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Endocrinology and Metabolism Clinics of... Dec 2021Calcium plays a key role in skeletal mineralization and several intracellular and extracellular homeostatic networks. It is an essential element that is only available... (Review)
Review
Calcium plays a key role in skeletal mineralization and several intracellular and extracellular homeostatic networks. It is an essential element that is only available to the body through dietary sources. Daily acquisition of calcium depends, in addition to the actual intake, on the hormonally regulated state of calcium homeostasis through three main mechanisms: bone turnover, intestinal absorption, and renal reabsorption. These procedures are regulated by a group of interacting circulating hormones and their key receptors. This includes parathyroid hormone (PTH), PTH-related peptide, 1,25-dihydroxyvitamin D, calcitonin, fibroblast growth factor 23, the prevailing calcium concentration itself, the calcium-sensing receptor, as well as local processes in the bones, gut, and kidneys.
Topics: Bone and Bones; Calcium; Calcium, Dietary; Homeostasis; Humans; Parathyroid Hormone; Vitamin D
PubMed: 34774235
DOI: 10.1016/j.ecl.2021.07.005 -
Clinical Journal of the American... Jul 2015Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis... (Review)
Review
Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.
Topics: Animals; Calcium; Gastrointestinal Absorption; Glomerular Filtration Rate; Homeostasis; Humans; Kidney; Magnesium; Metabolic Diseases; Phosphates; Renal Elimination; Renal Reabsorption
PubMed: 25287933
DOI: 10.2215/CJN.09750913 -
Clinical Journal of the American... Dec 2015Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a... (Review)
Review
Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Ammonia; Animals; Bicarbonates; Carbon Dioxide; Humans; Hydrogen-Ion Concentration; Kidney; Models, Biological; Renal Elimination; Renal Reabsorption
PubMed: 26597304
DOI: 10.2215/CJN.07400715 -
British Journal of Clinical Pharmacology Aug 2021Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca... (Review)
Review
Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often noninflammatory and bilateral, some drugs are associated with peripheral oedema that is readily erythematous (eg, pemetrexed) or unilateral (eg, sirolimus). Thus, drug-induced peripheral oedema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory oedema), sodium/water retention (renal oedema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability oedema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of a drug.
Topics: Edema; Heart Failure; Humans; Lymphedema; Pharmaceutical Preparations; Vasodilation
PubMed: 33506982
DOI: 10.1111/bcp.14752 -
Nature Reviews. Nephrology Jun 2020Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney... (Review)
Review
Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.
Topics: Cellular Senescence; Chlorides; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Glomerular Filtration Barrier; Glomerular Filtration Rate; Glucose; Humans; Hypertrophy; Inflammation; Kidney Glomerulus; Kidney Tubules; Nephrons; Nitric Oxide; Renal Reabsorption; Sodium; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32152499
DOI: 10.1038/s41581-020-0256-y -
The AAPS Journal Jan 2021Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate,... (Review)
Review
Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the "date-rape drug"; current use in popular culture includes recreational "chemsex," due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration-effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABA receptors in the brain, with pharmacological/toxicological effects mainly due to GABA agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1-4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses. Graphical abstract.
Topics: Alcoholism; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Overdose; Humans; Hydroxybutyrates; Metabolic Clearance Rate; Narcolepsy; Sodium Oxybate; Substance Abuse, Oral; Substance Withdrawal Syndrome
PubMed: 33417072
DOI: 10.1208/s12248-020-00543-z -
Nature Reviews. Nephrology Jun 2019Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity,... (Review)
Review
Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future.
Topics: Adipokines; Aldosterone; Angiotensin II; Humans; Hypertension; Kidney; Kidney Tubules; Leptin; Obesity; Oxidative Stress; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Mineralocorticoid; Renal Reabsorption; Renin; Sodium; Sympathetic Nervous System
PubMed: 31015582
DOI: 10.1038/s41581-019-0145-4 -
Cureus Jan 2021Calcium (Ca) is a divalent cation that plays a critical role in numerous body functions such as skeletal mineralization, signal transduction, nerve conduction, muscle... (Review)
Review
Calcium (Ca) is a divalent cation that plays a critical role in numerous body functions such as skeletal mineralization, signal transduction, nerve conduction, muscle contraction, and blood coagulation. Ca metabolism is linked to magnesium (Mg) and phosphate metabolism. Cahomeostasis is dependent on intestinal absorption, bone turnover, and renal reabsorption. The hormonal regulators of these processes are the parathyroid hormone (PTH), calcitriol {1,25-dihydroxyvitamin D [1,25(OH)D]}, and serum ionized Ca. Cloning of the Ca-sensing receptor (CaSR) has greatly advanced the understanding of Ca metabolism. Disorders of Ca metabolism are easily recognized because Ca is included in routine chemistry panels. Measurement of ionized Ca is the preferred way to ascertain the diagnosis of hypocalcemia and hypercalcemia.
PubMed: 33542868
DOI: 10.7759/cureus.12420 -
American Journal of Physiology. Renal... May 2016Furosemide is a widely used, potent natriuretic drug, which inhibits the Na(+)-K(+)-2Cl(-) cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to... (Review)
Review
Furosemide is a widely used, potent natriuretic drug, which inhibits the Na(+)-K(+)-2Cl(-) cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion.
Topics: Animals; Blood Pressure; Carbonic Anhydrase Inhibitors; Drug Resistance; Furosemide; GABA-A Receptor Antagonists; Humans; Natriuresis; Renal Insufficiency, Chronic; Renal Reabsorption; Renin-Angiotensin System; Solute Carrier Family 12, Member 1
PubMed: 26911852
DOI: 10.1152/ajprenal.00476.2015 -
Clinical Journal of the American... Dec 2014The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a... (Review)
Review
The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice.
Topics: Calcium; Cations, Divalent; Epithelial Sodium Channels; Humans; Kidney Tubules, Distal; Magnesium; Potassium; Potassium Channels, Inwardly Rectifying; Protein Serine-Threonine Kinases; Renal Reabsorption; Signal Transduction; Sodium; Sodium Chloride; Solute Carrier Family 12, Member 3
PubMed: 24855283
DOI: 10.2215/CJN.05920613