Sepsis is the leading cause of acute kidney injury (AKI), contributing almost half the cases of renal insufficiency in intensive care units [1]. The development of AKI during episodes of sepsis is a significant and independent prognostic indicator of extended hospital stays and in-hospital mortality [2]. Moreover, epidemiological data increasingly suggests that individuals who survive mild or brief episodes of AKI face an increased risk of subsequently developing chronic kidney disease (CKD) and end-stage renal disease [3]. The essential treatment for sepsis currently includes antibiotics, fluid resuscitation, and vasopressor support. Renal replacement therapy (RRT) is advised for patients experiencing severe septic AKI [4]. Nevertheless, these interventions are primarily palliative and aimed at sustaining life with the goal of kidney recovery. Consequently, a deeper understanding of the pathophysiological mechanisms underlying septic AKI is crucial for the development of effective, mechanism-based therapeutic strategies.

Ascorbic acid, commonly known as vitamin C, is a water-soluble vitamin integral to various bodily functions. This antioxidant acts as an electron donor to effectively neutralize free radicals. By inhibiting the NADPH oxidase (NOX) pathway, vitamin C limits the formation of new free radicals, which also increases the activity of other antioxidants [5]. The antioxidant properties of vitamin C can lead to decreased endothelial permeability, thereby improving the function of both microvascular and macrovascular systems, and diminishing cell apoptosis in pathological states [6, 7]. Vitamin C also plays a crucial role in the synthesis of endogenous vasopressin, and can influence the responsiveness of patients to this hormone. Consequently, we designed a prospective, randomized and controlled pilot study to investigate whether the administration of vitamin C to patients experiencing sepsis can reduce the incidence of AKI.

Under sepsis conditions, the body’s intake and absorption are known to decrease, while metabolism increases, resulting in a lower level of plasma vitamin C [8]. In about 90% of sepsis patients, the plasma vitamin C level is less than 23 µmol/L. Severe vitamin C deficiency can lead to multiple organ dysfunction, while exogenous supplementation of vitamin C is effective at reducing the mortality rate. A randomized controlled trial reported that giving high-dose vitamin C to patients with sepsis can reduce oxidative damage to endothelial cells and other cell types, thereby improving tissue perfusion and oxygenation and reducing subsequent organ dysfunction [9]. Vitamin C is widely used in clinical practice and can protect cell components from reactive oxygen and free radical-mediated oxidative stress responses, while also participating in collagen secretion and the biosynthesis of dopamine and other molecules.

The impact of vitamin C on clinical outcomes in critically ill patients remains controversial, and research findings are inconclusive. A retrospective observational cohort study [10] evaluated the effects of vitamin C treatment on AKI and mortality in patients with sepsis. The electronic medical records of 1390 patients from a single institute were analyzed, with the data revealing that vitamin C treatment was associated with an increased risk of AKI (OR = 2.07, 95% CI [1.46–2.93]) and in-hospital mortality (OR = 1.67, 95% CI [1.003–2.78]) after adjusting for demographic and clinical covariates. When stratifying for intensive care unit (ICU) patients, vitamin C treatment remained a significant risk factor for AKI (OR = 1.61, 95% CI [1.09–2.39]) and did not protect against mortality (OR = 0.79, 95% CI [0.48–1.31]) [11]. Given these reported associations with AKI and mortality, the continued use of high-dose vitamin C in sepsis patients requires further evaluation.

Statistical analysis of the data was conducted using SPSS 21.0 software (SPSS Inc., Chicago, IL, USA). The Shapiro-Wilk test and Levene’s test were used to assess the normality of data distribution and the equality of variance. For datasets exhibiting a normal distribution, results were expressed as the mean $\pm$ standard deviation ($\overline{x}$ $\pm$ sd). The t test was applied for comparisons between the two groups, while the q-q normal probability plot was employed to assess normality. When the measured data did not follow a normal distribution, the median (M) and interquartile range (QL, QU) was utilized to present the findings. Categorical data were summarized as n (%). Pearson’s test was applied for comparison of dichotomous variables between groups, and the Mann-Whitney U test for ordered classifications across multiple groups. All statistical tests were two-sided, with a significance threshold set at p 0.05.

Following application of the inclusion and exclusion criteria, a total of 40 patients with sepsis and septic shock were included in the trial, with 20 each in the experimental and control groups (Fig. 1). Table 1 presents the general characteristics for the two groups. Among the 40 sepsis patients included in the study, 5 (25%) in the experimental group and 14 (70%) in the control group developed AKI, with all requiring continuous RRT support. The main infection site in both groups was pulmonary (70% in the experimental group and 75% in the control group). The main pathogenic bacteria were gram-negative bacilli (26/40, 65%). The average length of stay in the ICU was 11.8 $\pm$ 2.7 days in the experimental group and 13.9 $\pm$ 2.1 days in the control group (p = 0.008), the frequency of vasoactive drug use was 35% and 75%, respectively (7 vs. 15, p = 0.011), the proportion of RRTs required within 72 h of admission was 25% and 70%, respectively (5 vs. 14, p = 0.004), the ICU mortality rate was 10% and 15%, respectively (2 vs. 3, p = 0.633), and the IL-6 level was 16.41 $\pm$ 1.93 pg/mL in the experimental group and 39.82 $\pm$ 4.61 pg/mL in the control group (p = 0.003). These results are shown in Table 2.

Fig. 1.

Flow diagram.

Vitamin C is an essential cyclic antioxidant that plays a vital role in directly neutralizing reactive oxygen species (ROS) and boosting the levels of endogenous glutathione, thereby helping to regenerate the host’s antioxidant defense system. It also acts as an immune enhancer to stimulate macrophage activity [14], while having the capacity to directly inhibit bacterial cations [15, 16]. Additionally, vitamin C can reduce the expression of adhesion molecule 1 in human endothelial cells in a dose-dependent manner following stimulation by TNF. This suggests a potential capacity to mitigate microvascular obstruction by white blood cells and the impairment of microcirculation. Furthermore, vitamin C serves as a crucial auxiliary factor for the synthesis of endogenous vasoconstrictors, such as norepinephrine, and for vessel compression, allowing patients to respond more effectively to vasoactive drug therapies. It is worth noting that critically ill patients often exhibit significantly lower plasma levels of vitamin C [17]. Humans cannot naturally synthesize vitamin C, partially explaining the decrease in vitamin C during sepsis. Because of the presence of saturated intestinal sodium-dependent vitamin C transfer protein (SVCTS), intake through the intestine is insufficient to ensure normal levels of plasma vitamin C, thus requiring intravenous treatment [18].

Monocytes and granulocytes in sepsis patients can be separated by differential sedimentation and centrifugation, and their vitamin C content measured with the dinitrophenylhydrazine method. The concentration of vitamin C in monocytes is 80-fold higher than in plasma, while its concentration in granulocytes is 25-fold higher [19]. Vitamin C is known to play an important role in both monocytes and granulocytes. In clinical trials involving intravenous injection of 1 g of vitamin C in septic shock patients and healthy controls, the vitamin C level decreased more rapidly in the septic shock patients, suggesting higher consumption in these patients and possible accumulation in monocytes and granulocytes [20].

In a randomized double-blind trial in the USA [21], 137 patients with sepsis were randomly divided into treatment and control groups. The treatment group was given vitamin C, hydrocortisone and thiamine, while the control group was given a combination of hydrocortisone and thiamine. The shock reversal time, sequential organ failure score, procalcitonin clearance rate, and hospitalization time for the two groups were compared to evaluate the therapeutic effect of vitamin C. The SOFA score in the treatment group was significantly lower compared to the control group (p 0.01), while the shock reversal time, PCT-c, and LOS were shorter. Since SOFA and PCT-c are closely related to sepsis-associated organ failure and mortality, these results indicate that supplementation with vitamin C can reduce patient mortality.

While animal studies on early sepsis have shown advantages with vitamin C, its effectiveness in human subjects is still debated. Two small-scale (n = 24 and n = 28), single-center randomized clinical trials demonstrated that intravenous vitamin C doses of between 50 and 200 mg/kg/day led to a reduction in inflammatory biomarkers and SOFA scores [22] and improved patient sensitivity to vasoactive drugs (25 mg/kg every 6 h) [23]. However, in three subsequent multicenter RCTs (VITAMINS [24], ACTS [25] and ATESS [26]), no difference in hospital mortality was observed when vitamin C (6 g/day) was combined with thiamine and corticosteroids, and RRT support was needed at 72 h.

The administration of vitamin C to patients with sepsis could reduce the occurrence of AKI. However, more studies with a larger sample size are needed to confirm this finding.

Data is provided within the manuscript.

Conducted the study: YC, FF. Collected all data: ML, XES, JQZ. Performed the statistical analysis: YC. All authors have contributed to the editorial changes made to the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was approved by the Ethics Committee of the Second Hospital of Lanzhou University (approval number 2024A-1348). The study was registered with the China Clinical Trial Center (registration number ChiCTR2400093794). Informed consent was signed by the patient or a family member in all 40 cases included in the study. If the patient was unable to complete the signature due to the use of sedative drugs, coma, etc., his or her immediate family members were consulted to provide informed consent. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Not applicable.

Gansu Provincial Science and Technology Plan Funding (Natural Science Foundation Project 23JRRA0965, 24JRRA357).

The authors declare no conflict of interest.