Fermented Ophiocordyceps sinensis mycelium products for preventing contrast-associated acute kidney injury: a systematic review of randomized controlled trials

Abstract

Background

To evaluate the efficacy, effectiveness and safety of fermented Ophiocordyceps sinensis mycelium (FOSM) products for preventing contrast-associated acute kidney injury (CA-AKI).

Methods

Randomized controlled trials were searched from four Chinese and four English electronic databases and three clinical trial registries up to July 2023. Methodological quality was assessed by using the Cochrane risk-of-bias tool 2.0. Risk difference (RD) or risk ratio (RR) and mean difference (MD) were calculated along with the 95% confidence intervals (CIs).

Results

Fourteen trials testing three types of FOSM products (Bailing, Zhiling, and Jinshuibao capsules) involving 1271 participants injected contrast agents were included. For the risk of bias, all trials were rated as some concerns. Compared with routine preventive procedure (RPP) (saline hydration and alprostadil), FOSM products plus RPP showed beneficial effects in reducing the incidence of CA-AKI (14.62% and 5.35%, respectively; RD −0.06, 95% CI −0.09 to −0.03). Subgroup analysis showed that Bailing/Jinshuibao plus RPP demonstrated lower incidence of CA-AKI compared to RPP. However, there was no statistically significant difference between Zhiling with RPP and RPP in the incidence of CA-AKI. Additionally, only when FOSM products were taken before injection of the contrast, it was superior to RPP in reducing the incidence of CA-AKI. There was no statistical difference in adverse events between these two groups.

Conclusions

Low certainty evidence suggests that preventive oral use of FOSM products as an adjuvant agent was safe and might decrease the incidence of CA-AKI. However, high-quality placebo-controlled trials are needed to confirm its benefit.

Keywords:

• Chinese patent medicine
• Ophiocordyceps sinensis
• contrast-associated acute kidney injury
• randomized clinical trials
• systematic review

1. Introduction

Contrast agents are widely used in radiology, but are associated with increased risk of renal impairment [1,2]. Contrast-associated acute kidney injury (CA-AKI) is defined as an increase in serum creatinine (Scr) levels by at least 25% above baseline or 44 µmol/L from the pre-contrast value within 48–72 h of administering a contrast agent [3,4]. The incidence of CA-AKI depends on the population and risk factors, with rates as high as 30–50% in high-risk groups [5–7]. CA-AKI was once regarded a leading cause of hospital-acquired renal failure, resulting in longer hospital stays, higher costs, and increased mortality [8]. With better design of contrast agents, improved recognition of risk factors, and preventive care, the prevalence of CA-AKI has reduced; however, it remains an important clinical concern, for which new prophylactic and therapeutic strategies are needed [1,2].

Prevention remains the most important strategy against CA-AKI. Current preventive strategies include risk assessment, selection of low osmolality and iso-osmolality, instead of high osmolality, contrast materials and discontinuation of nephrotoxic drugs, as well as using the lowest necessary doses of contrast agents and administering intravenous isotonic sodium chloride in high-risk populations, such as those with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² [3]. Drugs like antioxidants (N-acetylcysteine, ascorbic acid) and statins have been reported to be effective in preventing CA-AKI in small clinical trials [9,10], but none of them have shown benefits in properly designed large randomized controlled trials (RCTs) and current evidence supports hydration as the standard care for preventing CA-AKI in high-risk populations [1,11–14], although a RCT published in The Lancet in 2017 did not find any difference in the incidence of CA-AKI between the intravenous hydration group (2.7%) and the non-hydrated control group (2.6%) [15]. Besides, whether bicarbonate-based hydration is superior to normal saline for preventing CA-AKI is still controversial [16–18] and no conventional drugs can be not recommended for preventing CA-AKI [19,20].

Emerging preclinical and clinical evidence suggests that herbal and fungal drugs could be an important resource for the prevention and treatment of AKI, including CA-AKI [21]. For example, Cordyceps is a genus of fungi that include Ophiocordyceps sinensis, also widely known by its synonym Cordyceps sinensis, Cordyceps militaris, and Cordyceps cicadae, etc. [22,23]. The most famous and historically influential species of Cordyceps is O. sinensis, a precious tonic Chinese medicine, which was first recorded in the eighth century AD in Somaratsa [24]. O. sinensis has various physiological properties, such as anti-inflammatory, anti-oxidative, anti-fibrogenic, and renoprotective effects [21,25,26]. Due to the scarcity of natural resources and technical challenges in cultivating O. sinensis, there has been growing interests in exploring possible substitutes for natural O. sinensis, for example, using fermented O. sinensis mycelia (FOSM) or C. militaris, cultivation of which have been successfully, as discussed elsewhere [22,25,27]. At the moment, O. sinensis-based Chinese patent medicines sold in China all contain FOSM rather than natural O. sinensis, and these FOSM products include Jinshuibao, Bailing, Zhiling, Xinganbao, and Ningxinbao, none of which contains any ingredients other than FOSM. Additionally, North America was the largest region in the Cordyceps sinensis market in 2022. The regions covered in the Cordyceps sinensis market report are Asia-Pacific, Western Europe, Eastern Europe, North America, South America, Middle East, and Africa, said the business research company [28].

Several systematic reviews of clinical trials have documented the effects of FOSM products in treating patients with chronic kidney disease, including diabetic nephropathy, and patients with end-stage kidney disease on hemodialysis and after renal transplantation [29–32]. An earlier scoping review has found FOSM products among those herbal medicines that could be of value in AKI patients [21], but to date, there is no systematic review evaluating the clinical effects of FOSM products on CA-AKI. Hence, we conducted a synthesis of relevant RCTs to examine the efficacy, effectiveness, and safety of FOSM products in the prevention and treatment of CA-AKI.

2. Methods

This systematic review was reported following the PRISMA 2020 statement [33]. The protocol was registered with INPLASY (INPLASY202260098; https://inplasy.com/inplasy-2022-6-0098/).

2.1. Eligibility criteria

Original studies were included when they meet the following inclusion criteria: (1) participants: all participants who received intravascular injection of contrast agent, irrespective of age or presence of kidney disease; (2) interventions: FOSM products alone or in combination with other preventive procedure. Other Cordyceps species, such as C. militaris, were also included; (3) comparators: no intervention or any intervention that aimed to reduce the incidence of CA-AKI; (4) outcomes: primary: the incidence of CA-AKI; secondary: Scr level, eGFR, the need for dialysis, blood urea nitrogen (BUN) level, interleukin 18 (IL-18) level, kidney injury molecule-1 (KIM-1) level, superoxide dismutase (SOD) level, neutrophil gelatinase-associated lipocalin (NGAL) level, cystatin C (Cys C) level, malondialdehyde (MDA) level; safety outcomes: adverse events. (5) Studies: parallel-group RCTs.

2.2. Search strategies

PubMed, the Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), SinoMed, and WanFang Data were searched from inception to June 2022. We also explored the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the Chinese Clinical Trial Registry for ongoing or unpublished trials to July 2023. Search terms include ‘Cordyceps’ AND ‘contrast agent’ AND ‘acute kidney injury’. The additional search terms and strategies in different databases are displayed in Supplementary Appendix A1.

2.3. Study selection and data extraction

NoteExpress (Beijing Aegean Software company, Rev 3.4.0.8878, Beijing, China) was used to manage and check the literature. Two authors independently screened titles and abstracts for potential eligible studies. These selected studies were then assessed again independently in full text by the same authors to eliminate the duplicated studies and identify eligible studies. Any disagreement was resolved by discussion with third author.

Data were extracted independently by two authors using standard data extraction forms. Where specific data were not available from the included studies, more detailed information was sought by contacting the corresponding author of the trial.

2.4. Quality assessments and certainty of evidence

The version 2 of the Cochrane risk-of-bias tool (RoB 2) [34] was used to assess the risk of bias for included studies by two authors independently. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence grading system was used to evaluate the evidence quality of the main outcome indicators [35].

2.5. Data synthesis

This study used STATA (version 15.0, Stata SE, College Station, TX) for statistical analysis. Dichotomous data were expressed by risk ratio (RR) with 95% confidence interval (CI), and continuous data were expressed by mean difference (MD) with 95% CI. The standard mean difference (SMD) was used for results reported by various measurement methods or different measurement scales.

For multi-arm trials that met the inclusion criteria, we divided the shared control groups equally or combined all relevant experimental interventions from the study into one group. In addition, we used the risk difference (RD) to analyze studies with no events in either arm [36].

2.6. Assessment of heterogeneity and publication bias

Heterogeneity was determined by the Q-statistical test and I²-statistical test. According to the Cochrane Handbook of Heterogeneity Analysis, I² values between 50% and 90% may represent substantial heterogeneity; 75–100% means considerable heterogeneity [37]. A fixed-effects model was adopted if I² <50%; otherwise, a random-effects model would be applied. If 10 or more studies were included in the meta-analysis, the publication bias in these studies would be assessed using Egger’s test and funnel plots.

2.7. Subgroup analysis and sensitivity analysis

If sufficient study data were available, subgroup analyses of the primary outcomes were performed in the following groups: type and the starting time of application of FOSM products. p Value <.05 is considered statistically significant. We performed a sensitivity analysis for indicators with significant heterogeneity (I² >50%) to test the robustness of the results.

3. Results

3.1. Eligible studies

A total of 14 RCTs [38–51] were included in this study, and details of the literature search are shown in Figure 1. Records screened and exclusion reasons are shown in Supplementary Appendix A2. A total of 1271 participants received intravascular injections of contrast agents (688 in the experimental group and 583 in the control group), all from China. Eleven clinical trials [41–51] were published in Chinese and other three [38–40] in English, which were published between 2011 and 2021.

Figure 1. PRISMA flowchart of literature screening and selection.

3.2. Characteristics of included studies

Participants in nine studies [38–40,42,43,45,47,48,50] received the percutaneous coronary intervention (PCI) and two studies [41,46] received coronary angiography, both with an arterial injection of contrast. In addition, two studies [44,51] received coronary CT angiography (CTA), with an intravenous injection of contrast, and one study [44] did not mention the type of examination or injection method of contrast agents. Nine studies [38,39,41–44,48,49,51] used low-osmolar nonionic iodinated contrast agents, and three studies [40,47,50] used iso-osmolar nonionic iodinated contrast agents, with no statistical difference in the doses of contrast agents used in either the experimental or control groups. Besides, one study [46] only mentioned the contrast agent containing iodine and one study [45] did not report the type of contrast agent, none of which mentioned the osmotic pressure. The baseline Scr levels were not statistically different between the experimental and control groups in all studies. Eight studies [38,40,42,43,47–49,51] showed no statistical difference in eGFR between the two groups at baseline, and the mean eGFR was >30 mL/min·1.73 m² in all studies. Seven of the included trials reported detailed funding sources or conflicts of interest, while the other seven did not report funding sources.

A total of three FOSM products were involved in the included studies: Bailing capsule (six trials) [38–40], Jinshuibao capsule (seven trials) [41,44–48,50], and Zhiling capsule (one trial) [51]. The treatment groups of 12 trials used FOSM products in addition to the control group, the remaining two [44,45] used FOSM products alone. The control group includes saline hydration and alprostadil, so we summarized it as routine preventive procedure (RPP). The baseline Scr levels were not statistically different between the experimental and control groups in all studies. The basic information is shown in Table 1, other detailed information (publish language, study aim, study setting, funding, the definition of CA-AKI, contrast medium injection type, participants sex, complications, baseline creatinine, and baseline eGFR) is shown in Supplementary Table.

Table 1. Basic information of the included studies.

Study ID	Country	Contrast agent	Dose of contrast agent (mL)	N (T/C)	Mean age (SD)	Comparison	Treatment		Control				Maximum follow-up time	Outcomes
							Drug	Patterns of drug intake	Course of treatment	Drug	Patterns of drug intake	Course of treatment
Xu [49]	China	Low-osmolar nonionic contrast media	–	T: 30; C: 10	T: 47.57 ± 13.22; C: 48.60 ± 10.77	FOSM + control group vs. control group	Bailing capsule (1 g, tid)	Oral	7 d before till 7 d after injection of the contrast	Half-isotonic saline (1 mg/kg/h)	Injection	12 h before till 12 h after injection of the contrast	7 d	②④
Liao et al. [45]	China	–	–	T: 20; C: 20	T: 70.4 ± 5.4; C: 69.6 ± 6.1	FOSM vs. blank control	Jinshuibao capsule (1 g, tid)	Oral	7 d following the contrast injection	–	–	–	7 d	④⑤
Zhao et al. [39]	China	Low-osmolar nonionic contrast media	C: 248.9 ± 48.7; T: 246.8 ± 49.7	T: 52; C: 51	T: 62.58 ± 3.71; C: 63.9 ± 4.3	FOSM + control group vs. control group	Bailing capsule (3 g, tid)	Oral	3 d before till 3 d after injection of the contrast	Normal saline (1 mL/kg/h)	Injection	6 h before till 12 h after injection of the contrast	3 d	①④⑥⑦
Zhao et al. [40]	China	Iso-osmolar nonionic contrast media (iodixanol: 320 mg/mL)	C: 246.87 ± 49.76; Ts: 248.86 ± 48.68; Ti: 250.85 ± 50.73	Ts: 49; Ti: 50; C: 51	Ts: 63.95 ± 4.27; Ti: 65.13 ± 6.26; C: 64.59 ± 5.72	FOSM + control group vs. control group	Ts: Bailing capsule (2 g, tid); Ti: Bailing capsule (3 g, tid)	Oral	3 d before till 3 d after injection of the contrast	Half-isotonic saline (1 mg/kg/h)	Injection	12 h before till 12 h after injection of the contrast	3 d	①②③④⑥⑦⑧⑨
Shi [46]	China	Iodinated contrast	C: 107.2; T: 110.4	T: 40; C: 40	T: 65.1 ± 9.5; C: 66.2 ± 9.1	FOSM + control group vs. control group	Jinshuibao capsule (1 g, tid)	Oral	7 d following the contrast injection	Normal saline (1 mL/kg/h)	Injection	12 h before till 12 h after injection of the contrast	7 d	④⑤
Zhang et al. [50]	China	Iso-osmolar nonionic contrast media (iodixanol)	–	T: 30; C: 30	–	FOSM + control group vs. control group	Jinshuibao capsule (1 g, tid)	Oral	3 d before till 5 d after injection of the contrast	Normal saline (1 mL/kg/h)	Injection	2 h before till 12 h after contrast	2 d	③④⑤⑧⑨
Zhao et al. [38]	China	Low-osmolar nonionic contrast media (iopamidol)	C: 246.85 ± 49.74; Ts: 248.87 ± 48.69; Ti: 250.87 ± 50.72	Ts: 39; Ti: 40; C: 41	Ts: 63.94 ± 4.26; Ti: 65.12 ± 6.27; C: 64.58 ± 5.71	FOSM + control group vs. control group	Ts: Bailing capsule (2 g, tid); Ti: Bailing capsule (3 g, tid)	Oral	3 d before till 3 d after injection of the contrast	Normal saline (1 mL/kg/h)	Injection	6 h before till 12 h after injection of the contrast	3 d	①②③④⑥⑦⑧⑨
Liang et al. [44]	China	Low-osmolar nonionic contrast media (iopromide: 370 mg/mL)	The dosage was calculated according to the patient’s body mass index. The injection speed is 5–7 mL/min.	T: 40; C: 40	T: 62.5 ± 4.6; C: 64.5 ± 3.8	FOSM vs. control group	Jinshuibao capsule (1 g, tid)	Oral	2 d before till 3 d after injection of the contrast	Normal saline (350 mL)	Oral	30 min following the contrast injection	3 d	①
Cao et al. [41]	China	Low-osmolar nonionic contrast media (iohexol)	The dosage was calculated according to the patient’s body mass index. The injection speed is 5–6 mL/min.	T: 30; C: 30	–	FOSM + control group vs. control group	Jinshuibao capsule (1 g, tid)	Oral	2 d before till 3 d after injection of the contrast	Normal saline (1 mL/kg/h)	Injection	2 h before till 12 h after injection of the contrast	2 d	①③④⑤⑧⑨
Wang et al. [48]	China	Low-osmolar nonionic contrast media (iohexol)	C: 115.6 ± 28.1; T: 118.2 ± 23.2	T: 50; C: 50	T: 61.2 ± 10.5; C: 62.3 ± 9.3	FOSM + control group vs. control group	Jinshuibao capsule (1 g, tid)	Oral	1 d before till 4 d after injection of the contrast	Shenkang injection (40 mL, qd) + 5% glucose liquid (250 mL, qd)	Injection	1 d before till 4 d after injection of the contrast	3 d	①②③④⑤⑧
Song [47]	China	Iso-osmolar nonionic contrast media (iopromide)	C: 145.06 ± 10.38; T: 144.26 ± 10.21	T: 100; C: 100	T: 65.25 ± 12.34; C: 64.87 ± 12.51	FOSM + control group vs. control group	Jinshuibao capsule (1 g, tid)	Oral	12 h before till 4 d after injection of the contrast	Alprostadil (100–200 μg, qd)	Injection	12 h before till 4 d after injection of the contrast	4 d	①②③④⑤⑧⑨
Dong and Mao [42]	China	Low-osmolar nonionic contrast media (iohexol: 300 mg/mL)	C: 127.01 ± 14.84; T: 125.11 ± 13.08	T: 40; C: 40	T: 56.03 ± 5.17; C: 55.85 ± 4.83	FOSM + control group vs. control group	Bailing capsule (3 g, tid)	Oral	3 d before till 7 d after injection of the contrast	Alprostadil (10 μg, qd) + normal saline (100 mL, qd)	Injection	3 d before till 7 d after injection of the contrast	7 d	①②③④⑤⑧⑨
Li et al. [43]	China	Low-osmolar nonionic contrast media (iohexol: 300 mg/mL)	C: 127.01 ± 15.22; T: 127.11 ± 15.41	T: 51; C: 51	T: 61.03 ± 8.17; C: 60.91 ± 7.83	FOSM + control group vs. control group	Bailing capsule (3 g, tid)	Oral	1 d before till 3 d after injection of the contrast	Alprostadil (10 μg, qd) + normal saline (100 mL, qd)	Injection	1 d before till 3 d after injection of the contrast	3 d	①②③④⑤⑧⑨
Zhou [51]	China	Low-osmolar nonionic contrast media (iohexol: 350 mg/mL)	C: 100; T: 100	T: 27; C: 29	T: 65.56 ± 16.84; C: 71.45 ± 10.63	FOSM + control group vs. control group	Zhiling mycelium capsule (1 g, tid)	Oral	3 d before till 3 d after injection of the contrast	Baoshen tablet (9.68 g, tid)	Oral	3 d before till 3 d after injection of the contrast	1 m	①②③④⑤⑧⑨

T: trial group; C: control group; SD: standard deviation; FOSM: fermented O. sinensis mycelia; Ts: standard dosage of FOSM product; Ti: intensive dosage of FOSM product; ① the incidence of CA-AKI; ② eGFR (estimated glomerular filtration rate) level; ③ need for dialysis; ④ serum creatinine level; ⑤ blood urea nitrogen level; ⑥ interleukin 18 level; ⑦ kidney injury molecule-1 level; ⑧ adverse events; ⑨ other indicators.

3.3. Risk of bias in included studies

All 14 trials [38–51] showed ‘some concerns’ in terms of overall risk of bias. Regarding the randomization process, eight trials [38–40,42,43,47,48,51] used a random number table, two trials [44,49] used a simple random assignment method, one trial [50] used an incorrect randomization method, and the remaining three trials [41,45,46] only mentioned randomization and did not describe the detailed randomization method. All trials did not provide allocation concealment information. No blinded information was mentioned in any of the trials. None of the included trials reported any missed visits. The risk of bias due to selective reporting of outcomes was assessed as some concerns for all trials, as none of the trial protocols were available for review. Figure 2 shows the methodological quality of the included trials.

Figure 2. Risk of bias of the included trials. (A) Risk of bias summary; (B) risk of bias graph.

3.4. Primary outcomes

3.4.1. Incidence of contrast-associated acute kidney injury

Eleven trials compared FOSM products plus RPP versus RPP for the incidence of CA-AKI. The pooled results showed that the Cordyceps group was superior to the routine group in reducing the incidence of CA-AKI (5.35% and 14.62%, respectively; RD = −0.06, 95% CI −0.09 to −0.03, 11 trials [38–44,46–48,50,51], 1111 participants; low certainty) (Figure 3(A)).

Figure 3. Forest plot of incidence of contrast-associated acute kidney injury (A), serum creatinine level (B), and epidermal growth factor receptor level (C) for Fermented O. sinensis mycelia products plus routine preventive procedure versus routine preventive procedure.

The results of subgroup analysis based on the type of FOSM products showed that the bailing plus routine prevention (5.30% and 14.10%, respectively, p < .05) or Jinshuibao plus routine prevention (5.6% and 15.6%, respectively, p < .05) demonstrated lower incidence of CA-AKI compared to routine prevention. However, there was no statistical difference in Zhiling (3.7% and 10.34%, respectively, p > .05).

Subgroup analysis based on the moment of intervention of FOSM products showed that, FOSM products taken before injection of the contrast, the Cordyceps group was superior to the routine group in reducing the incidence of CA-AKI (RD = −0.06, p < .05). When FOSM products were taken after injection of the contrast, there was no statistical difference between the FOSM group and the routine group (RD = −0.02, p > .05) (Table 2).

Table 2. Subgroup analysis on the incidence of CA-AKI.

Subgroups	Number of trials	RD/MD	95% CI	p Value	Heterogeneity among trials
Incidence of CA-AKI
Type of FOSM products
BL	5	−0.06	−0.09 to −0.02	p = .001	p = .784; I^2 = 0.0%
ZL	1	−0.07	−0.21 to 0.07	p = .352	–
JSB	5	−0.07	−0.11 to −0.02	p = .007	p = .517; I^2 = 0.0%
The moment of intervention
Before injection of the contrast	10	−0.06	−0.09 to −0.03	p = .000	p = .672; I^2 = 0.0%
After injection of the contrast	1	−0.02	−0.10 to 0.06	p = .569	–

RD: risk difference; MD: mean difference; CI: confidence intervals; FOSM: fermented O. sinensis mycelia; BL: Bailing capsule; ZL: Zhiling capsule; JSB: Jinshuibao capsule; CA-AKI: contrast-associated acute kidney injury; Scr: serum creatinine.

Besides, one trial compared FOSM products alone with normal saline, including 80 participants. The results showed that the FOSM products alone were superior to normal saline in reducing the incidence of CA-AKI (RR = 0.063, 95% CI 0.025–0.100, p = .001, one trial [44], 80 participants).

3.5. Secondary outcomes

3.5.1. Serum creatinine level

Thirteen trials compared FOSM products plus RPP versus RPP for Scr. The pooled results showed that the FOSM product group was superior to the routine group in reducing Scr (MD = −4.61 μmol/L, 95% CI −6.45 to −2.76, I² = 15%, 12 trials [38–43,46–51], 1151 participants; very low certainty) (Figure 3(B)).

3.5.2. Epidermal growth factor receptor level

Eight trials comparing FOSM products plus RPP versus RPP reported eGFR. The pooled results showed that the FOSM product group was superior to the routine group in increasing eGFR (MD = 4.10 mL/min-1.73 m², 95% CI 2.24–5.96, I² = 74.8%, eight trials [38,40,42,43,47–49,51], 848 participants) (Figure 3(C)).

3.5.3. Kidney injury molecule-1 level

Three trials comparing FOSM products plus RPP versus RPP reported KIM-1. The pooled results showed that the Cordyceps group was superior to the routine group in reducing KIM-1 (MD = −2.18 ng/mL, 95% CI −3.35 to −1.01, I² = 99.7%, three trials [38–40], 373 participants) (Supplementary Appendix B1).

3.5.4. Need for dialysis

Ten trials comparing FOSM products plus RPP versus RPP reported the need for dialysis. The pooled results showed no difference in the reduction of need for dialysis between the Cordyceps and the routine groups (RD = −0.00, 95% CI −0.01 to 0.01, I² = 0%, 10 trials [38,40–43,45,47,48,50,51], 968 participants) (Supplementary Appendix B2).

3.5.5. Neutrophil gelatinase-associated lipocalin level

Two trials that reported on NGAL compared FOSM products plus RPP with RPP. The pooled results showed that the Cordyceps group was superior to the routine group in reducing NGAL (MD = −17.17 ng/mL, 95% CI −25.94 to −8.41, I² = 91.4%, two trials [38,40], 302 participants) (Supplementary Appendix B3).

3.5.6. Blood urea nitrogen level

Nine trials that reported on BUN compared FOSM products plus RPP with RPP. The pooled results showed that the Cordyceps group was superior to the routine group in reducing BUN (MD = −1.30 mmol/L, 95% CI −2.33 to −0.28, I² = 97.1%, nine trials [41–43,45–48,50,51], 778 participants) (Supplementary Appendix B4).

3.5.7. Cystatin C level

Three trials reporting Cys C compared FOSM products plus RPP with RPP. The pooled results showed that the Cordyceps group was superior to the routine group in reducing Cys C (MD = −0.23 mg/L, 95% CI −0.38 to −0.07, I² = 75%, three trials [41,50,51], 176 participants) (Supplementary Appendix B5).

3.5.8. Malondialdehyde level

Three trials that reported MDA compared FOSM products plus RPP with RPP. The pooled results showed that the Cordyceps group was superior to the routine group in reducing MDA (SMD = −1.58, 95% CI −1.89 to −1.28, I² = 0%, three trials [41,43,50], 222 participants) (Supplementary Appendix B6).

3.5.9. Superoxide dismutase level

Four trials reporting SOD compared FOSM products plus RPP with RPP. Pooled results showed that the Cordyceps group was superior to the routine group in increasing SOD (SMD = 2.82, 95% CI 2.19–3.45, I² = 73%, four trials [41–43,50], 302 participants) (Supplementary Appendix B7).

3.5.10. Interleukin 18 level

Three trials reporting IL-18 compared FOSM products plus RPP with RPP. The pooled results showed that the Cordyceps group was superior to the routine group in lowering IL-18 (MD = −14.23 ng/L, 95% CI −18.58 to −9.89, I² = 96.3%, three trials [38–40], 373 participants) (Supplementary Appendix B8).

3.6. Adverse events

Adverse events were reported in nine studies, and all studies compared FOSM products plus RPP with RPP. Seven of these studies [38,40,41,47,48,50,51] claimed no adverse events in either group. The pooled data from the other two studies [42,43] showed no statistical difference between the Cordyceps and the routine groups in terms of adverse events (Table 3).

Table 3. Adverse events reported in included studies.

Types of adverse events	Total events/total number		Risk ratio (95% CI)	p Value
	Intervention	Control
Acute heart failure	4/506	4/422	0.84 [0.21, 3.32]	.798
Death	2/506	4/422	0.42 [0.06, 2.28]	.314
Recurrent angina pectoris	3/506	7/422	0.36 [0.09, 1.39]	.138
Recurrent myocardial infarction	1/506	2/422	0.42 [0.04, 4.60]	.476
In total	10/506	17/422	0.50 [0.23, 1.08]	.078

CI: confidence intervals.

3.7. Sensitivity analysis

We performed a sensitivity analysis for the incidence of CA-AKI, the levels of eGFR, Scr, KIM-1, NGAL, BUN, Cys C, and IL-18, and all results except BUN level were not reversed, and the results were robust and reliable. Nine trials were included for the BUN level outcome indicator, and after excluding Liao K or Shi B, none of the remaining trials (eight) had statistically significant combined results that were inconsistent with the original combined results (MD = −1.30 mmol/L, 95% CI −2.33 to −0.28).

3.8. Publication bias

Egger’s test showed no publication bias for the incidence of CA-AKI (Figure 4) (t = −0.64, p value = .536).

Figure 4. Publication bias of the included trials on the incidence of contrast-associated acute kidney injury.

3.9. Certainty of evidence

The GRADE tool was applied to assess the certainty of the evidence for incidence of CA-AKI, Scr level, and eGFR level. Most of the evidence were assessed as low or very low certainty (Table 4).

Table 4. Evidence summary of CA-AKI: FOSM products + RPP versus RPP.

Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Treatment	Control	Relative (95% CI)	Absolute (95% CI)
Incidence of CA-AKI
11	Randomized controlled trial	Serious^a	Not serious	Serious^c	Not serious	Undetected	598	513	–	RD 0.06 lower (0.09 lower to 0.03 lower)	⨁⨁◯◯ Low certainty	Critical
Scr level
12	Randomized controlled trial	Serious^a	Serious^b	Serious^c	Not serious	Undetected	628	523	–	MD 10.19 μmol/L lower (17.05 lower to 3.33 lower)	⨁◯◯◯ Very low certainty	Important
eGFR level
8	Randomized controlled trial	Serious^a	Serious^b	Serious^c	Not serious	Undetected	476	372	–	MD 4.10 mL/min-1.73 m^2 higher (2.24 higher to 5.96 higher)	⨁◯◯◯ Very low certainty	Important

CA-AKI: contrast-associated acute kidney injury; FOSM: fermented Ophiocordyceps sinensis mycelia; RPP: routine preventive procedure; no.: number; RD: risk difference; MD: mean difference; CI: confidence interval; Scr: serum creatinine; eGFR: estimated glomerular filtration rate.

^a Selection of the reported result bias was assessed as some concerns.

^b I² value was large.

^c Indirectness of FOSM products intervention time (before and after injection of the contrast).

^d A small number of events of less than 300.

4. Discussion

4.1. Summary of main findings

This study shows that FOSM products plus RPP (saline hydration and alprostadil) was more beneficial than RPP alone in reducing the incidence of CA-AKI and Scr level, increasing eGFR and SOD level, and reducing the levels of KIM-1, NGAL, BUN (results were not robust), Cys C, MDA, and IL-18. Subgroup analysis showed that Bailing plus RPP or Jinshuibao plus RPP demonstrated lower incidence of CA-AKI compared to RPP. However, there was no statistically significant difference between Zhiling plus RPP and RPP in the incidence of CA-AKI. In addition, as for the time to injection of the contrast, only when FOSM products were taken before the injection, it was superior to RPP in reducing the incidence of CA-AKI. The overall certainty of the evidence was assessed as low or very low.

FOSM products alone can also play a positive role in the prevention of CA-AKI compared to normal saline. In terms of the need for dialysis and adverse events, FOSM products and RPP had no statistical difference.

4.2. Comparison with other studies or reviews

FOSM products as an adjunct drug in the treatment of chronic kidney disease [32], diabetic nephropathy [52,53], nephrotic syndrome [54], kidney transplant [55], etc., have been systematically reviewed. These reviews showed that FOSM products were effective and had good safety profiles. For example, a Cochrane systematic review [32] showed FOSM products, as an adjuvant to RPP, can reduce Scr and proteinuria, and mitigate CKD-related complications such as elevated hemoglobin and serum albumin. A pharmacological review revealed that FOSM products contain many active ingredients, among which cordycepic acid, ergosterol, nucleosides, and peptides have been extracted; they are confirmed to possess various pharmacological actions, including anti-inflammatory, antioxidant, antitumor, antiapoptosis, immunomodulatory, and nephroprotective [56,57].

In our study, we found that RPP plus FOSM products can further improve SOD and MDA in the prevention of CA-AKI compared with RPP alone, indicating that FOSM products have an antioxidant effect [58]. A previous systematic review showed that the use of antioxidant supplements (including N-acetyl cysteine, vitamin C, and vitamin E) reduced the risk of CA-AKI, suggesting that the pharmacological effects of FOSM products in the prevention of CA-AKI may contain antioxidants [59].

4.3. Strengths and limitations

As far as we know, this is the first systematic review based on RCTs to assess the effectiveness and safety of FOSM products for the prevention of CA-AKI. The relevant clinical studies were comprehensively analyzed in terms of risk factors for CA-AKI, use of FOSM products, and the preventive effect and safety of FOSM products on CA-AKI. Finally, several novel biomarkers for mechanism related to renal injury (such as the levels of NGAL, Cys C, IL-18, etc.) were included, which could more sensitively reflect the early renal injury induced by contrast media and the nephroprotective effect of FOSM products compared with the traditional renal function indicators (such as the levels of Scr, BUN, eGFR, etc.).

However, there are several limitations. First, all included studies were conducted in China, and further international studies are needed to determine whether this evidence is equally applicable to other countries outside of China. Second, based on the current evidence, it cannot be concluded that Zhiling capsule can reduce the incidence of CA-AKI and Scr level. Jinshuibao capsule, Bailing capsule, and Zhiling capsule were fermented from different FOSM strains that may have some different active ingredients and pharmacological effects [60]. Furthermore, studies have also shown that the quality of exclusively produced varieties such as Bailing capsule and Jinshuibao capsule is more stable, while the quality of Zhiling capsule produced by multiple manufacturers varies greatly between manufacturers, and even between samples from different batches from the same company [60,61]. Finally, the included trials had differences in clinical baseline characteristics, such as inclusion criteria, contrast medium dosage, patients’ baseline renal function, etc. We performed subgroup analysis to control some of these clinical baseline differences and used random-effect models to present outcomes more conservatively; nevertheless, we must be conscious that the accuracy of the pooled results might be influenced.

4.4. Inspiration for future research

In addition to focusing on the incidence of CA-AKI, we should follow up beyond 6 months when possible, looking at hospital stay and healing in patients needing dialysis in addition to renal outcomes. Future clinical trials should preregister their protocols and make them public to facilitate assessment of reporting bias and clearly disclose funding sources and any relevant conflicts of interest.

5. Conclusions

Currently, low certainty evidence suggests that preventive use of FOSM products as an adjuvant prevention was safe and might decrease the incidence of CA-AKI. Conducting trials with proper randomization, allocation concealment, double-blinding of patients and assessors, and larger sample sizes in the range of hundreds or thousands are needed to further improve the certainty of evidence.

Author contributions

Conceptualization: JP Liu and FL Pu. Methodology: FL Pu. Software: FL Pu and TL Li. Formal analysis: FL Pu. Data curation: FL Pu and TL Li. Writing – original draft: FL Pu. Writing – review and editing: JP Liu, TL Li, Q Xu, C Shen, YQ Wang, CM Tang, XW Zhang, and LJ Yan. Funding acquisition: JP Liu.

Ethical approval

This work did not require ethical approval as it does not involve any human or animal experiments.

Consent form

The author confirms that the work described has not been published before, that it is not under consideration for publication elsewhere, and that its publication has been approved by all coauthors.

Acknowledgements

We gratefully acknowledge the assistance of Qihe Xu, Jianping Liu, and Nicola Robinson in reviewing and modifying the article.

Disclosure statement

All authors declare that there is no conflict of interest.

Data availability statement

The original data and material are available in this article/supplementary material and further enquiries can be directed to the authors.

Additional information

Funding

This work was supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202006) and High-level Traditional Chinese Medicine Key Subjects Construction Project of National Administration of Traditional Chinese Medicine—Evidence-based Traditional Chinese Medicine (zyyzdxk-2023249).