Hepatorenal syndrome (HRS) is a lethal complication of end-stage liver diseases, which is a functional kidney injury developing as a consequence of the severe reduction in the renal perfusion secondary to splanchnic arterial vasodilation (1). HRS can occur spontaneously or is secondary to hypovolemia and bacterial infection (2,3). The prognosis of HRS remains dismal with a median survival time of approximately 3 months (4). Terlipressin, noradrenaline, midodrine, and octreotide have been used for the treatment of HRS (5-7), which can result in splanchnic vasoconstriction and then lead to an increase in effective circulating blood volume and renal blood flow (8,9).
According to the traditional Chinese medicine (TCM) theory, HRS, which is called as bulging, is caused by the “qi” stagnation, blood stasis, and phlegm-retained fluid. The current TCM expert consensus suggests that TCM may improve liver function, delay disease progression, alleviate symptoms, and improve quality of life in HRS patients (10).
A systematic review and meta-analysis aimed to evaluate the efficacy of TCM for the treatment of HRS.
The number of registration in PROSPERO was CRD42017076055.
Relevant publications were searched electronically from the China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, and EMBASE databases. The search items were “hepatorenal syndrome”, “traditional Chinese medicine”, “herb”, and “random”. The date of last search was September 9, 2017.
The eligibility criteria included: (I) patients with HRS; (II) TCM with and without conventional therapy as the TCM group; (III) conventional therapy without TCM as the control group; (IV) randomized controlled trials (RCTs); and (V) studies reporting the efficacy of TCM.
Exclusion criteria were as follows: (I) duplicate publications; (II) reviews; (III) basic researches; (IV) systematic reviews and meta-analyses; (V) irrelevant topics; (VI) unable to extract the data regarding patients with HRS; and (VII) catalogues, indexes, and conference reports. No language and publication status were limited.
Primary data were extracted, including characteristics of studies, baseline characteristics of patients, response of HRS, and changes of biomedical variables after the treatment. The characteristics of studies were as follows: first author, study design, year of publication, region, enrollment period, number of patients in TCM/control group, methods of intervention, treatment period, and follow-up time. The characteristics of patients were as follows: age, gender, serum creatinine, blood urea nitrogen, bilirubin, urine volume, and abdominal circumference.
Risk of bias assessment
The Cochrane Collaboration’s tool to assess the risk of bias was employed. It includes 7 domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias.
Outcomes of interest were: (I) the death of patients with HRS; (II) the response; and (III) the changes of biomedical variables. Response was divided into complete, partial, and no response according to the definitions established by original articles.
The meta-analyses were performed by the Review Manager 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata version 12 (StataCorp, College Station, Texas, USA). Continuous data were expressed as mean ± standard deviation (SD). Random-effect model was employed. Odds ratio (OR) with 95% confidence interval (CI) was calculated for binary variables. Standardized mean difference (SMD) with 95%CI was calculated for continuous variables. P<0.05 was considered to indicate statistical significance. Heterogeneity was quantified using the Cochrane Q-test and the I2 statistics. P<0.1 or I2>50% was considered to indicate a statistically significant heterogeneity. Subgroup, sensitivity, and meta-regression analyses were used to analyze the source of heterogeneity. Subgroup analyses were performed according to the type of HRS and diagnostic criteria for HRS. As the number of included studies was ≥9, we conducted meta-regression analyses. In meta-regression analyses, the covariates included publication year, type of HRS, and diagnostic criteria for HRS.
Characteristics of studies
A total of 1998 studies were identified. Fourteen studies were included (11-24) (Figure 1). The sample size ranged from 25 to 140. The publication year ranged from 2004 to 2017. The publication regions were all in China. Only two studies included patients with type 2 HRS alone, and others included patients with unclassified type of HRS. Characteristics of studies were summarized in Table 1. The diagnosis of HRS was based on the International Club of Ascites (ICA) in 7 studies or other diagnostic criteria in 5 studies and was unspecified in 2 studies.
Characteristics of patients
Age, gender, and urine volume were provided in 9 studies. Serum creatinine, blood urea nitrogen, and bilirubin were presented in 12, 11, and 5 studies, respectively. In 8 studies, the underlying liver disease was liver cirrhosis alone. In 3 studies, the underlying liver disease included liver cirrhosis, liver cancer, or severe hepatitis. In 3 other studies, the underlying liver disease remained unclear. Five studies provided information regarding etiology of liver disease. Viral hepatitis was the major etiology of liver disease followed by alcohol abuse. Characteristics of patients were summarized in Table S1.
Risk of bias
Only 2 studies reported the random sequence generation, of which one had a high risk and another had a low risk. All studies had low risks of attrition bias and reporting bias. Other risks of bias were unclear in most of studies (Figure S1).
Six studies with 279 patients were included in the meta-analysis regarding in-hospital death (Figure 2A). TCM led to a significant survival benefit (OR: 0.18, 95% CI: 0.08–0.39, P<0.0001). There was no significant heterogeneity (P=0.18, I2=32%).
Ten studies with 685 patients were included in the meta-analyses regarding response.
TCM led to a significantly higher complete response (OR: 3.20, 95% CI: 2.06–4.97, P<0.00001). There was no significant heterogeneity (P=0.35, I2=10%) (Figure 2B).
The rate of partial response was not significantly different between TCM and control groups (OR: 1.39, 95% CI: 0.90–2.15, P=0.14). There was a mild heterogeneity (P=0.06, I2=44%) (Figure 2C).
TCM led to a significantly lower no response (OR: 0.20, 95% CI: 0.14–0.30, P<0.00001). There was no significant heterogeneity (P=0.59, I2=0%) (Figure 2D).
Biomedical and clinical variables
The results of meta-analyses regarding biomedical and clinical variables were summarized in Table 2.
Serum creatinine, blood urea nitrogen, bilirubin, urine volume, plasma ammonia, and abdominal circumference were significantly improved in TCM group. Serum creatinine, blood urea nitrogen, urine volume, and abdominal circumference were also significantly improved in control group. TCM led to a significantly better improvement in terms of serum creatinine, blood urea nitrogen, bilirubin, urine volume, plasma ammonia, and abdominal circumference. In most meta-analyses regarding biomedical and clinical variables, there was significant heterogeneity.
The results of subgroup analyses were summarized in Table S2.
The subgroup analyses of HRS-1 patients were unavailable due to the absence of relevant data.
The subgroup analyses of HRS-2 patients demonstrated that TCM led to a significantly better improvement in terms of serum creatinine, blood urea nitrogen, and urine volume, and there was statistical significance. There was no significant heterogeneity.
The subgroup analyses of HRS patients diagnosed based on ICA criteria demonstrated that TCM led to a significantly better improvement in terms of serum creatinine, blood urea nitrogen, bilirubin, and urine volume. Heterogeneity remained significant.
The results of sensitivity analyses were summarized in Table S3. Heterogeneity remained significant.
The results of meta-regression analyses were summarized in Table S4.
Heterogeneity in the meta-analysis regarding serum creatinine in the control group was related to the publication year (P=0.022). Heterogeneity in the meta-analysis regarding serum creatinine in the TCM group was not related to the publication year, type of HRS, or diagnostic criteria for HRS. Heterogeneity in the meta-analyses regarding blood urea nitrogen and urine volume was not related to the publication year, type of HRS, or diagnostic criteria for HRS.
The present analysis shows that TCM treatment significantly improved the survival and response of patients with HRS compared with conventional treatment. In addition, serum creatinine, blood urea nitrogen, urine volume, and abdominal circumference were improved irrespective of TCM. Finally, the improvement of serum creatinine, blood urea nitrogen, bilirubin, urine volume, serum ammonia, and abdominal circumference was significantly better in TCM group.
China has a long history of TCM application. The theory of TCM is primarily based on the ancient Chinese philosophy. TCM can cure diseases by correcting the maladjustments and restoring self-regulation ability (25). Among the included studies, 7 applied rhubarb (12,13,15,16,18,22,24), 7 applied Salvia Miltiorrhiza Bunge (11,14,18,20,22-24), and 2 applied Ligusticum Wallichii (12,18) in TCM group.
Rhubarb has defecation-accelerating, heat-clearing, blood-cooling, toxin-relieving, blood stasis-dredging, dampness-dredging, jaundice-resolving effects according to the Chinese Pharmacopoeia. Rhubarb in the colon can regulate intestinal flora and reduce intestine-derived uremic toxins produced by gut bacteria (26). Rhubarb has a cathartic effect on accelerating the excretion of intestinal toxins, reducing the absorption of toxins, and preventing from liver and kidney damage (27).
Salvia Miltiorrhiza Bunge has a role in blood circulation-promoting, blood stasis-dredging, blood-nourishing, and mind-tranquilizing according to the Chinese Pharmacopoeia. Salvia Miltiorrhiza Bunge has a protective effect on the liver and kidney. Animal study showed that the anti-inflammatory properties of Salvia Miltiorrhiza Bunge extracts might prevent hepatocyte injury possibly by the inhibition of p38 and nuclear factor ƙB signaling in Kupffer cells (28). Salvia Miltiorrhiza Bunge extracts can significantly improve blood urea nitrogen levels associated with impaired renal function and improve renal structural changes (29).
Ligusticum Wallichii has a role in blood circulation-promoting, blood stasis-dredging, “qi” stagnation-regulating, pain-alleviating, and dampness-dredging. The mechanism of blood-activating and stasis-resolving medicine on renal hemodynamics is mainly manifested on the levels of vasomotor factors and the action of renin-angiotensin, prostaglandins, endothelin, and nitric oxide (30).
Tetramethylpyrazine is an alkaloid found in the roots of Ligusticum Wallichii, which includes the function of anti-inflammation, anti-oxidation, anti-atherosclerosis, and anti-fibrosis. Tetramethylpyrazine plays a protective role in hepatic and renal injury caused by ischemia-reperfusion by inhibiting the adhesion and activation of neutrophils mediated by P-selection and the interaction of neutrophils and endothelium (31).
Except for intravenous injection, oral, and external application, enema is also a major route of TCM among the included studies, which can improve the intestinal environment and reduce the production and absorption of enterotoxin (10).
There were some limitations in our study. First, although the studies included in the meta-analysis were reported as RCTs, the study quality was poor. The same situation was reported by Teschke et al. (32). Second, the sample size of each included study was relatively small. Third, the diagnostic criteria of HRS were inconsistent among the included studies. Fourth, the type of HRS was unspecified in some studies. Fifth, all the publication regions were in China. Sixth, the heterogeneity was mostly significant in the meta-analyses regarding biochemical and clinical variables. Despite subgroup analysis, sensitivity analysis, and meta-regression analysis were performed, the source of heterogeneity was not well explained. Seventh, only two included studies provided the follow-up time. One study reported that the follow-up time was 2 months. Another study reported that the follow-up time was 3 months. Therefore, it was impossible to explore the effects of follow-up times on the outcomes.
In conclusions, TCM may be effective for the treatment of HRS. However, our conclusions are hardly generalizable until more well-designed RCTs are performed.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Song T, Guo X, Shao L, Sun M, Romeiro FG, Han D, Bao W, Qi X. A systematic review and meta-analysis of treatment for hepatorenal syndrome with traditional Chinese medicine. Transl Gastroenterol Hepatol 2018;3:57.