Abstract
Hemorrhagic fever with renal syndrome (HFRS) is frequently complicated by acute kidney injury (AKI). Although most patients recover from AKI with supportive care, some progress to chronic kidney disease (CKD). The incidence and determinants of CKD progression in patients with HFRS-AKI remain uncertain. Here, 99 patients with HFRS-AKI treated at Jinling Hospital were analyzed retrospectively to determine the rate of CKD progression and identify associated risk factors. Patients were divided into complete recovery (CR) and incomplete recovery (ICR) groups according to CKD progression. Baseline clinical and laboratory data were collected and analyzed. Overall, 27.3% of patients with HFRS-AKI progressed to CKD despite receiving supportive care. Facial flushing was more frequent in the ICR group than in the CR group (40.7% vs. 18.1%, p = 0.033). Multivariate analysis revealed that treatment with Cordyceps sinensis preparations during the AKI phase was an independent protective factor against incomplete kidney recovery (OR: 0.323, 95% CI: 0.114–0.916, p = 0.034). Inverse probability weighting analysis further demonstrated that the use of Cordyceps sinensis preparations was inversely associated with incomplete kidney recovery (β: −1.184, 95% CI: −2.224 – −0.144, p = 0.026). Survival analysis confirmed that Cordyceps sinensis preparation therapy was associated with improved kidney outcomes (log-rank test, p = 0.004). This study provides the first clinical evidence that adjunctive therapy with Cordyceps sinensis preparations during HFRS-AKI is associated with improved kidney outcomes, suggesting that Cordyceps sinensis preparations represents a promising therapeutic approach for viral-induced AKI.
Keywords: Acute kidney injury, hemorrhagic fever with renal syndrome, HFRS, Cordyceps sinensis, kidney outcomes
GRAPHICAL ABSTRACT
1. Introduction
Chronic kidney disease (CKD) affects more than 10% of the adult population and contributes greatly to health burden worldwide [1]. CKD progression is characterized by kidney fibrosis and is associated with high morbidity and mortality. However, there are no effective treatments to prevent kidney fibrosis or cure CKD [2,3]. Acute kidney injury (AKI) is not merely an acute event but often leads to long-term consequences, promoting the transition to CKD [4]. Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne zoonosis caused by viruses of the genus Orthohantavirus [5]. Hantavirus infection in humans occurs primarily through inhalation of aerosolized excreta (urine, feces, or saliva) from infected rodents. Transmission can also occur through the gastrointestinal tract following ingestion of contaminated food or water, or via direct contact with infected rodent excreta, or blood, or through bites when the virus enters through broken skin or mucous membranes [6]. Additionally, vertical transmission has been documented [7]. HFRS is clinically characterized by an acute onset of fever, thrombocytopenia, and AKI. AKI is a key clinical feature of HFRS and a major contributor to its morbidity and mortality. The classical course of HFRS progresses through five overlapping phases, namely the febrile, hypotensive, oliguric, polyuric, and convalescent phases [8]. Currently, no specific therapy is available for HFRS and HFRS-AKI. Supportive care is the main treatment strategy for AKI in patients with HFRS. Although most patients achieve rapid kidney recovery from AKI with supportive care, some patients experience incomplete recovery and progress to CKD. Previous studies have shown that traditional Chinese medicines exert therapeutic effects in various acute and chronic kidney diseases [9–11]. However, the incidence of the AKI-to-CKD transition in patients with HFRS remains unclear. Furthermore, the factors associated with the kidney outcomes remain undefined. Therefore, in this study, we conducted a retrospective analysis of patients with HFRS-AKI admitted to Jinling Hospital, using available follow-up data to evaluate kidney outcomes and identify predictors of kidney outcomes.
2. Materials and methods
2.1. Patients
This study initially identified 113 patients diagnosed with HFRS and complicated with AKI at the National Clinical Research Center of Kidney Diseases, Jinling Hospital, between January 2014 and December 2018. Written informed consent was obtained from all participants. After excluding 14 patients without follow-up data, 99 eligible patients were included in the final retrospective analysis. The inclusion criteria were as follows: (1) HFRS diagnosis confirmed by positive serum hantavirus antibodies, characteristic clinical manifestations, and/or relevant exposure history; (2) availability of follow-up data for more than 90 days after discharge or achieved complete kidney recovery after discharge; (3) no preexisting chronic kidney disease; and (4) no other identified etiologies that could account for AKI. Patients were divided into complete recovery (CR) and incomplete recovery (ICR) groups on the basis of their progression to CKD at follow-up. The screening process for patients is shown in Figure 1.
Figure 1.
Procedure for screening eligible patients. A total of 113 patients with acute kidney injury (AKI) during hemorrhagic fever with renal syndrome (HFRS) were initially screened at Clinical Research Center of Kidney Diseases of China, Jinling Hospital from January 2014 to December 2018. After 14 patients without follow-up data after discharge were excluded, 99 eligible patients were included in this study. According to kidney outcomes (whether CKD progressed), the 99 patients were divided into a complete recovery group (n = 72) and an incomplete recovery group (n = 27).
2.2. Clinical and laboratory data
The demographic and clinical variables included sex, age, disease course, follow-up duration, key clinical manifestations (fever, oliguria, hypotension), the characteristic flushing triad (facial, neck, and chest flushing), as well as the pain triad (headache, retro-orbital pain, and low back pain).
Laboratory parameters included baseline and last-available follow-up serum creatinine levels, along with white blood cell count, red blood cell count, platelet count, hemoglobin, blood urea nitrogen, albumin, globulin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Urinary data included baseline proteinuria, hematuria, urinary N-acetyl-β-D-glucosaminidase (NAG), and urinary retinol-binding protein (RBP). Based on urinalysis results, urinary protein levels were categorized into grades 0, 1, 2, 3, and 4, while hematuria was classified into grades 0, 1, 2, and 3.
Treatment information during hospitalization was documented, including the use of continuous renal replacement therapy (CRRT), glucocorticoids, antiviral agents, and Cordyceps sinensis preparations. Cordyceps sinensis preparations included China Food and Drug Administration (CFDA)-approved products derived from Cordyceps sinensis mycelium, such as Jinshuibao capsule, Bailing capsule, and Jianshen pills. All the Cordyceps sinensis preparations were administered to patients in the hospital according to the standard protocol and the drug instructions.
2.3. Definition
AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines, using serum creatinine criteria. CKD was defined according to the KDIGO guidelines as the presence of urinary abnormalities, a decreased estimated glomerular filtration rate (eGFR), abnormalities in kidney structure, or the receipt of kidney replacement therapy for more than 3 months. In detail, CKD was defined as the presence of any of the following abnormalities that persisted for ≥3 months after hospital discharge: (1) Albuminuria; (2) Urinary sediment abnormalities; (3) Renal tubular disorders; (4) Histological abnormalities; (5) Structural abnormalities on imaging; (6) History of kidney transplantation; and (7) Decreased glomerular filtration rate (eGFR <60 mL/min/1.73 m2). The eGFR was calculated by the CKD-EPI equation.
2.4. Statistical analysis
Statistical analyses were performed using SPSS software (version 20) and R software (version 4.6.0). Continuous variables were assessed for normality using the Shapiro–Wilk test. Data with a normal distribution are presented as the mean ± standard deviation (SD) and were compared between groups using the t-test. Non-normally distributed data are presented as medians with interquartile ranges (IQR) and were compared using the Mann-Whitney U test. Categorical variables are expressed as numbers (percentages, %) and were compared using Fisher’s exact test. Logistic regression analysis was employed to identify independent factors associated with kidney outcomes. Sensitivity analyses were performed using inverse probability of treatment weighting (IPTW). Kidney outcomes were assessed using Kaplan–Meier survival analysis. A two-tailed P value of less than 0.05 was considered to indicate statistical significance.
3. Results
3.1. Baseline characteristics
Ninety-nine eligible patients were included in this study. Among the 99 patients, 78 (78.8%) were males and 21 (21.2%) were females. The median age of the 99 patients was 50 (IQR 42–54) years old. Regarding clinical manifestations, fever was present in 90 (90.9%) patients, hypotension in 10 (10.1%), and oliguria in 64 (64.6%). The characteristic signs of HFRS were observed as follows: facial flushing in 24 (24.2%), redness of the neck in 11 (11.1%), and redness of the chest in 16 (16.2%) of patients. The corresponding pain symptoms included headache 27 (27.3%), low back pain 40 (40.4%), and retro-orbital pain 10 (10.1%). Laboratory findings at baseline revealed proteinuria in 81 (81.8%) patients and hematuria in 73 (73.3%) of patients. The median baseline serum creatinine concentration was 5.23 (IQR: 3.22–7.23)mg/dL.
Twenty-seven of the 99 (27.3%) patients progressed to CKD after discharge. Based on whether the patients progressed to CKD, 99 patients were categorized into the CR group (n = 72) and the ICR group (n = 27). The proportion of patients who presented with facial flushing was significantly higher in the ICR group than in the CR group (40.7% vs. 18.1%, p = 0.033). No significant differences in sex, age, or any of the collected baseline parameters were detected between the two groups (p > 0.05). The baseline characteristics of the 99 patients with HFRS-AKI are shown in Table 1.
Table 1.
Baseline characteristics of the 99 patients with HFRS-AKI.
| Total (n = 99) |
Complete Recovery (n = 72) |
Incomplete Recovery (n = 27) |
P value | |
|---|---|---|---|---|
| Sex, male (%) | 78 (78.8) | 55 (76.4) | 23 (85.2) | 0.417 |
| Age (years) | 50 (42–54) | 50.00 (41.50–55.25) | 50.00 (42.00–54.00) | 0.602 |
| Course (days) | 9 (7–11) | 9.00 (6.00–11.00) | 8.00 (7.00–11.00) | 0.365 |
| Fever (%) | 90 (90.9) | 65 (90.3) | 25 (92.6) | >0.999 |
| Hypotension | 10 (10.1) | 7 (9.7) | 3 (11.1) | >0.999 |
| Oliguria | 64 (64.6) | 46 (63.9) | 18 (66.7) | >0.999 |
| Facial flushing | 24 (24.2) | 13 (18.1) | 11 (40.7) | 0.033* |
| Redness of the neck | 11 (11.1) | 7 (9.7) | 4 (14.8) | 0.485 |
| Redness of the chest | 16 (16.2) | 10 (13.9) | 6 (22.2) | 0.362 |
| Headache | 27 (27.3) | 16 (22.2) | 11 (40.7) | 0.079 |
| Low back pain | 40 (40.4) | 28 (38.9) | 12 (44.4) | 0.651 |
| Retro-orbital pain | 10 (10.1) | 7 (9.7) | 3 (11.1) | >0.999 |
| White blood cells | 9.8 (7.4-13.5) | 9.60 (7.35–13.80) | 10.40 (7.60–12.00) | 0.771 |
| Red blood cells | 4.13 ± 0.774 | 4.11 ± 0.797 | 4.21 ± 0.716 | 0.567 |
| Hemoglobin | 124.69 ± 23.010 | 124.89 ± 23.659 | 124.15 ± 21.603 | 0.887 |
| Platelets | 114 (42–209) | 99.00 (41.50–193.50) | 177.00 (42.00–240.00) | 0.112 |
| Serum creatinine | 5.23 (3.22–7.23) | 5.29 (2.69–7.12) | 4.70 (3.70–7.23) | 0.686 |
| Urea nitrogen | 34.1 (21.5-60) | 33.50 (21.00–62.43) | 40.00 (24.80–53.20) | 0.706 |
| Albumin | 31.43 ± 7.022 | 30.59 ± 6.277 | 33.64 ± 8.439 | 0.054 |
| Globulin | 27.3 (24.4–30.6) | 27.50 (24.15– 30.28) | 27.50 (25.00–32.60) | 0.355 |
| ALT | 61 (42–104) | 66.50 (44.00– 106.50) | 56.00 (38.00–99.00) | 0.270 |
| AST | 60 (42–105) | 68.00 (44.25–116.25) | 58.00 (35.00–86.00) | 0.206 |
| Urine NAG | 18.5 (10.85–37.75) | 19.7 (10.925–38.80) | 15.50 (10.60–33.30) | 0.280 |
| Urine RBP | 2.90(0.60–12.44) | 2.4 (0.50–11.9) | 4.30 (0.70–17.20) | 0.205 |
| Proteinuria | 0.438 | |||
| 0 | 18 (18.2) | 11 (15.3) | 7 (25.9) | |
| 1 | 28 (28.3) | 22 (30.6) | 6 (22.2) | |
| 2 | 30 (30.3) | 24 (33.3) | 6 (22.2) | |
| 3 | 15 (15.2) | 9 (12.5) | 6 (22.20 | |
| 4 | 8 (8.1) | 6 (8.3) | 2 (7.4) | |
| Hemturia | 0.881 | |||
| 0 | 26 (26.30) | 19 (26.4) | 7 (25.9) | |
| 1 | 41 (41.4) | 28 (38.9) | 13 (48.1) | |
| 2 | 18 (18.2) | 14 (19.4) | 4 (14.8) | |
| 3 | 14 (14.1) | 11 (15.3) | 3 (11.1) |
*p < 0.05. ALT, alanine aminotransferase; AST, aspartate aminotransferase; NAG, N-acetyl-β-D-glucosaminidase; RBP, retinol-binding protein; CRRT, continuous renal replacement therapy.
3.2. Treatment
Regarding therapeutic interventions during hospitalization, CRRT was administered to 42 (42.4%) patients, glucocorticoids to 34 (34.3%), antiviral agents to 6 (6.1%), and Cordyceps sinensis preparations to 77 (77.8%). There were no significant differences between the two groups regarding receiving CRRT, glucocorticoids, or antiviral agents. However, a significant difference in the administration of the Cordyceps sinensis preparations was observed between the CR group and the ICR group. The proportion of patients who received Cordyceps sinensis preparations was significantly higher in the CR group than in the ICR group (84.7% vs. 59.3%, p = 0.013). Information on the treatments used by the 99 patients during hospitalization is shown in Table 2.
Table 2.
Treatment of the 99 patients with HFRS-AKI during hospitalization.
| Treatments | Total (n = 99) |
Complete Recovery (n = 72) |
Incomplete Recovery (n = 27) |
P value |
|---|---|---|---|---|
| CRRT (%) | 42 (42.4) | 30 (41.7) | 12 (44.4) | 0.823 |
| Glucocorticoids (%) | 34 (34.3) | 23 (31.9) | 11 (40.7) | 0.479 |
| Cordyceps sinensis preparations (%) | 77 (77.8) | 61 (84.7) | 16 (59.3) | 0.013* |
| Antivirus (%) | 6 (6.1) | 4 (5.6) | 2 (7.4) | 0.663 |
*p < 0.05. CRRT, continuous renal replacement therapy.
3.3. Regression analysis
To identify factors associated with kidney outcomes in patients with HFRS-AKI, univariate logistic regression was performed on the baseline characteristics and treatment variables (Table 3). The results revealed that facial flushing (OR: 3.120, 95% CI: 1.177–8.269, p = 0.022) and high platelet count at baseline (OR: 1.005, 95% CI: 1.000–1.009, p = 0.004) may be risk factors for the poor kidney outcome. However, the use of Cordyceps sinensis preparations during hospitalization was significantly negatively associated with incomplete kidney recovery (OR: 0.227, 95% CI: 0.066–0.777, p = 0.018).
Table 3.
Univariate analysis of factors associated with poor kidney outcome in 99 patients.
| Infactors | OR (95% CI) | P value |
|---|---|---|
| Sex, male (%) | 1.777 (0.539–5.859) | 0.345 |
| Age (years) | 0.994 (0.960–1.029) | 0.724 |
| Course (days) | 1.045 (0.992–1.101) | 0.100 |
| Fever (%) | 1.346 (0.262–6.924) | 0.722 |
| Hypotension | 1.161 (0.277–4.856) | 0.838 |
| Oliguria | 1.130 (0.444–2.875) | 0.797 |
| Facial flushing | 3.120 (1.177, 8.269) | 0.022* |
| Redness of the neck | 1.615 (0.433–6.029) | 0.476 |
| Redness of the chest | 1.771 (0.574–5.465) | 0.320 |
| Headache | 2.406 (0.933–6.207) | 0.069 |
| Low back pain | 1.257 (0.514–3.076) | 0.616 |
| Retro-orbital pain | 0.713 (0.083–6.143) | 0.758 |
| White blood cells | 0.993 (0.924–1.066) | 0.840 |
| Red blood cells | 1.188 (0.662, 2.132) | 0.563 |
| Hemoglobin | 0.999 (0.980–1.018) | 0.886 |
| Platelets | 1.005 (1.000–1.009) | 0.044* |
| Serum creatinine | 0.971 (0.833–1.131) | 0.706 |
| Urea nitrogen | 1.000 (0.985–1.015) | 0.979 |
| Albumin | 1.064 (0.998–1.134) | 0.058 |
| Globulin | 1.063 (0.972–1.164) | 0.181 |
| ALT | 0.997 (0.990–1.003) | 0.332 |
| AST | 0.998 (0.992–1.003) | 0.393 |
| Urine NAG | 1.001 (0.990–1.013) | 0.815 |
| Urine RBP | 1.025 (0.998–1.064) | 0.188 |
| Proteinuria | 0.963 (0.660–1.407) | 0.847 |
| Hematuria | 0.877 (0.555–1.386) | 0.574 |
| CRRT (%) | 1.120 (0.459–2.733) | 0.803 |
| Glucocorticoids (%) | 1.465 (0.587–3.652) | 0.413 |
| Cordyceps sinensis preparations (%) | 0.262 (0.096–0.714) | 0.009* |
| Antivirus (%) | 1.360 (0.234–7.891) | 0.732 |
*p < 0.05. ALT, alanine aminotransferase; AST, aspartate aminotransferase; NAG, N-acetyl-β-D-glucosaminidase; RBP, retinol-binding protein; CRRT, continuous renal replacement therapy.
To identify independent factors influencing kidney outcomes in patients with HFRS-AKI, variables that showed statistical significance in both the intergroup comparisons and the univariate regression analysis were included in a subsequent multivariate regression model. Notably, although the baseline platelet count was significantly different in the univariate analysis (p < 0.05), its odds ratio (OR) was 1.005 (95% CI: 1.000–1.009) which indicating a negligible effect size in terms of clinical impact. Therefore, the platelet count was excluded from the multivariate analysis to focus on more robust predictors. In addition, baseline serum creatinine was retained in the final multivariate model to adjust for potential confounding effects related to AKI severity. After adjustment, the results confirmed that use of Cordyceps sinensis preparations during hospitalization was an independent protective factor against the poor kidney outcome (OR: 0.323, 95% CI: 0.114–0.916, p = 0.034) (Table 4).
Table 4.
Multivariate analysis of factors associated with poor kidney outcome in 99 patients.
| Infactor | OR (95% CI) | p-value |
|---|---|---|
| Facial flushing | 2.438 (0.872–6.814) | 0.089 |
| Serum creatinine | 0.968 (0.819, 1.143) | 0.698 |
| Cordyceps sinensis preparations (%) | 0.323 (0.114–0.916) | 0.034* |
*p < 0.05.
3.4. Sensitivity analysis
A sensitivity analysis was performed using IPTW to further adjust for potential confounding factors. Covariates included in the propensity score model were selected based on clinical relevance and prior knowledge, including age, sex, serum creatinine, hypotension, and oliguria. The balance diagnostic confirmed that all baseline covariates achieved adequate balance between the use of Cordyceps sinensis preparations group and the control group (standardized mean differences < 0.1) (Figure S1). After weighting, the association between the use of Cordyceps sinensis preparations and CKD remained statistically significant (β: −1.184, 95% CI: −2.224 – −0.144, p = 0.026).
3.5. Survival analysis
The median follow-up time for the 99 patients was 112 (IQR 41.75–169.75) days. To further investigate the effect of using Cordyceps sinensis preparations during HFRS-AKI, the Kaplan–Meier survival analysis was conducted. Patients were stratified into two groups on basis of whether they received Cordyceps sinensis preparations during hospitalization. The endpoint event was defined as the progression to CKD. Kaplan–Meier survival analysis revealed a significant improvement in kidney event-free survival for patients treated with Cordyceps sinensis preparations compared with those who did not (log-rank test, p = 0.004) (Figure 2).
Figure 2.
Kidney survival curves. Comparison of kidney survival curves between the Received Cordyceps sinensis Preparations group and the No Cordyceps sinensis Preparations group (log-rank test, p = 0.0004). Progression to chronic kidney disease (CKD) was defined as the primary endpoint. Patients were stratified into a received Cordyceps sinensis preparations group and a no Cordyceps sinensis preparations group on the basis of the use of cordyceps preparation during the acute phase of AKI. Kaplan–Meier analysis was performed to compare cumulative kidney survival between the two groups.
4. Discussion
This study is the first to demonstrate that the use of a Cordyceps sinensis preparations during AKI is associated with improved kidney outcomes in patients with HFRS-AKI. Moreover, we report that among patients with HFRS-AKI from China who received medical care, 27.3% progressed to CKD.
Hantaviruses belong to the genus Orthohantavirus within the family Hantaviridae, order Bunyavirales [12]. Infection can lead to HFRS in Europe and Asia or hantavirus cardiopulmonary syndrome (HCPS) in the Americas. HFRS is primarily caused by several viral species, including Puumala (PUUV), Hantaan (HTNV), Seoul (SEOV), and Dobrava-Belgrade (DOBV). PUUV is endemic mainly in Europe and Russia, causing a milder form of HFRS with a case fatality rate of less than 1%. HTNV, which is prevalent in East Asian countries such as China and South Korea, often leads to severe HFRS, with fatality rates ranging from 5% to 15%. SEOV is globally distributed and generally causes less severe illness, with a case fatality rate of approximately 1–2%. DOBV is found primarily in the Balkan region and is associated with a severe disease course, with a case fatality rate of up to 10–12% [5,8,13,14]. China with a high-incidence region for HFRS, accounting for approximately 90% of reported global cases [15]. The predominant hantavirus subtypes in China are HTNV and SEOV [16].
Kraft et al. [17] evaluated 156 individuals with a history of HFRS-AKI, up to 20 years after confirmed PUUV infection. CKD was diagnosed in 8% of the patients in their cohort. The incidence of CKD observed in our cohort was notably higher than that reported by Kraft et al. (27.3% vs. 8%). This inconsistency may be attributable to differences in the studied populations. The cohort in Kraft et al.’s study consisted of patients with PUUV-induced HFRS-AKI, which is generally associated with a milder disease course. In contrast, our study population was derived from China, where the dominant circulating hantavirus subtypes are HTNV and SEOV. Compared with PUUV, HTNV and SEOV are known to cause more severe HFRS. Additionally, the relatively short follow-up period in our study may limit the ability to fully capture long-term kidney outcomes. Future studies with extended follow-up are needed to evaluate the long-term kidney outcomes in these patients. However, differences in pathogenicity and the rate of progression to CKD may also exist between HTNV and SEOV infections. The individual-level viral typing was unavailable in our retrospective cohort, so we could not determine whether the risk of subsequent CKD differed according to the causative hantavirus. Future studies incorporating virological characterization are therefore warranted to clarify whether virus-specific pathogenicity contributes to heterogeneity in long-term kidney outcomes.
Currently, there is no specific therapy for patients with AKI during HFRS. Management primarily relies on supportive care, including fluid management and kidney replacement therapy. Glucocorticoids may be considered for severe cases. No specific antiviral agent targeting hantaviruses has been established. Although some teams have used ribavirin as an antiviral intervention, emerging evidence has shown that ribavirin does not improve overall kidney outcomes in patients with AKI during HFRS [18–20]. In our study, 6.1% of patients received the antiviral agent ribavirin. Our study showed no evidence that antiviral treatment improved kidney outcomes in patients with HRFS-AKI.
Cordyceps sinensis is a prized traditional Chinese medicine belonging to the fungus family Clavicipitaceae. Cordyceps sinensis preparations approved by the CFDA are widely used in China as adjunctive therapy for patients with CKD, because of their well-recognized antifibrotic effects [21–24]. However, the efficacy of Cordyceps sinensis preparations in treating virus-induced AKI remains unclear. Clinical evidence for the application of Cordyceps sinensis preparations in patients with HFRS-AKI patients still lacking.
Clinical observational studies suggest that Cordyceps sinensis preparations offer protection against the nephrotoxic effects of aminoglycoside antibiotics [25]. In patients receiving cisplatin chemotherapy, pre-administration of Cordyceps sinensis preparations significantly mitigated cisplatin-associated kidney injury. Moreover, systematic reviews have shown that the prophylactic use of Cordyceps sinensis preparations may reduce the incidence of contrast-associated AKI [26]. These clinical studies indicate the potential protective effects of Cordyceps sinensis on patients with HFRS-AKI.
Although Cordyceps sinensis is not considered an antiviral agent, several studies have reported its direct antiviral effects on HIV infection, HINI infection, and Dengue virus infection [27–29]. However, the role of Cordyceps sinensis in antihantavirus activity is completely unknown. Future research could explore the impact of Cordyceps sinensis preparations on the replication of hantavirus through in vivo and in vitro experiments.
Existing evidence suggests that the anti-inflammatory, anti-apoptotic, antioxidant, and pro-repair properties of Cordyceps sinensis [30–32]. It has been reported that Cordyceps sinensis upregulates the expression of the epidermal growth factor (EGF) in kidney tissue, enhancing the regeneration and proliferation of kidney tubular epithelial cells and accelerating kidney functional recovery in an AKI rat model [33]. Additionally, Cordyceps sinensis can improve kidney hemodynamics, enhance mitochondrial respiratory function, ameliorate endoplasmic reticulum stress, and facilitate the repair of damaged cells, thereby attenuating cyclosporine A-induced nephrotoxicity in mouse models [34,35]. A recent study revealed that Cordyceps sinensis suppresses perforin expression in natural killer cells through the STING/IRF3 pathway, thereby protecting the kidney from acute injury [36]. Cordyceps sinensis alleviates ischemia–reperfusion–induced AKI by reducing inflammatory responses and inhibiting kidney tissues apoptosis [37,38].
In addition to Cordyceps sinensis, a variety of traditional Chinese medicines are widely used in clinical practice for the treatment of kidney diseases. Emerging evidence indicates that bioactive compounds derived from traditional Chinese medicines exert protective effects on both acute and chronic kidney diseases through multitarget and multipathway mechanisms [39–42]. For instance, anthraquinones confer protection in AKI or CKD by modulating TGF-β1/Smad, IκB/NF-κB, Keap1/Nrf2, and Wnt/β-catenin signaling, as well as by regulating apoptosis and autophagy [43]. Natural flavonol fisetin has been shown to alleviate septic AKI by inhibiting inflammatory responses and mitigating fibrotic kidney diseases by inhibiting ACSL4-mediated tubular ferroptosis [44,45]. In addition, alginate oligosaccharides attenuate kidney ischemia-reperfusion-induced AKI via the MRC1-mediated pathway [46]. Collectively, these findings suggest that the use of Cordyceps sinensis preparations, as herbal-derived agents, may confer protection against the transition from HFRS-induced AKI to CKD by modulating key signaling pathways involved in AKI and CKD pathogenesis.
Viral infection-induced immune activation in the kidneys may also be an important factor influencing kidney outcomes in patients with HFRS-AKI. In HFRS, the development of AKI involves reduced effective circulating volume, decreased kidney blood flow, increased renin-angiotensin activity, microthrombosis in glomeruli, and injury to antigen–antibody complexes. Compared with kidney tissue from patients with purely ischemic AKI, kidney tissue from patients with HFRS-AKI shows marked overexpression of immune-related molecules such as human leukocyte antigen-DR (HLA-DR), intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated antigen-1 (LFA-1), which are positively correlated with the severity of tubular lesions. Furthermore, inflammatory cell infiltration is significantly observed in the kidney interstitium of patients with HFRS-AKI [47]. Our previous work also revealed that glomerulopathy coexists in some patients with HFRS-AKI, and that those with glomerular lesions are more prone to progression to CKD [48]. These observations suggest that immune mechanisms contribute to kidney injury in patients with HFRS and may affect long-term kidney outcomes. Notably, existing evidence indicates that Cordyceps sinensis possesses strong immunomodulatory properties [49,50]. Lupus nephritis, a classic immune-related nephritis, provides a clinical example. Clinical studies have shown that the combination of Cordyceps sinensis preparations and artemisinin significantly reduces relapse in patients with lupus nephritis [51]. Basic studies have shown that early administration of Cordyceps sinensis induces the redistribution of peripheral blood monocytes and mitigates disease severity in murine models of lupus [52]. In addition, Cordyceps sinensis improves the symptoms of lupus nephritis by inhibiting inflammatory signaling pathways, suppressing the differentiation of pro-inflammatory Th1 cells, and altering the intestinal barrier [53–55]. Furthermore, in a rodent model of allogeneic heart transplantation, Cordyceps sinensis synergized with cyclosporine A to significantly reduce CD8+ T-cell activity, thereby suppressing acute rejection and alleviating allograft vasculopathy [56,57]. These findings suggest that Cordyceps sinensis preparations may counteract hantaviruses-mediated kidney injury through their immunomodulatory effects, thereby improving kidney outcomes. The role of Cordyceps sinensis preparations in regulating the immune function of HFRS-AKI requires further investigation.
This study has several limitations. First, this was a single-center, retrospective investigation with a relatively small sample size, which may introduce selection bias and limit the generalizability of the findings. Second, the current study focused exclusively on kidney outcomes in patients with HFRS-AKI and did not systematically evaluate other organ systems that may be affected by hantavirus. Expanding these observation to include patients with multi-organ involvement in future studies will help clarify whether Cordyceps sinensis preparations also confer protective effects on extranephric manifestations of HFRS. In addition, the follow-up duration in this study was relatively short, which may have influenced the results. Longer-term follow-up is warranted to validate further the effects of Cordyceps sinensis preparations on long-term renal outcomes in patients with HFRS-AKI. Finally, different Cordyceps sinensis preparations were analyzed as a single exposure in this study. Given the potential variability in formulation, bioavailability, and pharmacological properties across products, these agents may not be directly equivalent. Future studies with standardized formulations are warranted. It should also be noted that the regulatory status of Cordyceps sinensis preparations varies across countries and they are not universally approved as pharmaceutical drugs outside China. Differences in regulatory status, product composition, standardization, and manufacturing practices should therefore be considered when extrapolating our findings to other settings.
5. Conclusion
This study demonstrated that the use of Cordyceps sinensis preparations in the acute phase of AKI is associated with improved kidney outcomes in patients with HFRS-AKI. Our findings provide clinical evidence supporting the application of Cordyceps sinensis preparations in the management of HFRS-AKI and highlight the broader, yet underexplored, therapeutic prospects of traditional Chinese medicine.
Supplementary Material
Acknowledgments
Thanks to the National Clinical Research Center of Kidney Diseases, Jinling Hospital, for providing the clinical data.
Funding Statement
This work was supported by Key Medical Research Project of Jiangsu Provincial Health Commission, “Application Research of Multimodal Imaging System for Renal Function in the Diagnosis, Prognosis, and Targeted Intervention of Acute Kidney Injury” (K2024051) and Jiangsu Provincial Medical Innovation Team “Chronic Kidney Disease Mineral and Bone Disorder” (CXTDA2017011).
Ethical approval
The protocol of this study was conducted in accordance with the Declaration of Helsinki and was approved by Institutional Review Boards evaluated at Jinling Hospital (Approval No. 2026DZKY-130-01).
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data of this 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.
Supplementary Materials
Data Availability Statement
The data of this study are available from the corresponding author upon reasonable request.