2. REVIEW OF LITERATURE:
2.1 Urinary System
The urinary system comprises of one pair of kidney, ureter, urinary bladder and urethra (Figure1).The kidneys
acts as excretory organ in human-beings which removes wastes, filter the blood and produces the urine.
Urinary system acts as a utility to empty out excretory product from the kidneys, apart from filteration and
elimination of waste from body, it also maintains water homeostasis, ions , pH and blood pressure. about one
a pair of litres of urine are made on a daily basis in a very healthy human though this quantity could vary in
keeping with circumstances appreciate fluid intake. The ureters propel urine from the kidneys into the bladder
by peristaltic contraction of the muscular walls. Peristalsis is stirred up by the presence of the urine. the
bladder acts as reservoir of urine. The accumulated urine in the bladder is excreted through urethral
opening Marieb and Hoehn, 2007.
Figure: 1 Diagrammatic Illustration of Urinary System
2.2 Common Renal Disease & Disorders Retrived from National Institute of Diabetes and Digestive and Kidney Diseases
1. Renal stone or renal calculi is the development of solid crystals of dissolved material in urine. They can
shift from granular size to bigger size. Kidney stones can frame anywhere in the urinary tract. They become
bigger and causes impediment in the urinary framework. They can bring about different distress like ureter
impediment, pain during urination, felt in flank and lower stomach area pain.
2. Diabetic nephropathy: Diabetic nephropathy is a dynamic renal malady described by increment in
excretion of albumin in urine.It is the major cause in the development of chronic renal disease. This disease is
considered as major cause of death in case of end stage kidney disease.
3. Nephritis: Nephritis is irritation of the nephrons in the kidneys which can prompt glomerulonephritis.
Nephritis is regularly caused by infections, toxins, and auto-immune infections. It can be caused by
contamination, however is most usually caused via immune system issue that influence the significant organs.
4. Glomerulonephritis: Irritation of the glomerular can be caused by immunologic irregularities, drugs or on
the other hand toxins, vascular disarranges, and fundamental maladies. Glomerulonephritis can be intense,
constant or dynamic. Two noteworthy changes in the urine are particular of glomerulonephritis: hematuria and
proteinuria with albumin as the significant protein. There is additionally a decline in urine as there is a
reduction in GFR (glomerular Filtration rate). Renal disappointment is related with oliguria.
5. Pyelonephritis: At the point when a disease of the renal pelvis and calices, called pyelitis, spreads to
include the Rest of the kidney also, the outcome is pyelonephritis. It for the most part comes about because of
the spread of fecal bacterium escherichia coli from the butt-centric district superiorly through the urinary tract.
In extreme cases, the kidney swells also, scars, abscesses frame, and the renal pelvis load with discharge. Left
untreated, the contaminated kidney might be extremely harmed, however organization of anti-infection agents
more often than not accomplishes an aggregate cure.
6. Diabetes insipidus: This is caused by the lack of or decline of ADH. The individual with diabetes Insipidus
(DI) has the failure to pack their urine in water limitation, thus they will void up 3 to 20 Liters/day. There are
two types of DI, neurogenic and nephrogenic. In nephrogenic di the kidneys don’t react to ADH. Generally the
nephrogenic di is described by the weakness of the urine concentrating capacity of the kidney alongside
convergence of water. The reason might be a hereditary characteristic, electrolyte confusion, or symptom of
medications, for example, lithium. In the neurogenic DI, it is generally caused by head damage close the
7. Renal failure: Uremia is a disorder of renal disappointment and incorporates raised blood urea and
creatinine levels. Intense renal disappointment can be turned around if analyzed early. Intense renal
disappointment can be caused by serious hypotension or extreme glomerular sickness. Symptomatic tests
incorporate bun and plasma creatinine level tests. It is thought to be endless renal disappointment if the decay
of renal capacity to under 25%.
Acute renal failure: Acute renal disappointment (ARF) is a quickly dynamic loss of renal capacity, for the
most part described by oliguria (diminished urine production, evaluated as under 400 ml for each day in
grown-ups, less than 0.5 ml/kg/h in youngsters or under 1 ml/kg/h in babies); and liquid and electrolyte
Chronic renal failure:Chronic renal disorder (CRF) additionally known as chronic renal disorder also
can develop slowly and, initially, show few symptoms. CRF could results from chronic nephritis,
pyelonephritis, polycystic renal disorder or traumatic loss of excretory organ tissue.
8. Urinary tract infections (UTI’S): The second most basic kind of bacterial contaminations seen by
wellbeing mind suppliers is UTI’S. Out of the considerable number of microscopic organisms that colonize and
cause urinary tract contaminations the huge weapon is escherichia coli.
9. Cystitis: Inflammation of the urinary bladder caused by the microorganism infection. The microorganism
usually ascend to the excretory organ from the lower tract, however they’ll conjointly enter the kidneys
through the blood or lymph.
10. Urinary retention: The strange collection of urine inside a urinary bladder. The condition comes about
from the powerlessness to void.
2.3 Disease Profile: Urolithiasis
Figure 2: Stones in the Urinary System.
The formation of stone in the urinary system, i.e. in the kidney, ureter, and urinary bladder or in urethra is
called urolithiasis. ‘Urolithiasis’ = ouron (urine) and lithos (stone) Vijaya et al., 2013 . It is known as
ashmari which means stone and small powder like pieces called as sharkara or sikata i.e. gravels.
The stone formation is the complex physio-chemical process which involves the sequence of
events as urinary saturation- supersaturation –nucleation- crystal growth- crystal retention-stone
formation rathod et al., 2015. Urinary stones are polycrystalline solidifications happening in the urinary
tract of people and creatures like bones and teeth, they are biominerals while the non-obsessiveresults of
biomineralization, framed in hereditarily decided procedures, show a high level ofnatural association.
Uroliths are an uncommon case. their development is administered by pathoanatomical and
physicochemical factors. Hesse and Stuttgart 1982. Around 97% of urinary stones are found in the kidneys
and ureters (kidney stones), the rest of the 3% in the urinary bladder and urethra Bichler et al., 2007. Stone
formation is one amongst the painful urologic disorders that occur in around12% of the global population
and its re-occurrence males 70-81% and 47-60% in female.Soundararajan et al., 2006.
2.3.1 Stones & Its Types:
Classification of kidney stones is done according to their chemical composition. Majority of the stones are
calcium containing stones occurring to an extent of 75-80% followed by struvite to the extent of 10-15%,
uric acid 3-10%, and cysteine 0.5-1%Williams and Wandzilak, 1989.
Figure 3: Percentage of Renal Stone Types
Calcium oxalate stone: Calcium salt is that the predominant element of most stones accounting for
quite 80% of stonesEskelinen, Ikonen and Lipponen, et.al.,1998.
Calcium salt exists in 3 totally different hydrous forms particularly calcium oxalate monohydrate
(COM), calcium oxalate dihydrate (COD) and calciumoxalate trihydrate (COT). The monoclinic COM
is that the thermodynamically most stable section, followed by the triclinic COT and the tetragonal
COD Pietrow and Karellas, 2007; Philip and Hall, 2009; Yadav et al., 2011. The most common
metabolic abnormalities related to Ca stone formation are hypercalciuria and hyperoxaluria
followed by hyperuricosuria, hypomagnesuria and hypocitraturia Tekin, Tekgul and Atsu et al., 2001.
Figure 4: Calcium Oxalate Stones
Calcium phosphate stone : Calcium phosphate stones develops in alkaline pH with the value of pH
greater than 7.2 . These types of stones are usually associated the patients with hyperparathyroidism,
renal tubular acidosis and urinary tract infections Skolarikosa et al., 2015.
Figure 5: Calcium Phosphate Stones
Magnesium ammonium phosphate (struvite) stone: struvite stones are caused by an infection of the
tract with urease-producing organisms comparable to Pseudomonas enteric bacteria proteus
staphylococci and E. coli species Williams Rodman and Peterson 1984. It’s a crystalline substance
composed of magnesium ammonium phosphate. These stones happens once urinary pH larger than
seven Chauhan and Joshi 2013
Figure 6: Struvite Stones
Uric acid stones : People with certain metabolic abnormalities; including obesity may produce uric
Stones Johri et al., 2010. This type of stones are smooth, round, yellow-orange and nearly
radiographically transparent unless mixed with calcium crystals or struvite . Diets high in purines,
especially those containing meats and fish, result in hyperuricosuria, and, in combination with low
urine volume and low urinary pH, can exacerbate uric acid stone formation Tiwari et al., 2012. They
account for 5 – 10% of all renal stones. They are more frequent in gouty patients. In a study of gouty
patients, it is found renal calculi in 66% of their cases. The chances of stone formation increase with
increasing serum uric acid levels and urine excretion rates Malhotra et al., 1973.
Figure 7: Uric Acid Stones
Cystine stone : Cystinuria is an autosomal recessive disorder that causes impaired renal tubular
reabsorption of cystine, ornithine, lysine and arginine. This leads to increased urinary excretion of
these compounds, but the only one that forms stonesis the cystine. These stones represent only a small
percentage of kidney stones. They form in people with a hereditary disorder that causes the kidneys to
excrete Liitjos et al.,2005.
Figure 8: Cystine Stones
2.3.2 Stone composition
Chemical Name Mineral Name Chemical Formula
Monohydrate (Com) Whewellite CAC2O4. H2O
Dehydrate Wheddelite CAC2O4. 2H2O
Basic Calcium Phosphate Apatite CA10(PA4)O6 .(OH)2
Phosphate Carbonite Apatite CA5(PA3)O3 .(OH)
B- Tricalcium Phosphate Whitlockite CA3(PA3)O2
Phosphate Dahllite CA5(PO4)3OH
Phosphate Brusite PO4..2H2O
Calcium Carbonate Aragonite CACO3
Octa Calcium Phosphate CA8H2(PO4).6H2O
Uric Acid Uricite C5H4N4O3
Uric Acid Dehydrate Uricite C5H4N4.2H2O
Ammonium Urate NH4C5H3N4O3
Sodium Acid Urate
Phosphate Struvite MGNH4PO4.6H2O
Foreign Bodies Calculi Magnesium Ammonium
Phosphte Monohydrate Dittmarite MGNH4(PO4).1H2O
Gypsum Calcium Sulphate
Zinc Phosphatetetrahydrate CASO4.2H2O
Table 1: Stone Composition (European Association of Urology 2015)
2.3.3 Pathophysiology of Stone Formation
Urine from healthy humans consists of an oversized amount of nitrogenous compounds, as well as
0.5 M urea, additionally as inorganic ions. Urine is neutral to slightly acidic, and beneath these
conditions, ammonia becomes protonated with the concomitant generation of hydroxide, that will
increase urinary pH. Kidney stones contain calcium, oxalate, phosphate, magnesium, uric acid and also
the formation of urinary calculi involves a crystallization method. Crystallization could be a
physiochemical method involving a modification of state from solution to solid. The supersaturation,
that could be a measure of the energy accessible for this, could be a crucial factor and governs all
aspects of crystallization resembling nucleation, growth and aggregation processes Kavanagh, 2006.
Figure 9: Schematic Representation of Stone Formation
Nucleation is the establishment of the smallest unit lattice species, it is the first step of crystal
formation. The term supersaturation refers to a solution that contains more of the dissolved material
that could be dissolved by the solvent under normal circumstances. Nucleation involves the
association of crystalloids in solution to form a submicroscopic particle of about 100 atoms. The
process requires energy and is facilitated when external surface can serve as a lattice, thereby lowering
the free energy requirement. Such a surface is provided by microscopic uric acid moieties, which
function as promoters of CaOx stone formation Finlayson,1978; Khan et al., 1999.
Homogeneous nucleation: The process by which the earliest crystal nuclei form in pure solution is
Called homogeneous nucleation. It occurs in the absence of a surface or lattice Finlayson, 1978.
Heterogeneous nucleation: The process in which the nuclei are formed on existing surfaces.
Epithelial cells, urinary casts, red blood cells, and other crystals can act as nucleating foci in urine
Crystal growth: Once the nucleus has reached a critical size and relative super saturation remains
above one, the overall free energy is decreased by adding new crystal components to the nucleus.
This process is called crystal growth. Crystal growth is one of the prerequisites for particle
Formation and thus for stone formation. Although crystal growth is definitely a step in CaOx renal
Stone formation, the process of growth is so slow that crystals cannot become large enough to
Obstruct the renal tubules Finlayson et al., 1984.
Crystal aggregation: Aggregation or crystal agglomeration is the process in crystal nuclei bind
to one another to form larger particles. 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 collecting duct,
where the diameter is 50 to 200 µm. In this processcrystals in solution stick together and form a
larger particle. 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, chemical or electrical forces bind these nuclei to each
other, a process called crystal aggregationHess et al., 1993.
5486402280920Figure 10: Flow diagram of renal stone formation
00Figure 10: Flow diagram of renal stone formation
-1149350383540002.3.4 Mechanism of Stone Formation
A stone can form only when urine is supersaturated with respect to its constituent crystals. urine of most
normal people is supersaturated with respect to calcium oxalate, so all people can form such stones.
however, normal urine is not supersaturated with respect to uric acid, cysteine or struvite. conditions that
raise calcium oxalate supersaturation raise the risk of calcium oxalate stones NIH Consens Statement,
Treatment ; Prevention March 1998. Formation of renal stones is a consequence of increased urinary
supersaturation with subsequent formation of crystalline particles. Since most of the solid particles
crystallizing within the urinary tract will be excreted freely, particle formation is by no means equivalent to
symptomatic stone disease. However, when solid particles are retained within the kidney, they can grow to
become full-size stones Finlayson et al.,1984. Crystals can be retained at many sites in the kidneys and
undergo the size-enhancing process of growth and aggregation. In order for stones to be formed, not only
do crystals need to be retained with in the kidney, but they must be located at sites from which crystals can
cause ulceration at the papillary surface to form a stone nidus. Renal tubular injury promotes crystal
retention and the development of a stone nidus on the renal papillary surfaceKhan et al., 1996. Crystals
attached to the surface of renal tubular cells are taken into the cells .and then the crystal aggregates, grow,
and ?nally a stone is formed.
2.3.5 Etiology of Stone Formation
A few variables which increment the danger of creating kidney stones, incorporate inadequate liquid
admission, lack of hydration, lessened urine flow/volume, high calcium, oxalate rich eating regimen or
low citrate in urine and a few medicinal conditions Kumar et al., 1991. Renal lithiasis is a
multifactorial disease and is strongly related to dietary lifestyle habits and practices. Obesity and
weight gain increases the risk of kidney stone formation Taylor et al.,2005; Lieske, 2014.
Increased rate of hypertension and diabetes which are linked to nephrolithiasis, also
additionally add to an expansion in stone formation.. Dietary factors in general which increase in stone
formation. Dietary factors in general which increase the risk of stone formation include low fluid
intake,a high dietary intake of animal protein, sodium refined sugars, fructose, high fructose corn syrup,
oxalate, grapefruit juice, apple juice, and cola drinks Borghi et al.,2006.
A protein-rich diet that enhances the chance for calcium salt and higher urinary tract stones. A
nutritionally-poor diet that’s low in animal protein, Ca and phosphate. However high in cereal also
leads to the development of bladder stones in children in under-developed countries Rizvi et al.,2002;
Grases et al., 2006.
Stone formers consumed less calcium, presumably to prevent more stones, and
displayed a bone mineral responsiveness to calcium loss. This lowered calcium consumption alters
bone responses in a direction that can predispose to mineral loss and eventual fracture. Sodium intake
contains a major risk issue for stone formation in sight of the actual fact that top urinary sodium
excretion has been repeatedly related to hypercalciuria in adult and pediatric population Menon and
An inverse relationship happens between nephritic potassium and calcium excretion that
brings attention to the role of potassium rich foods like vegetables and fruits within the interference of
stone formation. People with body mass index (BMI) greater than or equal to 27 had lower estimated
glomerular filtration rates (GFR) and had kidney stones Asplin et al., 2003; Grases et al., 2002.
Foods rich in oxalate are poorly absorbed from the gut. The exact etiology of increased
urinary oxalate excretion remains to be elucidated. Increased dietary protein intake, altered renal
excretion and increased hepatic oxalate production have all been postulated as possible causes. Renal,
urologic, endocrine and metabolic disorders may also lead to the development of crystallized materials
in the urinary system Menon and Koul, 1992; Holmes and Kennedy, 2000. Metal and non-metal
present in hard water at higher concentration might influence the outcome of the disease. Experiments
in rats have shown that fluoride once fed at high levels accelerated the incidence of CaOx crystalluria
and enhanced the incidence of bladder stone diseases considerably. The studies suggest that other
condition being conducive, excess intake of fluoride (through water) might aggravate the situation. This
is supported by reports that in punjab the incidence is high in areas where fluoride content in drinking
water is high Chitme et al., 2010.
2.3.6 Risk Factors for Urolithiasis
a) Age & Sex:
Normal women excrete more citrate and less calcium than normal men, perhaps a reason why men
form stones more often. Four of every five patients with stones are men. In both sexes the peak age of
onset is between 20 and 30 years NIH consens statement. in older women and men, greater intakes
of dietary calcium, potassium and total fluid reduce the risk of kidney stone formation, while
supplemental calcium, sodium, animal protein and sucrose may increase the risk Curhan et al., 2005,
Curhan et al., 1997.
b) Body Mass & Size:
The association between calcium intake and kidney stone formation varies with body size Taylor et
al., 2004. Larger body size may result in increased urinary excretion of calcium, oxalate and uric acid,
thereby increasing the risk for calcium-containing kidney stones. obesity and weight gain increase the
risk of kidney stone formation. The magnitude of the increased risk may be more in women than in
men Taylor et al., 2005.
Genetically inherited disorders account for some stone formation. Low urine pH from hereditary
causes promotes uric acid stones. Cystine stones occur only in cystinuria, a hereditary disorder of
amino acid transport. A slightly higher rate of renal stone disease emerged in white caucasians than in
blacks.Ramello et al.,2000.
d) Environmental Factors:
Environment plays a very important role in stone formation. Persons who live in a hot, arid climate,
and those who work outdoors in hot weather are at increased risk for stone formation due to excessive
fluid loss from sweating.Schade et al., 2010; Pearle et at., 2012; Romero et at., 2010.
e) Dietary Factors:
These are primarily related to fluid intake and dietary calcium. Drinking less than 1litre of fluids daily
is associated with an increased risk for forming stones; this risk is magnified when the urine volume is
also decreased. Increased dietary intake of animal protein can elevate the risk for formation of uric acid
stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate. Low dietary
calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also
exacerbate the risk for stones Romero et al.,2010; Curhan 2004; Grases et al.,2006.
f) Associated Diseases:
Bowel disease: Several bowel diseases increase calcium phosphate supersaturation. The Propensity
for renal stone formation is increased in patients with crohn’s disease due to increased Urinary
oxalate and decreased urinary magnesium and citrate concentrations Bohles et al.,1988.
Diabetes Mellitus: It is a risk factor for the development of kidney stones. However, additional
studies are needed to determine if the increased risk of diabetes mellitus in stone formers is due to
subclinical insulin resistance Taylor et al., 2005.
Others: People being regularly dehydrated or those having very poor mobility (e.g., being
confined to bed) have more chances to suffer from nephrolithiasis. A high frequency of stone
formation among hypertensive patients has been reported Romello et al., 2000. Whereas
cappuccio et al has already proved that an independent clinical association exists between
the occurrence of urolithiasis. And hypertension and the increased urinary calcium excretion
commonly detected in hypertension may be the pathogenetic link Cappuccio et al.,1990.
2.3.7 Stone Promoters ; Inhibitors.
Various physiological and biochemical components can promote or inhibit the stone formation.
Various such factors are enumerated in table.2
Urine contains substances that influence crystallization processes, and therefore regulate stone
formation. Substances that increase crystallization are termed promoters Coe et al., 1994. On the cell
surfaces of the kidney, cell debris, protein aggregates and other crystals may provide analogous site for
nucleation and promote it. Crystals of COM, uric acid and calcium phosphate may promote
heterogeneous nucleation. Ionic calcium is also a factor that may promote the formation and growth of
intra renal calcium. Hypercalciuria can decrease inhibitor function and lead to crystallization.
furthermore, cellular responses to newly formed crystals and factors that modulate these crystal-cell
interactions could stimulate initiation of an intra-renal stone formation Gupta et al., 2011.
Inhibitors: Inhibitors of calcium stone formation prevent crystal growth and aggregation by coating
the surface of growing calcium crystals or by complexing with calcium and oxalate Frietas et al.,
Citric Acid: Citric acid is a tricarboxylic acid that circulates in blood complexed to calcium,
magnesium and sodium at physiological pH at 7.4. Most of the circulating citrate is derived from
endogenous oxidative metabolism. The most established effect of citrate in urine is to complex with
calcium, thereby reducing the concentration of CaOx. Citrate is an inhibitor of crystallization and has
also been shown to be an important inhibitor of CaOx agglomeration Kok et al., 1986.
Pyrophosphate: Pyrophosphate and diphosphate inhibits the precipitation of calcium phosphate and
also inhibit the growth of apatite crystals. Robertson,1973. At low concentrations, 16µm,
pyrophosphate inhibits calcium oxalate monohydrate crystal growth by 50% Schwille et al., 1988.
Magnesium: Magnesium decreases the urinary saturation of calcium oxalate by combining with
urinary oxalate to form soluble magnesium oxalate Goldwasser et al., 1986. Oral intake of
magnesium appears to decrease the oxalate absorption and urinary excretion, in a manner similar to
calcium by binding to oxalate in the gut Liebman and Costa, 2000.
Osteopontin(uropontin): Osteopontin(OPN) is a negatively charged aspartate rich protein
synthesized within the kidney. This protein is involved in various biological processes including
inflammation, leukocyte recruitment, wound healing and cell survival. This protein also inhibit the
growth of CaOx crystals in a supersaturated solution Brien et al., 1994; Ophascharoensuk et al.,1999.
Tamm-Horsfall Protein: Tamm-horsfall protein (THP), also known as uromucoid, is an 80-kda
glycoprotein, isolated by tamm and horsfall. It is the most abundant protein in the urine of normal
mammals. May act on nucleation and inhibit crystal aggregation Carvalho et al., 2002. This protein is
extensively synthesized in thick ascending loop of henle Bachmann et al.,1991.THP is one of the
first line of host defences against both renal stone formation and bacterial infection Huang et
Glycosaminoglycans: Glycosaminoglycans (GAGS) identified as one of the macromolecules present
in the stone matrix, as heparin sulphate and hyaluronic acid Torzewska and Rozalski, 2014.They are
believed to play an important role in calcium oxalate crystallisation. They have the ability to inhibit
the growth and aggregation of calcium oxalate crystals by blocking the growth sites. They also prevent
crystal adhesion to renal cells, which is an important step in renal stone formation.Dussol,1996.
Nephrocalcin (NC) is an inhibitor of calcium oxalate monohydrate (COM) crystal aggregation in
Normal urine Hess et al., 1989.the 14 kd (kilodalton), gla-containing glycoprotein NC also strongly
Inhibits crystal aggregation Hess, 1991.
Table 2: Stone Promoters And Inhibitors
Uric Acid Osteopontin(Uropontin)
Cystein Renal Lithostathine
Low Urine pH High Urine Flow
Tamm-Horsfall Protein Urinary Prothrombin Fragment I
Low Urine Flow Glycosaminoglycans
2.3.8 Clinical Features (Kumar et al., 2012; Portis et al., 2001)
Flank Pain: Pain in the side, due to kidney pain
Hematuria: Blood in the urine
Renal Colic:Intense, cramping pain due to stones in the urinary tract
Urinary Tract Infections
Pyuria: Pus in the urine
Nausea and Vomiting
2.3.9 Diagnostic Evaluation
Standard evaluation includes a detailed medical history and physical examination Wimpissinger,turk ,
Kheyfets, et al., 2007. Confirmation of the presence of stones is vital. The presence of renal calculi is
diagnosed by the symptoms explained by the patients and the stones are recognized in the body
Suman et al., 2011.
Diagnostic Imaging: Ultrasound should be used as the primary diagnostic imaging tool, although
pain relief, or any other emergency measures should not be delayed by imaging assessments. It is safe
(no risk of radiation), reproducible and inexpensive. It can identify stones located in the calices, pelvis,
and pyeloureteric and vesicoureteric junctions Ray,Ghiculete,Pace, et al.,2010.
Intravenous pyelography (IVP) is a technique in which iodinated contrast media is administered to the
patient intravenously that travels in blood and ultimately gets filtered from the kidneys and cleared
from the ureters and bladder during micturition. Meanwhile, series of x-rays of the kidneys, ureters and
bladder are taken at defined intervals where the contrast media provides a clear picture of the structure
and function of the urinary system and of any obstruction or stone therein Strohmaier 2015.
Computed Tomography (CT) utilizes x-ray beam for imaging, which is rotated around the patient’s
body to produce series of images followed by three dimensional reconstructions of the images.
Noncontrast helical CT has become increasingly popular owing to its speed, accuracy and its efficiency
in detecting all types of stones at any location Chen 2012; Portis and Sundaram 2001; Worster et
Magnetic Resonance Imaging uses magnets, radio waves and body’s natural magnetic properties for
imaging urinary stones, and sometimes requires administration of paramagnetic contrast media for the
same Mackenzie and Hall 2013; Villa et al.,2015; Berger 2012.
Urine Analysis: It is the investigative step for diagnosing the presence of stones in the urinary
tract. It includes visualisation of the presence of blood and determination of urine volume, pH, calcium,
creatinine, sodium, phosphate, oxalate, citrate, uric acid and cystine levels in urine Pietrow and
Karellas 2007; Nicoletta and Lande 2006.
Stone Analysis: Stone analysis involves examining the entire crust and core of stones in quest for the
Stone components and their respective location in the stone. X-ray crystallography and infrared
spectroscopy are most popular techniques for stone analysisMandel 1987; Cloutier, Villa,Traxer and
Serum Analysis: Serum analysis includes determination of serum levels of urea, uric acid, creatinine,
sodium, potassium, bicarbonate albumin, calcium, magnesium and phosphate, which serve as indicators
of renal function and underlying metabolic causes Thomas and Hall 2005; Ajayi et al., 2007
2.3.10 Disease Management
The accepted management of stone disease ranges from observation to surgical removal of the stone
Nabi, Downey, Keeley, Watson, and Clinton 2007. Management of stone disease needs
individualization. Clinical presentation, proper history and laboratory tests help to identify whether one
needs urgent surgical or medical treatment.Gettman and Segura, 2005; Hussain et al., 2009.
Non-Steroidal Anti-Inflammatory drugs (NSAIDS) and opioids are used to relieve the pain
associated with urolithasis Micali et al., 2006.
Allopurinol is prescribed in case of uric acid and calcium oxalate stones Grosser,Smyth and
Thiazide diuretics decrease sodium reabsorption by inhibiting the NaCl cotransporter in the
Distal convoluted tubule and increase calcium reabsorption by an unknown mechanism
Nijenhuis et al., 2003
Acetohydroxamic Acid is prescribed in case of struvite stones Saklayen 1997.
d-Penicillamine is used in treating cystinuria in case of cysteine stones Reynolds 2005.
Sodium Cellulose Phosphate (SCP): is used to restore normal calcium excretion by reducing
intestinal calcium absorption Zaki 2007; Tiselius 2001; Marangella 2008.
Potassium Citrate inhibit calcium phosphate and calcium oxalate crystal aggregation. it also
tends to inhibit uric acid stone formationHeilberg and Schor 2006; Moe 2006; Moran et
Oral Magnesium Or Phosphate Therapy is beneficial in the prevention of calcium stone
recurrence Lukas, 2007.
Calcium Channel Blockers are good in expelling ureteral stones Micali et al., 2006.
2.3.11 Herbal Remedies and Urolithiasis
Due to immense biodiversity, India is a vast repository of medicinal plants that are used in traditional
medical treatments. Almost, 70% modern medicines in India are derived from natural products and the
various indigenous systems of India such as siddha, ayurveda, umami and allopath use several plant
species to treat different ailments. Herbal medicine has always been a part of Indian culture and
gaining popularity due to toxicity and side effects of allopathic medicines. This led to sudden increase
in the number of herbal drug manufactures in India. It’s reported that more than 500 Indian traditional
communities use about 800 plant species for curing different diseases among 20,000 medicinal plant
Species that are available in the country Vadhana et al.,2015.
The mother nature has provided cures for every disease, the only need is to search for the proper
natural cure. Hence the mankind has started searching for new herbal cures that could be more cost
effective and dependable with respect to their side effects. India is blessed with rich traditional
knowledge which could be harnessed in order to search for herbal remedies. Since ancient times
ayurveda has played a major role in providing successful cures for a variety of diseases. It has also
provided cures for stone disease. Many plants having the property of disintegrating and dissolving the
stone are referred to as “pashanbheda” in ayurveda. Although the herbal cures confer least side effects
still their use is limited to only those who have faith in it. But things proven by scientific research can
generate its worldwide acceptance. So an urgent need exists for proving the potential of herbal
medicines by analyzing them through scientific research. This will not only help in providing safer
remedies for various diseases as well as it will help in preserving the floral diversity and ancient
medicinal knowledge from permanent eradication Narendra et al.,2012; Agarwal et al., 2014.
Some of the important medicinal plants listed in table 3.which are traditionally used in treatment of
Table.3 List of medicinal plants which are traditionally used in the treatment of kidney stones other
urinary related disorders.
s.no botanical name common name part use uses
01 Amaranthus caudatus (L.)
(Amaranthaceae) Love-Lies-Bleeding Leaves Extract In Kidney
02 Amaranthus spinosus (L.) (Amaranthaceae) Spiny Amaranth Root Or
Plant One Cup Of Whole
Plant Is Taken
03 Aegle marmelose(L.)
(Rutaceae) Wood Apple, Bael Leaves And
Fruit 1 Spoon Of Fruit Pulp
Powder Is Taken Orally
With Coconut Milk For
14 Days To Dissolve
04 Bombex ceiba (L.)
(Bombacaceae) Cotton Tree Stem &
Bark Urinary Problems
05 Berberis vulgaris (L.) (Berberidaceae) Barberry Roots Bark Urolithiasis,
06 Bridolia montana
(Euphobiaceae) Sugar Beet Rhizomes Two Glass Rhizome
Juice Is Given In
07 Cassia fistula (L.)
Tree Fruit Fruit Powder Is Given
With Water For 3-4
Month To Expel
The Kidney Stone
08 Curcuma longa
(Zingiberaceae) Haldi Rhizome Diuretic,Choleretic, Hepatoprotective
09 Cynodon dactylon (L.)
(Poaceae) Dog’s Tooth Grass Root Root Decoction Is
Given In Case Of
10 Cuminum cyminum (L.)
Umbelliferae Jeera Fruit The Boiled Decoction
Of The Fruits Is Used In
11 Daucas carota(L.)
(Apiaceae) Wild Carrot Rhizome One Glass Juice Is Given
Fornight To Remove
12 Dolichos Biflorus
(Leguminaceae) Horse Gram Seeds Diuretic, Astringent,
13 Dichrostachys cinerea (L.) (Mimosaceae)
Bell Mimosa Roots Urolithiasis,
14 Elettaria cardamomum (Zingiberaceae) Cardamom Seeds Diuretic, Carmanative
15 Fogonia bruguieri (Umbelliferae) Fagonia Fruit Diuretic, Mildly Carminative
Retrived from Neha sharma et al., 2011; Ghatapanadi et al, 2010; Samra bashir et al., 2010; Prachi et al., 2009; Drury,2010; Sharma et al.,2011; Jayakumari et al, 2011; Rana gopal singh et al., 2010
2.3.12 Herbal Based Commercial Formulation
Marketed based herbal formulations have been commercially used to dissolve renal stones i.e. Cystone
an ayurvedic polyherbal formulation from the himalaya drug co. is widely accepted and used extensively
in dissolving kidney stones. Which is often prescribed by the physicians to the patients suffering from
urinary calculi. Other herbal based formulations which are frequently prescribed by the physicans are
Calculi from charak pharmaceutical bombay india, Uriflush (inti-sumatera global, indonesia) Uriflow (
discovery herbs, usa) and Chandraprabha Bati from baidynath india.
2.3.13 Medicinal Plants Possessing Stone Dissolving Activity.
Asparagaus racemosus (Shatavari Root): Christina et al reported antilithatic effect using ethylene
glycol-induced lithiasis in male albino wistar rats Christina, et al, 2005.
Berberis vulgaris (Barberry): Bashir et al, reported that the aqueous extract of root bark of Berberis
vulgaris possesses kidney damage preventive action caused by oxidative stress Bashir et al., 2010.
Nigella sativa (Black Cumin Seed): Ethanolic extract of Nigella sativa seeds on ethylene glycol-
induced kidney calculi in rats significantly prevent the crystallization of calcium stones Hadizadeh et
Phyllanthus niruri (Stonebreaker): In in-vitro and in-vivo studies on animal it is found that this herb
helps in prevention of kidney stones Freitas et al., 2002.
Oenothera biennis (Evening Primrose): The oil obtained from the seeds of this plant was able to
increase urinary citrate excretion and thus prevent kidney stones Rodgers, et al, 2009.
Trigonella foenum graecum (Fenugreek Seed): Laroubi And Touhami reported reduction in
calcification in kidney when treated with the herbal extract of fenugreek seed Lasonbi et al., 2007.
Hibiscus sabdariffa (Hibiscus Flowers): Flowers of hibiscus significantly reduced the deposition of
oxalate in the kidneys of the test animal Wooltisin, et al, 201.
Crataeva nurvala (Varuna bark): bark of varuna herb prevent the renal stone formation by increasing
the urinary excretion of calcium by daily intaking this herb Prasad and Bharuth, 2007.
Tribulus terrestris (Gokshura): Aggarwal et al reported aqueous extract of tribulus protected renal
tubular epithelial injury caused by experimently induced calcium oxalate in rats Aggarwal, et al, 2010
2.3.14 Surgical Management
Extracorporeal Shock Wave Lithotripsy (ESWL) :
Figure 11: Extracorporeal Shock Wave Lithotripsy
ESWL is the most popular and nonivasive technique which uses shock waves to breakdown stones .
in this technique lithotripter is used to generate non electric shock waves using electrohydraulic,
Electromagnetic or piezoelectric energy sources Alessandra and Elvino, 2003. Renal, pelvic or
calyceal stones of size upto 2cm in diameter fragmented effectively using this technique and now it is
also being used for disintegrating ureteric calculi, struvite calculi and staghorn calculi Sarica 2008;
Chaussy et al.,1984. Shock waves generated by the lithotripter travels through the skin and body tissue
hitting the denser stones and breaking them into smaller particles that can easily flushed out of the body
through urine Chaussy et al., 1980.This one is the most widely used technique to manage renal and
ureteral stones Knoll, 2007.
Ureteroscopy (URS): It is the most invasive technique than eswlin which a small fiberoptic
instrument called ureteroscope that passes through urethra via bladder up to the ureter. The stone is
captured and removed or broken up with a laser beam or shock waves. This whole surgical operation is
done by giving a general anesthesia to the patient before this surgery by the surgeon Preminger,2006;
Sarica,2008.The major drawbacks of this technique is that it is more invasive than ESWL and
Narrowing and perforation in the ureter remains around 2 to 4% Pearle et al., 2001.
Percutaneous Nephrolithotomy (PCNL): Stones which are larger than 2cm are primarly treated with
PCNL. In this surgical procedure an small incision is made through the skin at the back mainly in the
pelvic region. In order to dilate the tract for the insertion of nephroscope to pull the stone or break it up.
The puncture can be performed under combined ultrasound and x-ray control or under biplanar
fluoroscopy. The use of ultrasound allows easy identification of neighbouring organs and therefore
lowers the risk of injuries to adjacent organs Shah et al., 2006.
figure 12: ureteroscopy figure 13:percutaneous nephrolithotomy
Laparoscopic Surgery: Laparoscopic surgery is more invasive compared to other methods requires
three to four incisions. Surgeon makes small incisions into the abdomen to insert a narrow fibre optic
tube called as ports in order to break bigger renal stones. Through one of the port nephroscope is passed
in order to visualize stone during surgery. This surgical operation is beneficial when stones are larger in
size Thomas and Hall,2005; Nadu et al.2009; Kijvikai,2011.
Open Surgery: Most complicated surgical procedure involving single but large incision involving
excessive pain and blood loss. This is the most expensive method for stone removal.open surgery is
done usually when stone is lodged inside kidney or ureter or in case of abnormal anatomy Morton,
2002. These surgical operations mentioned above are iiustrated in figure12,13(a)and13(b) respectively.
2.3.11 Preventive Measures
Daily Fluid Intake: Increasing fluid intake mainly water (about 2-3 litre/day) increasing the urinary
volume and decreasing the supersaturation of urine and thus preventing from the risk of forming stones.
Fluids rich in citrate, oxalate and magnesium content should be recommended and fluid with increasing
Sodium content should be avoided Pearle et al., 2014; Yilmaz et al, 2008.
Citric Acid: Increasing the consumption of citrus fruits may reduce the chances of stone formation. They
not prevent the supersaturation of urine but also prevent crystal growth by binding with calcium oxalate
crystals Penniston et al, 2008.
Animal Protein: Limiting animal protein in diet or shifting animal protein to vegetable protein
not only increases the excretion of calcium and uric acid but also decrease the urinary citrate
concentration Taylor, et al, 2004.
Calcium: Dietary calcium has the binding ability with the oxalate to form a non-absorbable complex and
decrease the intestinal absorption of oxalate and hence decreasing the risk of stone formation Park et al,
Oxalate: Excessive intake of oxalate should be avoided in diet to prevent the supersaturation and risk of
calcium oxalate stones Siener et al, 2003.
Phylate : Dietary fibres rich in phylate must be included in diet. grases et al found that it is a strong
inhibitor of formation of calcium oxalate crystals Grases et al., 1998.
Probiotics: The use of lactic acid probiotics can reduce oxalate production via their ability to metabolize
oxalates Siva, et al, 2009.
2.4 Antioxidant and Urolithiasis
Antioxidants are the phytochemical entities produced by various plants to control oxidative stress caused
by the production of free radicals. Anitoxidant plays an important role in scavenging these free radicals
Hall et al, 2001. Free radicals are the reactive chemical species bearing odd numbers of unpaired
electrons. They can be anionic, cationic and neutral based upon the charge possessed by them
Classification of Free Radicals
Oxygen Derived Reactive Oxygen Species (ROS) : superoxide(O2.-), hydroxyl radical(HO.),hydroperoxyl(HO2), peroxy(ROO-), alkoxyl(RO.) H2O2, HOCl, and O3 etc.
Nitrogen Derived Species : nitric oxide(NO), nitrogen dioxide(NO2), peroxynitrite(ONOO-)
and dinitrogen trioxide(N2O3)
Properties of Free Radicals:
Paramagnetic behavior due to presence of unpaired electrons..
Highly reactive at body temperature (370C).
Free radicals can be detectable using esr(electron spin resonance) spectroscopic technique.
Reactivity of free radicals can be influenced by various factors i.e. temperature, concentration, nature of
solvent and pH etc.
They can be chemically interacted by chain type chemical reactions Pryor,1973, 1976; Freeman and
Antioxidant Defense Strategies in Combatting Oxidative Stress
Plants have developed different strategies to defense against oxidative stress caused by free radicals.
Antioxidant defense system are classified into two different machinery namely enzymatic system and non
enzymatic system to detoxify or scavenge these reactive species (table 4).
Table 4: Different Types Of Enzymatic Defense System
Enzymatic Antioxidant Non-Enzymatic Antioxidant
Superoxide dismutase (SOD) Ascorbic Acid
Catalase (CAT) Reduced Glutathione
Ascorbate peroxidase (APX) Tocopherol
Monodehydroascorbate reductase (MDHAR) Carotenoids
Dehydroascorbate reductase (DHAR) Flavonoids
Glutathione reductase (GR) Proline
Guaiacol peroxidase (GPX) Cysteine
Superoxide dismutase (SOD): this line of enzymatic system defense mainly against superoxide(O2•?).
sod catalyse the dismutation of O2•? into O2 and H2O2 Mittler,2002.
O2- + O2- 2H+ SOD H2O2 + O2
Catalase (CAT) : cat are the class of enzymatic antioxidant which breakdown the H2O2 into H2O and
O2 Rhee, 2005.
2H2O2 CAT 2H2O + O2
Ascorbate peroxidase (APX): Ascorbate peroxidase catalyses the coversion of H2O2 into water and
dehydroascorbate (DHA) Sharma and Dubey, 2004.
H2O2 +ascorbic acid ?2H2O+DHA
Monodehydroascorbate reductase (MDHAR): this enzyme catalysis the NADPH dependent reduction
of MDHA (monodehydroascorbate) to ascorbic acid Mittler, 2002.
MDHA+NADPH ?ascorbic acid + NADP+
Glutathione reductase (GR): glutathione reductase catalysis the reduction of GSSG to GSH(reduced
glutathione) by utilizing NADPH Stohs et al, 1995.
GSSG+NADPH ?2GSH + NADP+
Ascorbicacid : Fat soluble vitamin cannot be synthesized in the human body obtained from the dietary
Sources. Also known as vitamin c. Citrus fruits and amla are excellent sources of ascorbic acid. Ascorbic
Acid oxidized to monohydroascorbate(MHA). Further monohydroascorbate to dehydroascorbate
(DHA).later on these reduced forms recycled back to ascorbic acid by utilizing NADPH (Shao et al.,
Tocopherol: Tocopherol or vitamin e is the most biologically active fat soluble vitamin. Tocopherols are
synthesized by green plants in their chloroplast. There are four different types of tocopherol isomers ?-,
?- , ?- and ?- . Among all ?-form is more active. Tocopherols undergoes lipid peroxidation chain reaction
to oxidise free radicals into their oxidized form ?-tocopheroxyl radicals. These forms further recycled
back to their reduced active form Wang et al., 1999; Warner et al., 2004.
Flavonoids: Flavonoids plays an crucial role in scavenging ROS. Based upon their structure they can be
classified as flavons, flavonols, isoflavons and anthocyanins they reduce oxidative stress by different
mechanism like lipid peroxidation chain reaction and chelation. Flavonoids are mainly present in leaves ,
floral parts and pollen grains. They are defense against various plant pathogens Fini et al., 2011; Agati et
Cysteine: Cysteine is sulfur containing non essential aminoacid. It cannot directly obtained from dietary
Source. It can be synthesized in liver from methionine aminoacid. Cysteine plays an essential role in
Antioxidant defensive system and blocks the production of ROS by donating the hydrogen ion Bisson
Carotenoids: Carotenoids belongs to the lipophilic class of antioxidant. they are found in both
microorganisms and plants. Their mechanism to reduce oxidative stress is by quenching the singlet
oxygen Vertuani et al. 2004; Halli-well and Gutteridge 2006.
2.5 Plant Profile: Anogeissus latifolia wall
Anogeissus latifolia wall is one of the plants belonging to the combretaceae family. Commonly known as
26670002647950Axle-wood, Button tree and Ghatti tree Orwa, 2006; khare, 2007.
2.5.1 Taxonomical Classification Orwa et al.,2009
Species: Anogeissus latifolia (DC.) Wallis. ex Bedd. Figure 14 : Anogeissus latifolia
Synonym: Conocarpus latifolius Roxb. ex DC.
English – Axle-wood
Hindi – Dhawa, Bakali, Dhaura
Sanskrit – Baka, Dhava, Dhavala
Bengali – Dhaoya
Gujrat – Dhuvado , Dabina
Tamil – Vellanagai
Telgu – Cherimanu
Common name: Ghatti
Habit and Habitat: Dry deciduous forest distribution throughout India and Ceylon.
Uses: This tree is commercially important due to its leaves and bark used for tanning purposes. It yields gum and wood.
An erect tree with height of 20-40 m with smooth whitish or greyish green bark. Alternate, broader, ovate
or ovate-lencolate leaves. Small, sessile and in globose headed flowers. Fruits are small, several and
crowded with globular head.
2.5.3 Medicinal and Ethanobotanical use:
Ethanobotanically bark of Anogeissus latifolia is used to treat various skin conditions Roy et al., 1986.
According to Jain et al, this tree is effective in treating stomach diseases, snake and scorpion bite Jain et
al., 1970.It is also effective in treatment of stomach colic Apparanantham et al., 1986 and diarrhea
Ramcharan et al., 1981.Stem bark is useful in urinary discharge, piles and in anemia Kirtikar and
Basu,1975.Tribal peoples residing in Udaipur Rajasthan uses bark of Anogeissus in treating feverNag,
Galav and Kateva,2007.Bark decoction of this tree is effective in Cough while leaf decoction is remedy
for epilepsyPawar and Patil,2008.Stem bark paste is useful remedy in scorpion sting Ratan and Raju,
2008.Tree of Anogeissus is beneficial in diarrhea, dysentery, ulcers, urinary disorders and dysuria
Khare, 2007.Gum obtained from this tree is used as a tonic after delivery Pawar and
Patil,2008.Anogessius bark is also useful in treatment of leprosy Patil and Gaikwad,2011.2.5.3 Phytochemistry
The plant was reported to contain tannins and ellagic acid Reddy et al.,1965. Govindarajan and
Vijaykumar reported large concentration of Potassium nitrate, volatile substances, flavonoids and resinous
matter in Anogeissus latifolia Govindarajan and Vijaykumar, 2004. Dextrorotatary leucocyanidin was
also found Reddy et al.,1965. 3,3′-di-O-methyle ellagic acid-4′-? -D-Xyloside and 3,4,3′-tri-O-
methylflavellagic acid-4′-? -D-glucoside were also reported in stem bark Deshapande et al., 1976. Stem
bark of Anogeissus latifolia also contains steroids and triterpenoidal derivativesRahman et al., 2007.
2.5.4 Pharmacological Profile
Wound healing activity: Ethanolic extract of stem bark of this plant possess wound healing activity as
reported by Govindarajan et al Govindrajan et al.,2004.
Hypolipidemic activity: This plant also reported for its significant hypolipidmic activity done on swiss
albino ratsParvathi et al., 2009.
Hepatoprotective potential: In in-vivo studies Hulikere et al. evaluated hepatoprotective action of this
plant Hulikere et al., 2009.
Antioxidant activity: In vitro studies Govindarajan et al., reported the presence of antioxidants
Govindarajan et al., 2004.
Antimicrobial activity: Patil and Gaikwad, 2010 demonstrated antibacterial potential in methanolic
extract of Anogeissus latifolia stem bark.
Anticancer potential: Anticancer activity was also reported by Daib et al in human cancer cell lines
Daibe et al., 2015.