Guest Editorial.

As we continue to advance in the field of medicine, the role of loop diuretics remains crucial in the management of a wide range of conditions associated with fluid retention. The introduction of torsemide has brought a new dimension to diuretic therapy, offering unique benefits that distinguish it from its counterparts.

Preface.

The field of diuretic therapy has witnessed significant advancements over the decades. Loop diuretics and other diuretic agents are crucial in the management of various conditions characterized by fluid overload. Torsemide, a loop diuretic agent, has unique pharmacological properties, safety profiles, and varied clinical applications. This special journal supplement aims to provide a comprehensive examination of torsemide, highlighting its role in contemporary medical practice.

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.

Emerging Role of Low-dose Loop Diuretics in the Management of Heart Failure Patients to Maintain Euvolemia.

The current scenario of employing loop diuretics in combination with guideline-directed medical therapy (GDMT) demonstrates a comprehensive approach to improving clinical outcomes in individuals with heart failure (HF). GDMT uses four types of drugs: angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Torsemide, furosemide, and bumetanide are common loop diuretics used to control fluid overload in HF and provide symptomatic relief. Furthermore, loop diuretics are frequently used in advanced and decompensated HF. The combination of GDMT and loop diuretics is designed to improve quality of life, reduce hospitalization rates, and increase survival. Guidelines suggest the use of low-dose loop diuretics in patients with HF who have a previous history of congestion to maintain euvolemia. According to recent studies and guidelines, individualized regimens for the use of GDMT and loop diuretics are required to optimize therapeutic efficacy in terms of clinical status, fluid retention, electrolyte balance, and renal function.

Torsemide in Edema Associated with Chronic Kidney Disease.

Torsemide is a loop diuretic used to manage edema associated with chronic kidney disease (CKD) and acute kidney injury (AKI). It acts by inhibiting sodium and chloride ions reabsorption in the ascending limb of the loop of Henle, thereby increasing urine output and reducing fluid accumulation. Compared to other diuretics, torsemide has an extended duration of action, higher bioavailability, and its elimination route is primarily through the hepatic route, making it effective in patients with CKD and AKI. Clinical studies indicate that torsemide can improve symptoms of fluid overload and potentially enhance renal function.

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 as a Primary Choice in Edema Associated with Heart Failure.

Heart failure (HF) is the fastest-growing disease with a higher fatality rate. The most differentiating feature of HF is pulmonary or peripheral edema, which is characterized by a gradient between intravascular and extravascular pressure. Loop diuretics were chosen as the primary treatment for edema associated with HF due to their efficacy and early onset of action. If an oral dose had not been provided, intravenous (IV) administration of torsemide, or equal doses of furosemide and bumetanide, was preferred. However, the key variables for selecting and administering loop diuretics are their pharmacological qualities as well as their clinical efficacy. Torsemide has greater bioavailability, a higher rate of absorption, a longer duration of action, and lesser ototoxicity, making it the primary choice in the management of edematous HF.

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.

Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury in rats.

AIM: We aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism. METHODS: Rats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post-injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post-injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord. RESULTS: CLP290 and bumetanide alleviated SCI-associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate-Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K+-Cl-cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na+-K+-Cl-cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non-significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group. CONCLUSION: Combined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhances GABAA receptor-mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short-term effect.

Effect of dapagliflozin on readmission and loop diuretics use in patients with acute heart failure: a retrospective propensity score-matched cohort study.

BACKGROUND: The efficacy of dapagliflozin in patients with acute heart failure remains unclear. OBJECTIVE: To investigate the impact of dapagliflozin (DAPA) on loop diuretics use and 90-day readmission in patients with acute heart failure. METHODS: In a retrospective cohort study, patients diagnosed with acute heart failure or chronic heart failure with acute exacerbation admitted to Fuyang People's Hospital from January 2021 to April 2023, this study used DAPA (at a dose of 10 mg once daily) in combination with standard treatment. The patients were divided into DAPA group and DAPA-Free group based on whether they used DAPA in acute heart failure. To minimize the influence of confounding factors and ensure comparability between groups, we used propensity score matching (PSM). RESULTS: A total of 399 patients were included, with 206 patients (51.63%) in the DAPA group and 193 patients (48.37%) in the DAPA-Free group. PSM produced 160 pairs. After PSM, there were no statistically significant differences between the DAPA and DAPA-Free groups in terms of readmission of all causes (16.88% vs. 18.12%, OR 0.9141, 95% CI 0.5385-1.552, log rank P = 0.739) or readmission for heart failure (11.88% vs. 15.0%, OR 0.9077, 95% CI 0.4441-1.469, log rank P = 0.484) after 90-day follow-up. Patients in the DAPA group had a lower mean daily dose of intravenous loop diuretics compared to the DAPA-Free group (20 mg/d vs. 30.00 mg/d, P<0.001), lower total loop diuretic dose during hospitalization (106.06 ± 31.23 mg vs. 144.50 ± 45.39 mg, P = 0.038) and a decreased number of diuretic types used (11.88% vs. 23.12%, P = 0.008). CONCLUSIONS: DAPA reduced the dose of intravenous loop diuretics. However, it did not improve all-cause readmission for 90 days or readmission for heart failure after discharge.

Prevalence of heart failure and trends in its pharmacological treatment between 2000 and 2017 among very old people.

PURPOSE: The aim of this study was to describe a population of very old people with heart failure (HF), to analyse the use of cardiovascular drugs over time, and to explore factors influencing cardiovascular drug treatment for this group. METHODS: All participants with information regarding HF diagnosis were selected from the Umeå 85+/Gerontological Regional Database (GERDA). The people in GERDA are all ≥85 years old. Trained investigators performed structured interviews and assessments. Information regarding medications and diagnoses was obtained from the participants and from medical records. Medical diagnoses were reviewed and confirmed by an experienced geriatrician. RESULTS: In this very old population, the prevalence of HF was 29.6% among women and 30.7% among men. Between 2000 and 2017, there was an increase in the use of renin-angiotensin (RAS) inhibitors (odds ratio [OR] 1.107, 95% confidence interval [CI] 1.072-1.144) and beta-blockers (BBs) (OR 1.123, 95% CI 1.086-1.161) among persons with HF, whereas the prevalence of loop diuretics (OR 0.899, 95% CI 0.868-0.931) and digitalis (OR 0.864, 95% CI 0.828-0.901) decreased (p < 0.001 for all drug classes). Higher age was associated with lower use of RAS inhibitors and BBs. CONCLUSION: In this HF population, the use of evidence-based medications for HF increased over time. This may be a sign of better awareness among prescribers regarding the under-prescribing of guidelines-recommended treatment to old people. Higher age associated with a lower prevalence of RAS inhibitors and BBs. This might indicate that further improvement is possible but could also represent a more cautious prescribing among frail very old individuals.

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease.

INTRODUCTION: Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimer's disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross-sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established. METHODS: We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association between time-dependent use of bumetanide and time to first AD diagnosis while controlling for patient characteristics. Multiple sensitivity analyses were conducted to test the robustness of the findings. RESULTS: We sampled 833,561 Medicare beneficiaries, 60.8% female, with mean (standard deviation) age of 70.4 (12). Bumetanide use was not significantly associated with AD risk (hazard ratio 1.05; 95% confidence interval, 0.99-1.10). DISCUSSION: Using a nationwide dataset and a retrospective cohort study design, we were not able to identify a time-dependent effect of bumetanide lowering AD risk. HIGHLIGHTS: Bumetanide was identified as a candidate for repurposing for Alzheimer's disease (AD). We evaluated the association between bumetanide use and risk of AD. We used Medicare data and accounted for duration of bumetanide use. Bumetanide use was not significantly associated with risk of AD.

Hypertonic saline and heart failure: "sodium-centric" or "chlorine-centric"?

Up to 50% of patients admitted for heart failure (HF) have congestion at discharge despite diagnostic and therapeutic advances. Both persistent congestion and diuretic resistance are associated with worse prognosis. The combination of hypertonic saline and loop diuretic has shown promising results in different studies. However, it has not yet achieved a standardized use, partly because of the great heterogeneity in the concentration of sodium chloride, the dose of diuretic or the amount of sodium in the diet. Classically, the movement of water from the intracellular space due to an increase in extracellular osmolarity has been postulated as the main mechanism involved. However, chloride deficit is postulated as the main up-regulator of plasma volume changes, and its correction may be the main mechanism involved. This "chloride centric" approach to heart failure opens the door to therapeutic strategies that would include diuretics to correct hypochloremia, as well as sodium free chloride supplementation.

The Effect of Early Administration of Hypertonic Saline Solution In Acute Decompensated Heart Failure. / O Efeito da Administração Precoce de Solução Salina Hipertônica na Insuficiência Cardíaca Descompensada Aguda.

BACKGROUND: There was no scientific evidence about the initial treatment of hypertonic saline solution (HSS) in acutely decompensated heart failure (ADHF). OBJECTIVES: This study assessed the impact of using HSS along with a loop diuretic (LD) as the first diuretic treatment for ADHF, focusing on renal function, electrolyte levels, and clinical outcomes. METHODS: In this retrospective case-control study, 171 adult patients (93 females/78 males) with ADHF were included between January 1, 2022, and December 31, 2022. Patients were allocated into two groups: upfront combo HSS+LD and standardized LD. The primary endpoint was worsening renal function (WRF). Hospitalization for HF and all-cause mortality were evaluated during 6 months of follow-up. The significance level adopted in the statistical analysis was 5%. RESULTS: The groups exhibited similarities in baseline characteristics.A significantly higher diuresis on the 1st day (3975 [3000-5150] vs. 2583 [2000-3250], p=0.001) and natriuresis on the 2nd hour (116.00 [82.75-126.00] vs. 68.50 [54.00-89.75], p=0.001) in the initial upfront combo HSS+LD were found in comparison with the standardized LD.When compared to the standardized LD, the utilization of HSS led to an increase in serum Na+ (137.00 [131.75-140.00] vs. 140.00 [136.00-142.25], p=0.001 for upfront combo HSS, 139.00 [137.00-141.00] vs. 139.00 [136.00-140.00], p=.0470 for standardized LD), while chloride (99.00 [94.00-103.25] vs. 99.00[96.00-103.00], p=0.295), GFR (48.50 [29.75-72.50 vs. 50.00 [35.50-63.50, p=0.616), and creatinine (1.20 [0.90-1.70] vs. 1.20 [1.00-1.50], p=0.218) remained stable in the upfront combo HSS group when compared to standardized LD group (Cl-: 102.00 [99.00-106.00] vs. 98.00 [95.00-103.00], p=0.001, eGFR: 56.00 [41.00-71.00] vs. 55.00 [35.00-71.00], p=0.050, creatinine:1.10 [0.90-1.40] vs. 1.20 [0.90-1.70], p=0.009). Worsening renal function (16.1% vs 35.5%, p=0.007), and length of stay in the hospital (4 days [3-7] vs. 5 days [4-7], p=0.004) were lower in the upfront combo HSS+LD in comparison with the standardized LD. In-hospital mortality, hospitalization for HF, and all-cause mortality were similar between the two groups. CONCLUSION: HSS as an initial therapy, when combined with LD, may provide a safe and effective diuresis without impairing renal function in ADHF. Therefore, HSS may lead to a shorter length of stay in the hospital for these patients.

FUNDAMENTO: Não houve evidência científica sobre o tratamento inicial com solução salina hipertônica (SSH) na insuficiência cardíaca agudamente descompensada (ICAD). OBJETIVOS: Este estudo avaliou o impacto do uso de SSH junto com um diurético de alça (DA) como o primeiro tratamento diurético para ICAD, com foco na função renal, níveis de eletrólitos e resultados clínicos. MÉTODOS: Neste estudo retrospectivo de caso-controle, 171 pacientes adultos (93 mulheres/78 homens) com ICAD foram incluídos entre 1º de janeiro de 2022 e 31 de dezembro de 2022. Os pacientes foram alocados em dois grupos: combinação inicial de SSH+DA e DA padronizada. O desfecho primário foi piora da função renal (PFR). A hospitalização por IC e a mortalidade por todas as causas foram avaliadas durante 6 meses de acompanhamento. O nível de significância adotado na análise estatística foi de 5%. RESULTADOS: Os grupos exibiram semelhanças nas características basais. Diurese significativamente maior no 1º dia (3975 [3000-5150] vs. 2583 [2000-3250], p=0,001) e natriurese na 2ª hora (116,00 [82,75-126,00] vs. 131,75-140,00] vs. 94,00-103,25] vs. 99,00 [96,00-103,00], p=0,295), TFG (48,50 [29,75-72,50 vs. 50,00[35,50-63,50, p=0,616) e creatinina (1,20 [0,90-1,70] vs. 1,20 [1,00-1,50], p=0,218) permaneceu estável no grupo SSH combinado inicial quando comparado ao grupo DA padronizado (Cl-: 102,00[99,00-106,00] vs. 98,00[95,00-103,00], p=0,001, TFGe: 56,00 [41,00-71,00] vs. 55,00[35,00-71,00], p=0,050, creatinina: 1,10[0,90-1,40] vs. 1,20 [0,90-1,70], p=0,009). A piora da função renal (16,1% vs. 35,5%, p = 0,007) e o tempo de internação hospitalar (4 dias [3-7] vs. 5 dias [4-7], p = 0,004) foram menores na combinação inicial SSH+DA em comparação com o DA padronizado. A mortalidade hospitalar, a hospitalização por IC e a mortalidade por todas as causas foram semelhantes entre os dois grupos. CONCLUSÃO: SSH como terapia inicial, quando combinada com DA, pode proporcionar uma diurese segura e eficaz sem prejudicar a função renal na ICAD. Portanto, a SSH pode levar a um menor tempo de internação hospitalar para esses pacientes.

Use of drugs for hypertension or heart failure and the risk of death in COVID-19: association with loop-diuretics.

PURPOSE: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. METHODS: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. RESULTS: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17-1.35] and thiazides with reduced risk (0.78; 0.69-0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. CONCLUSION: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation.

Efficacy of bumetanide in animal models of ischemic stroke: a systematic review and meta-analysis.

This meta-analysis aimed to describe the efficacy of bumetanide in improving infarct volume, brain edema, and behavioral outcomes in animal models of cerebral ischemia. Embase, PubMed and Web of Science databases were searched from their inception to February 2024 (INPLASY:202430023). Data on the animal species, stroke model, drug dose, time of treatment, method of administration, study quality, and outcomes were extracted and pooled in a meta-analysis. The combined standardized mean difference (SMD) or mean difference (MD) estimates and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models. Thirteen eligible studies involving >200 animals fulfilled the inclusion criteria and were included in this meta-analysis. Meta-analyses demonstrated that bumetanide treatment significantly reduced cerebral infarct volume (SMD: -0.42; 95% CI: -0.75, -0.09; p < 0.01; n = 186 animals) and consistently relieved brain edema (SMD: -1.39; 95% CI: -2.06, -0.72; p < 0.01; n = 64 animals). Subgroup analyses demonstrated that bumetanide treatment reduced infarct volume in transient but not permanent cerebral ischemia models. When administered after the stroke, it was more effective than treatment initiation before the stroke. Eight studies assessed the effect of bumetanide on behavioral function and the results showed that bumetanide treatment significantly improved neurobehavioral deficits (SMD: -2.35; 95% CI: -2.72, -1.97; p < 0.01; n = 250 animals). We conclude that bumetanide appears to be effective in reducing infarct volume and brain edema and improving behavioral recovery in animal models of cerebral ischemia. This mechanism needs to be confirmed through further investigation.

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).

Renal function in PUSH-AHF: a summary of newly released data from the 2024 Annual Congress of the Heart Failure Association of the ESC.

The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) study, published in August of 2023, was the first randomized clinical trial to compare natriuresis-guided decongestion (based on spot urinary sodium measurement) to standard of care in patients with acute heart failure with congestion receiving loop diuretic therapy. Based on results from their trial, the authors concluded that natriuresis-guided loop diuretic treatment was safe and improved natriuresis and diuresis without impacting long-term clinical outcomes. The original PUSH-AHF trial included limited information about renal outcomes and left clinicians with important questions about how natriuresis-guided decongestion might affect their patients' renal function. On May 12, 2024, however, at the 2024 Annual Congress of the HFA-ESC, Dr. Kevin Damman provided an in-depth exploration of renal outcomes from the trial when he presented a pre-specified, secondary analysis, renal function in the PUSH-AHF trial. This review puts the sub-study findings into context by considering the history of the original trial from which they came from and explaining the need for a close study of its renal outcomes particularly. It highlights the potential impact of renal function in PUSH-AHF on clinical practice and future directions that should be considered by the cardiology research community.

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.