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.

Cost-effectiveness of single-pill and separate-pill administration of antihypertensive triple combination therapy: a population-based microsimulation study.

BACKGROUND: Single-pill combination (SPC) of three antihypertensive drugs has been shown to improve adherence to therapy compared with free combinations, but little is known about its long-term costs and health consequences. This study aimed to evaluate the lifetime cost-effectiveness profile of a three-drug SPC of an angiotensin-converting enzyme inhibitor, a calcium-channel blocker, and a diuretic vs the corresponding two-pill administration (a two-drug SPC plus a third drug separately) from the Italian payer perspective. METHODS: A cost-effectiveness analysis was conducted using multi-state semi-Markov modeling and microsimulation. Using the healthcare utilization database of the Lombardy Region (Italy), 30,172 and 65,817 patients aged ≥ 40 years who initiated SPC and two-pill combination, respectively, between 2015 and 2018 were identified. The observation period extended from the date of the first drug dispensation until death, emigration, or December 31, 2019. Disease and cost models were parametrized using the study cohort, and a lifetime microsimulation was applied to project costs and life expectancy for the compared strategies, assigning each of them to each cohort member. Costs and life-years gained were discounted by 3%. Probabilistic sensitivity analysis with 1,000 samples was performed to address parameter uncertainty. RESULTS: Compared with the two-pill combination, the SPC increased life expectancy by 0.86 years (95% confidence interval [CI] 0.61-1.14), with a mean cost differential of -€12 (95% CI -9,719-8,131), making it the dominant strategy (ICER = -14, 95% CI -€15,871-€7,113). The cost reduction associated with the SPC was primarily driven by savings in hospitalization costs, amounting to €1,850 (95% CI 17-7,813) and €2,027 (95% CI 19-8,603) for patients treated with the SPC and two-pill combination, respectively. Conversely, drug costs were higher for the SPC (€3,848, 95% CI 574-10,640 vs. €3,710, 95% CI 263-11,955). The cost-effectiveness profile did not significantly change according to age, sex, and clinical status. CONCLUSIONS: The SPC was projected to be cost-effective compared with the two-pill combination at almost all reasonable willingness-to-pay thresholds. As it is currently prescribed to only a few patients, the widespread use of this strategy could result in benefits for both patients and the healthcare system.

Spot urinary sodium in CKD patients: correlation with 24h-excretion and evaluation of commonly used prediction equations.

BACKGROUND: Salt intake in CKD patients can affect cardiovascular risk and kidney disease progression. Twenty-four hour (24h) urine collections are often used to investigate salt metabolism but are cumbersome to perform. We assessed urinary sodium (U-Na) concentration in spot urine samples and investigated the correlation with 24h U-Na excretion and concentration in CKD patients under nephrological care. Further, we studied the role of CKD stage and diuretics and evaluated the performance of commonly used formulas for the prediction of 24h U-Na excretion from spot urine samples. METHODS: One hundred eight patients of the German Chronic Kidney Disease (GCKD) study were included. Each participant collected a 24h urine and two spot urine samples within the same period. The first spot urine sample (AM) was part of the second morning urine. The second urine sample was collected before dinner (PM). Patients were advised to take their medication as usual without changing dietary habits. U-Na concentrations in the two spot urine samples and their average ((AM + PM)/2) were correlated with U-Na concentration and total Na excretion in the 24h urine collections. Correlations were subsequently studied after stratification by CKD stage and diuretic intake. The usefulness of three commonly applied equations to estimate 24h U-Na excretion from spot urine samples (Kawasaki, Tanaka and Intersalt) was determined using Bland-Altman plots, analyses of sensitivity, specificity, as well as positive (PPV) and negative predictive values (NPV). RESULTS: Participants (42 women, 66 men) were on average (± SD) 62.2 (± 11.9) years old, with a mean serum creatinine of 1.6 (± 0.5) mg/dl. 95% had arterial hypertension, 37% diabetes mellitus and 55% were on diuretics. The best correlation with 24h U-Na total excretion was found for the PM spot U-Na sample. We also found strong correlations when comparing spot and 24h urine U-Na concentration. Correction of spot U-Na for U-creatinine did not improve strength of correlations. Neither CKD stage, nor intake of diuretics had significant impact on these correlations. All examined formulas revealed a significant mean bias. The lowest mean bias and the strongest correlation between estimated and measured U-Na excretion in 24h were obtained using the Tanaka-formula. Also, application of the Tanaka-formula with PM U-Na provided best sensitivity, specificity, PPV and NPV to estimate U-Na excretion > 4g/d corresponding to a salt consumption > 10g/d. CONCLUSION: U-Na concentration of spot urine samples correlated with 24h U-Na excretion especially when PM spot U-Na was used. However, correlation coefficients were relatively low. Neither CKD stage nor intake of diuretics appeared to have an influence on these correlations. There was a significant bias for all tested formulas with the Tanaka-formula providing the strongest correlation with measured 24h U-Na excretion. In summary, using spot urine samples together with the Tanaka-formula in epidemiological studies appears feasible to determine associations between approximate salt intake and outcomes in CKD patients. However, the usefulness of spot-urine samples to guide and monitor salt consumption in individual patients remains limited.

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).

Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

Effects of thiazides and new findings on kidney stones and dysglycemic side effects.

Thiazide and thiazide-like diuretics (thiazides) belong to the most frequently prescribed drugs worldwide. By virtue of their natriuretic and vasodilating properties, thiazides effectively lower blood pressure and prevent adverse cardiovascular outcomes. In addition, through their unique characteristic of reducing urine calcium, thiazides are also widely employed for the prevention of kidney stone recurrence and reduction of bone fracture risk. Since their introduction into clinical medicine in the early 1960s, thiazides have been recognized for their association with metabolic side effects, particularly impaired glucose tolerance, and new-onset diabetes mellitus. Numerous hypotheses have been advanced to explain thiazide-induced glucose intolerance, yet underlying mechanisms remain poorly defined. Regrettably, the lack of understanding and unpredictability of these side effects has prompted numerous physicians to refrain from prescribing these effective, inexpensive, and widely accessible drugs. In this review, we outline the pharmacology and mechanism of action of thiazides, highlight recent advances in the understanding of thiazide-induced glucose intolerance, and provide an up-to-date discussion on the role of thiazides in kidney stone prevention.

A review regarding the article 'Basal natriuresis as a predictor of diuretic resistance and clinical evolution in acute heart failure'.

Acute heart failure (AHF) is characterized by the emergence or intensification of symptoms and signs indicative of congestion or systemic hypoperfusion, stemming from an underlying structural or functional cardiac disorder. Intravenous loop diuretics play a pivotal role in achieving effective decongestion and ensuring clinical stability; the efficacy of these medications is crucial for determining the patient's hospital course and early outpatient progression. Individuals who exhibit a suboptimal response to diuretics or develop diuretic resistance (DR) are at an elevated risk for cardiovascular mortality and readmission due to AHF. However, there is a lack of standardized definition and diagnostic criteria for DR. Early identification of patients with DR is critical, as they may benefit from more aggressive decongestion strategies to mitigate this resistance. Natriuresis, the excretion of sodium in urine, serves as a direct measure of a diuretic's effectiveness. Low levels of natriuresis have been linked to poorer outcomes. Several studies have underscored the prognostic significance of natriuresis across various heart failure scenarios. However, the relationship between natriuresis and in-hospital DR has not been extensively studied. Observational research has indicated that inadequate natriuresis following the administration of loop diuretics correlates with a diminished diuretic response and an increased likelihood of mortality and heart failure rehospitalization. Further investigation is warranted to assess the predictive value of basal natriuresis concerning DR, in-hospital outcomes, and early outpatient cardiovascular events. This would help in identifying patients who are likely to respond poorly to diuretic therapy and may require alternative or more intensive treatment approaches.

Basal natriuresis as a predictor of diuretic resistance and clinical evolution in acute heart failure.

BACKGROUND: Some clinical guidelines recommend serial measurement of natriuresis to detect diuretic resistance (DR) in acute heart failure (AHF) patients, but it adds complexity to the management. OBJECTIVES: To correlate a single measurement of basal natriuresis (BN) on admission with the development of DR and clinical evolution in AHF hospitalized patients. METHODS: Prospective and multicenter study included AHF hospitalized patients, without shock or creatinine >2.5mg%. Patients received 40mg of intravenous furosemide on admission, then BN was measured, and diuretic treatment was guided by protocol. BN was considered low if <70 meq/L. DR was defined as the need of furosemide >240mg/day, tubular blockade (TB), hypertonic saline solution (HSS) or renal replacement therapy (RRT). In-hospital cardiovascular (CV) mortality, CV mortality and AHF readmissions at 60-day post-discharge were evaluated. RESULTS: 157 patients were included. BN was low in 22%. DR was development in 19% (12.7% furosemide >240mg/day, 8% TB, 4% RRT). Low NB was associated with DR (44% vs 12%; p 0.0001), persistence of congestion (26.5% vs 11.4%; p 0.05), furosemide >240 mg/day (29% vs 8%; p 0.003), higher cumulative furosemide dose at 72 hours (220 vs 160mg; p 0.0001), TB (20.6 vs 4.9%; p 0.008), RRT (11.8 vs 1.6%; p 0.02), worsening of AHF (27% vs 9%; p 0.01), inotropes use (21% vs 7%; p 0.48), respiratory assistance (12% vs 2%; p 0.02) and a higher in-hospital CV mortality (12% vs 4%; p 0.1). No association was demonstrated with post-discharge endpoints. CONCLUSIONS: In AHF patients, low BN was associated with DR, persistent congestion, need for aggressive decongestion strategies, and worse in-hospital evolution.

Effect of antihypertensive agents on sleep apnea and ambulatory blood pressure in patients with hypertension: A randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) and hypertension are common conditions that may be linked through sympathetic activation and water retention. We hypothesized that diuretics, which reduce the body water content, may be more effective than amlodipine, a blood pressure (BP)-lowering agent implicated with edema, in controlling OSA in patients with hypertension. We also aimed to compare the effects of these treatments on ambulatory blood pressure monitoring (ABPM). METHODS: In a randomized, double-blind clinical trial, we compared the effects of chlorthalidone/amiloride 25/5 mg with amlodipine 10 mg on OSA measured by portable sleep monitor and BP measured by ABPM. The study included participants older than 40 who had moderate OSA (10-40 apneas/hour of sleep) and BP within the systolic range of 140-159 mmHg or diastolic range of 90-99 mmHg. RESULTS: The individuals in the experimental groups were comparable in age, gender, and other relevant characteristics. Neither the combination of diuretics nor amlodipine alone reduced the AHI after 8 weeks of treatment (AHI 26.3 with diuretics and 25.0 with amlodipine. P = 0.713). Both treatments significantly lowered office, 24-h, and nighttime ABP, but the two groups had no significant difference. CONCLUSION: Chlorthalidone associated with amiloride and amlodipine are ineffective in decreasing the frequency of sleep apnea episodes in patients with moderate OSA and hypertension. Both treatments have comparable effects in lowering both office and ambulatory blood pressure. The notion that treatments could offer benefits for both OSA and hypertension remains to be demonstrated. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT01896661.

Comparison of preventive effects of combined furosemide and mannitol versus single diuretics, furosemide or mannitol, on cisplatin-induced nephrotoxicity.

Cisplatin (CDDP)-induced nephrotoxicity is a common dose-limiting toxicity, and diuretics are often administered to prevent nephrotoxicity. However, the efficacy and optimal administration of diuretics in preventing CDDP-induced nephrotoxicity remain to be established. This study aimed to evaluate the efficacy of combining furosemide and mannitol to prevent CDDP-induced nephrotoxicity. This was a post-hoc analysis of pooled data from a multicenter, retrospective, observational study, including 396 patients who received one or two diuretics for CDDP-based chemotherapy, compared using propensity score matching. Multivariate logistic regression analyses were used to identify risk factors for nephrotoxicity. There was no significant difference in the incidence of nephrotoxicity between the two groups (22.2% vs. 28.3%, P = 0.416). Hypertension, CDDP dose ≥ 75 mg/m2, and no magnesium supplementation were identified as risk factors for nephrotoxicity, whereas the use of diuretics was not found to be a risk factor. The combination of furosemide and mannitol showed no advantage over a single diuretic in preventing CDDP-induced nephrotoxicity. The renal function of patients receiving CDDP-based chemotherapy (≥ 75 mg/m2) and that of those with hypertension should be carefully monitored. Magnesium supplementation is important for these patients.

Preoperative use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and diuretics increases the risk of dehydration after ileostomy formation: population-based cohort study.

BACKGROUND: Readmission rates following ileostomy formation are high. Dehydration and consecutive renal failure are common causes of readmission, potentially pronounced by drugs affecting the homeostasis. The aim of the study was to assess the risk of dehydration after ileostomy formation in patients treated with angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) or diuretics. METHOD: This nationwide population-based cohort study used data derived from the Colorectal Cancer Data Base of several Swedish healthcare registers. The study included all patients operated on with elective anterior resection and temporary ileostomy for rectal cancer clinically staged I-III in Sweden in 2007-2016. Exposure was at least two dispensations of ACEI, ARB or diuretics within 1 year prior to surgery. Outcome was 90-day readmission due to dehydration including acute renal failure. RESULTS: In total, 3252 patients were included with 1173 (36.1%) exposed to ACEI, ARB or diuretics. The cumulative incidence for 90-day readmission due to dehydration was 29.0% (151 of 520) for exposed versus 13.8% (98 of 712) for unexposed. The proportion of readmissions due to any reason was 44.3% (520 of 1173) for exposed compared to 34.2% (712 of 2079) for unexposed. The incidence rate ratio for readmission due to dehydration was 2.83 (95% c.i. 2.21 to 3.63, P < 0.001). The hazard rate ratio was 2.45 (95% c.i. 1.83 to 3.27, P < 0.001) after adjusting for age, gender and comorbidity. CONCLUSION: Medication with ACEI, ARB or diuretics defines a vulnerable patient group with increased risk of readmission due to dehydration after ileostomy formation.

Kidney Replacement Therapies and Ultrafiltration in Cardiorenal Syndrome.

BACKGROUND: Some patients with cardiorenal syndrome 1 and congestion exhibit resistance to diuretics. This scenario complicates management and is associated with a worse prognosis. In some cases, rescue treatment may be considered by starting kidney replacement therapies or ultrafiltration. This decision is complex and necessitates a profound understanding of these techniques and the pathophysiology of this syndrome. These modalities are classified into continuous, intermittent, and ultrafiltration therapies, each with its own advantages and disadvantages that are pertinent in selecting the optimal treatment. SUMMARY: In patients with diuretic-resistant cardiorenal syndrome, extracorporeal ultrafiltration and kidney replacement therapies have the potential to relieve congestion, restore the neurohormonal system, and improve quality of life. KEY MESSAGES: (i) In cardiorenal syndrome, the resistance to diuretics is common. (ii) Extracorporeal ultrafiltration and renal replacement therapies are rescue options that may improve the management of these patients. (iii) Better understanding of these modalities will help the development of new devices which are friendlier, safer, and more affordable for patients in these clinical settings.

Renal function and natriuresis-guided diuretic therapy - a pre-specified analysis from the PUSH-AHF trial.

AIM: In a randomized controlled trial, we recently showed that a natriuresis-guided diuretic approach improved natriuresis and diuresis in patients with acute heart failure (HF). In this pre-specified analysis, we investigated the association between (worsening) renal function, outcomes and the effect of intensive natriuresis-guided loop diuretic therapy as compared with standard of care. METHODS AND RESULTS: The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) trial randomized patients to natriuresis-guided diuretic therapy or standard of care. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at fixed timepoints, and worsening renal function (WRF) was assessed at 72 h. The primary outcome was the interaction between randomized treatment allocation, baseline eGFR and the dual primary outcome of PUSH-AHF: total natriuresis at 24 h and time to all-cause mortality or HF rehospitalization at 180 days. In 309 patients, median baseline eGFR was 53 (35-73) ml/min/1.73 m2, and 58% had eGFR <60 ml/min/1.73 m2. Baseline eGFR did not significantly modify the treatment effect of natriuresis-guided diuretic therapy on natriuresis at 24 h (p for interaction = 0.730). However, baseline eGFR significantly modified the effect on all-cause mortality and HF rehospitalization (p for interaction = 0.017): the risk of this second primary outcome was lower in patients with lower eGFR who were randomized to the natriuresis-guided group. In the natriuresis-guided arm, eGFR decreased more (-11.0 vs. -6.91 ml/min/1.73 m2; p = 0.002) during the first 3 days, but this effect was attenuated at discharge (-10.3 vs. -8.69 ml/min/1.73 m2; p = 0.38). WRF was more frequently observed in patients randomized to natriuresis-guided treatment, but was not associated with worse clinical outcomes. CONCLUSIONS: Natriuresis-guided diuretic treatment improved diuresis and natriuresis irrespective of baseline eGFR and occurrence of WRF, was effective even in patients with low eGFR, and the observed effect on eGFR was transient and not associated with worse clinical outcomes.

Acetazolamide As A Valuable Addition to Acute Heart Failure?

Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure.1.

[Acute heart failure (AHF)].

INTRODUCTION: Acute heart failure (AHF) is a frequent cause for emergency consultations, leads to long hospital stays and is characterized by high mortality and rehospitalization rates, with the first months after hospitalization having the highest risk («vulnerable phase¼). The clinical presentation is usually characterized by fluid accumulation. Over the last three decades, few advances have been achieved in the treatment of AHF, as most studies with diuretics or vasodilators failed to show positive effects in terms of mortality and rehospitalization rates. In this context, the treatment of AHF must have an integrative approach, consisting of rapid correction of systemic congestion on the one hand, and specific therapies for the precipitating factors, the underlying cardiac pathology, and non-cardiac comorbidities on the other. Recently, it has been shown that a rapid and intensive up-titration of oral heart failure medical therapy during and immediately after hospitalization can improve the prognosis during the vulnerable phase after AHF. In this article, the principles of optimization and personalization of diuretic therapy and oral heart failure medication during hospitalization and the early outpatient phase after AHF are discussed.

Serial direct sodium removal in patients with heart failure and diuretic resistance.

AIMS: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance. METHODS AND RESULTS: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved. CONCLUSIONS: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS. CLINICAL TRIAL REGISTRATION: RED DESERT (NCT04116034), SAHARA (NCT04882358).