Effect of maneuvers, diuresis, and fluid administration on ultrasound-measured liver stiffness after Fontan.

BACKGROUND: To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls. METHODS: In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis. RESULTS: Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (-0.05 m/s, -3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (-0.79 m/s, -26.5%, p = 0.004) and 60 minutes (-0.78 m/s, -26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (-0.12 m/s, -8.70%, p = 0.002), 30 minutes (-0.15 m/s, -10.9%, p = 0.003), and 60 minutes (-0.1 m/s, -10.9%, p = 0.005). CONCLUSIONS: LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients.

Loop Diuretics Unique Mechanism of Action.

Loop diuretics, including torsemide, furosemide, bumetanide, and piretanide, act by inhibiting the sodium-potassium-chloride (Na+/K+/2Cl-) cotransporter in the thick ascending limb of the loop of Henle within the nephron. This mechanism is pivotal in managing fluid retention associated with conditions such as heart failure, cirrhosis, chronic kidney disease, and hypertension. A comprehensive understanding of how these diuretics uniquely target this transporter provides crucial insights into effectively addressing fluid overload across diverse clinical conditions.

Loop Diuretics: An Overview of Its History and Evolution.

The loop of Henle plays a key role in kidney function, especially in retaining solutes and concentrating urine. Diuretic agents, crucial for managing fluid overload and related conditions like hypertension and heart failure (HF), enhance water and electrolyte excretion. The history of diuretics dates back to 1775 with the discovery of Digitalis, evolving significantly with the introduction of chlorothiazide in 1957, which revolutionized diuretic therapy. Loop diuretics, developed in the 1950s and including drugs like torsemide, furosemide, and ethacrynic acid, are potent agents acting on the loop of Henle. They are vital for treating severe fluid overload conditions and require careful monitoring to manage potential side effects.

Torsemide in the Management of Pulmonary Edema.

Pulmonary edema, either cardiogenic or noncardiogenic, is caused by fluid accumulation in the alveolar spaces. Cardiogenic pulmonary edema (CPE), one of the causes of congestive heart failure (CHF), is treated with loop diuretics. Torsemide and furosemide were found to be useful in the treatment of CHF-associated pulmonary edema due to their ability to lower pulmonary capillary pressure and left ventricular end-diastolic pressure, respectively. Pharmacological features of torsemide, such as greater bioavailability, higher absorption rate, and efficacy, make it a better alternative for treating pulmonary edema than the regularly used loop diuretic, furosemide. Torsemide administered intravenously was found to be both efficacious and well tolerated in CPE. However, more research is needed to determine its usefulness in non-CPE.

Unique Pharmacological Properties and Safety Profiles of Loop Diuretics.

Loop diuretics are regarded as essential for the treatment of edematous conditions in heart failure, cirrhosis, and renal disease. The principal mechanism of action involves inhibiting the reabsorption of ions (Na+, 2Cl-, and K+) from the ascending loop of Henle. The pharmacokinetic (PK) and pharmacodynamic (PD) features of the commonly used diuretics (torsemide, furosemide, and bumetanide) influence the selection of diuretics in various disease states and dosing regimens. However, torsemide demonstrates superior PK and PD qualities, making it the preferred choice. Genetic polymorphisms must be explored to better understand the diversity of PK and PD parameters of loop diuretics between individuals.

Diuretic resistance in acute heart failure: proposal for a new urinary sodium-based definition.

BACKGROUND: Diuretic resistance is a relevant clinical issue in acute heart failure (AHF), but a standardized, quantitative definition is still missing. The aim of this analysis was to highlight discrepancies between previously proposed definitions of diuretic response and to propose a new urinary sodium (NaU)-based definition of diuretic efficiency (DE) to identify diuretic resistant (DR) patients. METHODS: Three historical definitions of diuretic response and a new NaU-based DE definition, evaluating total NaU after the first diuretic bolus per 40 mg furosemide administered, were applied in a retrospective analysis to an AHF population treated with intravenous (i.v.) loop diuretics. Baseline characteristics, in-hospital clinical data and outcomes at discharge and mid-term follow-up were collected and compared among DR and non-DR patients for each definition. RESULTS: Among 53 patients, 39 (73.6%), 51 (96.2%) and 3 (5.7%) were DR according to weight-derived, diuresis-derived, and spot NaU definition, respectively. The median value of the new NaU-based definition was 31 mmol/40 mg and patients were stratified accordingly. DR patients showed lower cumulative diuresis (5200 mL, 3300-6700 vs 9825 mL, 6200-12200, p = 0.007) and weight loss (4 kg, 1-5 vs 6 kg, 3-8.5, p = 0.023), higher BNP levels (808 pg/mL, 443-1037 vs 351 pg/mL, 209-859, p = 0.062) at the conclusion of protocol-guided i.v diuretic therapy, which was less frequently stopped due to decongestion in DR as compared to non-DR patients (57.7% vs 85.2%, p = 0.026). Six-months mortality or HF hospitalizations were more frequent in DR patients (OR 18.6, 95% CI 2.1-161.2, p = 0.008). CONCLUSIONS: The NaU-based DE definition might solve discrepancies of other previously proposed definitions.

Depolarization of mouse DRG neurons by GABA does not translate into acute pain or hyperalgesia in healthy human volunteers.

The majority of somatosensory DRG neurons express GABAA receptors (GABAAR) and depolarise in response to its activation based on the high intracellular chloride concentration maintained by the Na-K-Cl cotransporter type 1 (NKCC1). The translation of this response to peripheral nerve terminals in people is so far unclear. We show here that GABA (EC50 = 16.67µM) acting via GABAAR produces an influx of extracellular calcium in approximately 20% (336/1720) of isolated mouse DRG neurons. In contrast, upon injection into forearm skin of healthy volunteers GABA (1mM, 100µl) did not induce any overt sensations nor a specific flare response and did not sensitize C-nociceptors to slow depolarizing electrical sinusoidal stimuli. Block of the inward chloride transporter NKCC1 by furosemide (1mg/100µl) did not reduce electrically evoked pain ratings nor did repetitive GABA stimulation in combination with an inhibited NKCC1 driven chloride replenishment by furosemide. Finally, we generated a sustained period of C-fiber firing by iontophoretically delivering codeine or histamine to induce tonic itch. Neither the intensity nor the duration of histamine or codeine itch was affected by prior injection of furosemide. We conclude that although GABA can evoke calcium transients in a proportion of isolated mouse DRG neurons, it does not induce or modify pain or itch ratings in healthy human skin even when chloride gradients are altered by inhibition of the sodium coupled NKCC1 transporter.

Intravenous delivery of furosemide using lipid-based versus polymer-based nanocapsules: in vitro and in vivo studies.

OBJECTIVES: Furosemide (FSM), a potent loop diuretic, is used to treat edema due to hypertension, congestive heart failure, and liver and renal failures. FSM applications are limited by its low bioavailability. Our aim is to use different nanoencapsulation strategies to control the release of FSM and enhance its pharmacokinetic properties. METHODS: Two types of FSM-loaded nanocapsules, namely FSM-loaded lipid nanocapsules (LNCs) and polymeric nanocapsules (PNCs), were developed, physicochemically characterized, and subjected to pharmacokinetic and pharmacodynamic studies. Lipid nanocapsules were prepared by the simple phase inversion method using LabrafacTM lipid, while the polymeric nanocapsules were prepared by nanoprecipitation method using polycaprolactone polymer. RESULTS: Transmission electron microscopy ascertains spherical structures, corroborating the nanometric diameter of both types of nanocapsules. The particle size of the optimized FSM-loaded LNCs and FSM-loaded PNCs was 32.19 ± 0.72 nm and 230.7 ± 5.13 nm, respectively. The percent entrapment efficiency was 63.56 ± 1.40% of FSM for the optimized PNCs. The in vitro release study indicated prolonged drug release compared to drug solutions. The two loaded nanocapsules systems succeeded in enhancing the pharmacokinetic parameters in comparison to the marketed FSM solution with superior diuretic activity (p < 0.05). The results of the stability study and the terminal sterilization by autoclave indicated the superiority of LNCs over PNCs in maintaining the physical parameters under storage conditions and the drastic conditions of sterilization. CONCLUSIONS: LNCs and PNCs are considered promising nanosysems for improving the diuretic effect of FSM.

FIRE Stones: impact of forced diuresis on the residual fragment rate after flexible ureteroscopy for destruction of kidney stones with laser-protocol for a randomized controlled two-parallel group multicenter trial with blinding evaluation.

BACKGROUND: Lithiasis is a common and recurrent disease. Flexible ureteroscopy (fURS) is the cornerstone of laser treatment of kidney stones. Kidney stones destruction requires its laser pulverization into small fragments in order to remove them through the ureter or improve their spontaneous expulsion along the urinary tract. However, most of the time, all the micro-fragments and dust created cannot be extracted using our surgical tools and may stay intra-renally at the end of the procedure. Adjuvant treatments (such as forced diuresis, inversion or mechanical pressure) were previously described to improve the expulsion of stone fragments after extra-corporeal shock wave lithotripsy. Nevertheless, the impact of adjuvant treatment after fURS remains unclear and mainly theoretical. OBJECTIVE: The primary objective is to show that the injection of 40 mg of furosemide in slow intravenous during 10 min, after the procedure, increases the stone-free rate 3 months after a fURS for destruction of kidney stones with laser. METHODS/DESIGN: The study will be a two-parallel group randomized, controlled, multicentric trial with a blinding evaluation. Nine French departments of urology will participate. Patients will be randomized in 2 groups: the experimental group (injection of 40 mg of furosemide at the end of the surgery) and a control one (usual care). Patients will be followed up for 3 months (± 2 weeks) after the surgery. Then, we will perform a low dose abdomino-pelvic CT scan. The primary outcome is the stone-free rate at 3 months. A centralized review of the images will be performed by two specialized radiologists, in a blind and crossed way to allow a homogenization of the results. The secondary outcomes will include the rate of early post-operative urinary tract infection (UTI), the evaluation of post-operative pain, and the safety of the use of furosemide in patients treated by fURS for renal stone laser destruction. As secondary objectives, it is also planned to look at the effect of the prescription of an alpha-blocker as usual treatment on stone-free rate and to assess the agreement between the imaging analysis of the urologist and the specialized radiologist. DISCUSSION: Lithiasis is a public health problem. It affects about 10% of the general population. This prevalence is increasing (multiplied by 3 in 40 years), partly due to changes in the population's eating habits over the years. The lithiasis patient is a patient with a chronic disease requiring annual follow-up and who may suffer from multiple recurrences, with a recurrence rate at 5 years of 50%. Recurrences are partly due to residual fragments left in the kidneys at the end of the operation. Other risk factors for recurrence include dietary hygiene and the presence of an associated metabolic disease. The metabolic blood and urine tests recommended by the Association Française d'Urologie (AFU) can be used to manage these last two problems. As far as residual fragments are concerned, their presence leads to an early recurrence of stones because they form the bed for a new aggregation of crystals in the kidneys. Being able to reduce the rate of residual fragments in patients with the use of furosemide at the end of the intervention therefore seems essential in the management of recurrences in our patients. This will also improve our patients' quality of life. Indeed, lithiasis disease leads to chronic pain associated with acute pain that motivates consultations to the emergency for specialized management. This study is the first to evaluate the impact of forced diuresis with the use of furosemide on the stone-free rate after a fURS for destruction of kidney stone with laser. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05916963 , first received: 22 June 2023. EU Clinical Trials Register EudraCT Number: 2022-502890-40-00.

Torsemide versus Furosemide in the Treatment of Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. / Torsemida em Comparação com Furosemida no Tratamento da Insuficiência Cardíaca: Uma Revisão Sistemática e Metanálise de Ensaios Clínicos Randomizados.

Furosemide is the most used diuretic for volume overload symptoms in patients with heart failure (HF). Recent data suggested that torsemide may be superior to furosemide in this setting. However, whether this translates into better clinical outcomes in this population remains unclear. To assess whether torsemide is superior to furosemide in the setting of HF. We performed a systematic review and meta-analysis of RCTs comparing the efficacy of torsemide versus furosemide in patients with HF. PubMed, Embase, and Web of Science were searched for eligible trials. Outcomes of interest were all-cause hospitalizations, hospitalizations for HF (HHF), hospitalizations for all cardiovascular causes, all-cause mortality, and NYHA class improvement. Echocardiographic parameters were also assessed. We applied a random-effects model to calculate risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) and a 0.05 level of significance. 12 RCTs were included, comprising 4,115 patients. Torsemide significantly reduced HHF (RR 0.60; 95% CI, 0.43-0.83; p=0.002; I2=0%), hospitalization for cardiovascular causes (RR 0.72; 95% CI, 0.60-0.88; p=0.0009; I2=0%), and improved LVEF (MD 4.51%; 95% CI, 2.94 to 6.07; p<0.0001; I2=0%) compared with furosemide. There was no significant difference in all-cause hospitalizations (RR 0.93; 95% CI, 0.86-1.00; p=0.04; I2=0%), all-cause mortality (RR 0.98; 95% CI, 0.87-1.10; p=0.73; I2=0%), NYHA class improvement (RR 1.25; 95% CI, 0.92-1.68; p=0.15; I2=0%), or NYHA class change (MD -0.04; 95% CI, -0.24 to 0.16; p=0.70; I2=15%) between groups. Torsemide significantly reduced hospitalizations for HF and cardiovascular causes, also improving LVEF.

A furosemida é o diurético mais utilizado para o tratamento de sintomas de sobrecarga de volume em pacientes com insuficiência cardíaca. Dados recentes sugerem que a torsemida pode ser superior à furosemida neste contexto. No entanto, ainda não é claro se isso se traduz em melhores resultados clínicos nesta população. Avaliar se a torsemida é superior à furosemida no contexto da insuficiência cardíaca. Realizamos uma revisão sistemática e metanálise de estudos clínicos randomizados (ECRs) comparando a eficácia da torsemida em comparação com a furosemida em pacientes com insuficiência cardíaca. PubMed, Embase e Web of Science foram as bases de dados pesquisadas em busca de estudos elegíveis. Os desfechos de interesse foram internações por todas as causas, internações por insuficiência cardíaca (IIC), internações por todas as causas cardiovasculares, mortalidade por todas as causas, e melhoria de classe da NYHA. Parâmetros ecocardiográficos também foram avaliados. Foi aplicado um modelo de efeitos aleatórios para calcular as razões de risco (RR) e as diferenças médias (DM) com intervalos de confiança (IC) de 95% e nível de significância de 0,05. Foram incluídos 12 ECRs, envolvendo 4.115 pacientes. A torsemida reduziu significativamente a IIC (RR de 0,60; IC de 95%, 0,43-0,83; p=0,002; I2=0%), internação por causas cardiovasculares (RR de 0,72; IC de 95%, 0,60-0,88; p=0,0009; I2=0%), e melhora da fração de ejeção do ventrículo esquerdo (FEVE) (DM de 4,51%; IC de 95%, 2,94 a 6,07; p<0,0001; I2=0%) em comparação com a furosemida. Não houve diferença significativa no número de internações por todas as causas (RR de 0,93; IC de 95%, 0,86-1,00; p=0,04; I2=0%), mortalidade por todas as causas (RR de 0,98; IC de 95%, 0,87-1,10; p=0,73; I2=0%), melhora da classe NYHA (RR de 1,25; IC de 95%, 0,92-1,68; p=0,15; I2=0%), ou mudança de classe NYHA (DM de -0,04; IC de 95%, -0,24 a 0,16; p=0,70; I2=15%) entre os grupos. A torsemida reduziu significativamente as internações por insuficiência cardíaca e causas cardiovasculares, melhorando também a FEVE.

Magnetic molecularly imprinted polymer based on coordination for the determination of trace banned substance furosemide in human urine.

Furosemide (FUR), banned in sports events by the World Anti-Doping Agency, is a key target in drug tests, necessitating a pretreatment material capable of selectively, rapidly, and sufficiently separating/enriching analytes from complex matrices. Herein, a metal-mediated magnetic molecularly imprinted polymer (mMIP) was rationally designed and synthesized for the specific capture of FUR. The preparations involved the utilization of chromium (III) as the binding pivot, (3-aminopropyl)triethoxysilane as functional monomer, and Fe3O4 as core, all assembled via free radical polymerization. Both the morphologies and adsorptive properties of the mMIP were characterized using multiple methods. The resulting Cr(III)-mediated mMIP (ChM-mMIP) presented excellent selectivity and specificity toward FUR. Under optimized conditions, the adsorption capacity reached 128.50 mg/g within 10 min, and the imprinting factor was 10.41. Moreover, it was also successfully applied as a dispersive solid-phase extraction material, enabling the detection of FUR concentration as low as 20 ng/mL in human urine samples when coupled with a high-performance liquid chromatography/photodiode array. Overall, this study offers a valuable strategy for the development of novel recognition material.

Spot urine sodium-to-creatinine ratio surpasses sodium in identifying poor diuretic response in acute heart failure.

AIMS: We aim to identify the most accurate marker for early prediction of poor diuretic response in acute heart failure (AHF) patients with signs of congestion requiring intravenous diuretic treatment. METHODS: In this single-centre, prospective observational study, AHF patients with signs of congestion received a standardized intravenous furosemide dose (1 mg/kg of body weight; 40 mg in bolus and remaining dose in 2 h continuous infusion). Subsequently, we assessed spot urine composition at 2 h post-administration, comparing it with total urine output at 6 h. Various potential urine markers were analysed for predicting urine output using receiver operating characteristic (ROC) curves and logistic regression models. We investigated guideline-recommended markers, including spot urine sodium (UNa+) and its cut-off, and introduced the UNa+/UCr (urine creatinine concentration) ratio adjusting UNa+ for urine dilution. RESULTS: Out of 111 patients (85% males, 66.4 ± 13.9 years old, NTproBNP 7290 [4493-14 582] pg/ml), there were 18 (16%) with a poor diuretic response (cumulative urine output <600 ml during the first 6 h). The mean 6 h cumulative diuresis in patients with poor and good diuretic response was 406 ± 142 and 2114 ± 1164 ml, respectively, P < 0.005. After an initial evaluation of several potential biomarkers, only UNa+, UCr and UNa+/UCr were selected as candidates with the highest predictive value. The cut-off for UNa+ adjusted for urine dilution: UNa+/UCr ratio <0.167 mmol/mg × 10-1 was determined by ROC analysis with the highest area under the curve (95% confidence interval): 0.956 (0.915-0.997), P < 0.001. When compared with the guideline-recommended cut-off (UNa+ <50 mmol/L as a reference, specificity-0.97; sensitivity-0.83), the odds ratio (OR) for UNa+/UCreat to identify a poor diuretic response was 2.5 times greater, regardless of kidney function (OR for estimated glomerular filtration rate in the logistic regression model was 0.978 [0.945-1.013, P = 0.222]). CONCLUSIONS: The UNa+/UCr ratio in a spot urine sample 2 h after intravenous diuretic administration is a simple, highly predictive marker for the identification of AHF patients with poor diuretic response, surpassing guidelines-recommended markers like UNa+.

Phenotype and outcomes according to loop diuretic use in pulmonary arterial hypertension.

AIMS: The use of loop diuretics in pulmonary arterial hypertension (PAH) is less frequent compared with heart failure. The clinical and prognostic characteristics of PAH patients according to loop diuretic use remain unexplored. In this study, we retrospectively analysed the characteristics and survival of PAH patients requiring different doses of loop diuretics. METHODS AND RESULTS: Patients diagnosed with PAH between 2001 and 2022 at seven European centres for the management of PAH. According to the median equivalent dose of furosemide in the overall cohort, patients were divided into two subgroups: no/low-dose loop diuretic and high-dose loop diuretic. Primary outcome was 5 year all-cause mortality. Among the 397 patients included, 227 (57%) were treated with loop diuretics. Median daily furosemide equivalent dose was 25 mg, and accordingly patients were divided in no/low dose (i.e. ≤25 mg, n = 257, 65%) vs. high dose (i.e. >25 mg, n = 140, 35%). Patients in the high-dose group were older, more likely to have comorbidities, and had a more severe disease according to the ESC/ERS risk category. Crude 5 year survival was significantly shorter in patients in the high-dose group, but after adjustment for age, sex, and risk category, high loop diuretic dose was not significantly associated with the primary outcome. CONCLUSIONS: Use of high dose of loop diuretics in PAH is associated with a higher burden of comorbidities, more severe disease, and worse survival. However, in PAH, the need of high loop diuretic dose is a marker of disease severity and not an independent prognostic factor.

The acute effects of furosemide in acute heart failure assessed by remote dielectric sensing. A protocol.

INTRODUCTION: Intravenous loop diuretics have been a key component in treating pulmonary oedema since the 1960s and have a Class 1 recommendation in the 2021 guidelines for acute heart failure (AHF). While the diuretic effect of loop diuretics is well established, it remains unclear how furosemide influences pulmonary congestion and cardiac filling pressures in the hyperacute phase before significant diuresis occurs. METHODS: This was a prospective study of adult patients with AHF and objective signs of pulmonary congestion admitted to the cardiac ward. Remote dielectric sensing (ReDS) will directly measure lung fluid content, and cardiac filling pressures will be assessed by echocardiography with Doppler and strain analysis. CONCLUSIONS: This study will examine if furosemide leads to a hyperacute reduction in pulmonary congestion assessed by ReDS independent of diuretic effects in patients with AHF. We hypothesise that the haemodynamic effect of furosemide shown on pulmonary congestion may explain the subjective instant relief in patients with AHF receiving furosemide. FUNDING: Dr. Grand's salary during this project is supported by a research grant from the Danish Cardiovascular Academy funded by Novo Nordisk Foundation grant number NNF20SA0067242 and by the Danish Heart Foundation. TRIAL REGISTRATION: This protocol was approved by the Scientific Ethical Committee, H-23029822, and the Danish Data Protection Agency P-2013-14703. The protocol was registered with ClinicalTrial.org on 29 August 2023 (Identifier: NCT06024889).

Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. METHODS AND RESULTS: The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). CONCLUSIONS: Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

Amiloride versus furosemide for the treatment of edema in patients with nephrotic syndrome: A pilot study (AMILOR).

AIM: In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS. METHODS: The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. RESULTS: Median baseline OH was +26.4 (interquartile range 15.5-35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1-29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80-6.40) and 5.15 (0.90-8.30)% ECW after 8 days, respectively, and by 10.10 (1.30-14.40) and 7.40 (2.80-10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. CONCLUSION: The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).

Hypocitraturia as a biomarker of renal tubular acidosis in patients with Sjögren's disease.

INTRODUCTION: Sjögren's disease (SD) is an immune-mediated chronic inflammatory disease that affects epithelial tissues, mainly salivary and lacrimal glands. It also presents extraglandular manifestations. The main renal manifestation is tubulointerstitial nephritis (TIN), which can manifest as renal tubular acidosis (RTA). Urinary citrate may be a biomarker of RTA in these patients. The objective of this study was to evaluate whether hypocitraturia is a predictive biomarker of RTA in a sample of patients with SD in a tertiary hospital in southern Brazil. METHODS: All patients with SD who met the inclusion criteria and who participated in the rheumatology outpatient clinic of the Irmandade Santa Casa de Misericórdia de Porto Alegre were included. Demographic, SD, serological and urinary data were obtained. RTA was considered in those patients who persistently presented urinary pH above 5.5 and serum pH below 7.35. Patients who persistently had urinary pH above 5.5 underwent a urinary acidification test with furosemide and fludrocortisone. These patients received 1 mg of fludrocortisone and 40 mg of furosemide and had their urine samples tested 2, 4 and 6 h after taking the medications. The test was stopped at any urine sample with pH 5.5 or less. The variables were expressed as mean and standard deviation or interquartile range. The association between hypocitraturia and RTA was assessed using the chi-square. RESULTS: Forty-two patients were included, 95.2% female with a median age of 61.73 years. The prevalence of complete distal RTA was 4.88%. Twenty-eight patients underwent urine acidification testing. Five patients had hypocitraturia, and two of them had complete distal RTA. The association between hypocitraturia and RTA was statistically significant (p < 0.012), with a sensitivity of 100%, specificity of 91.2% and accuracy of 91.7%. The negative predictive value was 100%. The global renal assessment of the population demonstrated two patients with RTA, one patient with decreased renal function and six patients with proteinuria greater than 0.5 g/24 h. CONCLUSION: The prevalence of RTA in the studied population was 4.88%. Hypocitraturia had high sensitivity and accuracy for the diagnosis of RTA.

Hypocalcemia in the Immediate Postoperative Period Following Metabolic Bariatric Surgery - Hype or Harm?

PURPOSE: Hypocalcemia post-metabolic bariatric surgery (MBS) is a known long-term complication after hypoabsorptive procedures. However, data on immediate postoperative calcium are limited. Our aim was to evaluate the prevalence of hypocalcemia on the 1st postoperative day after MBS and correlate it with potential associated factors. MATERIALS AND METHODS: We analyzed data from all consecutive index MBS over 1 year. We collected data on demographics and on preoperative and postoperative values of serum calcium (TC), albumin, adjusted calcium (AC-Payne formula), magnesium, phosphorus, preoperative vitamin-D, and postoperative 24-h urine output, intravenous fluids (IVF), bolus intravenous furosemide, and creatine phosphokinase (CPK). Continuous data are expressed as means ± SD (range). Categorical data are presented as frequencies (%). Linear regression was implemented to designate potential correlations. RESULTS: The cohort included 86 patients (58.1% females). The mean preoperative TC was 9.4mg/dL ± 0.4 (8.5-10.5) and mean postoperative TC 7.8mg/dL ± 0.6 (6.3-9.3, 17.0% decrease). The mean preoperative AC was 10.1mg/dL ± 0.4 (9.2-11.2) and mean postoperative AC 8.5mg/dL ± 0.6 (7.0-10.0, 15.8% decrease). Seventy-three patients (84.8%) had abnormally low TC (< 8.5mg/dL), and 43 (50%) abnormally low AC. There was only weak correlation between postoperative TC and AC with magnesium (r = 0.258), phosphorus (r = 0.269), vitamin-D (-0.163), 24-h urine output (r = -0.168), IVF (r = -0.237), bolus furosemide (r = 0.155), and mean operative time (r = 0.010). CONCLUSIONS: In our cohort of patients, hypocalcemia was a real problem but we did not find any significant correlation with the examined factors. Further studies are warranted to validate our findings and investigate other potential correlations.

Intralesional combined digoxin and furosemide versus intralesional 5-flurouracil for the treatment of recalcitrant plantar warts: a prospective, randomized study.

There are many therapeutic modalities for plantar warts, however treating it remains challenging. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide were observed to be effective and safe, however no comparison study between them was done. Our study was conducted to evaluate the efficacy of both therapies in the treatment of plantar warts. 90 adult patients with multiple recalcitrant plantar warts were included in our study. They were randomly allocated to one of three groups; combined digoxin and furosemide, 5-fluorouarcil, or normal saline group. Fortnightly injections were done into all studied warts till complete clearance or up to 5 sessions. Warts were evaluated clinically and dermoscopically. Clinical response was reported in 24 patients (80%) of the combined digoxin and furosemide group with 40% complete response and in 24 patients (80%) of the 5-fluorouarcil group with 33.3% complete response. No statistically significant difference was observed between the two groups concerning efficacy and safety. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide are nearly equivalent in efficacy and safety for plantar wart treatment. Dermoscopy helps to take the truthful judgment about complete clearance of warts.