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Nutrients Jul 2016Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of... (Review)
Review
Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60-100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Supplements; Evidence-Based Medicine; Global Health; Glucose Intolerance; Humans; Hypertension; Intestinal Absorption; Kidney; Models, Biological; Potassium; Potassium Deficiency; Potassium, Dietary; Renal Elimination; Renal Reabsorption
PubMed: 27455317
DOI: 10.3390/nu8070444 -
Cardiovascular Diabetology May 2022Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of... (Review)
Review
Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
Topics: Adult; Diabetes Mellitus, Type 2; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Sodium; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 35614469
DOI: 10.1186/s12933-022-01512-w -
Nutrients Oct 2019Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to... (Review)
Review
Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications.
Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Dietary Supplements; Folic Acid; Folic Acid Deficiency; Homeostasis; Humans; Kidney; Nutritional Status; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Renal Reabsorption; Risk Assessment; Risk Factors
PubMed: 31581752
DOI: 10.3390/nu11102353 -
Experimental Biology and Medicine... Apr 2017Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through... (Review)
Review
Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through childhood and adolescence until peek mineral density is reached in early adulthood. Thereafter, bone mineral density remains static until it eventually declines in later life. A positive calcium balance, i.e. more calcium absorbed than excreted, is crucial to bone deposition during growth and thus to peek bone mineral density. Dietary calcium is absorbed from the intestine into the blood. It is then filtered by the renal glomerulus and either reabsorbed by the tubule or excreted in the urine. Calcium can be (re)absorbed across intestinal and renal epithelia via both transcellular and paracellular pathways. Current evidence suggests that significant intestinal and renal calcium transport changes occur throughout development. However, the molecular details of these alterations are incompletely delineated. Here we first briefly review the current model of calcium transport in the intestine and renal tubule in the adult. Then, we describe what is known with regard to calcium handling through postnatal development, and how alterations may aid in mediating a positive calcium balance. The role of transcellular and paracellular calcium transport pathways and the contribution of specific intestinal and tubular segments vary with age. However, the current literature highlights knowledge gaps in how specifically intestinal and renal calcium (re)absorption occurs early in postnatal development. Future research should clarify the specific changes in calcium transport throughout early postnatal development including mediators of these alterations enabling appropriate bone mineralization. Impact statement This mini review outlines the current state of knowledge pertaining to the molecules and mechanisms maintaining a positive calcium balance throughout postnatal development. This process is essential to achieving optimal bone mineral density in early adulthood, thereby lowering the lifetime risk of osteoporosis.
Topics: Age Factors; Animals; Biological Transport; Bone Density; Calcium, Dietary; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Kidney Tubules
PubMed: 28346014
DOI: 10.1177/1535370217699536 -
The Journal of Clinical Endocrinology... Feb 2022In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.
METHODS
After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab.
RESULTS
Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity.
MAIN CONCLUSIONS
In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab.
CLINICALTRIALS.GOV
NCT02163577.
Topics: Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Dose-Response Relationship, Drug; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Humans; Male; Phosphates; Renal Reabsorption; Severity of Illness Index
PubMed: 34636899
DOI: 10.1210/clinem/dgab729 -
Pediatric Nephrology (Berlin, Germany) Apr 2019Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na-dependent phosphate... (Review)
Review
Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH) vitamin D as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date.
Topics: Animals; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Genetic Predisposition to Disease; Heredity; Humans; Kidney Tubules, Proximal; Mutation; Pedigree; Phenotype; Phosphates; Prognosis; Renal Reabsorption; Renal Tubular Transport, Inborn Errors; Risk Assessment; Risk Factors; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type III; Sodium-Phosphate Cotransporter Proteins, Type IIa; Sodium-Phosphate Cotransporter Proteins, Type IIc
PubMed: 29275531
DOI: 10.1007/s00467-017-3873-3 -
Journal of the American Society of... Sep 2021Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a... (Review)
Review
Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a central role in maintaining serum magnesium within a narrow range (0.70-1.10 mmol/L). Along the proximal tubule and thick ascending limb, magnesium reabsorption occurs via paracellular pathways. Members of the claudin family form the magnesium pores in these segments, and also regulate magnesium reabsorption by adjusting the transepithelial voltage that drives it. Along the distal convoluted tubule transcellular reabsorption via heteromeric TRPM6/7 channels predominates, although paracellular reabsorption may also occur. In this segment, the NaCl cotransporter plays a critical role in determining transcellular magnesium reabsorption. Although the general machinery involved in renal magnesium reabsorption has been identified by studying genetic forms of magnesium imbalance, the mechanisms regulating it are poorly understood. This review discusses pathways of renal magnesium reabsorption by different segments of the nephron, emphasizing newer findings that provide insight into regulatory process, and outlining critical unanswered questions.
Topics: Claudins; Humans; Magnesium; Nephrons; Protein Serine-Threonine Kinases; Renal Reabsorption; TRPM Cation Channels
PubMed: 34045316
DOI: 10.1681/ASN.2021010042 -
Physiological Reports Apr 2018Inorganic sulfate is essential for normal cellular function and its homeostasis is primarily regulated in the kidneys. However, little is known about renal sulfate...
Inorganic sulfate is essential for normal cellular function and its homeostasis is primarily regulated in the kidneys. However, little is known about renal sulfate handling in humans and particularly in populations with impaired kidney function such as renal transplant recipients (RTR). Hence, we aimed to assess sulfate reabsorption in kidney donors and RTR. Plasma and urinary sulfate were determined in 671 RTR and in 251 kidney donors. Tubular sulfate reabsorption (TSR) was defined as filtered load minus sulfate excretion and fractional sulfate reabsorption (FSR) was defined as 1-fractional excretion. Linear regression analyses were employed to explore associations of FSR with baseline parameters and to identify the determinants of FSR in RTR. Compared to kidney donors, RTR had significantly lower TSR (15.2 [11.2-19.5] vs. 20.3 [16.7-26.3] μmol/min), and lower FSR (0.56 [0.48-0.64] vs. 0.64 [0.57-0.69]) (all P < 0.001). Kidney donation reduced both TSR and FSR by circa 50% and 25% respectively (both P < 0.001). In RTR and donors, both TSR and FSR associated positively with renal function. In RTR, FSR was independently associated with urinary thiosulfate (β = -0.18; P = 0.002), growth hormone (β = 0.12; P = 0.007), the intakes of alcohol (β = -0.14; P = 0.002), methionine (β = -0.34; P < 0.001), cysteine (β = -0.41; P < 0.001), and vitamin D (β = -0.14; P = 0.009). In conclusion, TSR and FSR are lower in RTR compared to kidney donors and both associated with renal function. Additionally, FSR is determined by various dietary and metabolic factors. Future research should determine the mechanisms behind sulfate handling in humans and the prognostic value of renal sulfate reabsorption in RTR.
Topics: Adult; Aged; Cross-Sectional Studies; Female; Healthy Volunteers; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Renal Reabsorption; Sulfates; Transplant Recipients
PubMed: 29671959
DOI: 10.14814/phy2.13670 -
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