-h urinary glucose excretion (24hUG) than single-variant carriers (291.0 vs 40.0 mmol/1.73 m). Patients with homozygous missense or in-frame indels had mean 24hUG of 457.2 mmol/1.73 m, comparable to those with homozygous truncating variants (445.0 mmol/1.73 m) and significantly more than those with homozygous splicing variants (196.6 mmol/1.73 m). Patients with homozygous missense variants involving conservative residues (582.0 mmol/1.73 m) had more 24hUG than those with variants at non-conservative residues (257.6 mmol/1.73 m). Four out of 14 tested patients had mild aminoaciduria. The RT of FRG patients had no significant correlation to phosphate reabsorption but a potential negative correlation to the fractional excretion of uric acid. Postprandial suppression of glucagon secretion was absent in most FRG patients.
CONCLUSIONS
We built a comprehensive map showing the impact of variant type and variant location on glucosuria severity. Our results highlighted the role of key residues in maintaining the transport function of SGLT2 and the functional link between glucosuria and reabsorption of amino acid and uric acid in FRG patients.
PubMed: 38344682
DOI: 10.1093/ckj/sfad265 -
Journal of Advanced Research Feb 2024Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure.
INTRODUCTION
Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure.
OBJECTIVE
We aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation.
METHODS AND RESULTS
Collecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished.
CONCLUSIONS
NCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.
PubMed: 38341030
DOI: 10.1016/j.jare.2024.02.003 -
Acta Pharmaceutica Sinica. B Feb 2024Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in... (Review)
Review
Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (.., SLC2A4/GLUT4), glucose reabsorption (.., SLC5A2/SGLT2), thermogenesis (.., SLC25A7/UCP-1), and ATP production (.., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (/) and metformin (-/- and , /, ). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
PubMed: 38322335
DOI: 10.1016/j.apsb.2023.09.004