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Nephrology Reviews 2012; volume 4:e14

Pathophysiology of nephrolithiasis
Christos Paliouras, Eirini Tsampikaki, Polichronis Alivanis, Georgios Aperis
Nephrology Department, General Hospital of Rhodes, Rhodes, Greece

ogenesis have been proposed, including the with that of metabolic syndrome.25 The main
Abstract free and fixed particle theories, and Randal’s types of renal stones and their relative preva-
plaque hypothesis. Among the different types lence are listed in Table 1.26
The incidence of nephrolithiasis has risen of kidney stones, those containing calcium are We conducted a literature review of English
over the last twenty years and continues to the most common, followed by those contain- language publications and reviews from 2000-
rise. Although it is often referred to as a dis- ing uric acid, struvite and cystine. 2011 on the recent advances in the pathophys-
ease, recent advances in the understanding of Supersaturated urine, acidic urine pH and iology of nephrolithiasis using the terms calci-
the pathophysiology suggest that it is a sys- reductions in kidney stone inhibitors in the um or calcium oxalate or calcium phosphate or
temic disorder. We conducted a PubMed based urine are the main recognized causes that cysteine or struvite stones or nephrolithiasis
contribute to the formation of all these stone- and uric acid. However, landmark studies and

ly
literature review on the recent advances in the
pathophysiology of kidney stone formation. types. Nephrolithiasis is considered a sys- critical reviews prior to 2000 were also includ-

on
There is a link between diabetes, metabolic temic pathology that may lead to end-stage ed when appropriate.
syndrome, obesity, insulin resistance and renal disease. Although much progress has
nephrolithiasis. Along with the aging popula- been made, the underlying pathophysiological

e
tion and a Western diet, these are the main mechanisms of kidney stone formation are
still not fully understood. Pathophysiology of different
reasons for the rising incidence and preva-
lence of nephrolithiasis. Different theories as
to the pathophysiological mechanisms of lith-
us types of kidney stones
al
Basic pathophysiological mecha-
Introduction
nisms
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Nephrolithiasis is a major health problem Renal stone formation progresses in suc-


er

Correspondence: Georgios Aperis, Nephrology


Department, General Hospital of Rhodes, Agioi with a worldwide prevalence of between 2% cessive steps.27 i) Nucleation: this regards the
Apostoloi, Rhodes 85100, Greece. and 20%.1-3 According to epidemiological data, phase change of dissolved salts into a solid. It
m

Tel.: +30.22410.80047 - Fax: +30.22410.65652 over the last decades the incidence of is dependent on the degree of saturation of
E-mail gaperis@yahoo.com nephrolithiasis has risen in the United States urine in one solvent. It is possible for one salt
om

and in other parts of the world.3-8 to remain dissolved in urine even though its
Key words: calcium stones, calcium oxalate A more detailed analysis of these data concentration exceeds its solubility. In such
stones, calcium phosphate stones, cysteine reveals an increasing prevalence of kidney cases, the urine is characterized as meta-
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stones, struvite stones, nephrolithiasis, uric acid stable. The limit of supersaturation above
stones with increasing age, and higher preva-
stones. which precipitation of the dissolved salts takes
lence rates in men than in women. Further-
on

more, nephrolithiasis is more common in place is the upper limit of metastability.28


Contributions: CP and ET wrote the introduction,
whites than in blacks and Asians.9 Kidney Nucleation can be either homogenous when
CP and GA prepared the basic pathophysiological
N

mechanisms and the calcium-contained stones stones are responsible for about 10% of uro- crystal precipitation happens spontaneously in
sections; ET and GA prepared the uric acid logical hospital admissions per annum and a supersaturated urine or heterogeneous
stones; ET wrote the struvite stones and cystine account for a significant number of visits to when it occurs at lower degrees of saturation
stones; GA, wrote about the conclusions and the the hospital emergency departments.10 It is in the presence of nucleating agents (i.e. cells,
abstract; PA revised the manuscript. estimated that almost 50% of stone formers crystals, urinary proteins or components of the
will have a recurrence within ten years.11 epithelial cells). ii) Retention of the initial
Received for publication: 13 September 2011. Genetic as well as environmental factors nucleus in sites of the urothelium; iii)
Revision received: 26 March 2012. are considered the main causes of these Crystal’s growth; iv) Crystal’s aggregation.
Accepted for publication: 16 April 2012. There are three proposed pathogenetic
changes. The most important environmental
Conflict of interests: the authors report no con- factors are diet and climate. More specifically, mechanisms of lithogenesis.29,30
flict of interests. high-fructose consumption, which promotes
obesity, reduced fluid intake, and increased The free particle theory
This work is licensed under a Creative Commons calcium, oxalate, sodium and animal protein Crystal precipitation is the result of homog-
Attribution NonCommercial 3.0 License (CC BY- intake have all been identified as risk factors enous nucleation of supersaturated urine in
NC 3.0).
for kidney stones.12-23 the tubular lumen of the distal nephron and
©Copyright C. Paliouras et al., 2012
Furthermore, studies have documented the necessitates high levels of ionic concentra-
Licensee PAGEPress, Italy association between increased environmental tions. The initial nucleus grows progressively
Nephrology Reviews 2012; 4:e14 temperatures and nephrolithiasis.24 Finally, in size and obstructs the collecting ducts. This
doi:10.4081/nr.2012.e14 the incidence of nephrolithiasis rises along is the presumed mechanism in the case of

[page 58] [Nephrology Reviews 2012; 4:e14]


Review

cystinuria and CaOx stones after gastric by- ecules bind on the crystal's surface increasing re-absorption;
pass surgery in obese patients.31,32 These the supersaturation needed to initiate nucle- - resorptive hypercalciuria, i.e. a primary
patients present high urinary levels of cystine ation and inhibit crystal growth and aggrega- increase in bone mineral turnover.
and oxalate, respectively, which favor tion.42 Citrate is a powerful inhibitor of calci- Beyond this organ-specific classification,
intratubular homogenous nucleation. um lithogenesis and correction of hypocitra- idiopathic hypercalciuria is rather a state of
Histologically, there is no evidence of epithe- turia represents a main therapeutical target. increased calcium metabolic turnover where
lial cell injury or interstitial fibrosis. Its chemical ability to bind calcium ions the above-mentioned alterations coexist.
increases their solubility in urine and impedes The exact pathogenetic mechanisms are
The fixed particle theory nucleation of calcium salts. Furthermore, cit- unclear and include:52
Intratubular crystals adhere to the tubular rate binds the crystal’s surface and inhibits - increased levels of vitamin D or vitamin D
epithelium inducing cell injury and formation crystal growth and aggregation. Anionic pep- receptors (VDRs) with a subsequent
of nuclei. Fixed nuclei contact with hypersatu- tides, such as urinary prothrombin fragment, increased tissue response;54
rated urine and crystals grow in size. These
1,43
Tamm-Horsfall protein, albumin or uropon- - a defect in renal re-absorption of calcium
mechanisms induce intratubular nephrocalci- tin,44,45 interact with calcium ions and inhibit and phosphorus,55 possibly in the proximal
nosis and may lead to nephrolithiasis and lithogenesis. tubule;
obstructive tubulopathy.33 Another factor that promotes stone forma- - increased dietary ingestion of Na, protein or
This type of nephrocalcinosis is observed in tion is the presence of a congenital or acquired carbohydrates;52
pre-term infants after furosemide-induced anatomic abnormality, such as cystic kidney
crystalluria and in renal allografts.34,35 Papillary disease or stenosis of ureteropelvic junction. It
biopsies in patients with brushite,36 cystine is thought urinary stasis leads to infections
and apatite stones secondary to distal tubular and stagnation of crystals.46

ly
acidosis revealed plugging of the inner
Table 1. Main types of renal stones.

on
medullary collecting ducts and ducts of Bellini
with apatite crystals,31,37 epithelial cell damage, Types of renal stones %
inflammation and focal interstitial fibrosis. Calcium-containing stones
Calcium oxalate stones 59

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This type of lesion has also been seen in
patients with primary hyperparathyroidism.36 This is the most common type of kidney Calcium phosphate stones 10
Protrusion of these mineral plugs in the lumen
may initiate crystal growth.
us
stones with an incidence of 70-80%.26,47 There
are two main types of calcium-containing
stones: calcium oxalate and calcium phos-
Uric acid stones
Struvite or infection stones
17
12
The above-mentioned mechanisms could
al
Cystine and other stones 2
induce intratubular nephrocalcinosis and may phate.
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lead to nephrolithiasis and obstructive tubu-


lopathy.33 However, lithogenesis secondary to Calcium oxalate stones
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free and fixed particle mechanisms presuppos- Supersaturation of acidic urine in calcium Table 2. Kidney stone inhibitors.
es stone formation in the lumen of the papil- and oxalate is the main mechanism in their
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lary ducts or in the pelvis. formation.47 However, several other factors Inhibitor
have been implicated (Table 3).48
om

Citrate
Interstitial apatite plaque In the following section, we will present Magnesium
(Randall’s plaque hypothesis) each one of these factors separately. Calcium
Pyrophosphate
oxalate stones are built on a plaque of intersti-
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In contrast to the above theories, it has


tial apatite stone at the tip of the renal papilla Glycosaminoglycans (chondroitin, heparin,
been proven that calcium oxalate stones are hyaluronic acid)
(Randall’s plaque).
on

formed upon an interstitial plaque of apatite


Tamm-Horsfall protein
called Randall’s plaque.38 The initial nidus is
composed of apatite, and organic matrix is Hypercalciuria Osteopontin (uropontin)
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found in the basement membrane of thin Increased urinary calcium (>300 mg/d for Prothrombin F1 fragment
descending loops of Henle.39 It then propagates men and >250 mg/d for women or >4 mg/kg of Renal lithostatine
to the interstitium of the renal papilla. Damage body weight/day) leads to precipitation of insol- Bikunin
to the overlying epithelial cells exposes the uble calcium salts. This can be primary or sec-
Calgranulin
plaque to the supersaturated urine and oxalate ondary to hypercalcemic states.49 Several rare
calcium stones grow.40 Hypercalciuria, reduced congenital monogenic disorders can also
volume and acidic urinary pH all correlate with induce hypercalciuria with subsequent nephro-
plaque formation.41 calcinosis and stone formation (Table 4).50 Table 3. Promoters of calcium oxalate
Although small amounts of plaque can be The majority of calcium oxalate stone form- stones.
found in cases of apatite stones (i.e. brushite, ers present increased urinary calcium that can- Promoter
secondary to distal tubular acidosis), the above not be attributed to any known cause.
mechanism is a common feature of idiopathic Idiopathic hypercalciuria is characterized by Hypercalciuria
CaOx stone formers.29 the presence of normal plasma calcium and is Hyperoxaluria
Independently of the above separate mecha- traditionally classified into three subtypes:51-53 Hypocitraturia
nisms, there are also common pathophysiolog- - absorptive hypercalciuria, i.e. increased uri- Hyperuricosuria
ical conditions that may predispose to kidney nary calcium excretion due to increased Dietary factors (high-salt, high-protein diet)
stone formation. More specifically, urine con- intestinal absorption;
Acidic urinary pH
tains inorganic and organic molecules, which - renal leak hypercalciuria, i.e. a primary
may inhibit lithogenesis (Table 2). These mol- tubular defect leading to decreased calcium Low urine volume

[Nephrology Reviews 2012; 4:e14] [page 59]


Review

- genetic factors. In about 50% of cases, the is associated with increased oxalate absorp- (NaDC-1).76
disease has familial characteristics.20 tion and oxalate calcium nephrolithiasis.70 In Urine citrate excretion is regulated by uri-
Idiopathic hypercalciuria seems to be rather patients with type 1 primary hyperoxaluria, nary pH. Systemic and intracellular acidosis
a polygenic disease. Several potential loci recolonization with O. fomigenes after oral decreases renal excretion by multiple mecha-
have been studied and defects have been administration reduced urinary oxalate.71 nisms:
identified in VDR,56 calcium sensitive recep- - increasing the concentration of divalent cit-
tor (CaSR)57 and human soluble adenyl- Hypocitraturia rate and favors its reabsorption;77
cyclase genes.58 Defined as urinary excretion of less than - stimulating NaDC-1 co-transporter;78
320 mg/d for adults, hypocitraturia occurs in - increasing citrate’s renal intracellular
Hyperoxaluria 20-60% of patients with nephrolithiasis.72 metabolism.72
Urinary excretion of more than 45 mg/d Citrate is the dissociated anion of citric acid Metabolic alkalosis has the opposite effects
oxalate is present in 8-50% of kidney stone for- synthesized in mitochondria and enters into while hypokalemia also decreases renal citrate
mers.59 Urinary oxalate is equally important to the tricarboxylic acid cycle. In plasma it forms excretion by inducing intracellular acidosis.
calcium in supersaturation.60 complexes with the divalent anions calcium Hypocitraturia is most often idiopathic but
Hyperoxaluria can be the result of primary and magnesium and is filtered freely in the can be secondary to acid-base disorders (Table
overproduction, increased dietary consump- glomerulus. 6).79 Systemic acidosis, distal renal tubular aci-
tion or enhanced intestinal absorption (Table In the tubular lumen it binds calcium anions dosis, hypocalciuria and hypomagnesemia are
5).61 Oxalate is produced in the liver from gly- increasing their solubility and inhibits the common acid-base disturbances that can
oxalate metabolism. Normally, in hepatic per- nucleation of CaOx crystals.73 Furthermore, cit- cause calcium oxalate nephrolithiasis.
oxisomes, glyoxalate is metabolized to glycine rate inhibits crystal aggregation and growth.74 Furthermore, electrolyte disorders,80 drugs,81,82
and glycolate by alanine-glyoxylate amino- Between 65% and 90% of the filtered citrate changes in diet83 or other disorders can be

ly
transferase (AGT) and glyoxalate reductase/ is reabsorbed actively in its bivalent form.75 Re- associated with low urine citrate.84-86 Genetic
hydroxypyruvate reductase (GRHPR), respec- absorption takes place in the proximal tubule polymorphisms of VDR and NaDC-1 genes

on
tively.62 Inherited defects of these enzymes via Na+-dependent decarboxylate transporter have also been linked with hypocitraturia
lead to oxalate hyperproduction.
Primary hyperoxaluria is classified into

e
three types with recessive autosomal inheri-
tance.63
Type 1 is more common with an incidence of
1 per 100,000 live births. In Europe, it is caused
us
Table 4. Classification of hypercalciuria.
1. Idiopathic
al
by a deficiency of AGT. It is characterized clin- Type I: unresponsive to dietary modifications
ically by early onset with nephrocalcinosis,
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Type II: responsive to dietary calcium restriction


stone formation, renal failure and systemic Type III: (renal phosphate leak)
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deposition of oxalate (bones, joints, heart, ves- 2. Secondary to hypercalcemic states


sels, peripheral nerves, retina). Prognosis is Primary hyperparathyroidism
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poor with rapid evolution to end-stage renal Sarcoidosis


disease in young age. Malignancy
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Type 2 is caused by a deficiency of GRHPR. Milk-alkali syndrome


It has milder clinical manifestations and rarely Hypervitaminosis D
leads to renal failure.64 Prolonged immobilization
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Type 3 has recently been identified as being Paget’s disease


caused by a defect in the DSDPSL gene on 3. Congenital monogenic diseases
on

chromosome 10 which encodes the mitochon- Dent’s disease


drial enzyme 4-hydroxy-2-oxoglutarate aldola- Bartter’s syndrome types I, II, III, V
se.65 Daily dietary oxalate varies between 50 Autosomal dominant hypocalcemic hypercalciuria
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and 1,000 mg/d and contributes to approxi- Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
Distal renal tubular acidosis
mately 45% of urinary excretion.66 In the intes-
tinal lumen, calcium binds oxalate forming
unabsorbed complexes. In malabsorptive syn-
dromes, enteric inflammation or, after a bowel Table 5. Classification of hyperoxaluria.
resection, fatty and bile acids bind to calcium 1. Primary hyperoxaluria
with subsequent increased oxalate absorption Type 1: deficiency of alanine-glyoxylate aminotransferase
and urinary excretion. Type 2: deficiency of glyoxalate/hydroxypyruvate reductase
Recently, it was found that the Cl-/HCO3- Type 3: deficiency of 4-hydroxy-2-oxoglutarate aldolase
exchange transporter Slc26a6 in the apical 2. Dietary
membrane of the small intestine is very impor- Ingestion of oxalate-rich food: chocolate, almond, nuts, spinach, tea
tant for oxalate secretion. Absence of this Hypervitaminosis C
transporter leads to increased oxalate absorp- Low dietary calcium and magnesium
tion and stone formation.67 3. Increased enteric absorbtion in malabsorbtive syndromes
Oxalobacter fomigenes is a gram negative Inflammatory bowel disease
anaerobic enteric bacterium which regulates Bacterial overgrowth syndromes
oxalate homeostasis by utilizing oxalate for its Gastric by-pass surgery, small bowel resection
biosynthesis and promoting oxalate secre- Pancreatic insufficiency
tion.68,69 Its absence from the intestinal lumen Chronic biliary diseases

[page 60] [Nephrology Reviews 2012; 4:e14]


Review

(Table 6).87 Table 6. Causes of hypocitraturia.

Hyperuricosuria 1. Disorders of acid-base balance and electrolytes


Systemic acidosis
Uric acid is a weak organic acid with pKa of Distal renal tubular acidosis
5.5 and its solubility depends mainly on uri- Hypokalemia
nary pH. Urate is more soluble than uric acid, Hypocalciuria
but in high urinary concentration it promotes Hypomagnesuria
the crystallization of calcium oxalate salts by 2. Dietary factors
inducing a salting out effect reducing the High intake of protein and sodium
metastability limit.88 Low intake of fruit and vegetables
Starvation
Dietary factors and acidosis 3. Drugs
High intake of sodium increases urinary cal- Acetazolamide
Topiramate
cium excretion and the risk of nephrolithiasis.
ACE inhibitors
The correlation between urinary sodium and Thiazide diuretics
urinary calcium is linear.89 4. Other disorders
The main mechanisms of this salt-calciuret- Renal failure
ic effect are:90 Primary hyperaldostaronism
- the hypervolemia-induced inhibition of Type 1 glycogen storage disease
reabsorption in the proximal tubule and in 5. Genetic factors
the loop of Henle;

ly
VDR polymorphisms
- the competition between these two cations NaDC-1 gene polymorphisms

on
for reabsorption in the distal segments of
the nephron.
Institution of a low-salt diet has favorable

e
effects on hypercalciuria and stone forma- epithelial cell injury, interstitial fibrosis, tubu- ionization constant pKa 5.5.107 At a urine pH of
tion.91,92
Protein-rich diets generate a metabolic acid
load. Systemic acidosis affects calcium metab-
us
lar atrophy and glomerulosclerosis.98 Repeated
sessions of ESWL may contribute to these
lesions.
6.75, 90% of urate is in the soluble urate anion
(salt), while at a pH of 7.0, 95% is in the solu-
ble form.108 In contrast, at a urine pH below 5.5
al
olism by increasing bone resorption to buffer There is an increase in the prevalence of the supersaturation with the less soluble uric acid
the excess of acidas well as intestinal calcium calcium phosphate contained in stones over occurs.109
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absorption.93,94 Additionally, the metabolism of time.99 This is associated with the number of The causes of low urinary pH in idiopathic
sulfur-containing amino acids leads to ESWL treatments.100 ESWL-induced renal
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uric acid nephrolithiasis are considered to be


increased urinary net acid excretion and acid- injury and consequent altered urinary acidifi- defective ammonium excretion along with
ification of urine, decreased citrate levels and
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cation may contribute to alkalinization of increased net acid excretion.102


increased concentration of urinary uric acid.95 urine pH and growth of calcium phosphate Recent data suggest that patients with nor-
These mechanisms lead to hypercalciuria
om

stones.101 mouricosuric uric acid nephrolithiasis have a


and decreased solubility of calcium salts which renal acidification disease. Despite their low
favor crystal precipitation. Diets rich in fruit baseline urinary pH, uric acid stone formers
and vegetables provide an alkali load and tend
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further acidify their urine after an acid load


to reverse these metabolic alterations.62 because of a severely impaired ammonia
Uric acid stones
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excretory response.109
Uric acid stones can result from low urine
Calcium phosphate stones
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volume, hyperusicozuria, and acidic urine


pH.102 The result is uric acid precipitation.48
Calcium phosphate stones include apatite A recent follow-up study showed that gout,
Metabolic syndrome and uric
(carbapatite or hydroxyapatite) and brushite characterized by hyperuricemia, recurrent acid stones
(calcium monohydrogen phosphate) stones monoarthritis and hyperuricosuria independ-
with an occurrence rate of 4-10% and 2-6%, ently increase the risk for incident kidney Metabolic syndrome is characterized by
respectively.63 Promoting factors of calcium stones in men.103 abdominal obesity, dyslipidemia, high blood
phosphate stone formation are hypercalciuria A landmark study in uric acid research was pressure, elevated fasting blood glucose and
and alkaline urinary pH which induces super- that of Enomoto et al. who identified the anion insulin resistance.110-112 The observation that
saturation of monohydrogen phosphate and exchanger URAT1 as a urate transporter in the patients with recurrent uric acid nephrolithia-
crystal precipitation.96 renal proximal tubule and showed that inacti- sis had clinical and metabolic abnormalities
They share similar chemical components, vating mutations in the gene coding for similar to those with metabolic syndrome
but their crystalline structure and clinical fea- URAT1, SLC22A12 caused idiopathic hyperuri- prompted investigators to explore a possible
tures differ. Brushite stones appear more cozuria, hypouricemia or renal acid leak.104, 105 correlation between them.109,113 Abate et al.
resistant to conservative therapy and usually However, low urinary pH is the most com- found that insulin resistance is closely related
need more extracorporeal shock wave mon and by far the most important risk factor to highly acidic urine, a condition that predis-
lithotripsy (ESWL) treatments or even surgical in uric acid nephrolithiasis. In the absence of poses to uric acid nephrolithiasis.114 The
intervention.97 Biopsies from patients with hyperuricosuria, low urinary pH alone can con- authors hypothesized that insulin resistance
brushite stones showed interstitial apatite vert urinary urate into the sparingly soluble causes a defective ammonia genesis in the
plaques, collecting ducts plugged with apatite, uric acid.106 Uric acid is a weak acid with an proximal tubular cell and a reduced ammoni-

[Nephrology Reviews 2012; 4:e14] [page 61]


Review

um excretion in the tubular lumen. This view Urease-positive microorganisms (some


has been also suggested by others.109,115-118 The Proteus spp., Klebsiella spp., Pseudomonas Conclusions
abnormal excretion of ammonium is consid- spp., Staphylococcus saprophyticus, Ureapla -
ered to be due, at least in part, to reduced prox- sma urealyticum) produce two ammonium and In this paper, we have aimed to describe the
imal tubule brush border Na/H exchanger 3 one bicarbonate for each urea, thereby con- main pathophysiological mechanisms of kid-
(NHE3).119 NHE3 has a bimodal action, either verting urinary divalent phosphate to the triva- ney stones emphasizing both the proven and
as an Na+/NH4+ exchanger or by extruding lent form and providing ample ammonium for published theories.
hydrogen ions into the tubular lumen.120-122 crystallization of struvite. The rate of growth of Nephrolithiasis is considered a systemic
They found that recurrent stone formers had struvite can be rapid and extensive, and disorder that may evolve into end-stage renal
more insulin resistance and lower urine pH staghorn, a calcareous cast of the collecting disease. The term stone former is used for this
compared with non-stone formers. Another system, is a common feature of this stone reason. It is a worldwide problem with a rising
mechanism proposed for the decreased renal type.48 incidence parallel to that of diabetes mellitus,
ammonia genesis in metabolic syndrome is metabolic syndrome and the aging population.
the substitution of circulatory free fatty acids Substantial progress has been made over
for glutamine. Free fatty acids are increased in the last ten years in the pathogenesis of kidney
patients with metabolic syndrome, and gluta- Cystine stones stones, including the discovery of URAT1 in
mine is decreased. Thus, there is a reduced the formation of uric acid stones, the upgrad-
glutamine utilization in the proximal tubule ing role of Randall’s plaque in calcium-contain-
Cystine stones are caused by inherited
and decreased renal ammonia genesis.102,123 ing stones, and the mechanisms that put dia-
defects of renal transport.135 betics and individuals with metabolic syn-
Other investigators have also emphasized the The main apical resorption system for cys-
increasing importance of insulin resistance in drome at risk of forming kidney stones.
tine in the kidney is a heteromeric transporter

ly
the pathogenesis of uric acid stones. High However, the pathogenesis of nephrolithiasis
composed of a light chain catalytic subunit, b0, includes complicate mechanisms that are still
body-mass index, glucose intolerance and type

on
plus amino acid transporter (b0,+AT), and not fully clarified suggesting that kidney
2 diabetes is common in uric acid stone form-
rBAT (related to b0,+AT), a heavy chain sub- stones are just a phenotype of a syndrome in
ers.109,113,124
unit.136 which genetic, environmental and metabolic

e
Inactivating mutations in one of the two factors each contribute to a different extent.

Type 2 diabetes mellitus us


subunits (rBAT or b0+AT1) leads to urinary
wasting of a host of amino acids, such as cys-
tine, arginine, lysine and ornithine.137 The
Understanding the pathophysiological path-
ways of lithogenesis encourage physicians to
treat nephrolithiasis as part of this syndrome
al
phenotype is cystine stones because only cys- rather than as an isolated disease.
Although calcium stones are the most com-
tine is soluble in urine. The solubility of cys- Although many theories have been proposed
ci

mon type of nephrolithiasis, patients with dia-


tine is improved with alkaline pH and homod- and much research has been carried out, fur-
betes more frequently have uric acid
ther investigation in this field is required.
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imerization of cystine to cysteine.


stones.125,126 Diabetic stone formers have a 30-
Incidence and prevalence rates vary greatly Widening our understanding of the pathogen-
40% rate of uric acid stones, compared with
esis of renal stone formation will improve the
m

depending on geographical area and screening


the 5-8% rate of uric acid nephrolithiasis in current therapeutic and preventive strategies.
method, so the actual allelic frequency is diffi-
the general population of stone formers.1,127-129
om

Hari Kumar and Modi found that increased cult to estimate. However, an incidence of one
body weight is inversely related to urine pH. per 20,000 is often quoted.138
Furthermore, older age and duration of dia- The traditional clinical classification is now
References
-c

betes are positively correlated with an correlated with a molecular classification. In


increased incidence of uric acid nephrolithia- type I cystinuria (rBAT mutations), heterozy-
on

gotic carriers have concentrations of urinary 1. Buchholz NP, Abbas F, Afzal M, et al. The
sis.130 Uric acid forms crystals at a concentra- prevalence of silent kidney stones--an
tion above 200 mg/dL when pH is 7.0, while at cystine within the normal range; in non-type I
ultrasonographic screening study. J Pak
N

a pH of 5.0 uric acid solubility is only 15 (i.e. type II and III; b0+AT mutations) interme-
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mg/dL.131 Decreased urine volume explains the 2. Indridason OS, Birgisson S, Edvardsson
increased incidence of uric acid kidney stones However, patients of either type I or II are
VO, et al. Epidemiology of kidney stones
with advanced age and duration of diabetes clinically indistinguishable.139
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Scand J Urol Nephrol 2006;40:215-20.
pH can cause uric acid kidney stones even tine stones are young age at presentation,
3. Soucie JM, Thun MJ, Coates RJ, et al.
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Demographic and geographic variability
diabetes.115,132-134 characteristic hexagonal cystine crystals.48 The of kidney stones in the United States.
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ammonium phosphate (MgNH4PO4·6H2O), are be reduced by increasing urine pH, reducing al. Time trends in reported prevalence of
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istry during microbial proliferation. Recurrent treatment, such as d-penicillamine, α-mercap- 1994. Kidney Int 2003;63:1817-23.
urinary infections and anatomic predisposi- topropionylglycine, or captopril, which form 6. Amato M, Lusini ML, Nelli F. Epidemiology
tion are the main recognized causes. soluble heterodimers with cysteine.140 of nephrolithiasis today. Urol Int

[page 62] [Nephrology Reviews 2012; 4:e14]


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