Abstract
Sepsis often causes sepsis-associated acute kidney injury (S-AKI) and is a leading cause of death in critically ill cancer patients. This study aims to assess the prognostic value of loop diuretic use in cancer patients with S-AKI. A retrospective cohort of 117 cancer patients with S-AKI admitted to the ICU between 2009 and 2023 was analyzed. Among them, 90 patients treated with loop diuretics were categorized into four groups according to AKI stage and furosemide dose: early-stage with low-dose, early-stage with high-dose, late-stage with low-dose, and late-stage with high-dose. Additionally, 27 early-stage patients who did not receive diuretics were included as a comparator group. The primary outcome was 28-day mortality. Patients receiving low-dose furosemide at early-stage AKI had significantly lower 28-day mortality (22.7%, p = 0.049), lower CRRT initiation (18.2 vs. 44.0, 76.2, and 81.8%, p = 0.001), and higher shock reversal (83.3%, p = 0.042), with no difference in ICU stay (p = 0.276). In early-stage patients treated with low-dose furosemide who did not require CRRT, serum creatinine (p = 0.030) and lactate (p = 0.002) declined significantly, while urine output markedly increased (p < 0.0001) during the first three ICU days. Compared with early-stage patients who did not receive diuretics, the low-dose group also showed lower 28-day mortality (22.7%, p = 0.039). These findings suggest that low-dose loop diuretics administered in the early stage of S-AKI (stages 1 and 2) may improve survival and renal function in cancer patients, warranting confirmation in large-scale prospective randomized controlled trials.
Keywords: Sepsis-associated acute kidney injury, loop diuretics, cancer, intensive care unit
Introduction
With advances in cancer therapies, the survival time of cancer patients has significantly increased. In China, the five-year survival rate improved from 30.9 to 40.5% between 2003 and 2015 [1]. With the increasing complexity of cancer care, a growing number of patients require intensive care unit (ICU) admission for complications, such as postoperative recovery, respiratory failure, or sepsis. Sepsis is an independent risk factor for ICU mortality in cancer patients [2], with reported 30-day and 1-year mortality rates as high as 52.1 and 81.3%, respectively [3].
Sepsis was defined at the 2016 Third International Consensus on Infections as a life-threatening organ dysfunction caused by a dysregulated host response to infection [4]. Sepsis-associated acute kidney injury (S-AKI) occurs in ∼45–70% of septic patients and is independently associated with worse outcomes [5]. Patients with S-AKI have significantly higher in-hospital mortality and longer hospital stays compared to those without sepsis-related AKI [6,7]. According to the 28th Acute Disease Quality Initiative (ADQI) [6], S-AKI is a heterogeneous syndrome driven by infection, host response, or treatment complications.
The prevention of S-AKI remains centered on the treatment of sepsis and early fluid resuscitation, which relies on the appropriate use of resuscitative fluids and vasoactive agents [8]. While fluid resuscitation is central to sepsis management, excessive fluid can result in fluid overload (FO), contributing to renal venous congestion, impaired perfusion, and further kidney injury. The 28th ADQI [6] also recommends that for S-AKI patients experiencing fluid overload, the use of loop diuretics, such as furosemide, may be considered to maintain fluid balance.
Furosemide, the most commonly used loop diuretic, promotes natriuresis and diuresis by inhibiting sodium reabsorption in the loop of Henle. It also reduces renal oxygen consumption and improves renal perfusion, particularly in ischemic settings, by decreasing tubular workload and enhancing cortical blood flow through prostaglandin-mediated vasodilation [9–12]. In ICUs, furosemide is commonly used for acute pulmonary edema, AKI, and circulatory overload [13,14], though studies on its efficacy and safety present mixed results [15]. Recent studies emphasize the prognostic implications of fluid overload, suggesting that achieving a negative fluid balance through diuretic therapy may improve outcomes [16,17]. For instance, low-dose furosemide combined with aminophylline was reported to reduce mortality in septic shock, though renal function benefit was limited [18].
Overall, studies on the use of loop diuretics for treating S-AKI or circulatory overload show conflicting results, with the timing and dosage of loop diuretics remaining unclear.
To date, few studies have systematically evaluated the therapeutic use of loop diuretics in oncology patients with S-AKI. Furthermore, the efficacy and safety of loop diuretics for treating S-AKI in oncology patients have not been systematically evaluated. This study aims to explore the use of loop diuretics in the treatment of S-AKI in cancer patients. We believe that our findings can serve as a foundation for future investigations, and we encourage subsequent large-scale, prospective randomized clinical trials to validate and expand upon our observations. It is our hope that this work may inspire and contribute to ongoing academic dialogue in the field.
Methods
Subjects
A total of 117 cancer patients with S-AKI admitted to the ICU at Sun Yat-Sen University Cancer Center between June 2009 and June 2023 were included (Figure 1). Our inclusion criteria were as follows: patients with a confirmed cancer diagnosis; sepsis diagnosed according to the Sepsis 3.0 guidelines (2016) [4]; and AKI diagnosed according to the KDIGO criteria (2023) [19]. Patients were excluded if they met any of the following criteria: ICU stay duration of <24 h; age under 18 years; primary cause of death attributed to acute coronary syndrome, acute cerebral infarction, or cerebral hemorrhage; poor primary tumor control resulting in rapid tumor progression; or history of severe cardiac insufficiency, significant hepatic or renal dysfunction, or chronic kidney disease. Of these patients, 90 who received loop diuretics were included in the primary analysis and categorized into four groups according to AKI stage and furosemide dosage. Additionally, a comparator group of 27 early-stage AKI patients who did not receive diuretics was included for supplementary comparison.
Figure 1.
Flowchart of patient selection and grouping. Patients were grouped by loop diuretic use, AKI stage, and maximum daily diuretic dose. The 100 mg/day cutoff was defined by ROC analysis.
Outcome
The primary outcome of this study was 28-day all-cause mortality. Secondary outcomes included continuous renal replacement therapy (CRRT) initiation rate, shock occurrence rate, shock reversal rate, ICU length of stay, and renal recovery. To ensure a homogeneous study population, patients with non-sepsis-related deaths, such as those caused by acute coronary syndrome, acute cerebral infarction, cerebral hemorrhage, or rapidly progressive malignancies due to poor tumor control were excluded during the screening stage. As a result, all deaths in the final cohort were attributable to complications related to sepsis.
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center (No. SL-B2021-410-01). Individual consent for this retrospective analysis was waived.
Data collection
In this study, data collected included patients’ demographic information, past medical history, tumor staging and treatment plan, infection sites, the use of vasoactive drugs and antibiotics, laboratory and imaging results. Baseline laboratory parameters, including complete blood count and serum biochemistry (such as serum creatinine and lactate), were defined as the results obtained on the day of ICU admission. The highest Acute Physiology and Chronic Health Evaluation II (APACHE-II) score within 24 h of meeting inclusion criteria, ICU length of stay, and duration of shock (shock reversal defined as maintaining systolic blood pressure ≥90 mmHg for at least 24 h without vasopressor support) were also recorded.
Patient grouping and study flow
A total of 117 cancer patients with S-AKI admitted to the ICU between June 2009 and June 2023 met the inclusion criteria. Of these, 90 patients received loop diuretics and were categorized into subgroups based on AKI stage and furosemide dosage, while 27 early-stage AKI patients who did not receive loop diuretics served as the comparator group. On the day of ICU admission, AKI staging was determined by attending clinicians according to the KDIGO criteria, based on the patients’ laboratory and clinical parameters. Loop diuretic dosage was categorized based on the maximum daily dose administered within the first 7 days after ICU admission, rather than cumulative doses or dose adjustments over time. Ten milligrams of intravenous torsemide is equivalent to 20 mg of furosemide in diuretic effect. The cutoff for loop diuretic dosage was determined via receiver operating characteristic (ROC) curve analysis to optimize sensitivity and specificity for clinical outcomes, rather than being arbitrarily selected or based on the median dose, and was set at 100 mg/day. For patients who received loop diuretics, subgrouping was further performed based on stage of AKI (early stage: AKI stages 1 and 2; late stage: AKI stage 3) and the total daily dose of furosemide (low dose:≤100 mg/day; high dose: >100 mg/day), all patients were divided into four groups: early-stage AKI with low-dose loop diuretics (n = 22), early-stage with high-dose (n = 25), late-stage with low-dose (n = 21), and late-stage with high-dose (n = 22). Additionally, a comparator group of early-stage AKI patients who did not receive any loop diuretics (n = 27) was included in the analysis (Figure 1).
Treatment
Continuous renal replacement therapy (CRRT)
Patients who required CRRT received treatment based on standard guidelines, which included specifications on the machine and filter used, treatment modality, anticoagulation method, treatment dosage, replacement fluids, and criteria for discontinuation. In our setting, CRRT was performed in the ICU by physicians who have both clinical experience in CRRT and in managing sepsis-related acute kidney injury in critically ill cancer patients. Additionally, oncologists, nurses, and emergency department physicians were involved in the care of these patients. The primary indications for initiating CRRT included volume overload unresponsive to diuretic therapy, refractory hyperkalemia (serum potassium >6.5 mmol/L) despite medical management, severe metabolic acidosis (pH < 7.2) not corrected by conservative measures, and uremic complications, such as encephalopathy or pericarditis. These indications align with established guidelines for CRRT initiation in critically ill patients.
Loop diuretic therapy
Diuretic administration was determined by the attending intensivists based on individualized clinical judgment, considering factors, such as fluid overload, urine output, and overall hemodynamic stability. All patients had undergone standard sepsis fluid resuscitation upon ICU admission and were clinically assessed to be hypervolemic at the time of loop diuretic initiation. All patients received loop diuretics within the first 7 days of ICU admission, with treatment durations ranging from 3 to 5 days. In this study, 90 patients received furosemide (2 mL, 20 mg), manufactured by Sancai Shiqi Pharmaceutical Co., Ltd., Zhongshan, China. Additionally, 16 patients were treated with torsemide (4 mL, 20 mg), manufactured by Youcare Pharmaceutical Group Co., Ltd., Nanjing, China. To date, no established clinical guidelines specify definitive indications for loop diuretic use in the setting of S-AKI; thus, this study was designed as a hypothesis-generating investigation to explore the potential benefits of early low-dose administration in patients with early-stage S-AKI.
Sepsis treatment
Following the diagnosis of sepsis, all patients received standard sepsis treatments in accordance with the Surviving Sepsis Campaign guidelines, including antibiotics, fluid resuscitation, mechanical ventilation, and vasopressors.
Statistical analysis
All baseline-eligible cancer patients with sepsis-associated acute kidney injury were included in this analysis. Data analysis was performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R programming language (version 4.3.1). All statistical tests were two-sided, with a significance level set at p < 0.05. Continuous variables were analyzed using analysis of variance (ANOVA) or the Kruskal-Wallis H test, while categorical variables were analyzed using the chi-square test or Fisher’s exact test. Kaplan-Meier curves with the log-rank test were used to compare 28-day mortality rates across the different patient groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models.
Results
Baseline characteristics of cancer patients with S-AKI
This retrospective study included 90 cancer patients with S-AKI who received loop diuretics (Table 1) at Sun Yat-Sen University Cancer Center between June 2009 and June 2023. Patients were stratified into four groups based on AKI stage and diuretic dosage: early-stage with low-dose (n = 22), early-stage with high-dose (n = 25), late-stage with low-dose (n = 21), and late-stage with high-dose (n = 22). The cohort was predominantly male (75.6%), with no significant gender differences across groups. The mean age was 59.1 ± 11.98 years (p = 0.204). Baseline clinical parameters, including heart rate, respiratory rate, and mean arterial pressure, were similar across all groups (p > 0.05). Hypertension (31.1%) and diabetes (15.6%) were the most common comorbidities. Tumor types included abdominal (35.6%), thoracic (23.3%), and hematologic malignancies (21.1%), with 42.2% of patients presenting with stage IV tumors. Infection sites were primarily pulmonary (72.2%), followed by abdominal (15.6%) and bloodstream infections (6.7%). No significant differences were found between groups regarding infection sites, pathogens, tumor characteristics, or comorbidities (p > 0.05). All patients received standard sepsis management, including fluid resuscitation and antibiotics. Mechanical ventilation was required in 74.4% of patients, and 85.6% received norepinephrine, with no differences between groups. The mean SOFA score was 14.1 ± 4.18, and the APACHE II score recorded within the first 24 h of ICU admission did not differ significantly between groups (p = 0.224 and p = 0.246), indicating comparable disease severity across the cohort. No significant differences were observed in baseline demographic or clinical characteristics between early-stage AKI patients who received loop diuretics and those who did not. Age, sex, comorbidities, tumor type and stage, infection site, SOFA score, APACHE II score, and use of vasopressors or mechanical ventilation were comparable between the two groups (Table 2).
Table 1.
Demographic characteristics of S-AKI patients treated with loop diuretics.
| Characteristics | Total | Early-stages AKI |
Late-stage AKI |
p-Valve | ||
|---|---|---|---|---|---|---|
| Low-dose loop diuretic (n = 22) | High-dose loop diuretic (n = 25) | Low-dose loop diuretic (n = 21) | High-dose loop diuretic (n = 22) | |||
| Sex (%) | 0.154 | |||||
| Male | 68 (75.6) | 16 (72.7) | 19 (76.0) | 13 (61.9) | 20 (90.9) | |
| Female | 22 (24.4) | 6 (27.3) | 6 (24.0) | 8 (38.1) | 2 (9.1) | |
| Age (years) | 59.1 (11.98) | 61.5 (10.48) | 61.4 (11.83) | 54.8 (15.97) | 58.1 (7.97) | 0.204 |
| Hight, cm (mean ± SD) | 166.2 (6.61) | 166.0 (5.95) | 167.0 (6.52) | 164.3 (7.83) | 167.3 (6.10) | 0.440 |
| Weight, kg (mean ± SD) | 60.7 (12.98) | 58.0 (10.02) | 57.7 (11.51) | 65.4 (17.89) | 62.4 (10.59) | 0.145 |
| Vital signs (mean ± SD) | ||||||
| HR (bpm) | 125.2 (26.26) | 133.7 (24.86) | 125.7 (26.83) | 121.3 (28.64) | 120.0 (24.10) | 0.303 |
| RR (bpm) | 24.8 (6.17) | 23.7 (6.32) | 25.8 (5.68) | 24.0 (5.90) | 25.6 (6.91) | 0.569 |
| MAP (mmHg) | 69.5 (18.59) | 70.7 (21.10) | 67.3 (15.33) | 73.2 (21.33) | 67.2 (17.06) | 0.660 |
| Underlying disease (%) | ||||||
| HBP | 28 (31.1) | 4 (18.2) | 8 (32.0) | 7 (33.3) | 9 (40.9) | 0.425 |
| CHD | 6 (6.7) | 3 (13.6) | 0 (0.0) | 2 (9.5) | 1 (4.5) | 0.204 |
| DM | 14 (15.6) | 3 (13.6) | 1 (4.0) | 4 (19.0) | 6 (27.3) | 0.146 |
| HBV | 7 (7.8) | 3 (13.6) | 2 (8.0) | 1 (4.8) | 1 (4.5) | 0.735 |
| Tumor (%) | 0.560 | |||||
| Thoracic | 21 (23.3) | 6 (27.3) | 7 (28.0) | 2 (9.5) | 6 (27.3) | |
| Abdominal | 32 (35.6) | 9 (40.9) | 4 (16.0) | 10 (47.6) | 9 (40.9) | |
| Hematologic | 19 (21.1) | 2 (9.1) | 11 (44.0) | 3 (14.3) | 3 (13.6) | |
| Others | 18 (20.0) | 5 (22.7) | 3 (12.0) | 6 (28.6) | 4 (18.2) | |
| Solid tumor stage (%) | 0.096 | |||||
| Stage 0 | 18 (20.0) | 1 (4.5) | 11 (44.0) | 3 (14.3) | 3 (13.6) | |
| Stage I | 10 (11.1) | 2 (9.1) | 2 (8.0) | 3 (14.3) | 3 (13.6) | |
| Stage II | 6 (6.7) | 3 (13.6) | 1 (4.0) | 0 (0.0) | 2 (9.1) | |
| Stage III | 18 (20.0) | 5 (22.7) | 4 (16.0) | 3 (14.3) | 6 (27.3) | |
| Stage IV | 38 (42.2) | 11 (50.0) | 7 (28.0) | 12 (57.1) | 8 (36.4) | |
| Tumor treatment (%) | 0.359 | |||||
| Chemotherapy | 30 (33.3) | 8 (36.4) | 9 (36.0) | 4 (19.0) | 9 (40.9) | |
| Surgery | 23 (25.6) | 7 (31.8) | 3 (12.0) | 7 (33.3) | 6 (27.3) | |
| Comprehensive | 37 (41.1) | 7 (31.8) | 13 (52.0) | 10 (47.6) | 7 (31.8) | |
| Myelosuppression grade (%) | 0.613 | |||||
| Grade 0 | 11 (12.2) | 4 (18.2) | 1 (4.0) | 5 (23.8) | 1 (4.5) | |
| Grade I | 3 (3.3) | 1 (4.5) | 1 (4.0) | 1 (4.8) | 0 (0.0) | |
| Grade II | 8 (8.9) | 2 (9.1) | 2 (8.0) | 2 (9.5) | 2 (9.1) | |
| Grade III | 14 (15.6) | 5 (22.7) | 4 (16.0) | 2 (9.5) | 3 (13.6) | |
| Grade IV | 54 (60.0) | 10 (45.5) | 17 (68.0) | 11 (52.4) | 16 (72.7) | |
| Transfusion of blood products (%) | 0.420 | |||||
| No | 16 (17.18) | 2 (9.1) | 4 (16.0) | 6 (28.6) | 4 (18.2) | |
| Yes | 74 (82.2) | 20 (90.9) | 21 (84.0) | 15 (71.4) | 18 (81.8) | |
| GM-CSF (%) | 0.066 | |||||
| No | 47 (52.2) | 12 (54.5) | 8 (32.0) | 15 (71.4) | 12 (54.5) | |
| Yes | 43 (47.8) | 10 (45.5) | 17 (68.0) | 6 (28.6) | 10 (45.5) | |
| Site of infection (%) | 0.249 | |||||
| Lung | 65 (72.2) | 10 (45.5) | 21 (84.0) | 16 (76.2) | 18 (81.8) | |
| Abdominal | 14 (15.6) | 7 (31.8) | 2 (8.0) | 3 (14.3) | 2 (9.1) | |
| Bloodstream | 6 (6.7) | 3 (13.6) | 1 (4.0) | 1 (4.8) | 1 (4.5) | |
| Undefined | 5 (5.6) | 2 (9.1) | 1 (4.0) | 1 (4.8) | 1 (4.5) | |
| Culture of humoral specimen (%) | 0.452 | |||||
| Undefined | 18 (20.0) | 2 (9.1) | 4 (16.0) | 7 (33.3) | 5 (22.7) | |
| Gram-positive bacteria | 11 (12.2) | 2 (9.1) | 4 (16.0) | 4 (19.0) | 1 (4.5) | |
| Gram-negative bacteria | 34 (37.8) | 12 (54.5) | 9 (36.0) | 5 (23.8) | 8 (36.4) | |
| Fungi | 27 (30.0) | 6 (27.3) | 8 (32.0) | 5 (23.8) | 8 (36.4) | |
| PCT, ng/ml (median [IQR]) | 15.5 [3.73, 30.92] | 21.6 [7.80,52.69] | 8.6 [2.00,19.70] | 17.8 [2.33, 28.70] | 17.4 [5.07, 31.81] | 0.117 |
| The biochemical test | ||||||
| Sodium, mmol/L (mean ± SD) | 138.9 (9.01) | 140.1 (9.32) | 140.2 (8.36) | 135.2 (6.55) | 139.7 (10.89) | 0.200 |
| Potassium, mmol/L (mean ± SD) | 4.5 (1.40) | 4.4 (1.44) | 4.1 (0.95) | 5.0 (1.68) | 4.7 (1.41) | 0.096 |
| ALT, U/L (median [IQR]) | 47.7 [23.50, 350.80] | 35.9 [28.50, 131.10] | 39.3 [23.00, 116.10] | 47.4 [21.10, 351.90] | 320.3 [21.20, 1,298.00] | 0.287 |
| ALB, g/L (mean ± SD) | 28.4 (5.16) | 28.3 (4.38) | 28.9 (6.20) | 29.4 (4.46) | 26.9 (5.20) | 0.414 |
| TBIL, umol/L (median [IQR]) | 27.8 [13.43, 83.38] | 24.8 [15.20, 40.45] | 38.4 [13.50, 111.90] | 23.6 [10.80, 37.30] | 37.9 [13.67, 155.35] | 0.374 |
| CRP, mg/L (mean ± SD) | 180.4 (107.81) | 194.8 (105.25) | 136.1 (90.56) | 180.7 (117.62) | 217.6 (108.17) | 0.066 |
| Complete blood count | ||||||
| WBC, ×109/L (median [IQR]) | 12.4 [5.62, 19.05] | 8.9 [2.97, 17.82] | 12.7 [4.80,17.40] | 12.3 [9.51, 20.82] | 13.8 [7.24, 20.53] | 0.512 |
| HGB, g/L (mean ± SD) | 90.5 (25.47) | 97.4 (25.87) | 87.1 (24.00) | 96.9 (30.12) | 81.3 (19.06) | 0.097 |
| PLT, ×109/L (median [IQR]) | 83.0 [25.25, 176.50] | 106.0 [35.67, 179.50] | 50.0 [12.00, 177.00] | 150.0 [53.00, 181.00] | 59.6 [26.25, 128.50] | 0.271 |
| Arterial blood gas analysis | ||||||
| PH (mean ± SD) | 7.3 (0.14) | 7.4 (0.13) | 7.3 (0.14) | 7.3 (0.12) | 7.3 (0.17) | 0.235 |
| Lactate, mmol/L (median [IQR]) | 5.1 [3.23, 9.12] | 5.1 [4.15, 6.78] | 5.1 [2.90, 10.00] | 5.5 [3.40, 9.09] | 4.8 [2.33, 9.43] | 0.958 |
| Treatment of sepsis (%) | ||||||
| Fluid resuscitation | 90 (100) | 22 (100) | 25 (100) | 21 (100) | 22 (100) | 1 |
| Antibiotic therapy | 90 (100) | 22 (100) | 25 (100) | 21 (100) | 22 (100) | 1 |
| Mechanical ventilation | 67 (74.4) | 15 (68.2) | 20 (80) | 12 (57.1) | 20 (90) | 0.630 |
| Norepinephrine therapy | 77 (85.6) | 18 (81.8) | 23 (92) | 20 (95.2) | 16 (72.7) | 0.132 |
| SOFA Score (mean ± SD) | 14.1 (4.18) | 15.3 (2.86) | 12.8 (4.23) | 14.1 (4.93) | 14.4 (4.33) | 0.224 |
| APACHE II Score (mean ± SD) | 31.3 (8.06) | 31.7 (5.91) | 28.8 (7.80) | 31.7 (9.04) | 33.5 (8.94) | 0.246 |
SOFA: Sequential Organ Failure Score; APACHE II: Acute Physiology and Chronic Health Score; HR: heart rate; RR: respiratory rate; MAP: mean arterial pressure; HBP: hypertension; CHD: coronary heart disease; DM: diabetes mellitus; HBV: hepatitis B virus; GM-CSF: granulocyte-macrophage colony-stimulating factor; ALT: alanine aminotransferase; ALB: albumin; TBIL: total bilirubin; CRP: C-reactive protein; WBC: white blood cell; HGB: hemoglobin; PLT: platelet; IQR: interquartile range; PCT: procalcitonin; pH: potential of hydrogen. Baseline vital signs, laboratory results, and exposure variables were assessed on the day of ICU admission, prior to AKI diagnosis.
Table 2.
Demographic characteristics of early-stage S-AKI with/without loop diuretic.
| Characteristics | Early-stage AKI with low-dose loop diuretic (n = 22) | Early-stage AKI without low-dose loop diuretic (n = 27) | p-Valve |
|---|---|---|---|
| Gender (%) | 0.549 | ||
| Male | 16 (72.7) | 17 (63.0) | |
| Female | 6 (27.3) | 10 (37.0) | |
| Age, years (mean ± SD) | 61.5 (10.48) | 55.63 (13.91) | 0.109 |
| Hight, cm (mean ± SD) | 166.0 (5.95) | 164.44 (6.84) | 0.42 |
| Weight, kg (mean ± SD) | 58.0 (10.02) | 60.98 (11.41) | 0.34 |
| AKI (%) | 0.782 | ||
| Stage 1 | 9 (40.9) | 10 (37) | |
| Stage 2 | 13 (59.1) | 17 (63) | |
| Vital signs (mean ± SD) | |||
| HR (bpm) | 133.7 (24.86) | 127.07 (25.60) | 0.364 |
| RR (bpm) | 23.7 (6.32) | 25.52 (12.08) | 0.523 |
| MAP (mmHg) | 70.7 (21.10) | 77.37 (22.56) | 0.297 |
| Underlying disease (%) | |||
| HBP | 4 (18.2) | 5 (18.5) | 1 |
| CHD | 3 (13.6) | 1 (3.7) | 0.314 |
| DM | 3 (13.6) | 1 (3.7) | 0.314 |
| HBV | 3 (13.6) | 3 (11.1) | 1 |
| Tumor (%) | 0.344 | ||
| Thoracic | 6 (27.3) | 3 (11.1) | |
| Abdominal | 9 (40.9) | 9 (33.3) | |
| Hematologic | 2 (9.1) | 6 (22.2) | |
| Others | 5 (22.7) | 9 (33.3) | |
| Solid tumor stage (%) | 0.214 | ||
| Stage 0 | 1 (4.5) | 6 (22.2) | |
| Stage I | 2 (9.1) | 0 (0.0) | |
| Stage II | 3 (13.6) | 2 (7.4) | |
| Stage III | 5 (22.7) | 4 (14.8) | |
| Stage IV | 11 (50.0) | 15 (55.6) | |
| Tumor treatment (%) | 1 | ||
| Chemotherapy | 8 (36.4) | 10 (37.0) | |
| Surgery | 7 (31.8) | 8 (29.6) | |
| Comprehensive | 7 (31.8) | 9 (33.3) | |
| Myelosuppression grade (%) | 0.428 | ||
| Grade 0 | 4 (18.2) | 2 (7.4) | |
| Grade I | 1 (4.5) | 0 (0.0) | |
| Grade II | 2 (9.1) | 6 (22.2) | |
| Grade III | 5 (22.7) | 5 (18.5) | |
| Grade IV | 10 (45.5) | 14 (51.9) | |
| Transfusion of blood products (%) | 0.159 | ||
| No | 2 (9.1) | 7 (25.9) | |
| Yes | 20 (90.9) | 20 (74.1) | |
| GM-CSF (%) | 0.779 | ||
| No | 12 (54.5) | 16 (59.3) | |
| Yes | 10 (45.5) | 11 (40.7) | |
| Site of infection (%) | 0.659 | ||
| Lung | 10 (45.5) | 17 (63.0) | |
| Abdominal | 7 (31.8) | 6 (22.2) | |
| Bloodstream | 3 (13.6) | 3 (11.1) | |
| Undefined | 2 (9.1) | 1 (3.7) | |
| Culture of humoral specimen (%) | 0.843 | ||
| Undefined | 2 (9.1) | 5 (18.5) | |
| Gram-positive bacteria | 2 (9.1) | 2 (7.4) | |
| Gram-negative bacteria | 12 (54.5) | 13 (48.1) | |
| Fungi | 6 (27.3) | 7 (25.9) | |
| PCT, ng/ml (median [IQR]) | 21.6 [7.80,52.69] | 28.70 [10.38, 41.74] | 0.968 |
| The biochemical test | |||
| Sodium, mmol/L (mean ± SD) | 140.1 (9.32) | 136.58 (7.93) | 0.158 |
| Potassium, mmol/L (mean ± SD) | 4.4 (1.44) | 4.31 (1.25) | 0.912 |
| ALT, U/L (median [IQR]) | 35.9 [28.50, 131.10] | 41.20 [19.40, 123.90] | 0.92 |
| ALB, g/L (mean ± SD) | 28.3 (4.38) | 30.50 (5.16) | 0.117 |
| TBIL, umol/L (median [IQR]) | 24.8 [15.20, 40.45] | 18.50 [9.50, 25.35] | 0.134 |
| CRP, mg/L (mean ± SD) | 194.8 (105.25) | 152.73 (91.76) | 0.142 |
| Complete blood count | |||
| WBC × 109/L (median [IQR]) | 8.9 [2.97, 17.82] | 11.30 [3.76, 13.80] | 0.904 |
| HGB, g/L (mean ± SD) | 97.4 (25.87) | 86.09 (20.12) | 0.091 |
| PLT × 109/L (median [IQR]) | 106.0 [35.67, 179.50] | 69.00 [32.65, 181.70] | 0.702 |
| Arterial blood gas analysis | |||
| PH (mean ± SD) | 7.4 (0.13) | 7.36 (0.08) | 0.901 |
| Lactate, mmol/L (median [IQR]) | 5.1 [4.15, 6.78] | 4.40 [1.60, 5.84] | 0.056 |
| Treatment of sepsis (%) | |||
| Fluid resuscitation | 22 (100) | 27 (100.0) | 1 |
| Antibiotic therapy | 22 (100) | 27 (100.0) | 1 |
| Mechanical ventilation | 15 (68.2) | 14 (51.9) | 0.381 |
| Norepinephrine therapy | 18 (81.8) | 19 (70.4) | 0.507 |
| SOFA Score (mean ± SD) | 15.3 (2.86) | 14.59 (4.01) | 0.507 |
| APACHE II Score (mean ± SD) | 31.7 (5.91) | 30.22 (5.94) | 0.381 |
SOFA: Sequential Organ Failure Score; APACHE II: Acute Physiology and Chronic Health Score; AKI: acute kidney injury; HR: heart rate; RR: respiratory rate; MAP: mean arterial pressure; HBP: hypertension; CHD: coronary heart disease; DM: diabetes mellitus; HBV: hepatitis B virus; GM-CSF: granulocyte-macrophage colony-stimulating factor; ALT: alanine aminotransferase; ALB: albumin; TBIL: total bilirubin; CRP: C-reactive protein; WBC: white blood cell; HGB: hemoglobin; PLT: platelet; IQR: interquartile range; PCT: procalcitonin; pH: potential of hydrogen. Baseline vital signs, laboratory results, and exposure variables were assessed on the day of ICU admission, prior to AKI diagnosis.
In this study, serum creatinine was incorporated into AKI staging based on the 2023 KDIGO criteria. GFR and urea, both indicators related to renal function, were not included in the analysis because GFR estimation formulas are unreliable in acute kidney injury, particularly in critically ill patients, and urea has low specificity and is susceptible to multiple non-renal influences.
28-day mortality: S-AKI patients treated with loop diuretics
This study revealed a 28-day mortality rate of 22.7% in the early-stage with low-dose group, compared to 56.0% in the early-stage with high-dose group, 33.3% in the late-stage with low-dose group, and 59.0% in the late-stage with high-dose group. Kaplan-Meier survival analysis demonstrated that the early-stage with low-dose group had a significantly lower mortality rate than the other groups (log-rank test: χ2 = 7.865, p = 0.049) (Figure 2).
Figure 2.
Kaplan-Meier curve analysis of 28-day mortality in the early-stage AKI + low-dose loop diuretic group, the early-stage AKI + high-dose loop diuretic group, the late-stage AKI + low-dose loop diuretic group, the late-stage AKI + high-dose loop diuretic group (log-rank test: χ2 = 7.865, p = 0.049). Time 0 was defined as the day of ICU admission.
Cox regression analysis: S-AKI patients treated with loop diuretics
Using Cox regression analysis, Model 1 was established to adjust for the effects of age and sex. Model 2 further adjusted for additional factors, including height, weight, tumor type, tumor stage, cancer treatment modality, SOFA score, APACHE II score, fluid resuscitation, antibiotic use, norepinephrine administration, mechanical ventilation, CRRT, and infection site. Results showed that, compared to the early-stage with low-dose group, the mortality risk increased in the early-stage with high-dose group, the late-stage with low-dose group, and the late-stage with high-dose group, with respective HRs and 95% CIs of 6.736 (1.735–26.154), 3.034 (0.668–13.782), and 6.228 (1.613–24.050) (Table 3).
Table 3.
Association of group with 28-day mortality in S-AKI patients treated with loop diuretics.
| Group | N | Model 1 | Model 2 |
|---|---|---|---|
| Early-stage AKI + low-dose loop diuretic | 22 | 1 | 1 |
| Early-stage AKI + high-dose loop diuretic | 25 | 3.67 (1.306–10.317) | 6.736 (1.735–26.154)• |
| Late-stage AKI + low-dose loop diuretic | 21 | 1.208 (0.368–3.958) | 3.034 (0.668–13.782)* |
| Late-stage AKI + high-dose loop diuretic | 22 | 3.60 (1.248–10.393) | 6.228 (1.613–24.050)# |
Model 1 adjusted for age and sex; Model 2 further adjusted for height, weight, tumor type, tumor stage, tumor treatment modality, SOFA score, Apache II score, fluid resuscitation, antibiotics, norepinephrine, mechanical ventilation, CRRT initiation, and site of infection based on Model 1. .p = 0.006; *p = 0.151; #p = 0.008.
CRRT initiation rate: S-AKI patients treated with loop diuretics
The CRRT initiation rate was 18.2% (four cases) in the early-stage with low-dose group, 44.0% (11 cases) in the early-stage with high-dose group, 76.2% (16 cases) in the late-stage with low-dose group, and 81.8% (18 cases) in the late-stage with high-dose group. The early-stage with low-dose group had a significantly lower CRRT initiation rate compared to the other groups (p = 0.001) (Table 4).
Table 4.
Hospitalization observation indicators and secondary observation indicators in S-AKI patients treated with loop diuretics.
| Characterization | Early-stages AKI |
Late-stage AKI |
p-Valve | ||
|---|---|---|---|---|---|
| Low-dose loop diuretic (n = 22) | High-dose loop diuretic (n = 25) | Low-dose loop diuretic (n = 21) | High-dose loop diuretic (n = 22) | ||
| Primary observation index | |||||
| 28-day mortality | 5 (22.7%) | 14 (56.0%) | 7 (33.3%) | 13 (59.0%) | 0.049 |
| Secondary observations | |||||
| CRRT uptake rate | 4 (18.2%) | 11 (44.0%) | 16 (76.2%) | 18 (81.8%) | 0.001 |
| Shock incidence | 12 (54.5%) | 23 (92.0%) | 11 (52.4%) | 15 (68.2%) | 0.013 |
| Shock reversal rate | 10 (83.3%) | 8 (34.8%) | 7 (63.6%) | 7 (46.7%) | 0.042 |
| ICU length of stay | 8.5 (4.3,14.0) | 10 (5.0, 30) | 8 (5.0, 12.0) | 13 (5.0, 20.3) | 0.276 |
Shock occurrence rate: S-AKI patients treated with loop diuretics
Shock occurred in 54.5% (12 cases) of the early-stage with low-dose group, 92.0% (23 cases) of the early-stage with high-dose group, 52.4% (11 cases) of the late-stage with low-dose group, and 68.2% (15 cases) of the late-stage with high-dose group. The incidence of shock differed significantly among the four groups (p = 0.013) (Table 4).
Shock reversal rate: S-AKI patients treated with loop diuretics
The shock reversal rate was 83.3% (10 cases) in the early-stage with low-dose group, 34.8% (eight cases) in the early-stage with high-dose group, 63.6% (seven cases) in the late-stage with low-dose group, and 46.7% (seven cases) in the late-stage with high-dose group. The early-stage with low-dose group demonstrated a significantly higher shock reversal rate compared to the other groups (p = 0.042) (Table 4).
ICU length of stay: S-AKI patients treated with loop diuretics
The median ICU stay was 8.5 days in the early-stage with low-dose group, 10 days in the early-stage with high-dose group, 8 days in the late-stage with low-dose group, and 13 days in the late-stage with high-dose group. No statistically significant difference in ICU stay duration was observed among the four groups (p = 0.276) (Table 4).
Trends in creatinine, lactate, and urine output in early-stage AKI patients treated with low-dose furosemide (excluding those who required CRRT)
On the day of ICU admission, the median creatinine level was 141.2 μmol/L. By Day 3, following low-dose loop diuretic treatment, creatinine levels had significantly decreased to 111.4 μmol/L (p = 0.030). Lactate levels had a median value of 3.2 mmol/L on ICU admission (Day 1). After low-dose loop diuretic administration, this level significantly declined to 2.4 mmol/L by Day 3 (p = 0.002). Urine output showed a median of 300 mL/day on the day of ICU admission. By Day 3, after treatment with low-dose loop diuretics, urine output had significantly risen to 1,792 mL/day (p < 0.0001) (Figure 3).
Figure 3.
Trends in creatinine, urine output, and lactate levels in the early-stage AKI with low-dose loop diuretics group (ICU day 1, day 2, and day 3).
28-day mortality: early-stage AKI with low-dose loop diuretics group vs. early-stage AKI without diuretics group
This study revealed a 28-day mortality rate of 22.7% in the early-stage with low-dose group, compared to 51.8% in the early-stage without loop diuretic group. Kaplan–Meier survival analysis showed a significantly lower 28-day mortality in the early-stage AKI group receiving low-dose loop diuretics compared to those without diuretic treatment (log-rank test: χ2 = 4.272, p = 0.039) (Figure 4).
Figure 4.
Kaplan-Meier curve analysis of 28-day mortality in the early-stage AKI + low-dose loop diuretic group, the early-stage AKI without loop diuretic group (log-rank test: χ2 = 4.272, p = 0.039). Time 0 was defined as the day of ICU admission.
Discussion
AKI is a clinical syndrome that can be caused by various factors, including sepsis, hypovolemia, infection, and medications. It is characterized by a rapid decline in renal function over a short period, leading to the accumulation of metabolic waste, fluid-electrolyte imbalance, acid-base disturbances, and azotemia [20]. Sepsis is the most common cause of AKI in critically ill patients. In a retrospective study of 126,148 patients in China, Xu [21] found that ∼47.1% of sepsis cases were associated with AKI. AKI occurring within seven days of sepsis onset is referred to as S-AKI [6]. Treatment strategies for S-AKI include: anti-infective therapy; use of vasoactive agents; renal replacement therapy; and fluid resuscitation [22–25].
Currently, the use of furosemide in treating AKI remains controversial. Laboratory studies [9–12] have shown that furosemide can increase renal blood flow, reduce renal oxygen consumption, improve glomerular filtration rate, and alleviate the metabolic demands and oxidative stress induced by AKI. Theoretically, furosemide could improve renal function and increase urine output by enhancing renal blood flow. Although these theoretical benefits have been demonstrated under experimental conditions, they have not been consistently validated in clinical practice. Previous studies and meta-analyses [26–29] do not support the use of furosemide in AKI patients, and the KDIGO clinical practice guidelines [30] for AKI also advise against using diuretics in AKI treatment. A recent meta-analysis of 28 randomized controlled trials [13] found that furosemide administration did not increase mortality in patients with AKI or at risk for AKI and may even reduce mortality as a preventive measure, though the severity of AKI was not factored into this analysis. Current critical care guidelines do not provide specific recommendations on diuretics for AKI, indicating the need for further analysis to understand the effects of furosemide on outcomes across different AKI patient subgroups.
In this study, the 28-day mortality rate in the early-stage AKI with low-dose loop diuretics group was significantly lower than in the other three groups (p = 0.049), and the CRRT initiation rate was also significantly lower in this group (p = 0.001). Additionally, within three days of loop diuretic administration, patients in the early-stage AKI with low-dose loop diuretics group experienced significant reductions in creatinine and lactate levels, along with increased urine output. These results suggest that, in cancer patients with sepsis-associated acute kidney injury, using low-dose loop diuretics in the early stages of AKI may reduce mortality and improve renal function. In our study, we further compared early-stage AKI patients receiving low-dose furosemide with those who did not receive diuretic therapy, and found that low-dose intervention was also associated with a potential survival benefit.
A study by Guang-Ju Zhao [31] found that the use of furosemide was associated with reduced in-hospital mortality (HR 0.67, 95% CI 0.61–0.74; p < 0.001) and facilitated renal recovery in AKI patients (HR 1.44, 95% CI 1.31–1.57; p < 0.001). Furosemide administration helped reduce in-hospital mortality risk for AKI patients in stages 0–1 (according to serum creatinine staging), and doses below 1.1 mg/kg/day were associated with a reduced risk of in-hospital death, which is consistent with the findings of this study. However, another study indicated that diuretic use was significantly associated with increased risks of mortality or non-recovery of renal function (HR 1.77; 95% CI 1.14–2.76). It should be noted that this study analyzed all types of diuretics, with furosemide accounting for 62.0% of cases; however, no subgroup analysis was conducted, leaving it unclear whether furosemide alone increased mortality or hindered renal recovery [26]. Furthermore, Zhenhua’s research [18] showed that low-dose furosemide combined with aminophylline significantly reduced 28-day mortality in septic shock patients (25.9% in the intervention group vs. 49.1% in the control group, p = 0.012) but did not improve renal function. This difference from our study may be due to the combined use of furosemide and aminophylline, as both have diuretic effects and may have a synergistic action, potentially causing excessive diuresis, exacerbating inadequate tissue perfusion in septic shock, and thus failing to improve renal function.
This study demonstrated that the early-stage AKI with low-dose loop diuretics group had a better survival rate and lower mortality risk compared to the other three groups, which may be influenced by several factors. Diuretics used in clinical practice act on different segments of the renal tubules and need to be secreted into the tubules to exert their effects. Compared to early-stage AKI patients, those in the late stage of AKI have poorer renal perfusion, more extensive tubular damage, and a greater reduction in functional nephron units. Consequently, in late-stage AKI patients, loop diuretics may not effectively reach the tubules to produce a diuretic effect [32]. Additionally, late-stage AKI patients may experience more pronounced hypovolemia, potentially leading to acute resistance to furosemide [33]. Prolonged or high-dose loop diuretic use can induce adaptive changes in the distal tubules, causing compensatory hypertrophy that increases sodium reabsorption and activates the renin-angiotensin-aldosterone system (RAAS), thereby reducing sodium and water excretion and failing to resolve the fluid overload observed after fluid resuscitation in septic patients [34]. In patients receiving high doses of loop diuretics, excessive diuresis may also occur, leading to inadequate tissue perfusion and worsening hypotension, which can increase sodium chloride delivery to the macula densa, activating tubuloglomerular feedback, reducing glomerular filtration, and ultimately raising creatinine levels [35]. Research by Ben [36] found that intravenous administration of high-dose furosemide in AKI patients increased urinary F2-isoprostanes (F2-IsoPs), exacerbating oxidative stress in the kidneys and causing damage. Furthermore, the extent of F2-IsoPs increase in urine was positively correlated with the severity of AKI, with the most severe cases showing the greatest increase. However, Ni [37] found that in cases where conventional doses of furosemide were ineffective for early AKI, high-dose furosemide might improve urine output and promote renal recovery. Additionally, a study by Cantarovich [38] demonstrated that high-dose furosemide significantly reduced the need for renal replacement therapy, although it did not significantly improve mortality. These findings differ from those of the present study and warrant further investigation.
Lactic acidosis is common in critically ill patients and is an independent risk factor for poor prognosis in both critically ill and sepsis-associated AKI patients [39]. Severe hyperlactatemia can lead to reduced catecholamine responsiveness, hemodynamic instability, and arrhythmias [40]. The population in this study consisted of cancer patients with sepsis-associated AKI, where lactate production is closely related to anaerobic metabolism. In sepsis-associated AKI, increased lactate production often results from hypoxia due to inadequate tissue perfusion and organ dysfunction, which accelerates anaerobic metabolism. A study by Legouis [41] also showed that during AKI, gluconeogenesis and lactate clearance by proximal tubular cells decrease. Tumor tissue further increases lactate levels through glycolysis triggered by the Warburg effect, making hyperlactatemia more likely due to multiple contributing factors. Research has shown that lactate clearance primarily occurs in the liver, followed by the kidneys, and renal lactate clearance adjusts with changes in blood lactate levels; as lactate levels increase, the clearance capacity also rises. This mechanism operates through gluconeogenesis using lactate as a substrate, mitochondrial oxidation for energy, glycogen synthesis, and renal excretion via the tubules [42]. In this study, patients in the early-stage AKI with low-dose loop diuretics group showed a decreasing trend in lactate levels and gradually increased urine output within the first three days after ICU admission. This may be attributed to fluid resuscitation upon ICU admission, which partially improved tissue perfusion, thereby preventing further lactate production. Additionally, loop diuretic administration may have increased renal blood flow, reduced renal oxygen consumption, improved glomerular filtration rate, promoted gluconeogenesis, and enhanced lactate excretion through increased urine output, ultimately reducing lactic acidosis associated with sepsis.
In this study, aside from the early-stage AKI with low-dose loop diuretics group, which exhibited a lower mortality risk, the late-stage AKI with low-dose loop diuretics group showed no significant difference in mortality risk compared to the early-stage low-dose group (p = 0.151). Additionally, for outcomes, such as mortality rate and shock reversal rate, the late-stage AKI with low-dose group was closer to the early-stage low-dose group than to the other two groups, which may be associated with the earlier initiation of CRRT in this group. Alexander’s study [43] demonstrated that early CRRT use can improve 90-day mortality rates and enhance renal function recovery.
In summary, this study found that the use of low-dose loop diuretics in the early stages of AKI may improve patient survival and renal function. However, clinical research findings remain inconsistent, highlighting the need for further investigation into the role of loop diuretics in the treatment of S-AKI. Larger, more detailed studies are required to confirm these results. Future research should aim to elucidate the specific mechanisms of loop diuretics in S-AKI treatment to provide stronger evidence for clinical practice. Additionally, individualized treatment protocols for different S-AKI patient subgroups should be developed to both enhance survival rates and improve renal function.
This study has several limitations to consider. First, the retrospective study design may be subject to source bias, which could affect the reproducibility of the results. Second, as a small, single-center study, the findings are inevitably influenced by bias. Therefore, larger, more detailed studies are needed to thoroughly assess the value of loop diuretic treatment in this patient population.
Conclusion
Low-dose loop diuretics administered in the early stage of S-AKI (stages 1 and 2) may improve survival and renal function in cancer patients. These findings should be validated in large-scale prospective randomized controlled trials.
Funding Statement
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets analyzed during the current study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets analyzed during the current study are available from the corresponding author upon reasonable request.