Abstract Volume overload is a major cause of recurrent hospitalization in patients with heart failure, and sodium retention is a central pathophysiological component, and blood ultrafiltration is the “gold standard” for the treatment of fluid retention. Available evidence suggests that ultrafiltration improves heart failure regression and reduces rehospitalization rates. This review describes the mechanism, efficacy, safety, indications, and future research directions of ultrafiltration in the treatment of heart failure. Keywords: ultrafiltration, heart failure, sodium retention, The Future and Current Role of Ultra?ltration in Patients with Heart Failure Abstract The high readmission rates of heart failure is due The high readmission rates of heart failure is due mainly to fluid overload and sodium retention plays a pivotal role in the pathophysiologic process. The available evidence supports Ultrafiltration improve outcomes in patients with acute decompensated heart failure. This review illustrates technical issues, mechanisms, efficacy, safety, indications and directions of ultrafiltration in heart failure. Ultrafiltration, heart failure, sodium and water retention Patients with congestive heart failure (CHF) often require repeated hospitalization due to cardiac failure, which is a huge social and economic burden and has become one of the most serious global health problems. It has become one of the most serious global health problems. Volume overload and pulmonary congestion are the main reasons for hospitalization in the majority of patients with acute decompensated heart failure (ADHF). Blood ultrafiltration is the “gold standard” for the treatment of sodium and water retention, and the use of ultrafiltration for effective management of congestion has shown great promise and has become a hot topic of international research. The main cause of edema in CHF patients is the increase in total body sodium, not water, which is the result of increased tubular sodium reabsorption due to activation of the sympathetic-adrenal and renin-angiotensin-aldosterone systems. The increase in sodium is inevitably accompanied by the accumulation of water in the body, which eventually leads to an increase in the amount of extracellular fluid. At the same time, sodium retention forms part of a feedback loop that amplifies neuroendocrine activation. Sodium retention leads to increased pulmonary congestion and ventricular filling pressures, which are clinically manifested by dyspnea, telangiectatic breathing, and decubitus M. Increased ventricular wall tension leads to decreased coronary perfusion, resulting in subendocardial myocardial ischemia and accelerated apoptosis and necrosis. In addition, ventricular chamber enlargement and ventricular spherical remodeling cause or aggravate mitral and tricuspid regurgitation, resulting in further deterioration of cardiac function. These adverse pathophysiological consequences are the eventual further deterioration of ventricular systolic and diastolic function. Elevated right heart pressure causes interstitial myocardial edema and decreased myocardial contractility. Elevated venous pressure clinically leads to decreased renal blood flow, reduced glomerular filtration rate, and decreased sodium excretion. Therefore, how to safely and effectively manage volume load is an important target for CHF treatment. Challenges facing diuretics Diuretics are currently the most commonly used drugs to correct volume overload and relieve symptoms of pulmonary congestion, but the effectiveness of diuretics is not satisfactory. In the ADHERE registry study, 21% of patients were discharged with no change or even an increase in weight; 74% lost less than 10 pounds over the course of their hospitalization, meaning that nearly 3/4 of the patients did not meet weight targets. diuretic resistance is also one of the diuretic treatment challenges in heart failure Furosemide activates the neuroendocrine system and decreases glomerular filtration rate. Intravenous administration of furosemide increases renin, aldosterone, and norepinephrine, and Bayliss et al. showed that 4 weeks of furosemide administration resulted in a sustained increase in plasma renin and aldosterone levels. In fact, neuroendocrine activation is directly related to morbidity and mortality. As early as 1987, a study found that a single intravenous dose of furosemide decreased glomerular filtration rate by 15% with a corresponding decrease in renal blood flow. in a study of 63 patients with CHF, Gottlieb et al. found that furosemide significantly decreased glomerular filtration rate. The lower the glomerular filtration rate, the higher the diuretic dose required and the higher the morbidity and mortality rate. There are no data to date from randomized controlled clinical trials on the effect of diuretics on the long-term regression of CHF. However, the ADHERE study found higher mortality and longer hospital stays in those using diuretics and with elevated creatinine levels. The mortality rate was 7.8% for those with renal insufficiency and concurrent diuretic use and 5.5% for non-users, and 3.3% for those with normal renal function and concurrent diuretic use and 2.7% for non-users. The highest mortality rate was found in patients with elevated creatinine and long-term diuretic use. The study also found that mortality was higher with long-term diuretic therapy, regardless of initial renal function. In the era of evidence-based medicine, this current “best” treatment tool for symptomatic relief may lead to results that are contrary to the original intent because of its pharmacologic limitations and contrary to the overall treatment goal. Blood ultrafiltration is the “gold standard” for correcting sodium retention. Blood ultrafiltration for dehydration has been used for over 30 years to correct sodium retention. Similar to the principle of glomerular filtration, the filter uses the pressure gradient established on both sides of the semi-permeable membrane to filter out water and small and medium-sized molecules under the negative pressure attraction of the ultrafiltration pump, while proteins and blood cells cannot pass through the membrane pores and are retained, forming ultrafiltrate. The formation of ultrafiltrate does not depend on the solute concentration gradient, and small molecule solutes such as sodium and water can freely pass through the semi-permeable membrane. The total amount of sodium and water to be removed can be determined clinically according to the patient’s specific load status, enabling adjustable, controllable and predictable mechanical dehydration. The ultrafiltrate composition is equivalent to that of raw urine, with the same electrolyte concentration and crystal osmolality as plasma. Therefore, changes in plasma potassium, sodium, chloride, and bicarbonate before and after ultrafiltration alone are not significant and do not cause disturbances in electrolyte and acid-base balance. Ultrafiltration relieves sodium retention better than diuretics. The core of relieving sodium retention is sodium, and the total amount of sodium in the body determines the total amount of extracellular fluid and the degree of congestion symptoms. Diuretics represented by furosemide produce hypotonic urine with a urinary sodium concentration of about 60 mEq/L. With a normal blood sodium concentration of 140, 80 mEq of sodium will be retained in the body for every 1 L of urine excreted, and if there is 10 L of sodium-water retention in the body, 800 mEq (18.4 g) of sodium will be retained in the body after adequate diuresis. The ultrafiltrate sodium concentration is equal to that of plasma, therefore, ultrafiltration has more sodium excretion and stronger sodium excretion capacity than diuretics when compared with diuretics for equivalent fluid removal. Ultrafiltration mechanical dehydration has a good hemodynamic effect in patients with CHF. marenzi et al. measured the hemodynamic response before and after ultrafiltration in 24 patients with CHF. The total ultrafiltration volume was 4880±896 ml. As the ultrafiltration volume increased, the gross pulmonary pressure (PWP) and right atrial pressure (RAP) gradually decreased and the cardiac output (CO) and volume per beat (SV) increased. Clinical trials have demonstrated the superiority of ultrafiltration treatment over diuretics Blood ultrafiltration has been clinically observed in the treatment of CHF for more than 30 years, and more than 100 papers have been published in major journals. However, early studies used conventional CRRT or hemodialysis devices, and because of the inconvenience of clinical use, these studies were mostly single-center and sporadic with small samples, making it difficult to develop strong evidence. With the advent of portable heart failure-specific ultrafiltration-only devices, ultrafiltration for CHF has regained great clinical interest. The study by Dahle et al. first demonstrated the feasibility of blood ultrafiltration using peripheral veins to establish extracorporeal circulation in patients with ADHF. 9 patients with ADHF underwent superficial static-venous ultrafiltration using two 18G intravenous catheters for 33.3±20 hours, with a total ultrafiltration volume of 7.0±4.9 L and a weight loss of 6.2±5.0 kg. The RAPID-CHF trial [1 In the RAPID-CHF trial [9], a total of 40 patients with ADHF were randomly assigned to the early ultrafiltration or diuretic group within 24 hours of admission, and the ultrafiltration group was limited to a single 8-hour treatment session. The mean 24-hour fluid clearance was 4650 ml and 2838 ml in the ultrafiltration and diuretic groups, respectively (p = 0.001), and the primary endpoint weight loss was 2.5 kg and 1.86 kg, respectively (p = 0.240). In terms of fluid removal, ultrafiltration treatment was superior to diuretics, and the ultrafiltration procedure was safe and well tolerated by patients. Costanzo et al [10] started ultrafiltration therapy early in the admission (4.7 ± 3.5 hours) in 20 patients with ADHF with diuretic resistance. The results showed that a mean total ultrafiltration volume of 8654 ± 4205 ml was achieved and 12 patients (60%) were discharged within 3 days. Compared with the pre-ultrafiltration baseline data, there was a significant decrease in weight (p=0.06) and a significant improvement in symptoms (p=0.003) on days 30 and 90 of follow-up, with no significant change in blood creatinine. Ultrafiltration was safe and effective in reducing the length of hospital stay and improving cardiac status, with clinical benefit lasting for 3 months. The UNLOAD study is the largest randomized controlled trial to date evaluating ultrafiltration for ADHF. A total of 28 centers participated in the study, enrolling 200 patients hospitalized with systolic heart failure and randomized to either the early ultrafiltration group (within 24 hours of hospitalization) or the conventional diuretic group. The ultrafiltration group did not use diuretics for 48 hours after hospitalization, and the amount and rate of ultrafiltration (maximum 500 ml/h) was determined by the physician in charge. Intravenous diuretics were used more than twice the outpatient dose in the conventional diuretic treatment group. The results showed more weight loss in the ultrafiltration group than in the intravenous diuretic group (5.0±3.1 vs. 3.1±3.5 kg, p=0.001), and relief of dyspnea was similar in both groups. The 90-day rehospitalization rate was lower in the ultrafiltration group (18.6% vs 32.2%, p=0.04). As for safety indicators, hypokalemia was less in the ultrafiltration group (1% vs. 12%, p=0.018), and the rate of creatinine elevation (>0.3 mg/dl) at discharge was similar in both groups (22.6% 19.8%, p=0.709). The UNLOAD trial answered several important questions about ultrafiltration for ADHF. Ultrafiltration was superior to conventional drug therapy in terms of endpoints such as weight reduction and reduction in readmissions. For long-term regression of CHF, ultrafiltration significantly reduced rehospitalization and the use of health care resources. Trials have demonstrated that ultrafiltration is safe in the treatment of CHF. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) is an important study that was recently published. The study enrolled 188 patients with acute decompensated heart failure with worsening renal function and randomized them to either a stepwise pharmacologic or a hemodialysis group, in which diuretics and other medications were adjusted until daily urine output reached 3-5 L. The primary endpoints of the study were changes in patient weight and creatinine levels at 96 h. The results showed that both treatment strategies had similar effects on weight loss (5.5±5.1 kg vs. 5.7±3.9 kg, p=0.58); there was no significant change in creatinine in the step drug treatment group, while creatinine was significantly higher in the ultrafiltration group (-3.5±46.9 μmol/L vs. 20.3±61.9 μmol/L, p=0.003); mortality and hospitalization due to heart failure did not differ between the two groups. There was no difference in hospitalization rates between the two groups, but the blood ultrafiltration group had more serious adverse events (72% versus 57%, p=0.03). This is a very relevant study in the context of the lopsided positive results of the ultrafiltration for ADHF study. In patients with ADHF with worsening renal function, ultrafiltration therapy is not superior to intensive drug regimens, which can cause more deterioration of renal function. Also, the investigators noted that for this specific patient population with cardiorenal syndrome, the overall prognosis was poor regardless of the treatment strategy, with 1/3 of patients dying or being rehospitalized at 60 days due to heart failure. Treating these patients remains a challenge and better treatments need to be found. Blood ultrafiltration is a good alternative in patients who respond poorly to diuretics, and the study did not include such patients. The reason for the deterioration of renal function in the patients in the study is unclear, and deterioration of renal function may be responsible for the increase in adverse events. It has also been suggested that the transient increase in blood creatinine does not necessarily reflect deterioration in renal function, but may also be related to hemoconcentration, and that slowing ultrafiltration may have a better effect. In daily clinical practice, medication is used to relieve congestion and varies greatly from hospital to hospital. Reaching the 3-5 L daily urine volume of the CARRESS-HF study drug step therapy is unrealistic. 73% of ADHF hospitalizations in the ADHERE database resulted in weight loss of <4.5 kg compared to a mean weight loss of 5.5 kg in that study. The presence of cardiorenal syndrome in ADHF is a manifestation of maximal neuroendocrine activation and severe cardiorenal axis disturbance, and targeting ADHF pathophysiology Any treatment downstream (including ultrafiltration) will not radically improve clinical regression. The use of ultrafiltration early in life may have the greatest benefit, rather than as salvage therapy in advanced stages. The AVOID-HF study is an ongoing randomized controlled trial that plans to enroll 800 patients with ADHF with creatinine <3 mg/dl. The aim of the study is to examine whether ultrafiltration reduces heart failure events in this group of patients compared to intravenous diuretics. This is the largest sample size study enrolled to date and is expected to answer the question of the effect of ultrafiltration therapy on heart failure events. Published clinical studies of ultrafiltration as a new approach to the treatment of CHF have deepened our understanding of heart failure and have shown promising therapeutic promise. However, many questions remain to be answered, such as, what is the best indication for ultrafiltration and the best time for ultrafiltration treatment, and what types of patients benefit the most? Are there other unpredictable side effects? More and larger clinical trials are needed to answer these questions in the future.