Exploring the Efficacy of Herbal Plants in Nephrolithiasis: An In-Depth Review

Payal N. Vaja¹, Hiral S. Popaniya², Chetan H. Borkhataria³, Chintankumar J. Tank⁴,

Khushbu H. Parmar⁵, Piyush V. Tank⁶

¹Assistant Professor, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

²Assistant Professor, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

³Assistant Professor, Department of Pharmaceutics,

B. K. Mody Government Pharmacy College, Rajkot (360003), Gujarat, India.

⁴Professor, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

⁵Research Scholar, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

⁶Research Scholar, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

*Corresponding Author E-mail: payalvaja55@gmail.com

ABSTRACT:

Nephrolithiasis, or kidney stones, is a common urological disorder affecting millions worldwide. Traditional and complementary medicine systems have long used medicinal plants to prevent and treat the condition. This in-depth review examines the types of nephrolithiasis, causative and risk factors, composition of stone, major causes of stone formation, mechanism of nephrolithiasis as well as the ethnobotanical properties of these plants like bijora fruit, varuna, and manjishta etc, including anti urolithiatic, diuretic, and anti-inflammatory effects. The review encompasses an extensive search of published scientific literature, traditional knowledge, and ethnobotanical records, yielding a wealth of information on plants with potential anti-nephrolithiatic properties. These plants offer diverse mechanisms of action, including inhibition of crystallization, dissolution of stones, reduction of oxidative stress, and alleviation of pain and inflammation. Several bioactive compounds, such as phytochemicals, antioxidants, and anti-inflammatory agents, have been identified in these plants, contributing to their therapeutic efficacy. This in-depth review underscores the potential of medicinal plants in the prevention and treatment of nephrolithiasis. It advocates for the integration of traditional knowledge with modern scientific approaches to develop evidence-based strategies for managing kidney stones.

KEYWORDS: Kidney stone, Medicinal plant, Nephrolithiasis, Bijora fruit, Herbs.

INTRODUCTION:

Nephrolithiasis disease, affecting 12% of the global population, is a multifactorial urological disease-causing crystal concretion in the kidneys, increasing the risk of end-stage renal failure¹. Calcium oxalate (Caox) is the main component of stones, which form on Randall's plaques on renal papillary surfaces. High prevalence, increasing rates, and recurrence rates are linked to obesity, diabetes, hypertension, and metabolic syndrome. Minimally invasive endourological procedures have

improved kidney stone-free rates, reduced patient morbidity, and enhanced quality of life, while pharmacological therapies, behavioural and dietary measures are crucial for recurrence prevention. Mineral concretions called kidney stones are located in the renal calyces and pelvis and are affixed to the renal papillae. While nephrolithiasis or urolithiasis originate in the urinary tract, diffuse renal parenchymal calcification is referred to as nephrocalcinosis. Around 80% of kidney stones worldwide are made of calcium oxalate (caox) and calcium phosphate (cap). Additionally typical, struvite, cystine, and uric acid stones make up about 9%, 10%, and 1% of all stones, respectively. Therefore, research is needed to better understand the biology of kidney stone development in order to treat urolithiasis with new medications. As a result, the purpose of this study was to consolidate current knowledge on the pathophysiology, etiology, and prevention of kidney stones². One of the earliest diseases recognised by medicine is kidney stone disease, often known as nephrolithiasis or urolithiasis. According to estimates, 1 to 15% of people will have kidney stones at some point in their lives, and the prevalence and incidence of kidney stones are both said to be rising globally^3,4.

Types of Nephrolithiasis:

Figure 1: Types of Nephrolithiasis¹

1. Calcium stone: calcium oxalate and calcium phosphate:

Calcium stones, comprising 80% of urinary calculi, are primarily composed of calcium oxalate (50%), calcium phosphate (5%), and a mixture of both (45%). The main constituent is brushite or hydroxyapatite. CaOx stones are more common than COD in clinical stones. Factors contributing to their formation include hypercalciuria, hyperuricosuria, and hypocitraturia. Urinary pH levels promote CaOx stones, while calcium phosphate stones occur at higher pH levels.

2. Struvite or magnesium ammonium phosphate stone:

Struvite stones, also known as infection or triple phosphate stones, are common in 10-15% of cases and are caused by chronic urinary tract infections caused by urease-producing organisms like proteus mirabilis, klebsiella pneumonia, pseudomonas aeruginosa, and enterobacter. Urease breaks down urea into ammonia and CO₂, raising urine pH. Phosphate, less soluble at alkaline pH, precipitates on insoluble ammonium products, resulting in huge staghorn stones. This form of stone is more common in women than men. Escherichia coli is not connected to struvite stones and cannot breakdown urea.

3. Uric acid stones or urate:

Uric acid-rich diets, particularly those heavy in animal protein, increase uric acid stones, which account for 3 to 10% of all stone types. Patients with gouty arthritis are also at risk, and the majority of instances of uric acid nephrolithiasis are due to idiopathic reasons. Uric acid stones are more common in men than in women.

4. Cystine stones:

Less than 2% of all stone kinds are these stones. It is a hereditary condition that affects how an amino acid and cystine are transported. It leads to an overabundance of cystinuria, an autosomal recessive illness marked by defective cystine tubular absorption or cystine leakage into urine, and is brought on by a genetic deficiency in the rbat gene on chromosome 2. It causes the production of cystine stones because it does not dissolve in urine. Cystinuria homozygotes excrete more than 600 millimoles of insoluble cystine per day. The sole clinical sign of this cystine stone illness is the formation of urine cystine⁵.

Causative crystals and risk factor:

Figure 2: Causative Crystals and Risk Factor⁶

The composition of stone:

The stone matrix, comprising 2-3% of the stone’s dry weight, is composed of 64% protein, 9.6% non-amino carbohydrates, 5% hexosamine converted to glucosamine, 10% bound water, and inorganic ash. Lipids are also important, but proteins dominate research, making them more accessible than lipids and glycosaminoglycans. The amount of CaOx deposited from urine or the size of crystal particles formed can be influenced by urinary molecules, which may have an impact on the possibility that crystalline particles will be retained in the renal collecting system and lead to stone disease. While certain urinary proteins, such as albumin, have little to no impact on crystallisation in urine but are present in stones, other urinary proteins, such as inorganic solutions and concentrated whole urine, increase CaOx crystal nucleation. Numerous urine proteins, some of which are multifunctional, have been demonstrated in studies to prevent CaOx crystal formation and aggregation. Tamm-Horsfall mucoprotein can prevent CaOx crystal aggregation, but it can also encourage the formation of new crystals. When immobilised on surfaces, polyelectrolytes and proteins that prevent crystallisation in solution can become promoters. Urinary macromolecules become more potent⁷.

Mechanism of nephrolithiasis:

Urinary supersaturation and crystallization, primarily caused by inherited or acquired renal function impairments, are influenced by urine pH and substance excess concentrations, including CaOx, Ca₃(PO₄)₂, uric acids, urates, struvite, amino acids, purines, and drugs like atazanavir, sulfamethoxazole, amoxicillin, and ceftriaxone Crystal formation and development are also influenced by multiple modulator molecules, such as receptors, promoters, and inhibitors⁸.

1. Mechanism of calcium oxalate renal formation:

Figure 3: Mechanism of calcium oxalate renal stone formation

Renal stones develop as a result of increased urine supersaturation and crystalline particle production. The majority of solids are evacuated readily, but if they are held in the kidney, they can develop into large stones. Crystals can develop and aggregate at a number of different places in the kidneys. They must be situated where they can result in ulceration at the papillary surface, creating a stone nidus, for them to produce stones. This process is greatly aided by renal tubular damage, which encourages crystal retention and the formation of a stone nidus on the renal papillary surface. Additionally, crystal nucleation at low supersaturation is enhanced by renal tubular damage. Renal tubular damage further encourages crystal-cell contact because kidney stones need aberrant retention of produced particles⁹.

2. Mechanism of struvite or magnesium ammonium phosphate stone:

Due to the presence of ammonia-producing or urea-splitting bacteria such proteus, klebsiella, pseudomonas, mycoplasma, and staphylococcus, struvite urinary stones develop in the urine of sick people or animals. These microorganisms convert urea to ammonia, raising the pH of urine to an alkaline state. Ammonia then reacts with phosphate and magnesium ions to produce struvite stones¹⁰.

3. Mechanism of uric acid stone or urate:

The glomerulus produces urinary filtrate, which then travels into tubules for reabsorption or secretion. While small modifications take place in the distal tubule and collecting ducts, the proximal tubules are where the majority of solute reabsorption takes place. The henle loop concentrates urine into a combination of 95% water, 2.5% urea, and 2.5% minerals, salts, hormones, and enzymes. While the distal tubule controls the blood salt and acid-base balance, the proximal tubules reabsorb glucose, sodium, chloride, and water¹¹.

4. Mechanism of cystine stones:

Cystine solubility in urine is 250mg/L at a pH of 7, increasing to 750mg/L at a pH of 8. However, maintaining a urinary pH above 7.5 can be challenging in clinical practice due to the risk of calcium phosphate precipitation. The actual solubility of cystine in urine is slightly greater than standard guidelines due to the actions of electrolytes, ions, and macromolecules. Standard solubility estimates can be a guide, but the actual solubility in an individual patient's urine can only be estimated from published data. A specialized laboratory can measure relative solubility using urinary cystine supersaturation ratio or a "cystine capacity" test for patients on thiol medications¹².

Table 1. Scientific classification of plants

Plants	Kingdom	Division	Class	Order	Family	Genus	Species
Bijora Fruit^13	Plantae	Magnoliophyta	Magnoliopsida	Sapinadales	Rutaceae	Citrus	Medica L.
Gokhru^14	Plantae	Magnoliophyta	Magnoliopsida	Caryophyllales	Pedaliaceae	Pedalium	P Murex L.
Punarnava^15	Plantae	Magnoliophyta	Magnoliopsida	Caryophyllales	Nyctaginaceae	Boerhavia	Boerhavia Diffusa L.
Cucumber^16	Plantae	Teacheophytes	Angiosperms	Cucurbitales	Cucurbitaceae	Cucumis	C. Sativus
Varuna^17	Plantae	Magnoliophyta	Magnoliopsida	Brassicales	Capparidaceae	Crataeva	Nurvala
Akkapana^18	Plantae	Magnoliophyta	Magnoliophyta	Rosales	Crassulaceae	Bryophyllum	B. pinnatum Lam.
Manjishtha^19	Plantae	Dcotyledon	Gamopetalac	Rubiales	Rubiaceae	Rubia	Cordifolia
Gulvel^20	Plantae	Magnoliophyta	Magnoliopsia	Ranunculales	Menispermaceae	Tinospora	Cordofolia

1. Bijora Fruit:

It is obtained from the large fragrant citrus fruit with thick rind, belonging to the family rutaceae²¹. Bijora fruit contains the main bioactive constitute of iso-limonene (39.37%) and citral (23.12%). Other chemical constitutes of peel are limonene (21.78%), neryl acetate (2.51%), neryl alcohol (2.25%), β-myrcene (2.70%), other chemical constitutes of leaf are erucylamide (28.43%), limonene (18.36%), mehp (8.96%), citral (12.95%), 2,6-Octadien-1-ol, 3,7-dimethyl-, acetate, (z) (5.23%), 6-octenal, 3,7-dimethyl (4.39%), methoprene (3.51%)²².

Figure 4: Citral²³

Uses:

Citrate inhibits the spontaneous nucleation and agglomeration of calcium oxalate crystals. It is serves multiple roles as an antioxidant, anti-inflammatory, antimicrobial, antiviral, and antihyperglycemic properties. Flowers have antidepressants characteristic, astringent to the intestines, treat vomiting, tumors, asthma, cough and hiccough. Their roots have also antiparasitic properties and it’s helpful in constipation, tumors, stomachache, vomiting, kidney stones, and tooth caries²⁴.

2.  Gokhru:

It consists from the dried ripe seeds of Tribulus terrestris Linn., which belongs to the family of Pedaliaceae.

The main chemical components present in tribulus terrestris are diosegenin and vanillin. Other chemical constitute are flavonoids, saponins, terpenoids and phenols. Flavonoids components are pedalitin, diosmetin, quercetin, kaempferol, luteolin, and 20, 40, 50,-trihytlroxy 5,7-dimethoxyflavone. Saponins components are sitosterol and diosegenin, Terpenoids components are lupeol acetate and urosolic acid which are considered as pentacyclic triterpenoid. Phenols components are vanillic acid and luteolin^25,26.

Figure 5: Diosegenin ²⁷

Uses:

It is used as an anti-nephrolithiasis activity and it has also other properties of gokhru churna may help against the production of kidney stones and breaking or reducing the size of those that may have already developed. It may also work against polycystic kidney disease, kidney stones, and cystitis²⁸.

3. Punarnava:

The whole plant of B. diffusa is a very useful source of the drug punarnava, which is documented in Indian pharmacopoeia as a diuretic. It belongs to the family of Nyctaginaceae. The main chemical constituents of B. diffusa are punaemavoside, boeravinone A-F, hypoxanthine 9-L arabinofuranoside, ursolic acid, liiriodendrin. The root contains 14 amino acids, including 7 essential amino acids (total 11.54 %). These are: alanine 1.18%, arginine 0.75%, aspartic acid 0.95%, glutamic acid 1.45%, leucine 0.88%, methionine 0.45%, ornithine 0.96%, phenylalanine 0.71%, proline 0.5%, serine 0.85%, threonine 0.79%, tryptophan 0.65%, tyrosine 0.72%, asparagines 0.0%, glycine 0.0% and valine 0.75 %²⁹.

Figure 6: Liriodendrin³⁰

Uses:

It helps to pass the stone through urine by increasing urine flow. This is due to its diuretic property. Anti-diuretic and anti-inflammatory properties. In an experimental study histopathological changes showed that acetaminophen caused significant structural damages to kidneys like tubular necrosis, degeneration of epithelial cells, glomerular damage and congestion which was reversed with B. diffusa proved to be nephroprotective agent. It has many other uses the punarnava plant's leaves have anti-bacterial qualities, making it a great choice for reducing bacterial illnesses caused by both gram-positive and gram-negative bacteria. The aqueous form of root extract of punarnava possesses good liver protective activity. The extract from the leaves of punarnava consists of antiproliferative and antiestrogenic activity that can act on breast cancer cells to control them. Punarnava is an excellent medication for convulsions. It helps to reduce corneal (stromal) oedema, inflammation, and tortuosity of glands^31,32.

4. Cucumber:

It is comprising dried seeds of Cucumis sativus L. it is belonged to the Cucurbitaceae family of the 30 species of Cucumis C. sativus has the greatest economic significance. The main chief chemical constitutes are the major fatty acids in cucumber fruit constitute are palmitic acid (23.6-27.5%), linoleic acid (22.7-26.3%), and linolenic acid (40-46%). phosphatidylcholines (23.1%), phosphatidylethanolamines (16.6%), phosphatidylglycerols (2.0%), phosphatidy linositols (2.0%), monogalactosyl diglycerides (5.5%), cucumber seeds constitutes are, linoleic (52.43%), oleic (34.78%), α-amyrin (2%), β-amyrin (5%), cycloartenol (10%), 24-methylenecycloartanol (13%), 24-methyl-25(27)-dehydrocycloartanol (1%), 24-methylene-24-dihydrolanosterol (7%), 24-methlenene-24-dihydroparkeol (1%), euphol (2%), tirucallol (1%)³³.

Figure 7: Palmitic acid³⁴

Uses:

Suri cucumber plants (cucumis sativus) contain potassium salts and other compounds– potentially it can dissolve calcium oxalate (cac2o4). It has ability to dissolve to calcium oxalate stone. Regulat intestinal process. It has other properties anti-oxidants, anthelmintic, hypolipidemic, hypoglycaemic activity and anticancer skin whitening and anti-wrinkle activity. A decoction of root is used as diuretic³⁵.

5. Varuna:

It consists from leaves, root and bark of Crataeva nurvula belonging to the family capparidaceae. Varuna stem bark mainly contains rutin, varunol, and quercetin³⁶.

Figure 8: Rutin³⁷

Uses:

Varuna bark is used extensively for healing painful kidney stone. Treat urinary infection anti septic, anti-diuretic and litholytic. It helps to stimulate digestion improve appetite. It is good blood purifier that helps to maintain homeostasis. It has other medical activity, anti urolithiasis activity, anti diabetic activity, anti diarrhoeal activity, anthelmintic activity, antinociceptive activity, hepatoprotective activity, anti-oxidant activity³⁸.

6. Akkapana:

Figure 9: Astragalin⁴²

It is consisting of dried leaves and steam of Bryophyllum pinnatum., belonging to the family Crassulaceae^39,40. The plant contains α-amyrin, α-amyrinacetate, β-amyrin, β-amyrinacetate, bryophollenone, bryophollone. The leaves contain a group of chemicals called bufadienolides which are very active. Leaves contains chemical component are astragalin, 3,8-dimethoxy-4,5,7- trihydroxy flavone, friedelin, epigallocatechin-3-o-syringate, luteolin, kaempferol, quercetin, quercetin3l-rhamonsido-l-arabino furanoside⁵⁶. The plant steam contain (e)-2-nonenal (3.30%), (e,e)2,4-decadienol(1.95%), β-bisabolene(2.95%), 2,7-dimethyl-3,6-bis(methylene)-1,7-octadiene(1.62%), 1-tetradecanol(2.10%) etc⁴¹.

Uses:

It is medically use for diabetes, diuresis, dissolving kidney stones, respiratory tract infections, as well as applied to wounds, boils, and insect bites. It is useful for preventing alcoholic, viral and toxic liver damages. Other activities are anti-inflammatory and analgesic activity, urolithic activity, nephroprotective effects, antimicrobial and antifungal activity, anti-oxidant activity, hepatoprotective activity, antihypertensive activity, anti leishmanial activity⁴³.

7. Gulvel:

It consisting of dried steam, leaves, flowers of Tinospora cordifolia belonging to the family of Menispermaceae. Major constituent of tinospora cordifolia: terpenoid, alkaloid, lignans, steroids. Terpenoid: tinosporide, furanolactone diterpene, furanolactone clerodane diterpene, furanoid diterpene, tinosporaside etc. Alkaloid: tinosporine, magnoflorine, berberine, choline, jatrorrhizine etc. Ligan: 3(a,4-dihydroxy-3-methoxybenzyl)-4-(4-hydroxy-3-methoxybenzyl). Steroids: giloinsterol, ß-Sitosterol, 20 a hydroxy ecdysone etc^44,45.

Figure 10: Tinosporide⁴⁶

Uses:

It is medically used for treatment of jaundice, rheumatism, urinary diseases, lever and intestinal disorders, diabetes, skin diseases and anaemia. Other activities: immunomodulatory/immunostimulatory activity, anti-cancer/anti-tumor activity, anti-neoplastic activity, anti-tuberculosis activity, hepatoprotective and anti-oxidant activity⁴⁷.

8.  Manjishtha:

It consists of the steam, root, flower, and leaves of Rubia cordifolia, which belongs to the family Rubiaceae^21,22. It has different classes of bioactive compounds such as malic, citric, quinic, rosmarinic acids and saccharides are xylose, ribose, fructose, glucose, sucrose, primverose. The roots contain a mixture of purpurin, munjistin, small amounts of xanthopurpurin and pseudopurpurin. Alizarin, rubimallin, β sitosterol and daucosterol etc. dihydromollugin and 2-carbomethoxy-2,3- epoxy-3-prenyl-1,4-naphthoquinone. Rubiasins, anthracene derivatives have been isolated from the roots and stems of Rubia cordifolia⁴⁸.

Figure 11: Daucosterol⁴⁹

Uses:

It is medically used to reduce growth of urinary crystals. It used to invigorate spleen and soothing liver, dysmenorrhea, diuresis, paralysis, jaundice, amenorrhea, skin disorders of many varieties, renal stone and blood detoxification and other uses are neuroprotective, antitumor, antibacterial, anti-inflammatory, anti-oxidant, immunosuppressive effects⁵⁰.

CONCLUSION:

An in-depth review on herbal plants used in nephrolithiasis reveals a diverse range of potential therapeutic options for the management and prevention of kidney stones. Nephrolithiasis, commonly known as kidney stones, is a painful and recurrent condition that affects a significant portion of the population. The use of herbal plants in traditional and alternative medicine for treating kidney stones has gained considerable attention. Herbal plants which used in nephrolithiasis have demonstrated potential anti-lithogenic properties. They can inhibit the formation of crystals and stones in the kidneys, dissolve existing stones, and help in their passage through the urinary tract. Herbal remedies in nephrolithiasis are diverse and may include diuretic effects, antioxidant properties, and the prevention of crystal aggregation. Some herbs may also inhibit calcium oxalate crystal formation. There is a wide variety of herbal plants used in the treatment of nephrolithiasis, representing different traditional healing systems across the world. There are some herbal plants like Citrus medica linn., Tribulus terrestris, Boerhaavua diffusa, Cucumis sativus L., Crataeva nurvula, Bryophyllum pinnatum etc, which are used in nephrolithiasis. The majority of herbal remedies used in nephrolithiasis appear to be safe when taken in moderation. They may help in reducing the risk factors associated with stone formation, such as excessive calcium or oxalate excretion. Herbal remedies can also be employed for the prevention of kidney stone recurrence.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENT:

The authors express their sincere thanks to Dean, Staff of School of Pharmacy, Dr. Subhash University, Junagadh, Gujarat, India for providing guidance and support to this review work.

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Received on 11.01.2024         Modified on 15.05.2024

Accepted on 26.07.2024   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2024; 14(3):263-269.

DOI: 10.52711/2231-5691.2024.00040