Furosemide-Hydration Matching with RenalGuard® in Decompensated Heart Failure: An Alternative Way to Use Diuretics and Saline

The vast majority of acute heart failure (HF) episodes are characterized by progressive worsening symptoms and signs of congestion with volume overload. The aim of therapy in those cases is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic therapy.1 The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and electrolyte disturbances occur. In particular, in the presence of particularly low renal function values accompanied by anasarca, the presence of resistance to diuretic therapy is one of the main factors that can lead to hospitalization with the need for intravenous diuretic therapy. RenalGuard® (PLC Medical Systems, USA) is a system for the prevention of Contrast-Associated Acute Kidney Injury (CA-AKI), engineered to ensure adequate hydration while providing contrast medium clearance; the system delivers intravenous fluids matched to urine output with a combination of hydration with normal saline at an initial dose bolus plus a low dose of furosemide (priming) and continuous monitoring for a urine output flow of >150–300 mL/h, in the attempt to prevent conditions of either hyperlaemia or hypovolaemia.2-4 In this case report, our team employed RenalGuard® in a patient with acute decompensated HF, setting a net negative fluid balance in order to achieve a reduction in congestion and fluid retention. A 41-year-old man was admitted in September 2022 to the HF Unit at the Monzino Cardiology Center, Milan, with signs and symptoms of worsening HF: worsening dyspnoea in New York Heart Association (NYHA) class IV, with bendopnoea, orthopnoea, massive ankle swelling leading to a weight gain of +11 kg in the last 3 weeks despite an increase in the home dose of loop diuretic to furosemide 150 mg/day. At the age of 17, the patient was found to have T-wave inversion in the right precordial leads and mild dilation of the right ventricle (RV) at electrocardiogram (ECG) and echocardiography, respectively, in the absence of a family history of cardiomyopathy or sudden cardiac death; no further examinations were performed at that time. In 2004, based on his clinical history, ECG, and echocardiographic findings, the patient was diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC). In 2015, at the age of 38, a cardiac magnetic resonance imaging (CMR) revealed severe RV dilation and dysfunction, as well as mild left ventricular (LV) dysfunction with an ejection fraction (EF) of 46%. Biventricular late gadolinium enhancement was observed (subepicardial, nonischaemic pattern) with sings consistent with fibro-fatty replacement. In June 2016, the patient was admitted to the emergency department with ventricular tachycardia that rapidly degenerated into ventricular fibrillation. Cardiopulmonary resuscitation was immediately initiated, and rapid return of spontaneous circulation was achieved after a single 200 J direct current shock. Coronary angiography demonstrated normal coronary arteries, and an implantable cardioverter-defibrillator (ICD) was subsequently implanted for secondary prevention of sudden cardiac death. In May 2017, the patient experienced his first episode of acute HF. At home, the patient was on a regimen of ramipril 5 mg twice daily, bisoprolol 5 mg twice daily, potassium canrenoate 25 mg once daily, furosemide 150 mg/day, and metolazone 5 mg once a week. Therapy with sodium-glucose co-transporter 2 inhibitors (SGLT2-i) had never been introduced, also because the patient had not attended regular follow-up visits since 2017. Upon admission, chest X-ray demonstrates a mild bilateral pleural effusion, mediastinal widening and cardiomegaly (Figure 1, lower panel). Low voltages in the peripheral leads and an epsilon wave were noted on the ECG (Figure 1, upper panel). A transthoracic echocardiogram was performed, revealing severe biventricular dysfunction, with a LVEF of 21%, a tricuspid annular plane systolic excursion (TAPSE) of 10 mm and a RV fractional area change (FAC) of 16% (Figure 2). Complete blood count and basic metabolic panel lab were furthermore performed (Table 1). In brief: haemoglobin 15.2 g/dL, creatinine 1.65 mg/dL, blood urea nitrogen (BUN) 110 mg/dL; sodium and potassium levels 135 and 4.24 mmol/L, respectively. During hospitalization, the patient underwent a cardiopulmonary exercise test (CPET), which revealed a severe reduction in functional capacity (peak oxygen uptake (VO2) of 13.34 mL/min/kg, corresponding to 39% of the predicted VO2), an increased ventilation/carbon dioxide production (VE/VCO2) slope (59, normal values < 30). Periodic breathing was also observed (Figure 3). A 2-year mortality risk of 45.6% was estimated by the MECKI score.5 A CMR was repeated, but the images were found to be non-evaluable due to magnetic ICD interference (Figure 4A). To exclude a coronary artery disease as a cause of the LVEF reduction, a new coronary angiography was performed on admission, which confirmed the normality of the major epicardial coronary vessels (Figure 4B). Early after admission, furosemide infusion, preceded by a loading dose, was started. To achieve a negative fluid balance of 100 mL/h (−2400 mL/day), an infusion of isotonic saline matched to urinary output was initiated using the RenalGuard system (Figure 5). Moreover, due to initial signs of hypoperfusion, dopamine was first initiated, followed on the fourth day by an infusion of levosimendan. Figure 6 and Table 1 summarize the main treatment during the hospital admission. Over the 5-day RenalGuard® treatment period, the patient maintained consistently negative fluid balances, ranging from a minimum of −1067 mL on the second day to −2395 mL on the fifth day. Urine output persistently exceeded 195 mL/h. By the end of the treatment, the patient experienced a weight reduction of 7.5 kg (corresponding to a weight loss of about 75% of the total weight gain reported upon admission). From a biochemical perspective (Table 1), there was a substantial improvement in renal function, with a decrease in creatinine levels (from 1.65 to 1.27 mg/dL) and BUN (from 110 to 63 mg/dL), and an increase in glomerular filtration rate (GFR), from 51 to 70 mL/min, was estimated. Brain natriuretic peptide (BNP) levels also decreased from 2741 to 1928 pg/mL. A transient hypokalaemia (2.8 mmol/L) following significant diuresis was rapidly corrected via intravenous administration. At discharge, which occurred after five more days, the patient reported an improvement in symptoms (NYHA Class III), with no observable peripheral oedema or jugular venous distension. Renal function remained stable, allowing for therapeutic optimization with the initiation of sacubitril/valsartan and dapagliflozin. Given the clinical, metabolic and echocardiographic picture of advanced HF, the patient was referred to a transplant centre for evaluation of listing for cardiac transplantation. We report the case of a young man diagnosed with biventricular arrhythmogenic cardiomyopathy according to the 2024 revised Padua criteria,6 with an acute decompensated HF episode efficiently treated with a furosemide matched infusion system (RenalGuard®). In this case, the choice to use the device was motivated by the attempt to achieve a negative fluid balance in a linear and controlled manner in a patient with anasarca, avoiding both excessively negative or positive diuresis targets. To date, RenalGuard® has been mainly employed as a strategy for the prevention of CA-AKI in patients undergoing cardiac procedures (i.e., coronary angiography), with promising results in small randomized clinical trials.4, 7-10 Recently, a meta-analysis demonstrates a 46% significant reduction of CA-AKI displaying a 99.9% probability of reducing the risk of CA-AKI.2 Acute decompensated HF is a complex clinical syndrome caused by cardiac abnormalities compromising the ability of the heart to provide a blood supply adequate to the metabolic needs of peripheral tissues and it is characterized by systemic and pulmonary fluid retention, with weight gain, peripheral oedema, needing diuretic therapy. Moreover, acute HF is associated with neurohormonal hyper-activation with enhanced sympathetic nervous and renin-angiotensin-aldosterone system (RAAS), that sustain the vicious circle of cardiac dysfunction and fluid retention. The administration of high doses of diuretics, usually required in acute decompensated HF treatment, can induce hypovolaemia-induced neurohormonal activation and transient deterioration of kidney function, that, in turn, counteracts the effect of diuretics and limits recovery from fluid overload. Thus, in the setting of acute HF, fluid retention and redistribution results in systemic congestion, eventually causing organ dysfunction due to hypoperfusion.11 Aggressive intravenous furosemide infusion tailored to maximize urine flow and effective volume loss results in improved haemodynamics and HF symptoms and normalized renal function in most cases.12 Diuretics are often given at subtherapeutic dosage and discontinued prematurely before haemodynamic improvement and euvolaemia are achieved,13 so far multiple observational studies found aggressive yet ineffective diuretic use is associated with worsening renal function and increased morbidity and mortality.14-17 Blood volume represents a small component of extracellular volume from which fluid losses are mobilized in the short term by diuretics, while reductions in extracellular fluid volume are further limited by the degree of plasma refill from the extracellular fluid into the intravascular space.18 Excessive and rapid blood volume depletion induced by loop diuretics may activate RAAS, promoting sodium retention and increasing afterload, along with deleterious neurohormonal effects on cardiac remodelling. Thus, a careful clinical assessment of the degree of plasma refill is critical in minimizing triggering of the adaptive neurohormonal responses to impaired plasma refill when decongestive therapies are administered.18 Nevertheless, using furosemide with no adequate matching hydration, decreasing the effective circulating volume, impairs prostaglandin mediated vasodilation, potentially resulting in dehydration and increasing the risk of tubular damage.19 Data from nonrandomized studies showed that decongestive therapy supported by RenalGuard® system for 24 h was safe and effective in acutely decompensated HF patients with pre-existing chronic renal disease.20 Importantly, the good diuretic responders during RenalGuard® therapy, showed significantly lower levels of creatinine and BUN with a statistically significant greater ability to dilute urine in the 12th and 24th hour of therapy.21 Unfortunately, in this case, plasma albumin levels were not measured, which were likely low in a patient with RV dysfunction and anasarca. As documented in the literature,22 these data would have contributed to better therapeutic optimization by ensuring the mobilization of interstitial fluids through oncotic pressure. However, the impact of techniques such as RenalGuard® at different albumin levels remains unknown. RenalGuard® system could ensure adequate urinary output without causing rapid volume depletion. By monitoring urinary output and adjusting the isotonic infusion accordingly, the circulating intravascular volume is kept as constant as possible, preventing the activation of the RAAS. One of the advantages of RenalGuard® is the ease of setting the parameters, with only the values for intravenous infusion and fluid intake needing to be defined. This strategy may have positive repercussions for patient monitoring during diuretic therapy, obviating the need for calculations of input/output fluid balances at set intervals (typically every 6 or 12 h) leading to clinical decisions (increase or decrease diuretic therapy) that cannot be monitoring on a minute by minute basis. Thus, in an ideal setting, the nursing monitoring during the treatment can be simplified. To enhance the cost–benefit ratio, RenalGuard® system could be specifically targeted at patients with acute HF undergoing interventional procedures or at those with known chronic renal insufficiency where adequate decongestion is desired without compromising the effective circulating blood volume and consequently renal function. It is important to note, however, that this procedure is not a method of renal replacement; rather, it is a more efficient means of controlling patients' fluid loss through the use of saline and diuretics. Consequently, in instances of reduced urinary output resulting from a significant deterioration in renal function that is unresponsive to diuretic therapy, this method may prove inadequate. In this case, the choice to start with RenalGuard® was motivated by GFR values that were not severely depressed, the presence of preserved (though reduced) diuresis, and the absence of signs of severe clinical renal failure (such as severe hyperkalaemia, severe increase in BUN, or anuria). It is important to note that, in the event of failure of this strategy, possible renal replacement therapies [e.g., continuous veno-venous haemofiltration (CVVH)] could have been employed. Moreover, a possible alternative (or at least complementary) solution to the use of intravenous diuretic therapy could have been the introduction of an additional diuretic (e.g., acetazolamide), also considering the favourable results of the recently published ADVOR study.23 However, at the time of the patient's hospitalization, this data was not yet known, the intravenous formulation of acetazolamide was not (and still is not) available in hospital formularies, and the patient was already taking a combination of diuretics at home (furosemide and metolazone) with poor control of the congestion. Finally, current data does not allow us to understand how the diuretic response in HF patients treated with RenalGuard® may be influenced by their baseline therapy and or their HF severity assessed by serum biomarkers. This information seems worthy of potential dedicated studies, especially considering the effectiveness showed by some HF therapies (i.e., sacubitril/valsartan) in improving diuresis and natriuresis secondary to increased intravascular fluids,24 as well as the recently demonstrated non-response observed after a fluid challenge in more severe WHF subjects with higher levels of troponin, or NT-proBNP, or cystatin C.25 Despite the positive outcome observed in our clinical case, which demonstrated excellent fluid decongestion without affecting renal function, randomized clinical trials are needed to assess the system's efficacy in a larger cohort of patients with acute HF. In this regard, we are conducting a randomized trial in our centre on this aspect (Clinical Trials number NCT05807152), also to understand a possible protective effect of this strategy in terms of neurohormonal activation. Furosemide-induced diuresis with maintenance of intravascular volume through matched hydration (RenalGuard system) could be an effective tool for achieving adequate decongestion in patients with acute heart failure, by mitigating the adverse effects of rapid intravascular volume depletion induced by aggressive yet ineffective diuretic administration. Further clinical studies are warranted to explore this approach. Open access funding provided by BIBLIOSAN. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Nicola Cosentino, is an MD, PhD and holds a full-time position at AstraZeneca as a medical area lead outside the submitted work. A patient informed consent was obtained to publish this case report.