Tag: review

Chronic kidney disease (CKD) is one of the leading causes of death globally, which affects 13.4{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of the world’s population [1]. With deterioration in renal function, this leads to the onset of CKD-related complications, such as uremia, anemia, and electrolyte disorders [2]. These complications often manifest as symptoms ranging from pruritus, pain, and insomnia to muscle cramps. This in turn has negative implications on patients’ quality of life [3,4]. Importantly as CKD patients approach end-stage renal disease (ESRD), the prevalence and severity of such symptoms increase [5].

Despite medical breakthroughs and the advent of new therapies in the past decades, optimal treatments for some of the symptoms resulting from CKD-related complications remained unclear, possibly due to their complex pathophysiology. A case in point is uremic pruritus, which is found in around 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of pre-dialysis CKD patients and 40{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of ESRD patients [6]. Although prevalent treatments include the use of emollients, gabapentin, and antihistamines, data related to their efficacy were often derived from small studies and their use is limited by adverse effects [7].

The use of alternative medical systems (AMS) which forms a key pillar of complementary and alternative medicine (CAM) has increased in the past 20 years [8]. AMS is defined as “entire systems of health theory and practice that developed separately from conventional medicine” [9]. Notably, around 18{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of dialysis patients have utilized some form of AMS [10,11]. In addition, prescription of AMS therapies such as traditional Chinese medicine (TCM) by professional practitioners often aids in minimizing the risk of side effects, hence increasing their appeal as potential therapeutic alternatives [11].

Prior studies have shown that AMS is effective in reducing symptoms such as pain, nausea, and fatigue in non-CKD patient populations. For instance the use of TCM formulas, such as Liu Junzi Tang and Xiao Banxia Plus Fuling have demonstrated efficacy in treating cancer-related pain and chemotherapy-related nausea and vomiting [12]. In addition, Chinese herbs such as Curcuma longa and Panax ginseng among patients with malignancies have shown efficacy in promoting apoptosis of cancer cells and inhibiting tumor metastasis [13]. Another study showed that a multi-modal Ayurvedic treatment approach was effective in reducing knee osteoarthritis symptoms, such as pain and stiffness, and improving function [14]. With increasing research supporting the use of AMS, this has led to a rise in healthcare institutions adopting and providing such integrated services which are supported by insurance coverage [15].

Among CKD patients, multiple studies have also been conducted to assess the efficacy of AMS in the treatment of CKD-related conditions and symptoms such as uremic pruritis and anemia. For instance, a study that assessed the efficacy of homeopathy verum among CKD patients showed a reduction in pruritus symptoms by 49{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} after 30 days of treatment [16]. Another study that evaluated the use of TCM patients with glomerulonephritis showed improvement in hemoglobin after 24 weeks of therapy [16,17].

Existing reviews which have assessed the role of AMS are currently limited to specific indications, such as uremic pruritus [18], use of subtypes of AMS in specific CKD subgroups, such as consumption of Chinese herbal medicine in diabetic kidney disease [19], and specific AMS therapies, such as use of Astragalus [20,21]. This review aimed to summarize and evaluate the broad roles and efficacy of AMS as potential alternative therapeutic options for CKD patients. Findings from the review will aid physicians in gaining a better understanding of the efficacy of AMS for CKD patients, which can aid in facilitating purposeful discussions with patients who are using or considering these therapies.

Methods

Protocol and Registration

The protocol for this study was registered on Open Science Framework (https://osf.io/ymks8/) and was composed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Synthesis without Meta-Analysis (SWiM) reporting guidelines [22,23].

Information Sources and Search

A literature search was conducted in MEDLINE, Embase, Scopus, CENTRAL, CINAHL, and PsycINFO. There was no start date restriction, and studies up to April 2022 were included. Key terms related to CKD, randomized controlled trials (RCT), and AMS were included in the searches. The search terms were adapted from other systematic reviews and the full search strategy is available in Appendix 1 [18,24-26].

Eligibility Criteria

With regards to inclusion criteria, full-text articles in English language which involved RCTs evaluating the use of AMS in adult CKD patients (>18 years old) were included. As defined by the National Center for Complementary and Integrative Health (NCCIH), AMS is a broad category encompassing a variety of medical modalities and refers to an entire system of theory and practice which developed separately from conventional medicine [15]. In this review, we included TCM, naturopathy, homeopathy, and ayurvedic medicine. Non-RCTs, case series, other systematic reviews, and meta-analyses were excluded.

Description of Main Types of AMS

TCM: TCM is a system of medical practice which originated in China and adopts a holistic approach to the medical treatment of a patient based on “syndrome differentiation.” It focuses on the integrity of the human body by emphasizing the intimate relationship between the body and its social and natural environment, as well as dynamic balance of movement [27]. The basic tenet of TCM is based on the flow and balance of vital energy, Qi, which flows through channels in the body called meridians that connect various organs and tissues [28]. Diseases are believed to be brought about by the imbalance of Qi. Hence, by restoring balance via acupoints or intake of herbs, TCM seeks to promote individual wellness and prevent diseases [29].

Naturopathy: Naturopathy is a form of medical practice which is rooted in vitalism and folk medicine and, promotes natural and self-healing ideologies [30]. The unique attribute of naturopathic medicine lies in the reprioritization of the order of therapeutics with increased emphasis on preventive behaviors, lifestyle modifications, nutrition, and exercise, over medical or surgical interventions [31].

Homeopathy: Homeopathy entails the therapeutic administration of substances derived from plants, minerals, or animals that produce effects that correspond to the clinical manifestation of diseases [32]. Its practice is centered on two following theories: “like cures like” and “law of minimum dose.” “Like cures like” refers to the belief that diseases can be treated with substances that produce similar symptoms in healthy individuals, and “law of minimum dose” refers to the belief that the lower the dose the greater its therapeutic efficacy [32].

Ayurvedic medicine: Ayurvedic medicine is one of the oldest alternative medical systems which involves the use of therapeutics derived predominantly from plants, animals, minerals, diet, exercise, and lifestyle changes. Its therapies are centered on the principle of “Panchakarma,” which comprises five karmas (actions) to rejuvenate and remove toxins from one’s body [33].

Study Selection and Data Collection Process

Citations retrieved from the six databases were extracted into Endnote X9 software (Philadelphia, PA: Clarivate) and duplicated citations were removed. During the initial article screening, two independent reviewers (WY and SW) reviewed the titles and abstracts of articles to select relevant articles. Thereafter, the full texts of the identified articles were evaluated. All discrepancies during the article screening process were resolved by discussion with a third reviewer (JJ). Hand-searching of references within identified articles was also performed to enhance the comprehensiveness of the search. A standardized Microsoft Excel data collection form was used for data extraction, and details related to the study characteristics, studied indications of intervention, efficacy, and safety were collected.

Management of Missing Data

For studies with missing data, authors were contacted for clarification to enhance the comprehensiveness of this review. Missing information that could not be retrieved after two email reminders were labeled as unavailable.

Risk of Bias in Individual Studies

The Cochrane Risk of Bias tool version 2.0 (Oxford, England: Cochrane) was utilized in the assessment of the included RCTs [34]. Two independent reviewers (Teo and Chu) performed the risk of bias assessment (Appendix 2). The instrument comprises of the following five domains: risk of bias arising from the randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selection of reported results. Using the responses derived from the five domains, the overall risk of bias for the individual studies was rated as “low,” “some concerns,” or “high” risk of bias.

Assessment of Heterogeneity

Clinical and methodological heterogeneity of included studies were analyzed to evaluate if meta-analyses could be performed for specific interventions in this study. Clinical heterogeneity describes variation in characteristics of study participants, intervention, or outcomes while methodological heterogeneity describes variation in study design and risk of bias. This was performed by two independent reviewers (Yeam and Seng). In view of the clinical and methodological heterogeneity across the included studies, a narrative review of the RCTs was conducted.

Synthesis of Data

With regard to the efficacy of AMS interventions, the response rates and any changes in patients’ quality of life were recorded. Additionally, the safety profile of each intervention was evaluated and the reported prevalence, severity, and outcomes of adverse effects were tabulated. The adverse events reported in included studies were categorized using the Common Terminology Criteria for Adverse Events (CTCAE) [35].

Summary Measures

Descriptive statistics were utilized to summarize the characteristics of all included studies. The principal summary measures evaluated in this study were the studied indications, efficacy of each AMS, and safety profile of each AMS.

Results

Study Selection

Out of 14,583 retrieved citations, 33 full-text articles were included in this review. The inclusion and exclusion criteria for the studies are shown in Figure 1. The percentage of agreement of articles between the reviewers was 94.0{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and all disagreements were resolved after discussion.

Figure
1:
Flow chart for the inclusion of articles in this systematic review.

Study Characteristics

Types of AMS studied: Table 1 shows the characteristics of included studies. Among the four main types of AMS, TCM was the most studied (n=20, 60.6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [3,7,17,36-52], followed by Ayurveda (n=6, 18.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [53-58], naturopathy (n=5, 15.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [59-63], and homeopathy (n=2, 6.1{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [16,64].

Overview of study design and patient characteristics in included studies are as follows: the majority of the studies were conducted in Asia (n=31, 93.9{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), whereas most of the studies were performed in China (n=18, 54.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). Out of all reviewed studies, 20 (60.6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) were blinded to randomized controlled trials. The sample size was greater than 50 patients in 21 (63.6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) trials (Table 1). Non-dialysis patients were recruited in seven studies (21.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), whereas ESRD patients were recruited in five studies (15.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). The average duration of follow-up for all studies was 4.9 months (Table 2).

Tools used for outcomes assessments of symptoms during interventions are as follows: the most frequently utilized tools were the abbreviated version of the World Health Organization Quality of Life-100 Questionnaire (n=2) and visual analog scale (n=2).

Risk of bias within studies: Out of all included studies, 14 (42.4{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) studies were assessed to be of “low” risk of bias, nine (27.3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and 10 (30.3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) studies were scored as “some concerns” and “high” risk of bias, respectively.

Results of Individual Studies

Traditional Chinese medicine: The most commonly utilized interventions in the studies were herbal treatments (n=14, 70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [17, 37-43, 45-49, 51, 52] followed by acupuncture (n=6, 30{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [3,7,36,38,44,50]. For acupuncture treatment, five studies used conventional acupuncture [3,7,36,38,50] while one study used infrared stimulation of acupoints [44]. The common acupoints administered during conventional acupuncture treatment were Li11 (n=3, 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), ST36 (n=2, 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and Li4 (n=2, 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). The frequency of acupuncture ranged from once a week to once a day, whereas the duration of studies lasted between six weeks to six months. Uremic pruritus (n=3, 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) was the most commonly studied indication, with reductions in pruritus score observed between 54.7{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 60.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} [7,36,38]. Infrared stimulation was used on RN6, RN4, and RN3 thrice a week for three months [44]. The indication studied was quality of life (QoL). According to QoL scores that were evaluated using the EQ-5D questionnaire, utility increased by 15.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.

Herbal treatments include six single-herb (n=6, 42.9{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [39-42,48,49,51] and eight multi-herbs formula granules (n=8, 57.1{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [17,37,41,43,45-47,52]. Common single-herb treatments used are Huangkui (n=2, 33.3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and TWHF (n=2, 33.3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). The frequency of treatment was once to three times a day, for two to 12 months. Proteinuria was the most studied indication (n=4, 66.7{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), where the various treatments reduced proteinuria between 27.0{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 61.8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} [39,42,48,51]. Common herbs used in the multi-herb formula granules studies included Huang Qi (n=6, 75{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), Danggui (n=4, 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), Salvia miltiorrhiza (n=3, 37.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and Poria (n=3, 37.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). The most commonly studied indication was improvement in renal function (n=5, 62.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [17,41,43,47,52]. Serum creatinine decreased (2.76-12.4{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and eGFR increased (7.07-15.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) across the various treatments.

Ayurveda: The included studies evaluated both plant-based (n=3, 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [53,54,56] and animal-based (n=3, 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) treatments [55,57,58]. The most common treatment studied was plant-based silymarin tablets (n=2, 33.3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) while that for clinical indication was improvement in renal function (n=4, 66.6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [53-56]. The eGFR increased between 16.9{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 86.8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} across the various treatments [53-56].

Naturopathy: Keto amino acids were the most studied naturopathic treatment (n=2, 40{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). Common indications studied included anemia and glucose control, where hemoglobin and fasting blood glucose levels in subjects improved by 19.8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 20.8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, respectively [60,61]. The use of watercress and garlic extract was also studied for inflammation, where the total oxidant status and IL-6 levels were shown to improve by 38.9{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 68.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, respectively.

Homeopathy: Homeopathic verum was studied for relief of uremic pruritus with improvement in pruritus score between 29.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 41.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} [16]. For Brazilian green propolis pills, it was studied for proteinuria where a 27.6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} reduction in proteinuria was noted [64].

Safety Profile of AMS Interventions

The adverse events reported by all included studies are shown in Table 3. Adverse events reported were of grade 1 (n=13, 39.4{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), grade 2 (n=8, 24.4{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and grade 3 (n=6, 18.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) severity. There were no life-threatening consequences or death related to adverse effects (grades 4 and 5) reported.

Adverse effects associated with traditional Chinese medicine: the use of acupuncture is associated with mild pain, bleeding, bruising, and elbow soreness (grade 1) [36,40]. These symptoms resolved spontaneously without additional treatment. For single-herb treatments, TWHF treatment was associated with vomiting (38.2{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 1), itchy skin (6.45{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 1), nausea (3.22{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 1), and rash (1.61{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 1) [39,48]. Grade 2 adverse events associated with its use included hyperkalemia (23.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), leukopenia (2.9{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and photosensitive dermatitis (8.8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), while grade 3 adverse effects included liver dysfunction (19.4{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and severe leukopenia (1.61{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). Subjects who developed leukopenia were withdrawn from the study.

For Huangkui treatment, adverse effects observed included elevated cholesterol (2.94-3.76{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) (grade 1), upper respiratory tract infection (2.94-3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) (grade 2 and grade 3), and liver injury (2.26{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) (grade 3) [42,51]. The use of Shenqi particles was associated with interstitial pneumonia (1.1{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 2), lung infection (5.26{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 3), and liver injury (3.15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 3) [37]. Anemia (grade 2) and acute myocardial infarction (grade 3) were observed for subjects using Tangshen formula granules [41]. The use of QDDHG tablets was associated with insomnia (1.96{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 1) [47].

Adverse effects associated with ayurveda: Silymarin treatment was associated with nausea and vomiting (10{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), as well as headache (6.67{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [54,56]. Beleric capsule treatment was associated with mild gastrointestinal intolerance (11.1{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) [58]. Adverse effects from both studies were of grade 1 severity. Abdominal pain (4.5{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, grade 2) was observed with the treatment of camel milk [55].

Adverse effects associated with naturopathy: All adverse effects reported for naturopathy treatments are of grade 1 severity (Table 3). They include nausea (6.25{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and diarrhea (6.25{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with the use of alpha-keto amino acid [60], as well as stomach discomfort (4.54{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with the use of pomegranate juice [59].

Adverse effects associated with homeopathy: No adverse effects were reported with the use of homeopathy (Table 3).

Summary of Efficacy and Safety Profile of AMS Interventions

Table 4 shows a summary related to the efficacy and safety profiles of AMS interventions.

Discussion

To the best of our knowledge, this is the first review that has summarized findings related to the therapeutic uses of AMS for CKD patients in RCTs. Among the four classes of AMS, TCM was the most studied class which has demonstrated efficacy in improving CKD-related symptoms and outcomes [3,7,36-52]. Among the TCM interventions evaluated, Huangkui, TWHF, and acupuncture have shown efficacy in reducing proteinuria and relieving uremic pruritus symptoms. The therapeutic basis of TCM for CKD is rooted in the restoration of vital energy and nourishment of blood, dispelling of heat and reduction of dampness, and regulation of Yin and Yang in the body [65]. In Western medicine, this is seen in a reduction in inflammation and oxidative stress, as well as boosting micro-circulation and enhancement of metabolism [52]. For example, Huangkui, also known as Abelmoschus manihot, reduces proteinuria by removing oxygen radicals, improving the circulation, and clearance of immune complexes as well as reducing inflammation and renal tubular epithelial injury [66]. It is also noted that triptolide, the key constituent of TWHF, suppresses the nuclear factor kappa b (NF-κB) signaling pathway and prevents the trigger of T lymphocytes and some inflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ), in addition to its podocyte-protective capabilities [67-70]. Notably, two of the included studies demonstrated that a combination of TCM and Western medicine, such as the intake of Huangkui capsule and losartan tablet to alleviate proteinuria, is more efficacious than taking TCM or Western medicine alone. This adds to existing evidence on potential applications of TCM alongside conventional medical therapy. Among patients on TWHF, regular checks of potassium and liver enzymes should be performed due to the risk of hyperkalemia and raised liver enzymes.

With regards to the use of acupuncture, it results in the release of endogenous opiate-like substances that have been proposed to dull the peripheral and central perception of itching [71]. Stimulation of acupoints via far infrared (FIR) treatments has also been revealed to boost skin microcirculation, lessen emotional anxiety and promote excretion of waste products by improving the autonomic nervous system [44,72-76]. Enhanced circulation via a stronger autonomic nervous system is postulated to relieve CKD-related symptoms as the development of renal failure is attributed to poor circulation in the field of TCM [73,77]. Currently, renowned hospitals in the United States such as the Mayo Clinic and Duke University Medical Center have started providing acupuncture, along with other treatments. With growing evidence related to the efficacy and safety of TCM, there has been greater receptivity from medical doctors related to applications and use of TCM in clinical practice [78]. It is however important to note that TCM is not without any side effects. For example, the use of Huangkui should be cautioned in patients with hyperlipidemia or liver disease as its use has been associated with elevated lipid levels and liver injury. On the other hand, acupuncture appears to be relatively safe with mild side effects, such as elbow soreness. More studies related to TCM are required to further assess their long-term safety profile, and they should be prescribed with careful consideration of each patient’s health condition.

For Ayurveda, silymarin was one of the most studied interventions which demonstrated efficacy in improving renal function. Ayurvedic therapies are derived predominantly from plants, animals, minerals, exercise, and lifestyle changes. They are believed to rejuvenate and remove toxins from one’s body. In conventional medicine, the therapeutic effects of ayurveda for CKD are ascribed to their anti-inflammatory and anti-oxidant properties. For instance, silymarin has shown efficacy in in vitro studies in attenuating inflammatory stress in renal tissue by suppressing the NF-κB signaling pathway and hence TNF production [79-85]. Other Ayurvedic treatments, such as the application of capsaicin ointment, were also found to alleviate uremic pruritus. Topical capsaicin, a natural alkaloid derived from red chili pepper, has been discovered to relieve uremic pruritus by binding specifically to type C sensory neurons and resulting in the release of substance P, as well as suppressing its synthesis, transport, and storage thereafter [57]. Relatively few side effects were observed for the Ayurvedic therapies discussed above. Despite the promising benefits associated with Ayurvedic treatments, it is currently less globally recognized as compared to TCM [86]. Further research is necessary to evaluate their efficacy and safety profile to improve their acceptance in clinical practice as adjunctive treatments, in particular for CKD patients.

For naturopathy, its unique attribute lies in the reprioritization of the order of therapeutics, with increased emphasis on non-invasive treatments, such as lifestyle modifications and nutrition, over medical or surgical interventions. In this review, one of the more studied interventions is the use of ketoanalogues of essential amino acids (KAs). The addition of KAs to a low-protein diet has been shown to improve renal function and uremia. Notably, while lowering protein intake may improve renal function in CKD patients by altering immunologic events and reducing hypertrophy and hyperfiltration in the remaining nephrons, it may result in malnutrition [87-89]. However, the supplementation of KAs not only averts malnutrition by ensuring adequate consumption of amino acids but also alleviates uremia [61]. The absence of amino nitrogen in KAs allows them to become transaminated by taking nitrogen from non-essential amino acids and hence, reducing the production of urea via re-using the amino group [90,91]. Relatively few and mild adverse effects were observed for the included naturopathic therapies, rendering them attractive treatment options. Additionally, as naturopathic treatments are usually non-invasive, they can be easily combined with conventional medications. Of note, 28 health systems, hospitals, and cancer treatment centers in the United States currently have at least one licensed naturopathic physician at their premises [92]. With increasing research evaluating the efficacy and safety profile of naturopathic treatments, its role as potential adjunctive treatment for CKD patients is also likely to expand in the future.

Lastly, homeopathy has also shown efficacy in improving CKD-related symptoms and outcomes. Homeopathy entails the therapeutic administration of substances derived from plants, minerals, or animals which produce effects that correspond to the clinical manifestation of diseases. In this review, the use of Brazilian green propolis pills and homeopathic verum medication were found to improve renal function and alleviate uremic pruritus, respectively. Brazilian green propolis was reported to improve renal function via a few mechanisms. Firstly, it decreases proteinuria via its ability to reduce urinary oxidative stress and macrophage infiltration into the kidneys [93]. Secondly, chrysin, a flavonoid in propolis has been shown to decrease podocyte apoptosis in patients with diabetic nephropathy and lessen glomerular injury [94]. Lastly, propolis has also been shown to decrease blood pressure via acetylcholine-induced vasodilation and from its antioxidant properties [93,95-97]. With regard to the safety of homeopathic treatment, no adverse effects were reported across included studies. However, the practice of homeopathy is relatively restricted, with 36{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of states in the United States requiring homeopathic practitioners to either be licensed Western medicine or Naturopathic practitioners [32]. Consequently, more research is necessitated to validate the efficacy and safety of homeopathic treatment as adjunctive therapy for CKD patients.

Limitations

The following limitations should be considered in conjunction with this review. Firstly, due to the clinical and methodological heterogeneity of the studies, meta-analyses were not performed. As the pool of evidence for AMS trials for CKD patients grows, subsequent reviews should consider conducting meta-analyses for the efficacy of AMS treatments for CKD patients. In addition, there could have been exclusion of potentially applicable studies even though an extensive search strategy was used. To prevent this, the references of included studies were also hand-searched as part of our search strategy. Another limitation of the study relates to the inclusion of only articles in English language. Researchers should consider the inclusion of studies in other languages such as Chinese and Tamil in future reviews. Finally, although results of the included studies were reported normalized Z scores, care should be taken when interpreting these values and comparing the efficacy of various AMS classes. This is due to considerable diversity in types of outcomes evaluated and comparator arms and tools adopted for evaluation of outcomes. Overall, it is hoped that with greater standardization of study outcomes for AMS therapies in future studies, these normalized Z scores can enable more purposeful comparisons of the efficacy of the different AMS classes.