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
ci
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-
-c
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
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
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
e
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.
ci
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
m
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-
-c
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
- 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,
ci
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
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
ci
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
er
excretory response.109
Uric acid stones can result from low urine
Calcium phosphate stones
N
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.
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
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