Atlas chapter 15 · Renal

Cordyceps-related preparations

Ophiocordyceps sinensis; Cordyceps militaris; cultured medicinal fungal lineages associated with defined commercial preparations

NOT ASSIGNABLE AT CATEGORY LEVEL. Individual preparation × indication × outcome programmes approximately E2–4 ±. The absence of a single category-level E grade is itself a conclusion of the audit, not a gap in it.± — heterogeneous / proposition-specific. Potentially meaningful positive signals exist within defined programmes, but direction cannot responsibly be generalized across the Cordyceps therapeutic category.NOT ASSIGNABLE AT CATEGORY LEVEL. Intervention-specific clusters approximately R1–4. Trial count is not replication count. The category contains multiple preparation-specific programmes, and heterogeneous trials cannot be compressed into repeated confirmations of one Cordyceps intervention.

Proposition / claim: Cordyceps-related medicinal preparations have a large human clinical literature, including potentially favourable adjunctive renal surrogate outcomes in diabetic kidney disease programmes, but intervention heterogeneity, methodological limitations and evidence-ownership uncertainty prevent a single category-level efficacy conclusion.
Evidence owner: Individual defined preparations within preparation × population × outcome programmes. Evidence ownership is unresolved at the Cordyceps category level and must be reconstructed from the underlying trials. No clinical grade transfers automatically between wild Ophiocordyceps sinensis, cultured or fermented medicinal preparations, Cordyceps militaris, or arbitrary commercial Cordyceps products.
Dominant uncertainty: Evidence ownership within the enormous heterogeneous literature: which preparation produced which effect, in which population, on which outcome?

Organism: Cordyceps-related preparations
Tested intervention: Multiple defined Cordyceps-related medicinal preparations represented across distinct clinical programmes; including cultured/fermented preparations associated with Ophiocordyceps sinensis medicinal traditions. No single intervention owns the category-level evidence.
Evidence target: Therapeutic category containing multiple preparation-specific clinical evidence programmes; no single organism or standardized preparation owns the category-level evidence.
Intervention description: The human literature grouped under "Cordyceps" includes biologically and chemically distinct interventions: wild Ophiocordyceps sinensis material, cultured or fermented medicinal preparations such as Cs-4 and related products, Cordyceps militaris preparations, and other defined commercial preparations. Species, cultured lineage, manufacturing process, dose, route and chemical composition may differ. Evidence must remain attached to the preparation actually tested and cannot be transferred automatically across the category.
Population: Multiple clinical populations across distinct Cordyceps-related evidence programmes. The strongest broad evidence area highlighted in the Master concerns people with diabetic kidney disease receiving renin-angiotensin-system inhibitor therapy, but Chapter 15 is not restricted to a single population.
Comparator: Varies by preparation-specific clinical programme. In the large diabetic-kidney-disease literature highlighted by the Master, Cordyceps-related preparations were generally investigated adjunctively alongside conventional therapy rather than as one uniform stand-alone intervention.
Outcome: Varies by programme. In the diabetic-kidney-disease literature highlighted by the Master, reported favourable outcomes frequently concern renal surrogate measures such as serum creatinine, proteinuria and related laboratory indicators. These are not equivalent to prevention of kidney failure, dialysis, transplantation, cardiovascular events or improved survival.
Evidence maturity (E): NOT ASSIGNABLE AT CATEGORY LEVEL. Individual preparation × indication × outcome programmes approximately E2–4 ±. The absence of a single category-level E grade is itself a conclusion of the audit, not a gap in it.
Direction: ± — heterogeneous / proposition-specific. Potentially meaningful positive signals exist within defined programmes, but direction cannot responsibly be generalized across the Cordyceps therapeutic category.
Historical flag (H): Not specified at dossier level
Replication (R): NOT ASSIGNABLE AT CATEGORY LEVEL. Intervention-specific clusters approximately R1–4. Trial count is not replication count. The category contains multiple preparation-specific programmes, and heterogeneous trials cannot be compressed into repeated confirmations of one Cordyceps intervention.
Claim Gap (CG): CG0–1 — Systematic-review evidence of defined Ophiocordyceps sinensis-related medicinal preparations in diabetic kidney disease reports favourable effects on several renal surrogate outcomes, while methodological quality and intervention heterogeneity limit confidence. CG1–2 — Some Cordyceps-related preparations may improve particular kidney-function measures. CG3 — Cordyceps protects the kidneys. CG4 — Cordyceps prevents kidney failure. CG4 — Wild Cordyceps clinically protects the kidneys. Claim ceiling: CG1–2 for carefully specified preparation/outcome statements. The ladder preserves two distinct failure modes: Surrogate Inflation (renal laboratory measures read as patient-important kidney outcomes) and intervention transfer (evidence from cultured medicinal preparations read as evidence for wild material or arbitrary commercial products).
Evidence Transfer Vector: Transferred proposition: "Wild Ophiocordyceps sinensis prevents kidney failure." T / I / O / D / R T — Taxon: cultured fungal identities → Ophiocordyceps sinensis I — Intervention: cultured medicinal preparations → wild organism O — Outcome: renal surrogate measures → kidney-failure prevention D — Dose/route: studied medicinal products → arbitrary consumption R — Replication: heterogeneous category literature → one wild intervention
Taxonomic Transfer Confidence: LOW-VARIABLE across the therapeutic category. Historical nomenclature, wild Ophiocordyceps sinensis, Cordyceps militaris and cultured medicinal fungal lineages — including historical cultured identities associated with Paecilomyces-related names and later placements such as Samsoniella — must not be treated as automatically interchangeable. Commercial continuity or shared use of the name "Cordyceps" does not establish biological identity.
Intervention Transfer Confidence: LOW across different Cordyceps preparations unless equivalence is demonstrated. Evidence cannot transfer automatically among wild Ophiocordyceps sinensis, cultured or fermented preparations, Cs-4 and related products, Cordyceps militaris, powders, extracts, and arbitrary commercial Cordyceps products.
Safety: S2 for defined studied preparations. Safety belongs to specific studied interventions. Wild material, cultured products, commercial preparations, manufacturing systems, doses and contaminant profiles differ. "Cordyceps is safe" is not a justified category-level conclusion.
Conservation: Wild Ophiocordyceps sinensis — C3; cultivated alternatives — C+. C+ denotes conservation-positive potential through cultivation/fermentation and reduced pressure on wild harvest. It does not establish therapeutic or pharmacological equivalence with wild material.
Resolution zone: RZ-5 → RZ-4 → RZ-3: map identity → reanalyse like with like → run the clinically meaningful confirmatory trial.
Next best experiment: Stage One — intervention reconstruction: for every grade-driving study record the commercial preparation, cultured organism or strain, manufacturing process, dose, route, chemical characterization, clinical population, outcome and risk of bias; then cluster like with like. Stage Two — identify the strongest evidence-owning preparation: if one well-defined preparation has a credible cluster of randomized trials showing a consistent effect on the same renal outcome, that preparation — not Cordyceps generally — becomes the evidence owner. Stage Three — test a patient-important outcome: where existing evidence primarily concerns surrogate renal measures, conduct an appropriately designed confirmatory programme examining clinically meaningful outcomes such as disease progression, dialysis, hospitalization, quality of life, cardiovascular events or another justified patient-important endpoint.
Primary references: Xue X, Jin X-Y, Ye X-L, Li K-Y, Li J-X, Liu X-H, Bai J, Liu Q, Zhang B-R, Zou X-R, Yuan J, Lu C-L, Zhao F-F, Liu J-P, Wang X-Q. Ophiocordyceps sinensis preparations combined with the renin-angiotensin system inhibitor for diabetic kidney disease treatment: an umbrella review of systematic reviews and network meta-analysis. Front Pharmacol. 2024 Apr 22;15:1360633. PMID: 38716236. PMCID: PMC11075507. DOI: 10.3389/fphar.2024.1360633. — SYSTEMATIC REVIEW / SECONDARY SYNTHESIS; also PREPARATION IDENTITY. Preparation: named marketed Ophiocordyceps sinensis preparations (Jinshuibao capsules and tablets, Bailing capsules and tablets, Zhiling capsules) — not one intervention. Population: diabetic kidney disease receiving renin-angiotensin-system inhibitors. Comparator: RASi alone. Outcomes: 24-h urinary total protein, serum creatinine, blood urea nitrogen, blood glucose — all surrogate renal/metabolic measures. 14 systematic reviews (13/14 critically low AMSTAR 2), 157 RCTs, 13,143 participants; RoB 2 "some concerns" in 155/157 and high risk in 2/157. Highest certainty reported: moderate, for Jinshuibao capsules plus RASi on urinary protein, serum creatinine, urea nitrogen and glucose. Role: source of the "157 randomized trials" figure and of the preparation-level disaggregation on which Chapter 15 rests. NOT grade-owning at category level; the Jinshuibao cluster within it is the strongest candidate preparation-level cluster. Counted toward replication only within single-preparation clusters. Limitations: near-universal risk-of-bias concerns, heavy geographical and language concentration in Chinese-language literature, pooling across distinct commercial products, no patient-important endpoints. Transferability: none to wild Ophiocordyceps sinensis, Cordyceps militaris or arbitrary commercial products.
Zhang HW, Lin ZX, Tung YS, Kwan TH, Mok CK, Leung C, Chan LS. Cordyceps sinensis (a traditional Chinese medicine) for treating chronic kidney disease. Cochrane Database Syst Rev. 2014 Dec 18;2014(12):CD008353. PMID: 25519252. PMCID: PMC10632742. DOI: 10.1002/14651858.CD008353.pub2. — SYSTEMATIC REVIEW / SECONDARY SYNTHESIS. Preparation: heterogeneous "Cordyceps preparations", frequently PREPARATION IDENTITY INSUFFICIENTLY REPORTED at trial level. Population: chronic kidney disease, largely non-dialysis. Comparator: placebo, no treatment or conventional treatment; Cordyceps used adjunctively. Outcomes: serum creatinine (14 studies, 987 participants, MD -60.76 umol/L), creatinine clearance (6 studies, 362 participants, MD 9.22 mL/min), 24-h proteinuria (4 studies, 211 participants, MD -0.15 g/24 h), haemoglobin, serum albumin — all surrogate. 22 studies, 1746 participants; risk of bias high in 4 and unclear in 18. Authors state definitive conclusions could not be made because of low quality of evidence. Role: independent, methodologically strict synthesis that corroborates surrogate-level signal while refusing an efficacy conclusion. NOT grade-owning; not counted as replication. Limitations: low study quality, poor intervention reporting. Transferability: does not license any wild-organism or product-specific claim.
Yan G, Chang T, Zhao Y, Yu M, Mi J, Wang G, Wang X, Liao X. The effects of Ophiocordyceps sinensis combined with ACEI/ARB on diabetic kidney disease: a systematic review and meta-analysis. Phytomedicine. 2023 Jan;108:154531. PMID: 36375237. DOI: 10.1016/j.phymed.2022.154531. (PROSPERO CRD42021248634.) — SYSTEMATIC REVIEW / SECONDARY SYNTHESIS. Preparation: Ophiocordyceps sinensis preparations, pooled across products. Population: diabetic kidney disease. Comparator: ACEI/ARB alone. Outcomes: serum creatinine, blood urea nitrogen, beta-2 microglobulin, cystatin C, 24-h urinary protein, urinary microalbumin, urinary albumin excretion rate. 38 RCTs, 3167 patients. Critically, the review records that NO included trial reported kidney disease progression or cardiovascular events. Role: the decisive surrogate-versus-patient-important-outcome citation for Chapter 15. NOT grade-owning; not counted as independent replication (substantial trial overlap with the other syntheses). Limitations: pooled heterogeneous preparations, low trial quality. Transferability: outcome transfer to kidney-failure prevention is unsupported.
Luo Y, Yang SK, Zhou X, Wang M, Tang D, Liu FY, Sun L, Xiao L. Use of Ophiocordyceps sinensis (syn. Cordyceps sinensis) combined with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) versus ACEI/ARB alone in the treatment of diabetic kidney disease: a meta-analysis. Ren Fail. 2015 May;37(4):614-634. PMID: 25682973. DOI: 10.3109/0886022X.2015.1009820. — SYSTEMATIC REVIEW / SECONDARY SYNTHESIS. Preparation: Ophiocordyceps sinensis-related preparations, pooled. Population: DKD stage III-IV. Comparator: ACEI/ARB alone. Outcomes: 24-h urinary protein, urinary albumin excretion rate, microalbuminuria, blood urea nitrogen, serum creatinine, C-reactive protein, triglycerides, total cholesterol, systolic blood pressure; no effect on diastolic blood pressure, fasting glucose or HbA1c. 60 trials, 4288 participants. Role: CORROBORATIVE for the surrogate-level direction and for directional heterogeneity (several outcomes null). NOT grade-owning; overlapping trial pool, so not counted as independent replication. Limitations: authors themselves cite low quality and significant heterogeneity. Transferability: limited to studied adjunctive preparations.
Sung G-H, Hywel-Jones NL, Sung J-M, Luangsa-ard JJ, Shrestha B, Spatafora JW. Phylogenetic classification of Cordyceps and the clavicipitaceous fungi. Stud Mycol. 2007;57:5-59. PMID: 18490993. PMCID: PMC2104736. DOI: 10.3114/sim.2007.57.01. — TAXONOMIC / IDENTITY. Establishes that Cordyceps sensu lato is not monophyletic, validates Cordycipitaceae on the type species Cordyceps militaris, and erects Ophiocordycipitaceae for Ophiocordyceps — the basis for separating Ophiocordyceps sinensis (formerly Cordyceps sinensis) from Cordyceps militaris. Role: underwrites the LOW-VARIABLE taxonomic transfer confidence and the refusal to treat "Cordyceps" as one biological entity. Not clinical; never grade-owning; not counted toward replication.
Moon BC, Kim WJ, Park I, Sung GH, Noh P. Establishment of a PCR assay for the detection and discrimination of authentic Cordyceps and adulterant species in food and herbal medicines. Molecules. 2018 Aug 2;23(8):1932. PMID: 30072640. DOI: 10.3390/molecules23081932. — PREPARATION IDENTITY / TAXONOMIC. Documents routine substitution and adulteration among Ophiocordyceps sinensis, Cordyceps militaris, Isaria tenuipes, Cordyceps pruinosa and Isaria cicadae in commercial food and herbal products, and that morphological discrimination fails in processed material. Role: empirical support for the ITC position that a product labelled "Cordyceps" cannot be assumed to be the tested intervention. Not clinical; never grade-owning.
Wu TN, Yang KC, Wang CM, Lai JS, Ko KN, Chang PY, Liou SH. Lead poisoning caused by contaminated Cordyceps, a Chinese herbal medicine: two case reports. Sci Total Environ. 1996 Apr 5;182(1-3):193-195. PMID: 8854946. DOI: 10.1016/0048-9697(96)05054-1. — SAFETY. Two cases of lead poisoning from Cordyceps powder containing lead at up to 20,000 ppm; blood lead 130 and 46 microg/dL, resolving after cessation (with chelation in the symptomatic case). Role: demonstrates that safety attaches to the specific product and its manufacturing and contaminant profile, not to "Cordyceps" as a category; supports retaining S2 for defined studied preparations rather than any category-level safety claim. Not grade-owning for efficacy; not counted toward replication.
Hopping KA, Chignell SM, Lambin EF. The demise of caterpillar fungus in the Himalayan region due to climate change and overharvesting. Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11489-11494. PMID: 30348756. PMCID: PMC6233077. DOI: 10.1073/pnas.1811591115. — CONSERVATION. Range-wide evidence that Ophiocordyceps sinensis production has declined through habitat degradation, overexploitation and warming, with risk of system collapse. Role: supports C3 for wild Ophiocordyceps sinensis and the conservation-positive rationale for cultivated or fermented alternatives (C+), while establishing nothing about therapeutic equivalence. Not clinical; never grade-owning.
Source chapter: Chapter 15, The Fungal Evidence Atlas