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International Journal of Molecular... Jun 2023The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills... (Review)
Review
The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.
Topics: Humans; Glucose; Diabetic Nephropathies; Sodium-Glucose Transporter 2 Inhibitors; Kidney; Nephrons; Sodium; Oxygen; Glomerular Filtration Rate
PubMed: 37373108
DOI: 10.3390/ijms24129957 -
Frontiers in Cardiovascular Medicine 2022A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2... (Review)
Review
A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors might be effective alone or in combination with any other drugs. This therapeutic class currently includes five agents: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. SGLT2 inhibitors prevent the renal reabsorption of filtered glucose and sodium by blocking the SGLT2 co-transporters in the proximal convoluted renal tubule, facilitating glucose excretion in the urine (glycosuria) and lowering blood glucose levels. SGLT2 inhibitors have also shown to have pleiotropic effects and determine cardiovascular and renal prevention, thus leading to an extension of their therapeutic indication to include the heart failure. Despite their clinical benefits, warnings about adverse events have been implemented by Regulatory Agencies in the product's information since their introduction to the market. In particular, SGLT2 inhibitors have shown a strong impact on a high number of risk factors. They can cause hypoglycaemia, hypotension, lower limb amputation, fractures, genito-urinary infections, and diabetic ketoacidosis with different frequencies of onset. Despite some of these events are rare, they can lead to serious and dangerous complications, highlighting the importance of a strict monitoring of patients. Overall, SLGT-2 inhibitors are effective antidiabetic drugs with favorable advantages in renal and cardiovascular protection, and with a generally well-tolerated safety profile. This review aims to summarize the safety profile of SGLT2 inhibitors available in the market.
PubMed: 36211584
DOI: 10.3389/fcvm.2022.1010693 -
Australian Prescriber Aug 2022Sodium-glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose by reducing the reabsorption of glucose in the kidney. They are a second-line therapy for type 2... (Review)
Review
Sodium-glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose by reducing the reabsorption of glucose in the kidney. They are a second-line therapy for type 2 diabetes. During clinical trials it was noticed that SGLT2 inhibitors had favourable effects on cardiovascular and renal disease. This led to further trials that included patients without diabetes. In studies of heart failure, SGLT2 inhibitors were beneficial in treating patients with a reduced left ventricular ejection fraction. A recent study has also reported benefits in patients with a preserved ejection fraction. In chronic kidney disease, SGLT2 inhibitors may reduce disease progression. However, a decline in the glomerular filtration rate may be seen at the start of treatment. As most experience with SGLT2 inhibitors is in diabetes, patients without diabetes need to be aware of why they are being prescribed these drugs. Some of the potential indications for SGLT2 inhibitors beyond diabetes are not yet approved by regulatory authorities.
PubMed: 36110166
DOI: 10.18773/austprescr.2022.036 -
International Journal of Molecular... Dec 2019The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation,... (Review)
Review
The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation, electrolyte-free water reabsorption, and acid-base homeostasis. The collecting duct epithelium is comprised of a tight epithelial barrier resulting in a strict separation of intraluminal urine and the interstitium. Tight junctions are key players in enforcing this barrier and in regulating paracellular transport of solutes across the epithelium. The features of tight junctions across different epithelia are strongly determined by their molecular composition. Claudins are particularly important structural components of tight junctions because they confer barrier and transport properties. In the collecting duct, a specific set of claudins (Cldn-3, Cldn-4, Cldn-7, Cldn-8) is expressed, and each of these claudins has been implicated in mediating aspects of the specific properties of its tight junction. The functional disruption of individual claudins or of the overall barrier function results in defects of blood pressure and water homeostasis. In this concise review, we provide an overview of the current knowledge on the role of the collecting duct epithelial barrier and of claudins in collecting duct function and pathophysiology.
Topics: Animals; Claudins; Epithelial Cells; Humans; Ion Transport; Kidney Tubules, Collecting; Renal Reabsorption
PubMed: 31905642
DOI: 10.3390/ijms21010221 -
Physiological Reviews Jul 2019The identification of genes causing inherited kidney diseases yielded crucial insights in the molecular basis of disease and improved our understanding of physiological... (Review)
Review
The identification of genes causing inherited kidney diseases yielded crucial insights in the molecular basis of disease and improved our understanding of physiological processes that operate in the kidney. Monogenic kidney disorders are caused by mutations in genes coding for a large variety of proteins including receptors, channels and transporters, enzymes, transcription factors, and structural components, operating in specialized cell types that perform highly regulated homeostatic functions. Common variants in some of these genes are also associated with complex traits, as evidenced by genome-wide association studies in the general population. In this review, we discuss how the molecular genetics of inherited disorders affecting different tubular segments of the nephron improved our understanding of various transport processes and of their involvement in homeostasis, while providing novel therapeutic targets. These include inherited disorders causing a dysfunction of the proximal tubule (renal Fanconi syndrome), with emphasis on epithelial differentiation and receptor-mediated endocytosis, or affecting the reabsorption of glucose, the handling of uric acid, and the reabsorption of sodium, calcium, and magnesium along the kidney tubule.
Topics: Animals; Humans; Kidney; Kidney Diseases; Rare Diseases
PubMed: 31215303
DOI: 10.1152/physrev.00008.2018 -
Life (Basel, Switzerland) Nov 2022Serum uric acid levels are altered by kidney disorders because the kidneys play a dominant role in uric acid excretion. Here, major kidney disorders which accompany... (Review)
Review
Serum uric acid levels are altered by kidney disorders because the kidneys play a dominant role in uric acid excretion. Here, major kidney disorders which accompany hyperuricemia or hypouricemia, including their pathophysiology, are discussed. Chronic kidney disease (CKD) and hyperuricemia are frequently associated, but recent clinical trials have not supported the pathogenic roles of hyperuricemia in CKD incidence and progression. Diabetes mellitus (DM) is often associated with hyperuricemia, and hyperuricemia may be associated with an increased risk of diabetic kidney disease in patients with type 2 DM. Sodium-glucose cotransporter 2 inhibitors have a uricosuric effect and can relieve hyperuricemia in DM. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an important hereditary kidney disease, mainly caused by mutations of uromodulin (UMOD) or mucin-1 (MUC-1). Hyperuricemia and gout are the major clinical manifestations of ADTKD-UMOD and ADTKD-MUC1. Renal hypouricemia is caused by URAT1 or GLUT9 loss-of-function mutations and renders patients susceptible to exercise-induced acute kidney injury, probably because of excessive urinary uric acid excretion. Hypouricemia derived from renal uric acid wasting is a component of Fanconi syndrome, which can be hereditary or acquired. During treatment for human immunodeficiency virus, hepatitis B or cytomegalovirus, tenofovir, adefovir, and cidofovir may cause drug-induced renal Fanconi syndrome. In coronavirus disease 2019, hypouricemia due to proximal tubular injury is related to disease severity, including respiratory failure. Finally, serum uric acid and the fractional excretion of uric acid are indicative of plasma volume status; hyperuricemia caused by the enhanced uric acid reabsorption can be induced by volume depletion, and hypouricemia caused by an increased fractional excretion of uric acid is the characteristic finding in syndromes of inappropriate anti-diuresis, cerebral/renal salt wasting, and thiazide-induced hyponatremia. Molecular mechanisms by which uric acid transport is dysregulated in volume or water balance disorders need to be investigated.
PubMed: 36431026
DOI: 10.3390/life12111891 -
International Journal of Molecular... Apr 2024To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This... (Review)
Review
To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.
Topics: Humans; Phosphates; Animals; Renal Reabsorption; Kidney; Kidney Tubules, Proximal
PubMed: 38731904
DOI: 10.3390/ijms25094684 -
International Journal of Molecular... Dec 2021The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration... (Review)
Review
The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is unable to pass through the lipid bilayer on its own; therefore, transport takes place using carrier proteins localized to the plasma membrane. Both sodium-independent glucose transporters (GLUT proteins) and sodium-dependent glucose transporters (SGLT proteins) are expressed in kidney tissue, and mutations of the genes coding for these glucose transporters lead to renal disorders and diseases, including renal cancers. In addition, several diseases may disturb the expression and/or function of renal glucose transporters. The aim of this review is to describe the role of the kidney in glucose homeostasis and the contribution of glucose transporters in renal physiology and renal diseases.
Topics: Animals; Glucose; Homeostasis; Humans; Kidney; Kidney Diseases; Sodium-Glucose Transport Proteins
PubMed: 34948317
DOI: 10.3390/ijms222413522 -
Cureus Feb 2023Renal tubular acidosis (RTA) refers to a group of disorders in which the elimination of hydrogen ions from the kidney or the reabsorption of filtered bicarbonate is...
Renal tubular acidosis (RTA) refers to a group of disorders in which the elimination of hydrogen ions from the kidney or the reabsorption of filtered bicarbonate is impaired, resulting in metabolic acidosis. Hypokalemia is also prominent in different types of RTA. We are presenting an interesting case about a chronic alcoholic patient who presented to the emergency department and was found to be severely hypokalemic. During her hospital stay, she had multiple cardiac arrests likely secondary to her hypokalemia despite adequate treatment with potassium supplementation. We came to the conclusion of distal RTA in our patient based on hyperchloremic metabolic acidosis, sodium bicarbonate of 10 mmol/L, low potassium, blood urea nitrogen, and creatinine within normal limits, alkaline urine, and a positive urinary anion gap. It is likely that the cause of our patient's underlying type 1 RTA was secondary to her chronic alcohol abuse. Her potassium eventually returned to baseline, and she was discharged.
PubMed: 36942187
DOI: 10.7759/cureus.35034 -
Anatomical Record (Hoboken, N.J. : 2007) Oct 2020Per gram of tissue, the kidneys are among our most highly perfused organs. Yet the renal cortex and, in particular, the renal medulla are susceptible to hypoxia. In... (Review)
Review
Per gram of tissue, the kidneys are among our most highly perfused organs. Yet the renal cortex and, in particular, the renal medulla are susceptible to hypoxia. In turn, hypoxia is a major pathophysiological feature of both acute kidney injury and chronic kidney disease. We identify seven factors that render the kidney susceptible to hypoxia: (1) the large metabolic demand imposed by active reabsorption of sodium; (2) limitations on oxygen delivery to cortical tissue imposed by the density of peritubular capillaries; (3) the poor capacity for angiogenesis in the adult kidney; (4) the limited ability of the renal vasculature to dilate in response to hypoxia; (5) diffusive oxygen shunting between arteries and veins in the cortex and descending and ascending vasa recta in the medulla; (6) the physiological requirement for low medullary blood flow to facilitate urinary concentration; and (7) the topography of vascular-tubular arrangements in the outer medulla that limit oxygen delivery to the thick ascending limb of Henle's loop. Recent collaborative efforts between anatomists, physiologists, and mathematicians have improved our understanding of the roles of these factors in both physiological regulation of intrarenal oxygenation and development of renal hypoxia under pathophysiological conditions. We are also better able to understand these apparent maladaptations in the context of evolution. That is, they can be explained by the combined effects of historical contingency (our ancestral life in the sea) and selection pressures imposed by the multiple functions of the kidney to regulate extracellular fluid volume, retain water, and control erythrocyte production.
Topics: Animals; Hemodynamics; Humans; Hypoxia; Kidney; Vasodilation
PubMed: 31566903
DOI: 10.1002/ar.24260