Stone 20 years. The National Health and Nutrition

Stone disease: An

Worldwide kidney
stone is a common problem and its prevalence has increased over the past 20
years. The National Health and Nutrition Examination Survey (NHANES 2007-2010)
report that the prevalence of kidney stones among American adults is 8.8%:
10.6% among men and 7.1% among women, and it is anticipated that there will be
an increase in kidney stones in the future due to global warming, lifestyle changes,
diet and obesity.1 In the
Middle East, the lifetime risk of kidney stone appears to be even higher. The
awareness of renal stone disease in children is high and recurrence rates of
50% after 10 years and 75% after 20 years have been reported.2


Kidney stones
are characterised by sudden onset of lumbar pain that may be accompanied by
nausea and vomiting, gross or microscopic haematuria. The location of the pain
depends on the location of stone in the urinary tract.2 Apart from being costly due to both medical
treatment and time lost from work, kidney stones are also associated with
increased rates of chronic kidney disease, hypertension and myocardial
infarction.  The recurrence rate of
kidney stones is high. After an initial stone, there is a 50% chance of forming
a second stone within 7 years if left untreated. Since most patients with stone disease have
identifiable risk factors, it is advisable to evaluate the underlying causes of
stone formation.1


Roughly 80% of
kidney stones contain calcium, and the majority of them are composed mainly of
calcium oxalate. Most of calcium oxalate stones contain some calcium phosphate,
while 5% have hydroxyapatite or brushite as their main constituent and 10%
contain some uric acid. Pure uric acid, cystine and infection stones are less common.
Although composition of each stone correlates with supersaturation values in
the urine, calculi are seldom found without an admixture of many salts and not
every passed stone can be retrieved for chemical analysis.2


Calcium stone formation
involves different phases of increasing accumulation of CaOx and calcium
phosphate (CaP) – nucleation, crystal growth, crystal aggregation and crystal


Nucleation is
the process by which free ions in solution associate into microscopic
particles. Crystallization can occur in solution micro-environments, such as
may be present in certain points in the nephron, as well as on surfaces, such
as those of cells and on extracellular matrix. There is considerable dispute
about the importance of free solution crystallization versus crystallization at
other sites, in renal tubules or on bladder walls, on normal or damaged cells,
on areas denuded of cells by certain forms of injury, or at interstitial sites.3

Crystal growth

Crystal growth
is the next major step of stone formation after nucleation. Reduction in the
potential energy of the atoms or molecules when they form bonds to each other
is the driving force for crystallisation. In a supersaturated liquid several
atoms or molecules start forming clusters; the bulk free energy of the cluster
is less than that of the liquid.3

The total free
energy of the cluster is increased by the surface energy (surface tension). Molecular
size and shape of the molecule, the physical properties of the material, SS
levels, pH, and defects that may form in the crystal’s structure determine the
crystal growth. Crystal growth is one of the prerequisites for particle
formation. Using the powerful atomic-force microscope (AFM), Laboratory researchers
are discovering complex growth mechanisms and three-dimensional structures of solution-based

Crystal aggregation
(crystal agglomeration)

In crystal aggregation,
crystals in the solution stick together and form larger particles.  Aggregation of particles in solution is
determined by a balance of forces, some with aggregating effects and some with
disaggregating effects. A small interparticle distance increases attractive
force and favours particle aggregation. In addition, Tamm-Horsfall glycoprotein
and other molecule may act as glue and increase viscous binding.3 

aggregate may be stabilised by solid bridges formed by crystalline material connecting
two particles. The main force that inhibits aggregation is the repulsive
electrostatic surface charge, known as Zeta potential. In various steps of
stone formation, crystal aggregation is a more important factor than nucleation
and growth because aggregation occurs within seconds.3

Crystal retention

requires formation of crystals followed by their retention and accumulation in
the kidney. Crystal retention can be caused by the association of crystals with
the epithelial cells lining the renal tubules. Crystal formation predominantly depends
on the composition of the tubular fluid, while crystal retention might depend
on the composition of the renal tubular epithelial cell surface. A non-adherent
surface of the distal tubules, collecting ducts, ureters, bladder, and the
urethra may provide a natural defence mechanism against crystal retention, and
may become defective when the anti-adherence properties are compromised. In a
cell culture model, Verhulst et al.,observed
upregulated cell surface expression of hyaluronic acid, osteopontin, and their
receptor CD44, as well as the formation of a hyaluronic acid-dependent cell
coat, and suggested that it may play a crucial role in the process of crystal retention.3

Risk factors

Professional chefs and
taxi drivers who often try to minimise their fluid intake to avoid too many
‘toilet stops’ are at higher risk of getting stone disease. Apart from
environmental and lifestyle factors diet-related factors are also known to
increase stone risk. Diet-related factors that are known to increase stone risk
are listed in Table 1.4

1: Dietary risk factors associated with increased stone risk

Tea or coffee
(particularly instant coffee) without milk has been shown to increase oxalate excretion,
although this effect is probably offset by their diuretic action. Dietary
calcium has a biphasic risk curve: stone risk is greater in those on a high or
low calcium diet. The link between vitamin D intake and renal stones is less
clear: while excessive active (1,25-OH) vitamin D supplementation, increases
the risk of stone formation, there is no evidence that correction of native
(25-OH) vitamin D deficiency has the same effect; moreover, correction, especially
if there is secondary hyperparathyroidism, is likely to be a health benefit. Excess
of vitamin C could also increase the risk of calcium oxalate stone formation, but
in practice this is rarely encountered. High dietary intake of potassium or
magnesium is inversely related to stone formation because potassium promotes urinary
citrate excretion, and both citrate and magnesium inhibit crystal formation.
However, the impact of low urinary magnesium on stone risk is at best modest.4

Sites of stone

Randall’s plaques

Supersaturation of
calcium phosphate may exist in the loop of Henle even though urine is not
generally supersaturated with it. This may lead to precipitation of calcium
phosphate in interstitial sites in the inner medulla. These deposits often
become extensive enough to be visible macroscopically in the form of Randall’s
Plaques. Some studies have demonstrated stones that appear to have been
attached directly to the Randall’s plaque which has eroded through the
overlying uroepithelium at the surface of a renal papilla. Although Randall’s
plaques appear to be a risk factor for stone formation, it is still unclear
whether they are necessary in every stone that is formed, since intratubular
crystals as well and  prominent
crystalluria are features of stone disease.5

Calcium oxalate
“receptors” in collecting duct epithelium

Crystalluria is
commonly observed in hyperoxaluric patients, as well as in patients with the
usual sort of calcium oxalate nephrolithiasis where intratubular crystals of
calcium oxalate have also been demonstrated.5

Cells internalise the
crystals, where they fate may undergo dissolution or transcytosis through the
epithelial layer. This process may have consequences for cell function;
initiating mitogenesis, activation of arachidonic acid and other signaling
pathways. The interaction of stone crystals of various types with primary
cultures of inner medullary collecting duct cells demonstrates saturability and
inhibition to some degree of one crystal type by others. Thus, it seems like
there are some receptor-like features of cells to which stone crystals adhere.5

Loss of cell
polarity increases adherence of calcium oxalate crystals. This suggests that
the basolateral membranes of tubule cells have components to which the crystals
can attach. Enrichment of cell membranes with phosphatidylserine also leads to
enhanced calcium oxalate adherence. Also, proteins and glycosaminoglycan
expressed at the cell surface have also been implicated as attachment sites for
calcium oxalate at least. These include hyaluronan, nucleolin, annexin II, and
osteopontin. It is likely that a number of different structure or molecular
components are responsible for crystal attachment. As noted above, these may
include phosphatidylserine component of the lipid bilayer, the acidic side
chains of proteins (carboxyl groups of amino acids or sialic acid-containing
glycosidic side chains). Atomic force microscopy has been used to measure the
force of attraction of carboxyl and amidinium groups to the surface of


Clinical feature of
stone disease

Stone passage

Stones that are
nonobstructing produce no symptoms or signs apart from haematuria. Stone
passage produces renal colic that usually begins as a mild discomfort and
progresses to a plateau of extreme severity over 30–60 minutes. In case of obstruction
in the uretero-pelvic junction, pain localizes to the flank, and as the stone
moves down the ureter the pain moves downward and anterior. Stones at the
uretero-vesicular junction often cause dysuria and urinary frequency mistaken
for infection. Colic is free of body position or motion and is described as a
boring or burning sensation associated with nausea and vomiting.6

Urological management of

Sound waves are
used to break the stone into small pieces that can more easily pass into the bladder.
 Extracorporeal shock wave lithotripsy
(ESWL) is widely used and valuable for small stones. Modern instruments permit
local stone disruption with high-powered lasers by facilitating passage of
endoscopes up the ureter into the kidney pelvis. Percutaneous stone removal via
instruments introduced into the kidney through a small flank incision permits
disruption and removal of even very large stones.6

Renal function reduction
in stone forming people

The National Health and
Nutrition Examination Survey III data set states that subjects with a BMI
greater than or equal to 27 who had kidney stones had lower estimated
glomerular filtration rates than non–stone formers (non-SFs) matched for age,
sex, race, and BMI. SFs also have higher blood pressures than non-SFs. Urinary
tract obstruction, sequelae of urological interventions, and the processes that
cause stone formation may all injure renal tissue, reduce renal function and
raise blood pressure.6

Stone inhibitors

Stone inhibitors
are defined as molecules that increase the supersaturation (SS) required to
initiate nucleation, decrease crystal growth rate and aggregation, and inhibit
secondary nucleation. Inhibitors of calcium stone formation act by preventing crystal
growth and aggregation by coating the surface of growing calcium crystals or by
complexing with calcium and oxalate.3


Citrate, a
tricarboxylic acid, circulates in the blood and is derived from endogenous
oxidative metabolism. It is complexed to calcium, magnesium and sodium at
physiological pH of 7.4. Citrate has been widely studied for its stone inhibiting
action in urine and it has been found to be particularly effective against the
calcium oxalate and phosphate stones.  Citrate appears to alter both calcium oxalate
monohydrate and calcium phosphate crystallisation. It reduces the concentration
of calcium oxalate by complexing with calcium and this is possibly due to
direct effects on the crystal surface rather than to an alteration of the availability
of free calcium.3


Pyrophosphate at
low concentration of 16 ?M, inhibits CaOx monohydrate (COM) crystal growth by
50%. The urinary pyrophosphate levels are (20–40 mM)
enough to inhibit CaOx and CAP crystallisation. Pyrophosphate and diphosphate
inhibits the precipitation of CaP, while diphosphates inhibit the growth of
apatite crystals.3


reduces the absorption of calcium in the intestine and this action is probably
mediated by formation of 1,25 (OH)2 – vitamin D. A study by Sharma et al., reported low 24-hour urinary
excretion of pyrophosphate in stone formers (50.67-2.16 mmol/24 h) as compared
to normal subjects (71.46-5.46 mmol/24 h) (p < 0.01). Oral administration of orthophosphate has shown little benefit in prevention of stone recurrence. Scientific evidence that support preventive role of orthophosphate is also lacking.3 Magnesium Magnesium is the fourth most abundant mineral in the body and is largely found in bones and only 1% of total body magnesium circulates in blood. Dietary magnesium is absorbed in the small intestines and excreted through the kidney. Magnesium (2 mmol/L) in a supersaturated CaOx solution reduced particle number by 50%. Oral intake of magnesium will decrease the oxalate absorption and urinary excretion, in a manner similar to calcium by binding to oxalate in the gut. In subjects with magnesium deficiency, magnesium supplementation increases the excretion of citrate in urine. However, there is little evidence to recommend magnesium therapy in patients with urolithiasis.3 Osteopontin Osteopontin (OPN) also called uropontin is a negatively-charged aspartic acid rich protein that is intimately involved in the regulation of both physiological and pathological mineralisation.  OPN is synthesised within the kidney and present in the human urine at levels in excess of 100 nM. The bone derived and kidney derived forms of this protein appear to be very similar to amino acid sequence. OPN inhibits growth of CaOx crystals in a supersaturated solution and it is involved in various biologic processes like inflammation, leucocyte recruitment, wound healing and cell survival.3   In vitro studies have suggested that OPN may inhibit the nucleation, growth and aggregation of CaOx crystals. Also, it inhibits the crystal adhesion to cultured epithelial cells. Although clinical studies report inconclusive data regarding the relationship between OPN and renal stone disease, a few investigators have reported decreased concentrations of OPN in urine from stone formers compared to normal individuals.3 Inter-alpha-trypsin inhibitor family of proteins Inter-?-inhibitor (IaI) is a glycoprotein that belongs to the Kunitz-type protein superfamily, a group of proteins possessing a common structural element (kunin) and the ability to inhibit serine proteases. It is composed of 2 heavy chains HC1 and HC2 and one light chain, also known as bikunin. Bikunin circulates free in plasma and is excreted in urine where it degrades further to fragments HI14 and HI8. It is expressed mainly in the proximal tubules and the thin descending segment near the loop of Henle and may contribute to the regulation of crystal adhesion and retention within tubules during kidney stone formation. The potent inhibition of CaOx crystal growth by these proteins, along with the known presence of bikunin and its fragments in urine, suggest the possible existence of a relationship between IaI and CaOx stone formation.3 Urinary prothrombin fragment 1 Prothrombin, a blood clotting factor, is made of three fragments – thrombin, fragment 1 and fragment 2. Fragment 1 that is excreted in urine and is named urinary prothrombin fragment (UPTF1) and is a potent inhibitor of CaOx stone formation in vitro. Presence of UPTF1 in the organic matrix CaOx crystals provides evidence that links the role of blood coagulation proteins with urolithiasis. UPTF1 is an important inhibitor of CaOx crystal aggregation and adherence of crystals to renal cells.3 Tamm-Horsfall protein Tamm-Horsfall protein (THP) is an 80-kDa glycoprotein synthesised exclusively in the thick ascending limb of the loop of Henle's loop (TAL). The protein was isolated from the human urine nearly 50 years ago by Tamm and Horsfall. Most authors believe that it is an effective inhibitor of COM crystal aggregation in solutions with high pH, low ionic strength and low concentration of divalent ions and THP.3   Glycosaminoglycans Glycosaminoglycans (GAGs) is one of the macromolecules present in the stone matrix. Main GAGs found in stone matrix were identified as heparan sulphate and hyaluronic acid and are thought to play an important role in CaOx crystallization. In vitro studies have shown that GAGs act as inhibitors of CaOx crystal growth and crystal aggregation.3 Renal lithostathine Lithostathine is a protein of pancreatic secretion that inhibits calcium carbonate crystal growth. This protein is localised to the cells of the proximal tubules and thick ascending limbs of the loop of Henle. Because of its structural and functional similarities with pancreatic lithostathine, it was called renal lithostathine (RL). RL appears to control growth of calcium carbonate crystals.3 Other macromolecules Human urinary trefoil factor (THF1) belongs to the trefoil factor family proteins that may act as a potent inhibitor of CaOx crystal growth. Calgranulin, an S100 protein, is present in the kidney and human urine and can inhibit growth of CaOx crystals, which is the major component of kidney stones. The inhibitory properties of calgranulin may be due to its ability to bind to the crystal surface.3   Recommendations for stone inhibition American Urological Association (AUA) Guidelines The purpose of AUA 2014 guidelines is to provide a clinical framework for the prevention, diagnosis, and follow-up of adult patients with kidney stones. Out of the many guideline statements few are described below.7 Evaluation ·         A clinician should perform a screening evaluation consisting of a detailed medical and dietary history, serum chemistries and urinalysis on a patient newly diagnosed with kidney or ureteral stones.7 ·         Clinicians should obtain serum intact parathyroid hormone (PTH) level as part of the screening evaluation if primary hyperparathyroidism is suspected. ·         When a stone is available, clinicians should obtain a stone analysis at least once. ·         Clinicians should obtain or review available imaging studies to quantify stone burden.7 Diet therapies   ·         Clinicians should recommend to all stone formers a fluid intake that will achieve a urine volume of at least 2.5 liters daily.7 ·         Clinicians should counsel patients with calcium stones and relatively high urinary calcium to limit sodium intake and consume 1,000-1,200 mg per day of dietary calcium. ·         Clinicians should counsel patients with cystine stones to limit sodium and protein intake.7 ·         Clinicians should counsel patients with uric acid stones or calcium stones and relatively high urinary uric acid to limit intake of non-dairy animal protein. Pharmacologic Therapies   ·         Clinicians should offer thiazide diuretics to patients with high or relatively high urine calcium and recurrent calcium stones.7 ·         Clinicians should offer potassium citrate therapy to patients with recurrent calcium stones and low or relatively low urinary citrate. ·         Clinicians should offer allopurinol to patients with recurrent calcium oxalate stones who have hyperuricosuria and normal urinary calcium. 7 ·         Clinicians should offer potassium citrate to patients with uric acid and cystine stones to raise urinary pH to an optimal level. Follow-up ·         Clinicians should obtain a single 24-hour urine specimen for stone risk factors within six months of the initiation of treatment to assess response to dietary and/or medical therapy.7 ·         After the initial follow-up, clinicians should obtain a single 24-hour urine specimen annually or with greater frequency, depending on stone activity, to assess patient adherence and metabolic response. ·         Clinicians should obtain a repeat stone analysis, when available, especially in patients not responding to treatment.7 ·         Clinicians should monitor patients with struvite stones for reinfection with urease-producing organisms and utilize strategies to prevent such occurrences. The European Association of Urology (EAU) Guidelines The European Association of Urology (EAU) guidelines help urologists assess evidence-based management of stones/calculi and incorporate recommendations into clinical practice. Few recommendations of the guidelines are mentioned below.8 Recommendations ·         Offer ?-blockers as MET as one of the treatment options.8 ·         With fever or solitary kidney, and when diagnosis is doubtful, immediate imaging is indicated. ·         Prescribe potassium citrate. ·         Advice patients to follow a diet reduced in fat and oxalate.8 ·         Perform a contrast study if stone removal is planned and the anatomy of the renal collecting system needs to be assessed. ·         Use enhanced CT in complex cases because it enables 3D reconstruction of the collecting system, as well as measurement of stone density and skin-to-stone distance. IVU may also be used.8 ·         In pregnant women, use MRI as a second-line imaging modality.8 ·         In pregnant women, use low-dose CT as a last-line option. ·         Urgently decompress the collecting system in case of sepsis with obstructing stones, using percutaneous drainage or ureteral stenting.8 ·         Delay definitive treatment of the stone until sepsis is resolved. ·         Offer perioperative antibiotic prophylaxis to all patients undergoing endourological treatment.8 Conclusion Stone formation is a complex process involving crystal nucleation, aggregation and/or secondary nucleation, fixation within the kidney, and more aggregation and secondary nucleation. Deficiency of inhibitors in the urine is almost certain to predispose to stone disease. Citrate, pyrophosphate, and perhaps magnesium are the main inhibitors for calcium phosphate and calcium oxalate precipitation.   References   1.       Xu H, Zisman AL, Coe FL, Worcester EM. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013 Mar;14(4):435-47. 2.       Heilberg IP, Schor N. Renal Stone Disease: Causes, Evaluation and Medical Treatment. Arq Bras Endocrinol Metabol. 2006 Aug;50(4):823-31. 3.       Basavaraj DR, Biyani CS, Browning AJ, Cartledge JJ. The Role of Urinary Kidney Stone Inhibitors and Promoters in the Pathogenesis of Calcium Containing Renal Stones. EAU-EBU Update Series. 2007;5(3):126-136. 4.       Johri N, Cooper B, Robertson W. An update and practical guide to renal stone management. Nephron Clin Pract. 2010;116(3):c159-71. 5.       Ratkalkar VN, and Kleinman JG. Mechanisms of Stone Formation. Clin Rev Bone Miner Metab. 2011 Dec; 9(3-4): 187–197. 6.       Coe FL, Evan A, and Worcester E. Kidney stone disease. J Clin Invest. 2005 Oct 1; 115(10): 2598–2608. 7.       Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA guideline. J Urol. 2014 Aug;192(2):316-24. 8.       Türk C, Knoll T, Petrik A, et al. EAU Guidelines on Urolithiasis. 2016. Available from: Accessed on 4th November 2017.  


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