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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 -
Advances in Therapy Feb 2021Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid-base homeostasis because of tubular defects in acid excretion or bicarbonate ion... (Review)
Review
Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid-base homeostasis because of tubular defects in acid excretion or bicarbonate ion reabsorption. Using illustrative clinical cases, this review describes the main types of RTA observed in clinical practice and provides an overview of their diagnosis and treatment. The three major forms of RTA are distal RTA (type 1; characterized by impaired acid excretion), proximal RTA (type 2; caused by defects in reabsorption of filtered bicarbonate), and hyperkalemic RTA (type 4; caused by abnormal excretion of acid and potassium in the collecting duct). Type 3 RTA is a rare form of the disease with features of both distal and proximal RTA. Accurate diagnosis of RTA plays an important role in optimal patient management. The diagnosis of distal versus proximal RTA involves assessment of urinary acid and bicarbonate secretion, while in hyperkalemic RTA, selective aldosterone deficiency or resistance to its effects is confirmed after exclusion of other causes of hyperkalemia. Treatment options include alkali therapy in patients with distal or proximal RTA and lowering of serum potassium concentrations through dietary modification and potential new pharmacotherapies in patients with hyperkalemic RTA including newer potassium binders.
Topics: Acidosis, Renal Tubular; Bicarbonates; Humans; Hyperkalemia; Kidney; Potassium
PubMed: 33367987
DOI: 10.1007/s12325-020-01587-5 -
Kidney360 Dec 2021SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 g (1 mol) of glucose from the glomerular... (Review)
Review
SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 g (1 mol) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream, where theyremain in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50%-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.
Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Phlorhizin; Sodium-Glucose Transport Proteins; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 35419546
DOI: 10.34067/KID.0002772021 -
Endocrinology and Metabolism Clinics of... Dec 2021This review focuses on the commonly prescribed medicaments that can be responsible for hypercalcemia, considering the prevalence, the predominant pathophysiological... (Review)
Review
This review focuses on the commonly prescribed medicaments that can be responsible for hypercalcemia, considering the prevalence, the predominant pathophysiological mechanisms, and the optimal medical management of each drug-induced hypercalcemia. Vitamin D supplements and 1α-hydroxylated vitamin D analogues increase intestinal calcium absorption, renal calcium reabsorption as well as bone resorption. In patients with hypoparathyroidism receiving recombinant human PTH, transient hypercalcemia can occur because of overtreatment, usually during acute illness. Thiazide-induced hypercalcemia is mainly explained by enhanced renal proximal calcium reabsorption, changing preexistent asymptomatic normocalcemic or intermittently hypercalcemic hyperparathyroidism into the classic hypercalcemic hyperparathyroidism. Lithium causes hypercalcemia mainly by drug-induced hyperparathyroidism.
Topics: Calcium; Humans; Hypercalcemia; Hyperparathyroidism; Hypoparathyroidism; Vitamin D
PubMed: 34774245
DOI: 10.1016/j.ecl.2021.08.001 -
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 -
Annual Review of Physiology Feb 2021Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release.... (Review)
Review
Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater understanding of how renal nerves control the kidney under physiological and pathophysiological conditions is needed. In this review, we provide an overview of the current knowledge of the anatomy of efferent and afferent renal nerves and their functions in normal and pathophysiological conditions. We also suggest further avenues of research for development of novel therapies targeting the renal nerves.
Topics: Afferent Pathways; Animals; Catheter Ablation; Humans; Hypertension; Kidney
PubMed: 33566672
DOI: 10.1146/annurev-physiol-031620-091656 -
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 -
Frontiers in Endocrinology 2021X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to... (Review)
Review
X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.
Topics: Antibodies, Monoclonal, Humanized; Calcium; Child; Familial Hypophosphatemic Rickets; Humans; Parathyroid Hormone; Vitamin D
PubMed: 34421819
DOI: 10.3389/fendo.2021.688309