Clinical Efficacy and Safety of Chinese Herbal Medicine in the Treatment of Uremic Pruritus: A Meta-Analysis of Randomized Controlled Trials

Uremic pruritus is a disturbing and refractory symptom in patients with advanced chronic kidney disease. Chinese herbal medicine has been reported to alleviate uremic pruritus. To investigate the effects of Chinese herbal medicine, we conducted a systematic review and meta-analysis on patients with uremic pruritus. We searched databases (prior to 3 May 2022) for randomized controlled trials on the effects of Chinese herbal medicine in treating uremic pruritus. Our meta-analysis included 3311 patients from 50 randomized controlled trials. In patients with uremic pruritus, adjunctive Chinese herbal medicine significantly improved overall effectiveness (risk ratio 1.29, 95% CI 1.23 to 1.35), quality of life, renal function, reduced pruritus score, and inflammatory biomarkers compared to control groups with hemodialysis alone or with anti-pruritic treatments. Chinese herbal medicine treatment showed a time-dependent tendency in improving the visual analog scale of dialysis patients. Compared to control groups, no significantly higher risk of adverse events in patients taking Chinese herbal medicine (risk ratio 0.60, 95% CI 0.22 to 1.63). Chinese herbal medicine appears to be effective and safe in complementing the treatment of patients with uremic pruritus.


Introduction
Uremic pruritus (UP) or chronic kidney disease-associated pruritus is a serious and burdensome symptom of advanced chronic kidney disease [1].The prevalence of uremic pruritus in dialysis patients is about 40% [2], but the pathophysiology of uremic pruritus remains unclear.Previous studies of patients with UP have found elevated levels of blood urea nitrogen (BUN), calcium (Ca), phosphorus (P), and parathyroid hormone (PTH) [3].However, the relationship between electrolyte concentrations and severity of UP is controversial.High Ca concentrations have been reported in association with UP [4].In conducting a cross-sectional study, Makhlough [5] showed that level of intact parathyroid hormone (iPTH) is correlated with severity of UP.In contrast, a randomized-controlled trial (RCT) [6] and a multicenter study [7] displayed no association in dialysis patients between pruritus severity and serum concentrations of P, iPTH, PTH, or Ca.In addition, recent studies have shown that UP is associated with inflammation, specifically in elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-6, C-reactive protein (CRP), high-sensitivity CRP, and β2-microglobulin (MG) [3,[8][9][10][11][12].For instance, Kimmel Pharmaceuticals 2022, 15, 1239 2 of 25 et al., reported that CRP and IL-6 were significantly higher in dialysis patients with UP than patients without UP and that UP patients also showed a nonsignificant elevation of TNF-α [10].Besides inflammation, UP impacts on quality of life (QOL) of patients.One study with two hundred dialysis patients showed significantly lower quality of life indices in patients with UP [13].
Systemic and topical agents, phototherapy, and alternative medicines have been reported as treatments for UP.As a recent therapeutic algorithm, complementary alternative medicine was considered as adjunctive treatment while refractory status after systemic treatments such as anticonvulsants, opioid receptor agonists, or antihistamines [14].However, gabapentin and antihistamine have been shown to cause dizziness, drowsiness, and somnolence [15,16].In addition, sunburn and tanning have been noted as side effects of phototherapy [1,17].Acupuncture and topical capsaicin appear to ameliorate UP, although topical capsaicin treatment often causes burning sensations or erythema [18].Identifying effective and safe complementary treatments for UP patients, such as Chinese herbal medicine (CHM), is desired.
Chinese herbal formula, such as uremic clearance granules (UCG), has been reported to improve renal function and lower the serum concentration of BUN, serum creatinine (SCr), PTH, iPTH, P, and inflammatory biomarkers in UP patients, without significant adverse effects [14].In addition, there has been limited evidence regarding the effects of CHM in treating UP patients.Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of CHM in UP patients.

Characteristics of Included Studies
We used a PRISMA flowchart to illuminate the process of identifying and selecting RCTs in evaluating the effects of CHM for UP patients (Figure 1).We identified 2145 articles from electronic databases and 18 additional records obtained through other sources.We excluded 1544 articles based on their titles and abstracts.We then reviewed the full texts of the remaining 137 articles.We excluded 87 articles due to the following reasons: 19 studies were review articles, 19 studies were not RCTs, 33 studies involved different interventions, 5 studies did not involve UP patients, 8 studies did not report data, 2 studies involved overlapping populations, and 1 study was retrospective.We qualitatively and quantitatively synthesized the remaining 50 articles.

Risk of Bias
Risk of bias is presented in Figure 2. In the randomizing process, thirty-four studies mentioned the methods of randomization.Only four studies [19,27,28,34] revealed details about their allocation concealment.Five studies [20,22,23,56,60] did not describe the baseline conditions of patients or provide statistical data, both of which could result in baseline imbalances.In addition, no double blinding was performed in the reviewed trials.Three studies [27,34,54] were not intention-to-treat analyses and had more than 5% of losing outcome data.Bias of outcome measurements, including visual analog scale, itch-intensity ratings, overall effectiveness, and quality of life scale, were high based on self-assessment.Two studies [32,63] were potentially biased because they only reported a subset of their data.3c).

Publication Bias
We conducted funnel plots to detect publication bias of VAS scores and overall effectiveness (Figure S6).Both funnel plots were asymmetrically distributed, demonstrating potential publication bias in our study.

Quality of Evidence
Given the high risk of bias for primary outcomes, the quality of evidence was low for assessing the efficacy of CHM in ameliorating symptoms associated with UP in patients (Table S3).S3).Significantly elevated levels of hemoglobin (MD 4.52, 95% CI 0.23 to 8.80, I 2 = 85%) were observed after administering CHM to UP patients (Figure S4).

Publication Bias
We conducted funnel plots to detect publication bias of VAS scores and overall effectiveness (Figure S6).Both funnel plots were asymmetrically distributed, demonstrating potential publication bias in our study.

Quality of Evidence
Given the high risk of bias for primary outcomes, the quality of evidence was low for assessing the efficacy of CHM in ameliorating symptoms associated with UP in patients (Table S3).

Discussion
Our meta-analysis suggests that CHM significantly reduces various pruritus scores in UP patients (VAS, Duo, and Dirk R. Kuypers itch-intensity scores), improves sleep quality (PSQI) and quality of life (QOL), renal function (eGFR, BUN, and SCr), and alleviates inflammation (CRP, TNF-α, β2-MG, and IL-6).Different Chinese herbal formulas (Touxie-Jiedu-Zhiyang decoction, UCG, and other decoctions) were associated with significant reductions in the severity of pruritus in overall effectiveness and VAS scores.Compared to control groups, CHM significantly increased the overall effectiveness of relieving symptoms in UP patients both undergoing dialysis and not undergoing dialysis.In dialysis patients, CHM demonstrated significantly higher overall effectiveness for periods from less than 8 weeks to over 12 weeks.We expect that longer-duration treatments with CHM should further alleviate symptoms (decrease VAS scores) in patients.Our review detected no significant increase in ADRS after administering CHM to UP patients.
Based on the theory of Chinese medicine, UCG is used to improve intestinal motility, promote blood circulation, and remove pathogenic ingredients including toxins, dampness, and stasis [43].Shi et al., showed that Touxie-Jiedu-Zhiyang decoction is used to remove toxins, invigorate qi, and replenish blood [50]; other decoctions, such as Si-Wu decoction and Zhi-Yang decoction are used to alleviate UP by nourishing blood and dispelling wind [57,60].
Regarding the unclear mechanism and pathogenesis of UP, a literature review proposed possible mechanisms of UP, including central stimulus from opioid receptors, deposited toxins, and systemic inflammation associated with histamines and proinflammatory cytokines such as CRP and IL-6 [14].
Xue et al. [69] reported that Chinese herbal bath therapy improves pruritus, decreases VAS scores, and increases effectiveness scores in UP patients.Moreover, the herbs most commonly used in bath therapies to treat UP patients are Difuzi, Baixianpi, Kushen, Chantui, Danggui, Xixin, Chuanxiong, Jingjie, Tufulin, and Dahuang [70], comprised of ingredients similar to the CHM reviewed in our study.
Our study suggests that the Touxie-Jiedu-Zhiyang decoction ameliorated UP symptoms.Huangqi, Dahuang, and Baishao are several important herbs comprising the Touxie-Jiedu-Zhiyang decoction [48].Huangqi is beneficial for alleviating inflammation by decreasing TNF-α levels and suppressing the expression of Th2 cytokines in topical treatments [71].Rhubarb (Dahuang), used as a laxative, is used for alleviating constipation [72] and showing nephroprotective effects in CKD [73].Baishao has been shown to reduce inflammation by significantly inhibiting cAMP-phosphodiesterase (PDE) activity [74] and by displaying synergistic anti-inflammatory effects with Huangqin (another herb in the formula) in a cell model [75].Huangqi, Dahuang, Fuling, and Danshen are important ingredients in UCG [42].Fuling (Poria cocos) regulates by activating Th1 and alleviating Th2 immune response in murine tumor models [76].Cryptotanshinone (CRT), extracted from Danshen (Salvia miltiorrhiza), was reported to possess anti-inflammation properties and alleviate pruritus by mitigating proinflammatory cytokines, such as TNF α and IL-1β, and by inhibiting mast cell degranulation [77].Other decoctions contain common herbs, such as Danggui and Chantui, often used to alleviate skin disorders.Topical application of Danggui (Angelica sinensis) has been reported to attenuate inflammation and severity of pruritus symptoms by reducing the number of mast cells, serum IgE concentrations, and by reducing the concentration of inflammatory cytokines, such as IL-6, TNF-α, and IFN-γ [78].Chantui (Cicadidae Periostracum) has been found to reduce IgE and histamine concentrations and suppress NLRP3, all of which are thought to help alleviate inflammation and itching sensations caused by UP [79].Although the most beneficial combination of herbs, dosages, and routes for administering CHM should be further explored, we believe that CHM can be successfully used as a potential complementary treatment for UP symptoms.
Our meta-analysis revealed that CHM reduced symptoms of UP with a time-dependent tendency.Yang et al. [80] found that Gan-Lu-Yin, a Chinese herbal formula, significantly decreases the mRNA expression of TNF-α in a time-dependent manner.Paeonol, an ex-traction from CHM, has been shown to attenuate solar UV-induced skin inflammations by decreasing T-LAK cell-originated protein kinase (TOPK) activity in a time-dependent manner [81].A variety of CHM ingredients display anti-inflammation effects over time, which might explain why longer durations of CHM treatments are associated with improved alleviation of symptoms in UP in our included studies.
In our study, CHM improved quality of life and sleep quality of UP patients.Several studies suggested that UP might reduce quality of life and increase sleep disturbances in patients [82][83][84].Traditional Chinese medicine (TCM), such as acupuncture, has been shown to improve hemodialysis-related complications, including symptoms of UP, and insomnia in chronic kidney disease (CKD) patients, by regulating the sympathetic nervous system Cochrane's systematic review [86] demonstrated that manual acupressure significantly reduced depression and improved sleep quality and fatigue in patients with CKD, although those results had very low quality of evidence.Based on the previous reports, we suggest that TCM, including CHM, acupressure, and acupuncture is beneficial for UP patients, whereas a higher quality of studies should be conducted to verify the evidence.
CHM appears to play a role in balancing concentrations of Ca and P, improving renal functions, and delaying progression in chronic renal failure in patients [87,88].PTH has also been associated with mast cell activation, which releases histamine and causes pruritus [63].A rat model demonstrated that CHM combined with acupoint thread implantation could reduce PTH concentrations in rats with CKD [89].In our meta-analysis, CHM improved renal function and efficacy in UP patients both undergoing and not undergoing dialysis.Wang et al. [90] found that traditional Chinese medicines improved eGFR and hemoglobin in stage III CKD patients.In two meta-analyses, UCG were also shown to significantly reduce SCr and increase eGFR in stages III-V CKD [91] and in dialysis patients [14].Huangqi (Astragalus membranaceus), an important herb in Touxie-Jiedu-Zhiyang decoctions and UCG, has been reported to reduce proteinuria and SCr, while also increasing albumin and hemoglobin in CKD patients [92].In our meta-analysis, CHM appeared to improve renal function in UP patients by significantly lowering SCr, BUN, P, and PTH levels and increasing eGFR.However, no significant difference after CHM administration was noted in Ca concentrations, a finding that is similar to the meta-analysis conducted by Lu et al. [14].More studies should be conducted to clarify how CHM ameliorates symptoms in CKD patients and compare different responses in patients undergoing and not undergoing dialysis.
Our meta-analysis suggested that CHM significantly reduces inflammation in patients with UP.Xuebijing injections, which are composed of five Chinese herbal extracts (including Honghua, Chishao, Danggui, Chuanxiong, and Danshen), are similar to ingredients in Touxie-Jiedu-Zhiyang decoctions and in UCG.Xuebijing injections attenuated renal inflammation and reduced levels of IL-6 and TNF-α in a mice model [93].One meta-analysis demonstrated that an injection of ligustrazine (a compound extracted from Chuanxiong) and Danshen (Salvia miltiorrhiza) appeared to reduce inflammation in diabetic kidney diseases [94].In addition, previous reviews also demonstrated that elevated IL-31 is associated with UP in dialysis patients [95,96].Furthermore, Wang et al., demonstrated that a Chinese herbal formula, Yangxue-Runfu-Yin, significantly lowers the level of IL-31, ameliorates pruritus severity, and improves sleep and quality of life in hemodialysis patients.All these findings suggest that CHM could ameliorate UP symptoms by improving renal function and by attenuating inflammation.
Hypoalbuminemia is common in patients on dialysis, which is associated with malnutrition and inflammation [97,98].Huangqi, an important herb in Touxie-Jiedu-Zhiyang decoction and UCG, has been shown to be beneficial in alleviating nephrotic syndrome by increasing plasma albumin and reducing excretion of urine albumin [99].However, one study showed no significant difference in serum albumin levels between UP and non-UP patients undergoing dialysis [100].Besides hypoalbuminemia, CKD patients often develop renal anemia [101].One study reported therapeutic effects on renal fibrosis and renal ane-mia after providing UCG, which was likely achieved by modulating transforming growth factor-β and erythropoietin signaling pathways in a mouse model [102].Yin et al., [90] found that Niaoduqing granules increased hemoglobin level [91].Consistent with results of previous meta-analyses, our study suggests that the administration of CHM also helps increase hemoglobin and albumin concentrations.
ADRSs are commonly reported in the treatment of UP with CHM; the ADRSs include nausea, vomiting, allergy, headache, and dizziness.Mild diarrhea, nausea, and abdominal discomfort have also been identified following treatment with the Shufeng-Liangxue decoction, a drug similar in formulation to the Touxie-Jiedu-Zhiyang decoction [103].Regarding herb-induced liver injury, a recent systematic review [104] revealed He-Shou-Wu has been reported as a culprit of herb-induced liver injuries.However, we found no significant elevation of liver enzymes in our meta-analysis.Additional studies should examine possible ADRSs in the treatment of CHM in UP patients.
Selected studies in our meta-analysis showed heterogeneity in response to certain clinical factors, as outlined below.First, heterogeneity in efficacy was associated with different types of Chinese herbal formulas, such as in other decoction groups.Second, frequencies and dosages of CHM administered differed across the studies.Third, there were some discrepancies in the interventions of the control groups.Lastly, our metaanalysis included studies using different tools for pruritus assessment, which may lead to heterogeneity.
There were several limitations to our study.First, the method of randomization applied in most of the studies was unclear.No trial reported double-blinding.Second, the included RCTs were a small sample size.Third, only a few studies could be included when performing subgroup analyses due to the different components of various Chinese herbal formulas.Fourth, inconsistent symptomatic treatments and lack of appropriate controls might lead to a modest reduction of VAS score in the CHM.However, higher quality studies should be executed that involve examining a larger population of data sets and examining the efficacy of head-to-head comparisons among different Chinese herbal formulas.

Materials and Methods
We searched seven databases from their inception to 3 May 2022: PubMed, Embase, Cochrane Library, CINAHL, Chinese National Knowledge Infrastructure, Airiti library, and Wanfang.We used MeSH and Emtree search headings, as follows: Chinese medicine (including herbal medicine, pill, powder, san, granule, and formula), pruritus, uremia, chronic kidney disease, dialysis, and their synonyms.We searched for free text words using these terms and their combinations (Table S4).In addition, we manually searched the reference sections of accessed papers and contacted known experts in the field to identify other studies.Finally, unpublished studies were inspected from the ClinicalTrials.govregistry (http://clinicaltrials.gov/, accessed on 1 August 2022).Our search was not restricted by language, and our method of systematic review was deemed acceptable by the online PROSPERO registry of the National Institute for Health Research (CRD 42022334701).
RCTs were included to evaluate the efficacy of CHM for UP patients.Our predetermined inclusion criteria included patients with UP, administration of oral CHM to patients, and the availability of quantitative data to assess pruritus severity.We excluded review articles, studies examining other traditional Chinese medicine interventions (e.g., acupuncture, acupressure, herbal bath, enema), and studies of patients not diagnosed with UP.We included studies in our analysis without regard to the type of pruritus evaluations utilized.To obtain raw or missing data in specific studies, we contacted investigators of those studies by e-mail.
Two reviewers (Chien-Cheng Lai and Ping-Hsun Lu) independently extracted the following information from each study: first author, publication year, sample size, age, period of intervention, dosage and frequency of interventions and comparisons thereof, specific means for assessing pruritus severity, quantified data on pruritus severity, quality of life and sleep quality indices, rates of overall effectiveness, and rates of adverse events.Other laboratory data were also extracted, including renal function, inflammation biomarkers, and serum concentrations for electrolytes and hormones.
The preliminarily selected studies were assessed for eligibility for meta-analysis by the two reviewers according to the above-listed inclusion criteria.The decisions of the two reviewers were individually recorded and compared, and any disagreement was resolved by a third reviewer (Po-Hsuan Lu).The risk of bias for the selected RCTs was evaluated with Cochrane Collaboration's Risk of Bias 2 tool [105].
We evaluated the efficacy of CHM using outcome measures as described below.The primary outcomes examined included mean difference (MD) in: VAS scores, Duo pruritus scores, scores on the Dirk R. Kuypers itching scale, quality of life and sleep quality indices, and the risk ratios (RR) for overall effectiveness.Secondary outcomes included the mean differences in serum concentrations of albumin, hemoglobin, electrolytes (K, Ca, and P), enzymes, and hormones (ALT, AST, and PTH), renal function index (SCr, eGFR, and BUN), inflammation biomarkers (CRP, TNF-α, and B2-MG, IL-6), and the RR of adverse event rates.We measured dichotomous outcomes as RR and continuous outcomes as weighted mean differences (WMDs).Both summary statistics were reported with 95% CIs.We conducted our meta-analysis using the RevMan 5.4 software (Cochrane Collaboration, Copenhagen, Denmark).Our meta-analysis was conducted following recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [106].The I 2 statistic and Cochran Q statistic were used to quantify statistical heterogeneity across the included studies, whereby substantial heterogeneity was detected when the I 2 statistic was > 50% or probability (p) was < 0.1.Considering clinical heterogeneity, we performed a random-effects model meta-analysis.Subgroup analyses were performed to assess between-group differences and explain the heterogeneity.We conducted funnel plots to detect publication bias.Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [107].

Conclusions
This systematic review and meta-analysis demonstrates that CHM, including Touxie-Jiedu-Zhiyang decoctions, UCG, and other decoctions reduce pruritus severity based on overall effectiveness and VAS scores.In addition, adjunctive CHM improves quality of life, renal function, and attenuates inflammation, whereas no statistically significant difference in adverse drug reaction is found compared to UP patients only who received hemodialysis alone or with antipruitic treatments.Compared to control groups, CHM increases overall effectiveness in both UP patients undergoing dialysis and those not undergoing dialysis.In dialysis patients, CHM alleviates UP and reduces the VAS score over time, especially after more than 12 weeks of use.However, for future research, we recommend examining studies with more patients and higher-quality studies that focus on head-to-head comparisons among CHM interventions in UP patients.

Figure 3 .
Figure 3. Forest plot of pruritus score (visual analog scale (VAS)) in patients with uremic pruritus treated with Chinese herbal medicine (CHM): (a) VAS score in included studies; (b) VAS score in durations of CHM treatment in dialysis patients; (c) VAS score in different Chinese herbal formulas.

Figure 3 .
Figure 3. Forest plot of pruritus score (visual analog scale (VAS)) in patients with uremic pruritus treated with Chinese herbal medicine (CHM): (a) VAS score in included studies; (b) VAS score in durations of CHM treatment in dialysis patients; (c) VAS score in different Chinese herbal formulas.

Figure 4 .
Figure 4. Forest plot of pruritus score: (a) Duo; (b) Dirk R. Kuypers itching scale in patients with uremic pruritus treated with Chinese herbal medicine.

Figure 4 .
Figure 4. Forest plot of pruritus score: (a) Duo; (b) Dirk R. Kuypers itching scale in patients with uremic pruritus treated with Chinese herbal medicine.

Figure 5 .
Figure 5. Forest plot of overall effectiveness of patients with uremic pruritus treated with Chinese herbal medicine (CHM): (a) overall effectiveness of included studies; (b) overall effectiveness of patients with uremic pruritus undergoing dialysis or not undergoing dialysis; (c) overall effectiveness of durations of CHM treatment in dialysis patients; (d) overall effectiveness of different Chinese herbal formulas.2.3.3.Pittsburgh Sleep Quality Index (PSQI), Quality of Life (QOL)

Figure 6 .
Figure 6.Forest plot of quality of life: (a) Pittsburgh Sleep Quality Index (PSQI); (b) Quality of Life (QOL) scale in patients with uremic pruritus treated with Chinese herbal medicine.

Figure 6 .
Figure 6.Forest plot of quality of life: (a) Pittsburgh Sleep Quality Index (PSQI); (b) Quality of Life (QOL) scale in patients with uremic pruritus treated with Chinese herbal medicine.

Table 1 .
Characteristics of selected studies.

Table 1 .
Characteristics of selected studies.