SYSTEMATIC REVIEW OF MEDICINAL PLANTS AS POTENTIAL ANTI-UROLITHIATIC AGENTS

1. M. Tech Scholar, Biotechnology Department, G.B.P.I.E.T Ghurdauri, Pauri Garhwal (246194) Uttarakhand India. 2. Ph.D. Research Scholar, Biotechnology Department, G.B.P.I.E.T Ghurdauri, Pauri Garhwal (246194) Uttarakhand India. 3. Assistant Prof. Biotechnology Department, G.B.P.I.E.T Ghurdauri, Pauri Garhwal (246194) Uttarakhand India. 4. Associate Prof. Biotechnology Department, G.B.P.I.E.T Ghurdauri, Pauri Garhwal (246194) Uttarakhand India. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 15 June 2020 Final Accepted: 17 July 2020 Published: August 2020 Chemical compounds from different plant sources and plant products are referred to as ‘Phyto-constituents’. These are mainly extracted from the plants either in fresh or dried forms. These bioactive compounds are necessary mediator in the pathophysiology of kidney stones. Unlike allopathic medicine that target only one aspect, most of plant-based therapies have been shown to be effective at different stages of stone pathophysiology. A number of ethno-medicinal plants from different countries are used against urolithiasis. However, the knowledge of health-promoting plants is limited to few elderly people of villages. This review aims to highlight the current trends in research of ethnomedicinal plants possessing potential anti-urolithiatic activity. The results as presented in this review demonstrate the promising role of phyto-extracts in the management and treatment of kidney stones. The study would help investigators to identify lead chemical compounds or formulate herbal products responsible for urolithiatic activity.


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are possessed by plants that works in a synergistic manner in different stages of urolithiasis with no or less side effects and are available to a large population. Hence, compounds with properties such as antioxidant, antiinflammatory and antispasmodic are an obvious choice for the development of antiurolithiatic drugs [3] . Unlike allopathic medicines which majorly target only one aspect of urolithiatic pathophysiology, most of the plant-based therapies have been shown to be effective at different stages of stone pathophysiology. Currently known extracts exert their anti-lithogenic properties by multiple mechanisms like: [4] 1. Spontaneously transit of calculi by enhancing urine volume, pH and anti-calcifying activity (Diuretic activity). 2. Balance the inhibitor and promoters of crystallization in urine and affects the crystal nucleation, aggregation and growth (Crystallization inhibition activity). 3. Relieve the binding mucin of calculi (Lithotriptic activity). 4. Improve renal function. 5. Regulate oxalate metabolism. 6. Regulate the crystalloid colloid imbalance and improve renal function, thus prevents recurrence of urinary calculi. 7. Improve renal tissue antioxidant status and cell membrane integrity and prevents recurrence (Antioxidant activity). 8. Relieve pain, burning micturition and haematuria (Analgesic and anti-inflammatory activity).
Current therapies, involve extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy which are costly and pose a threat of recurrence and have serious after effects. Few drugs available are Thiazides, allopurinol and potassium magnesium citrate which are useful in the secondary treatment of urolithiasis. Lithogenic substances can be prevented by Cystone drug which is marketed in herbal formulation. Cystone causes disintegration of urinary calculi, followed by antibacterial activity which is useful in the prevention of stoneassociated urinary tract infections. Hence, compoundswhich directly inhibits CaOx crystallization in urine would represent a novel class of agents for the treatment of urolithiasis [5] . To determine the plant species acting as clinical diuretic, we reviewed all available literature with the intention of identifying these phyto-remedies with their beneficial traditional effect.
Epidemiology: -Urolithiasis affects all ages, sexes and races; however, it mainly occurs in men than in women, about one out of 20 people at some time in their lives are affected with it. Nevertheless, lifetime recurrence rate is higher in males, although the incidence of nephrolithiasis is growing among females. Global data suggested that kidney stone disease is frequent in western hemisphere (5-9%) in Europe, 13-15% in USA, 12% in Canada) than eastern hemisphere (15%). Asian countries like Saudi Arabia ruled by the disease with 20% occurrence rate. Whereas other Asian countries like India, China, Pakistan, Myanmar, Thailand, Indonesia, Philippines shows overall (4-20%) of kidney stones occurrence rate [6] . In Indian 13-14% of the population are affected by kidney stones. There are two 'stone belts' more prone to kidney stones, one belt stretched from Amritsar to Uttar Pradesh via Delhi and Agra. Another belt starts from Gujrat to Jabalpur in central India. In south India, Kerala is leading with kidney stone disease with prevalence rate of 2643 per 100,000 adults. This significant increase is due to the fact that the life style diseases like obesity and diabetes are more common and steadily increasing with risk rate of 43% in Kerala. There is positive relation between diabetes and kidney stone [7] .
Aetiology: -Stone formation is usually multi-factorial with more than one element increasing a patient's risk for stone formation. Hypertension and obesity increase rates are linked to nephrolithiasis which give rise to stone formation [8] . Stones are made up of multiple constituents but the first step in any stone formation is super-saturation of the urine. This result in crystallization of constituents and a nucleus for further stone growth and aggregation. This step is usually inhibited by compounds in our urine but in some patients, these are absent or defective. About 25% of patients with urolithiasis may be the result of a polygenic defect with partial penetrance. Several disorders that cause renal stones are hereditary and they are Renal Tubular Acidosis [9] and Cystinuria. Xanthinuria and dihydroxyadeniuria are rare hereditary disorders. Recent evidence has shown an increase in paediatric cases [10] . Increase, in water intake and urinary output decreases the incidence of stone formation in patients who are suffering from the disease.
Dietary intake of various foods and fluids that result in greater urinary excretion of substances that produce stones has a significant effect on incidence of urinary calculi. The risk of formation of urinary calculi was increased in most 472 affluent countries, regions, societies and individuals. These inhabitants have more disposable income to spend on animal protein, which leads to increased urinary concentrations of calcium, oxalate and uric acid [11] .

Material and Method: -
The present review involves the studies related to the urolithiasis and work carried out to understand the pathophysiology of kidney stones with possible activities of compounds to inhibit stone formation. Regular Collection of data was done by studying various research papers, PUBCHEM and Ayurvedic literature. In order to explore indigenous and traditional knowledge of people, questionnaire on documented plants for nephrolithiasis was used to understand more about plant properties, their secondary metabolite's structures. Functional properties were determined on the basis of GC-MS and HPLC analysis data which is already reported in literature.

Figure1
:-Morphology of human kidneys and areaof stone formation.According to the fixed-molecule component, stones start as statements of calcium phosphate (CaP) in the interstitial (apatite), become outwards arriving at the renal papillary surface, become presented to the pelvic urine and set up a core for the testimony of calcium oxalate (CaOx), prompting the development of CaOx stones joined to a CaP base, known as Randall's plaques. By differentiate, in the free-molecule instrument, for instance, CaP, uric acid orcystine crystal structure in the renal tubules, move with the urine, aggregate and attach to the terminal collecting duct. These plugs, called Randall's attachments or plugs, are presented to the pelvic urine. Accumulation of CaOx crystal on the CaP plugs prompts the arrangement of CaOx kidney stones [12] (constructed in biorender.com).

Mechanism of kidney stone development: -
Stone development is brought about by a strange mix of elements that impact the thermodynamic main impetus (supersaturation) and the (motor rate-controlling) forms engaged with the crystallization of the different stoneframing minerals. The foremost thermodynamic main thrust for the two phases is the level of supersaturation of the liquid inside which inception happens. Regardless of whether this happens intracellularly or extracellularly, the laws of crystallization science ought to apply. The processes of stone formation encompass a number of steps as described in Figure 2 473 Treatment and prevention of kidney stone: -Sodium intake increases calcinuria due to competition between sodium and calcium for passive reabsorption along the nephron. Low dietary salt intake thus decreases urine calcium. A daily sodium intake less than 2-3 mEq/kg/day for young children or less than 2.4 grams in adolescents or adults is recommended for patients with hypercalciuria or calcium-based stones.
At the point when dietary alteration is ineffective, pharmacological treatment ought to be started. The principal compelling hypocalciuric specialists are thiazide diuretics whose hypocalciuric activity upgrades calcium reabsorption inside the distal renal tubules. However, because of side-reactions including weakness, discombobulation, feebleness, musculoskeletal indications, or gastrointestinal objections, these are banned [13] . Another confusion is thiazide-incited potassium exhaustion, which causes intracellular acidosis and may bring about hypokalaemia and hypocitraturia [14] . Natural drugs could close a spot during this respect.
In hyperuricosuric uric acid stones and moderate-to serious hyperuricosuria with calcium oxalate stones, allopurinol may be useful in re-establishing ordinary urinary uric acid [15] . The utilization of probiotic (colonization with the oxalate expending microorganisms Oxalobacterformigenes) has not been overwhelmingly fruitful. The way that it lessens oxaluria in patients with essential hyperoxaluria recommends that it may advance intestinal oxalate discharge.
The only available medical treatment for primary hyperoxaluria is pyridoxine, which promotes conversion of glyoxylate to glycine [16] . Pharmacological treatment of cystinuria depends on its severity. For moderate cystinuria (<500 mg per day), raising urine pH (>6·5) with potassium citrate or sodium bicarbonate, and fluid intake (>4 L per day) can suffice. In more severe cystinuria, chelating agents should be added (alphamercaptopropionylglycine or tiopronin, angiotensin converting enzyme inhibitors, and d-penicillamine) to promote formation of mixed disulfidelinked compounds with cystine [17] . 474

Traditional medicinal plants: -
The advertised composite herbal formulations, Cystone (Himalaya Drug Company, India), Calcuri (Charak Pharmaceuticals, Bombay, India) and Chandraprabhabati (Baidyanath, India) have been broadly utilized clinically to break down urinary calculi in the kidney and urinary bladder. Pharmacological and clinical examinations completed on a composite natural plan, Trinapanchamool comprising of five herbal medications to be specific Desmostachyabipinnata, Saccharum officinarum, Saccharum nunja, Saccharum spontaneum and Imperatacylindrica was seen as compelling both as prophylactic in forestalling the arrangement and as remedial in dissolving the pre-shaped stones in rodents (albino rats). The anti-urolithiatic movement of this definition has been credited to its diuretic action. List of some chosen plants which have been utilized for the treatment of urolithiasis is given in Table 1 and Figure 3.

Cynodon dactylon (Gramineae):
Cynodon dactylon (L.) Pers. (Fam: Poaceae) is normally known as "Doob" in India (Arugampul: Tamil). It is a weed and has shifted restorative properties. Leaf, root and rhizome of the plant have been utilized in people medicat ion in various nations. In India the plants are utilized in the treatment of jungle fever, thirst, anorexia, consuming sensations in the body pruritus, unsuccessful labor and erysipelas, Ethanol extract of aerial parts of C. dactylon has marked CNS depressant and antioxidant activity  .

Asparagus racemosus (Liliaceae):
Parts utilized are roots. Regular name is Nunggarei-angouba. Its compound phyto-constituents are tannic acid, unpredictable oil, adhesive, saponin, flavonoids, asparagine, sitosterol, sapogenin, and asparagine. It is valuable in removing stones from the urinary tract. A. racemosus was explored for its inhibitory impact on stone development. Lithiasis was incited by controlling 0.75 % ethylene glycolated water to grown-up male albino rats (rodents) orally for 28 days. Ethylene glycol changed the urine science by raising the degrees of phosphate, oxalate, and calcium that are answerable for kidney stones. Raised degrees of phosphate, calcium, and oxalate were diminished by utilization of ethanolic concentrate of A. racemosus. Creatinine level was likewise decreased by this concentrate and magnesium level was expanded that is inhibitor of stone arrangement. Histological discovering gives that A. racemosus improves indications of disintegration incited by ethylene glycol. These perceptions show that A. racemosus represses ethylene glycol-incited stone development [19] .

Cedrus deodara:
This is the plant of Pinaceae family having very good medicinal value. In old ancient medicinal system, it was used as diuretic and for the treatment of kidney stones reported the petroleum-ether concentrate of the heart wood (PECD) for its diuretic and hostile behaviour to urolithiatic movement. The urolithiasis was tentatively incited by managing sodium oxalate (70 mg/kg, i.p) for 10 days. PECD (100 and 200 mg/kg) was orally gavaged every day 1 h before sodium oxalate (NaOx) organization for 10 days. In NaOx rewarded rodents, crystal was seen in urine under light microscope and rise of serum boundaries demonstrated the improvement of nephrolithiasis in the benchmark group. Associative organization of PECD for 10 days alongside NaOx forestalled raised serum biochemical levels because of the disposal of these in urine. Histology of the kidneys likewise showed that PECD treatment had secured against NaOx actuated nephroliathiasis. These outcomes acquired, affirmed the recipient impact of C. deodara in urolithiasis [20] .

Macrotyloma uniflorum:
It is a leguminous plant belonging to the family Fabaceae (alt. Leguminosae). It is an excellent source of iron and molybdenum and proteins. The seeds are ovoid and colour differs from light red, brown, or black sometimes with small, scattered black spots. Its therapeutic uses are known to Ayurveda and Uttarakhand conventional doctors for quite a long time. Different therapeutic arrangements are for the most part utilized as a tonic, astringent, diuretic and furthermore suggested in stiffness, neuralgia and other a few infections. Urolithiasis is a multifaceted procedure that happens from arrangement of many physicochemical occasions including super immersion, nucleation, development, total and maintenance inside the kidneys. Natural foodstuffs are more useful for livings because they encourage the repair mechanism in natural way [21] .  [22] .

Raphanus sativus:
Radish, biologically known as Raphanus sativus linn belongs to Brassicaceae family. It is an annual herb and used as a vegetable commonly known as Mooli. Radish is called by various names in many states, such as Mullangi, Moolika, Mooli etc. The fresh juice which is extracted from the leaves have properties like diuretic, laxatives, etc. The extract from the root has been stated to have antiurolithiatic property. Ascorbic acid, folic acid, and potassium are rich sources and fine source of vitamin B6, riboflavin, magnesium, copper, and calcium are found. They are very low in cholesterol because they are low in saturated fat. Researches have been done on the antimicrobial prospective in Raphanus sativus. "Raphanin" is a constituent which is present in seeds and leaves has already been reported for its antibacterial and antifungal activities. Radish is good source of vitamin C. Approximately all parts of the plant along with leaves, seeds and roots are also used in medicines for a variety of ailments including liver dysfunction and poor digestion, radish is used as medicinal food [23] .

Chenopodium album L:
Chenopodium album L. (family: Chenopodiaceae) is an herbaceous vegetable plant privately known as Bathua. The therapeutic property of this plant is basically present in leaves and seeds. The leaves are utilized in ethno-restorative practices for treatment of kidney infections and urinary stones. Ethnobotanical investigations of Aravalli area of Rajasthan (India) report the people restorative employments of cooked leaves of C. album in kidney stones and urinary plot inconveniences. Cooked leaves of C. album are utilized as conventional medication in the Shekhavati district of Rajasthan for treatment of urinary difficulties and colic. In Ladakh, leaves are additionally utilized customarily for controlling difficult urine. C. album is a significant restorative weed of Moradabad helpful in the treatment of urinary maintenance and kidney diseases [24] .  481

Phyto-compounds for prevention and treatment of Kidney Stones: -
The viability of a few dietary intercessions, as a great technique for assurance from kidney illnesses has been suggested by a few investigations either as a piece of, or separate from the acquired or hereditary elements. So as to limit the likelihood of kidney stone repeat alongside treating urolithiasis, a few wholesome plants and their phytochemicals can be utilized as dietary enhancements or included into the fundamental eating routine. In spite of the fact that there is an absence of information about the sub-atomic premise fundamental, the prophylactic impact of these phyto-therapeutics, various remedial spices and their parts are utilized for treatment of kidney issues. These phytomolecules also have specific mechanism of action ( Table 2). With in excess of 8,000 basic variations, phytophenols have been found in a few vegetables and organic products that comprise the most plentiful dietary cancer prevention agents, which show prominent oppressive exercises against the oxidative pressure related kidney dysfunctions. The antioxidative impact of primary cell reinforcements, epicatechin and catechin found in plants sources like grape seeds and green tea [33] is licensed prevalently to either metal chelating and radical searching properties or to the patching up consequences for chemicals and interpretation factors, which gives protecting impact against arrangement of renal stones, oxidative pressure associated (with renal disappointment, and renal wounds) [34] . In COM-rewarded NRK-52E renal proximal cylindrical cell line, catechins restored the proteolysis of caspase 3 and mitochondrial layer potential as a result of its expanded SOD movement. This raised SOD action of catechins effectively delivered inhibitory impacts on the renal papillary calcification and improvement of COM papillary calculi [35] . A basic catechin, epigallocatechin-3-gallate (EGCG) intensely decreased the capacity of Madin-Darby canine kidney (MDCK) cells to tie to calcium oxalate monohydrate crystals which after organization, diminished the α-enolase protein articulation (liable for official) on the renal cylindrical cell surface which was chiefly liable for such a weakening response [36] . Dosmin, a flavonoid glycoside, shows defensive impacts in the kidney against oxidative pressure, nephro-poisonousness and diabetic nephropathy. Generally found in vegetables and citrus organic products, dosmin is a polyphenol with natural anti-urolithiatic action.
Table2:-Phytoconstituents with promising anti-urolithiatic activity and their possible activity.

S.No. Compound names Molecular formula
Possible Activities References Asperuloside-2 C18H22O11 Anti-obesity, Antimetabolic syndrome [40] Conclusion:-Dietary plants have been proved to play major role in treating kidney stone diseases however the underlying mechanism used by these phytoconstituents is not well studied. Literature surveys provide evidence of the large number of in vitro and in vivo studies that were performed to analyze the effects of dietary plants extract in the management of kidney stone diseases. However, till date limited number of human studies has been done to establish the role of particular phytoconstituents from these dietary plants in the prevention of urolithiasis. Plants, fruits and vegetables whose efficacy have been confirmed by clinical trials were Agropyron repens L.,