Organic acid is an organic compound (excluding amino acid) that contains a carboxyl group. This compound widely exists in plants. Aristolochic acid (1) is the most representative nephrotoxic component among the HM organic acids, and its representative HMs are A. manshuriensis Kom, A. obliqua S. M. Hwang, and A, debilis Sieb. Et Zucc. Aristolochic acid can cause necrosis and apoptosis of renal tubular epithelial cells.

Alkaloid is a nitrogen-containing organic compound that exists in nature and is obtained from plants. It is a toxic component of many HMs, such as matrine (2) and genistein in Sophora flavescens Ait., glycoside alkaloid in Alisma orientale (Sam.) Juzep., arecoline (3) in Areca catechu L., and colchicine (4) detected in Gremastra appendiculata (D. Don) Makino. Other examples are Tetrandrine (5), Ephedrine (6), Leonurine (7). Most types of nephrotoxic alkaloid are organic amines, pyrrolidines, pyridines, and isoquinolines.

Terpenoids and lactones are ubiquitous compounds in the plant kingdom. Terpenoids are derivatives with a general formula of (C₅H₈) _n, oxygen content, and different saturation degrees. Lactone is an organic compound with one ester group formed by the esterification of one molecule. They have important physiological activities and are important resources for the research of natural products and the development of new drugs. This kind of nephrotoxic component includes cinnamaldehyde (8), thujone (9) and triptolide (10). Representative HMs include Cinnamomum cassia Presl, Magnolia officinalis Rehd. et Wils., Melia toosendan Sieb.et Zucc., and Leonurus japonicus Houtt., and the nephrotoxicity of these substances is weaker than that of aristolochic acid. In clinical use, doctors often focus on its efficacy and ignore its toxicity. This substance can cause renal tubulointerstitial damage, the sufferers of which may show symptoms of uremia and proteinuria.

A virulent protein is obtained from a normal cellular protein, PrPc, which has been changed but does not have the function of a normal protein. It is the smallest known infectious medium with a single component. It is nearly only composed of protein, but without nucleic acid. It can strongly resist proteolytic enzymes. These toxic substances are obtained from protein components in animal and plant medicinal materials, such as trichosanthin in Trichosanthes kirilowii Maxim, histamine-like substance hemolytic protein in S. subspinipes mutilans L. Koch, and leech protein in Hirudo nipponica Whitman.

Most of the toxic components of minerals contain heavy metals, which include arsenic, mercury, and lead. The representative drugs are Ae₂S₂ in Realgar, HgS in cinnabaris, and Pb in Red lead. After taking these drugs in large quantities, heavy metals accumulate in the kidneys because of metabolic difficulties, resulting in kidney damage. For example, cinnabars accumulate in the kidney and lead to the apoptosis of renal tubular epithelial cells in the renal cortex.

Flavonoid glycosides are widely found in plants and berries with strong antioxidant properties. Even low amounts of flavonoid glycosides cause kidney damage in HM. Some of these flavonoid glycosides come from dry mature seeds of Ginkgo biloba, the toxic component of which is ginkgo neuter. Flavonoid glycosides are a series of compounds formed by the interconnection of two benzene rings (A- and B-rings) with phenolic hydroxyl groups through the central three carbon atom. Their basic parent nucleus is 2-phenylchromogenic ketone.

Saponin is a plant glycoside that can form colloid solution and soap-like foam. The representative HMs containing saponins are Xanthium sibiricum Patr., Bupleurum chinense DC., Clematis chinensis Osbeck, and Pulsatilla chinensis (Bge.) Regel. In addition to Pulsatilla chinensis (Bge.) Regel, the toxic component of C. chinensis Osbeck is also anemonin (11). Long-term administration of C. chinensis Osbeck lead to acute renal tubular injury, necrosis, or chronic interstitial nephritis. Other components with nephrotoxicity are saikosaponin A (12), geniposide (13), esculentoside A (14). Saponins are glycosides composed of aglycones and sugars, glucuronic acids, or other organic acids. According to the known molecular structure of aglycones, the saponins of c-27 steroids are called steroids and those of triterpenoids are called triterpenoids.

According to statistics, more than 100 kinds herbs may cause kidney toxicity in HM, and their toxic components are not fully understood. In addition to the representative toxic compounds listed above, anthraquinones in Polygonum cuspidatum Sieb.et Zucc. are toxic components, and the main toxic components in rhubarb are emodin (15), aloe emodin (16) and other anthraquinones. The toxic component of Eugenia caryophyllata Thunb. is eugenol (17), which is an aromatic compound. Aloin (18) is a nephrotoxic component in Aloe barbadmsis Miller. The toxic components of fish gall, such as histamine or oxide, are complex. Other known nephrotoxic HMs such as Schizonepeta tenuifolia Briq., Bolbostemma paniculatum (Maxim.) Franquet, Euphorbia pekinensis Rupr., and Eugenia caryophyllata Thunb. These need further experimental analysis to determine their toxic components. Table 1 shows the HM nephrotoxicity and their toxic ingredients. Figure 1 shows the representative structure of nephrotoxic components.

Aristolochic acid can cause renal interstitial fibrosis. The occurrence of renal interstitial fibrosis is related to the increase of extracellular matrix (ECM) synthesis and the decrease of ECM degradation. TGF-β is one of the important cytokines that promote ECM synthesis (Sun et al., 2018). The expression of TGF-β, CTGF, and ECM increase considerably in kidney tissues of patients (Zhang et al., 2005; Bai et al., 2014; Tsai et al., 2014). Exogenous aristolochic acid I could increase the mRNA expression of TGF-β and ECM in renal tubular epithelial cells and renal interstitial fibroblasts (Zhu et al., 2007; Tian et al., 2014; Lu et al., 2016; Li M. et al., 2018). The specific anti-TGF-β1 neutralizing antibody could partially block the expression of FN and HK-2 cell apoptosis induced by aristolochic acid I (Li et al., 2004). The abnormal expression of FN could promote cell proliferation, leading to renal interstitial fibrosis (Nortier et al., 2015; Chen et al., 2018; Li M. et al., 2018; Yin et al., 2018). TGF-β1 partially mediates the occurrence of FN and the apoptosis of renal tubular epithelial cells induced by aristolochic acid I.

Continuous administration of esculentoside A for 7 days causes renal injury. In this case, p-IκBα protein expression increases significantly, whereas IκBα protein expression decreases obviously. TNF-α and IL-1β expression are remarkably upregulated. Hence, the nephrotoxicity induced by esculentoside A in rats is very closely related to NF-κB. The potential nephrotoxic mechanism of esculentoside A may be the activation of the NF-κB signal, phosphorylation of the target protein of IκB α, and the overexpression of the downstream inflammatory factors TNF-α and IL-1β to induce renal damage (Yang X. et al., 2019).

The cultivation and growth of HM plants are inevitably affected by their surrounding environment. Large differences may exist in the compositions of the same kind of medicinal materials from different places of origin. Patients often opt to increase dosages for treatment when the content of effective ingredients is low. In this case, the toxic components ingested by patients also increase, thus resulting in kidney damage. When the soil, air, and water of the habitat of the HM plants are polluted, adverse phenomena, such as heavy metal concentrations exceeding standards, may occur (Gao and Shi, 2020).

Homonyms and synonyms are common in HM but may represent drugs from completely different plants and with greatly different compositions. These drugs are often misused given their identical or similar names. In Belgium, cases of kidney damage caused by taking HM for weight loss (Vanherweghem et al., 1993) are due to the use of A. obliqua S. M. Hwang as Stephaniae tetrandra Radix. Although the names of the two drugs are similar, the drugs themselves are different. A. obliqua S. M. Hwang has a high content of aristolochic acid, which can cause a series of diseases, such as the apoptosis or necrosis of renal tubular epithelial cells and renal ischemia (Zhang et al., 2019).

Ancient and modern Chinese medicine practitioners have developed a series of symptomatic prescriptions during practice over the thousand years of HM use. In clinical application, prescriptions are often adjusted to increase their applicability in accordance with the needs of the disease and the differentiation and treatment of syndromes. Excessively high dosages result in the accumulation of toxic components in the body because of untimely metabolism; this effect will cause kidney damage in the long run (Wang and Liu, 2009).

Given the lack of the understanding of HM, users may be confused by folk traveling doctors and refer to folk prescriptions, thus resulting in the misuse or abuse of HM and ultimately in kidney damage.

Processing has played an important role in the history of HM as a major measure for reducing the toxicity and increasing the efficiency of HM drugs. If drugs are properly processed, the toxicity of HM drugs can be greatly reduced or even eliminated, and at the same time, efficacy may be increased (Zhang et al., 2020). In addition, the selection of processing utensils, time, and temperature for the boiling process is crucial. For example, casseroles, rather than iron, aluminum, and other metal utensils, are often selected for processing and boiling HM preparations.

Compatibility is also a vital measure for reducing toxicity and increasing the efficiency of HM. HM drugs should not only be compatible with each other but also with Western medicine. However, inappropriate compatibility can lead to injury. For example, when Shuanghuanglian injection is used in combination with glucose, insoluble particles are produced, thus affecting metabolism and causing kidney damage (Zhang et al., 2013). Radix Aconiti Kusnezoffii in combination with Radix Trichosanthis and Bulbus Fritillariae thunbergii cause a series of adverse reactions (Li, 2016; Li et al., 2016).

A small number of patients with allergic constitution and special genetic diseases may not tolerate certain drugs. Intolerance results in kidney damage.

Although some drugs are toxic, adverse reactions can be avoided when they are used correctly in the clinic. For example, most mineral drugs often lead to kidney damage when used internally but can exert a bacteriostatic and bactericidal effect when used externally (Bai et al., 2011; Ding, 2012; Liu, 2020).

Acute renal failure Yin Guang analyzed 31 cases of patients with AAN and found eight cases of patients with acute renal failure (ARF) caused by taking large doses of Caulis A. manshuriensis decoction (dose > 10 g/day). The cases exhibited renal injury accompanied by gastrointestinal or liver injury and high levels of small-molecular proteins in urine (Yin et al., 2010). In addition, 58 cases of patients with AAN were examined via renal puncture. Light microscopy showed that in the patients, renal tubular epithelial cells were severely denatured, necrotic, and disintegrated, and a small amount of lymphoid and mononuclear cells were sporadically infiltrated. The results of electron microscopy revealed that the surfaces of tubular epithelial cells had lost microvilli. Moreover, mitochondrial swelling was found in renal tubular epithelial cells. In addition to secondary lysosome formation, organelle disintegration and renal interstitial edema were discovered. Furthermore, the foot process of glomerular visceral epithelial cells exhibited mild segmental fusion, and the mesangial matrix increased slightly; however; electronic compacts were not observed (Chen et al., 2001).

Chronic renal failure Longdan Xiegan pill has the effects of relieving the dampness and heat of liver and gallbladder, as well as dizziness, tinnitus, and deafness. One of its prescriptions is Caulis A. manshuriensis, which contains a large amount of aristolochic acid that causes renal damage. A total of 21 cases of patients with chronic renal failure caused by taking Longdan Xiegan pills were analyzed. Most of the patients took the medicine for more than 1 year or even for more than 10 years (Li S. H. et al., 2018). In patients with chronic renal failure, light microscopy showed that the renal interstitium appeared multifocal or exhibited massive fibrosis, renal tubules showed multiple or large areas of atrophy, and some glomeruli presented ischemic basement membrane shrinkage and sclerosis. Electron microscopy results revealed a large number of fascicular collagen fibers in the renal interstitium, and the basement membrane of renal tubules and glomeruli had thickened and shrunk (Chen et al., 2001).

In the treatment of glomerular diseases, T. regelii Sprague. et Takeda. can eliminate urinary protein. Although its curative effect is exact, its toxic and side effects are severe. Six patients with nephrotic syndrome due to taking T. regelii Sprague. et Takeda. were observed. Among them, four developed ARF within 21–120 days after taking T. regelii Sprague. et Takeda. Liver and kidney functions were slightly damaged in two cases, and blood cell counts (red blood cells, white blood cells, and platelets) decreased and menstrual disorders were observed. Renal biopsy indicated severe renal interstitial and tubular lesions. Under light microscopy, obvious inflammatory cell infiltration was found in tubules and interstitium, and the obvious degeneration, necrosis, and atrophy of tubular epithelium cells were observed (Wang et al., 1996). The causes of death of 83 patients who died from taking T. regelii Sprague. et Takeda. were analyzed. Among them, 65 cases were due to ARF or circulatory failure (Wang et al., 1999).

Leonurus ja ponicus Houtt. was first published in Shennong’s Classic Materia Medica. It is considered to be a safe and nontoxic HM drug that is widely used in the clinic. It has the functions of activating blood and regulating menstruation, disinhibiting urine, dispersing swelling, clearing heat, and removing toxins. A poisoning death caused by Leonurus ja ponicus Houtt. was reported in the late 1980s. The patient took a 400 g decoction of Leonurus ja ponicus Houtt. and died of abdominal pain, headache, lower back pain, and multiple organ bleeding 1 day later. Analytical results showed that the excessive dosage and repeated use of Leonurus ja ponicus Houtt. resulted in renal failure and death by poisoning (Luo et al., 2018c).

Fructus Xanthii is the fruit of Xanthium Caulis et Folium, which is mainly used to treat wind cold headache. A patient experienced acute liver and kidney damage and coagulation dysfunction by ingesting a large number of unprocessed Fructus Xanthii. Light microscopy showed that the patient’s renal tubulointerstitial lesions were severe. Moreover, in the patient, the tubular structure was clear, and diffuse renal tubular epithelial cells were swollen and degenerative. The patient exhibited occasional renal tubular atrophy and renal interstitial fibrosis with a small amount of inflammatory cell infiltration, and also presented a small number of eosinophils (Wang et al., 2013). Another patient experienced upper abdominal discomfort, nausea, vomiting, diarrhea, and reduced urine production accompanied by facial and lower limb edema; the patient was clinically diagnosed with acute renal failure and toxic hepatitis (Sun and Hei, 1997).

Cinnabar has the effect of tranquilizing the mind. It is mainly used in the treatment of palpitations, insomnia, and seizures. A man developed abdominal pain, nausea, and vomiting after taking cinnabar (4.5 g/day) for 1 month to treat palpitations and insomnia in accordance with a folk prescription. After he continued taking cinnabar for 1 month, he developed general weakness, lower-limb edema, proteinuria, and oliguria and gradually stopped producing urine. His blood urea, urea nitrogen, nonprotein nitrogen, and creatinine levels increased significantly. In addition, his liver function transaminase and blood potassium levels increased, whereas his blood chlorine and blood glucose levels decreased. He was diagnosed with mercury poisoning and acute renal failure (Guo and Li, 2001). One woman took more than 100 g of cinnabar within 30 days to treat palpitations. She developed nausea, vomiting, severe abdominal pain, and diarrhea. Her stool was brown likely because of the corrosion of gastrointestinal mucosa. On the first day after her gastrointestinal symptoms appeared, she exhibited oliguria; on the second day, she did not produce urine and her BUN was 50.5mg%. She was diagnosed with acute renal failure (Zhang and Wang, 1985).