Xinyin Liu
Xiaoran Wang
Hongzhen Ma3†
Wen Zhang- 1The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- 2Department of Nephrology, The First People’s Hospital of Hangzhou Lin’An District, Hangzhou, China
- 3Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
Chronic kidney disease (CKD) is associated with high incidence, low awareness, and high disability rates among the population. Moreover, the disease significantly affects the physical and mental health of patients. Approximately 25% of patients with CKD develop end-stage renal disease (ESRD) within 20 years of diagnosis and have to rely on renal replacement therapy, which is associated with high mortality, heavy economic burden, and symptoms including fatigue, pain, insomnia, uremia pruritus, and restless leg syndrome. Currently, the means to delay the progress of CKD are insufficient; therefore, developing strategies for delaying CKD progression has important practical implications. In recent years, more and more people are accepting the traditional Chinese medical technique “acupuncture.” Acupuncture has been shown to improve the uncomfortable symptoms of various diseases through stimulation (needling, medicinal moxibustion, infrared radiation, and acupressure) of acupoints. Its application has been known for thousands of years, and its safety and efficacy have been verified. As a convenient and inexpensive complementary therapy for CKD, acupuncture has recently been gaining interest among clinicians and scientists. Nevertheless, although clinical trials and meta-analysis findings have demonstrated the efficacy of acupuncture in reducing albuminuria, improving glomerular filtration rate, relieving symptoms, and improving the quality of life of patients with CKD, the underlying mechanisms involved are still not completely understood. Few studies explored the correlation between acupuncture and renal pathological diagnosis. The aim of this study was to conduct a literature review summarizing the currently known mechanisms by which acupuncture could delay the progress of CKD and improve symptoms in patients with ESRD. This review help provide a theoretical basis for further research regarding the influence of acupuncture on renal pathology in patients with CKD, as well as the differences between specific therapeutic mechanisms of acupuncture in different renal pathological diagnosis. The evidence in this review indicates that acupuncture may produce marked effects on blocking and reversing the critical risk factors of CKD progression (e.g., hyperglycemia, hypertension, hyperlipidemia, obesity, aging, and anemia) to improve the survival of patients with CKD via mechanisms including oxidative stress inhibition, reducing inflammatory effects, improving hemodynamics, maintaining podocyte structure, and increasing energy metabolism.
1 Introduction
Chronic kidney disease (CKD) refers to abnormal renal structure or function caused by various reasons or an unexplained decrease in the glomerular filtration rate (GFR<60 mL/min) for >3 months (1). In 2012, the Lancet published the first nationwide cross-sectional survey of CKD in China, showing that there were approximately 120 million patients with CKD, which had a 10.8% prevalence rate among adults (2). According to the five insights of the 2019 Global Disease Burden Study, exposure rate to the risk factors of injury and disability caused by CKD has also increased, second only to hypertension, hyperglycemia, obesity, environmental pollution, and social factors (3). Furthermore, approximately 25% of patients with CKD develop end-stage renal disease (ESRD) within 20 years of diagnosis (4). Patients with ESRD have a high mortality rate and require long-term maintenance dialysis, which incurs substantial medical costs and places a heavy economic burden on families, society, and the country. Currently, the etiology and pathogenesis of CKD are unclear, and there is a lack of effective treatments.
1.1 Treatment of CKD in Western medicine
The main treatments of CKD target preventing ESRD to reduce mortality. Modern medicine has made several attempts to treat this disease, including dealing with its complications (e.g., renal hypertension, hyperlipidemia, proteinuria) using glucocorticoids, cytotoxic drugs, immunosuppressants, and biological agents based on individual patient characteristics and renal pathology (5). However, there are currently no ideal treatment schemes, and this disease has become a significant public health concern worldwide. Hence, it is necessary to explore novel methods for its prevention and treatment.
1.2 Associated symptoms and symptomatic treatment
The considerable symptomatic burden associated with CKD greatly affects the quality of life of patients. Common symptoms include fatigue, pain, sleep disorders, restless leg syndrome (RLS), and chronic pruritus, although with considerable variations related to symptom definition, period of prevalence, and levels of severity (6–8). The first-line intervention of pain and pruritus is mainly medication, but their use and management have limitations, and nonpharmacologic approaches have therefore attracted attention. For example, replacement therapy has been shown to be feasible and effective against fatigue and sleep disorders (9).
1.3 Acupuncture and CKD
Acupuncture is an essential component of traditional Chinese medicine (TCM) and substitute auxiliary therapies. According to the TCM theory, there are 12 main and collateral channels on the human body surface and 361 classical acupuncture points on these channels (10). Acupuncture can adjust the qi and blood of the meridians and viscera, improve various uncomfortable symptoms, and treat diseases by stimulating different acupoints. For the purpose of this review, acupuncture is considered as a generalized concept, including procedures involving insertion of fine needles into the skin or deeper tissues at specific locations (acupoints) of the body which are then manipulated manually, electrically, or with combined moxibustion; pressure on the acupoints with fingers; or application of infrared radiation on acupoints instead of fine needles.
1.3.1 Effectiveness
Acupuncture has been proven to reduce urine protein levels and improve estimated GFR (11–18). Meanwhile, some studies also focused on the effects of acupuncture on hemodynamics (19) and renal interstitial fibrosis (20–24). Factors such as hyperglycemia, hypertension, hyperlipidemia, obesity, pain, aging, and anemia have a profound relationship with CKD progression (25). Considering that acupuncture can be effective in improving these aspects (26–30), it is believed that acupuncture may improve the prognosis of patients with CKD by controlling the above risk factors. In addition, acupuncture has the potential to alleviate various ESRD-related symptoms (e.g., pain, uremic pruritus [UP], RLS, and sleep disorders) (31–33). The therapeutic effect of acupuncture on CKD cannot be explained entirely by the bidirectional regulation of nerves, which is generally considered the main effective mechanism (34). However, a number of large-scale, randomized controlled clinical trials are still needed to clarify the indications of acupuncture before it can be used widely in clinical practice, especially as the mechanisms by which acupuncture affects disease mechanisms can be quite complex.
1.3.2 Security
The safety of acupuncture has been widely confirmed in clinical practice. A prospective observational study on acupuncture for chronic pain in Germany included 454920 patients, of whom more than 30% were over 60 years old, and reported mild side-effects (pain, hematoma, and bleeding) in 7.9% of patients. Only 13 patients suffered serious adverse events, including pneumothorax, hypertension, hypotension, asthma attacks, and aggravation of suicidal thoughts (35). The safety of acupuncture for CKD has also been proved. A systematic review of 55 randomized controlled trials showed that the most common side-effects associated with needling therapy and acupressure therapy were elbow soreness and bleeding and intradialytic hypotension and dizziness, respectively, and that no adverse effects were reported for moxibustion therapy (36). Some researchers believe that some side-effects of acupuncture are due to malpractice by acupuncturists, which can be avoided by strengthening training (37). The World Health Organization recommends at least 1568 hours of training to meet the basic requirements of acupuncture practitioners of ensuring clinical efficacy and patient safety (38).
However, although acupuncture is one of the safest replacement therapies, especially when provided by well-trained acupuncturists, to the best of our knowledge, the recent progress related to the use of acupuncture in treating CKD has not been summarized. This review aimed to assess the beneficial effects and current known mechanisms of acupuncture with regard to CKD and ESRD-related symptoms. We believe that acupuncture may have a significant impact on the associated risk factors for blocking or reversing the progress of CKD and alleviating the discomfort of patients, thus improving their prognosis.
2 Methods
We designed our literature review to include basic and clinical studies that addressed the effects and mechanisms underlying the effects of acupuncture treatment in CKD. The PubMed databases were queried for full-text studies published between January 1, 2000 and August 31, 2022 in English or Chinese using the following keywords: “acupuncture” and “kidney”.
Inclusion criteria:
1. Description of specific mechanisms of how the acupuncture treatment exerted its effects
2. Exclusive use of acupuncture to treat CKD and related symptoms
3. Related studies cited in these articles
Initially, 747 published articles were identified, of which only 46 articles matched the inclusion criteria and were reviewed. We excluded one withdrawn article, two articles unable to find partial results of changes in renal function, and two articles with imprecise test design that does not control variables. The references of the remaining 41 articles identified an additional 6 articles that also matched our inclusion criteria, which were also included in the final review, resulting in 47 articles in total (Table 1). The studies included randomized controlled animal experiments and clinical experiments and involved kidney injury. Additionally, we conducted a supplementary literature search on hyperlipidemia, which was not identified in the previous search but has been proved to be an important independent risk factor for the development of CKD.
Table 1 Summary of studies in chronic renal injury, and renal physiological function and ESRD-related symptoms (2000-2022).
3 Results
The 47 studies included in this review employed the use of Sprague Dawley rats, Wistar rats, Golden Syrian hamsters, New Zealand white rabbits, which were used to model ischemic nephropathy, diabetic nephropathy (DN), or hypertensive nephropathy. According to the risk factors of CKD, including hyperglycemia, hypertension, hyperlipidemia, obesity, aging, and anemia (25), we classified and summarized the potential mechanisms of action of the beneficial effects of acupuncture on the progress of CKD (Figure 1) and the common symptoms of ESRD.
Figure 1 Mechanisms Underlying the Effects of Acupuncture Therapy in Chronic Kidney Disease. The gray grids are the known possible main mechanism/target/downstream product of acupuncture in treating chronic kidney disease. EPO, erythropoietin; GABA, γ-aminobutyric acid; SNS, sympathetic nervous system; PGC, proliferator γ coactivator; SNGFR, single nephron glomerular filtration rate; ET-1, endothelin-1; Ang II, angiotensin II; FSGS, focal segmental glomerulosclerosis; TIF, tubulointerstitial fibrosis; MDA, malondialdehyde; RCT, reverse cholesterol transport; CHOL, cholesterol; NF-κb, nuclear factor-kappa B; ROS, reactive oxygen species.
3.1 Risk factors of CKD and the corresponding mechanism of acupuncture
3.1.1 Hyperglycemia
DN is rapidly becoming the most common cause of ESRD worldwide (25). The pathogenesis of DN is complex and involves various mechanisms, resulting in poor therapeutic outcomes (71). It is generally accepted that the developmental mechanism of DN results from abnormal homeostasis (72). There are many critical links in the progression of DN, e.g., oxidative stress, inflammation, and podocyte structural damage. A reciprocal relationship exists between inflammation and oxidative stress (73, 74). Various Chinese meta-analyses point out that acupuncture can reduce the urine protein, serum creatinine, fasting blood glucose, postprandial blood glucose, glycosylated hemoglobin, total cholesterol, and triglycerides of patients with DN, as well as enhance the efficacy when combined with conventional drugs (26, 75, 76).
3.1.1.1 Oxidative stress
The increase in reactive oxygen species (ROS) caused by blood glucose is at the core of the pathogenesis of DN. Hyperglycemia-induced oxidative stress is believed to cause both local and systemic inflammation (77).
Forkhead transcription factor O1 (FOXO1) overexpression reduced ROS in rat mesangial cells and protected mitochondrial function by activating peroxisome proliferator γ coactivator 1 α (PGC-1α) (78). A study on rats with DN showed that electroacupuncture (EA) increased the levels of FOXO1 and PGC-1α in kidney tissue, thus improving renal function (39).
Nitric oxide synthase (NOS), superoxide dismutase (SOD), and malondialdehyde (MDA) are essential indicators of oxidative stress. Reactive species may also be produced enzymatically by uncoupled NOS (79). SOD is an antioxidant that can effectively remove superoxide anions and protect cells from oxidative damage (80). MDA is a metabolite of lipid peroxidation, which can reflect the level of free radicals in tissues and lipid peroxidation caused by free radicals, and indirectly reflects cell damage (40). A study on rats with DN showed that acupuncture and moxibustion have synergistic effects on antioxidant stress, which may be related to their function in downregulating the expression of MDA and upregulating the expressions of NOS and SOD in the kidney (40). Another trial revealed that EA could improve renal function and reduce microcirculation disorders in early DN by up-regulating the levels of serum endothelial NOS and NO (41).
Oxidative stress can directly damage podocytes, mesangial cells, and endothelial cells, resulting in proteinuria and tubulointerstitial fibrosis. One study suggested that EA may effectively alleviate renal injury in rats with DN by promoting renal autophagy. The number of podocytes in rats with DN treated with EA was more than that in the untreated group, while the levels of 24-h urine protein, blood urea nitrogen, and serum creatinine were lower (42).
Nuclear factor 2 related factor 2 (Nrf2) regulates oxidative stress in the antioxidant response system by controlling the expression of more than 250 genes (72, 79). A study on rabbits with acute kidney injury revealed that EA treatment enhanced the expression of phosphorylated Akt, heme oxygenase-1 protein, Nrf2 total protein, and nuclear protein to resist oxidative stress (81).
3.1.1.2 Inflammation
Continuous inflammation of the circulatory system and renal tissue is the fundamental pathological basis for the development of DN (82). Inflammatory factors such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β, IL-1, and IL-18 are elevated in the blood and have been related to the occurrence and progression of DN (83, 84). Several studies have shown that acupuncture can improve insulin resistance by reducing serum IL-6, IL-8, and IL-1β levels, which might help protect islet B cell function (43, 85).
Increasing evidence has shown the central role of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (71) in DN pathogenesis. JAK and STAT subtypes expressed on the renal tubulointerstitial increase along with the development of DN and negatively correlated with the estimated GFR. Nuclear factor-kappa B (NF-κB) is a key transcription factor in the inflammatory process of DN and is activated by the JAK-STAT pathway. NF-κB regulates inflammatory cytokines and chemokines, e.g., monocyte chemoattractant protein-1 (MCP-1) and cell adhesion proteins, leading to kidney damage. A study on diabetic mice revealed that acupuncture could suppress the inflammatory response of DN through the NF-κB-related pathway (43). Zhang et al. designed a series of multicenter, randomized, and blinded studies, showing that the needling method of harmonizing the spleen and stomach on patients with early DN might inhibit the NF-κB-related pathway by inhibiting the expression of MCP-1, which can improve renal blood flow and GFR, decrease urinary albumin secretion, protect the glomerulus and renal tubules, thus reducing the inflammatory levels and delaying the progress of DN (44, 45).
3.1.1.3 Energy metabolism
The kidney requires a large number of mitochondria to provide the energy to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function (86, 87). Figueiredo et al. (88) found that in non-exercised hyperglycemic rats, under the same dose of anesthesia (ketamine, 90 mg/kg body weight), the lactic acid concentration and blood glucose level of the experimental group treated with EA decreased significantly, indicating that acupuncture might reduce blood glucose by enhancing aerobic metabolism and increasing ATP output.
NAD-dependent isocitrate dehydrogenase is present in the mitochondria. It is a momentous rate-limiting enzyme of the tricarboxylic acid cycle (TCA) and plays a crucial role in energy production and anabolism. As the most important source of adenosine triphosphate (ATP), TCA is closely related to the occurrence of nephropathy. Two other studies reached similar conclusions; after needling the “Taixi” (KI 3) point, increased expression of NAD-dependent isocitrate dehydrogenase and quinone reductase was observed in rat kidney tissue, suggesting that targeted acupuncture improves energy metabolism (46, 47).
Metabonomics has also been applied to study EA’s effects on renal metabolism. Alanine is a characteristic metabolite in the kidney, an important energy source for human beings, and is involved in lymphocyte regeneration, thus maintaining immune homeostasis (89). Threonine participates in energy metabolism and promotes the cellular immune system’s defense function (89). Research suggested that the levels of the two metabolites in the kidneys of mice with premature ovarian failure were elevated, and the levels were down-regulated after electroacupuncture stimulation of “Sanyinjiao” (SP6) and “Guanyuan” (CV4), close to the level of healthy mice (90). Another study revealed that the effect of EA on the abnormal increase of metabolites might suggest that it can regulate the disordered amino acid metabolism, thereby improving energy metabolism and regulating the kidney’s immune function (91).
3.1.1.4 Maintaining the podocyte structure
Podocytes are important functional cells in the glomerulus that cannot regenerate when they suffer from injury. Their damage and apoptosis could result in the destruction of the glomerular filtration membrane and induce DN (92). Podocalyxin is one of the main structures responsible for the negative charge on the glomerular membrane (93). CD2-associated protein (CD2AP) is a transmembrane protein that interacts with nephrin to maintain cytoskeleton and slit diaphragm function. Damage to CD2AP leads to the destruction of the podocyte skeleton and marked proteinuria (94). Desmin also maintains the mechanical stability of podocytes to enable morphological changes on the tensile glomerular capillary wall (95). Zhang et al. found that acupuncture partly prevented DN rats from podocyte foot process effacement—which exhibited fusion, complete destruction, or disappearance—and thick glomerular basement membrane. It also upregulates nephrin expression, CD2AP, and podocalyxin but downregulates desmin, thus protecting and maintaining podocytes’ physical and chemical structure (27).
The transient receptor potential-6 channel (TRPC6) is an integral player in the calcium processing in podocytes and in the maintenance of their cellular structure (96, 97). Möller et al. reported that overexpression of TRPC6 in healthy mice leads to the restructuring of the podocyte actin cytoskeleton and alterations in calcium flux, which causes proteinuria (97). Hyperglycemia and elevation in angiotensin II (Ang II) levels are sufficient to cause overexpression of TRPC6, resulting in increased calcium influx and eventual podocyte dysfunction and death (98). Li et al. proved that EA preconditioning could alleviate renal injury in hyperglycemic mice by reducing renal TRPC6 and nephrin expression and inhibiting podocyte activation (48, 49).
3.1.2 Hypertension
Hypertension is considered a result of renal damage and a significant contributor to the progression of CKD (25). Approximately 80–90% of patients with CKD have renal hypertension, which accelerates renal dysfunction (99, 100). Therefore, controlling blood pressure is critical in preventing progressive deterioration of renal function. Renal hypertension is difficult to cure and usually requires the combined use of several antihypertensive drugs with possible non-compliance. The pathological mechanism of renal hypertension is complex, including activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), oxidative stress, increased endothelin-1 (ET-1), and inflammation. Acupuncture has been shown to have certain clinical effects on renal hypertension (50). A network meta-analysis on acupuncture therapy for essential hypertension, which included 31 trials with 2,649 patients, revealed that acupuncture might have similar effects as common medication. However, the quality of this evidence is not high (101).
3.1.2.1 Angiotensin II type 1 receptor-ET-1-endothelin-1 type A receptor pathway
ET-1 is a crucial molecule that regulates renal hypertension, and its release is induced by the combination of Ang II and angiotensin II type 1 receptor (AT1R). ET-1 combines with endothelin-1 type A receptor (ETAR), which causes marked renal vasoconstriction (102). A previous study revealed that Ang II and ET-1 receptor blockers could reduce blood pressure in animal models and patients (103). Acupuncture reduces blood pressure by lowering the ET-1 level (104, 105). Additionally, long-term EA blocks the AT1R-ET-1-ETAR pathway by inhibiting the expression of AT1R and ETAR (106). Therefore, it is believed that the AT1R-ET-1-ETAR pathway may be a target for acupuncture treatment of renal hypertension.
3.1.2.2 Renin-angiotensin-aldosterone system
The RAAS is a vital blood pressure regulation system that maintains the homeostasis of water and electrolytes in the internal environment. There are two main pathways. 1) The angiotensin-converting enzyme/Ang II (ACE/Ang II) pathway constricts blood vessels and promotes tissue proliferation and remodeling (107). 2) The ACE2/Ang-(1-7) pathway has the opposite effects (108). Moreover, Liu et al. found that acupuncture and moxibustion showed good antihypertensive effects by reducing the content of Ang II and atomic layer deposition in the plasma of hypertensive rats (109).
3.1.2.3 SNS
The development of hypertension partly depends on the increased sympathetic outflow and impaired baroreflex function. The nucleus tractus solitarii (NTS) is the main integration center regulating the autonomic reflex and sympathetic outflow. In the NTS, inhibition of γ-aminobutyric acid (GABA) is essential for pressure reflection signal processing. Evidence shows that an increase in GABA inhibition leads to hypertension (110–112). Therefore, neuronal activity in the NTS is a significant target for acupuncture to regulate the sympathetic excitatory reflex function. A study revealed that EA could reduce sympathetic activity and significantly inhibit the sympathetic excitatory reflex in rats, which may be achieved by regulating functional GABA (113). Moreover, acupuncture reduced local renal sympathetic nerve activity by inhibiting the extracellular regulated protein kinase ½-MAPK pathway to lower blood pressure (51). Another study also verified the relationship between acupuncture and renal sympathetic activity (52).
3.1.2.4 Oxidative stress
Renal hypertension induced by ischemic nephropathy is affected by oxidative stress mechanisms involving molecules such as NOS and heme oxygenase (HO-1/2) (114–116). In one study, EA was shown to prevent the reduction of endothelial NOS and nitric NOS levels associated with hypertension (53).
Inducible NOS (iNOS) and HO-1/2 expression is involved in the secretion of insulin-like growth factor-I (IGF-I) in MCF-7 cells (117). IGF-I has been proved to be related to proliferation, differentiation, survival, apoptosis, and cell protection related to oxidative stress (118). Another study showed that EA can reduce the levels of iNOS and HO-1/2 and upregulate IGF-1 levels, thus reducing glomerulosclerosis and renal interstitial fibrosis as well as blood pressure in rats with renal failure (54). Additionally, the possibility of acupuncture being able to directly affect the process of renal fibrosis in hypertensive rats has also been suggested (55, 56).
3.1.3 Hyperlipidemia/obesity
Recent studies have shown that hyperlipidemia and obesity are two adverse factors associated with the progression of CKD via different mechanisms. However, obese patients are typically at higher risk of hyperlipidemia (119). Obesity is associated with high glomerular filtration and other glomerular hemodynamic alterations, which may aggravate CKD progression (120, 121). Adipocytes produce various hormones and pro-inflammatory molecules, which may lead to progressive renal damage (122). According to the lipid nephrotoxicity hypothesis, hyperlipidemia can lead to inflammation, oxidative stress, and endogenous electrical stress (123).
A study on 1528 obese patients with hyperlipidemia treated with acupuncture suggested that acupuncture had dual effects on obesity and hyperlipidemia. The patients not only effectively lost weight (the total effective rate of the mild obesity group was 98.9%), but they also reduced their levels of total cholesterol, triglycerides, and low-density lipoprotein and improved their high-density lipoprotein (HDL) level (28). Some scholars believe that acupuncture combined with moxibustion reduces the adverse effects of hyperlipidemia and obesity better than acupuncture alone (124). Another study found that different acupoint combinations had different effects on reducing blood lipid levels. The “Quchi” (Li 11), “Zhongwan” (CV 12), and “Fenglong” (ST 40) points had a superior performance on blood lipid metabolism (125).
3.1.3.1 Anti-oxidative stress
Nitric oxide (NO) is an endothelium-derived messenger molecule that alleviates oxidative stress. Several studies revealed that EA and moxibustion increase the level of NO to resist oxidative stress and that the effect of moxibustion is regulated by temperature (126–130). Transient receptor potential vanilloid subfamily 1 (TRPV1) is an essential molecular regulator that provides moxibustion with temperature dependence of its hypolipemic properties. There is a relationship between the cholesterol-lowering effect of moxibustion and the activation of TRPV1 (131).
3.1.3.2 Reverse transport mechanism
Reverse cholesterol transport (RCT), which is partly mediated by ATP-binding cassette transporter A1 (ABCA1), is a significant physiological link that delays hyperlipidemia progression. ABCA1 regulates intracellular RCT and HDL production, thereby controlling lipid metabolism. As transcription factors, activated peroxisome proliferator-activated receptor (PPAR)-α and liver X receptor α (LXRα) enhance ABCA1 transcription activity (132, 133). Zou et al. believed that moxibustion upregulated PPARγ and scavenger receptor B1 (SR-B1) protein and gene expression in the liver to promote cholesterol reversal (134). HDL binds to SR-B1 and transports cholesterol to the liver for selective metabolism. Another research study found that EA stimulation of the “Fenglong” (ST 40) point contributed to increased expressions of ABCA1, PPARα, LXRα, and retinoid X receptor α messenger RNA, thus contributing to RCT, and somehow had a therapeutic effect on hyperlipidemia (135, 136).
ABCA1 dysfunction leads to excessive cholesterol ester accumulation as lipid droplets in macrophages, thereby contributing to foam cell formation (137). EA at the “Fenglong” (ST 40) point can prevent macrophage transformation into foam cells and increase cholesterol outflow rate in macrophages, thus preventing and reversing foam cell formation (138).
3.1.3.3 Lipids synthesis reduction
Sterol regulatory element binding protein-1C (SREBP-1C) is a transcription factor involved in the transcriptional regulation of the fatty acid synthase (FAS) gene that controls the synthesis of lipids from glucose in the liver (139). Recent research indicated that FAS could catalyze the de novo synthesis of fatty acids and impact liver physiology through signaling and energy storage (140). It is believed that acupuncture downregulates SREBP-1C and FAS to control the expression of key enzymes regulating cholesterol synthesis in the liver to prevent hyperlipidemia (141).
3.1.3.4 Inflammation reduction
CKD is an inflammatory state that results in glomerular and tubular lesions and adversely affects lipid balance (142, 143). Several inflammatory markers have been associated with lipid levels (144). Some studies revealed that acupuncture could reduce intercellular cell adhesion molecule-1, MCP-1, TNF-α, IL-6, and IL-1γ, slowing the inflammatory process (145–147).
Adiponectin (ADPN) is the only adipocyte-specific protein negatively associated with obesity. It has anti-diabetic, antiatherosclerotic, anti-inflammatory, and antiangiogenic properties. Hand acupuncture and EA intervention positively affect hyperlipidemia by reducing blood fat content and upregulating serum HDL-C and ADPN levels in hyperlipidemic rats (148).
3.1.4 Aging
A longitudinal study among individuals without nephropathy found that the GFR decreases with age, indicating that nephron loss might be part of normal aging (149). Other studies have shown that proteinuria, CKD, and ESRD incidence rates increase with age (149–151). Acupuncture can delay the aging of the kidney tissue by suppressing oxidative stress and reducing apoptosis. An experiment suggested that the apoptosis rate of renal cells and the levels of hydrogen peroxide and malondialdehyde decreased after acupuncture in adult rats (29).
3.1.5 Anemia
Renal anemia is one of the most common complications of CKD and affects the quality of life and survival time of patients with CKD (152). In a study of 131 patients with CKD, elevated hemoglobin levels were independently associated with reduced mortality (153). Renal anemia is usually caused by the hyposecretion of erythropoietin (EPO). EPO is a protein hormone synthesized by proximal convoluted tubular cells, essential for erythrocytes’ growth. Medical treatments sometimes show poor efficacy, including recombinant human erythropoietin and polysaccharide iron complexes (154). Therefore, there is an urgent need for supplemental therapies to improve the curative effect. One study found that acupoint injection could reduce the level of C-reactive protein, improve the micro-inflammatory state, and help reduce EPO dosage, which is better than the traditional injection method (30). Acupoint injection reduces costs and meets the requirements of patients’ health and the economy.
3.2 Control of ESRD-related complications
CKD and ESRD have attracted attention worldwide, and the number of patients on hemodialysis (HD) has increased dramatically. Patients on HD often have many painful complications, such as UP, RLS, insomnia, fatigue, sleep disorders, and hypotension. Acupuncture can alleviate these problems. A systematic review of randomized controlled trials showed that acupuncture had demonstrated efficacy in alleviating sleep disturbance, fatigue, and UP symptoms among patients with CKD (36).
3.2.1 Pain
Pain can be one of the most debilitating symptoms of CKD (155). Patients suffer several types of pain, including peripheral neuropathic pain, joint pain, autosomal dominant polycystic kidney disease (ADPKD)-related pain, and pain caused by renal biopsy. A multicenter, cross-sectional study evaluated the impact of pain on the quality of life of patients with ESRD on HD, with the results suggesting that pain significantly impacted their life quality (156). Pain management in patients with CKD is challenging. Non-opioid analgesia using acetaminophen, topical analgesics, and gabapentinoids is preferred, but cannot relieve pain to a great extent (155). Furthermore, the long-term use of non-steroidal, anti-inflammatory drugs poses a risk of liver and further kidney damage. A study on over 400,000 patients with ESRD showed that an opioid prescription was accepted by over half of them (157), even though opioid use is associated with an increased risk of altered mental status, falls, fractures, hospitalizations, and mortality, in a dose-dependent manner (158, 159).
Nevertheless, opioids play a central role in the analgesic mechanism, desensitizing peripheral nociceptors, reducing pro-inflammatory cytokines, and activating the descending inhibitory system (160). A previous study showed that high- and low EA frequencies could relieve heat, mechanical, and spontaneous pain by regulating μ and δ opioid receptors (161). This shows that acupuncture has the prospect of reducing or even replacing opioid use.
Besides, the role of acupuncture in the treatment of chronic lower back pain has been well proven and addressed in the Clinical Practice Guideline of the American College of Physicians (162). It is also effective against chronic lower back pain caused by polycystic kidney disease (163). Unfortunately, at present, there is a lack of large-scale studies on verifying the efficacy of acupuncture and moxibustion on lower back pain in other types of CKD.
3.2.2 Uremic pruritus
Chronic pruritus associated with ESRD is one of the most important causes of systemic pruritus (164). UP is an unpleasant and painful condition causing the desire to scratch, invalidating the skin’s protective barrier, and affecting patients’ health-related quality of life (HR-QOL) (31). A large multicenter study of 18801 patients on HD showed that 42% of them had UP (165). The pathogenesis of UP may involve inflammatory states, such as increased levels of pro-inflammatory cytokines (IL-6, IL-2, and TNF-α), immune changes, and neuropathy. Current drug treatment regimens (e.g., antihistamines, bupropion, and tacrolimus) often lead to many side-effects, including sleepiness, nausea, vomiting, and epilepsy. Patients are unlikely to extract many benefits, and the symptoms usually recur after drug discontinuation (164). Acupuncture, an economical and safe complementary therapy, has obvious advantages in treating pruritus, with one meta-analysis even suggesting the potential of acupuncture to treat UP (166). Studies have shown that one of the mechanisms of acupuncture in treating chronic pruritus is regulating inflammatory cytokines, including reducing IL-4 and IL-2 levels in serum, enhancing the anti-inflammatory cytokine IL-10, and inhibiting the level of the inflammatory cytokine TNF-α (the acupoints are all “Quchi” (LI11), “Hegu” (LI4), “Xuehai” (SP10), and “Yinlingquan” (SP9)) (167–169). Another animal study found that EA increased the serum levels of interferon-γ of mice with atopic dermatitis, with no significant change in IL-4 levels (the acupoints are “Quchi” (LI11) and “Neiguan” (PC6)) (170). This finding suggests that different acupoints lead to different effects.
Karjalian et al. conducted a randomized, double-blind, pre- and post-control clinical trial among 90 patients on HD and found that acupoint pressing could effectively reduce pruritus in patients on HD (31). Four other randomized controlled trials showed that acupuncture, acupoint pressing, transcutaneous acupoint electrical stimulation, and auricular finger pressing could reduce UP symptoms (57–59, 171). Yi et al. believed this effect could continue after the treatment course (57).
3.2.3 Restless leg syndrome
RLS is a common chronic sensorimotor disorder characterized by a strong demand to move the legs during rest and bedtime. The development of this disease in patients undergoing HD is progressive (32). The prevalence among European and American adults varies from 7% to 10% (172, 173). Further, the prevalence of RLS has been reported to increase with age (174). RLS affects sleep quality and leads to dysfunction of emotion, cognition, energy, and other daily activities. RLS is associated with an increased risk of cardiovascular disease, osteoporosis, musculoskeletal pain, and mortality (175–177). A single-center, single-blinded, randomized controlled study attempted to treat 60 HD patients with RLS by irradiating lower limb acupoints with near-infrared light, but the symptoms of RLS recurred after irradiation was stopped (32). The mechanism was unknown, and the effects might have been related to the selection of acupoints, treatment cycle, and treatment mode, which require further study.
3.2.4 Sleep disorders
Sleep disorders in patients on HD can lead to psychosocial function and interpersonal relationship disorders and reduce their HR-QOL (60). More than 85% of patients on HD experience serious sleep problems (178). Zahra et al. and Shariati et al. found that acupoint pressing positively affects sleep quality in patients on HD, but the specific mechanism is still unknown (60, 61).
Acupuncture has been proved to have a significant effect on sleep disorders. Various meta-analyses, which included thousands of patients each, suggested that acupuncture could improve the sleep quality of patients with primary insomnia and patients with insomnia-related primary diseases and conditions (stroke, ESRD, perimenopause, pregnancy, and mental illness) of all ages, with few and mild adverse reactions (33, 179–182). However, because most of the included studies were heterogeneous and the sample size of each experiment was small, and there are few studies related to ESRD, it is still necessary to design randomized controlled trials with larger sample sizes to prove the essential of acupuncture to treat sleep disorders in patients on HD.
3.2.5 HR-QOL
HR-QOL is a measure of the value assigned to duration of life as modified by impairments, functional states, perceptions and opportunities, as influenced by disease, injury, treatment and policy (183). Due to the progress of ESRD, the lifestyle restrictions and changes imputed to HD usually lead to fatigue, depression, anxiety, which have a profound impact on HR-QOL. The mental health of elderly patients is an especially serious problem (184). Mid- and long-term fatigue may even increase the risk of cardiovascular events and is associated with higher mortality (185). The clinical trials of this subsection were evaluated through the following questionnaires: Pittsburgh Sleep Quality Index, Piper Fatigue Scale; Visual Analog Scale, Kidney Disease Quality of Life-Short Form, a questionnaire authenticated and approved by the World Health Organization and Patient-Reported Outcomes Measurement Information System. Two studies showed that acupoint pressing could improve the fatigue state of HD patients (62, 63), and several randomized controlled studies found that moxibustion, acupressure, transcutaneous electrical acupoint stimulation, and acupuncture had positive impacts on aspects such as physical functions, general health, and vitality (64–69). However, in 2018, a study on living conditions of 101 HD patients who received short-term acupuncture/massage suggested that although the original Patient-Reported Outcomes Measurement Information System psychological scores of patients improved, the improvement was not significant, and might have been related to the sample capacity and treatment duration (70).
4 Discussion
CKD is a significant public health problem worldwide and is characterized by a high incidence rate and complex pathogenesis. The clinical treatment scheme needs to be improved urgently, as currently the main clinical therapeutic strategy is to delay the progress of CKD, which mostly relies on medication. According to Kidney Disease Improving Global Outcome (KDIGO) guidelines, dealing with the complications of CKD (e.g. renal hypertension, hyperlipidemia, proteinuria) is essential, and the use of angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and statins is common (5). Different medication schemes, including glucocorticoids, cytotoxic drugs, immunosuppressants, and biological agents are used to treat patients with CKD after assessing their renal pathologies and personal conditions (5). Moreover, if the kidney damage is secondary to other basic diseases, such as diabetes, it is necessary to control the primary disease (186). However, an ideal treatment plan has not yet been found, and the drugs used are usually accompanied by several side-effects, including digestive tract reaction, obesity, liver and kidney damage, bone marrow suppression, and reproductive damage; furthermore, the therapeutic effects may take weeks to months to manifest, which often leads to intolerance (187). About 25% of patients with CKD will eventually progress to ESRD within 20 years of diagnosis and need renal replacement therapy (4).
The evidence of this review reveals several beneficial effects of acupuncture on CKD and ESRD-related symptoms, and a summary of studies on acupuncture therapy in chronic renal injury, renal physiological function and ESRD-related symptoms is presented in Table 1. It is believed that acupuncture may have a significant impact on the risk nodes of the progress of CKD through multiple pathways, so as to improve the prognosis of patients with CKD. This is mainly realized through the following mechanisms: 1. reduced inflammatory reactions and protection of podocytes, mesangial cells, and endothelial cells from antioxidant stress; 2. delaying glomerular and tubular lesions by downregulating inflammatory factors to regulate relevant signal pathways, including NF-κB-related pathways; 3. reducing podocyte apoptosis and protecting the glomerular filtration membrane by reducing renal TRPC6 levels and maintaining podocyte structural proteins; 4. improving glomerular hemodynamics through blood pressure regulation systems (SNS, RAAS, etc.); 5. improving energy metabolism to regulate renal immune function via regulating enzymes involved in aerobic metabolism in mitochondria. The major mechanisms by which acupuncture can relieve ESRD-related symptoms are: 1. activating the descent inhibition system to relieve pain by regulating the release of bioactive chemicals, especially opioids; 2. regulating inflammatory cytokines to relieve chronic pruritus.
This review fully illustrates the advantages of acupuncture in treating CKD. First, acupuncture can act in cooperation with drug therapy to improve its the curative effects (18). Second, the potential mechanisms by which acupuncture may help in treating CKD are diverse; compared with single target therapy, acupuncture improves CKD prognosis through various pathways. Third, acupuncture is a simple supplementary therapy with mild side-effects, which prevent patients from taking additional drugs, especially opioids (161), to improve patient compliance. Fourth, the schedule of acupuncture treatment is flexible and varied (Table 1). Fifth, acupuncture has a wide range of applications with few contraindications and is suitable for the elderly and children (35, 188). Sixth, the cost of acupuncture in China is low, which most patients can afford regardless of economic status.
Furthermore, we focused on other methods that have the potential to help improve the quality of life or relieve symptoms of CKD, including taking TCM prescriptions and Chinese patent medicine, including Tripterygium Wilfordii Hook. f. and Artemisinin, which can effectively reduce albuminuria and protect kidney tissue (189, 190). However, the compositions of traditional Chinese herbs are extremely complex; moreover, patients with advanced CKD may suffer from electrolyte disorders due to metabolic issues. Therefore, more detailed studies and monitoring is required to ensure the safety of patients. The KDIGO guidelines suggest that proper exercise and dietary management, including low sodium, high-quality protein, and low-fat diets, can help improve patients’ quality of life; acupuncture should also be recommended as an effective physical therapy (5).
There are some obvious limitations of this literature review. First, because of the involvement of various acupuncture points, complex physiological aspects, and differing patient characteristics and disease processes, acupuncture-based treatment of CKD is highly personalized, and the specific therapeutic mechanism and indications needs further study. Second, there is still a lack of large-scale, double-blind, multicenter, large sample size, randomized studies to verify the observed effects and provide a high-quality theoretical basis for them. Third, the mechanisms of acupuncture in improving ESRD-related symptoms, especially RLS and sleep disorder, cannot be clarified for now. Finally, the review could only cover studies that focused on therapeutic mechanisms that were not specific to renal pathology, on which there are very few studies. Some literatures mentioned renal interstitial fibrosis without specific pathological diagnosis. Only one clinical trial revealed the effectiveness of moxibustion on membranous nephropathy. Two animal studies mentioned focal segmental glomerulosclerosis (FSGS), one research revealed that moxibustion delay the progress of FSGS via alleviating podocyte injury, the other one did not mention the underlying mechanism.
5 Conclusions
This review suggests that acupuncture can be beneficial for CKD through several mechanisms, including oxidative stress inhibition, reducing inflammatory effects, improving hemodynamics, maintaining podocyte structure, and increasing energy metabolism. In general, acupuncture has the potential to become a new, simple, safe, and inexpensive treatment modality that can be used to treat CKD, slow the progress of renal dysfunction, and improve patient symptoms. However, the review only covers non-specific therapeutic mechanisms, lacking content related to renal pathology due to a lack of studies on this topic. Moreover, it is unclear whether acupuncture can improve CKD with different pathologies, and rigorous clinical and mechanistic studies are required to design future protocols for the use of acupuncture in such cases. This could prove conducive to understanding the potential mechanisms involved in different renal pathological diagnosis as well as the impact that acupuncture may have on them.
Author contributions
All authors contributed to one or more of the following aspects of the manuscript: conception, acquisition of data, drafting, and revising the article. WZ and XL researched data and wrote the manuscript. XW and HM reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: complementary therapy, acupuncture, therapeutic mechanism, chronic kidney disease, end-stage renal disease
Citation: Liu X, Wang X, Ma H and Zhang W (2022) Mechanisms underlying acupuncture therapy in chronic kidney disease: A narrative overview of preclinical studies and clinical trials. Front. Nephrol. 2:1006506. doi: 10.3389/fneph.2022.1006506
Received: 29 July 2022; Accepted: 18 October 2022;
Published: 09 November 2022.
Edited by:
Samar Abd ElHafeez, Alexandria University, EgyptReviewed by:
Alex Siu-Wing Chan, Hong Kong Polytechnic University, Hong Kong SAR, ChinaKarem Salem, Fayoum University, Egypt
Copyright © 2022 Liu, Wang, Ma and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wen Zhang, 306762827@qq.com
†These authors have contributed equally to this work and share first authorship