Research Progress in the Treatment of Gouty Nephropathy with Dai and Western Medicine

Lijie ZHENG, Yuanmei BAI, Peixin GUO

Yunnan University of Chinese Medicine, Kunming 650500, China

Abstract If gouty nephropathy is not treated properly, repeated attacks can gradually lead to nephrotic syndrome. This may bring pain to patients and affect their quality of life. The main goal of Western medicine in the treatment of gouty nephropathy is to stop acute attacks, control serum uric acid and avoid recurrence. Yet there are many adverse reactions to long-term use. Dai medicine has unique efficiency in improving clinical symptoms and controlling relapses. Meanwhile it can avoid the potential risks associated with too low control of blood uric acid. Therefore, this paper reviewed the research status of Dai and Western medicine in the treatment of gouty nephropathy in order to provide reference for clinical medication.

Key words Gouty nephropathy, Dai medicine, Western medicine, Research progress

1 Introduction

Gouty nephropathy (GN), also known as hyperuricemic nephropathy[1], is a disorder of purine metabolism in the body and is caused by excessive production and/or decreased excretion of blood uric acid, deposition and crystallization of uric acid salts in the kidneys causing renal damage and resulting in interstitial inflammation of the kidneys and uric acid stones[2]. Clinically, it is classified into chronic GN, acute GN and uric acid kidney stones according to their pathogenesis[3]. The pathology is characterized by inflammatory cell infiltration and deposition of large quantities of uric acid crystals in the renal tubules and macrophages, with fibrotic changes at the crystalline deposits and compensatory dilation of tubules without crystalline deposits[4]. With the increasing incidence of gout, the number of patients with GN is also increasing and it poses a serious threat to health[5].

2 Advances in Western medical treatment research

2.1 Diagnostic criteriaBased on the clinical manifestations of gout combined with increased blood uric acid >357 μmol/L (6 mg/dl), increased urinary uric acid excretion (>1.0 g/d), urinalysis and renal function showing interstitial nephritis-like manifestations, it can be diagnosed as gouty nephropathy[6].

2.2 PathogenesisThe types of renal damage in gout patients mainly include direct damage and indirect damage. Direct damage refers to the deposition of urate in the distal tubules, collecting ducts and interstitium, especially in the renal medulla, forming monosodium urate crystals surrounded by a large number of inflammatory cells and macrophages, which can lead to small renal arteriosclerosis, glomerular damage, tubulointerstitial fibrosis, and further development of interstitial nephritis, nephrosclerosis and renal failure[7]. In addition, indirect damage means that high blood uric acid levels induce oxidative stress, mitochondrial dysfunction, inflammatory response and activation of the renin-angiotensin-aldosterone system, leading to endothelial dysfunction, vascular smooth muscle cell proliferation and interstitial inflammation andetc., leading to chronic kidney disease (CKD)[8]. In addition, hyperuricemia is often combined with hypertension and atherosclerosis, which is also an important factor in renal damage[9], and renal disease is one of the important causes of hyperuricemia, and they often interact with each other. Hence hyperuricemia can also independently predict the progression of CKD and arterial lesions. Moreover, the damage to the kidney caused by drugs used in the treatment of gout and hyperuricemia cannot be ignored.

2.3 Current status of Western medical treatmentThe current main treatment strategy for GN is uric acid-lowering therapy. The therapeutic drugs include drugs for inhibiting the synthesis of uric acid, drugs for promoting the excretion of uric acid, and drugs for facilitating the oxidative metabolism of uric acid. They are used to reduce uric acid. The representative drugs that inhibit uric acid synthesis are allopurinol, febuxostat, tolbesostat andetc.Among them, allopurinol and its metabolites can not only reduce the conversion of hypoxanthine to xanthine, but also inhibit the conversion of xanthine to uric acid. Therefore, allopurinol can effectively lower uric acid, and is suitable for the treatment of uric acid nephropathy and uric acid stones with or without gout, and is the first-line drug for the treatment of hyperuricemia. However, the side effects include gastrointestinal symptoms, rash, liver damage, and especially the fatal "allopurinol hypersensitivity syndrome"[10]. Febuxostat, selectively inhibiting xanthine oxidase without affecting other purine and pyrimidine synthesis and metabolism enzymes, can reduce blood uric acid concentrations. Studies have shown that febuxostat can improve inflammation of the synovial membrane and reduce the rate of early gout attacks through a hypouric acid effect[11-12]. The results of a recent clinical trial showed that among patients with gout and major cardiovascular coexisting diseases, febuxostat had higher all-cause mortality and cardiovascular mortality than allopurinol[13].

Representative drugs that promote uric acid excretion include benzbromarone, probenecid, and resinad. Benzbromarone can reduce serum uric acid concentration by inhibiting the active reabsorption of uric acid by the renal tubules. Since more than 90% of hyperuricemia (both partially primary and partially secondary) is due to decreased uric acid excretion, benzbromarone is widely used in clinical practice[14]. Probenecid can inhibit active reabsorption of urate in the renal tubules, increase urate excretion, and decrease urate concentration in the blood, thus reducing uric acid deposition. Studies have shown that probenecid also exerts a good uric acid-lowering effect after failure of allopurinol therapy, but is weaker than allopurinol[15]. Resinad is a novel URAT1 inhibitor. The current indication for this drug is that it should be used in combination with xanthine oxidase inhibitors only after target blood uric acid levels have not been achieved with xanthine oxidase inhibitors alone. Previous clinical research data show that the fixed dose combination of racinald and allopurinol can improve compliance and reduce the risk of adverse renal events[15].

The main pro-uric acid oxidative metabolism drugs are recombinant uric acid oxidase preparations. This drug is an artificially recombinant uric acid oxidase that rapidly oxidizes uric acid to allantoic acid and is excreted directly without being absorbed by the renal tubules. It is effective for gout, gout kidney stones and hyperuricemia caused by nephropathy failure. The representative drugs are aflatoxin uric acid oxidase (lablase), polyethylene glycolized recombinant uric acid oxidase (pegolase),etc.In recent years, an increasing number of studies have proven their effectiveness and safety in the treatment of hyperuricemia and they can be used as a drug option for patients whose conventional treatment is ineffective[16].

3 Advances in Dai medical treatment research

3.1 Etiology and pathogenesis of Dai medicineIn Dai medicine, it is believed that the basic elements of nature, namely wind, earth, water, and fire, are called the four towers. Human body is also composed of these four towers and the four elements of wind, earth, water and fire are interconnected, balanced and coordinated to complete the physiological activities of the human body together. The four towers are innately endowed to the parents and maintain a relative balance in the human body, thus maintaining the normal life activities of the body[17]. The kidneys, called "mah call" in Dai language, are responsible for the retention, distribution and excretion of water in the four towers of the human body. In Dai medicine, the kidney is considered as the root of the four towers of the human body. Gouty nephropathy is a complication caused by severe gout, which involves damage to the kidneys[17]. In Dai medicine, it is believed that gouty nephropathy is caused by the dysfunction of the four towers (wind, fire, water, and earth), the deficiency of Tafei (fire) and Talong (wind and qi), and the overabundance of Ta’nan (water), coupled with the external "Payalonghuang, Payalongga"(wind-heat, wind, and cold evil) or the simultaneous disease of the three pagodas, and the inability to transport and excrete water and dampness, resulting in the swelling of the head and face, eyelids, limbs, sunken, heavy limbs, large abdomen like a drum, little or no urine. Secondly, the patients are overworked, have improper diet, eat by mistake, or like to eat sour cold products, or feel external cold and hot diseases, or suffer from other diseases, lose treatment and mistreatment, improper treatment, internal and external consistency, damage the water and earth towers, resulting in the dysfunction of the four towers in the body. If the fire is insufficient, the water will be cold, if the fire does not control the water, the earth will be warm, and if the water is not wet, the disease will stop accumulating the skin and the whole body[18].

3.2 Dialectical treatmentThe clinical characteristics exhibited by GN patients are different, but there is a certain commonality in the pathogenesis, which is mostly treated by draining water channels, inducing diuresis to reduce edema, and clearing dampness. The treatment of Dai medicine especially emphasizes that the treatment of kidney disease should first regulate the four towers, using the "doctrine of detoxification" of Dai medicine. The doctrine of "solution" is one of the characteristics of the treatment of Dai medicine. In Dai medicine, it is found that in the process of living and treating diseases, various internal and external pathogenic factors can lead to the imbalance and physiological disorders of the four towers and five yin, the four towers are not in harmony and produce various toxins, leading to the development and deterioration of diseases. Therefore, the clinical treatment of diseases mostly uses antidotes, which are taken first to release toxins, and then treated and prescribed for the disease in order to achieve good therapeutic effects and prevent the deterioration of the disease[19]. The Dai medicine experts agreed that gouty nephropathy is divided into two types of evidence, namely, Longshahoutafeitalongxiang (wind and fire poisonous evil prevalent type) and Lashahoutalongtalingruan (earth tower disorder type)[20].

3.2.1Longshahoutafeitalongxiang (wind and fire poisonous evil prevalent type). The treatment for Longshahoutafeitalongxiang (wind and fire poisonous evil bias type) is to clear the fire and detoxify, remove wind and relieve pain. The prescriptions commonly used in Dai medicine are: (i) Dai pain elimination[21-22]: 15 g of oleander, 5 g of Maibie, decoction in water, 200 mL each time, 3 times a day, within half an hour after meals. (ii) Koro wind-like decongestant soup[23-24]: 15 g of Hey Koro (green cow bile), 30 g of Huai free king (hook vine), 20 g of Hey Tao Han (rhubarb vine), 30 g of Heyhaiguan (inverted heart shield wing vine), 20 g of Halein’niu (wild rutabaga root), 20 g of bud Nuomiao (kidney tea), decoction in water, 3 times daily, 150 mL each time. In addition, the commonly used Dai drugs are Guoyuanliang (Rasayana tree), Xilie (black heart tree), Guandi (three-leaved cranberry), Maofang (Sumac), Deng Heyhan (fixed heart vine), Mao Roll (herringbone tree), Hegu (nine-winged cardamom root), Gaigey (blood-through incense), Madiao (Dian Zao Zao), Guang Artemisiaxiu (Penglai Kudzu), Mihuowo (mountain rhubarb), Xigailiang (red and white flowered stinky peony).

3.2.2Lashahoutalongtalingruan (earth tower disorder type). The treatment for Lashahoutalongtalingruan (earth tower disorder type) is to tonify the earth and promote water, remove wind and relieve pain. The commonly used formula of Dai medicine is 30 g of Maoroll (human character tree), 20 g of Hahanman (plucking poison), 30 g of Gaihey (blood incense), 25 g of Guandi (three-leaved vine), 30 g of Hengzhang (big dog ringing bell), 30 g of Heygaiguan (inverted heart shield wing vine), 20 g of bud Nuomiao (kidney tea), decoction with water, 3 times a day, 150 mL each time, for 12 weeks. In addition, the commonly used Dai medicines for the treatment of Dai include Hahanman (Poison Extract), Maoroll (Human Character Tree), Heiduoma (Chicken Yak Vine), Mianlei (Purple Ginger), Hao Ming (Turmeric), Hegu (Nine-winged Cardamom Root), Gaihey (Blood Incense), Guandi (Three-leaved Cranberry), Heygaiguan (Inverted Heart Shield Wing Vine), Wenshanghai (Hundred Kinds of Solution), Denghey Han (Fixed Heart Vine), Guang Artemisia Xiu (Ponglai Kudzu); Mifuwa (Mountain Rhubarb), Genglongliang (Lachrymum), Koumouzhu (Black-skinned Bruise), buds along the off (Plantain), and Yazhenglun (Smilacis Glabrae Rhizoma)[24-28].

4 Discussion

GN pathogenesis is closely related to hyperuricemia and deposition of urate crystals in the body, but the specific pathogenesis has not been clarified. Hence the treatment is mainly symptomatic and aimed at protecting the kidneys and improving renal function. The lack of specific therapeutic drugs and the adverse effects of drugs commonly used in the treatment of gout and hyperuricemia have made the Western medical treatment of GN face many difficulties[29]. According to Dai medicine, the pathogenesis of GN is based on the dysfunction of the four towers, coupled with the external sensation of "Payalonghuang, Payalongga" or the simultaneous disease of the three disks as the pathogenesis[21]. Clinically, the treatment principle is "to solve the disease before it happens, to solve the disease before it happens, and to solve the disease at the same time". Modern studies have shown that Dai medicine treatment can reduce kidney damage by lowering blood uric acid levels, reducing inflammatory reactions in kidney tissues, scavenging oxygen free radicals and antioxidant effects. And kidney pathological damage can be improved by promoting glomerular filtration repair and improving blood supply to the kidneys, slowing down the process of renal fibrosis and renal failure[30]. However, there are also many drawbacks of Dai medicine treatment, for instance, the guidelines for identifying and treating GN and clinical grouping are mainly based on the clinical experience of physicians, and it is difficult to form a unified standard. The Dai medicine compound used for treatment lacks the necessary pharmacodynamic experimental verification. Also the sample size of clinical studies is small, the sample source is single, and there is a lack of reasonable control,etc.To solve the above mentioned problems, based on known pathogenic targets and pathways, and combined with advanced technical means such as network pharmacology and histology, through scientific and rigorous experimental design and objective and reasonable clinical trial research on the premise of clarifying the material basis for achieving efficacy, the study of some Dai medicines and Dai prescriptions with definite efficacy in GN prevention and treatment is of practical significance for the development of efficient and safe new anti-GN drugs. Meanwhile it may provide new ideas for further exploration of the pathogenesis of GN and provide reference for the prevention and treatment of other diseases.