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Abstract Aims Early diuresis and natriuresis are commonly used to assess the efficacy of decongestive therapy following an acute heart failure episode. There is limited knowledge regarding which parameter better predicts adverse clinical outcomes, especially in the outpatient setting. This study investigated the prognostic value of both metrics in predicting 30-day adverse clinical events in an ambulatory worsening heart failure (WHF) scenario. Methods and results This is a post-hoc analysis of the SALT-HF trial involving 167 patients with ambulatory WHF randomized to receive intravenous furosemide with or without hypertonic saline solution. Early diuretic response was assessed through 3-h urine output and 3-h urinary sodium (uNa+) levels following intravenous (IV) diuretic infusion. We analysed their association with 30-day adverse events (defined as death, heart failure hospitalization, or the need for outpatient IV diuretics) using logistic regression analysis. Both exposures were examined along the continuum and dichotomized in their median. The discriminative ability between the exposures and endpoints was assessed by receiver operating characteristic curves (AUC-ROC). Results The median age of participants was 81 years, predominantly male (69.5%). Patients with lower 3-h urinary sodium and diuresis were older and exhibited reduced kidney function and haemoglobin levels. At 30 days, 50 (29.9%) of the sample experienced the composite endpoint. Multivariate analyses revealed that lower 3-h uNa+ was associated with a higher risk of 30-day adverse events (P = 0.008). Conversely, 3-h diuresis did not significantly predict 30-day adverse outcomes (P = 0.424). There was a trend towards a higher AUC-ROC for the inverse of 3-h natriuresis compared with 3-h diuresis: 0.680 versus 0.601, P = 0.092. Conclusions In patients with ambulatory WHF treated with IV furosemide, 3-h urinary sodium predicted 30-day outcomes whereas 3-h diuresis did not.

Background Poor response to diuretics is associated with worse prognosis in patients with acute heart failure (AHF). We hypothesized that treatment with tolvaptan improves diuretic response in patients with AHF. Methods We performed a secondary analysis of the AQUAMARINE open-label randomized study in which a total of 217 AHF patients with renal impairment (eGFR < 60 mL/min/1.73 m 2 ) were randomized to either tolvaptan or conventional treatment. We evaluated diuretic response to 40 mg furosemide or its equivalent based on two different parameters: change in body weight and net fluid loss within 48 h. Results The mean time from patient presentation to randomization was 2.9 h. Patients with a better diuretic response showed greater relief of dyspnea and less worsening of renal function. Tolvaptan patients showed a significantly better diuretic response measured by diuretic response based both body weight [−1.16 (IQR −3.00 to −0.57) kg/40 mg vs. −0.51 (IQR −1.13 to −0.20) kg/40 mg; P  < 0.001] and net fluid loss [2125.0 (IQR 1370.0–3856.3) mL/40 mg vs. 1296.3 (IQR 725.2–1726.5) mL/40 mg; P  < 0.001]. Higher diastolic blood pressure and use of tolvaptan were independent predictors of a better diuretic response. Conclusions Better diuretic response was associated with greater dyspnea relief and less WRF. Early treatment with tolvaptan significantly improved diuretic response in AHF patients with renal dysfunction.

Behavior and physiology are orchestrated by neuropeptides acting as central neuromodulators and circulating hormones. An outstanding question is how these neuropeptides function to coordinate complex and competing behaviors. In Drosophila, the neuropeptide leucokinin (LK) modulates diverse functions, but mechanisms underlying these complex interactions remain poorly understood. As a first step towards understanding these mechanisms, we delineated LK circuitry that governs various aspects of post-feeding physiology and behavior. We found that impaired LK signaling in Lk and Lk receptor (Lkr) mutants affects diverse but coordinated processes, including regulation of stress, water homeostasis, feeding, locomotor activity, and metabolic rate. Next, we sought to define the populations of LK neurons that contribute to the different aspects of this physiology. We find that the calcium activity in abdominal ganglia LK neurons (ABLKs), but not in the two sets of brain neurons, increases specifically following water consumption, suggesting that ABLKs regulate water homeostasis and its associated physiology. To identify targets of LK peptide, we mapped the distribution of Lkr expression, mined a brain single-cell transcriptome dataset for genes coexpressed with Lkr, and identified synaptic partners of LK neurons. Lkr expression in the brain insulin-producing cells (IPCs), gut, renal tubules and chemosensory cells, correlates well with regulatory roles detected in the Lk and Lkr mutants. Furthermore, these mutants and flies with targeted knockdown of Lkr in IPCs displayed altered expression of insulin-like peptides (DILPs) and transcripts in IPCs and increased starvation resistance. Thus, some effects of LK signaling appear to occur via DILP action. Collectively, our data suggest that the three sets of LK neurons have different targets, but modulate the establishment of post-prandial homeostasis by regulating distinct physiological processes and behaviors such as diuresis, metabolism, organismal activity and insulin signaling. These findings provide a platform for investigating feeding-related neuroendocrine regulation of vital behavior and physiology.

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.SGLT2 inhibitors induce a number of metabolic adaptations in response to increased glucose and Na+ excretion. This Perspective article describes how these adaptations suggest that SGLT2 inhibition triggers a body water-conserving mechanism, and discusses how these metabolic adjustments may contribute to the favourable cardiovascular and renal outcomes of this class of therapeutics.

Immediate responses to hypoxia at high altitude are hyperventilation and successive respiratory alkalosis. Alkalosis, in turn, can affect cerebrospinal fluid pH and ventilatory control. The kidneys compensate metabolically for respiratory alkalosis. The time line and detailed sequence of these renal compensatory processes have not been explored thoroughly. We examined the initial adjustments of acid–base and fluid balances during the first 2 days at high altitude.  Twelve unacclimatized adults of either sex were transported to 3100 m a.s.l. at the Sonnblick Observatory (Austria). Measurements (fluid and acid–base balance and arterial blood gases) were performed before and 24 and 44 h after arrival. Exposure to high altitude provoked hyperventilation, resulting in hypocapnia and alkalosis. Altitude diuresis started immediately after arrival at altitude. The only metabolic response within the first 24 h was a slight reduction in plasma bicarbonate, but after 44 h distinct reductions in bicarbonate and a trend change in altitude‐corrected base excess and arterial pH were observed. Hyperventilation and increased diuresis appeared immediately upon exposure to high altitude, whereas compensatory bicarbonate excretion showed the first influence on the arterial pH at the 44 h measurement. Further research is needed to explore differences in individual responses in the setting of antedated or carry‐over acclimatization. What is the central question of this study? Hyperventilation, the immediate response to hypoxia, leads to respiratory alkalosis at high altitude. Renal compensation of altitude‐alkalosis is thought to take days. We studied this during a 44 h sojourn at 3100 m. What is the main finding and its importance? After 24 h at altitude, respiratory alkalosis was compensated only by a subtle reduction in plasma bicarbonate, while base excess and arterial pH remained at the alkalotic end of their normal ranges. After 44 h at altitude, bicarbonate had fallen by 12%, and the base excess and pH had started to normalize. Despite immediacy of the renal response, relevant alkalosis compensation begins with a delay of >24 h.

Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium‐glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto‐Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24‐hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na+ excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute‐free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin‐treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin‐induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV. We show in this study that SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin‐induced aquaporin‐2 phosphorylation and solute‐free water reabsorption in proportion to the reduced fluid balance to maintain body fluid volume These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain body fluid volume.

Significance Endocrine control of chloride shunt conductance in Malpighian tubules of many insects is mediated by kinin diuretic peptides, but the route for chloride transport is unknown. We use Drosophila transgenics, combined with physiology, imaging, electrophysiology, and transgenic chloride reporter technology, to show that a chloride channel (CLC) encoded by ClC-a/CG31116 is uniquely localized to stellate cells and is essential for neuropeptide-stimulated, but not resting, levels of secretion. Therefore, we have resolved this issue in Drosophila ; kinin stimulates chloride flux by a transcellular route that is confined to the stellate cells. Epithelia frequently segregate transport processes to specific cell types, presumably for improved efficiency and control. The molecular players underlying this functional specialization are of particular interest. In Drosophila , the renal (Malpighian) tubule displays the highest per-cell transport rates known and has two main secretory cell types, principal and stellate. Electrogenic cation transport is known to reside in the principal cells, whereas stellate cells control the anion conductance, but by an as-yet-undefined route. Here, we resolve this issue by showing that a plasma membrane chloride channel, encoded by ClC-a , is exclusively expressed in the stellate cell and is required for Drosophila kinin-mediated induction of diuresis and chloride shunt conductance, evidenced by chloride ion movement through the stellate cells, leading to depolarization of the transepithelial potential. By contrast, ClC-a knockdown had no impact on resting secretion levels. Knockdown of a second CLC gene showing highly abundant expression in adult Malpighian tubules, ClC-c , did not impact depolarization of transepithelial potential after kinin stimulation. Therefore, the diuretic action of kinin in Drosophila can be explained by an increase in ClC-a –mediated chloride conductance, over and above a resting fluid transport level that relies on other ( ClC-a –independent) mechanisms or routes. This key segregation of cation and anion transport could explain the extraordinary fluid transport rates displayed by some epithelia.

Oxalic acid, a toxic metabolic end product, accumulates when kidney function deteriorates. Apart from its direct tubulotoxicity, it crystallizes at concentrations above 30-40 µmol/L. High oxalic acid concentrations at transplantation might negatively influence kidney transplant function. The influence of the concentrations of oxalic acid and its precursors and residual diuresis on kidney transplant outcomes was studied. In this prospective cohort study, patients who received a kidney transplant between September 2018 and January 2022 participated. Concentrations of oxalic acid and precursors were determined in pre-transplant blood samples. Data on residual diuresis and other recipient, donor or transplant related variables were collected. Follow-up lasted until July 1st 2023. 496 patients were included, 154 were not on dialysis. Median residual diuresis was 1000 mL/day (IQR 200; 2000 mL/day). There were 230 living donor transplantations. Oxalic acid concentrations exceeded the upper normal concentration in 99% of patients, glyoxylic acid in all patients. There were 52 (10%) graft failures. As the influence of oxalic acid on the risk of graft failure censored for death was non-linear, it was categorized into two groups: ≤ 60 and > 60 μmol/L. In multivariable Cox analysis the graft failure censored for death risk was significantly influenced by residual diuresis, donor type (living versus deceased), donor age and oxalic acid. In 180 patients oxalic acid concentration shortly after transplantation was significantly lower than pre-transplant concentrations, suggesting excretion by the new graft. A better eGFR at day 7 was associated with lower oxalic acid concentration. Oxalic acid and residual diuresis did not influence patient survival. Residual diuresis and oxalic acid concentration are important and independent predictors of graft survival censored for death. These results underline the importance of pre-emptive transplantation, or optimizing the pre-transplant patients' condition regarding waste product concentrations.

Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver in response to metabolic stress. In addition to its well-characterized effects on energy homeostasis, FGF21 has been shown to increase water intake in animals. In this study, we sought to further explore the effects of FGF21 on fluid homeostasis in rats. A single dose of a long-acting FGF21 analog, PF-05231023, significantly increased water consumption, which was accompanied by an elevation in urine output that appeared prior to a significant change in water intake. We observed that FGF21 rapidly and significantly increased heart rate and blood pressure in telemeter-implanted rats, before changes in urine output and water intake were observed. Our data suggest that sympathetic activation may contribute to the pathogenesis by which FGF21 increases blood pressure as the baroreceptor unloading induced reflex tachycardia was significantly elevated in FGF21-treated animals. However, FGF21 was still capable of causing hypertension in animals in which approximately 40% of the sympathetic post-ganglionic neurons were ablated. Our data suggest that FGF21-induced water intake is in fact secondary to diuresis, which we propose to be a compensatory mechanism engaged to alleviate the acute hypertension caused by FGF21.

Background The optimal time for initiating kidney replacement therapy (KRT) in acute kidney injury (AKI) has been extensively studied in recent years. In contrast, there are currently insufficient data on the best time to discontinue KRT. One diagnostic option to unmask tubular reserve and indirectly estimate the glomerular filtration rate is the furosemide stress test (FST). Methods We conducted a prospective, observational single-center trial. A FST was carried out in patients who developed spontaneous diuresis (SD) during ongoing KRT with a urine output of at least 400 ml in 24 h without any diuretic therapy. A positive FST was defined with urine output > 200 ml within 2 h following intravenous furosemide application. Follow-up was performed for 7 days and the need to restart KRT was assessed daily. Results After 100 patients were enrolled in the trial, 98 patients were eligible for further evaluation. 76 patients were FST-positive, while 22 patients were FST-negative. Resumption of KRT within the 7-day follow-up was required in only 14.5% of the FST-positive, but 72.7% of the FST-negative patients ( p  < 0.001). The urine output after FST was also significantly associated with successful release from KRT (AUC 0.87; p  < 0.001). Conclusions In critically ill patients with recovery of SD > 400ml/d during ongoing KRT, the FST helps to identify patients who can be successfully liberated from KRT. By detecting the tubular reserve using FST, the possibility of short-term kidney recovery after AKI can be estimated. Trial registration German Clinical Trials Registry (DRKS00030560); date of registration 18/11/2022. https://drks.de/search/de/trial/DRKS00030560 .