Chinese Herbal Medicines 15 (2023) 526–532

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Review

Therapeutic effects of Chinese herbal medicines for treatment of

urolithiasis: A review
Chen Jiang a, Lingyun Wang b, Yang Wang a, Rongjia Xu a, Hongtao Yang a,⇑, Jibin Peng b,c,⇑
a
Division of Nephrology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional
Chinese Medicine, Tianjin 300384, China
b
Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham 35294, United States
c
Department of Urology, University of Alabama at Birmingham, Birmingham 35294, United States

a r t i c l e i n f o a b s t r a c t

Article history: Urolithiasis is a common and complex disease of the urinary system, which can cause urinary tract block-
Received 13 August 2023 age, urinary tract infection, and even damage to urinary system-related tissues. Although urolithiasis can
Revised 2 September 2023 be cured, its high recurrence rate and the development of chronic kidney disease in some patients have
Accepted 12 September 2023
drawn the attention of nephrologists. Although the application of extracorporeal lithotripsy, percuta-
Available online 27 September 2023
neous nephrolithotomy and other minimally invasive techniques have made the treatment of urolithiasis
more efficient, pharmacotherapy plays an indispensable role in reducing their morbidity and recurrence
Keywords:
rates. Traditional Chinese medicine (TCM) has been used for treatment and prevention of urolithiasis in
Chinese herbal medicines
chronic kidney disease
developing countries for centuries, known for its unquestionable efficacy and safety. This article reviews
mechanism the progress of clinical trials and pharmacological studies on the treatment of urolithiasis with Chinese
pharmacology herbal medicines (CHMs). The mechanism of CHMs in the treatment of urolithiasis mainly involve pre-
urolithiasis venting further growth and aggregation of urolithiasis, reducing the PH of urine, promoting calculus dis-
solution. Furthermore, some CHMs can increase urine output, relax smooth muscles, and promote the
removal of calculus. These findings provide new treatment strategies and options for urolithiasis and sec-
ondary kidney damage.
Ó 2023 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V. This is an open access article
under the CC BY-NC-ND license ([Link]

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
2. TCM theory of urolithiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
3. Effect of CHM in treatment of urolithiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
4. Pharmacological studies of anti-urolithiasis medicinal materials and their formulations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
4.1. Single medicinal material for treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
4.1.1. Lysimachia christinae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
4.1.2. Alisma orientale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
4.1.3. Tribulus terrestris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
4.1.4. Lygodium japonicum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.5. Salvia miltiorrhiza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.6. Boerhavia diffusa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.7. Aquilaria sinensis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.8. Crocus sativus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.9. Carthamus tinctorius . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.10. Paeonia lactiflora . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
4.1.11. Pyrrosia petiolosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
4.2. Chinese medicinal formulae for treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531

⇑ Corresponding authors.
E-mail addresses: tjtcmht@[Link] (H. Yang), jibinpeng@[Link] (J. Peng).

[Link]
1674-6384/Ó 2023 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.
This is an open access article under the CC BY-NC-ND license ([Link]
C. Jiang, L. Wang, Y. Wang et al. Chinese Herbal Medicines 15 (2023) 526–532

5. Notice in use of CHMs in practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
CRediT authorship contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532

1. Introduction (Fig. 1), has been used to prevent and treat urolithiasis and its
related diseases for thousands of years. It has been proven to have
Urolithiasis is a global health burden with an increasing preva- definite curative effect by regulating the PH of urine, promoting
lence ranging from 5% to 15% in different regions. According to the dissolution of stones, increasing urine output, relaxing smooth
location of the stone, it contains kidney stones, ureteral stones, muscle, and promoting the removal of stone (Sachs, 2003; Shah
bladder stones and urethra stones. The increasing incidence and & Whitfield, 2002). Moreover, because of the abundant resources
prevalence of urolithiasis worldwide can be attributed to changes in CHMs and the clear curative effect, CHMs is the mainstay of
in dietary structure and living habits (Raheem et al., 2017; medical treatment in developing countries. According to the World
Romero, Akpinar & Assimos, 2010). The incidence of urolithiasis Health Organization, CHMs serves 75%–80% of the world popula-
ranged from 4.6% to 6.5% in Asian countries (Bae et al., 2014; tion as a complement (Bardia, Nisly, Zimmerman, Gryzlak, &
Yang, Deng, & Wang, 2016). Actually, the consequences of urolithi- Wallace, 2007).
asis, such as urinary tract infections, obstructive nephropathy, even Nowadays, the Committee of Complementary and Alternative
renal function injury and squamous cell carcinoma impose signifi- Medicine within the American Urological Association (AUA) recog-
cant burdens. And the risk of developing chronic kidney disease nize the integration of non-conventional therapies into urological
due to urolithiasis is being paid more attention by nephrologist clinical practice. As a kind of complementary and alternative med-
(Gambaro et al., 2017). Pharmacotherapy, extracorporeal litho- icine, TCM has played an extremely important role in the treat-
tripsy and the application of some minimally invasive techniques ment of urolithiasis. Although the principles of TCM treatment
are the main treatment at present. are not clear, TCM has been proven effective in relieving symp-
Although modern interventional procedures and surgery are toms, helping stone discharge and preventing recurrence of
being improved, such as the extra corporeal shock wave lithotripsy urolithiasis. In this article, we will focus on CHMs in the treatment
(ESWL), percutaneous nephrolithotomy (PCNL) and open surgery, of urolithiasis, which would be benefit for the treatment of
there are still occasional complications, including infection, hema- urolithiasis and secondary kidney damage.
toma and adjacent organ damage, and the recurrence of stones.
About 50% of patients with urolithiasis after the initial episode
2. TCM theory of urolithiasis
treatment have to experience stone(s) recurrence within 10 years
(Bitsori & Galanakis, 2004). Therefore, preventing stone recurrence Five centuries BC ago, diagnostic and treatments about urolithi-
has become the focus of urolithiasis treatment. It is of great scien- asis were already mentioned in the Hippocratic Collection (An
tific and immediate significance to alleviate symptoms of urolithi- ancient medical books) (Bitsori & Galanakis, 2004; Shah &
asis, prevent the recurrence of urolithiasis, and delay the progress Whitfield, 2002). Records of the typical abdominal pain of patients
of CKD caused by urolithiasis. with urolithiasis and Celsic surgical method were found in Greek
China is one of the major urolithiasis incidence areas in the medicine book since the first century BC (Sachs, 2003; Shah &
world due to its geographical characteristics, dietary habits, and Whitfield, 2002). In China, the records about urolithiasis, symp-
lifestyle. Traditional Chinese medicine (TCM), which includes Chi- toms and treatments of urinary stones diseases can be traced back
nese herb medicines (CHMs), acupuncture and even massage to several ancient texts of traditional medicines. In Qin and Han

Fig. 1. TCM treatment system in urolithiasis.

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C. Jiang, L. Wang, Y. Wang et al. Chinese Herbal Medicines 15 (2023) 526–532

dynasties (in the first century AD), Shennong’s Classic of Materia regular self-administration of P. niruri may increase stone-free rate,
Medica, a traditional Chinese medicine book, has mentioned the especially in patients with lower caliceal location.
diseases as ‘‘Shi Lin”, which were described as sand-like substances CHM in the treatment of urolithiasis is mainly based on the fol-
discharged from the urine, urination pain, or failure to urinate due lowing aspects (Gohel & Wong, 2006; Kasote et al., 2017): 1. The
to stone-induced uremic obstruction. The records of the causes of active components of CHM including carboxyl, hydroxyl, amino
urolithiasis can be traced back to Huangdi’s Internal Classic at the acid and oxygen heterocycles, which can form a coordination com-
first century BC. According to the theory of TCM, the cause of plex with calcium ion. These components reduce the saturation of
urolithiasis involved not only blood stasis and inflammation of the urine and prevent hypercalcemia, exhibiting inhibitory proper-
the metabolites condensed leading to blocks, but also urine alka- ties. 2. The organic components of CHM and macromers such as
line substances condensed into stone in urinary system. During flavonoids, anthraquinones, polysaccharides, alkaloids, saponins,
the Sui and Tang dynasties, acupuncture and moxibustion were and proteins can form molecular complex with calcium ions
used to treat the stone expulsion. The treatment strategies mainly through hydrophobic, overlapping, electrostatic, and other interac-
involved promoting heat clearance, disinhibiting dampness, facili- tions (Fig. 2). 3. Some CHMs have been shown to reduce the pH
tating urine flow, and expelling stones, which are generally value of urine, promoting dissolution of stones and preventing
achieved by CHM, acupuncture and moxibustion. Based on our the formation of stones. 4. The effective components of CHM
experiences today, medicinal herb are known to potentially adhere to the growth site of the crystal to prevent the further
increase urine volume, alleviate pain, or possess anti- aggregation of urolithiasis, thus inhibiting the formation of
inflammatory components (López & Hoppe, 2010; Sachs, 2003). urolithiasis. 5. Some CHMs can also increase the amount of urine,
relax smooth muscle, and promote the removal of stone. 6. Some
3. Effect of CHM in treatment of urolithiasis CHMs can help to reduce the accumulation of inflammatory lesions
from the crystallization of urolithiasis in the epithelial cells in the
Many clinical studies have proved the effectiveness of TCM in urinary tract. However, because of the complexity of the chemical
the treatment and prevention of urolithiasis (Kasote, Jagtap, composition, it is still difficult to research all of the effective com-
Thapa, Khyade, & Russell, 2017). Wu-Ling-San (WLS) formula, a ponents of CHMs. Hence, the discovery of effective ingredients has
TCM compound, has been used in the treatment of urinary diseases always been one of the focus about the research of CHM on the
over the centuries. Active therapy effect with WLS formula was treatment of urolithiasis.
proved in a prospective, randomized and placebo-controlled clini-
cal trial (Lin, Ho, Lin, Huang, & Chen, 2013). WLS formula (2 g, three 4. Pharmacological studies of anti-urolithiasis medicinal
times daily for one month) was given to 14 patients with recurrent materials and their formulations
calcium oxalate nephrolithiasis. After treatment, the mean urine
output level was found to be significantly increased compared to CHM have been used to treat and prevent urolithiasis in China,
placebo group. No patient complained of side effects, such as fati- Brazil, India, the United States and many other countries for many
gue, dizziness, musculoskeletal symptoms, or gastrointestinal dis- years in folk. However, the modern pharmacological research
turbance. Recently, a clinical trial reported the preventive effect of seemed to be weak. Nowadays, many scientists and medical per-
Salvia miltiorrhiza Bge. (Danshen in Chinese) in treatment of sonnel have studied the effect of CHM on the treatment of urolithi-
urolithiasis from Taiwan’s database (Chen et al., 2018). Anti- asis. In the following, the CHM that used in treament of urolithiasis
urolithiasis efficacy of Phyllanthus niruri Linn. was also ensured in are introdued (Table 1).
a clinic trial within 150 patients with calcium oxalate renal stones
after extracorporeal shock wave lithotripsy (Micali et al., 2006). 4.1. Single medicinal material for treatment
The stone-free rate was 93.5% in treatment group and 83.3% in con-
trol group, among 52% patients who underwent therapy with P. 4.1.1. Lysimachia christinae
niruri extract (2 g/day) for at least three months. In the case of L. christinae Hance. (Jinqiancao in Chinese) is a wild species
patients with lower caliceal stones, the treatment group showed found in almost every part of China. In the western country, L.
a statistically significant stone-free rate of 93.7%. It means that a christinae is also known as Desmodium styracifolium (Obs.) Merr.

Fig. 2. Active ingredients of CHMs in treatment of urolithiasis.

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Table 1
CHMs used in treatment of urolithiasis.

No. CHMs Chinese Parts used Dosage used

names
1 Lysimachia christinae Hance Jinqiancao Whole plant A daily dose of 150 to 200 g for
over six months
2 Alisma orientale (Sam.) Juzep. Zexie Roots 5 to 10 g
3 Tribulus terrestris L. Jili Fruits 6 to 10 g
4 Lygodium japonicum (Thunb.) Sw. Haijinsha Seeds 6 to 12 g
5 Salvia miltiorrhiza Bge. Danshen Roots 5 to 15 g
6 Boerhavia diffusa L. Laolaiqing/ Roots 3 to 9 g
Huangxixin
7 Aquilaria sinensis (Lour.) Gilg. Chenxiang Wood 1 to 5 g, Decocted later
8 Crocus sativus L. Fanhonghua Flowers 1.5 to 3 g
9 Carthamus tinctorius L. Honghua Flowers 3 to 10 g
10 Paeonia lactiflora Pall. Baishao Roots 6 to 12 g, An overdose or long-
term use may damage liver
function
11 P. petiolosa Shiwei Leaves 6 to 12 g, decocted later
12 Wuling San (Polyporus umbellatus (Pers.) Fries, Poria cocos (Schw.) Wolf, Atractylodes Wuling San Chinese 200 mL twice a day
macrocephala Koidz, Alisma orientale (Sam.) Juzep., Cinnamomum cassia Presl) herbal
compound
13 Zhuling Tang (Polyporus umbellatus (Pers.) Fries, Poria cocos (Schw.) Wolf, Alisma orientale Zhuling Tang Chinese 200 mL twice a day
(Sam.) Juzep., Equus asinus L., Talcum) herbal
compound

(Guangjinqiancao in Chinese) and Glechoma longituba (Nakai) Kupr. 4.1.2. Alisma orientale
(Lianqiancao in Chinese). L. christinae is commonly used in urinary A. orientale (Sam.) Juzep. (Zexie in Chinese) is an aquatic plant
system diseases in TCM. The effect of this herb is diuretic, that distributes nearly worldwide. Its roots are used to treat uri-
detumescent, and detoxifying. In China, this herb is believed to nary system diseases, such as nephritis, edema and urination.
prevent and treat urolithiasis as a diuretic, to promote urine acid- The extracts of A. orientale could prevent calcium oxalate stone for-
ification for thousands of years. Its boiled extract has been demon- mation and osteopontin expression in a rat model (Yasui et al.,
strated in vitro to inhibit crystal growth and aggregation (Gohel & 1999). It has been found that Kampo extracts, Gardeniae Fructus
Wong, 2006). In recent years, a large number of studies have con- (fruits of Gardenia jasminoides Ellis) and A. orientale strongly inhib-
firmed that L. christinae has inhibited the formation of urinary and ited oxalate monohydrate crystal aggregation in vitro, and also pre-
gallstones, with diuretic, liver protection, anti-inflammatory, vented the crystal adhesion to Madin–Darby canine kidney cells at
antioxidant, immunomodulatory and other functions (Zhong & concentration 10 lg/mL (Nishihata, Kohjimoto, & Hara, 2013).
Ling, 2018). Hirayama et al. studied the anti-lithogenic properties Kawamura et al. observed the inhibitory effects of A. orientale on
of the main components of L. christinae, which is called D. the formation, growth and aggregation of calcium oxalate crystals
styracyfolium-triterpenoide (Ds-t) (Hirayama et al., 1993). They in the diluted urine system and undiluted urine system. A. orientale
used an ethylene glycol and 1-alpha (OH)D3 to induce oxalate had a strong inhibitory effect on the aggregation and growth of
stone rat model. The results confirmed that Ds-t reduces stone for- crystals when the concentration was above 10 lg/mL. In measur-
mation of pure Ca oxalate crystals in rat kidney. Ds-t is believed to ing the metastable limit by the microplate method, A. orientale
block urinary calcium excretion by either inhibiting the endoge- had a mild inhibitory effect on the formation of crystals above
nous synthesis of 1–25(OH)2D from 1-alpha(OH)D3 in the kidney the concentration of 1 mg/mL. In the undiluted urine system, after
or inhibiting the action of 1–25(OH)2D on increased intestinal determining the metastable limit, the formation and growth of cal-
absorption of calcium. They also found that Ds-t promoted calcium cium oxalate crystals which precipitated in response to a load of
reabsorption in the renal. Meanwhile, Zhang et al. demonstrated sodium oxalate were measured. A. orientale had a strong inhibitory
that the extract of L. christinae was able to inhibit calcium oxalate effect on the formation and growth at the concentration of 0.1–
stone formation and protect renal function by inhibiting the P38- 1 mg/mL. Therefore, A. orientale might be useful for preventing
MAPK pathway (Zhiyuan et al., 2022). Recently, in vivo and stones in recurrent stone formers (Kawamura et al., 1993). Cao
in vitro studies also showed the most potent antioxidant and et al. found that the extraction of A. orientale could regulate the
endothelial protective effects in the treatment of urolithiasis with expression of bikunin protein, which in turn inhibited the forma-
n-butanol fractions of the ethanolic extract of L. christinae (Wu tion of calcium oxalate crystals in the kidney (Cao, Liu, Yin, Zhu,
et al., 2018). Zhou et al. investigated the anti-urolithiatic effect of & Wu, 2006).
total flavonoids of D. styracifolium on calcium oxalate (CaOx) renal
stones in hydroxy-l-proline fed rats. They found that D. styraci- 4.1.3. Tribulus terrestris
folium decreased urinary oxalate excretion, alleviated the proaci- In China, T. terrestris L. (Jili in Chinese) is used to improve mood,
dosis condition, improved the impaired renal functions and renal blood circulation, diuresis and detumescence. Current in vitro stud-
epithelial cell injury. Moreover, their results indicated that D. ies demonstrated that the aqueous extract of T. terrestris inhibited
styracifolium had benefit on inhibition of CaOx formation in the the nucleation and growth of the calcium oxalate crystals. In addi-
rat kidney probably through antioxidant, anti-inflammatory, urine tion, it found to have a cytoprotective role in NRK 52E cells, which
alkalinizing activities, and lowering the concentration of urinary was mediated by lowering LDH leakage and increasing the cell via-
stone-forming constituents (Zhou et al., 2018). Furthermore, net- bility (Aggarwal, Tandon, Singla, & Tandon, 2010). The antiurolithi-
work pharmacology has confirmed that extracts of L. christinae asis potential of T. terrestris has also been confirmed in an albino
can treat renal calculus by modulating multiple targets and path- rat model (Anand, Patnaik, Kulshreshtha, & Dhawan, 1994).
ways (Yu, Zhang, & Xie, 2020). Kaushik et al. observed that the extract of T. terrestris not only
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attenuated kidney stones in rats, but also attenuated the cium oxalate monohydrate and dihydrate crystals. In another
ephrolithiasis-mediated inflammatory response via regulating the study, aqueous root extract of B. diffusa showed protective effects
expression of p38MAPK (Kaushik et al., 2019). An antilithiatic pro- against hyperoxaluric oxidative stress and renal cell injury in rats
tein purified from T. terrestris could play an important role in med- due to potent antioxidant activity (Pareta, Patra, Mazumder, &
ical management of urolithiasis (Aggarwal, Tandon, Singla, & Sasmal, 2011).
Tandon, 2012).
4.1.7. Aquilaria sinensis
4.1.4. Lygodium japonicum A. sinensis (Lour.) Gilg. (Baimuxiang in Chinese) is a medicine
Lygodii Spora (Haijinsha in Chinese) is also a kind of CHM com- plant from Thymelaeaceae family. It refers to the highly resinous
monly used in treating urolithiasis for a long history. It is the dried wood of agarwood. In TCM, A. sinensis is commonly used to relieve
spore of L. japonicum (Thunb.) Sw. (Schizaeaceae) and is widely dis- pain in abdominal region, arrest vomiting, and control respiring to
tributed in eastern Asia and Australia. L. japonicum is rich in carbo- relieve asthma. Pharmacological studies suggest that A. sinensis can
hydrates, phenols and flavonoids. Cho et al. proved the inhibitory relieve ureteral smooth muscle spasm and relieve stone incarcera-
effect of an ethanol extract of the spores of L. japonicum on ethy- tion (Wu et al., 2014).
lene glycol-induced kidney calculi in rats (Cho et al., 2014). The
results revealed that treatment with the ethanol extract of L. japon- 4.1.8. Crocus sativus
icum 400 mg/kg significantly decreased the levels of urinary cal- C. sativus L. (Fanhonghua in Chinese), commonly known as Saf-
cium, oxalate and uric acid, and increased the levels of urinary fron crocus, or Autumn crocus, is a species of flowering plant of Cro-
citrate as compared to those groups. L. japonicum can dilate the cus genus in the Iridaceae family. The constituents of C. sativus are
ureteral sinus and increase the pressure in the upper ureteral cav- pigments, flavonoids, phenolic acid etc. It is a CHM that has been
ity, which can promote the stone movement. In both preventive prescribed since centuries for treating various symptoms related
and therapeutic protocols, the extract significantly decreased kid- to blood circulation improvement. Amin et al. evaluated the pro-
ney peroxides, renal calcium, oxalate content, and the number tective effects of the aqueous extract of C. sativus against ethylene
of kidney oxalate deposits. Therefore, they concluded that L. japon- glycol-induced urolithiasis in rat. They found that C. sativus did not
icum is useful as a preventive and therapeutic agent against the show diuretic effect; However, it significantly reduced the elevated
formation of oxalate kidney stones. urinary oxalate in prophylactic (50 and 100 mg/kg) and curative
(100 mg/kg) studies. Only the high dose of prophylactic regimen
4.1.5. Salvia miltiorrhiza restored citrate concentration of urine. Increased number of cal-
S. miltiorrhiza is a frequently used medicinal plant in CHM with cium oxalate crystals deposits in the kidney tissue of calculus rats
its dried roots possessing pharmacological properties (Chen et al., was significantly reverted by the prophylactic and high dose of
2014; Guo et al., 2014). In modern medicine, S. miltiorrhiza is used curative saffron treatment. The results of this study indicated that
for the treatment of cardiovascular diseases (Yang et al., 2011), C. sativus can protect against calcium oxalate (CaOx) nephrolithia-
osteoporosis (Yuan, Wu, Shi, & Chen, 2015). S. miltiorrhiza has been sis. The mechanisms might be related to the urinary concentration
proved to be one of the effective CHMs for prevention of stone dis- of stone-forming constituents and an antioxidant effect (Amin
ease in previous study. They tested the effect of protection to et al., 2015).
urolithiasis with 16 CHMs including S. miltiorrhiza using Droso-
phila melanogaster model. They found that S. miltiorrhiza reached 4.1.9. Carthamus tinctorius
the crystal formation rate of 0% (Wu et al., 2014). In a cohort C. tinctorius L. (Honghua in Chinese), also known as Safflower,
research (Chen et al., 2018), they investigated the effect of S. milti- has been used to treat muscles, bones injuries and hemostasis
orrhiza in treating urolithiasis through the incidence of calculus swelling pain for centuries in TCM. C. tinctorius has been further
surgical during 12 years. This study included a total of 8568 studied for its potential effects on urinary calculus, and a positive
patients using S. miltiorrhiza (S. miltiorrhiza-users) and 56 502 result was obtained when it was applied to a rat model (Lin
patients not using S. miltiorrhiza (non-S. miltiorrhiza-users) suffer- et al., 2012). In another study, C. tinctorius was also proved to pre-
ing from calculus disease after the initial diagnosis of calculus. vent urolithiasis. Especially, they found that the extract of C. tincto-
They showed that the incidence of calculus surgical treatment in rius was unable to completely inhibit PE-induced ureteral
the S. miltiorrhiza-users was less than that in the non-S. miltior- peristalsis, suggesting the antilithic effect of C. tinctorius extract
rhiza-users. S. miltiorrhiza decreased the ratio of subsequent stone is related to mechanisms other than modulation of ureteral peri-
treatment after the first treatment in the study population, and stalsis (Wu et al., 2014).
there was no increased bleeding risk due to long-term S. miltior-
rhiza use. 4.1.10. Paeonia lactiflora
Paeoniae Radix Alba (Baishao in Chinese, PRA), the dried roots of
4.1.6. Boerhavia diffusa Paeonia lactiflora Pall. without bark, has been used as a medicinal
B. diffusa L. (Huangxixin in Chinese) is useful in the treatment of herb in TCM for centuries based on its wide range of pharmacolog-
a wide range of urologic disease including urolithiasis in traditional ical activities. In ancient pharmacology, PRA was used to inhibite
Chinese medicinal system (Yasir & Waqar, 2011). In an in vitro inflammatory response, relieve pain, and suppress sweating. In
study, an ethanolic extract of whole B. diffusa plant was found to morden pharmacology, PRA decoctions are used to treat rheuma-
have an effect on calcium oxalate crystallization process in a dose toid arthritis, systemic lupus erythematosus, hepatitis, dysmenor-
dependent manner. It completely dissolved the urinary calcium rhea, muscle cramping and spasms, and long-standing fever. Li
salts at a concentration of 100 mg/mL (Yasir & Waqar, 2011). The et al. found that an aqueous extract of PRA is also a useful agent
noticeable antiurolithic activity of B. diffusa roots has also been that prevented the formation of CaOx kidney stones (Li et al.,
observed in animal model. It has been observed that aqueous root 2017). Gou et al. found that the extract of PRA reduced urinary
extract of B. diffusa mediated antiurolithic activity through inhibi- and renal oxalic acid levels while increasing the level of urinary
tion of calcium oxalate crystallization, diuresis and hypo-oxaluria calcium and citric acid in the kidney. This effect may be related
(Amin, Feriz, Hariri, Meybodi, & Hosseinzadeh, 2015). In the cal- to the fact that the extract of PRA regulated the expression of
cium oxalate crystallization assay, the incorporation of its extract osteopontin (Gou, You, Wang, & Li, 2020). Another experment also
increased calcium oxalate crystallization but with reduce sized cal- proved the potential antilithic effect of PRA (Wu et al., 2014).
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C. Jiang, L. Wang, Y. Wang et al. Chinese Herbal Medicines 15 (2023) 526–532

4.1.11. Pyrrosia petiolosa of kidney stones associated with Ephedrae Herba (Mahuang in Chi-
Pyrrosiae Folium (Shiwei in Chinese) is the dried leaves of P. peti- nese) originated from Ephedra sinica Stapf, which is commonly
olosa (Christ) Ching, a plant in the Polypodiaceae family, and it has used in treatment of respiratory conditions (Blau, 1998). Both
been used to treat urolithiasis for thousands of years in TCM. In patients in these two case reports were young adult men with a
recent years, the pharmacological studies have revealed that the history of ingesting 40–3000 mg/d Ephedrae Herba over several
extracts of P. petiolosa have anti-inflammatory, antibacterial, anti- months. The components of Ephedrae Herba associated with these
colithic, and oxidative stress-regulating effects (Cheng et al., 2014; patients with urolithiasis were ephedrine, norephedrine, and pseu-
Mi et al., 2012). It has been confirmed that P. petiolosa can inhibit doephedrine. Because of these events and other adverse events
the growth and aggregation of calcium oxalate stones in vitro associated with Ephedrae Herba, the FDA prohibited the sale of
(Gohel & Wong, 2006). In addition, P. petiolosa can not only inhibit Ephedrae Herba-containing dietary supplements in April 2004 in
the formation of oxalate stones by suppressing oxidative stress and the United States (Gabardi, Munz & Ulbricht, 2007).
inflammation, but also alleviate renal injury induced by renal In addition, excessive and too long-term use should be avoided.
stones and thus protect the kidneys in urolithiasis rats (Cheng To achieve efficacy, such that the active components of the
et al., 2014; Mi et al., 2012). decocted herbs reach the intended site, kidney, ureter and bladder,
the registered herbalists will prepare 5–20 g of dried herbs for
decoction. For severe cases, the dosage can be increased up to
4.2. Chinese medicinal formulae for treatment
60–80 g of dried weight. Although these dosages are empirical
and proportioned through a long history of traditional experience,
Wuling San (WLS), which is a classical TCM formula, is widely
they are now optimized for modern prescription to reduce serious
used in China for the treatment of urinary stones. This formula
side-effects.
has been proved its importance in prevention of calcium oxalate
Finally, flexible application of TCM and modern technologies is
nephrolithiasis both in vitro and in vivo studies (Lin et al., 2013;
optimized way to treat and prevent urinary calculi. For example,
Tsai et al., 2008). WLS extract was found to inhibit the calcium oxa-
patients after lithotripsy surgery, can use appropriate CHM to pre-
late nucleation and aggregation under in vitro conditions, and may
vent recurrence of calculus. The small kidney stones (<6 mm),
have the ability to prevent stone recurrence. At a concentration of
postoperative residual small stones, and ‘‘Stone Street” after litho-
50 mg/mL, it inhibited nucleation and aggregation of calcium oxa-
tripsy, TCM treatment becomes necessary. In summary, to maxi-
late crystals by 94.3% and 92.49%, respectively. In addition, it was
mize the effects of TCM for the treatment of renal calculus, we
also found that WLS formula prevented the renal deposition of cal-
should choose the appropriate treatment method according to
cium oxalate crystal in ethylene glycol-fed rats (Tsai et al., 2008).
the patient’s different physique and the nature of stone. And
Zhuling Tang (ZLT) is also a CHM formula. It has been used for
CHM should be used normatively according to the dosage and
centuries to treat urological diseases in Chinese medicine. ZLT is
decoction method to reduce the toxic and side effects.
composed of five dried herbs: Polyporus (Zhuling in Chinese), Poria
(Fuling in Chinese), Alismatis Rhizoma (Zexie in Chinese), Talcum
(Huashi in Chinese) and Asini Corii Colla (Ejiao in Chinese). This for-
mula was initially used in the treatment of low urine output, fever, 6. Conclusion
thirst and floating pulse. It has been prescribed as a CHM to treat
urinary stones as well. In Tsai’s study, they evaluated the antilithic CHM was confirmed to be a useful pharmacotherapy for the
effects of experimentally induced calcium oxalate (CaOx) treatment of urolithiasis by clinical and experimental verification.
nephrolithiasis in ethylene glycol-fed rats. They found that ZLT CHMs with the traditional functions of promoting urination and
reduced the severity of CaOx crystallization and slowed down draining dampness, purgation, activating blood and resolving sta-
the body weight loss effects. Therefore, ZLT was proved to be an sis can be a useful approach to prevent the stone recurrence or
effective reagent for kidney stone prophylaxis (Tsai et al., 2009). improve renal failure. TCM could treat urolithiasis and the sec-
ondary kidney diseases by forming a coordination complex with
calcium ion, hydrophobic, overlapping and electrostatic, regulating
5. Notice in use of CHMs in practice the pH value of urine, adhereing to the growth site of the crystal,
increasing the amount of urine, relaxing smooth muscle and reduc-
The effect of CHM on the prevention and treatment of urolithi- ing the accumulation of inflammatory lesions. However, to make it
asis have been proven in the history of the development of TCM, more efficient and low toxicity, there remains a considerable
and have been constantly confirmed by modern pharmacology. amount of research required in the fields of analytical chemistry,
However, because of the different nature of stones, and different molecular biology, pharmacology and coordination chemistry.
physique and character of patients, some questions should be Above all, CHM would be benefit for providing new treatment
noted in practice. Attention should be paid to nephrotoxicity of strategy for urolithiasis and secondary kidney damage.
CHM. For example, many herbs containing aristolochic acid (which
was confirmed to have obvious nephrotoxicity) have been found,
but the CHMs metioned in this article for the treatment of urolithi- CRediT authorship contribution statement
asis is not included. Some nephrotoxic concerns have been recently
mentioned about T. terrestris (Talasaz, Abbasi, Abkhiz, & Dashti- Chen Jiang: Conceptualization, Writing – review & editing. Lin-
Khavidaki, 2010), overdose of T. terrestris and hypoposia led to gyun Wang: Writing – review & editing. Yang Wang: Writing –
nephrotoxicity. In addition to aristolochic acid, excessive dosage, review & editing. Rongjia Xu: . Hongtao Yang: Conceptualization.
improper processing, change of extraction methods of herbal med- Jibin Peng: Conceptualization.
icine, contamination of CHM and improper compatibility may
reduce the curative effect and increase toxicity. Further investiga-
tions of the molecular modes of CHMs are needed to better under- Declaration of Competing Interest
stand pathophysiological mechanisms (Yang et al., 2018).
On the other hand, is it possible that CHM can lead to the occur- The authors declare that they have no known competing finan-
rence or aggravation of stones? It’s not commonly known that cial interests or personal relationships that could have appeared
CHM induced nephrolithiasis. There are two published case reports to influence the work reported in this paper.
531
C. Jiang, L. Wang, Y. Wang et al. Chinese Herbal Medicines 15 (2023) 526–532

Acknowledgments randomized controlled trial. African Journal of Traditional, Complementary and

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