Kidney Stone Journal

S P E C I A L
C l i n i c a l
F E A T U R E
R e v i e w
Kidney Stones 2012: Pathogenesis, Diagnosis,

and Management
Khashayar Sakhaee, Naim M. Maalouf, and Bridget Sinnott
Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical
Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390
Context: The pathogenetic mechanisms of kidney stone formation are complex and involve both
metabolic and environmental risk factors. Over the past decade, major advances have been made
in the understanding of the pathogenesis, diagnosis, and treatment of kidney stone disease.
Evidence Acquisition and Synthesis: Both original and review articles were found via PubMed
search reporting on pathophysiology, diagnosis, and management of kidney stones. These resources were integrated with the authors knowledge of the field.
Conclusion: Nephrolithiasis remains a major economic and health burden worldwide. Nephrolithiasis is considered a systemic disorder associated with chronic kidney disease, bone loss and
fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus, and the
metabolic syndrome. Further understanding of the pathophysiological link between nephrolithiasis and these systemic disorders is necessary for the development of new therapeutic options.
(J Clin Endocrinol Metab 97: 18471860, 2012)
he increased prevalence of kidney stone disease is pandemic (1). The lifetime risk of kidney stones is currently at 6 12% in the general U.S. population (2). Nephrolithiasis has become increasingly recognized as a
systemic disorder (3) that is associated with chronic kidney disease, nephrolithiasis-induced bone disease (4), increased risk of coronary artery disease, hypertension, type
2 diabetes mellitus, and the metabolic syndrome (MS) (5).
Without medical treatment, nephrolithiasis is a chronic
illness with a recurrence rate greater than 50% over 10 yr
(6). Given that the annual expenditure in the United States
exceeds $5 billion, the economic and social burden of
nephrolithiasis is immense (7).
seen in kidney stone disease, primarily occurring in

Caucasian males and least prevalent in young AfricanAmerican females. The prevalence in Asian and Hispanic ethnicities is intermediate (1).
The incidence of nephrolithiasis is highest in Caucasian
males (2), where the incidence of kidney stones rises after
age 20, peaks between 40 and 60 yr of age (at approximately 3 per 1000 per year), and then declines (8). In
females, the incidence rate is higher in the late 20s, decreases by age 50, and remains relatively constant thereafter (2, 8).
Pathophysiological Mechanism(s) of
Calcium Stones
Epidemiology
The prevalence of nephrolithiasis in the United States
has doubled over the past three decades. This increase
has also been noted in most European countries and
Southeast Asia (1). Racial and ethnic differences are
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright 2012 by The Endocrine Society
doi: 10.1210/jc.2011-3492 Received December 29, 2011. Accepted March 6, 2012.
First Published Online March 30, 2012
Approximately 80% of calcium kidney stones are calcium

oxalate (CaOx) (9), with a small percentage (15%) of calcium phosphate (CaP) (10). The pathophysiological
mechanisms for calcium kidney stone formation are complex and diverse and include low urine volume, hypercalAbbreviations: Ca:Cr, Calcium:creatinine (ratio); CaOx, calcium oxalate; CaP, calcium
phosphate; dRTA, distal renal tubular acidosis; MS, metabolic syndrome; 1,25(OH)2D,
1,25-dihydroxyvitamin D; PBMC, peripheral blood mononuclear cells; RS, relative supersaturation; UA, uric acid; VDR, vitamin D receptor.
J Clin Endocrinol Metab, June 2012, 97(6):18471860
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 December 2015. at 18:35 For personal use only. No other uses without permission. . All rights reserved.
1847
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Sakhaee et al.
TABLE 1.
Kidney Stones 2012
Causes and treatment of kidney stone formation
Etiology
Prevalence
Physiological mechanism(s)
Calcium kidney stones

Hypercalciuria
30 60%
1,25(OH)2D-dependent
1,25(OH)2D-independent
Intrinsic renal calcium leak
Intrinsic renal phosphorus leak
Resorptive hypercalciuria: PTH-dependent
(primary hyperparathyroidism); PTHindependent
Exogenous: diet-induced (purine-rich
food)
Endogenous: urate overproduction
Low extracellular fluid pH: chronic
diarrhea; exercise-induced lactic
acidosis; dRTA; drug-induced
(acetazolamide, topiramate)
Normal extracellular fluid pH: potassium
deficiency; excess dietary protein;
urinary tract infection
Hydrochlorothiazide (50 mg/d)

Chlorthalidone (2550 mg/d)
Indapamide (1.22.5 mg/d)
Amiloride
hydrochlorothiazide (5 mg/
d 50 mg/d)
Hypokalemia
Glucose intolerance
Hypomagnesemia
Hypertriglyceridemia
Allopurinol (100 300 mg/d)
Rare, severe skin hypersensitivity
Alkali treatment (30 60 mEq/d)
Alkali treatment is generally safe
Intestinal hyperabsorption of oxalate:

imbalance between intestinal calcium
and oxalate content; diet-induced high
oxalate intake (chocolate, brewed
tea, spinach, nuts; vitamin C, 2 g/d);
role of Oxalobacter formigenes
Primary hyperoxaluria: enzymatic
disturbances (types I, II, or undefined
primary hyperoxaluria)

to avert metabolic acidosis
Potassium alkali is preferred to avert complications

with calcium stone formation
Although it has not been proven, high doses of
alkali may increase the risk of CaP stones
Both alkali and pyridoxine treatments are generally
safe
Acidic urine: diet, diarrhea, low urine

ammonium
Alkaline urine: infection; drug-induced
(alkali overtreatment, topiramate,
acetazolamide); defective renal acid
excretion
Low urine volume

Hyperuricosuria

Allopurinol (100 300 mg/d)
Hyperuricosuria
10 40%
Hypocitraturia
20 60%
Hyperoxaluria
Urine pH
10 50%
Unknown
Non-calcium kidney
stones
UA
510%
Pharmacological treatment
Pyridoxine (2550 mg/d) in type

I primary hyperoxaluria
Infection
5%
Unknown

Unduly acidic urine
Cystine
Potential side effects
Renal tubular defect in dibasic amino acid

transport

d-Penicillamine (1000 2000
mg/d)
-Mercaptopropionylglycine
(400 1200 mg/d)
Urease-producing bacteria
Acetohydroxamic acid (10 15

mg/kg/d)

Allopurinol rarely causes severe skin
hypersensitivity
Both d-penicillamine and mercaptopropionylglycine may cause nausea,
vomiting, diarrhea, fever, skin rashes,
arthralgia, lupus-like syndrome, dysgeusia,
insomnia, leukopenia, thrombocytopenia, and
proteinuria
-Mercaptopropionylglycine has generally less
frequent severe side effects than dpenicillamine
This treatment should only be used if surgical
removal of infectious stone followed by
eradication of infection with antibiotics is
ineffective
Severe side effects of acetohydroxamic acid
include intractable headache, hemolytic
anemia, and thrombophlebitis
1849
ciuria, hyperuricosuria, hypocitraturia, hyperoxaluria,

and abnormalities in urine pH (Table 1) (11).
ports the intestinal origin (20) and the other suggests calcium
mobilization from bone (28).
Hypercalciuria
Hypercalciuria is the most prevalent abnormality in calcium kidney stone formers. It is detected in 30 60% of
adults with nephrolithiasis (12). In 1939, Flocks (13) initially
described the link between hypercalciuria and nephrolithiasis. In 1958, Albright and Henneman (14, 15) applied the
term idiopathic hypercalciuria. The pathophysiological
mechanisms for hypercalciuria are numerous and may involve increased intestinal calcium absorption, decreased
renal calcium reabsorption, and enhanced calcium mobilization from bone (4, 16 18). However, intestinal calcium hyperabsorption is the most common abnormality in
this population (19). Hence, some have adopted the term
absorptive hypercalciuria (19). Nevertheless, all the
aforementioned physiological defects may coexist in individual patients, leading to decreased bone mineral density and bone fracture (4).
Hypercalciuria is a heterogeneous disorder in which
intestinal calcium hyperabsorption may be dependent (20,
21) or independent (19, 2225) of 1,25-dihydroxyvitamin
D [1,25(OH)2D]. Classically, hypercalciuria is classified
into two different groups. The most severe variant is characterized by normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, and normal or suppressed serum PTH and/or urinary cAMP. However, a less severe
form shares many of the same biochemical characteristics,
but hypercalciuria normalizes after a restricted calcium
diet (400 mg/d) (26).
1,25(OH)2D-independent hypercalciuria
Despite reports of high circulating 1,25(OH)2D in hypercalciuric stone formers (20, 21), several studies have shown
that hyperabsorption of calcium is independent of vitamin D,
with over two thirds of idiopathic hypercalciuric patients
exhibiting increased intestinal calcium absorption with normal prevailing serum 1,25(OH)2D concentration (19, 22
25). To probe this possibility, short-term administration
of ketoconazole, an antimycotic agent known to reduce
serum 1,25(OH)2D, was shown to significantly lower serum 1,25(OH)2D concentration without a significant alteration in intestinal calcium absorption in hypercalciuric
subjects (29). Similarly, treatment with thiazide, glucocorticoids, and phosphate was not shown to influence intestinal calcium absorption in this population, suggesting
that calcitriol has a limited pathophysiological role in hypercalciuria (25, 30, 31).
Several studies have exhibited similar phenotypic characteristics in a model of hypercalciuric stone-forming rat
(GHS rat). These studies demonstrated normal serum calcium and calcitriol concentrations, increased intestinal
calcium absorption with the presence of CaP and CaOx
stones (32, 33), enhanced bone resorption, and diminished renal tubular calcium reabsorption (32, 34, 35). In
this rat model, an increased abundance of vitamin D receptor (VDR) was shown with normal circulating calcitriol levels and increased VDR protein in the intestine,
kidney, and bone that was attributed to increased VDR
half-life (34, 36). These results support the notion that
prolonged VDR half-life increases VDR tissue expression,
resulting in hypercalciuria mediated via VDR-regulated
genes controlling vitamin D-regulated calcium transport
mechanisms (36). The biological action of the VDR1,25(OH)2D complex was supported by increased expression of both 9- and 28-kDa calbindin levels in the duodenum and renal cortical tissue of the GHS rat (36).
In human subjects with hypercalciuria, peripheral
blood mononuclear cells (PBMC) were used as an organ
model to further explore the functionality of the VDR1,25(OH)2D complex (37). When the PBMC were activated with phytohemagglutinin, these patients showed a
significantly greater concentration of VDR in the presence
of normal serum calcitriol levels, suggesting 1,25(OH)2Dindependent VDR up-regulation (37). In addition, higher
VDR levels were detected in hypercalciuric subjects in
PBMC without stimulation (38).
1,25(OH)2D-dependent hypercalciuria
In two studies, increased serum 1,25(OH)2D concentration was reported in the majority of kidney stone formers
with hypercalciuria (20, 21). Insogna et al. (21) demonstrated increased 1,25(OH)2D production rather than disturbed clearance in well-characterized patients with hypercalciuria. The underlying mechanism(s) of enhanced
1,25(OH)2D production have yet to be elucidated. However,
in the majority of well-defined hypercalciuric stone formers,
the main regulators of 1,25(OH)2D production, namely serum PTH, phosphorus, and tubular maximum renal phosphorus reabsorption, were all at comparable levels to those
of normal non-stone-forming subjects (24). Few studies have
suggested a link between renal tubular phosphorus abnormalities and serum 1,25(OH)2D levels (20, 27). Further supporting the role of 1,25(OH)2D-mediated hypercalciuria,
several studies have shown excessive urinary calcium excretion in normal subjects challenged with a large dose of
1,25(OH)2D (20, 28). However, a disagreement has arisen
between the origin of hypercalciuria in which one study sup-
Renal leak hypercalciuria

Renal leak hypercalciuria is a second, less common variety of hypercalciuria in which defective renal tubular
1850
Sakhaee et al.
Kidney Stones 2012
calcium reabsorption is accompanied by enhanced PTH,

calcitriol, and net intestinal calcium absorption (39). Studies using a single dose of hydrochlorothiazide in both unselected and selected groups of calcium stone formers have
linked defective renal calcium reabsorption to a proximal
renal tubular defect (16, 17).
Resorptive hypercalciuria
The most common prototype of resorptive hypercalciuria is primary hyperparathyroidism. However, due to the
more frequent early diagnosis of primary hyperparathyroidism, the prevalence of nephrolithiasis in this condition
is nowadays approximately 2 8% (11). Hypercalciuria is
perceived as a cause of kidney stones in this population.
Nevertheless, the exact relationship between hypercalciuria and the risk of nephrolithiasis with primary hyperparathyroidism is not fully agreed upon (40, 41). It has
been disputed whether hypercalciuria originates from increased calcium mobilization from bone or reflects increased
intestinal calcium absorption (40, 42, 43). It is suggested that
kidney stones are more prevalent in younger populations
with primary hyperparathyroidism due to enhanced synthesis of 1,25(OH)2D with intact kidney function, and consequent increased intestinal calcium absorption (42). Bone disease may occur in older subjects due to their lower serum
1,25(OH)2D levels and consequently diminished intestinal
calcium absorption.
Hyperuricosuria
Hyperuricosuria as an isolated abnormality is detected
in 10% of calcium stone formers. However, in combination with other metabolic abnormalities it may be present
in 40% of this population (44). The pathophysiological
mechanism underlying hyperuricosuria is attributed to a
high purine diet (45). However, in approximately one
third of patients, endogenous uric acid (UA) overproduction prevails, and dietary restriction does not significantly
alter urinary UA excretion (46). The physicochemical basis involved in this process has not been well established.
Although one study has attributed the physicochemical
process to urinary supersaturation with colloidal monosodium urate-induced CaOx crystallization (47), another
study has shown a lack of effect of monosodium urate and
attributes CaOx stone formation to decreased solubility of
CaOx in solution, a process described as salting out
(48). Additionally, a retrospective population-based study
in a large number of patients has not shown a relationship
between urinary UA and CaOx stone formation (49).
Hypocitraturia
Citrate is an endogenous inhibitor of calcium stone formation, and low urine citrate excretion (hypocitraturia) is
encountered in 20 60% of calcium nephrolithiasis (50).

The major determinant of urinary citrate excretion is acidbase balance (51). Hypocitraturia commonly occurs with
metabolic acidosis or acid loading mediated through upregulation of proximal renal tubular reabsorption of citrate (52). The main conditions include distal renal tubular
acidosis (dRTA) (53), carbonic anhydrase inhibitors (54,
55), and normal bicarbonatemic states (56), including incomplete dRTA (57), thiazide treatment with hypokalemia (58), primary aldosteronism (59), high protein consumption (60), excessive salt intake (61), and converting
enzyme inhibitors (62). The physicochemical basis for the
inhibitory role of citrate involves the formation of soluble
complexes and reduction of urinary saturation with respect to calcium salts in addition to direct inhibition of
CaOx crystallization processes (63).
Hyperoxaluria
Urinary oxalate and calcium are equally important in
raising urinary CaOx supersaturation (5). Hyperoxaluria
is detected in 10 50% of calcium stone formers (5). The
underlying mechanisms of hyperoxaluria can be divided
into: 1) oxalate overproduction as a result of an inborn
error in metabolism; 2) increased dietary intake and bioavailability (64); and 3) increased intestinal oxalate absorption. Inborn errors in metabolism include type I hyperoxaluria resulting from a deficiency or mistargeting of
hepatic alanine glyoxylate transferase, type II primary hyperoxaluria due to a deficiency in glyoxylate reductase/
hydroxypyruvate reductase, and the rare type III hyperoxaluria as a result of the gain of function of hepatic or
renal mitochondrial 4-hydroxy-2-oxoglutarate aldolase
(65 67). Subsequent investigation substantiated such a
mutation; however, it remains unknown how changes in
enzyme activity result in hyperoxaluria (68). Recently,
Oxalobacter formigenes in humans have been proposed to
participate in intestinal oxalate metabolism (69). Although a putative anion exchange transporter SLC26A6
has been shown to play a key role in intestinal oxalate
absorption in mice, phenotypic and functional analysis
has excluded a significant effect of identified variants in
the corresponding human gene on oxalate excretion in
humans (70, 71).
The most important circumstances in clinical practice
are intestinal malabsorptive disorders including chronic
diarrhea, inflammatory bowel diseases, and intestinal resection as occurs post-gastric bypass surgery (72) leading
to enteric hyperoxaluria. Normally, oxalate absorption
takes place throughout the small intestine and, to a certain
extent, in the colon (73). In enteric hyperoxaluria, the
underlying mechanisms are purported to be increased permeability to oxalate with unabsorbed bile acid and fatty
acids interacting with divalent cations in the lumen of the

intestine, thereby raising intestinal luminal oxalate content and resulting in excessive urinary oxalate excretion
(74). In addition to hyperoxaluria, these disorders are associated with multiple other kidney stone risk factors including low urine volume, hypocitraturia, hypomagnesuria, and highly acidic urine.
Disturbances in urinary pH
Both highly acidic urine (pH 5.5) and highly alkaline
urine (pH 6.7) predispose patients to calcium kidney
stone formation. With unduly acidic pH, urine becomes
supersaturated with undissociated UA that participates in
CaOx crystallization (47). Significantly alkaline urine increases the abundance of monohydrogen phosphate [dissociation constant (pKa) 6.7], which, in combination
with calcium, transforms to thermodynamically unstable
brushite (CaHPO4.2H2O) and finally to hydroxyapatite
[Ca10(PO4)6(OH)2]. In clinical practice, conditions associated with CaP stone formation include dRTA, primary
hyperparathyroidism, and use of carbonic anhydrase inhibitors (75, 76).
Histopathological mechanisms of calcium kidney
stone formation
One suggested mechanism for the formation of calcium
stones is increased urinary supersaturation of stone-forming salts, which leads to homogeneous nucleation in the
lumen of the nephron, followed by crystal growth and
consequent obstruction in the distal nephron (5). However, over the past decade it has become apparent that
CaOx stone formation differs histologically from that of
CaP (77). CaOx stones have been shown to anchor on and
grow from an interstitial apatite plaque (Randalls plaque)
that covers the renal papillary surface (77). The extent of
plaque in the renal papilla has been positively correlated
with urinary calcium excretion and negatively correlated
with urinary volume (77). The decreased proximal tubular
reabsorption of calcium and enhanced renal tubular calcium reabsorption at the thick ascending limb have been
purported as the potential pathophysiological mechanism
resulting in interstitial plaque formation. Unlike CaOx, in
CaP stone formers there is apatite crystal deposition in the
inner medullary collecting duct, producing plugs associated with interstitial scarring (77).
Genetic basis of calcium stone formation
A higher percentage of kidney stones has been reported
in first-degree relatives and family members with kidney
stones (78). This genetic link was further documented in a
study showing a greater concordance with renal stone incidence in monozygotic than dizygotic twins (79). How-
1851
ever, due to the complex nature of idiopathic hypercalciuria, many putative candidate genes have been identified
that participate in this polygenic illness. Genome-wide
linkage approach in three families with absorptive hypercalciuria discovered polymorphisms in the putative soluble adenylyl cyclase (ADCY10) gene on chromosome
1q23.4 1q24 (80). Another genome-wide screening in a
large population from Iceland and The Netherlands with
documented radio-opaque kidney stones found polymorphisms in sequence variants in the Claudin 14 (CLDN14)
gene, which encodes for the tight junction protein in the
kidney, liver, and inner ear (81). Another study has suggested an association between the calcium sensor receptor
(CASR) gene polymorphism and recurrent nephrolithiasis
(82). However, none of these instances established the
functional significance of these polymorphisms. Future
phenotype-genotype studies are needed to identify the associated gene defect.
Pathophysiological Mechanism(s) of
Non-Calcium Stones
UA stone formation and its link to the MS
The etiological causes of UA stone formation are genetic, acquired, or a combination of both (60, 83). Over
the past decade, the MS has been characterized as the most
prevalent cause of UA stone formation (Fig. 1A) (84, 85).
The underlying pathophysiological mechanisms responsible for UA nephrolithiasis are: 1) low urine volume; 2)
hyperuricosuria; and 3) unduly acidic urine.
Unduly acidic urine (urinary pH 5.5) is an invariable
feature in UA nephrolithiasis (5). In such an acidic milieu,
the urinary environment becomes supersaturated with
sparingly soluble undissociated UA (84). The two principal causes for acidic urine are: 1) impaired ammonium
(NH4) excretion; and 2) increased endogenous acid production (84, 85). Impaired NH4 excretion in this population is shared with patients with the MS and type II
diabetes mellitus without kidney stones (85). Recent experimental evidence using an established rodent model of
obesity (Zucher diabetic fatty rat) and a renal proximal
tubular cell line have demonstrated a causal role of renal
steatosis in the pathogenesis of disturbed urinary acidification (86, 87). Increased endogenous acid production has
been shown in both UA stone formers and diabetic nonstone formers (84, 85). However, the nature and source of
this putative organic anion has not been fully elucidated.
Hyperuricosuria may be encountered in certain clinical
circumstances and/or rare genetic disorders linked to the
UA synthetic pathway and as a result of a genetic mutation
in renal UA transporters (83, 88).
1852
Sakhaee et al
found in both SLC3A1 alleles, type B if

mutations are found in both SLC7A9 alleles, and type AB if one mutation is
found in each gene (93). With digenic inheritance, one would expect 50% of AB
individuals to be affected by nephrolithiasis. However, cystine stones are rarely
encountered in this genotype (94).
FIG. 1. Causes of non-calcium kidney stone formation. A, UA stones; B, cystine stones; C,

infectious stones.
Genetic basis of UA stone formation

Many monogenic mutations are associated with hyperuricosuria, hyperuricemia, gout, renal failure, and kidney
stone formation (83, 88). However, most UA stone formers have a low fractional excretion of urate and low urinary pH (84). In one study conducted in a Sardinian cohort, most subjects exhibited low urinary pH with high
urinary titratable acidity, with only one third showing
elevated urinary UA excretion (89). In this study, genetic
analysis identified a locus on chromosome 10q21-22 associated with increased propensity to UA nephrolithiasis.
A subsequent study identified the putative gene as zinc
finger protein 365 (ZNF365) (90). However, the functional importance of this finding and the role of the protein
encoded by this gene have not been fully established.
Cystinuria
Cystine nephrolithiasis comprises only a small fraction of
kidney stones in adults but is more prevalent among children
and adolescents with stones (91). Cystinuria is either autosomal recessive (obligate heterozygotes with normal urinary
cystine excretion) or autosomal dominant with incomplete
penetrance (obligate heterozygotes with increased urinary
cystine excretion but typically not enough to cause cystine
stones). It is characterized by an inherited defect in renal
cystine reabsorption expressed as b0, (SLC3A1 and
SLC7A9). Although the defective renal tubular reabsorption
affects other dibasic amino acids including arginine, lysine,
and ornithine, cystine stones are the main complication of
this genetic defect due to the low solubility of cystine in the
urinary environment (Fig. 1B) (92). In a recent genetic classification, cystinuria is defined as type A if mutations are
Infection and rare stones

The most important factors for the
formation of infectious stones are
highly alkaline urine pH (7.2) in the
presence of urease-producing organisms and supersaturated urinary environment with respect to magnesium,
ammonium, and phosphate ions (Fig.
1C) (95). Rare forms of kidney stones
such as dihydroxyadanine, ammonium
urate, and stones resulting from protease inhibitor drugs may also occur.
Diagnosis
Medical history
In the diagnosis of these patients, systemic and environmental influences must be carefully identified. Systemic abnormalities include intestinal disease, disorders of calcium
homeostasis such as primary hyperparathyroidism, conditions accompanied by extra renal 1,25(OH)2D production
such as granulomatous diseases, obesity, type II diabetes,
recurrent urinary tract infection, bariatric surgery, medullary
sponge kidney, and various drug treatments.
Diet plays a crucial role in the formation of kidney
stones. High dietary salt and protein consumption are the
two most common dietary aberrations that increase the
risk of nephrolithiasis (61, 96). Epidemiological studies
have shown an association between a higher risk of kidney
stone formation and lower dietary calcium intake (97, 98).
Although the exact pathophysiological mechanism has
not been established, it has been suggested to be due to
lowered urinary oxalate excretion or possibly a rise in
urinary antilithogenic factors with a high-calcium diet. In
contrast, increased calcium and vitamin D supplementation is reportedly accompanied by a higher risk of nephrolithiasis (99). Aside from dietary risk factors, it has been
suggested that kidney stone risk increases in hot climates
as well as with frequent and/or intense exercise, largely due
to extra renal fluid loss as a result of perspiration, resulting
in a significant fall in urine volume (83). It has also been
suggested that certain professions associated with de-
creased fluid intake and/or increased perspiration are at

high risk for kidney stones.
Although hypercalciuric nephrolithiasis is typically a
polygenetic complex trait, in rare instances it may be a
monogenetic disorder. The occurrence of hypercalciuric nephrolithiasis among male subjects accompanied
by renal impairment and low-molecular-weight proteinuria is suggestive of x-linked recessive disorder detected in patients with Dents disease (100). The occurrence of kidney stones and nephrocalcinosis in male
subjects with early cataracts, glaucoma, and neurological deficit is suggestive of Lowe syndrome (101). Aggressive nephrolithiasis, nephrocalcinosis, retarded
growth, and deafness can be seen in patients with dRTA
presenting with both autosomal dominant and autosomal recessive inheritance (102).
Laboratory diagnosis
Laboratory diagnosis includes stone analysis, imaging
studies, blood profiles, and a urine metabolic evaluation
(Table 2). Stone analysis plays a valuable role in the diagnosis of kidney stone patients, specifically in infrequently encountered kidney stones such as UA, cystine,
infection-induced, drug-induced, and NH4 urate stones.
Imaging studies are valuable in the diagnosis of kidney
stone disease. Despite numerous imaging methodologies,
computed tomography is the most sensitive and specific
mode of diagnosis (103). High fasting blood calcium, low
phosphorus, and elevated PTH are suggestive of primary
hyperparathyroidism. In that case, the patient must be
considered for a noninvasive localization study followed
by parathyroidectomy. Normal serum calcium, low serum
phosphorus, elevated 1,25(OH)2D, and normal PTH are
suggestive of renal phosphorus leak. The finding of low
serum potassium and low CO2 is suggestive of dRTA.
Hyperuricemia and high serum triglycerides are encountered in patients with UA stones.
Metabolic evaluation
A simplified metabolic evaluation starts with a random
24-h urinary profile (Table 2). However, there is disagreement whether a single collection or duplicate random 24-h
urine collections are necessary to document kidney stone
risk (104, 105). In some optional instances, 2-h fasting
urinary calcium:creatinine ratio (Ca:Cr) and fasting urinary phosphorus are obtained to establish the diagnosis of
renal leak calcium, excessive calcium mobilization from
bone, and renal phosphorus leak. A 4-h urinary Ca:Cr
after 1 g oral calcium load may follow the 2-h fasting
Ca:Cr for indirect assessment of intestinal calcium absorption (19). An extensive metabolic evaluation may also include bone density analysis because the prevalence of bone
1853
fracture has been shown to be higher in kidney stone formers than in the general population (4). Although it is opinion-based, extensive metabolic evaluation may be performed in recurrent kidney stone formers, those with a
family history of kidney stones, a history of bone fractures,
dRTA, and chronic diarrheal state.
Urinary supersaturation
The utility of urinary supersaturation measurement as
a surrogate of kidney stone incidence has not been fully
studied. To date, only a single study has provided evidence
that a reduction in CaOx supersaturation is associated
with a fall in stone incidence (106). However, urinary supersaturation is reported in stone risk profiles by most
commercial laboratories. Two methods applied for urinary supersaturation measurements are relative supersaturation (RS) ratio and urinary RS (106, 107). With RS
ratio, values greater than 1 indicate supersaturation for all
stone types. With RS, the upper limit of normal for oxalate, brushite, monosodium urate, and UA is defined as 2.
Treatment
Acute treatment for symptomatic stone passage is beyond
the scope of this review and has previously been extensively described (108).
Conservative management
High oral fluid intake must be considered in all stone
formers. A prospective controlled study has shown that
increasing water intake to ensure a urinary volume of approximately 2.5 liters/d was associated with reduced urinary supersaturation with CaOx and a significant reduction in stone recurrence (109). Another study suggests that
fluid intake as fruit juice, specifically orange juice, is also
effective in reducing urinary CaOx saturation and increasing urinary citrate excretion (110). This effectiveness is not
shared with apple juice, grapefruit juice, cola, and some
sport drinks due to their elevated oxalate and fructose
content (110 112). Based on one study in Italian men with
hypercalciuria, great emphasis has been placed on low
dietary sodium (100 mEq/d) and animal protein consumption (50 60 g/d) as well as normal calcium intake
(1200 mg/d) in the reduction of calcium stone recurrence
(113). However, another study using only a low-fiber,
low-protein diet in a cohort in the United States did not
show decreased stone recurrence (114). Dietary oxalate
restriction (100 mg/d) is also useful in lowering urinary
oxalate excretion. Foods that are known to raise urinary
oxalate excretion include fruits such as raspberries, figs,
and plums; vegetables such as spinach, rhubarb, and beets;
and most nuts, tea, wheat bran, chocolate, and high
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Sakhaee et al.
TABLE 2.
Kidney Stones 2012
Diagnostic evaluation and interpretation of laboratory profiles
Simplified ambulatory
metabolic evaluation
Random 24-h urinary profile
Extensive ambulatory
metabolic evaluation
Expected daily values
Total volume
Random 24-h urine profile and

24-h urine profile after 1 wk
of dietary restrictions
Total volume
2.5 liter
pH
pH
5.9 6.2
Creatinine
Creatinine
1525 mg/kg body weight
Sodium
Sodium
100 mEq
Potassium
Calcium
Potassium
Calcium
40 60 mEq
250 300 mg
Magnesium
Magnesium
30 120 mg
Oxalate
Oxalate
45 mg
Phosphorus
Phosphorus
1100 mg
UA
UA
600 800 mg
Sulfate
Sulfate
2530 mmol
Citrate
Citrate
320 mg
Ammonium
Ammonium
30 40 mEq
Chloride
Cystine
Chloride
Cystine
2-h fasting Ca:Cr ratio
100 mEq
30 60 mg
0.11 mg/100 ml glomerular
filtrate
4-h Ca:Cr ratio after a 1-g oral

calcium load
Extensive fasting blood
chemistries
Complete metabolic panel
0.20 mg/mg Cr
Variablea
PTH
10 65 pg/mla
1,25(OH)2D
Variablea
Other evaluations
Bone mineral density
measurements (DXA)
Z-score 2; T-score 2.5
Simplified fasting blood

chemistries
Complete metabolic panel
PTH
Results interpretation
Indicative of daily fluid intake. This value diminishes with low fluid
intake, sweating, and diarrhea
Values 5.5 increase UA precipitation. Commonly found in UA
stone patients, subjects with intestinal disease and diarrhea,
and in those with intestinal bypass surgery. Values 6.7
increase CaP precipitation. Commonly found in patients with
dRTA, primary hyperparathyroidism, alkali overtreatment, and
carbonic anhydrase treatment. Values 7.0 7.5 indicate a
urinary tract infection as a result of urease-producing bacteria
1520 mg/kg body weight in females; 20 25 mg/kg body weight
in males
Reflective of dietary sodium intake, given a lack of excessive
sweating and/or diarrhea
Reflective of dietary potassium intake, given a lack of diarrhea
There may be differences in male and female subjects. A higher
value is expected in males
Low urinary magnesium is detected with low magnesium intake,
intestinal malabsorption (small bowel disease), and after
bariatric surgery
Commonly encountered with intestinal fat malabsorption and
after bariatric surgery. Values 100 mg/d may indicate
primary hyperoxaluria
Indicative of dietary phosphorus intake and absorption. A higher
excretion may increase the risk of CaP stone formation
Hyperuricosuria is encountered with the overindulgence of
purine-rich foods such as red meat, poultry, and fish
Sulfate is a marker of an acid-rich diet that occurs as a result of
increased oxidation of sulfur-rich amino acids (methionine)
found in meat and meat products
An inhibitor of calcium stone formation. Hypocitraturia is
commonly encountered in metabolic acidosis, dRTA, chronic
diarrhea, excessive protein ingestion, strenuous physical
exercise, hypokalemia, intracellular acidosis, with carbonic
anhydrase inhibitor drugs (acetazolamide, topiramate, and
zonisamide), and rarely with ACE-inhibitors
Ammonium is a major buffer that neutralizes hydrogen protons
secreted by the kidney. Its excretion corresponds with urinary
sulfate (acid load). A higher ammonium:sulfate ratio indicates
gastrointestinal alkali loss
Chloride values also correspond with sodium intake
Cystine has a limited urinary solubility at 250 mg/liter
Elevated fasting Ca:Cr, high serum calcium, and elevated PTH are
suggestive of primary hyperparathyroidism. Elevated fasting
Ca:Cr, normal serum calcium, and normal or suppressed PTH
are suggestive of resorptive hypercalciuria. Elevated fasting Ca:
Cr, normal serum calcium, and elevated PTH are suggestive of
renal hypercalciuria
Elevated Ca:Cr after a 1-g oral calcium load is suggestive of
absorptive hypercalciuria
Low serum potassium, high serum chloride, and low serum total
CO2 content are suggestive of a diarrheal state of dRTA
High serum calcium, low serum phosphorus, and high PTH are
suggestive of primary hyperparathyroidism
Normal serum calcium, normal PTH, and elevated 1,25(OH)2D are
suggestive of absorptive hypercalciuria. Normal serum calcium,
normal PTH, low serum phosphorus, and elevated 1,25(OH)2D
are suggestive of renal phosphorus leak
Z-score 2 or T-score 2.5 indicates bone loss. This finding
may be more prevalent in hypercalciuric kidney stone formers
These limits are mean 2 SD (for calcium, oxalate, UA, pH, sodium, sulfate, and phosphorus) or mean 2 SD (for citrate, pH, and magnesium)
from normal. ACE, Angiotensin-converting enzyme; DXA, dual-energy x-ray absorptiometry.
a
Expected values should be cross-checked with reference laboratory recommendations because these values may differ.
TABLE 3.
1855
Major clinical trials in pharmacotherapy of calcium and non-calcium nephrolithiasis
First author (Ref.)

Thiazide diuretics
Laerum (117)
Treatment
Hydrochlorothiazide vs. placebo
No. of
patients
Design
Outcome
50
RCT
Decreased new stone formation and prolonged

stone-free interval
Chlorthalidone more effective than Mg
hydroxide or placebo in reducing stone events
Decreased calciuria and stone formation rate
Diet pharmacotherapy better than diet alone
Ettinger (118)
Chlorthalidone vs. Mg hydroxide vs. placebo
124
RCT
Ohkawa (119)
Borghi (120)
Trichlormethiazide vs. no treatment

Diet vs. diet indapamide vs.
diet indapamide allopurinol
Hydrodiuril
175
75
RCT
RCT
33
NNT
Trichlormethiazide
Trichlormethiazide vs. allopurinol vs. both
Hydrochlorothiazide
Bendroflumethiazide
Hydrochlorothiazide amiloride vs.
both allopurinol
Hydrochlorothiazide
37
222
139
44
519
NNT
NNT
NNT
NNT
NNT
Decreased number of stone events or invasive

and noninvasive procedures
Decreased new stone formation
Decreased new stone formation or stone growth
37
NNT
89
NNT
Decreased stone events
9
18
57
NNT
NNT
RCT
50
64
110
RCT
RCT
RCT

Decreased new stone formation and increased
urinary citrate
No difference in stone formation
Decreased stone recurrence
226
NCT
Decreased stone recurrence
60
202
RCT
RCT

Decreased stone events vs. pretreatment
89
66
R
R
16
NNT
Decreased stone event and dissolution of stones

Both drugs equally effective in reducing stone
events
Decreased stone event
27
RCT
RCT
RCT
Decreased stone size

Decreased stone growth
Decreased stone growth
Yendt (121)
Coe (122)
Coe (123)
Yendt (124)
Backman (125)
Maschio (126)
Pak (127)
Alkali treatment
Pak (129)
Preminger (57)
Pak (130)
Barcelo (131)
Hofbauer (132)
Ettinger (133)
Soygr (134)
Kang (135)
Allopurinol treatment
Ettinger (137)
Coe (123)
Other treatment
Dahlberg (139)
Pak (140)
Chow (141)
Barbey (138)
Williams (142)
Griffith (143)
Griffith (144)
Potassium citrate vs. pretreatment in calcium and UA

stone formers
Potassium citrate
Potassium citrate
Potassium citrate vs. placebo
Diet sodium potassium citrate vs. diet
Potassium magnesium citrate vs. placebo
Potassium citrate vs. no treatment after shock wave
lithotripsy
Mix of potassium citrate, thiazide, allopurinol vs. no
treatment after percutaneous nephrolithotomy
Allopurinol vs. placebo
Thiazide vs. allopurinol vs. both
d-Penicillamine
d-Penicillamine or -mercaptopropionylglycine vs.
conservative Rx
conservative Rx
conservative Rx
Acetohydroxemic acid vs. placebo
18
210
94
R, Retrospective; RCT, randomized controlled trial; NCT, nonrandomized controlled trial; NNT, nonrandomized, non-placebo controlled trial.
amounts of vitamin C (115, 116). There is no specific

report detailing the amount of vitamin D intake for these
subjects. However, 800 IU/d is generally recommended.
Pharmacological treatment
Pharmacological treatment is needed in most recurrent
calcium kidney stone formers as well as in specific stoneforming populations such as UA, cystine, and infectioninduced stones due to the lack of availability and/or consensus regarding the effectiveness of dietary restrictions
(Tables 1 and 3) (113, 114).
These results were consistent with a number of open studies showing reduced kidney stone formation with thiazides (121127). Thiazides are effective in treating hypercalciuria and reducing stone recurrence regardless of the
underlying pathophysiological mechanism (127). The optimal effect of thiazides is achieved with a low-salt diet that
attenuates urinary calcium excretion and the provision of
sufficient potassium supplementation to avoid hypocitraturia (58). Potassium citrate holds an advantage over potassium chloride (128).
Thiazide diuretic treatment

Thiazide diuretics and their analogs are commonly used
medical treatments for lowering calcium excretion in recurrent calcium stone formers (108). In several randomized controlled trials, thiazide diuretics were effective in
significantly reducing kidney stone recurrence (117120).
Alkali treatment
Potassium citrate is used either alone or in combination
with thiazide treatment in recurrent calcium or UA stone
formers. In four randomized controlled trials, three nonrandomized nonplacebo controlled studies, and one nonrandomized controlled trial, this treatment was shown to
1856
Sakhaee et al.
Kidney Stones 2012
reduce the risk of kidney stone events (57, 129 135). Alkali treatment is effective in lowering urinary calcium excretion, raising urinary citrate, and reducing urinary
CaOx, CaP, and undissociated UA supersaturation (136).
Because bone loss and fracture are prevalent in patients
with nephrolithiasis, both alkali and thiazide treatments
have been shown to increase bone mineral density in the
kidney stone-forming population (4). However, no randomized data have been obtained showing decreased fracture rate.
Allopurinol treatment
In a randomized controlled trial in hyperuricosuric calcium stone formers, treatment with allopurinol was
shown to reduce urinary UA excretion as well as stone
recurrence (137). Because multiple metabolic abnormalities may coexist in hyperuricosuric patients, one study has
shown that combined thiazide and allopurinol treatment
is more effective in reducing stone events compared with
either treatment alone (123).
Other drug treatment for stone prevention
Although urinary cystine solubility is pH dependent, alkali treatment alone has limited effectiveness in the management of cystine stone formers. This is due to the high pKa of
cystine at 8.0, requiring a large dose of alkali that is difficult
to achieve. Furthermore, highly alkaline urine can predispose
the patient to CaP stones. The main treatments used in those
who suffer from severe cystinuria (500 mg/d) are thiolderivatives that split cystine molecules into two cysteines and
produce a highly soluble disulfide compound (92). Two such
drugs are d-penicillamine and -mercaptopropionylglycine.
In four retrospective, nonrandomized, nonplacebo, controlled trials, both drugs were shown to decrease stone events
(138 141). Both drugs share many side effects; however,
-mercaptopropionylglycine may have lower incidence of
side effects compared with d-penicillamine (92).
Acetohydroxamic acid is the only drug approved for
the treatment of infectious kidney stones. This treatment
should only be used if surgical removal of an infectious
stone followed by eradication of infection with antibiotics
is ineffective. This medication causes an irreversible inhibition of the enzyme urease, therefore attenuating the rise
in both urinary pH and NH4. Three randomized controlled studies have found reduced stone growth with this
treatment (142144). However, compliance is very poor
due to severe side effects.
Clinical Follow-Up
Follow-up treatment is typically indicated with an annual
clinical visit. This evaluation includes medical history,
physical examination, and laboratory examination for full

serum chemistries and urine profiles.
Future Directions
The current management of nephrolithiasis lacks a reliable
surrogate marker of kidney stone formation to correlate
with stone incidence. The development of practical and
novel techniques to easily assess the physicochemical processes involved in crystal growth, aggregation, agglomeration, and attachment will immensely benefit the field.
Further effort must also be aimed at understanding the
molecular and genetic basis of both calcium and non-calcium kidney stones. Such an effort is necessary for the
development of targeted therapy based on the underlying
pathophysiological mechanisms of nephrolithiasis. To accomplish these goals, a close interaction between bed and
bench investigation is crucial.
Acknowledgments
The authors acknowledge Ms. Hadley Palmer for her primary
role in the preparation and review of this manuscript.
Address all correspondence and requests for reprints to: Khashayar Sakhaee, M.D., 5323 Harry Hines Boulevard, Dallas,
Texas 75390. E-mail: khashayar.sakhaee@utsouthwestern.edu.
The authors were supported by the National Institutes of
Health (R01 DK081423, P01 DK20543, K23 RR021710).
Disclosure Summary: The authors have nothing to disclose.
References
1. Romero V, Akpinar H, Assimos DG 2010 Kidney stones: a global
picture of prevalence, incidence, and associated risk factors. Rev
Urol 12:e86 e96
2. Lieske JC, Pena de la Vega LS, Slezak JM, Bergstralh EJ, Leibson
CL, Ho KL, Gettman MT 2006 Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int 69:760 764
3. Sakhaee K 2008 Nephrolithiasis as a systemic disorder. Curr Opin
Nephrol Hypertens 17:304 309
4. Sakhaee K, Maalouf NM, Kumar R, Pasch A, Moe OW 2011
Nephrolithiasis-associated bone disease: pathogenesis and treatment options. Kidney Int 79:393 403
5. Sakhaee K 2009 Recent advances in the pathophysiology of nephrolithiasis. Kidney Int 75:585595
6. Uribarri J, Oh MS, Carroll HJ 1989 The first kidney stone. Ann
Intern Med 111:1006 1009
7. Saigal CS, Joyce G, Timilsina AR 2005 Direct and indirect costs of
nephrolithiasis in an employed population: opportunity for disease
management? Kidney Int 68:1808 1814
8. Hiatt RA, Dales LG, Friedman GD, Hunkeler EM 1982 Frequency
of urolithiasis in a prepaid medical care program. Am J Epidemiol
115:255265
9. Mandel NS, Mandel GS 1989 Urinary tract stone disease in the
United States veteran population. II. Geographical analysis of variations in composition. J Urol 142:1516 1521
10. Evan AP, Lingeman JE, Coe FL, Shao Y, Parks JH, Bledsoe SB,
Phillips CL, Bonsib S, Worcester EM, Sommer AJ, Kim SC, Tinmouth WW, Grynpas M 2005 Crystal-associated nephropathy in
patients with brushite nephrolithiasis. Kidney Int 67:576 591
11. Pak CY 1991 Etiology and treatment of urolithiasis. Am J Kidney
Dis 18:624 637
12. Pak CY, Britton F, Peterson R, Ward D, Northcutt C, Breslau NA,
McGuire J, Sakhaee K, Bush S, Nicar M, Norman DA, Peters P
1980 Ambulatory evaluation of nephrolithiasis. Classification,
clinical presentation and diagnostic criteria. Am J Med 69:19 30
13. Flocks RH 1939 Calcium and phosphorus excretion in the urine of
patients with renal or ureteral calculi. JAMA 113:1466 1471
14. Albright F, Henneman P, Benedict PH, Forbes AP 1953 Idiopathic
hypercalciuria: a preliminary report. Proc R Soc Med 46:1077
1081
15. Henneman PH, Benedict PH, Forbes AP, Dudley HR 1958 Idiopathic hypercaicuria. N Engl J Med 259:802 807
16. Sutton RA, Walker VR 1980 Responses to hydrochlorothiazide
and acetazolamide in patients with calcium stones. Evidence suggesting a defect in renal tubular function. N Engl J Med 302:709
713
17. Sakhaee K, Nicar MJ, Brater DC, Pak CY 1985 Exaggerated natriuretic and calciuric responses to hydrochlorothiazide in renal
hypercalciuria but not in absorptive hypercalciuria. J Clin Endocrinol Metab 61:825 829
18. Worcester EM, Coe FL 2008 New insights into the pathogenesis of
idiopathic hypercalciuria. Semin Nephrol 28:120 132
19. Pak CY, Oata M, Lawrence EC, Snyder W 1974 The hypercalciurias. Causes, parathyroid functions, and diagnostic criteria. J Clin
Invest 54:387 400
20. Broadus AE, Insogna KL, Lang R, Mallette LE, Oren DA, Gertner
JM, Kliger AS, Ellison AF 1984 A consideration of the hormonal
basis and phosphate leak hypothesis of absorptive hypercalciuria.
J Clin Endocrinol Metab 58:161169
21. Insogna KL, Broadus AE, Dreyer BE, Ellison AF, Gertner JM 1985
Elevated production rate of 1,25-dihydroxyvitamin D in patients
with absorptive hypercalciuria. J Clin Endocrinol Metab 61:490
495
22. Birge SJ, Peck WA, Berman M, Whedon GD 1969 Study of calcium
absorption in man: a kinetic analysis and physiologic model. J Clin
Invest 48:17051713
23. Pak CY, East DA, Sanzenbacher LJ, Delea CS, Bartter FC 1972
Gastrointestinal calcium absorption in nephrolithiasis. J Clin Endocrinol Metab 35:261270
24. Kaplan RA, Haussler MR, Deftos LJ, Bone H, Pak CY 1977 The
role of 1,25-dihydroxyvitamin D in the mediation of intestinal
hyperabsorption of calcium in primary hyperparathyroidism and
absorptive hypercalciuria. J Clin Invest 59:756 760
25. Zerwekh JE, Pak CY 1980 Selective effects of thiazide therapy on
serum 1,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias. Metabolism 29:1317
26. Pak CY, Sakhaee K, Moe OW, Poindexter J, Adams-Huet B, Pearle
MS, Zerwekh JE, Preminger GM, Wills MR, Breslau NA, Bartter
FC, Brater DC, Heller HJ, Odvina CV, Wabner CL, Fordtran JS,
Oh M, Garg A, Harvey JA, Alpern RJ, Snyder WH, Peters PC 2011
Defining hypercalciuria in nephrolithiasis. Kidney Int 80:777782
27. Van Den Berg CJ, Kumar R, Wilson DM, Heath 3rd H, Smith LH
1980 Orthophosphate therapy decreases urinary calcium excretion
and serum 1,25-dihydroxyvitamin D concentrations in idiopathic
hypercalciuria. J Clin Endocrinol Metab 51:998 1001
28. Maierhofer WJ, Gray RW, Cheung HS, Lemann Jr J 1983 Bone
resorption stimulated by elevated serum 1,25-(OH)2-vitamin D
concentrations in healthy men. Kidney Int 24:555560
29. Breslau NA, Preminger GM, Adams BV, Otey J, Pak CY 1992 Use
of ketoconazole to probe the pathogenetic importance of 1,25dihydroxyvitamin D in absorptive hypercalciuria. J Clin Endocrinol Metab 75:1446 1452
30. Barilla DE, Zerwekh J, Pak CY 1979 A critical evaluation of the
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
1857
role of phosphate in the pathogenesis of absorptive hypercalciuria.

Miner Electrolyte Metab 2:302309
Zerwekh JE, Pak CY, Kaplan RA, McGuire JL, Upchurch K, Breslau N, Johnson Jr R 1980 Pathogenetic role of 1,25-dihydroxyvitamin D in sarcoidosis and absorptive hypercalciuria: different response to prednisolone therapy. J Clin Endocrinol Metab 51:381
386
Bushinsky DA, Grynpas MD, Nilsson EL, Nakagawa Y, Coe FL
1995 Stone formation in genetic hypercalciuric rats. Kidney Int
48:17051713
Bushinsky DA, Asplin JR, Grynpas MD, Evan AP, Parker WR,
Alexander KM, Coe FL 2002 Calcium oxalate stone formation in
genetic hypercalciuric stone-forming rats. Kidney Int 61:975987
Li XQ, Tembe V, Horwitz GM, Bushinsky DA, Favus MJ 1993
Increased intestinal vitamin D receptor in genetic hypercalciuric
rats. A cause of intestinal calcium hyperabsorption. J Clin Invest
91:661 667
Tsuruoka S, Bushinsky DA, Schwartz GJ 1997 Defective renal
calcium reabsorption in genetic hypercalciuric rats. Kidney Int 51:
1540 1547
Karnauskas AJ, van Leeuwen JP, van den Bemd GJ, Kathpalia PP,
DeLuca HF, Bushinsky DA, Favus MJ 2005 Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric
stone-forming rats. J Bone Miner Res 20:447 454
Zerwekh JE, Yu XP, Breslau NA, Manolagas S, Pak CY 1993
Vitamin D receptor quantitation in human blood mononuclear
cells in health and disease. Mol Cell Endocrinol 96:1 6
Favus MJ, Karnauskas AJ, Parks JH, Coe FL 2004 Peripheral blood
monocyte vitamin D receptor levels are elevated in patients with
idiopathic hypercalciuria. J Clin Endocrinol Metab 89:4937 4943
Coe FL, Bushinsky DA 1984 Pathophysiology of hypercalciuria.
Am J Physiol 247:F1F13
Pak CY, Nicar MJ, Peterson R, Zerwekh JE, Snyder W 1981 A lack
of unique pathophysiologic background for nephrolithiasis of primary hyperparathyroidism. J Clin Endocrinol Metab 53:536 542
Rejnmark L, Vestergaard P, Mosekilde L 2011 Nephrolithiasis and
renal calcifications in primary hyperparathyroidism. J Clin Endocrinol Metab 96:23772385
Patron P, Gardin JP, Paillard M 1987 Renal mass and reserve of
vitamin D: determinants in primary hyperparathyroidism. Kidney
Int 31:1174 1180
Odvina CV, Sakhaee K, Heller HJ, Peterson RD, Poindexter JR,
Padalino PK, Pak CY 2007 Biochemical characterization of primary hyperparathyroidism with and without kidney stones. Urol
Res 35:123128
Preminger GM 1992 Renal calculi: pathogenesis, diagnosis, and
medical therapy. Semin Nephrol 12:200 216
Coe FL 1978 Hyperuricosuric calcium oxalate nephrolithiasis.
Kidney Int 13:418 426
Coe FL, Parks JH 1981 Hyperuricosuria and calcium nephrolithiasis. Urol Clin North Am 8:227244
Pak CY, Arnold LH 1975 Heterogeneous nucleation of calcium
oxalate by seeds of monosodium urate. Proc Soc Exp Biol Med
149:930 932
Grover PK, Ryall RL 1994 Urate and calcium oxalate stones: from
repute to rhetoric to reality. Miner Electrolyte Metab 20:361370
Curhan GC, Taylor EN 2008 24-h uric acid excretion and the risk
of kidney stones. Kidney Int 73:489 496
Pak CY 1994 Citrate and renal calculi: an update. Miner Electrolyte Metab 20:371377
Hamm LL 1990 Renal handling of citrate. Kidney Int 38:728 735
Aruga S, Wehrli S, Kaissling B, Moe OW, Preisig PA, Pajor AM,
Alpern RJ 2000 Chronic metabolic acidosis increases NaDC-1
mRNA and protein abundance in rat kidney. Kidney Int 58:206
215
Backman U, Danielson BG, Johansson G, Ljunghall S, Wikstrom
B 1980 Incidence and clinical importance of renal tubular defects
in recurrent renal stone formers. Nephron 25:96 101
1858
Sakhaee et al.
Kidney Stones 2012
54. Gordon EE, Sheps SG 1957 Effect of acetazolamide on citrate excretion and formation of renal calculi. N Engl J Med 256:1215
1219
55. Welch BJ, Graybeal D, Moe OW, Maalouf NM, Sakhaee K 2006
Biochemical and stone-risk profiles with topiramate treatment.
Am J Kidney Dis 48:555563
56. Alpern RJ, Sakhaee K 1997 The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. Am J Kidney Dis 29:291302
57. Preminger GM, Sakhaee K, Skurla C, Pak CY 1985 Prevention of
recurrent calcium stone formation with potassium citrate therapy
in patients with distal renal tubular acidosis. J Urol 134:20 23
58. Pak CY, Peterson R, Sakhaee K, Fuller C, Preminger G, Reisch J
1985 Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis. Am J Med 79:
284 288
59. Shey J, Cameron MA, Sakhaee K, Moe OW 2004 Recurrent calcium nephrolithiasis associated with primary aldosteronism. Am J
Kidney Dis 44:e7 e12
60. Reddy ST, Wang CY, Sakhaee K, Brinkley L, Pak CY 2002 Effect
of low-carbohydrate high-protein diets on acid-base balance,
stone-forming propensity, and calcium metabolism. Am J Kidney
Dis 40:265274
61. Sakhaee K, Harvey JA, Padalino PK, Whitson P, Pak CY 1993 The
potential role of salt abuse on the risk for kidney stone formation.
J Urol 150:310 312
62. Melnick JZ, Preisig PA, Haynes S, Pak CY, Sakhaee K, Alpern RJ
1998 Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia. Kidney Int 54:1670 1674
63. Kok DJ, Papapoulos SE, Bijvoet OL 1986 Excessive crystal agglomeration with low citrate excretion in recurrent stone-formers.
Lancet 1:1056 1058
64. Holmes RP, Goodman HO, Assimos DG 2001 Contribution of
dietary oxalate to urinary oxalate excretion. Kidney Int 59:270
276
65. Danpure CJ, Jennings PR 1986 Peroxisomal alanine:glyoxylate
aminotransferase deficiency in primary hyperoxaluria type I. FEBS
Lett 201:20 24
66. Giafi CF, Rumsby G 1998 Kinetic analysis and tissue distribution
of human D-glycerate dehydrogenase/glyoxylate reductase and its
relevance to the diagnosis of primary hyperoxaluria type 2. Ann
Clin Biochem 35:104 109
67. Belostotsky R, Seboun E, Idelson GH, Milliner DS, Becker-Cohen
R, Rinat C, Monico CG, Feinstein S, Ben-Shalom E, Magen D,
Weissman I, Charon C, Frishberg Y 2010 Mutations in DHDPSL
are responsible for primary hyperoxaluria type III. Am J Hum
Genet 87:392399
68. Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM,
Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE, Frishberg Y, Milliner DS 2011 Primary hyperoxaluria type III gene
HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol
6:2289 2295
69. Hoppe B, Beck B, Gatter N, von Unruh G, Tischer A, Hesse A,
Laube N, Kaul P, Sidhu H 2006 Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1.
Kidney Int 70:13051311
70. Monico CG, Weinstein A, Jiang Z, Rohlinger AL, Cogal AG,
Bjornson BB, Olson JB, Bergstralh EJ, Milliner DS, Aronson PS
2008 Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate
nephrolithiasis. Am J Kidney Dis 52:1096 1103
71. Jiang Z, Asplin JR, Evan AP, Rajendran VM, Velazquez H, Nottoli
TP, Binder HJ, Aronson PS 2006 Calcium oxalate urolithiasis in
mice lacking anion transporter Slc26a6. Nat Genet 38:474 478
72. Maalouf NM, Tondapu P, Guth ES, Livingston EH, Sakhaee K
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
2010 Hypocitraturia and hyperoxaluria after Roux-en-Y gastric

bypass surgery. J Urol 183:1026 1030
Lindsjo M, Danielson BG, Fellstrom B, Ljunghall S 1989 Intestinal
oxalate and calcium absorption in recurrent renal stone formers
and healthy subjects. Scand J Urol Nephrol 23:5559
Dobbins JW, Binder HJ 1976 Effect of bile salts and fatty acids on
the colonic absorption of oxalate. Gastroenterology 70:1096
1100
Pak CY, Poindexter JR, Adams-Huet B, Pearle MS 2003 Predictive
value of kidney stone composition in the detection of metabolic
abnormalities. Am J Med 115:26 32
Parks JH, Worcester EM, Coe FL, Evan AP, Lingeman JE 2004
Clinical implications of abundant calcium phosphate in routinely
analyzed kidney stones. Kidney Int 66:777785
Coe FL, Evan A, Worcester E 2011 Pathophysiology-based treatment of idiopathic calcium kidney stones. Clin J Am Soc Nephrol
6:20832092
Ljunghall S, Danielson BG, Fellstrom B, Holmgren K, Johansson
G, Wikstrom B 1985 Family history of renal stones in recurrent
stone patients. Br J Urol 57:370 374
Goldfarb DS, Fischer ME, Keich Y, Goldberg J 2005 A twin study
of genetic and dietary influences on nephrolithiasis: a report from
the Vietnam Era Twin (VET) Registry. Kidney Int 67:10531061
Reed BY, Heller HJ, Gitomer WL, Pak CY 1999 Mapping a gene
defect in absorptive hypercalciuria to chromosome 1q23.3-q24.
J Clin Endocrinol Metab 84:39073913
Thorleifsson G, Holm H, Edvardsson V, Walters GB, Styrkarsdottir U, Gudbjartsson DF, Sulem P, Halldorsson BV, de Vegt F,
dAncona FC, den Heijer M, Franzson L, Christiansen C, Alexandersen P, Rafnar T, Kristjansson K, Sigurdsson G, Kiemeney LA,
Bodvarsson M, Indridason OS, Palsson R, Kong A, Thorsteinsdottir U, Stefansson K 2009 Sequence variants in the CLDN14 gene
associate with kidney stones and bone mineral density. Nat Genet
41:926 930
Shakhssalim N, Kazemi B, Basiri A, Houshmand M, Pakmanesh H,
Golestan B, Eilanjegh AF, Kashi AH, Kilani M, Azadvari M 2010
Association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: a comprehensive gene analysis. Scand J Urol Nephrol 44:406 412
Maalouf NM, Cameron MA, Moe OW, Sakhaee K 2004 Novel
insights into the pathogenesis of uric acid nephrolithiasis. Curr
Opin Nephrol Hypertens 13:181189
Sakhaee K, Adams-Huet B, Moe OW, Pak CY 2002 Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney
Int 62:971979
Sakhaee K 2010 Uric acid metabolism and uric acid stones. In: Rao
NP, Preminger G, Kavanaugh J, eds. Urinary tract stone disease.
London: BC Decker Publisher, Springer-Verlag
Bobulescu IA, Dubree M, Zhang J, McLeroy P, Moe OW 2008
Effect of renal lipid accumulation on proximal tubule Na/H
exchange and ammonium secretion. Am J Physiol Renal Physiol
294:F1315F1322
Bobulescu IA, Dubree M, Zhang J, McLeroy P, Moe OW 2009
Reduction of renal triglyceride accumulation: effects on proximal
tubule Na/H exchange and urinary acidification. Am J Physiol
Renal Physiol 297:F1419 F1426
Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M,
Endou H, Hosoya T 2004 Clinical and molecular analysis of patients with renal hypouricemia in Japaninfluence of URAT1 gene
on urinary urate excretion. J Am Soc Nephrol 15:164 173
Ombra MN, Forabosco P, Casula S, Angius A, Maestrale G, Petretto E, Casu G, Colussi G, Usai E, Melis P, Pirastu M 2001
Identification of a new candidate locus for uric acid nephrolithiasis.
Am J Hum Genet 68:1119 1129
Gianfrancesco F, Esposito T, Ombra MN, Forabosco P, Maninchedda G, Fattorini M, Casula S, Vaccargiu S, Casu G, Cardia F,
Deiana I, Melis P, Falchi M, Pirastu M 2003 Identification of a
novel gene and a common variant associated with uric acid neph-
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
rolithiasis in a Sardinian genetic isolate. Am J Hum Genet 72:

1479 1491
Chillaron J, Font-Llitjos M, Fort J, Zorzano A, Goldfarb DS,
Nunes V, Palacn M 2010 Pathophysiology and treatment of
cystinuria. Nat Rev Nephrol 6:424 434
Sakhaee K 1996 Pathogenesis and medical management of cystinuria. Semin Nephrol 16:435 447
Dello Strologo L, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, de
Sanctis L, Ponzone A, Gallucci M, Bisceglia L, Zelante L, JimenezVidal M, Font M, Zorzano A, Rousaud F, Nunes V, Gasparini P,
Palacn M, Rizzoni G 2002 Comparison between SLC3A1 and
SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol 13:25472553
Font-Llitjos M, Jimenez-Vidal M, Bisceglia L, Di Perna M, de Sanctis L, Rousaud F, Zelante L, Palacn M, Nunes V 2005 New insights
into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype. J Med
Genet 42:58 68
Bichler KH, Eipper E, Naber K, Braun V, Zimmermann R, Lahme
S 2002 Urinary infection stones. Int J Antimicrob Agents 19:488
498
Maalouf NM, Moe OW, Adams-Huet B, Sakhaee K 2011 Hypercalciuria associated with high dietary protein intake is not due to
acid load. J Clin Endocrinol Metab 96:37333740
Curhan GC, Willett WC, Rimm EB, Stampfer MJ 1993 A prospective study of dietary calcium and other nutrients and the risk of
symptomatic kidney stones. N Engl J Med 328:833 838
Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ
1997 Comparison of dietary calcium with supplemental calcium
and other nutrients as factors affecting the risk for kidney stones in
women. Ann Intern Med 126:497504
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis
CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE,
Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT,
Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard
BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller
LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE,
Margolis KL, McGowan J, Ockene JK, OSullivan MJ, Phillips L,
Prentice RL, Sarto GE, Stefanick ML, Van Horn L, WactawskiWende J, Whitlock E, Anderson GL, Assaf AR, Barad D 2006
Calcium plus vitamin D supplementation and the risk of fractures.
N Engl J Med 354:669 683
Knohl SJ, Scheinman SJ 2004 Inherited hypercalciuric syndromes:
Dents disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1). Semin Nephrol 24:55 60
Bockenhauer D, Bokenkamp A, vant Hoff W, Levtchenko E, Kistvan Holthe JE, Tasic V, Ludwig M 2008 Renal phenotype in Lowe
syndrome: a selective proximal tubular dysfunction. Clin J Am Soc
Nephrol 3:1430 1436
Karet FE 2002 Inherited distal renal tubular acidosis. J Am Soc
Nephrol 13:2178 2184
Shokeir AA, Abdulmaaboud M 2001 Prospective comparison of
nonenhanced helical computerized tomography and Doppler ultrasonography for the diagnosis of renal colic. J Urol 165:1082
1084
Pak CY, Peterson R, Poindexter JR 2001 Adequacy of a single stone
risk analysis in the medical evaluation of urolithiasis. J Urol 165:
378 381
Parks JH, Goldfisher E, Asplin JR, Coe FL 2002 A single 24-hour
urine collection is inadequate for the medical evaluation of nephrolithiasis. J Urol 167:16071612
Parks JH, Coe FL 1996 The financial effects of kidney stone prevention. Kidney Int 50:1706 1712
Werness PG, Brown CM, Smith LH, Finlayson B 1985 EQUIL2: a
BASIC computer program for the calculation of urinary saturation.
J Urol 134:12421244
Moe OW, Pearle MS, Sakhaee K 2011 Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int 79:385392
1859
109. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A

1996 Urinary volume, water and recurrences in idiopathic calcium
nephrolithiasis: a 5-year randomized prospective study. J Urol 155:
839 843
110. Curhan GC, Willett WC, Speizer FE, Stampfer MJ 1998 Beverage
use and risk for kidney stones in women. Ann Intern Med 128:
534 540
111. Taylor EN, Curhan GC 2008 Fructose consumption and the risk
of kidney stones. Kidney Int 73:207212
112. Goodman JW, Asplin JR, Goldfarb DS 2009 Effect of two sports
drinks on urinary lithogenicity. Urol Res 37:41 46
113. Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U,
Novarini A 2002 Comparison of two diets for the prevention of
recurrent stones in idiopathic hypercalciuria. N Engl J Med 346:
77 84
114. Hiatt RA, Ettinger B, Caan B, Quesenberry Jr CP, Duncan D,
Citron JT 1996 Randomized controlled trial of a low animal protein, high fiber diet in the prevention of recurrent calcium oxalate
kidney stones. Am J Epidemiol 144:2533
115. Traxer O, Huet B, Poindexter J, Pak CY, Pearle MS 2003 Effect of
ascorbic acid consumption on urinary stone risk factors. J Urol
170:397 401
116. Meschi T, Maggiore U, Fiaccadori E, Schianchi T, Bosi S, Adorni
G, Ridolo E, Guerra A, Allegri F, Novarini A, Borghi L 2004 The
effect of fruits and vegetables on urinary stone risk factors. Kidney
Int 66:24022410
117. Laerum E, Larsen S 1984 Thiazide prophylaxis of urolithiasis. A
double-blind study in general practice. Acta Med Scand 215:383
389
118. Ettinger B, Citron JT, Livermore B, Dolman LI 1988 Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium
hydroxide does not. J Urol 139:679 684
119. Ohkawa M, Tokunaga S, Nakashima T, Orito M, Hisazumi H
1992 Thiazide treatment for calcium urolithiasis in patients with
idiopathic hypercalciuria. Br J Urol 69:571576
120. Borghi L, Meschi T, Guerra A, Novarini A 1993 Randomized
prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol
22(Suppl 6):S78 S86
121. Yendt ER, Guay GF, Garcia DA 1970 The use of thiazides in the
prevention of renal calculi. Can Med Assoc J 102:614 620
122. Coe FL, Kavalach AG 1974 Hypercalciuria and hyperuricosuria in
patients with calcium nephrolithiasis. N Engl J Med 291:1344
1350
123. Coe FL 1977 Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria,
or no metabolic disorder. Ann Intern Med 87:404 410
124. Yendt ER, Cohanim M 1978 Prevention of calcium stones with
thiazides. Kidney Int 13:397 409
125. Backman U, Danielson BG, Johansson G, Ljunghall S, Wikstrom
B 1979 Effects of therapy with bendroflumethiazide in patients
with recurrent renal calcium stones. Br J Urol 51:175180
126. Maschio G, Tessitore N, DAngelo A, Fabris A, Pagano F, Tasca
A, Graziani G, Aroldi A, Surian M, Colussi G, Mandressi A,
Trinchieri A, Rocco F, Ponticelli C, Minetti L 1981 Prevention of
calcium nephrolithiasis with low-dose thiazide, amiloride and allopurinol. Am J Med 71:623 626
127. Pak CY, Peters P, Hurt G, Kadesky M, Fine M, Reisman D, Splann
F, Caramela C, Freeman A, Britton F, Sakhaee K, Breslau NA 1981
Is selective therapy of recurrent nephrolithiasis possible? Am J Med
71:615 622
128. Nicar MJ, Peterson R, Pak CY 1984 Use of potassium citrate as
potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol 131:430 433
129. Pak CY, Fuller C, Sakhaee K, Preminger GM, Britton F 1985 Longterm treatment of calcium nephrolithiasis with potassium citrate.
J Urol 134:1119
130. Pak CY, Sakhaee K, Fuller C 1986 Successful management of uric
1860
131.
132.
133.
134.
135.
136.
Sakhaee et al.
Kidney Stones 2012
acid nephrolithiasis with potassium citrate. Kidney Int 30:422

428
Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CY 1993 Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 150:17611764
Hofbauer J, Hobarth K, Szabo N, Marberger M 1994 Alkali citrate
prophylaxis in idiopathic recurrent calcium oxalate urolithiasisa
prospective randomized study. Br J Urol 73:362365
Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A 1997 Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol 158:
2069 2073
Soygur T, Akbay A, Kupeli S 2002 Effect of potassium citrate
therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a
randomized controlled trial. J Endourol 16:149 152
Kang DE, Maloney MM, Haleblian GE, Springhart WP, Honeycutt EF, Eisenstein EL 2007 Effect of medical management on recurrent stone formation following percutaneous nephrolithotomy.
J Urol 177:17851788; discussion 1788 1789
Sakhaee K, Nicar M, Hill K, Pak CY 1983 Contrasting effects of
potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int 24:
348 352
137. Ettinger B, Tang A, Citron JT, Livermore B, Williams T 1986

Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 315:1386 1389
138. Barbey F, Joly D, Rieu P, Mejean A, Daudon M, Jungers P 2000
Medical treatment of cystinuria: critical reappraisal of long-term
results. J Urol 163:1419 1423
139. Dahlberg PJ, van den Berg, Kurtz SB, Wilson DM, Smith LH 1977
Clinical features and management of cystinuria. Mayo Clin Proc
52:533542
140. Pak CY, Fuller C, Sakhaee K, Zerwekh JE, Adams BV 1986 Management of cystine nephrolithiasis with -mercaptopropionylglycine. J Urol 136:10031008
141. Chow GK, Streem SB 1996 Medical treatment of cystinuria: results
of contemporary clinical practice. J Urol 156:1576 1578
142. Williams JJ, Rodman JS, Peterson CM 1984 A randomized doubleblind study of acetohydroxamic acid in struvite nephrolithiasis.
N Engl J Med 311:760 764
143. Griffith DP, Khonsari F, Skurnick JH, James KE 1988 A randomized trial of acetohydroxamic acid for the treatment and prevention
of infection-induced urinary stones in spinal cord injury patients.
J Urol 140:318 324
144. Griffith DP, Gleeson MJ, Lee H, Longuet R, Deman E, Earle N
1991 Randomized, double-blind trial of Lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi. Eur Urol 20:243247
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S P E C I A L

Kidney Stones 2012: Pathogenesis, Diagnosis,

seen in kidney stone disease, primarily occurring in

Approximately 80% of calcium kidney stones are calcium

J Clin Endocrinol Metab, June 2012, 97(6):18471860

Kidney Stones 2012

J Clin Endocrinol Metab, June 2012, 97(6):18471860

Causes and treatment of kidney stone formation

Calcium kidney stones

Hydrochlorothiazide (50 mg/d)

Allopurinol (100 300 mg/d)

Rare, severe skin hypersensitivity

Alkali treatment (30 60 mEq/d)

Alkali treatment is generally safe

Intestinal hyperabsorption of oxalate:

Alkali treatment (30 60 mEq/d)

Potassium alkali is preferred to avert complications

Acidic urine: diet, diarrhea, low urine

Alkali treatment (30 60 mEq/d)

Low urine volume

Alkali treatment (30 60 mEq/d)

Pyridoxine (2550 mg/d) in type

Potassium alkali is preferred to avert complications

Unduly acidic urine

Potential side effects

Renal tubular defect in dibasic amino acid

Alkali treatment (30 60 mEq/d)

Acetohydroxamic acid (10 15

Alkali treatment is generally safe

J Clin Endocrinol Metab, June 2012, 97(6):18471860

ciuria, hyperuricosuria, hypocitraturia, hyperoxaluria,

Renal leak hypercalciuria

Kidney Stones 2012

calcium reabsorption is accompanied by enhanced PTH,

J Clin Endocrinol Metab, June 2012, 97(6):18471860

encountered in 20 60% of calcium nephrolithiasis (50).

J Clin Endocrinol Metab, June 2012, 97(6):18471860

acids interacting with divalent cations in the lumen of the

found in both SLC3A1 alleles, type B if

FIG. 1. Causes of non-calcium kidney stone formation. A, UA stones; B, cystine stones; C,

Genetic basis of UA stone formation

Infection and rare stones

J Clin Endocrinol Metab, June 2012, 97(6):18471860

creased fluid intake and/or increased perspiration are at

Kidney Stones 2012

J Clin Endocrinol Metab, June 2012, 97(6):18471860

Diagnostic evaluation and interpretation of laboratory profiles

Expected daily values

Random 24-h urine profile and

1525 mg/kg body weight

4-h Ca:Cr ratio after a 1-g oral

Z-score 2; T-score 2.5

Simplified fasting blood

J Clin Endocrinol Metab, June 2012, 97(6):18471860

Major clinical trials in pharmacotherapy of calcium and non-calcium nephrolithiasis

First author (Ref.)

Decreased new stone formation and prolonged

Chlorthalidone vs. Mg hydroxide vs. placebo

Trichlormethiazide vs. no treatment

Decreased number of stone events or invasive

Decreased new stone formation

Decreased stone events

Decreased new stone formation

Decreased stone recurrence