Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging febrile illness caused by the Dabie bandavirus, a segmented negative stranded RNA virus. Formerly known as the SFTS virus (SFTSV), it belongs to the genus Bandavirus, within the family Phenuiviridae, and order Bunyavirales. The disease first emerged in China in 20091, and subsequently, cases have been reported in South Korea2, Japan3, Vietnam4, and Taiwan5. SFTSV is a zoonotic disease primarily transmitted by ticks such as Haemaphysalis longicornis. Clinical manifestations of SFTS include high fever, lymphadenopathy, thrombocytopenia, elevated hepatic enzyme levels, gastrointestinal disturbances, and hemorrhagic tendencies. In advanced and severe scenarios, patients can progress to multi-organ failure, culminating in a daunting fatality rate that exceeds 30%6. Although various risk factors associated with mortality have been identified, Jo et al. reported that SFTS viral RNA loads in the plasma can serve as valuable markers for predicting mortality7.

Acute kidney injury (AKI), a clinical sequela, has been observed in 14–36% of patients with SFTS8,9,10,11,12,13,14,15. Initial evidence indicated that AKI was a byproduct of the systemic deterioration observed in SFTS, which was predominantly attributed to multiorgan failure. However, emerging evidence suggests a more direct role for the SFTS virus in renal compromise. Autopsy-based evaluations of renal tissues from patients who died of SFTS detected SFTS viral antigens and nucleic acids using immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR)16. Furthermore, a recent study reported that the viral load excreted through urine via the kidney serves as a reliable predictor of mortality14. Therefore, AKI is a common complication that serves as a pivotal clinical marker associated with the pathogenesis of SFTS.

We designed our study to offer an in-depth exploration of AKI's prevalence and implications of AKI in patients with SFTS. Our objectives included a thorough analysis of AKI incidence, a detailed examination of mortality rates stratified by AKI stage, and an overarching investigation into how AKI affects overall mortality in patients with SFTS.

Methods

Ethics statement

This study followed the ethical guidelines outlined in the Declaration of Helsinki and was approved by the Institutional Review Board of the Kangwon National University Hospital (KNUH-A-2020–03-016–002). The requirement for informed consent was waived owing to the retrospective nature of the study.

Patients

In accordance with the SFTS screening criteria of Kangwon National University Hospital, we included patients who participated in recent outdoor activities such as farming, hiking, or exposure to ticks or animals, and exhibited clinical symptoms of SFTS, including fever, chills, myalgia, and diarrhea, along with thrombocytopenia. Patients younger than 18 years of age were excluded from the study.

Between January 2016 and December 2020, a total of 381 patients were screened for SFTSV at Kangwon National University Hospital. After excluding 3 patients below 18 years of age, 53 patients were confirmed to have SFTS. Diagnosis was confirmed through detection of the viral nucleic acids in plasma using RT-PCR. We retrospectively reviewed medical records, including demographics, comorbidities, clinical manifestations, laboratory data, and mortality.

In accordance with the prevailing national guidelines, a diagnosis of SFTS is established when patients exhibit distinct clinical symptoms of SFTS alongside one or more of the following laboratory findings: (1) isolation of SFTSV from the patient's blood, (2) detection of virus-specific IgM antibodies in the patient's blood, (3) identification of SFTSV RNA in the blood, and (4) a significant increase in virus-specific antibodies of at least four-fold between acute and convalescent serum samples. The presence of viral nucleic acids in SFTSV was confirmed by RT-PCR, which targeted the glycoprotein and nucleoprotein genes of SFTSV RNA. The test was conducted at the National Institute of Health and Environment according to the guidelines of the Korean Centers for Disease Control and Prevention.

Definition of AKI

We determined the presence and stage of AKI in all patients enrolled in our study.

AKI was defined using serial creatinine values in accordance with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) AKI guidelines17. AKI stage 1 was defined as 1.5−1.9 times the reference value or an increase of ≥ 0.3 mg/dL. Stage 2 was defined as 2.0 to 2.9 times the reference value. Stage 3 was defined as ≥ 3 times the reference value, an increase of ≥ 4.0 mg/dL, or the initiation of renal replacement therapy. In cases where patients presented to the hospital for the first time or after a long interval and where baseline creatinine values were unavailable, we adhered to the proposed criteria for retrospective diagnosis and staging of AKI suggested by Duff et al.18. According to this, AKI stage 1 is defined by a decrease to 0.66−0.49 times from the reference serum creatinine value in the following 7 days, Stage 2 by a decrease to 0.5−0.32 times, and Stage 3 by a decrease to ≤ 0.33 times the reference value or a reduction ≥ 4.0 mg/dL.

Statistical analysis

Clinical manifestations, comorbidities, and laboratory data were analyzed. Baseline characteristics were analyzed using descriptive statistics and were reported as n (proportions, %) or mean ± SD as appropriate. χ2-test or Fisher’s test was used to analyze categorical variables. Analysis of variance (ANOVA) and t-tests were used to analyze continuous variables. Cumulative survival rates were assessed using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox regression to identify risk factors for mortality. Statistical significance was set at P < 0.05. All statistical analyses were performed using SAS ver9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Seasonal trends and AKI incidence

Between January 2016 and December 2020, 381 patients were screened for SFTSV. Among them, 53 adult patients were diagnosed with SFTS using RT-PCR and were included in the analysis (Fig. 1). Of the 53 patients diagnosed with SFTS, the peak incidence was observed in September and October, which aligned with the patients' hospital visits between May and October (Supplementary Fig. 1).

Fig. 1
figure 1

Flowchart of participant selection. SFTS, severe fever with thrombocytopenia syndrome; RT-PCR, reverse-transcription polymerase chain reaction; AKI, acute kidney injury.

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AKI occurred in 27 (50.9%) patients. The distribution of AKI stages revealed that 17 (32.1%) patients were at stage 1 and 10 (18.9%) were at stage 2 or 3. Notably, 5 (9.3%) patients required renal replacement therapy, all of whom required continuous renal replacement therapy (CRRT). The average duration of CRRT was 10 days (range, 2 36 days). Of these five patients, 3 (60%) had hypertension and 3 (60%) had diabetes as underlying conditions.

Of the 27 patients categorized as having AKI, 23 had already developed AKI upon their initial presentation to the hospital. When determining the onset of AKI relative to the fever onset, the data indicated an average duration of 3.9 ± 3.6 days. Additionally, 24 (88.9%) of the 27 patients manifested AKI within one week of fever onset.

Baseline characteristics according to AKI stage

Detailed baseline characteristics categorized according to the AKI stage are presented in Table 1. Among the patients, 54.7% were male, with an average age of 66.5 years. An apparent trend suggested that the severity of AKI was correlated with advancing age (P = 0.041). Regarding comorbidities, 45.3% had hypertension, and 20.8% had diabetes mellitus. Patients with advanced AKI had a higher prevalence of diabetes mellitus (P = 0.019). Tick-bite lesions were observed in 49.1% of patients.

Table 1 Baseline characteristics of SFTS patients according to AKI stage.
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Fever was the most commonly recorded systemic sign—detected in 90.6% of patients—followed by myalgia and general weakness. General weakness was predominant in the AKI cohort (P = 0.047). Gastrointestinal symptoms were also frequently observed; diarrhea was the most common symptom (50.9%), followed by anorexia (45.3%) and nausea (30.2%). Among the neurological symptoms, altered mental status was confirmed in 37.7% of the patients. It was more frequently observed in patients with AKI, and even more so in patients with higher AKI stages (P = 0.012).

In laboratory assessments, patients with SFTS exhibit leukopenia, thrombocytopenia, and elevated serum levels of liver enzyme and lactate dehydrogenase (LDH). When stratified by the presence of AKI and its stage, we observed increased levels of blood urea nitrogen (BUN) and serum creatinine in the AKI group (P = 0.015 and P = 0.011, respectively) (Table 2). Serum sodium levels were similar in both groups; however, serum potassium levels were significantly higher in the AKI stages 2 and 3 groups than in the non-AKI and AKI stage 1 groups (P = 0.007). Additionally, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and C-reactive protein were significantly higher in advanced AKI stages. Proteinuria of 1 + or more was found to be significantly higher in the AKI group compared to the non-AKI group (P = 0.013).

Table 2 Baseline laboratory values.
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Complications of SFTS

The spectrum of severe medical complications is shown in Table 3. Hypotension, defined as a systolic blood pressure < 90 mmHg, was prominently observed, accounting for 26.4% of cases. Encephalopathy occurred in 20.8% of patients, whereas pneumonia, mechanical ventilation, and rhabdomyolysis were present in 13.2%. Specifically, complications such as hypotension, mechanical ventilation, and disseminated intravascular coagulation (DIC) were significantly prevalent in the AKI group, with the frequency increasing with higher AKI stages.

Table 3 Complications in SFTS patients.
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The overall mortality rate was 15.1%. The mortality rate significantly increased with AKI severity: 3.8% in the non-AKI group, 17.6% in AKI stage 1, and 50% in AKI stages 2 and 3 (P = 0.004) (Supplementary Fig. 2).

A notable observation in this study was the variation in mortality rates depending on the initial point of admission. Of the 53 patients, two were diagnosed and treated at outpatient clinics, 35 were admitted to the infectious disease department, and 16 were admitted across different departments, including nephrology (n = 4) and hepatology (n = 3). We compared the baseline characteristics and initial laboratory values of patients admitted to the infectious disease department and other departments and found that fever was more prevalent in patients admitted to the infectious disease department, whereas abdominal pain was more common in patients admitted to other departments (Supplementary Table 1). Initial laboratory values, such as white blood cell (WBC) count, blood urea nitrogen (BUN) levels, and serum creatinine levels, were significantly higher in patients hospitalized in other departments (Supplementary Table 2). Patients admitted to the Infectious Disease Department had a lower mortality rate than those admitted to other departments (5.7% vs. 43.8%).

When 27 patients of the AKI group were followed up for one year after discharge, there were 8 deaths, 11 patients were lost to follow-up, and only 1 of the 8 tracked patients was confirmed to have developed chronic kidney disease, with an estimated glomerular filtration rate below 60.

Survival analysis of AKI and non-AKI patients

Kaplan–Meier curves revealed that survival rates were lower in the AKI group than in the non-AKI group (Fig. 2A). Stratification into non-AKI, AKI stage 1, and AKI stages 2 and 3 groups revealed significant differences in survival (log rank P = 0.002) (Fig. 2B).

Fig. 2
figure 2

Kaplan–Meier curves of patient survival: (A) Comparison between non-AKI and AKI Groups, (B) Comparison according to AKI Stage.

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Risk factors for mortality

Using Cox regression analysis, we identified risk factors associated with mortality (Table 4). In univariate analysis, WBC count, BUN, creatinine, AST, ALT, and alkaline phosphatase (ALP) emerged as significant risk factors for mortality. Stage 3 AKI was identified as a significant risk factor compared to the group without AKI. In the multivariate analysis, only WBC and serum creatinine levels showed significant results.

Table 4 Risk factor of mortality.
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Discussion

In this study, we investigated the clinical implications of AKI in patients with SFTS. Half of the patients with SFTS in our cohort developed AKI with varying degrees of severity. The association between AKI severity and adverse outcomes, particularly the significant increase in mortality rates in patients with advanced AKI, highlights the importance of understanding and addressing renal compromise in patients with SFTS. Moreover, the average interval from the onset of fever to the occurrence of AKI was 3.9 days, suggesting the possibility of AKI as an early marker that can predict the severity of SFTS.

The clinical course of SFTS is categorized into febrile, multi-organ dysfunction, and convalescent stages. It was hypothesized that in severe cases, a one-week febrile stage would occur, followed by the development of multiorgan dysfunction, such as AKI, as a consequence of a cytokine storm. However, recent evidence indicates that SFTSV directly invades the renal tissue of patients with SFTS, and the increased viral load in the urine is associated with adverse outcomes14. Furthermore, within the AKI group of our study, AKI occurred in 88.9% of patients within the first week of fever onset. This suggests that the kidney is involved early in the course of SFTS and may be involved in its pathogenesis.

AKI is a major complication of SFTS. A previous Korean study conducted between 2013 and 2015 reported an acute renal failure occurrence rate of 14.2%9. Another study documented kidney dysfunction at baseline in 36% of 11 patients with SFTS15. In Chinese studies, renal insufficiency was observed in 27.8% of 115 patients with SFTS and in 36% of 25 patients with SFTS8,10. These reports, although valuable, did not focus on AKI and thus lacked a clear definition of kidney dysfunction. Recently, studies using the term AKI have been published11,12, and two studies investigated the incidence of AKI in patients with SFTS according to the KDIGO guidelines13,14. We reviewed the literature on the incidence of AKI and fatality among patients with SFTS and summarized the representative findings in a table (Table 5). Four studies reported that the incidence of AKI in patients with SFTS ranges from 21.6 to 27.5%. Our study revealed that AKI was documented in 50.9% of the patients with SFTS. Our study represents the highest reported AKI incidence, which we attribute to an older patient population with concurrent comorbidities (i.e., diabetes and hypertension) that likely manifest as preexisting chronic kidney disease. Additionally, this may be due to our comprehensive definition of AKI, following not only the KDIGO guidelines but also including patients for whom baseline creatinine values were unavailable, in alignment with the definition proposed by Duff et al.18. This allowed the inclusion of many patients who had already experienced AKI from their initial hospital admission to the AKI group. Furthermore, using a broader AKI definition to predict the severity of SFTS early is unlikely to pose a clinical concern.

Table 5 Literature review on incidence of acute kidney injury and fatality among patients with severe fever with thrombocytopenia syndrome.
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When examining the characteristics of the AKI group, old age and the presence of diabetes mellitus emerged as factors that contributed to the occurrence of AKI in the SFTS group, which is consistent with the results of a previous study13. Among the signs and symptoms, general weakness and mental changes occurred more frequently as AKI severity increased. Additionally, high initial serum creatinine, AST, ALT, CRP were significantly associated with AKI. These findings are consistent with those of a previous study, which reported a higher incidence of encephalopathy in the AKI group, along with significantly elevated levels of serum creatinine, AST, ALT, CRP, and other laboratory parameters13. In another study by Zhang et al., similar to our study, the AKI group had significantly higher serum creatinine and AST levels and increased mortality14.

The detection of viral nucleic acids in the kidney in SFTS has already been well established through both animal experiments and autopsies16,19. In a study using a pathogenic C57/BL6 mouse model of SFTS, the viral load in the kidney was found to be the second highest after the spleen at 1 d post-infection, which was accompanied by pathological glomerular changes in the kidney, with no overt tubular injury or inflammatory infiltrates at 14 days post-infection19. Furthermore, the presence of viral antigens and nucleic acids was observed by immunohistochemistry and RT-PCR in the renal tissue of a single SFTS victim during autopsy evaluations16. Although the kidney is directly invaded by the virus, and AKI is a common and significant complication, there is limited research on the role and significance of AKI in SFTS. Zhang et al.14 measured urine SFTS virus levels, which were significantly higher in the AKI group and closely related to patient mortality. In our study and in a previous study, the AKI group exhibited significantly higher mortality than the non-AKI group13. AKI can be easily detected using serial blood tests and is a remarkable prognostic tool. Given its ease of identification, it is imperative that its role in patient prognostication garner further attention in clinical practice. In this study, the rapid onset of AKI post-fever, averaging 3.9 days—in patients with SFTS accentuated AKI's pivotal role of AKI as an early and critical marker for gauging patient severity.

The mortality rate in the present study was 15.1%. Based on recent research findings, the SFTS mortality rate in South Korea from 2018 to 2022 is 18.7%20, the mortality rate in China from 2011 to 2021 is 5.1%21, and that in Japan from 2013 to 2017 is 27%22. After the SFTS was first introduced to the academic community in 2009, early studies reported a mortality rate as high as 30%23. However, recent studies reported decreased mortality rates. Despite the absence of a disease-specific therapeutic agent, the improvement in the mortality rate of SFTS can be attributed to a heightened understanding of disease progression as SFTS becomes more widely recognized. This enhanced knowledge will enable rapid diagnosis and more aggressive treatment of SFTS with meticulous attention. At our center, we adhere to a standardized protocol for managing SFTS. However, patients admitted to the infectious disease department are often suspected of having SFTS during the early course of the disease, whereas those in other departments are primarily diagnosed with hepatitis or pre-renal AKI. This difference may have led to a delayed diagnosis of SFTS and the application of our protocol. Our findings indicate that patients initially admitted to the infectious disease department had a higher likelihood of survival than those admitted to other departments. Although patients admitted to the infectious disease department may have milder disease, the difference in outcomes could be attributed to early suspicion and aggressive supportive treatments, such as early plasma exchange, providing valuable lessons for clinicians.

In terms of factors influencing mortality, AKI stage 3 was significant in the univariate analysis; however, its significance disappeared in the multivariate analysis, possibly because of a confounding effect. However, the initial serum creatinine level remained a significant factor in multivariate analysis. Kaplan–Meier analysis confirmed lower survival rates among AKI patients, especially those in advanced stages, compared to the non-AKI group. Increased vigilance is warranted in cases in which patients have high initial creatinine levels at admission or develop AKI during hospitalization.

This study has several limitations. First, this was a single-center study with a small number of patients. Therefore, further studies involving larger cohorts are required to confirm the significance of AKI. Second, some patients did not have baseline creatinine values, which limited our ability to confirm AKI using the KDIGO criteria. However, we attempted to identify all AKI cases using an alternative definition proposed by Duff et al.. Third, RT-PCR was exclusively employed as a confirmatory test for SFTS, potentially leading to the exclusion of patients with SFTS who tested negative on RT-PCR. Fourth, because of the retrospective nature of the study, urine RT-PCR data were not available. This limits our ability to correlate urine viral loads with AKI scores. Future prospective studies should include urine RT-PCR to provide a more comprehensive understanding of the relationship between the viral load and AKI in patients with SFTS.

Conclusions

In the present study, AKI was identified as a common complication in patients with SFTS. On average, it took 3.9 days from fever onset to AKI development. We found that old age and diabetes mellitus were risk factors for AKI, and initial serum creatinine level was an independent risk factor for fatality in patients with SFTS. Kaplan–Meier curves revealed lower survival rates among patients with AKI than among those without AKI, especially as the AKI stage advanced. Taken together, our findings highlight the high incidence of AKI in patients with SFTS and underscore its pivotal role as an early prognostic indicator of AKI severity.