Hyperoxaluria is a primary risk factor in calcium oxalate stone formation ⁽⁵⁾. Calcium containing stones are the most common comprising about 75% of all urinary calculi, which may be in the form of pure calcium oxalate (50%) or calcium phosphate (5%) and a mixture of both (45%) ⁽⁶⁾. The process of stone formation depends on urinary volume; concentrations of calcium, phosphate, oxalate, sodium, and uric acid ions; concentrations of natural calculi inhibitors (e.g. citrate, magnesium, Tamm-Horsfall mucoproteins, bikunin); and urinary pH ⁽²⁾.

Nephrolithiasis:

Nephrolithiasis is a complex process that results from a succession of several physicochemical events including super saturation, nucleation, growth, aggregation, and retention within the kidneys⁽^7,8). Lifestyle and dietary choices implicated in the complex of the metabolic syndrome are important factors contributing to such developments⁽⁹⁾. Furthermore, nephrolithiasis often indicates the existence of additional underlying disorders. Regardless of their mineralogy, two factors are fundamental in kidney stone development: supersaturation with respect to the forming mineral phase and crystal nucleation ⁽¹⁰⁾. Persons with long-standing history of kidney stones may be more likely to have had recurrence, thus increasing the likelihood of developing chronic kidney disease. Hypertension is a well known risk factor for chronic kidney disease. Chronic kidney disease attributed to interstitial nephritis (or chronic pyelonephritis), has long been known to develop in the presence of urinary tract infections. Diabetes is the most common cause of end-stage renal disease in the United States, accounting for 43.2% of all incident cases in 1998 ⁽¹¹⁾.

When the different types of stone composition are taken into account, evidence exists that insulin resistance is associated with uric acid stone disease. The association between insulin resistance and uric acid stone disease can be explained by a defect in urine acidification, namely to an impaired L-glutamine system and reduction of Na ⁺K ⁺transport at the proximal tubule. This change results in very low urine pH which is the main risk factor for uric acid stone formation. A defect of the Na ⁺K ⁺ and H ⁺ transport systems could also be associated with lower citrate excretion, which is a well known risk factor for calcium stone formation.

Epidemiologic studies showed that the incidence of nephrolithiasis increases in patients exhibiting an overweight condition, hypertension, dyslipidaemia and glucose intolerance ⁽¹²⁾. Urinary proteins are also believed to play a significant role in the development of kidney stones, through crystal enlargement and obstruction of the collecting system, through crystal adherence to renal epithelium, or through combinations of both these processes. In the early 1950s, Boyce and Sulkin were the first to extract protein from human calcium stones ⁽¹³⁾.

Role of Herbs in Nephrolithiasis

The use of botanical medicine is ancient, and plant chemicals are still the backbone of our pharmacopoeia because more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modification of chemicals first found in plants ⁽¹⁴⁾. Due to the high cost and adverse effects of minimally invasive techniques, and recurrence alternative treatment modalities with phytotherapeutic agents have become the mainstay of medical therapy. Recent studies have shown that the use of phytotherapy along with the watchful waiting approach can reduce the symptoms of nephrolithiasis and facilitate stone expulsion ⁽²⁾.

Table 1: Ethnobotanical distribution of plants used in kidney stone.

S.No.

Country

Plant

India

Sesbania grandiflora (L.)

Aerva lanata (L.)

Moringa oleifera Lam.

Asparagus racemosus Willd.

Rotula aquatica Lour.

Cyclea peltata (Lam.)

Tribulus terrestris L.

Musa sapientum L. (banana stem)

Mimosa pudica L.

Crataeva nurvala Buch-Ham.

Japan

Alisma orientale (Sam.)

Desmodium styracifolium

Quercus salicina

Brazil

Phyllanthus niruri L.

Costus spiralis

China

Polyporus umbellatus

Atractylodes macrocephala

Cinnamomum cassia (L.)

Iran

Nigella sativa L.

Plants with antinephrolithiatic activity

1. Bergenia ciliata

Family: Saxifragaceae

The antiurolithiatic effect of Bergenia ciliata (BCE) extract was evaluated for antilithiatic activity on adult female Wistar rats rendered Urolithiasis by administration of ethylene glycol. The kidneys excised from ethylene glycol treated group showed calcification inside the tubules which causes dilation of the proximal tubules. Co-treatment with BCE decreased the calcification in different parts of the renal tubules, prevented damages to the tubules and calyxes and also reduced and prevented the growth of urinary stones more effectively as compared to cystone treatment ⁽¹⁵⁾.

2. Bergenia ligulata

Family: Saxifragaceae

The crude aqueous-methanolic extract of Bergenia ligulata rhizome (BLR) inhibited calcium oxalate crystal aggregation as well as crystal formation in the metastable solutions and exhibited antioxidant effect against 1, 1-diphenyl-2-picrylhydrazyl free radical and lipid peroxidation in the in vitro. BLR caused diuresis in rats accompanied by a saluretic effect.

In an animal model of urolithiasis, developed in male Wistar rats by adding 0.75% ethylene glycol (EG) in drinking water, BLR (5–10 mg/kg) prevented calcium oxalate crystal deposition in the renal tubules ⁽¹⁶⁾.

3. Bergenia ligulata, Nigella sativa and Combination

Family: Saxifragaceae and Ranunculaceae respectively

Ethanolic extract of Bergenia ligulata and Nigella sativa and combination were evaluated for antilithiatic activity on rats rendered nephrolithiasis by administration of EG. After the administration of ethanolic extract of Bergenia ligulata and ethanolic extract of Nigella sativa and their combination to the group of rats urine analysis shows that the occurrence of stone was decreased when compared to the kidney stone control group and the combination (ethanolic extract of Bergenia ligulata and ethanolic extract of Nigella sativa) is as effective as the standard group (Cystine500 mg/kg) ⁽¹⁷⁾.

4. Ceiba pentandra

Family: Bombacaceae

Ethylene glycol and ammonium chloride feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and phosphate. Supplementation with aqueous and alcohol extracts of bark of Ceiba pentandra significantly reduced the elevated urinary oxalate showing a regulatory action on endogenous oxalate synthesis. The increased deposition of stone forming constituents in the kidneys of calculogenic rats was significantly lowered by preventive treatment using aqueous and alcohol extracts. The mechanism underlying this effect is still unknown, but is apparently related to increased diuresis and lowering of urinary concentrations of stone forming constituents ⁽¹⁸⁾.

5. Coleus aromaticus

Family: Labiatate

Water extract of the leaves of Coleus aromaticus Benth. was tested for its antiurolithiatic activity against calcium oxalate stones in male albino rats. Calcium oxalate stones were induced by feeding 3% w/w sodium oxalate along with normal feed. Administration of C. aromaticus water extract (0.5 g/kg and 1.0 g/kg, once, orally) reduced calcium (23% and 9% respectively) and oxalate (24% and 28% respectively) deposition in the kidney in calculi producing diet – fed rats ⁽¹⁹⁾.

6. Costus spiralis

Family: Zingiberaceae

The antiurolithiatic activity of the water extract of Costus spiralis Roscoe was tested on formation of calculi on implants of calcium oxalate crystals or zinc disc in the urinary bladder of rats. Oral treatment with the extract of Costus spiralis Roscoe (0.25 and 0.5 g/kg per day) after 4 weeks surgery reduced the growth of calculi. The effect, however, was unrelated to increased diuresis ⁽²⁰⁾.

7. Crataeva magna

Family: Capparaceae

The ethanol extract (400mg/kg body weight) reduced the elevated level of serum calcium , urine calcium, urine uric acid level, serum creatinine and oxalate, urine oxalate and kidney weight significantly with a marked increase in final body weight and urine volume output when compared with standard polyherbal drug (Cystone, 5ml/kg body weight) ⁽²¹⁾.

8. Dichrostachys cinerea

Family: Mimosaceae

Chronic administration of 0.75% (w/v) aqueous solution of ethylene glycol to male wistar rats resulted in hyperoxaluria, which is shown by increased elevation of calcium, phosphate, protein and oxalate. The serum levels of urea, uric acid and creatinine were remarkably increased in urolithatic rats indicating marked renal damage. However, ethanolic extract of root Dichrostachys cinerea lower the levels of oxalate as well as calcium excretion. .It restores phosphate level, thus reducing the risk of stone formation and hastens the process of dissolving the free form stones and prevents new stone formation ⁽²²⁾.

9. Grains of Eleusine coracana

Family: Poaceae

Chronic administration of 0.75% (v/v) ethylene glycol aqueous solution to male albino rats resulted in hyperoxaluria. Oxalate, calcium and phosphate excretion were grossly increased in calculi-induced animals. However, supplementation with aqueous and alcohol extracts of E. coracana grains significantly lowered the elevated levels of oxalate, calcium and phosphate in urine and kidney as compared to calculi-induced animal and also lowered the elevated serum levels of creatinine, uric acid and Blood urea nitrogen. Treatment with E. coracana grains extract restored phosphate level, thus reduced the risk of stone formation ⁽²³⁾.

10. Helianthus annuus

Family: Asteraceae

The effect of aqueous and ethanolic extracts of Helianthus annuus L. (Sunflower) leaves on calcium oxalate nephrolithiasis has been studied in male Albino Wistar rats. Ethylene glycol and ammonium chloride feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and phosphorus. Administration of aqueous and ethanolic extracts of Helianthus annuus Linn. Significantly reduces the elevated level of calcium oxalate ions which is consider as one of the inhibitor of crystallization ⁽²⁴⁾.

11. Herpestis monniera

Family: Scrophulariaceae

Methanolic and aqueous extracts of Herpestis monniera were found to be effective in reducing deposition of calcium oxalate in kidney. It also decreased urinary excretion of calcium and oxalate. Calcium oxalate stones were induced by feeding 0.75% ethylene glycol along with normal feed ⁽²⁵⁾.

12. Ichnocarpus frutescens

Family: Apocynaceae

Chronic administration of 0.75% (v/v) ethylene glycol aqueous solution to male Wistar rats resulted in hyperoxaluria. Supplementation with Ethyl acetate extract of Ichnocarpus frutescens root (250mg/kg) significantly lowered the elevated levels of oxalate, calcium, phosphate, BUN (Blood urea nitrogen), Creatinine and Uric acid ⁽²⁶⁾.

13. Jasminum auriculatum

Family: Oleaceae

Ethylene glycol feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and phosphate. Supplementation with aqueous and alcohol extracts of J. auriculatum flowers significantly lowered the elevated levels of oxalate, calcium and phosphate in urine and kidney as compared to cystone-treated animals ⁽²⁷⁾.

14. Lantana camara

Family: Verbenaceae

Ethanolic extract of Lantana camara L. (ELC) leaves were evaluated for antiurolithiatic activity against 0.75% v/v ethylene glycol and 2% w/v ammonium chloride induced calcium oxalate urolithiasis. Ethylene glycol and ammonium chloride administration increased the deposition of calcium and oxalate in the kidneys; also increased urinary excretion of calcium oxalate and creatinine. Treatment with ELC at 0.5 and 1.0 g/kg produced a significant dose dependent reduction in kidney calcium and oxalate deposition and dose dependent reduction in urinary calcium, oxalate and creatinine excretion ⁽²⁸⁾.

15. Lawsonia inermis

Family: Lythraceae

The hydroethanolic extract of Lawsonia inermis L. leaves (HELI) showed significant antiurolithiatic activity against calcium oxalate-type stones. Calcium Oxalate crystalluria could be induced by ethylene glycol and ammonium chloride in rats. When treated with HELI (200 and 400 mg/kg), showed significant reduction of calcium in urine. By inhibiting calcium excretion the drug decreases the supersaturation of the urine with respect to Cacium Oxalate and thereby decreased the risk of stone formation. Apart from urinary calcium excretion, decrease in serum calcium was evident in urolithiatic rats ⁽²⁹⁾.

16. Melia azadirachta

Family: Meliaceae

The aqueous extract of Melia azadirachta L.was studied against ethylene glycol induced nephrolithiasis in male albino wistar rats. The aqueous extract of M. azadirachta reduced urinary calcium, oxalate, phosphate and elevated urinary magnesium levels and urine volume ⁽³⁰⁾.

17. Mimusops elengi

Family: Sapotaceae

Hyperoxaluria induced by chronic administration of 0.75% (v/v) ethylene glycol increased oxalate, calcium, and phosphate excretion in male albino Wistar rats. Alcohol extract of M. elengi bark significantly lowered the elevated levels of oxalate, calcium and phosphate in urine and kidney, reduced the renal content of stone forming constituents, restores urinary phosphate level, thereby reducing the risk of stone formation ⁽³¹⁾.

18. Momordica charantia

Family- Cucurbitaceae

Antiurolithiatic activity of fruit extract of M. charantia L. was carried out on ethylene glycol (0.75% v/v) induced urolithiasis in rats. Administration of ethylene glycol significantly reduced the body weight, urine volume and pH of urine as compared to normal group. However, rats treated with cystone and M. charantia L. showed significant decreased in body weight, urine volume and pH of urine as compared to control group. Treatment with Aqueous Extract (200mg/kg, p.o) and Alcoholic Extract (250mg/kg, p.o) of fruits of M. charantia L. significantly lowered the increased levels of oxalate, calcium and phosphate in urine, reduced their retention in kidney and lowered the elevated serum levels of Blood urea nitrogen, creatinine and uric acid also ⁽³²⁾.

19. Moringa oleifera

Family: Moringaceae

Aqueous extract of bark of Moringa oleifera 400 mg/kg and 800 mg/ were evaluated for the antiurolithiatic potential in albino rats of Wistar strains. The method used for induction of stones in this study was zinc disc foreign body insertion technique supplemented with 1% ethylene glycol in drinking water. Administration of the extract has resulted in significant reduction in the weight of stones ⁽³³⁾.

20. Musa acuminata and Musa balbisiana

Family: Musaceae

Musa acuminata and Musa balbisiana plant extract was successful to reduce kidney stone in in-vitro condition. This is due to the presence of inorganic constituents like magnesium, potassium and nitrate. Magnesium nitrate and potassium nitrate are the major active constituents present in the Musa acuminata and Musa balbisiana stem juice was confirmed by chemical test and UV spectroscopy. Musa stem juice is effective to dissolve kidney stone ⁽³⁴⁾.

21. Pedalium murex

Family: Pedaliaceae

The ethanolic fruit extract of Pedalium murex to ethylene glycol intoxicated rats reverted the levels of the liver and kidney markers to near normal levels protecting liver and renal tissues from damage and also prevents the crystal retention in tissues ⁽³⁵⁾.

22. Pinus eldarica

Family: Pinaceae

Calcium oxalate nephrolithiasis in rats was induced by administering ethylene glycol (1%v/v). The prophylactic administration of P. eldarica fruit aqueous extract (500 mg/kg/day) significantly inhibited the formation of calculi without diuretic activity. Qualitative analysis of crystalluria and histopathologic examination showed that the administered dose of extract prevented stone formation in the kidneys significantly, by excretion of small particles from the kidney and reducing the chance of them being retained in the urinary tract. Therefore, the P. eldarica fruit’s extract can maintain calcium oxalate particles dispersed in the solution and thus, allow them to be eliminated easily from the kidney ⁽³⁶⁾.

23. Raphanus sativus

Family: Brassicaceae

The aqueous extract of Raphanus sativus showed antilithiatic activity on implants of calcium oxalate crystals or zinc discs in the urinary bladder of rats. The effect however is unrelated to increased diuresis or to a change of the muscarinic receptor affinity of the bladder smooth musculature to cholinergic ligands ⁽³⁰⁾.

24. Rubia cordifolia

Family: Rubiaceae

Ethylene glycol feeding resulted in hyperoxaluria, hypocalciuria as well as increased renal excretion of phosphate. Supplementations with (hydro-alcoholic extract of roots of Rubia cordifolia, HARC) significantly prevented change in urinary calcium, oxalate and phosphate excretion dose-dependently. The increased calcium and oxalate levels and number of calcium oxalate crystals deposits in the kidney tissue of calculogenic rats were significantly reverted by HARC treatment. The HARC supplementation also prevents the impairment of renal functions, indicating that the HARC can protect against ethylene glycol induced urolithiasis as it reduces and prevents the growth of urinary stones. Therefore, HARC is helpful to prevent the recurrence of the disease as it showed its effect on early stages of stone development. The mechanism underlying this effect is mediated possibly through an antioxidant, nephroprotection and its effect on the urinary concentration of stone-forming constituents and risk factors ⁽³⁷⁾.

25. Salix taxifolia

Family: Salicaceae

The aqueous extract of the bark of Salix taxifolia was tested for antilithiatic and diuretic activities. Urolithiasis was experimentally induced by implantation of a zinc disc in the urinary bladder of rats. A significant decrease in the weight of the stones was observed after treatment in animals with the aqueous extract. This extract caused an increase in the 24h urine volume ⁽³⁸⁾.

26. Terminalia arjuna

Family: Combretaceae

Preliminary studies on crude aqueous extract showed that Terminalia arjuna is capable of inhibiting formation of Calcium phosphate (CaP) and Calcium oxalate monohydrate (COM) crystals. Saponin rich fractions of other plants like, Herniaria hirsute has also been found to be a great inhibitor of calcium stone formation not only in vitro but in vivo too. Thus, after conducting a series of experiments it was observed that butanol fraction containing high amount of saponins was able to inhibit initial mineral phase formation of CaP and growth of COM crystals along with the crude aqueous extract of Terminalia arjuna ⁽³⁹⁾.

27. Tinospora cordifolia

Family: Menispermaceae

Ethanolic extract of T. cordifolia stem indicate the presence of alkaloids, glycosides, carbohydrates, phenolic compounds and tannins. The extract of plants inhibited the crystallization of Calcium oxalate in solution, thereby reduced supersaturation and the size of the particles. T. cordifolia also has claimed to have diuretic effect and diuretic effects may also reduce stone development ⁽⁴⁰⁾.

28. Tribulus terrestris

Family: Zygophyllaceae

T. terrestris extract contains high concentration of magnesium which inhibits calcium oxalate and calcium phosphate stone formation by inhibiting the formation and aggregation of calcium with oxalate and phosphate to form crystals in the urinary tracts. After the administration of T.terrestris extract, the levels of uric acid, oxalate, calcium, proteins and glycosaminoglycans in serum and urine changed significantly, while the citrate, inorganic phosphate and urine volume were not significantly affected. Therefore the T. terrestris extract may be useful in the treatment of urolithiasis ⁽⁴¹⁾.

29. Tridax procumbens

Family: Asteraceae

Ethanolic extract of T. procumbens (ETP) was evaluated against 0.75% v/v ethylene glycol and 2% w/v ammonium chloride induced calcium oxalate urolithiasis and hyperoxaluria induced oxidative stress in male albino rats. On administration, the dose dependent reduction in urinary and renal calcium and oxalate compared to the control rats indicates Tridax procumbens prevented urinary supersaturation of Calcium Oxalate. The antiurolithiatic effect of ETP may be attributed to its saponin principles as the extract was found to contain saponins in preliminary phytochemical screening and earlier researchers isolated, lupane type pentacyclic triterpene saponin derivative from T. procumbens. The effect of ETP in reducing calcium and oxalate excretion and deposition may be due to its flavonoid principles as earlier researchers isolated a flavonoid (procumbenetin) from T. procumbens ⁽⁴²⁾.

30. Cystone

This formulation has been approved by regulatory authorities in India and showed beneficial effects revealed by the improvement of various clinical symptoms, increased stone expulsion rate and the time required for expulsion as well as urine microscopy (WBC and RBC). The principal herbs of this Ayurvedic tablets include extracts of Didymocarpus pedicellata, Saxifraga lingulata, Rubia cordifolia, Cyperus scariosus, Achyranthes aspera, Onosma bracteatum, and Vernonia cineria. The beneficial actions of Ayurvedic formulation (Cystone) could be due to the complex spectrum of actions including antiinflammatory, antimicrobial, diuretic, antispasmodic, litholytic, and anticalcifying activities of its ingredients ⁽²⁾.

31. Jawarish Zarooni Sada

Jawarish Zarooni Sada is a reputed polyherbal preparation containing 15 ingredients like Cucumis melo Linn; Apium graveolens; Daucus carota; Trachyspermum ami Sprague; Feniculum vulgare Mill; Syzygium aromaticum Merr and Perry; Piper nigrum Linn.; Cinnamomum zeylanicum Blume. etc. It is a standardized pharmacopoeal preparation that has been described in Unani literature, to be diuretic, tonic to kidney and nephroprotective, useful in burning micturation, nephritis, and nephrotic syndrome like conditions ⁽⁴³⁾.

CONCLUSION:

Medicinal plants are used from centuries due to its safety, efficacy, cultural acceptability and lesser side effects as compared to synthetic drugs. Hence, to increase the acceptability and awareness among the people, there is an urgent need to develop trust and faith towards the safer indigenous system by establishing its validity in treatment for various diseases. Health care systems are going to become more and more expensive, therefore we have to introduce herbal medicine systems in our health care. The reviewed studies show that some possible mechanisms of action of plant extracts include an increased excretion of urinary citrate, decreased excretion of urinary calcium and oxalate or could be attributable to diuretic, antioxidant or antibacterial effects. The need of the hour is to develop an effective, safe and standardized herbal preparation for the management of nephrolithiasis. Systematic research needs to be undertaken, in an attempt to explore botanicals as alternative and/or complementary medicines for the treatment of nephrolithiasis.

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Received on 28.10.2012

Modified on 12.11.2012

Accepted on 19.11.2012

Research Journal of Pharmacognosy and Phytochemistry. 5(1): January–February 2013, 15-21

S.No.	Plant name	Family	Mechanism of Action
1	Achyranthes indica	Amaranthaceae	Inhibitory effect on crystal nucleation and aggregation, diuretic ⁽⁴⁴⁾.
3	Aerva lanata	Amaranthaceae	Reduced the activities of Glycolic acid oxidase and lactate dehydrogenase and oxalate levels to near normal control ⁽⁴⁵⁾.
4	Ammi visnaga	Apiaceae	Potent diuretic, khellin and visnagin prevent renal epithelial cell damage caused by oxalate and COM ⁽³⁰⁾.
5	Carica papaya	Caricaceae	Decreases the level of calcium phosphorus and oxalate in renal tissue and urine ⁽⁴⁶⁾.
6	Dolichos biflorus	Fabaceae	Decreases calcium phosphate precipitation ⁽³⁰⁾.
7	Herniaria hirsute	Caryophyllaceae	Decrease crystal size and increase COD, diuretic ⁽³⁰⁾.
8	Hygrophila spinosa	Acanthaceae	Lowered the level of calcium, phosphate, oxalate and protein excretion in urine ⁽⁴⁷⁾.
9	Nigella sativa	Ranunculaceae	Decreases urine concentration of oxalate and creatinine ⁽⁴⁸⁾.
10	Paronychia argentea	Illecebraceae	Reduced and prevented the growth of urinary stones ⁽⁸⁾.
11	Pergularia daemia	Asclepediaceae	Lowering of urinary concentration of stone forming constituents, diuretic ⁽⁴⁹⁾.
12	Phyla nodiflora	Verbenaceae	Reduce the supersaturation of urine with calculogenic ions, diuretic, antioxidant and restored the level of catalase and GSH ⁽⁵⁰⁾.
13	Quercus salicina	Fagaceae	Reduction in oxalate induced renal epithelial cell injury ⁽³⁰⁾.
14	Rotula aquatic	Boraginaceae	Lowers the level of oxalate and calcium excretion, restored phosphate level ⁽⁵¹⁾.
15	Smilax china	Liliaceae	Reduction of uric acid production by inhibiting Xanthine oxidase activity and enhancement of urate excretion by increasing urinary volume ⁽⁵²⁾.
16	Trachyspermum ammi	Umbelliferae	Maintain renal functioning; Reduce renal injury and decrease crystal excretion in urine and retention in renal tissues ⁽⁵³⁾.