Furosemide-induced Diuresis Research Articles

Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250mg; n=9), furosemide (20mg; n=10) or amiloride (10mg; n=7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8h post-treatment. The peak diuretic response occurred 2h (99.4±14.8mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1h (196.5±12.3mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1±3.8mmHg at baseline to 17.2±4.4mmHg at 3h and to 20.5±5.3mmHg at 6h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

Effects of phenylbutazone, firocoxib, and dipyrone on the diuretic response to furosemide in horses.

Treatment with phenylbutazone (nonselective COX inhibitor) decreases the diuretic and natriuretic effects of furosemide by nearly 30% but the effects of COX-2 specific inhibitors (firocoxib) and atypical NSAIDs (dipyrone) are unknown. Furosemide-induced diuresis after pretreatment with firocoxib or dipyrone is diminished to a lesser extent than after pretreatment with phenylbutazone. Eight healthy mares. Each mare received 4 treatments in a prospective experimental crossover study using a replicated 4 × 4 Latin Square design: furosemide alone (FU), furosemide and phenylbutazone (PB), furosemide and firocoxib (FX), and furosemide and dipyrone (DP). After 24 hours of NSAID treatment at recommended dosages, ureteral catheters were placed for continual urine collection. After a 30-minute baseline collection period, furosemide (1.0 mg/kg, IV) was administered, and urine and blood samples were collected for 4 hours. Data were assessed by repeated measures ANOVA. Four-hour urine volume was (mean ± SD) ~25% less (P < .001) after pretreatment with all NSAIDs (PB 19.1 ± 2.1 mL/kg, FX 17.7 ± 3.5 mL/kg, DP 19.1 ± 3.9 mL/kg), as compared to FU (23.4 ± 5.1 mL/kg) (P < .001), but there were no differences between PB, FX, or DP. Interindividual variability in furosemide diuresis after pretreatment with different NSAIDs was observed. Though COX-2 selective NSAIDs and dipyrone might have less severe or fever gastrointestinal adverse effects in horses, our data suggest minimal differences in effects on furosemide-induced diuresis, and possibly, risk of nephrotoxicosis.

Effect of periprocedural furosemide-induced diuresis with matched isotonic intravenous hydration in patients with chronic kidney disease undergoing transcatheter aortic valve implantation.

Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) is a serious complication which is associated with increased mortality. The RenalGuard system was developed to reduce the risk of AKI after contrast media exposition by furosemide-induced diuresis with matched isotonic intravenous hydration. The aim of this study was to examine the effect of the RenalGuard system on the occurrence of AKI after TAVI in patients with chronic kidney disease. The present study is a single-center randomized trial including patients with severe aortic valve stenosis undergoing TAVI. Overall, a total of 100 patients treated by TAVI between January 2017 and August 2018 were randomly assigned to a periprocedural treatment with the RenalGuard system or standard treatment by pre- and postprocedural intravenous hydration. Primary endpoint was the occurrence of AKI after TAVI, and secondary endpoints were assessed according to valve academic research consortium 2 criteria. Overall, the prevalence of AKI was 18.4% (n = 18). The majority of these patients developed mild AKI according to stage 1. Comparing RenalGuard to standard therapy, no significant differences were observed in the occurrence of AKI (RenalGuard: 21.3%; control group: 15.7%; p = 0.651). In addition, there were no differences between the groups with regard to 30-day and 12-month mortality and procedure-associated complication rates. In this randomized trial, we did not detect a reduction in AKI after TAVI by using the RenalGuard system. A substantial number of patients with chronic kidney disease developed AKI after TAVI, whereas the majority presented with mild AKI according to stage 1 (ClinicalTrials.gov number NCT04537325).

Diuresis inducida frente a hidratación combinada en pacientes sometidos a procedimientos cardiovasculares percutáneos: metanálisis de ensayos clínicos aleatorizados

Introduction and objectivesContrast-associated acute kidney injury (CA-AKI) is a potential complication of procedures requiring administration of iodinated contrast medium. RenalGuard, which provides real-time matching of intravenous hydration with furosemide-induced diuresis, is an alternative to standard periprocedural hydration strategies. The evidence on RenalGuard in patients undergoing percutaneous cardiovascular procedures is sparse. We used a Bayesian framework to perform a meta-analysis of RenalGuard as a CA-AKI preventive strategy. MethodsWe searched Medline, Cochrane Library and Web of Science for randomized trials of RenalGuard vs standard periprocedural hydration strategies. The primary outcome was CA-AKI. Secondary outcomes were all-cause death, cardiogenic shock, acute pulmonary edema, and renal failure requiring renal replacement therapy. A Bayesian random-effect risk ratio (RR) with corresponding 95% credibility interval (95%CrI) was calculated for each outcome. PROSPERO database number CRD42022378489. ResultsSix studies were included. RenalGuard was associated with a significant relative reduction in CA-AKI (median RR, 0.54; 95%CrI, 0.31-0.86) and acute pulmonary edema (median RR, 0.35; 95%CrI, 0.12-0.87). No significant differences were observed for the other secondary endpoints [all-cause death (RR, 0.49; 95%CrI, 0.13-1.08), cardiogenic shock (RR, 0.06; 95%CrI, 0.00-1.91), and renal replacement therapy (RR, 0.52; 95%CrI, 0.18-1.18)]. The Bayesian analysis also showed that RenalGuard had a high probability of ranking first for all the secondary outcomes. These results were consistent in multiple sensitivity analyses. ConclusionsIn patients undergoing percutaneous cardiovascular procedures, RenalGuard was associated with a reduced risk of CA-AKI and acute pulmonary edema compared with standard periprocedural hydration strategies.

Diuresis-matched versus standard hydration in patients undergoing percutaneous cardiovascular procedures: meta-analysis of randomized clinical trials

Introduction and objectivesContrast-associated acute kidney injury (CA-AKI) is a potential complication of procedures requiring administration of iodinated contrast medium. RenalGuard, which provides real-time matching of intravenous hydration with furosemide-induced diuresis, is an alternative to standard periprocedural hydration strategies. The evidence on RenalGuard in patients undergoing percutaneous cardiovascular procedures is sparse. We used a Bayesian framework to perform a meta-analysis of RenalGuard as a CA-AKI preventive strategy. MethodsWe searched Medline, Cochrane Library and Web of Science for randomized trials of RenalGuard vs standard periprocedural hydration strategies. The primary outcome was CA-AKI. Secondary outcomes were all-cause death, cardiogenic shock, acute pulmonary edema, and renal failure requiring renal replacement therapy. A Bayesian random-effect risk ratio (RR) with corresponding 95% credibility interval (95%CrI) was calculated for each outcome. PROSPERO database number CRD42022378489. ResultsSix studies were included. RenalGuard was associated with a significant relative reduction in CA-AKI (median RR, 0.54; 95%CrI, 0.31-0.86) and acute pulmonary edema (median RR, 0.35; 95%CrI, 0.12-0.87). No significant differences were observed for the other secondary endpoints [all-cause death (RR, 0.49; 95%CrI, 0.13-1.08), cardiogenic shock (RR, 0.06; 95%CrI, 0.00-1.91), and renal replacement therapy (RR, 0.52; 95%CrI, 0.18-1.18)]. The Bayesian analysis also showed that RenalGuard had a high probability of ranking first for all the secondary outcomes. These results were consistent in multiple sensitivity analyses. ConclusionsIn patients undergoing percutaneous cardiovascular procedures, RenalGuard was associated with a reduced risk of CA-AKI and acute pulmonary edema compared with standard periprocedural hydration strategies.

The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats

Acute kidney injury (AKI) diagnosis relies on plasma creatinine concentration (Crpl), a relatively insensitive, surrogate biomarker of glomerular filtration rate that increases only after significant damage befalls. However, damage in different renal structures may occur without increments in Crpl, a condition known as subclinical AKI. Thus, detection of alterations in other aspects of renal function different from glomerular filtration rate must be included in an integral diagnosis of AKI. With this aim, we adapted to and validated in rats (for preclinical research) the furosemide stress test (FST), a tubular function test hitherto performed only in humans. We also tested its sensitivity in detecting subclinical tubular alterations. In particular, we predisposed rats to AKI with 3 mg/kg cisplatin and subsequently subjected them to a triggering insult (ie, 50 mg/kg/d gentamicin for 6 days) that had no effect on nonpredisposed animals but caused an overt AKI in predisposed rats. The FST was performed immediately before adding the triggering insult. Predisposed animals showed a reduced response to the FST (namely, reduced furosemide-induced diuresis and K+ excretion), whereas nonpredisposed animals showed no alteration, compared to the controls. Computational modeling of epithelial transport of solutes and water along the nephrons applied to experimental data suggested that proximal tubule transport was only minimally reduced, the sodium-chloride symporter was upregulated by 50%, and the renal outer medullary potassium channel was downregulated by 85% in predisposed animals. In conclusion, serial coupling of the FST and computational modeling may be used to detect and localize subclinical tubular alterations.

Role of protease-activated receptor 2 in regulation of renin synthesis and secretion in mice.

It has been reported that the serine protease kallikrein stimulates and that aprotinin, a protease inhibitor, inhibits renal renin secretion. Since direct stimulation of the protease-activated receptor (PAR) 2 increases renin secretion in isolated perfused mouse kidneys, we hypothesized that activation of PAR2 receptors by serine proteases could be involved in the synthesis and secretion of renin in vivo. We therefore determined the response of plasma renin concentration (PRC) to acute intraperitoneal administration of the PAR2 agonist SLIGRL, isoproterenol, hydralazine, furosemide, losartan, or lipopolysaccharide in conscious wild-type (WT) and Par2-deficient mice. Basal PRC was not different in Par2-deficient mice compared with WT mice. All six acute treatments caused significant increases of PRC in both WT and Par2-deficient mice. The response was significantly lower only in endotoxin-treated Par2-deficient mice. Chronic treatment with losartan, low salt intake, the combination of both, or furosemide caused an increase of PRC and renin mRNA in WT mice, whereas a high salt intake caused a decrease. Alterations in PRC and renal renin mRNA expression were not different between WT and Par2 -/- mice in response to chronic treatments. Par2-deficiency did not alter furosemide-induced diuresis and natriuresis. Systolic blood pressure responses to chronic treatments were not different between WT and Par2 -/- mice. In conclusion, deficiency of Par2 receptors does not alter renin secretion and renin gene expression modulated by a variety of typical maneuvers. However, activation of Par2 receptors by serine proteases seems to be of importance for renin secretion in the context of inflammation.

Slc4a8 in the Kidney: Expression, Subcellular Localization and Role in Acid Base Homeostasis and Salt Reabsorption

BackgroundThe sodium‐dependent bicarbonate transporter Slc4a8 (a.k.a NDCBE) mediates the co‐transport of sodium and bicarbonate in exchange for chloride. It is abundantly detected in the brain, with low expression levels in the kidney. The cell distribution and subcellular localization of Slc4a8 in the kidney and its role in acid/base and electrolyte homeostasis has been the subject of conflicting reports. There are no conclusive localization or functional studies to pinpoint the location and demonstrate the function of Slc4a8 in the kidney.MethodsMolecular techniques, including in situ hybridization and RT‐PCR, were performed on kidney sections and tagged epitopes were used to examine the membrane targeting of Slc4a8 in polarized kidney cells. Crispr/Cas9 was used to generate and examine Slc4a8 KO mice.ResultIn situ hybridization and Zonal distribution studies showed no expression for Slc4a8 (NDCBE) in the cortex or in cortical collecting ducts (CCD). Slc4a8 was predominantly detected in the outer and inner medullary collecting ducts (OMCD and IMCD), and was targeted to the basolateral membrane of osmotically tolerant MDCK cells when confocal microscopy images were acquired. Slc4a8 KO mice did not show any abnormal salt or bicarbonate wasting under baseline conditions or in response to bicarbonate loading, salt restriction or furosemide‐induced diuresis.ConclusionsSlc4a8 (NDCBE) is absent in the CCD and is predominantly localized on the basolateral membrane of medullary collecting duct cells. Further, Slc4a8 deletion does not cause any acid base or electrolyte abnormality in pathophysiologic states such as furosemide‐induced salt wasting or salt restriction. We suggest that Slc4a8 is likely involved in intracellular pH and volume regulation in medullary collecting duct cells.Support or Funding InformationMerit Review 5 I01 BX001000‐06 award from the Department of Veterans Affairs, and funds from the Center on Genetics of Transport and Epithelial Biology at the University of Cincinnati.

Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model

IntroductionDiuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. AnimalsSix healthy male dogs. MethodsRaw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. ResultsUrine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. ConclusionsThere was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin–angiotensin–aldosterone activation as a cause of diuretic braking in this model.

Diuretic state affects ascending thin limb tight junctions

The nephron segments in the inner medulla are part of the urine concentrating mechanism. Depending on the diuretic state, they are facing a large range of extracellular osmolality. We investigated whether water homeostasis affects tubular transport and permeability properties in inner medullary descending thin limb (IMdTL) and ascending thin limb (IMaTL). Three experimental groups of rats under different diuretic states were investigated on metabolic cages: waterload, furosemide-induced diuresis, and control (antidiuresis). Urine production and osmolalities reflected the 3-day treatment. To functionally investigate tubular epithelial properties, we performed experiments in freshly isolated inner medullary thin limbs from these animals. Tubular segments were acutely dissected and investigated for trans- and paracellular properties by in vitro perfusion and electrophysiological analysis. IMdTL and IMaTL were distinguished by morphological criteria. We confirmed absence of transepithelial electrogenic transport in thin limbs. Although diffusion potential measurements showed no differences between treatments in IMdTLs, we observed increased paracellular cation selectivity under waterload in IMaTLs. NaCl diffusion potential was -5.64 ± 1.93 mV under waterload, -1.99 ± 1.72 mV under furosemide-induced diuresis, and 0.27 ± 0.40 mV under control. The corresponding permeability ratio PNa/Cl was 1.53 ± 0.21 (waterload), 1.22 ± 0.18 (furosemide-induced diuresis), and 0.99 ± 0.02 (control), respectively. Claudins are main constituents of the tight junction responsible for paracellular selectivity; however, immunofluorescence did not show qualitative differences in claudin 4, 10, and 16 localization. Our results show that IMaTLs change tight junction properties in response to diuretic state to allow adaptation of NaCl reabsorption.

Effectiveness of different correction methods of pyeloureteral segment according to the data of diuretic ultrasonography

Methods of estimation of effectiveness of the open and laparoscopic pyeloplasty, as well as endo-urological palliative methods – laser resection, balloon dilatation and endopyelotomy, which determine the anatomical and functional peculiarities of renal pelvis and pyelo-ureteral junction with the help of ultrasound diagnostics during the forced diuresis, have been proposed. Changes of the area of renal pelvis, the velocity of post-furosemide increase of the scope of renal pelvis, rate of its drainage, changes in the diameter of pyeloureteral junction have been studied. This methodical approach is non-invasive, informative and simple in application. It is shown that dispersions of samples of patients after the open surgery do not differ from the dispersions of samples of the same patients before the operation on such parameters as areas of renal pelvis before the induction of furosemide, areas of renal pelvis after 15 minutes administration of furosemide, the rate of drainage after furosemide, the original diameter of pyeloureteral junction. This may indicate the stability of surgery results. For example, the larger renal pelvis by kidney size before the operation corresponded to the larger designed pelvis after the operation; renal pelvis drained faster before the operation, features faster drainage after the operation as well. Variation in the areas of renal pelvis which decreased in 40 minutes after furosemide, percent rate of longitudinal pelvis area, rate of after-furosemide increase in pelvis area, diameter of pyeloureteral junction in 15 minutes administration of furosemide after the open pyeloplasty was significantly different compared to the variation in the same parameter for the same patients before the operations. More substantial difference was observed in the same patients before and after Anderson-Hynes surgery by parameters of relative rate of after-furosemide drainage of pelvis and increase in diameter of pyeloureteral junction after 15 min administration of furosemide. That is, the same principle of operation provides similar results by anatomical parameters, such as size and diameter of pyeloureteral junction, but quite different results by functional parameters which reflect the possibility of draining of kidney in forced diuresis. Successful open pyeloplasty leads to a significant decrease in the pelvis area at different time intervals after furosemide administration, the relative increase in the pelvis area on the background of the induction of diuresis, rate of pelvis drainage, increase (normalization) in diameter of pyeloureteral junction, including the larger (better) gap of pyeloureteral junction after administration of diuretic. Concerning laparoscopic pyeloplasty, the dispersion of mean values of S, SPR, Vpr, V, VOT, D, DD after the operation was significantly different from those before the operation. This means that as in the case with open surgery, satisfactory clinical results such as reduction in renal pelvis and restoring the passage of urine through sufficient diameter pyeloureteral junction after laparoscopic pyeloplasty lead nevertheless to significant differences in the digital parameters during the objectification of operation effect by means of diuretic ultrasonography using furosemide-induced diuresis. Endoscopic surgery such as laser resection, endopyelotomy and balloon dilatation stably provides similar results (equal variances) by such parameters as pelvis area, which decreases in 40 min after furosemide administration, formation of the wide enough diameter of pyeloureteral junction and its minor fluctuations with the diuretic load. The decrease to normal parameters of all planes of renal pelvis (both before and after loading) and significant improvement of pelvis drainage (parameters responsible for the functional state of kidneys and pyeloureteral junction) indicate the success of palliative surgery in elimination of the narrowing of pyeloureteral junction.

Forced diuresis with matched hydration in reducing acute kidney injury during transcatheter aortic valve implantation (Reduce-AKI): study protocol for a randomized sham-controlled trial.

BackgroundAcute kidney injury (AKI) is observed in up to 41% of patients undergoing transcatheter aortic valve implantation (TAVI) and is associated with increased risk for mortality. The aim of the present study is to evaluate whether furosemide-induced diuresis with matched isotonic intravenous hydration using the RenalGuard system reduces AKI in patients undergoing TAVI.Methods/DesignReduce-AKI is a randomized sham-controlled study designed to examine the effect of an automated matched hydration system in the prevention of AKI in patients undergoing TAVI. Patients will be randomized in a 1:1 fashion to the RenalGuard system (active group) versus non-matched saline infusion (sham-controlled group). Both arms receive standard overnight saline infusion and N-acetyl cysteine before the procedure.DiscussionThe Reduce-AKI trial will investigate whether the use of automated forced diuresis with matched saline infusion is an effective therapeutic tool to reduce the occurrence of AKI in patients undergoing TAVI.Trial registrationClinicaltrials.gov: NCT01866800, 30 April 30 2013.

Bilateral kidney sodium‐MRI: Enabling accurate quantification of renal sodium concentration through a two‐element phased array system

To develop a sodium-MRI ((23) Na-MRI) method for bilateral renal sodium concentration (RSC) measurements in rat kidneys at 9.4 Tesla (T). To simultaneously achieve high B1 -field homogeneity and high receive sensitivity a dual resonator system composed of a double-tuned linearly polarized (1) H/(23) Na volume resonator and a newly developed two-element (23) Na receive array was used. In conjunction with three-dimensional (3D) ultra-short Time-to-Echo sequence a quantification accuracy of ± 10% was achieved for a nominal spatial resolution of (1 × 1 × 4) mm(3) in 10 min acquisition time. The technique was applied to study the RSC in six kidneys before and after furosemide-induced diuresis. The loop diuretic agent induced an increase of cortical RSC by 22% from 86 ± 16 mM to 105 ± 18 mM (P = 0.02), whereas the RSC in the inner medulla decreased by 38% from 213 ± 24 mM to 132 ± 25 mM (P = 0.8×10(-4) ). The RSC changes measured in this study agreed well with the qualitative sodium signal intensity variations reported elsewhere. Furosemide-induced diuresis has been investigated accurately with herein presented quantitative (23) Na-MRI technique. In the future, RSC quantification could allow for defining pathological and nonpathological RSC ranges to assess sodium concentration changes, e.g., induced by drugs.

The effect of saponins from Ampelozizyphus amazonicus Ducke on the renal Na+ pumps’ activities and urinary excretion of natriuretic peptides

BackgroundIn a previous study, we showed that a saponin mixture isolated from the roots of Ampelozizyphus amazonicus Ducke (SAPAaD) reduces urine excretion in rats that were given an oral loading of 0.9 % NaCl (4 ml/100 g body weight). In the present study, we investigated whether atrial natriuretic peptides (ANP) and renal ATPases play a role in the SAPAaD- induced antidiuresis in rats.MethodsTo evaluate the effect of SAPAaD on furosemide-induced diuresis, Wistar rats (250-300 g) were given an oral loading of physiological solution (0.9 % NaCl, 4 ml/100 g body weight) to impose a uniform water and salt state. The solution containing furosemide (Furo, 13 mg/kg) was given 30 min after rats were orally treated with 50 mg/kg SAPAaD (SAPAaD + Furo) or 0.5 ml of 0.9 % NaCl (NaCl + Furo). In the SAPAaD + NaCl group, rats were pretreated with SAPAaD and 30 min later they received the oral loading of physiological solution. Animals were individually housed in metabolic cages, and urine volume was measured every 30 min throughout the experiment (3 h). To investigate the role of ANP and renal Na+ pumps on antidiuretic effects promoted by SAPAaD, rats were given the physiological solution (as above) containing SAPAaD (50 mg/kg). After 90 min, samples of urine and blood from the last 30 min were collected. Kidneys and atria were also removed after previous anesthesia. ANP was measured by radioimmunoassay (RIA) and renal cortical activities of Na+- and (Na+,K+)-ATPases were calculated from the difference between the [32P] Pi released in the absence and presence of 1 mM furosemide/2 mM ouabain and in the absence and presence of 1 mM ouabain, respectively.ResultsIt was observed that SAPAaD inhibited furosemide-induced diuresis (at 90 min: from 10.0 ± 1.0 mL, NaCl + Furo group, n = 5, to 5.9 ± 1.0 mL, SAPAaD + Furo group n = 5, p < 0.05), increased both Na+-ATPase (from 25.0 ± 5.9 nmol Pi.mg-1.min-1, control, to 52.7 ± 8.9 nmol Pi.mg-1.min-1, p < 0.05) and (Na+,K+)-ATPase (from 47.8 ± 13.3 nmol Pi.mg-1.min-1, control, to 79.8 ± 6.9 nmol Pi .mg-1.min-1, p < 0.05) activities in the renal cortex. SAPAaD also lowered urine ANP (from 792 ± 132 pg/mL, control, to 299 ± 88 pg/mL, p < 0.01) and had no effect on plasma or atrial ANP.ConclusionWe concluded that the SAPAaD antidiuretic effect may be due to an increase in the renal activities of Na+- and (Na+,K+)-ATPases and/or a decrease in the renal ANP.

TCT-332: Furosemide-Induced Diuresis with Matched Hydration Compared to Standard Hydration for Prevention of Contrast-Induced Nephropathy. The MYTHOS Trial

TCT-332: Furosemide-Induced Diuresis with Matched Hydration Compared to Standard Hydration for Prevention of Contrast-Induced Nephropathy. The MYTHOS Trial

Abstract 4843: Furosemide-induced Diuresis With Matched Replacement of Intravascular Volume Compared to Standard Hydration for Contrast-induced Nephropathy Prevention: The Mythos Trial

Hypothesis. We investigated the effect of a new preventive strategy strategy for contrast-induced nephropathy (CIN) based on a dedicated device (RenalGuard; PLC Medical System Inc., USA). The system is capable of delivering i.v. saline solution to a patient in an amount matched to the volume of urine produced after an i.v. bolus of furosemide. The aim of the study was to evaluate if furosemide-induced high-volume diuresis with concurrent maintenance of intravascular volume may prevent CIN. Methods . To date, 63 chronic kidney disease (CKD) patients (eGFR&lt;60 ml/min/1.73 m 2 ) undergoing percutaneous coronary interventions (PCI) were enrolled in the MYTHOS trial. They were randomized to matched hydration (RenalGuard group, n=30) or to i.v. isotonic saline hydration (control group; n=33) at a rate of 1 ml/kg/hour for 12 hours before and after PCI. Matched fluid replacement was started approximately 90 minutes pre-PCI, maintained during catheterization, and for up to 4 hours afterwards. Patients were given an initial i.v. bolus of 250 ml of normal saline over 30 minutes and then an i.v. bolus of furosemide (0.5 mg/kg). The RenalGuard measures the patient’s urine volume and then automatically adjusts the infusion pump rate to precisely replace the measured urine output in real time. When a &gt;300 ml/hour urine output rate was obtained, patients underwent PCI. CIN was defined as a ≥0.5 mg/dl or ≥25% rise in serum creatinine over baseline. Results . Overall, the mean eGFR was 40±9 ml/min/1.73 m 2 . The mean contrast volume was 190±92 ml in RenalGuard group and 212±118 ml in controls (P=0.4). In RenalGuard group, urine output ranged from 319 to 1788 ml/hr (mean 830±322 ml/hr). There were no serious device-or therapy-related complications, including clinically significant electrolyte changes (asymptomatic ipokalemia was corrected in 1 case). CIN occurred in no patient (0%) of the RenalGuard group and in 5 (15%) controls (P=0.03). Two controls (6%) required temporary renal replacement therapy. Conclusions. These preliminary results indicate that furosemide-induced high urine output with maintenance of intravascular volume through matched hydration can be safely obtained with the RenalGuard system and may reduce the risk of CIN in CKD patients undergoing PCI.

TCT-536: Furosemide-induced High-volume Diuresis with Matched Replacement of Intravascular Volume Compared to Standard Hydration for CIN Prevention: the MYTHOS Trial

TCT-536: Furosemide-induced High-volume Diuresis with Matched Replacement of Intravascular Volume Compared to Standard Hydration for CIN Prevention: the MYTHOS Trial

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

Previous evidence has implicated E prostanoid receptor 4 (EP4) in mechanical hyperalgesia induced by subplantar inflammation. However, its role in chronic arthritis remains to be further defined because previous attempts have generated two conflicting lines of evidence, with one showing a marked reduction of arthritis induced by a collagen antibody in mice lacking EP4, but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen. Here, we assessed the effect of a novel and selective EP4 antagonist MF498 [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide] on inflammation in adjuvant-induced arthritis (AIA), a rat model for rheumatoid arthritis (RA), and joint pain in a guinea pig model of iodoacetate-induced osteoarthritis (OA). In the AIA model, MF498, but not the antagonist for EP1, MF266-1 [1-(5-{3-[2-(benzyloxy)-5-chlorophenyl]-2-thienyl}pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol] or EP3 MF266-3 [(2E)-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide], inhibited inflammation, with a similar efficacy as a selective cyclooxygenase 2 (COX-2) inhibitor MF-tricyclic. In addition, MF498 was as effective as an nonsteroidal anti-inflammatory drug, diclofenac, or a selective microsomal prostaglandin E synthase-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile], in relieving OA-like pain in guinea pigs. When tested in rat models of gastrointestinal toxicity, the EP4 antagonist was well tolerated, causing no mucosal leakage or erosions. Lastly, we evaluated the renal effect of MF498 in a furosemide-induced diuresis model and demonstrated that the compound displayed a similar renal effect as MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], reducing furosemide-induced natriuresis by approximately 50%. These results not only suggest that EP4 is the major EP receptor in both RA and OA but also provide a proof of principle to the concept that antagonism of EP4 may be useful for treatment of arthritis.

Dominant Role of Prostaglandin E2 EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy

Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE2 in HPS/aBS awaits clarification. Chronic blockade of the Na-K-2Cl co-transporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wild-type (WT) mice and in mice lacking distinct PGE2 receptors (EP1-/-, EP2-/-, EP3-/-, and EP4-/-), the effect of chronic furosemide administration (7 d) on urine output, sodium and potassium excretion, and renin secretion was determined. Furthermore, furosemide-induced diuresis and renin activity were analyzed in mice with defective PGI2 receptors (IP-/-). In all animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1-/-, EP3-/-, and EP4-/- mice. Compared with WT mice, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice. The GFR in EP4-/- mice was not changed compared with that in WT mice, which indicated that blunted diuresis and salt loss seen in EP4-/- mice were not a consequence of lower GFR. In summary, these findings demonstrate that the EP4 receptor mediates PGE2-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE2-mediated salt and water excretion in the HPS/aBS model.

Renin-Dependent Hypertension Caused by Nonfocal Stenotic Aberrant Renal Arteries

We have identified 2 relatively young patients with significant hypertension, an elongated single aberrant renal artery supplying blood to a renal segment, and evidence for localization of the elevated plasma renin activity to the side and vein draining the affected kidney. Furosemide-induced diuresis and acute oral captopril stimulated the renal vein/contralateral renin ratios to 4.3:1 and 6.5:1 in patients 1 and 2, respectively. These renal vein ratios are significantly higher than normal (>3:1 under similar conditions). Partial resection of the portion of the kidney affected by the aberrant tortuous artery led to a marked reduction in blood pressure in patient 1. Patient 2, not an operative candidate, responded satisfactorily to use of a converting enzyme inhibitor, which helped to confirm the dependency of the blood pressure on the abnormal flow relationship existing within that aberrant artery and the kidney. We believe these 2 patients are representative of a small but distinct subgroup within the larger number of patients with elongated single or multiple renal aberrant arteries. Each aberrant artery had no focal stenosis, although a decrease in flow relative to the tissue perfusion demands was apparent from the marked activation of the renin-angiotensin system in the venous system draining that artery. The increased length of such vessels may contribute to their decreased flow, although their average diameter may reside just above such a critical value for a normal length vessel. This new syndrome, involving more than one component of the flow/resistance relationship, has been overlooked when renin-dependent forms of hypertension are considered.