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Drugs in Context 2023Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a... (Review)
Review
Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.
PubMed: 38188263
DOI: 10.7573/dic.2023-6-5 -
Clinical and Experimental Hypertension... Dec 2024Physical activity has profound benefits on health, especially in patients with cardiovascular and metabolic disease. Exercise training can reduce oxidative stress,...
BACKGROUND
Physical activity has profound benefits on health, especially in patients with cardiovascular and metabolic disease. Exercise training can reduce oxidative stress, improve renal function, and thus lower blood pressure. However, the effect of exercise training on angiotensin II type 1 receptors (ATR) and endothelin subtype B receptors (ETBR)-mediated diuresis and natriuresis in obese Zucker rats is unclear.
METHODS
Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. Blood pressure was measured by tail-cuff plethysmography, and functions of ATR and ETBR in the kidney were measured by natriuresis, respectively.
RESULTS
Our data showed that exercise training improved glucose and lipid metabolism, renal function and sodium excretion in obese Zucker rats, accompanied by decreased oxidative stress and GRK4 expression in obese Zucker rats. Moreover, exercise training reduced the Candesartan-induced an increase in diuresis and natriuresis and increased ETBR agonists (BQ3020)-mediated diuresis and natriuresis in obese Zucker rats, which were associated with decreased renal ATR expression and ETBR phosphorylation levels.
CONCLUSIONS
The results demonstrate that exercise training lowers blood pressure via improving renal ATR and ETBR function through modulating GRK4 expression in Obese Zucker Rats and provides potentially effective targets for obesity-related hypertension.
Topics: Humans; Rats; Animals; Rats, Zucker; Kidney; Hypertension; Obesity; Blood Pressure; G-Protein-Coupled Receptor Kinase 4
PubMed: 38471134
DOI: 10.1080/10641963.2024.2323532 -
Jornal Brasileiro de Nefrologia 2024Acute Kidney Injury (AKI) in the Intensive Care Unit (ICU) have concepts of diagnosis and management have water balance as their main point of evaluation. In our ICU,...
INTRODUCTION
Acute Kidney Injury (AKI) in the Intensive Care Unit (ICU) have concepts of diagnosis and management have water balance as their main point of evaluation. In our ICU, from 2004 to 2012, the nephrologist's participation was on demand only; and as of 2013 their participation became continuous in meetings to case discussion. The aim of this study was to establish how an intense nephrologist/intensivist interaction influenced the frequency of dialysis indication, fluid balance and pRIFLE classification during these two observation periods.
METHODS
Retrospective study, longitudinal evaluation of all children with AKI undergoing dialysis (2004 to 2016).
PARAMETERS STUDIED
frequency of indication, duration and volume of infusion in the 24 hours preceding dialysis; diuresis and water balance every 8 hours. Non-parametric statistics, p ≤ 0.05.
RESULTS
53 patients (47 before and 6 after 2013). There were no significant differences in the number of hospitalizations or cardiac surgeries between the periods. After 2013, there was a significant decrease in the number of indications for dialysis/year (5.85 vs. 1.5; p = 0.000); infusion volume (p = 0.02), increase in the duration of dialysis (p = 0.002) and improvement in the discrimination of the pRIFLE diuresis component in the AKI development.
CONCLUSION
Integration between the ICU and pediatric nephrology teams in the routine discussion of cases, critically approaching water balance, was decisive to improve the management of AKI in the ICU.
Topics: Child; Humans; Nephrologists; Renal Dialysis; Retrospective Studies; Acute Kidney Injury; Water
PubMed: 37115039
DOI: 10.1590/2175-8239-JBN-2022-0158en -
International Urology and Nephrology Oct 2021To investigate 50 week ultrasound imaging and ultrastructure changes of bladder in diuresis and diabetes rats.
PURPOSE
To investigate 50 week ultrasound imaging and ultrastructure changes of bladder in diuresis and diabetes rats.
METHODS
Forty-two healthy male Sprague-Dawley rats were randomly divided into control group, sugar-induced diuresis group and streptozotocin-induced diabetes group. The 24 h drinking and urine volume were calculated from 21 to 31 weeks. Using ultrasound to assess bladders after 49 weeks. Bladders were examined by transmission electron microscope after 50 weeks.
RESULTS
The drinking and urine volume significantly increased in the diuresis and diabetes groups. The bladder morphology and bladder wall thickness increased in the diuresis and diabetes groups. Bladder stones, bladder overdistension and urinary retention were seen in the diuresis and diabetes groups. Urothelium manifested degeneration, denudation and necrosis in the diuresis and diabetes groups. The mitochondrial vacuolar degeneration in the urothelial cells was seen in the diabetes group. The subepithelial vascular endothelial cells hyperplasia with a narrowed lumen were observed in the diabetes group. Abnormal mitochondria were rarely seen in the control group. The mitochondrial vacuolar degeneration in the detrusor was more severe in the diabetes group than in the diuresis group. The detrusor muscle and axon degeneration were observed in the diuresis and diabetes groups. Two rats in the diuresis group share similarities with diabetes group (2/6).
CONCLUSION
Long-term diabetes mellitus can cause increments of urinary bladder morphology and bladder wall thickness, urinary retention and bladder stones. Ultrastructural degeneration of the bladder might be the morphological bases of diabetic cystopathy.
Topics: Animals; Diabetes Mellitus; Diuresis; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Sugars; Time Factors; Ultrasonography; Urinary Bladder
PubMed: 34110574
DOI: 10.1007/s11255-021-02911-w -
American Journal of Physiology. Renal... Oct 2020Inhibitors of proximal tubular Na-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na-H...
Inhibitors of proximal tubular Na-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na-H exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.
Topics: Acid-Base Equilibrium; Animals; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Diabetes Mellitus; Disease Models, Animal; Glucosides; Glycosuria; Kidney Tubules, Proximal; Male; Mice, Inbred C57BL; Mice, Knockout; Natriuresis; Natriuretic Agents; Phosphorylation; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchanger 3
PubMed: 32893663
DOI: 10.1152/ajprenal.00264.2020 -
Peptides Jan 2022Irisin, a novel myokine, has been identified to exert a series of favorable effects on metabolic diseases, including diabetes and obesity. This study aimed to explore...
Irisin lowers blood pressure in Zucker diabetic rats by regulating the functions of renal angiotensin II type 1 receptor via the inhibition of the NF-κB signaling pathway.
BACKGROUND
Irisin, a novel myokine, has been identified to exert a series of favorable effects on metabolic diseases, including diabetes and obesity. This study aimed to explore the effects of chronic irisin administration on blood pressure and the related underlying mechanisms in Zucker diabetic fatty (ZDF) rats.
METHODS AND RESULTS
Male ZDF rats and Zucker lean (ZL) rats received a continuous subcutaneous infusion of irisin or saline for 4 weeks. Compared with ZL counterparts, ZDF rats reported higher systolic blood pressure (SBP), severer renal inflammation, increased oxidative stress, and impaired natriuresis and diuresis; they also had an elevated ATR expression in renal cortex and augmented candesartan-induced natriuresis and diuresis. The irisin administration lowered SBP, improved diuretic and natriuretic effects, and reduced renal inflammation and oxidative stress in ZDF rats, along with decreased renal expression of ATR and restored candesartan-mediated natriuresis and diuresis. Further experiments showed that irisin inhibited the translocation of NF-κB from the cytosol to the nucleus and the activation of NF-κB signaling pathway, which may contribute to the reduced ATR expression and function.
CONCLUSIONS
Irisin administration serves an anti-hypertensive role in ZDF rats by alleviating renal inflammation and oxidative stress, reducing the expression and impact of ATR, and restoring natriuresis and diuresis. The underlying mechanism may involve the irisin-induced inhibition of the NF-κB signaling pathway.
Topics: Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Fibronectins; Kidney; Male; NF-kappa B; Oxidative Stress; Rats, Zucker; Receptor, Angiotensin, Type 1; Signal Transduction; Rats
PubMed: 34800756
DOI: 10.1016/j.peptides.2021.170688 -
Journal of the American Society of... Aug 2022Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these...
BACKGROUND
Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs' role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known.
METHODS
Mice expressing epitope-tagged LRRC8 subunits were used to determine the renal localization of all VRAC subunits. Mice carrying constitutive deletions of -, or with inducible or cell-specific ablation of , were analyzed to assess renal functions of VRACs. Analysis included histology, urine and serum parameters in different diuresis states, and metabolomics.
RESULTS
The kidney expresses all five VRAC subunits with strikingly distinct localization. Whereas LRRC8C is exclusively found in vascular endothelium, all other subunits are found in the nephron. LRRC8E is specific for intercalated cells, whereas LRRC8A, LRRC8B, and LRRC8D are prominent in basolateral membranes of proximal tubules. Conditional deletion of LRRC8A in proximal but not distal tubules and constitutive deletion of LRRC8D cause proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms.
CONCLUSIONS
VRAC/LRRC8 channels are crucial for the function and integrity of proximal tubules, but not for more distal nephron segments despite their larger need for volume regulation. LRRC8A/D channels may be required for the basolateral exit of many organic compounds, including cellular metabolites, in proximal tubules. Proximal tubular injury likely results from combined accumulation of several transported molecules in the absence of VRAC channels.
Topics: Mice; Animals; Membrane Proteins; Biological Transport; Chlorides; Cell Membrane; Nephrons
PubMed: 35777784
DOI: 10.1681/ASN.2021111458 -
Circulation. Heart Failure Nov 2021Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and...
BACKGROUND
Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors.
METHODS
One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics.
RESULTS
FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [≥0.33 for all]) or neurohormonal activation (plasma or urine renin [≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (=0.44).
CONCLUSIONS
FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.
Topics: Aged; Aged, 80 and over; Diuresis; Diuretics; Female; Fibroblast Growth Factor-23; Heart Failure; Humans; Male; Middle Aged; Renin; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 34689571
DOI: 10.1161/CIRCHEARTFAILURE.121.008385 -
Biology of Sex Differences Sep 2020Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential...
BACKGROUND
Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na transport. Activation of these receptors inhibits epithelial Na channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y and P2Y receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y and P2Y) receptors regulating Na excretion compared to male and OVX rats.
METHODS
To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y and P2Y receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E, 0, 10, 100, and 1000 nM) to test whether E increases mRNA expression of P2Y and P2Y receptors.
RESULTS
Acute P2 inhibition attenuated urinary Na excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y and P2Y mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E dose-dependently upregulated P2Y and P2Y mRNA expression in mIMCD3.
CONCLUSION
These data suggest that ovary-intact females have enhanced P2Y and P2Y-dependent regulation of Na handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na handling in premenopausal females.
Topics: Animals; Cell Line; Dose-Response Relationship, Drug; Epithelial Sodium Channels; Estradiol; Female; Gene Expression Regulation; Kidney Medulla; Male; Natriuresis; Ovariectomy; Ovary; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Sex Factors; Suramin; Type C Phospholipases
PubMed: 32928299
DOI: 10.1186/s13293-020-00329-0 -
Annales D'endocrinologie May 2023The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Bartter and Schwartz, 1967) is defined as low effective plasma osmolality due to impaired renal... (Review)
Review
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Bartter and Schwartz, 1967) is defined as low effective plasma osmolality due to impaired renal water dilution together with impaired thirst center regulation once effective hypovolemia and corticotropin deficiency are ruled out (Robertson, 2006). Impaired water dilution is encountered following stimulation of voloreceptors triggering ADH (i.e., vasopressin) secretion through brain circumventricular organ stimulation [including notably the subfornical organ (SFO)] (Bichet, 2019). This condition is reversed as soon as volemia is restored: hyponatremia is corrected within hours, unlike withdrawal of drugs inducing SIADH, in which optimal water dilution recovery usually takes several days or weeks. Therefore, diuretics will be beyond the scope of this review.
Topics: Humans; Inappropriate ADH Syndrome; Hyponatremia; Diuresis; Thirst; Water
PubMed: 36965851
DOI: 10.1016/j.ando.2023.03.010