Herbal Therapy for Urolithiasis: A Brief Review

Archana R. Dhole, Vikas R. Dhole, Chandrakant S. Magdum, Shreenivas Mohite.

Rajarambapu College of Pharmacy, Kasegaon

ABSTRACT:

Range of plants and plant-derived products are used in folk medicine for the treatment of urolithiasis as a prophylactic agent or as curative agent. Most of them found to be effective, but still the complete mechanism of action of these herbal drugs remains to be unclear. In present review we are discussing the, Diagnosis and various mechanism of action through which phytotheraeupatic agents exert their antiurolithiatic effect. Unlike allopathic medicines which targets only one aspect of urolithiatic pathophysiology, most of plant based therapy have been shown to be effective at different stages of stone pathophysiology.

Only a few studies have suggested some evidence for the efficacy of herbal medicines, however, most are not evidence-based. Some preclinical research has proved the efficacy of some of these herbs in urolithiasis. Precise understandings of the pathophysiology of disease and mechanism of action of these herbal medicines have great importance in development of effective and safe antiurolithiatic agent. Herbal medicines is efficacious and has lesser side effects compared to modern medicines and also reduce the recurrence rate of renal stone (4). Although the complete mechanism of action of these remedies are lacking but, plant based phytotherapeutic agents represent the majority used in medicine for urolithiatic.

KEYWORDS: Urolithiatic, Stone formation, Diagnosis and various mechanism of action.

INTRODUCTION:

Stone formation in the kidney is one of the oldest and most wide spread diseases known to man. Urinary calculi have been found in the tombs of Egyptian mummies dating back to 4000 BC ⁽¹⁾ and in the graves of North American Indians from 1500- 1000 BC ^(2). Reference to stone formation is made in the early Sanskrit documents in India between 3000 and 2000 BC ^(3). Calcium-containing stones, especially calcium oxalate monohydrate (Whewellite), calcium oxalate dehydrate (Weddellite) and basic calcium phosphate (Apatite) are the most commonly occurring ones to an extent of 75-90% followed by magnesium ammonium phosphate (Struvite) to an extent of 10-15%, uric acid 3-10% and cystine 0.5-1%. In most of the cases the commonly occurring stones are calcium oxalate or magnesium ammonium phosphate type. Many remedies have been employed during the ages to treat urinary stones. In the traditional systems of medicine, most of the remedies were taken from plants and they were proved to be useful though the rationale behind their use is not well established

Herbal medicines is efficacious and have lesser side effects compared to modern medicines and also reduce the recurrence rate of renal stone ⁽⁴⁾.Although the complete mechanism of action of these remedies are lacking but, plant based phytotherapeutic agents represent the majority used in medicine for urolithiasis. Unlike allopathic medicines which targets only one aspect of urolithiatic pathophysiology, most of plant based therapy have been shown to be effective at different stages of stone pathophysiology.

Currently known extracts exert their antilithogenic properties by altering the ionic composition of urine eg., decreasing the calcium ion concentration or increasing magnesium and citrate excretion. These remedies can also express diuretic activity or lithotriptic activity. Drugs with multiple mechanisms of protective action may be one way forward in minimizing tissue injury in human disease ^(5).

The use of plant products with claimed uses in the traditional systems of medicine assumes importance. An excellent account of the ‘Pashanabheda’ group of plants, claimed to be useful in the treatment of urinary stones is given by Narayana Swami and Ali ⁽⁶⁾, Bahl and Seshadri ⁽⁷⁾and Mukerjee et al ⁽⁸⁾.In India, in the Ayurvedic system ofmedicine, Pashanabheda is the Sanskrit term used for a group of plants with diuretic and antiurolithiatic activities (Pashana=stone; Bheda=break). These reviews mainly discussed various plants accredited with diuretic and antilithiasis activities and their botanical identification.

Mechanism of stone formation

· Physical concepts

The major factors of urolithiatic are super saturation and crystallization, inhibitors, complexions, promoters and matrix. The sequence of events leading to stone formation is as follows, As shown in figure no 1

Fig1: Mechanism of stone formation

· Saturation, Supersaturation and Thermodynamic Solubility Product

Pathogenesis of stone formation

Renal stone formation requires that stone forming crystalloids in urine come out of solution. Because crystalloids in solution are in equilibrium with crystalloids in the solid phase, a minimum condition is that urine be supersaturated with relevant crystalloids. This condition is often met: many healthy persons, probably the majority, have concentrations of calcium and oxalate in urine such that their activity product exceeds the solubility threshold (i.e. urine is supersaturated with these crystalloids). But urine has a strong inhibitory action that prevents crystallization and other stone forming processes. Three processes promote stone formation is Nucleation, Aggregation, and Crystal growth.

Nucleation:

Nucleation involves the association of crystalloids in solution (e.g. calcium and oxalate) to form a submicroscopic particle of about 100 atoms. The process requires energy and is facilitated when an external surface can serve as a lattice or anchor, thereby lowering the free energy requirement. Such a surface is provided by microscopic uric acid moieties, which function as promoters of CaOx stone formation.

• Homogeneous nucleation: The process by which the earliest crystal nuclei form in pure solutions is called homogeneous nucleation. It occurs in the absence of a surface or lattice.

• Heterogeneous nucleation: In this process the nuclei usually form on existing surfaces. Epithelial cells, urinary casts, red blood cells and other crystals can act as nucleating foci in urine.

Aggregation:

Aggregation is the process by which nuclei or larger structures adhere to one another. The initial nuclei can grow by the precipitation of additional salt on the lattice framework. It takes between 5 and 7 min for urine to flow from the glomerulus to the collecting duct. The earliest site of stone formation in human is the papillary duct or the collecting tubule, where the diameter is 50 to 200 μm. Once nuclei are formed they bounce apart from each other, float freely and become kinetically active. If they remain independent and float freely, they are washed away by urine flow. However, under certain circumstances, these nuclei come in close contact and due to chemical or electrical forces can bind to each other, a process called crystal aggregation.

Crystal growth:

A third process is crystal growth, in which crystalloids come out of solution to associate with the solid phase of growing crystal in a geometrically precise arrangement. The combination of crystal aggregation and crystal growth can explain the genesis of urinary calculi. Another process that may lead to CaOx stone formation is crystal retention. In most instances, crystal aggregates are too fragile to occlude the collecting duct long enough to give rise to a stone ⁽⁹⁾.

Promoters, inhibitors and complexing agents:

Each process of stone formation has specific promoters and inhibitors. Glycosaminoglycans promote crystal nucleation but inhibit crystal aggregation. Tamm- Horsfall protein, a product of the thick ascending limb of Henle, may act as a promoter or inhibitor of crystal formation depending on its state of aggregation.

Nucleation of CaOx is inhibited by magnesium and citrate, which forms soluble complexes with calcium and so reduces its effective concentration. a highly negatively charged molecule rich in aspartame and γ-carboxyglutamic acid residues, is potent inhibitor of CaOx crystallization in simple solutions. Aggregation is inhibited by uropontin is an aspartic acid-rich protein that shares the N-terminal amino acid sequences with human osteopontin. It is an important inhibitor of CaOx crystal growth. Citrate is a potent complex of calcium and reduces the ionic calcium in the urine with consequent reduction in the supersaturation of calcium salt. Citrate exerts maximum effect at a pH of 6.5. Magnesium, a divalent cation, complexes oxalate in the CaOx system⁽¹⁰⁾.

Signs and symptoms:

Kidney stones on accumulation in the urinary tract exhibit specific symptoms and the most specific one is severe pain in the. The common symptoms include,

· back pain on one or both sides

· Progressive severe colicky (spasm-like) may radiate or move to lower in flank, pelvis, groin, genitals, Nausea, vomiting,

· Urinary frequency/urgency, increased (persistent urge to urinate),

· Blood in the urine ,

· Abdominal pain,

· Testicle pain ,

· Fever,

· Chills and

· Abnormal urine colour ⁽¹¹⁾

Diagnosis (Investigations)

A. Urine analysis: Urine analysis in most patients with ureteral calculi reveals the presence of microscopic or gross hematuria.

A urine analysis should be done promptly after collection. The pH is best measured in a morning urine specimen after an overnight fast. If the pH of urine is higher than 7.6, urea splitting organisms must be present, for the kidneys cannot produce urine in this range of alkalinity. Such a finding strongly suggests that the stones are composed of magnesium ammonium phosphate. Fixation of the pH at 6 to 6.5 is compatible with renal tubular acidosis. Consistently low pH is a common cause of the formation of uric acid calculi.

B. Blood investigations:

· Complete blood count: The white blood count may be increased as a result of complicating infection. If renal function is not adequate, anaemia may be found.

· Renal function tests: Blood urea nitrogen and serum creatinine will give an indication of the functional status of the kidney.

· Serum blood chemistry: This investigation is usually done in recurrent stone formers. Fasting serum calcium and phosphates should be determined on 3 occasions. Serum proteins should also be estimated, since almost half of the calcium is normally unionized and bound to proteins. Hypocalcaemia is most commonly seen in association with osteolytic or disseminated malignant disease, especially cancers of the breast and lung, multiply myeloma, leukemia and sarcoidosis, but serum phosphate is usually normal. Serum alkaline phosphatase is increased in hyperparathyroidism only if bone disease is present. Elevated serum uric acid is found in 50% of uric acid stone formers.

· Parathormone assay is sometimes required if hyperparathyroidism is suspected.

C. Plain X-Ray: A plain film of the abdomen may show a calcific body in the region of the kidney or in the ureter. This constitutes merely presumptive grounds for the diagnosis. Ureteric calculi often looks like root of a tooth, sometime it may be confused with pelvic phleboliths which are usually round.

D. Excretory Urography: Excretory urograms are useful in the diagnosis of ureteric calculus. The ureterogram places the calcification in the ureter and also demonstrates dilatation.

E. Ultrasonography: Ultrasonography is a non-invasive method of demonstrating both ureteral calculi and the consequent hydronephrosis. Colour dropper ultrasound examination may demonstrate the increased resistive index in the obstructed kidney and asymmetry or absence of ureteral jets in urinary bladder.ons of the ureter above the stone.

F. MRI: The study has potential usefulness when patients have renal impairment or allergy to intravenous contrast agents and when X-rays are contraindicated. In contrast to CT, not only MRI is unable to visualize most stones but invitro studies have determined that this modality is not useful for characterizing the composition of stones.

G. Radioisotope methods: Radioisotope renography and scanning have contributed to the diagnosis of obstruction and location of calculus in a number of patients, particularly those who are otherwise sensitive to contrast media. This technique is helpful not only to the patients sensitive to the intravenous contrast and knowing the location of the calculus but also the degree of urinary obstruction is clearly defined.

H. Instrumental examination: Cystoscope and ureteroscope is seldom needed for the diagnosis of ureteral calculus.

I. Analysis of stone: Chemical analysis of renal calculi has been all but abandoned. Significant error may occur because qualitative and semi quantitative chemical methods are not accurate. Studies have shown that X- ray diffraction; Infrared spectroscopy procedures are accurate in detecting components of urinary calculi.

Herbal medicines Treatment-

Herbal medicines has several phytoconstituent and exerts their beneficial effects urolithiasis by multiple mechanisms. mentioned mechanism schematically represented in Fig. 2 and described briefly here along with plants or phytothereupatic agent exert their mechanism in particular way (Table 1).

Herbal Products Used In the Treatments of Urolithiasis.

Ammannia baccifera¹²,Blackcurrant (Ribes nigrum)¹³, Coleus aromaticus ¹⁴, Costus spiralis Roscoe¹⁵, Cranberry (Vaccinium macrocarpon)¹⁶, Cyclea peltata¹⁷, Herniaria hirsute^18-19, Lupeol and Betulin^20-21, Moringa oleifera²², Musa paradisiaca^23-24, Phyllanthus niruri^25-26, Raphanus sativus²⁷, Salix taxifolia²⁸, Tribulus terrestris^29-31, Varuna (Crataeva nurvala)^32-33, Crataeva adansonii³⁴,Aerva lanata^35-36, Bergenia ligulata rhizome³⁷, Nigella Sativa³⁸, Eleusine Coracana³⁹, Hibiscus sabdariffa⁴⁰, Quercus salicina Blume/Quercus stenophylla Makino⁴¹, Ammi visnaga⁴², Cynodon dactylon⁴³, Orthosiphon stamineus⁴⁴, Rotula aquatica, Commiphora wightii and Boerhaavia diffusa⁴⁵, Herniaria hirsuta and Agropyron repens⁴⁶Tephrosia purpurea⁴⁷.

Increasing interest and use of herbal or plant based medicine is apparent worldwide and especially in Western countries in recent years. These plant based therapy used as adjunct therapy particularly in urolithiasis as there are no satisfactory drugs in modern medicine which can dissolve the stone and the physicians remain to be depend on alternative systems of medicine for better relief. Currently known herbal drugs exert their antilithogenic effect by altering the ionic composition of urine, e.g., decreasing the calcium and oxalate ion concentration or increasing magnesium and citrate excretion. Most of these remedies also express diuretic activity or lithotriptic activity. Some of the herbal drugs reported to disaggregate of mucoproteins, which are actually binds the crystal to the renal cells. Some medicinal plants contain chemical compounds like GAGs which themselves possess an inhibitory effect in the crystallization of calcium oxalate. Antioxidant constituents of the plants also help in ameliorating the crystal/oxalate induced renal cell injury. Thus, antiurolithiatic activity of plants or herbal formulation may be due to synergism of their diuretic activity, crystallization inhibition along with antioxidant activity. Although these herbal medicine are popular in folk culture but rationale behind their efficacy and safety are not well established. Only a few studies have suggested some evidence for the efficacy of herbal medicines, however, most are not evidence-based. Some preclinical research has proved the efficacy of some of these herbs in urolithiasis. Precise understandings of the pathophysiology of disease and mechanism of action of these herbal medicines have great importance in development of effective and safe antiurolithiatic agent. In this respect the absence of this information provide a fruitful area for scientific research by willing investigators.

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Received on 15.12.2012

Modified on 25.12.2012

Accepted on 08.01.2013

Research J. Pharmacology and Pharmacodynamics. 5(1): January –February 2013, 06-11