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Kidney Diseases (Basel, Switzerland) Oct 2023Renal tubular acidosis (RTA) is caused by various disruptions to the secretion of H by distal renal tubules and/or dysfunctional reabsorption of HCO by proximal renal... (Review)
Review
BACKGROUND
Renal tubular acidosis (RTA) is caused by various disruptions to the secretion of H by distal renal tubules and/or dysfunctional reabsorption of HCO by proximal renal tubules, which causes renal acidification dysfunction, ultimately leading to a clinical syndrome characterized by hyperchloremic metabolic acidosis with a normal anion gap. With the development of molecular genetics and gene sequencing technology, inherited RTA has also attracted attention, and an increasing number of RTA-related pathogenic genes have been discovered and reported.
SUMMARY
This paper focuses on the latest progress in the research of inherited RTA and systematically reviews the pathogenic genes, protein functions, clinical manifestations, internal relationship between genotypes and clinical phenotypes, diagnostic clues, differential diagnosis, and treatment strategies associated with inherited RTA. This paper aims to deepen the understanding of inherited RTA and reduce the missed diagnosis and misdiagnosis of RTA.
KEY MESSAGES
This review systematically summarizes the pathogenic genes, pathophysiological mechanisms, differential diagnosis, and treatment of different types of inherited RTA, which has good clinical value for guiding the diagnosis and treatment of inherited RTA.
PubMed: 37901710
DOI: 10.1159/000531556 -
Annual Review of Physiology Feb 2024The kidney proximal tubule is a key organ for human metabolism. The kidney responds to stress with altered metabolite transformation and perturbed metabolic pathways, an... (Review)
Review
The kidney proximal tubule is a key organ for human metabolism. The kidney responds to stress with altered metabolite transformation and perturbed metabolic pathways, an ultimate cause for kidney disease. Here, we review the proximal tubule's metabolic function through an integrative view of transport, metabolism, and function, and embed it in the context of metabolome-wide data-driven research. Function (filtration, transport, secretion, and reabsorption), metabolite transformation, and metabolite signaling determine kidney metabolic rewiring in disease. Energy metabolism and substrates for key metabolic pathways are orchestrated by metabolite sensors. Given the importance of renal function for the inner milieu, we also review metabolic communication routes with other organs. Exciting research opportunities exist to understand metabolic perturbation of kidney and proximal tubule function, for example, in hypertension-associated kidney disease. We argue that, based on the integrative view outlined here, kidney diseases without genetic cause should be approached scientifically as metabolic diseases.
Topics: Humans; Kidney Tubules, Proximal; Kidney; Energy Metabolism; Kidney Diseases
PubMed: 38012048
DOI: 10.1146/annurev-physiol-042222-024724 -
American Journal of Physiology. Renal... Nov 2023Ca transport along the nephron occurs via specific transcellular and paracellular pathways and is coupled to the transport of other electrolytes. Notably, Na transport...
Ca transport along the nephron occurs via specific transcellular and paracellular pathways and is coupled to the transport of other electrolytes. Notably, Na transport establishes an electrochemical gradient to drive Ca reabsorption. Hence, alterations in renal Na handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na transport but also indirectly affect renal Ca handling. To better understand the underlying mechanisms, we developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca handling are represented. Model simulations predicted in the female rat nephron lower Ca reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared with the male nephron. The male rat kidney model yielded a higher urinary Ca excretion than the female model, consistent with animal experiments. Model results indicated that along the proximal tubule and thick ascending limb, Ca and Na transport occurred in parallel, but those processes were dissociated in the distal convoluted tubule. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na and Ca transport. Simulation results revealed alterations in transepithelial Ca transport, with differential effects among nephron segments and between the sexes. The kidney plays an important role in the maintenance of whole body Ca balance by regulating Ca reabsorption and excretion. This computational modeling study provides insights into how Ca transport along the nephron is coupled to Na. Model results indicated that along the proximal tubule and thick ascending limb, Ca and Na transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.
Topics: Female; Male; Rats; Animals; Calcium; Sodium; Sex Characteristics; Membrane Transport Proteins; Kidney Tubules, Distal; Diuretics
PubMed: 37615047
DOI: 10.1152/ajprenal.00145.2023 -
Journal of the American Society of... Nov 2023Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the...
SIGNIFICANCE STATEMENT
Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies.
BACKGROUND
Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies.
METHODS
We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies.
RESULTS
Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes.
CONCLUSIONS
Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.
Topics: Humans; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Mitochondrial Diseases; Mitochondria; DNA, Mitochondrial; Water-Electrolyte Imbalance
PubMed: 37678265
DOI: 10.1681/ASN.0000000000000224 -
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 -
Biomedicines Mar 2024Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this... (Review)
Review
Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this condition. Initially, "the underfill hypothesis" suggested that proteinuria and hypoalbuminemia led to fluid extravasation into the interstitial space, causing the intravascular hypovolemia and activation of neurohormonal compensatory mechanisms, which increased the retention of salt and water. Consequently, the recommended management involved diuretics and human-albumin infusion. However, recent findings from human and animal studies have unveiled a kidney-limited sodium-reabsorption mechanism, attributed to the presence of various serine proteases in the tubular lumen-activating ENaC channels, thereby causing sodium reabsorption. There is currently no standardized guideline for diuretic therapy. In clinical practice, loop diuretics continue to be the preferred initial choice. It is noteworthy that patients often exhibit diuretic resistance due to various factors such as high-sodium diets, poor drug compliance, changes in pharmacokinetics or pharmacodynamics, kidney dysfunction, decreased renal flow, nephron remodeling and proteasuria. Considering these challenges, combining diuretics may be a rational approach to overcoming diuretic resistance. Despite the limited data available on diuretic treatment in nephrotic syndrome complicated by hypervolemia, ENaC blockers emerge as a potential add-on treatment for nephrotic edema.
PubMed: 38540182
DOI: 10.3390/biomedicines12030569 -
American Journal of Physiology. Renal... Jul 2024Pregnancy is associated with elevated demand of most nutrients, with many trace elements and minerals critical for the development of fetus. In particular, calcium (Ca)...
Pregnancy is associated with elevated demand of most nutrients, with many trace elements and minerals critical for the development of fetus. In particular, calcium (Ca) and magnesium (Mg) are essential for cellular function, and their deficiency can lead to impaired fetal growth. A key contributor to the homeostasis of these ions is the kidney, which in a pregnant rat undergoes major changes in morphology, hemodynamics, and molecular structure. The goal of this study is to unravel the functional implications of these pregnancy-induced changes in renal handling of Ca and Mg, two cations that are essential in a healthy pregnancy. To achieve that goal, we developed computational models of electrolyte and water transport along the nephrons of a rat in mid and late pregnancy. Model simulations reveal a substantial increase in the reabsorption of Mg along the proximal tubules and thick ascending limbs. In contrast, the reabsorption of Ca is increased in the proximal tubules but decreased in the thick ascending limbs, due to the lower transepithelial concentration gradient of Ca along the latter. Despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of Ca and Mg in pregnancy. Furthermore, we conducted simulations of hypocalcemia and hypomagnesemia. We found that hypocalcemia lowers Ca excretion substantially more than Mg excretion, with this effect being more pronounced in virgin rats than in pregnant ones. Conversely, hypomagnesemia reduces the excretion of Mg and Ca to more similar degrees. These differences can be explained by the greater sensitivity of the calcium-sensing receptor (CaSR) to Ca compared with Mg. A growing fetus' demands of minerals, notably calcium and magnesium, necessitate adaptations in pregnancy. In particular, the kidney undergoes major changes in morphology, hemodynamics, and molecular structure. This computational modeling study provides insights into how these pregnancy-induced renal adaptation impact calcium and magnesium transport along different nephron segments. Model simulations indicate that, despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of calcium and magnesium in pregnancy.
Topics: Female; Pregnancy; Animals; Magnesium; Calcium; Kidney; Glomerular Filtration Rate; Rats; Computer Simulation; Renal Reabsorption; Models, Biological
PubMed: 38721663
DOI: 10.1152/ajprenal.00001.2024 -
Clinical Kidney Journal Jan 2024The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of... (Review)
Review
The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of primary (essential) hypertension by 65%-75%. Hypertension is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and its prevalence is rapidly increasing following the pandemic rise in obesity. Although the causal relationship between obesity and high blood pressure (BP) is well established, the detailed mechanisms for such association are still under research. For more than 30 years sympathetic nervous system (SNS) and kidney sodium reabsorption activation, secondary to insulin resistance and compensatory hyperinsulinemia, have been considered as primary mediators of elevated BP in obesity. However, experimental and clinical data show that severe insulin resistance and hyperinsulinemia can occur in the absence of elevated BP, challenging the causal relationship between insulin resistance and hyperinsulinemia as the key factor linking obesity to hypertension. The purpose of Part 1 of this review is to summarize the available data on recently emerging mechanisms believed to contribute to obesity-related hypertension through increased sodium reabsorption and volume expansion, such as: physical compression of the kidney by perirenal/intrarenal fat and overactivation of the systemic/renal SNS and the renin-angiotensin-aldosterone system. The role of hyperleptinemia, impaired chemoreceptor and baroreceptor reflexes, and increased perivascular fat is also discussed. Specifically targeting these mechanisms may pave the way for a new therapeutic intervention in the treatment of obesity-related hypertension in the context of 'precision medicine' principles, which will be discussed in Part 2.
PubMed: 38186879
DOI: 10.1093/ckj/sfad282 -
Communications Biology Oct 2023Kidney organoids have shown promise as evaluation tools, but their in vitro maturity remains limited. Transplantation into adult mice has aided in maturation; however,...
Kidney organoids have shown promise as evaluation tools, but their in vitro maturity remains limited. Transplantation into adult mice has aided in maturation; however, their lack of urinary tract connection limits long-term viability. Thus, long-term viable generated nephrons have not been demonstrated. In this study, we present an approachable method in which mouse and rat renal progenitor cells are injected into the developing kidneys of neonatal mice, resulting in the generation of chimeric nephrons integrated with the host urinary tracts. These chimeric nephrons exhibit similar maturation to the host nephrons, long-term viability with excretion and reabsorption functions, and cisplatin-induced renal injury in both acute and chronic phases, as confirmed by single-cell RNA-sequencing. Additionally, induced human nephron progenitor cells differentiate into nephrons within the neonatal kidneys. Collectively, neonatal injection represents a promising approach for in vivo nephron generation, with potential applications in kidney regeneration, drug screening, and pathological analysis.
Topics: Mice; Rats; Animals; Humans; Kidney; Cisplatin; Regeneration; Nephrons; Stem Cells
PubMed: 37898693
DOI: 10.1038/s42003-023-05484-9 -
Pharmacology & Therapeutics Apr 2024Owing to renal reabsorption and the loss of uricase activity, uric acid (UA) is strictly maintained at a higher physiological level in humans than in other mammals,... (Review)
Review
Owing to renal reabsorption and the loss of uricase activity, uric acid (UA) is strictly maintained at a higher physiological level in humans than in other mammals, which provides a survival advantage during evolution but increases susceptibility to certain diseases such as gout. Although monosodium urate (MSU) crystal precipitation has been detected in different tissues of patients as a trigger for disease, the pathological role of soluble UA remains controversial due to the lack of causality in the clinical setting. Abnormal elevation or reduction of UA levels has been linked to some of pathological status, also known as U-shaped association, implying that the physiological levels of UA regulated by multiple enzymes and transporters are crucial for the maintenance of health. In addition, the protective potential of UA has also been proposed in aging and some diseases. Therefore, the role of UA as a double-edged sword in humans is determined by its physiological or non-physiological levels. In this review, we summarize biosynthesis, membrane transport, and physiological functions of UA. Then, we discuss the pathological involvement of hyperuricemia and hypouricemia as well as the underlying mechanisms by which UA at abnormal levels regulates the onset and progression of diseases. Finally, pharmacological strategies for urate-lowering therapy (ULT) are introduced, and current challenges in UA study and future perspectives are also described.
Topics: Animals; Humans; Uric Acid; Hyperuricemia; Mammals
PubMed: 38382882
DOI: 10.1016/j.pharmthera.2024.108615