Ultrafiltration in Elderly Patients with Type 1 Cardiorenal Syndrome: Efficacy and Safety Outcomes Open Access

The heart and kidneys sustain hemodynamic stability through a complex interaction involving cardiac output regulation, blood volume control, and vascular tone modulation. This intricate relationship is embodied in cardiorenal syndrome (CRS), a pathophysiological condition where dysfunction in one organ precipitates or exacerbates dysfunction in the other [1]. CRS comprises five distinct subtypes, with type 1 CRS characterized by acute cardiac decompensation leading to secondary acute kidney injury (AKI) [2]. This subtype is linked to poor clinical outcomes, including high in-hospital mortality and frequent readmissions [3].

Management of type 1 CRS requires a multimodal approach, encompassing pharmacological interventions (e.g., cardiotonic agents, diuretics, vasodilators) and nonpharmacological strategies (e.g., ventilatory support, ultrafiltration) [2]. Fluid overload, the primary reason for hospitalization, demands aggressive management. Although intravenous loop diuretics are the mainstay of fluid overload management [4, 5], their efficacy is often limited by diuretic resistance, suboptimal natriuretic response, and subsequent decline in estimated glomerular filtration rate (eGFR) [6, 7]. These limitations often lead to inadequate diuresis and weight reduction, contributing to frequent hospital readmissions [2, 8, 9].

In light of these therapeutic challenges, ultrafiltration has emerged as an alternative for fluid removal in decompensated heart failure with concomitant diuretic resistance, showing efficacy when used early [10]. This mechanical approach offers potential advantages, including precise control of fluid and sodium removal, reduced electrolyte disturbances compared to conventional diuretic therapy, and potential hemodynamic benefits through venous pressure reduction [9‒11]. The 2021 ESC Guidelines recommend ultrafiltration as a therapeutic option for type 1 CRS management [12]. However, evidence regarding its efficacy and safety in elderly patients with type 1 CRS remains insufficient. This study aims to compare ultrafiltration and diuretic therapy to establish evidence-based recommendations for optimal management in this vulnerable population.

This prospective pilot clinical trial enrolled consecutive patients hospitalized for Acute Decompensated Heart Failure (ADHF) with worsening renal function, meeting the criteria for type I CRS. Participants were aged >70 years and admitted to the cardiology service, regardless of underlying etiology.

Type I CRS was diagnosed using the 2008 classification by Ronco et al. [13] requiring concurrent AKI and ADHF at initial assessment. AKI was identified based on serum creatinine (sCr) elevation per Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [14], and ADHF was determined clinically [15]. Renal function deterioration was defined as sCr increase by 50% within 7 days before admission [14]. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) without racial adjustment [16], based on the most recent sCr measurement.

Inclusion criteria required at least two signs of volume overload: ≥2+ peripheral edema, jugular venous pressure >10 cm H₂O, or radiographic evidence of pulmonary edema/pleural effusion. Exclusion criteria included chronic kidney disease stage 5, current kidney replacement therapy, absence of baseline sCr values, history of organ transplantation, and pregnancy.

The study was single-blind, with outcome adjudicators blinded to treatment allocation, while patients and healthcare providers remained unblinded. Conducted at Yangzhou Friendliness Hospital and Northern Jiangsu People’s Hospital from June 2020 to June 2023, the study complied with the World Medical Association Declaration of Helsinki. Ethical approval was obtained from both Institutions’ Ethics Committees (Yangzhou Friendliness Hospital: Approval no. 2020-226; Northern Jiangsu People’s Hospital: Approval no. 2020-2-19), and written informed consent was secured from all participants before randomization.

Clinical data collection included comprehensive comorbidity assessment through direct patient interviews at initial evaluation. Daily diuresis was meticulously recorded as 24-h totals, ensuring accurate fluid balance monitoring throughout the study.

All patients were subjected to a daily fluid restriction of 2 L and a sodium restriction of 2 g. Based on physician judgment and contemporary practice guidelines, eligible patients were assigned to either ultrafiltration or diuretics [11]. The guidelines recommend ultrafiltration solely for patients exhibiting a level of diuretic resistance comparable to CARRESS-HF subjects. A poor diuretic response was defined as less than desired weight loss despite >120 mg infused furosemide [17].

Patients assigned to ultrafiltration underwent bedside ultrafiltration within 24 h of admission, discontinuing loop diuretics for the duration. This procedure involved sequential cannulation of both femoral veins to establish separate inflow and outflow circuits, with all patients receiving bilateral femoral access as per our institutional protocol for extracorporeal therapies. Specifically, the right femoral vein served as the outflow conduit (blood withdrawal) and the left femoral vein as the return conduit, with catheter positions confirmed by fluoroscopy. The lines were connected to the ultrafiltration circuit, preflushed with heparin saline. Following cannulation and heparin priming (activated clotting time: 180–230 s), the ultrafiltration rate (200–400 mL/h) was adjusted as per physician assessment. The blood flow rate was 20–40 mL/min, with each session lasting 6–8 h. Depending on the patient’s condition, 2–3 sessions were completed. The ultrafiltration equipment was the FQ-16 model (Beijing Heartcare Medical Technology Co., Ltd.) specifically configured for heart failure management, featuring dual-pump control system (blood flow range 10–100 mL/min) and pressure monitoring modules (±300 mm Hg range), using polyethersulfone membranes with 30 kDa molecular weight cutoff. The extracorporeal circulation pipeline (Jiangsu Shagang Medical Device Technology Development Co., Ltd.) had an internal diameter of 4.0 mm and total priming volume of 110 mL, combined with Hemocor HPH400 filter (Minitech Company, USA) containing 0.9 m² membrane surface area.

Both groups continued their assigned treatment until congestion symptoms were optimally reduced, with crossover discouraged. Diuresis or ultrafiltration could be adjusted or temporarily discontinued for technical or clinical reasons, as determined by the treating physician. This study has several methodological constraints that warrant acknowledgment. First, neither diuretic administration nor ultrafiltration parameters were strictly protocolized, reflecting real-world clinical practice where treatment individualization remains paramount. Second, the bilateral femoral vein access approach, while ensuring reliable extracorporeal flow rates, may limit generalizability to centers using alternative vascular access strategies.

All patients scheduled outpatient visits and telephone follow-ups at 30, 90, and 180 days post-discharge. Investigators reported all office and emergency department visits for HF and all adverse events during the 180-day follow-up period.

Efficacy outcomes included immediate (changes in weight and dyspnea score (Table 1) from baseline to 48 h posttreatment) and stable measures (length of hospital stay, unscheduled office and emergency department visits during the 180-day follow-up). Safety endpoints encompassed changes in systolic blood pressure, heart rate, sCr, blood urea nitrogen, blood potassium and sodium ion concentrations, and all adverse events, assessed pretreatment and 48 h posttreatment.

Categorical variables are reported as counts and percentages, while continuous variables are presented as mean ± SD for normal distributions or median (Q1, Q3) for non-normal distributions. Baseline clinical values were compared with those at 48 h post-therapy using SPSS 22.0. Normal data were analyzed using the independent T tests, and non-normal data were analyzed using the Mann-Whitney tests. Statistical significance was defined as p < 0.05.

A total of 167 patients who met the inclusion and exclusion criteria were enrolled in the study, among whom 159 patients had complete endpoint data available for analysis (8 patients were lost to follow-up or withdrew consent). A total of 159 patients were divided into two groups: 80 received diuretics (45 males, 35 females) and 79 underwent ultrafiltration (49 males, 30 females). Baseline characteristics were similar between the groups, with no statistically significant differences (p > 0.05; see Table 2).

Efficacy outcomes included immediate changes in weight and dyspnea score from baseline to 48 h posttreatment, as well as longer term outcomes such as hospital stay duration and heart failure-related medical visits within 180 days post-discharge. Patients in the ultrafiltration group demonstrated superior weight control compared to those in the diuretics group. At 48 h, the mean weight was 69.4 ± 8.2 kg in the ultrafiltration group and 70.2 ± 6.9 kg in the diuretics group, with significantly greater weight loss in the ultrafiltration group (5.4 kg vs. 1.2 kg, p < 0.05).

Dyspnea scores also improved more significantly in the ultrafiltration group (mean improvement: 10.2 ± 4.7 vs. 6.4 ± 2.8, p < 0.05), with scores of 12.6 ± 4.3 vs. 8.7 ± 2.4 at 48 h. Regarding stable efficacy outcomes, the ultrafiltration group had a significantly shorter mean hospital stay (5.7 ± 1.4 days vs. 9.3 ± 1.2 days, p < 0.05) and fewer heart failure-related medical visits within 180 days post-discharge (1.9 ± 0.3 vs. 3.5 ± 0.8, p < 0.05; see Table 3 and Fig. 1). A total of 9 (11.3%) patients in the ultrafiltration group required renal replacement therapy (RRT) compared to 14 (17.7%) patients in the diuretic group (p = 0.23, Table 3).

A comparison of safety indices at baseline and 48 h posttreatment revealed no significant differences between the diuretics and ultrafiltration treatment groups in systolic blood pressure (120.8 ± 23.6 mm Hg vs. 115.6 ± 18.5 mm Hg), sCr (167.3 ± 32.2 μmol/L vs. 161.5 ± 28.5 μmol/L), blood urea nitrogen level (9.8 ± 1.3 mmol/L vs. 11.9 ± 3.5 mmol/L), blood potassium ion concentration (3.9 ± 0.5 mmol/L vs. 4.5 ± 0.6 mmol/L), or blood sodium ion concentration (130.6 ± 5.1 mmol/L vs. 135.9 ± 4.6 mmol/L), except for heart rate (Table 4). No significant injection site reactions, major complications associated with the technique or major adverse cardiovascular event were observed during the study period.

Two trials – the Relief for Acutely Fluid-Overloaded Patients with Decompensated Congestive Heart Failure study and the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) study – demonstrated that ultrafiltration achieved greater fluid removal without hemodynamic instability and with alleviation of HF symptoms, albeit without improvement in kidney function [20, 21]. These results suggest a potential advantage for ultrafiltration, as it may be more efficacious in removing isotonic fluids compared to diuretics, which remove hypotonic fluids.

Subsequently, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF) randomized 188 patients with type 1 CRS to either stepped pharmacologic care or ultrafiltration. The primary endpoint was the change in sCr level and weight at 96 h. Although both strategies yielded comparable weight loss, ultrafiltration resulted in elevated sCr levels and side effects, primarily due to bleeding and intravenous catheter-related complications [22]. Unexpectedly, ultrafiltration in the CARESS-HF trial was less effective than pharmacological therapy in preserving renal function and was associated with a higher incidence of adverse events. However, this trial has been criticized because sCr levels do not necessarily reflect renal parenchymal damage, and more aggressive decongestive strategies with transient reductions in eGFR may be necessary for better long-term renal outcomes. Additionally, the ultrafiltration rate in the CARESS-HF study was fixed at 200 mL/h without adjustment, unlike the more adaptable stepped pharmacologic therapy. Our center’s practical experience shows that adjusting the ultrafiltration speed to maintain blood pressure stability can effectively reduce the risk of short-term renal deterioration.

In the subsequent Continuous Ultrafiltration for Congestive Heart Failure trial, Marenzi compared the long-term efficacy of diuretics and ultrafiltration over an extended follow-up period. Consistent with the UNLOAD trial results, the ultrafiltration group exhibited a significantly lower incidence of HF rehospitalization and stable renal function [23]. The more recent AVOID-HF trial, which compared the time to the first HF event and rehospitalization rates between diuretics and ultrafiltration in 810 patients with HF, found that the ultrafiltration group had a longer time to the first HF event but experienced more serious adverse events [24]. Unfortunately, this trial was hampered by issues such as premature termination and recruitment challenges, making its conclusions inconclusive.

Although ultrafiltration may offer benefits for fluid removal in CRS, particularly in patients unresponsive to diuretic therapy, current evidence does not support it as the primary therapy for effective decongestion in CRS. The relative shortcomings of ultrafiltration compared to diuretic therapy may be attributed to fixed rates of fluid removal, rather than adaptive control guided by volume assessment. Therefore, meticulous clinical evaluation of volume overload or venous congestion is imperative when administering ultrafiltration therapy.

Volume overload and pulmonary congestion are the primary reasons for hospitalization in most patients with acute decompensated type 1 CRS. Managing fluid retention and reducing capacity overload are essential to alleviate type 1 CRS symptoms, decrease readmission rates, and enhance quality of life [25, 26]. In this study, we observed that ultrafiltration significantly reduced volume overload and improved dyspnea scores in individuals with type 1 CRS. Notably, ultrafiltration therapy’s rapid alleviation of symptoms contributed to shortened hospital stays. Additionally, adequate dehydration treatment established a more solid foundation for subsequent pharmacological management, effectively decreasing the frequency of hospital visits due to HF exacerbations.

When comparing safety outcomes between the diuretics and ultrafiltration groups, we found no statistically significant differences, consistent with the UNLOAD study [23]. Similarly, a study by Hu et al. [27] found no significant differences in safety endpoints between early ultrafiltration and torsemide plus tolvaptan groups. However, in our investigation, patients in the ultrafiltration cohort demonstrated a notable reduction in heart rate 48 h posttreatment compared to baseline, attributed to the effective reduction of cardiac preload through adequate dehydration. Besides, as for RRT post-discharge, while not statistically significant, our study suggests a trend toward reduced RRT needs with ultrafiltration.

Multiple clinical studies have established the safety and efficacy of ultrafiltration in patients with type 1 CRS across various countries [20, 21, 23, 24]. However, research on ultrafiltration and its application for type 1 CRS in China commenced relatively later, following clinical studies that demonstrated the effectiveness and safety of the FQ-16 ultrafiltration dehydration device in alleviating sodium and water retention and relieving dyspnea and other type 1 CRS symptoms [28]. This study provides valuable information and evidence on the efficacy of ultrafiltration in elderly patients with type 1 CRS.

This study has several limitations, including a small sample size and the assessment of only short-term efficacy. Additionally, outcomes such as ejection fraction, B-type natriuretic peptide levels, were not evaluated, limiting the study’s comparability with other literature. Based on these promising findings, we intend to evaluate the long-term efficacy of ultrafiltration in future research. Furthermore, as this study only included elderly patients, the efficacy and safety results may not be generalizable to other geographic regions. Nonetheless, ultrafiltration demonstrated superior efficacy in patients with type 1 CRS compared to conventional therapy. Larger, multicenter studies with longer follow-up periods are necessary to validate these findings.

Although clinical studies have demonstrated the effectiveness of decongestive therapy in managing volume overload and improving symptoms in patients with CRS, the impact of diuretics and ultrafiltration in elderly patients remains unclear. In elderly patients specifically diagnosed with type 1 CRS, ultrafiltration has proven to be an effective and safe treatment option compared to diuretics. Further research is urgently needed to explore the potential role of ultrafiltration in the management of CRS.

Ethical approval was obtained from both Institutions’ Ethics Committees (Yangzhou Friendliness Hospital: Approval No. 2020-226; Northern Jiangsu People’s Hospital: Approval No. 2020-2-19), and written informed consent was secured from all participants before randomization.

All authors have no conflict of interest.

This study was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0513700), National Health Commission of the People’s Republic of China, Key Disciplines Group Construction Project of Shanghai Pudong New Area Health Commission (PWZxq2022-02), and the Key Research Center Construction Project of Shanghai (2022ZZ01008).

Zhen Wang and Hongxiao Li contributed in the conception and design of the study. Zhen Wang and Lijuan Xu contributed in data acquisition and analysis. Lei Sun, Bin Liu, and Hongxiao Li were involved in drafting and critically critical revision of the manuscript. All authors approved the final version of the manuscript submitted and agree to be accountable for all aspects of the work.

Lijuan Xu and Zhen Wang contributed equally to this work.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author Dr. Hongxiao Li upon reasonable request.