The effects of Ophiocordyceps sinensis combined with ACEI/ARB on diabetic kidney disease: A systematic review and meta-analysis

Background: Ophiocordyceps sinensis (OS), a medicinal fungus, has been made into OS preparations, which are frequently used as adjunctive therapy for patients with Diabetic Kidney Disease (DKD) in China. It is necessary to assess the efficacy and safety of OS preparations in the adjunctive treatment of DKD by conducting a systematic review and meta-analysis.Objective: Ophiocordyceps sinensis preparations were evaluated for their efficacy and safety as adjunctive therapy to conventional drugs (angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)) for DKD.Methods: We searched seven electronic literature databases for randomized controlled trials (RCTs) comparing ACEI/ARB and OS combined with ACEI/ARB from inception up to March 2022. Two reviewers extracted data and assessed the risk of bias independently. Evidence certainty was rated using the GRADE system. Standardized mean difference (SMD) or mean difference (MD) was pooled with random effects models and was reported with corresponding 95% confidence intervals (CIs). Meta-analysis, sensitivity analysis and Egger's test were per-formed using R software (version 14.2) (PROSPERO registration no. CRD42021248634).Results: Thirty eight RCTs involving 3167 patients met the inclusion criteria. No trials were reported with out-comes about kidney disease progression and cardiovascular events. In meta-analysis, compared with the control group of ACEI/ARB alone, OS combined with ACEI/ARB can achieve better effects in the treatment of DKD on reducing serum creatinine (Scr) [MDScr =-11.48 95% CI [-15.78,-7.18], p < 0.01], blood urea nitrogen (BUN) [MDBUN=-1.00, 95% CI [-1.44,-0.55], p < 0.01], 82-microglobulin (82-MG) [SMD82_ MG=-1.32, 95% CI [-2.27,-0.37], p < 0.01], cystatin C (CysC) [MDCysC=-0.64, 95% CI [-0.83,-0.45], p < 0.01], 24-h urine proteinuria (24hUP) [SMD24hUP=-1.99, 95% CI [-2.68;-1.31], p < 0.01], urine microalbumin (UALB) [MDUALB=-37.41,95% CI [-44.76,-30.06], p < 0.01] and decreasing urinary albumin excretion rate (UAER) [MDUAER=-24.11, 95% CI [-30.54,-17.68], p < 0.01] and albumin creatinine ratio (ACR) [SMDACR = 1.01, 95% CI [-1.73,-0.29], p < 0.01]. The OS adjuvant treatment also improved outcomes of blood pressure, blood glucose, blood lipid, inflammation and oxidative stress. No significant change in fasting blood glucose (FPG), glycated hemoglobin (HbA1c), malondialdehyde (MDA), and transforming growth factor beta 1 (TGF-beta 1) was detected. Yet, no sig-nificant difference was found about the adverse events between the two groups.Conclusions: Ophiocordyceps sinensis preparation combined with ACEI/ARB has beneficial influence on renal function, decrease proteinuria, dyslipidemia, and even oxidative stress and inflammation in DKD patients. However, there is no trial that evaluated outcomes of kidney disease progression and cardiovascular events. Future study should move beyond surrogate endpoints to actual cardiovascular or renal outcome benefits with an aim to explore effects of OS preparation in the long-term.