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Endocrinology and Metabolism (Seoul,... Aug 2023When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known... (Review)
Review
When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Natriuresis; Feedback; Glucose; Sodium
PubMed: 37482684
DOI: 10.3803/EnM.2023.1764 -
Frontiers in Cardiovascular Medicine 2023To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes.
PURPOSE
To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes.
METHODS
A single-center study was conducted on 60 patients (131 visits) at the Dartmouth-Hitchcock Medical Center (DHMC) from 1/2021-12/2022. Demographics, visit data, and outcomes were collected and compared to urban outpatient IV centers, and inpatient HF hospitalizations from DHMC FY21 and national means. Descriptive statistics, T-tests and chi-squares were used.
RESULTS
The mean age was 70 ± 13 years, 58% were male, and 83% were NYHA III-IV. Post-diuresis, 5% had mild-moderate hypokalemia, 16% had mild worsening of renal function, and 3% had severe worsening of renal function. No hospitalizations occurred due to adverse events. The mean infusion-visit urine output was 761 ± 521 ml, and post-visit weight loss was -3.9 ± 5.0 kg. No significant differences were observed between HFpEF and HFrEF groups. 30-day readmissions were similar to urban outpatient IV centers, DHMC FY21, and the national mean (23.3% vs. 23.5% vs. 22.2% vs. 22.6%, respectively; = 0.949). 30-day mortality was similar to urban outpatient IV centers but lower than DHMC FY21 and the national means (1.7% vs. 2.5% vs. 12.3% vs. 10.7%, respectively; < 0.001). At 60 days, 42% of patients had ≥1 clinic revisit, 41% had ≥1 infusion revisit, 33% were readmitted to the hospital, and two deaths occurred. The clinic avoided 21 hospitalizations, resulting in estimated cost savings of $426,111.
CONCLUSION
OP IV diuresis appears safe and effective for rural HF patients, potentially decreasing mortality rates and healthcare expenses while mitigating rural-urban disparities.
PubMed: 37304943
DOI: 10.3389/fcvm.2023.1155957 -
Hypertension (Dallas, Tex. : 1979) May 2023The endogenous purine 8-aminoguanine induces diuresis/natriuresis/glucosuria by inhibiting PNPase (purine nucleoside phosphorylase); however, mechanistic details are...
BACKGROUND
The endogenous purine 8-aminoguanine induces diuresis/natriuresis/glucosuria by inhibiting PNPase (purine nucleoside phosphorylase); however, mechanistic details are unknown.
METHODS
Here, we further explored in rats 8-aminoguanine's effects on renal excretory function by combining studies using intravenous 8-aminoguanine, intrarenal artery infusions of PNPase substrates (inosine and guanosine), renal microdialysis, mass spectrometry, selective adenosine receptor ligands, adenosine receptor knockout rats, laser doppler blood flow analysis, cultured renal microvascular smooth muscle cells, HEK293 cells expressing A receptors and homogeneous time resolved fluorescence assay for adenylyl cyclase activity.
RESULTS
Intravenous 8-aminoguanine caused diuresis/natriuresis/glucosuria and increased renal microdialysate levels of inosine and guanosine. Intrarenal inosine, but not guanosine, exerted diuretic/natriuretic/glucosuric effects. In 8-aminoguanine-pretreated rats, intrarenal inosine did not induce additional diuresis/natriuresis/glucosuria. 8-Aminoguanine did not induce diuresis/natriuresis/glucosuria in A-receptor knockout rats, yet did so in A- and A-receptor knockout rats. Inosine's effects on renal excretory function were abolished in A knockout rats. Intrarenal BAY 60-6583 (A agonist) induced diuresis/natriuresis/glucosuria and increased medullary blood flow. 8-Aminoguanine increased medullary blood flow, a response blocked by pharmacological inhibition of A, but not A, receptors. In HEK293 cells expressing A receptors, inosine activated adenylyl cyclase, and this was abolished by MRS 1754 (A antagonist). In renal microvascular smooth muscle cells, 8-aminoguanine and forodesine (PNPase inhibitor) increased inosine and 3',5'-cAMP; however, in cells from A knockout rats, 8-aminoguanine and forodesine did not augment 3',5'-cAMP yet increased inosine.
CONCLUSIONS
8-Aminoguanine induces diuresis/natriuresis/glucosuria by increasing renal interstitial levels of inosine which, via A receptor activation, increases renal excretory function, perhaps in part by increasing medullary blood flow.
Topics: Rats; Humans; Animals; Adenylyl Cyclases; HEK293 Cells; Diuresis; Diuretics; Natriuresis; Receptors, Purinergic P1; Inosine
PubMed: 36802842
DOI: 10.1161/HYPERTENSIONAHA.122.20760 -
Handbook of Experimental Pharmacology 2022The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system.... (Review)
Review
The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.
Topics: Analgesics, Opioid; Dynorphins; Humans; Ligands; Receptors, Opioid, kappa; Structure-Activity Relationship
PubMed: 33454858
DOI: 10.1007/164_2020_431 -
International Urogynecology Journal May 2021Nocturia, defined as the act of waking to pass urine during sleeping, is a common problem in older women and is associated with significant morbidity and impairments in... (Review)
Review
INTRODUCTION AND HYPOTHESIS
Nocturia, defined as the act of waking to pass urine during sleeping, is a common problem in older women and is associated with significant morbidity and impairments in health-related quality of life. The aim of this review was to synthesize the current evidence regarding the incidence, impact, pathophysiology, and specific diagnostic approach of nocturia in the postmenopausal population.
METHODS
We searched PubMed and Web of Science databases to identify relevant studies published through June 2020. Reference lists of the reviews obtained were screened for other articles deemed pertinent by the authors.
RESULTS
Genitourinary symptoms attributed to the menopause have been reported to occur in nearly 90% of postmenopausal women, and nocturia is one of the most common. The relative deficiency in endogenous estrogen production after the menopause is thought to exacerbate all major pathophysiological mechanisms that may underlie nocturia, including reduced bladder capacity, nocturnal polyuria, global polyuria, and sleep disorders. Diminished estrogen may induce anatomical and physiological bladder changes, contributing to a reduction in functional bladder capacity. Excess nocturnal urine production can also be provoked by estrogen depletion, either via free water-predominant diuresis by an impaired secretion of antidiuretic hormone, or a salt-predominant diuresis owing to diminished activation of the renin-angiotensin-aldosterone axis. Additionally, a relationship between the transition to menopause and impaired sleep has been described, mediated by increased incidence in vasomotor symptoms and obstructive sleep apnea signs during the menopause.
CONCLUSION
Further research is necessary to better characterize and manage nocturia in postmenopausal women.
Topics: Aged; Diuresis; Female; Humans; Menopause; Nocturia; Polyuria; Quality of Life
PubMed: 33439278
DOI: 10.1007/s00192-020-04640-7 -
World Journal of Nephrology Jan 2023Obstructive uropathy is an important cause of acute and chronic kidney disease. Decompression of the urinary tract is an essential aspect of treatment. The cause and... (Review)
Review
Obstructive uropathy is an important cause of acute and chronic kidney disease. Decompression of the urinary tract is an essential aspect of treatment. The cause and aetiology of obstruction typically determine the surgical approach. Acute relief of obstruction is frequently complicated by fluid and electrolyte imbalance. Standard therapeutic interventions for acute or chronic renal failure also apply for cases of obstructive uropathy. This narrative review summarises the early and long-term medical management of obstructive uropathy.
PubMed: 36704657
DOI: 10.5527/wjn.v12.i1.1 -
Pediatric Nephrology (Berlin, Germany) Mar 2023Nocturnal polyuria (NP) due to a suppressed vasopressin circadian rhythm is a well-documented pathogenetic mechanism in enuresis, mainly studied in monosymptomatic...
BACKGROUND
Nocturnal polyuria (NP) due to a suppressed vasopressin circadian rhythm is a well-documented pathogenetic mechanism in enuresis, mainly studied in monosymptomatic enuresis. A substantial percentage of patients do not respond to desmopressin. This suggests that NP may not only be related to vasopressin, but that other kidney components play a role. Solute handling and osmotic excretion have been investigated in the past, especially in refractory patients. Nevertheless, data in treatment-naïve populations with information on timing overnight are sparse. This study aims to investigate the diuresis and solute excretion in treatment-naïve patients with or without NP, with emphasis on circadian rhythms.
METHODS
Retrospective analysis of 403 treatment-naïve children 5-18 years with severe enuresis (> 8 nights/2 weeks). Circadian rhythms were evaluated by a 24-h urine collection in 8 timed portions (4 day, 4 nighttime) at in-home settings. Urine volume, osmolality, and creatinine were measured. Patients were subdivided into three groups according to nocturnal diuresis (ND) and Expected Bladder Capacity (EBCage) ratio: (a) < 100%, (b) 100-129%, (c) > 130%.
RESULTS
All groups maintained circadian rhythm for diuresis and diuresis rates. Patients with higher ND (100-129% and > 130% EBCage) had higher daytime volumes and less pronounced circadian rhythm. In the ND group > 130% EBCage, the ND rate was higher during the first night collection and osmotic excretion was significantly higher overnight.
CONCLUSIONS
Overall 24-h fluid intake (reflected by 24-h diuresis) and nutritional intake (24-h osmotic excretion) might play a role in enuresis. Increased diuresis rate early in the night can be important in some patients, whereas the total night volume can be important in others. A higher resolution version of the Graphical abstract is available as Supplementary Information.
Topics: Child; Humans; Nocturnal Enuresis; Polyuria; Retrospective Studies; Deamino Arginine Vasopressin; Water; Vasopressins; Circadian Rhythm
PubMed: 35748940
DOI: 10.1007/s00467-022-05645-8 -
Hormonal regulation and functional role of the "renal" tubules in the disease vector, Aedes aegypti.Vitamins and Hormones 2021The Aedes aegypti mosquito is a vector responsible for transmitting various arboviruses including dengue and yellow fever. Their ability to regulate the ionic and water... (Review)
Review
The Aedes aegypti mosquito is a vector responsible for transmitting various arboviruses including dengue and yellow fever. Their ability to regulate the ionic and water composition of their hemolymph is a major physiological phenomenon, allowing the mosquito to adapt to a range of ecological niches. Hematophagus insects, including the female A. aegypti, face the challenge of excess salt and water intake after a blood meal. Post-prandial diuresis is under rigorous control by neuroendocrine factors, acting on the Malpighian "renal" tubules (MTs), to regulate primary urine production. The MTs are made up of two cell types; mitochondria-rich principal cells, which facilitate active transport of Na and K cations across the membrane, and thin stellate cells, which allows for transepithelial Cl secretion. The active driving force responsible for ion transport is the apical V-type H ATPase, which creates a proton gradient allowing for Na and/or K cation exchange through cation/H antiporters. Additionally, the basolaterally localized Na-K-2Cl cotransporter (NKCC) is responsible for the transport of these ions from the hemolymph into the principal cells. Numerous studies have examined hormonal regulation of the mosquito MTs and identified several diuretics including serotonin (5HT), a calcitonin-related diuretic hormone 31 (DH), a corticotropin-related factor like diuretic peptide (DH), a kinin-related diuretic peptide, as well as anti-diuretic factors including CAPA peptides, all of which are known to regulate fluid and ion transport by the MTs. This review therefore focuses on the control of ionic homeostasis in A. aegypti mosquitoes, emphasizing the importance of the MTs, the channels and transporters involved in maintaining hydromineral balance, and the neuroendocrine regulation of both diuresis and anti-diuresis.
Topics: Aedes; Animals; Disease Vectors; Diuresis; Female; Malpighian Tubules; Mosquito Vectors
PubMed: 34420581
DOI: 10.1016/bs.vh.2021.06.007 -
Journal of Pharmacological and... 2022Metabolic chambers are routinely used for urine collection in rodents. In mice, due to small urination volume, evaporation in the metabolic chambers (≈50%) distorts...
Metabolic chambers are routinely used for urine collection in rodents. In mice, due to small urination volume, evaporation in the metabolic chambers (≈50%) distorts diuresis and urinalysis parameters. We have developed a new technique of bladder catheterization enabling long-term accurate and contamination-free urine collection in awake male and female mice for 30 days or longer. Daily diuresis in catheterized mice was twice higher as compared to metabolic cages. The twofold difference in urine recovery was preserved when the circadian variation of diuresis, the effects of furosemide, desmopressin and water load were estimated using the two techniques. Urine osmolarity, urinalysis, and microbiological parameters evidence higher quality of the catheter-collected urine. Using phenol red, we demonstrate utility of our technique for pharmacokinetic studies. 30 days after the surgery the catheters were patent and had minimal impact on the animals' heath. Bladder catheterization is a useful tool for physiological, pharmacological, and toxicological studies.
Topics: Animals; Diuresis; Female; Male; Mice; Urinary Bladder; Urinary Catheterization; Urine Specimen Collection; Wakefulness
PubMed: 34678429
DOI: 10.1016/j.vascn.2021.107128 -
Kidney360 Jun 2022
Topics: Creatinine; Glomerular Filtration Rate; Kidney Function Tests
PubMed: 35845325
DOI: 10.34067/KID.0002302022