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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 -
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 -
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 -
International Journal of Molecular... Oct 2020The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose... (Review)
Review
The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autonomic Nervous System Diseases; Cardio-Renal Syndrome; Clinical Trials as Topic; Diabetes Mellitus; Glomerular Filtration Rate; Hemodynamics; Humans; Ketosis; Kidney Glomerulus; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 33105763
DOI: 10.3390/ijms21217833 -
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 -
Diseases (Basel, Switzerland) May 2020Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents which increase urinary glucose excretion by suppressing glucose... (Review)
Review
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents which increase urinary glucose excretion by suppressing glucose reabsorption at the proximal tubule in the kidney. SGLT2 inhibitors lower glycated hemoglobin (HbA1c) by 0.6-0.8% (6-8 mmol/mol) without increasing the risk of hypoglycemia and induce weight loss and improve various metabolic parameters including blood pressure, lipid profile and hyperuricemia. Recent cardiovascular (CV) outcome trials have shown the improvement of CV and renal outcomes by treatment with the SGLT2 inhibitors, empagliflozin, canagliflozin, and dapagliflozin. The mechanisms by which SGLT2 inhibitors improve CV outcome appear not to be glucose-lowering or anti-atherosclerotic effects, but rather hemodynamic effects through osmotic diuresis and natriuresis. Generally, SGLT2 inhibitors are well-tolerated, but their adverse effects include genitourinary tract infection and dehydration. Euglycemic diabetic ketoacidosis is a rare but severe adverse event for which patients under SGLT2 inhibitor treatment should be carefully monitored. The possibility of an increase in risk of lower-extremity amputation and bone fracture has also been reported with canagliflozin. Clinical trials and real-world data have suggested that SGLT2 inhibitors improve CV and renal outcomes and mortality in patients with type 2 diabetes (T2DM), especially in those with prior CV events, heart failure, or chronic kidney disease. Results of recent trials including individuals without diabetes may change the positioning of this drug as ″a drug for cardiorenal protection″. This review summarizes the potential of SGLT2 inhibitors and discusses their role in the treatment of T2DM.
PubMed: 32403420
DOI: 10.3390/diseases8020014 -
American Journal of Physiology. Renal... Aug 2019Type 1 and type 2 diabetes, along with their accompanying hyperglycemia, are associated with a multitude of comorbidities including the development of diabetic kidney... (Review)
Review
Type 1 and type 2 diabetes, along with their accompanying hyperglycemia, are associated with a multitude of comorbidities including the development of diabetic kidney disease. Although the hallmarks of these metabolic disorders have been well characterized in population and animal studies, it is becoming increasingly apparent that diabetes manifests itself differently in men and women. This review summarizes the recent diabetic literature with a focus on known sex differences in clinical and preclinical studies. It explores the physiological differences of glucose handling and the development of diabetes between men and women. This review also uncovers potential mechanisms for these differences, honing in on the vital role that sex hormone signaling plays in the progression of diabetes and renal complications.
Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Sex Characteristics
PubMed: 31241989
DOI: 10.1152/ajprenal.00249.2019