International Journal of Urology (2017) 24, 32--38
13187
Review Article
Pathophysiology-based treatment of urolithiasis
Takahiro Yasui, Atsushi Okada, Shuzo Hamamoto, Ryosuke Ando, Kazumi Taguchi, Keiichi Tozawa
and Kenjiro Kohri
Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Abbreviations & Acronyms
CHD = coronary heart
disease
EPA = eicosapentaenoic acid
GWAS = genome-wide
association studies
MCP-1 = monocyte
chemoattractant protein 1
MPT = mitochondrial
permeability transition
NADPH = nicotinamide
adenine dinucleotide
phosphate
NIM811 = N-methyl-4-
isoleucine cyclosporine
OPN = osteopontin
OS = oxidative stress
PPAR = peroxisome
proliferator-activated receptor
ROS = reactive oxygen
species
SNP = single nucleotide
polymorphism
Correspondence: Takahiro
Yasui M.D., Ph.D., Department
of Nephro-urology, Nagoya City
University Graduate School of
Medical Sciences, 1 Kawasumi,
Mizuho-cho, Mizuho-ku,
Nagoya 467-8601, Japan. Email:
yasui@med.nagoya-cu.ac.jp
Received 19 April 2016;
accepted 18 July 2016.
Online publication 18 August
2016
32
doi: 10.1111/iju.
Abstract: Urolithiasis, a complex multifactorial disease, results from interactions
between environmental and genetic factors. Epidemiological studies have shown the
association of urolithiasis with a number of lifestyle-related diseases, including cardio-
vascular diseases, hypertension, chronic kidney disease, diabetes and metabolic
syndrome. Elucidation of the mechanisms underlying urinary stone formation will enable
development of new preventive treatments. The present article reviews the epidemiology,
pathophysiology and potential treatment of urolithiasis. Recent literature has shown that
oxidative stress and reactive oxygen species could be one such mechanistic pathway.
Calcium oxalate crystals adhering to renal tubular cells are incorporated into the cells
through the involvement of osteopontin. Stimulation of crystalcell adhesion impairs
acceleration of the mitochondrial permeability transition pore in tubular cells, resulting in
mitochondrial collapse, oxidative stress and activation of the apoptotic pathway in the
initial steps of renal calcium crystallization. With regard to genetic factors, studies show
that single nucleotide polymorphisms in genes encoding calcium-sensing receptor,
vitamin D receptor and osteopontin are correlated with urolithiasis. Genome-wide
association studies have shown that CLDN14 and NPT2 are associated with urolithiasis in
Caucasian and Japanese populations, respectively. Thus, single nucleotide polymorphism
analysis would aid in the prediction of urolithiasis risk and recurrence. New diagnostic
methods and preventive approaches, along with complete removal of stones, will improve
the management of urolithiasis.
Key words: calcium oxalate, kidney calculi, mitochondria, nephrolithiasis, oxidative
stress, urolithiasis.
Introduction
Urolithiasis, also known as the formation of urinary stones, is a health problem that affects
nearly all populations worldwide; it causes severe acute back pain and occasionally leads to
more severe complications, such as pyelonephritis or acute renal failure. Kidney stone formation
is a common urological problem with a lifetime prevalence of approximately 10% in men and
6% in women, and its prevalence has been increasing in many developed countries,14 with a
recurrence rate of nearly 60% within 10 years after initial treatment.5
Urolithiasis is a multifactorial disease resulting from complex interactions between environ-
mental and genetic factors. Environmental factors, such as lifestyle, obesity, dietary habits
and dehydration, have been implicated in urolithiasis development,6,7 whereas hormonal,
genetic or anatomical factors might also inuence its pathogenesis.8
Adequate uid intake and dietary modications might successfully prevent stone recur-
rence. Thiazide, potassium alkali, allopurinol and tiopronin have been shown to be effective
in the treatment of different types of stones. However, few novel therapies have emerged over
the past decade, and treatment of certain types of stones remains challenging. Studies evaluat-
ing the pathophysiology and pathogenesis of stone disease are currently ongoing.
More than 80% of patients with renal stones suffer from urolithiasis caused by calcium
oxalate.1 Although urolithiasis is a disease known from ancient times, even now, many
researchers are attempting to elucidate the mechanism of calcium oxalate renal stone forma-
tion. The physiochemical mechanisms of stone formation through precipitation, growth,
aggregation and concretion of various lithogenic salts in urine are still in dispute. In addition,
recent studies have emphasized that the interaction between crystals and renal tubular
2016 The Japanese Urological Association

epithelial cells, including the adhesion or endocytosis of crys-
tals by cells, is an important factor in stone formation.911
Furthermore, some reports have suggested that renal tubular
epithelial cell injury in crystalcell interactions occurs more
easily as a result of pre-existing cell injury.12,13 Some
researchers have suggested that calcium oxalate kidney stones
form while attached to Randall plaques, the subepithelial
deposits on renal papillary surfaces, and that this process is
triggered by ROS and OS.14
The present review primarily focuses on four topics: (i)
urolithiasis as a systemic disorder; (ii) renal cell injury and
OS in stone formation; (iii) potential preventive approaches
based on pathophysiological mechanisms; and (iv) genetic
factors of urolithiasis.
Urolithiasis as a systemic disorder and
epidemiological study-associated
disease
The annual incidence of upper urinary tract stones in Japan
has increased almost threefold, from 43.7 per 100 000 (63.8
for men and 24.3 for women) in 1965, to 134 per 100 000
(192 for men and 79.3 for women) in 2005.1 Although this
trend might be attributable in part to advances in diagnostic
imaging, increased diagnosis of asymptomatic stones by med-
ical checkup and an aging population, Westernized eating
habits and lifestyle changes in the Japanese population have
been proposed as the main reasons for this increase; this con-
clusion suggests that urolithiasis is a lifestyle-related disease.
Recent epidemiological studies have shown an increased
prevalence of kidney stones in patients with lifestyle-related
diseases, such as obesity,7 type 2 diabetes15 and hyperten-
sion.16,17 Collectively, these medical conditions are now
known as metabolic syndrome, which has received a great
deal of attention in recent years as a risk factor for cardiovas-
cular disease development.18 Metabolic syndrome has also
been associated with kidney stone disease,19,20 and several
studies have found increased urinary oxalate and calcium
excretion, and decreased citrate excretion in patients with
obesity or diabetes.2123 Other studies reported that hyperten-
sion was associated with hypercalciuria and hypocitra-
turia.24,25 These changes in urinary salt excretion observed in
patients with metabolic syndrome promote the formation of
calcium oxalate stones.
CHD risk factors, including overweight/obesity, hyperten-
sion, gout/hyperuricemia, dyslipidemia and chronic kidney
disease, are positively associated with kidney stone forma-
tion. Ando et al. investigated the association between con-
ventional risk factors of CHD, including overweight/obesity,
hypertension, diabetes mellitus, gout/hyperuricemia, dyslipi-
demia, and chronic kidney disease and kidney stone develop-
ment in 13 418 participants, of whom 404 patients with
current urolithiasis (3.0%) had kidney stones on ultrasound,
and 1231 former urolithiasis patients (9.2%) had a history of
kidney stones, but no kidney stones observed on medical
examination.26 Body mass index, systolic and diastolic blood
pressure, and serum uric acid were signicantly higher in past
and current urolithiasis patients than in controls. Logistic
2016 The Japanese Urological Association
Pathophysiology of urolithiasis
regression analysis showed that the multivariate adjusted odds
ratios for overweight/obesity, hypertension, gout/hyper-
uricemia and chronic kidney disease signicantly increased
progressively from controls to former urolithiasis patients and
then current urolithiasis patients. Therefore, individuals who
develop kidney stones, even in the past, are likely to have
accumulated risk factors for CHD. A Japanese study provided
additional evidence that clustering of metabolic syndrome
traits increased disease severity in patients with kidney
stones. These ndings suggest that kidney stone disease
might also be considered a systemic disorder linked to insulin
resistance.27 In the present study, after adjustment for age
and sex, the presence of metabolic syndrome traits was asso-
ciated with signicantly increased odds of having hypercalci-
uria, hyperuricosuria, hyperoxaluria and hypocitraturia.27
Furthermore, in ob/ob mice, a model of human metabolic
syndrome, adiponectin expression was decreased in renal
tubular cells. Administration of adiponectin, an adipose-
derived hormone, was shown to inhibit urinary stone forma-
tion in these mice.28 Furthermore, administration of glyoxy-
late, an oxalate precursor, results in more calcium oxalate
deposits in ob/ob mice compared with that in lean mice.28
Increases in luminal mineral and lipid density, and pro-
inammatory adipocytokines and macrophages facilitated
renal crystal formation in mice with metabolic syndrome.29
These results suggest that obesity creates an environment
favorable to urinary stone formation.
Given the strong association of kidney stones and CHD,
and the effectiveness of CHD prevention strategies, kidney
stones could be an indicator of patients at risk for CHD.
These ndings suggest that a health intervention program
designed to maintain normal blood pressure and serum uric
acid levels in current and former urolithiasis patients could
decrease the risk of urinary stone formation, chronic kidney
disease and subsequent CHD in this population.
Renal cell injury and oxidative stress in
renal stone formation
Experimental and clinical studies provide evidence for the
production of ROS and the development of OS in the kid-
neys of stone-forming patients. Khan et al. showed the path-
ways involved in NADPH oxidase regulation and ROS
production.14 Decreased anti-oxidant capacity or persistently
supersaturated urine, leading to increased crystallization,
might result in OS and stone disease. Hirose et al. recently
examined microstructural changes in renal tubular cells in the
early stage of urinary stone formation.30 The internal struc-
ture of mitochondria underwent destruction, vacuolization
and calcication. Microvilli decreased, shortened and disap-
peared.31 Subsequently, crystals adhering to epithelial cells
and occupying the tubular lumen were detected in the renal
cortexmedulla junction. OPN, which was identied as one
of the organic (matrix) components of urinary calcium
stones,32 is essential in urinary stone formation and promotes
stone formation.33 By using ultramicrostructural observations
and immuno-transmission electron microscopy, OPN expres-
sion was then observed on the luminal side of renal tubular
33
T YASUI ET AL.
cells and gradually detected in crystal nuclei in the tubular
lumen. Crystal nuclei contained collapsed mitochondria with
cell debris. Furthermore, crystals in mice receiving green tea,
an anti-oxidative drink, were markedly decreased.30,34
Renal tubular cell injury is regarded as a major risk factor
for the initial formation of urinary stones.30,35 Exposure to
calcium oxalate crystals induces OS, as shown by increased
lipid peroxidation, increased free radical generation and
increased levels of arachidonic acid released by phospholi-
pase A.36,37 We recently discovered that reducing OS with
compounds, such as green tea, vitamin E and superoxide dis-
mutase, was associated with decreased cellular injury and
crystal deposition.38,39
Khan has emphasized that ROS are produced during inter-
actions between crystals and renal cells, and are responsible
for various cellular responses.40 Exposure of renal epithelial
cells to crystals results in the increased synthesis of OPN,
bikunin, heparin sulfate, MCP-1 and prostaglandin E2, which
are known to participate in inammatory processes and extra-
cellular matrix production. Calcium oxalate crystal deposition
in rat kidneys also activates the reninangiotensin system.
Umekawa showed that pretreatment of renal epithelial cells
in vitro with diphenylene iodine chloride, an inhibitor of
NADPH oxidase, leads not only to a reduction in the produc-
tion of ROS, MCP-1 and OPN, but also to reduced oxalate
and calcium oxalate crystal-induced cell injury.41 They also
investigated the inuence of two free radical scavengers,
citrate and vitamin E, on prevention of the shock wave-
induced free radical surge.42 The results established the great
potential for the therapeutic application of anti-oxidants and
free radical scavengers to reduce stone recurrence, particu-
larly after shock wave lithotripsy, which is itself known to
generate ROS and cause renal damage.43 Umekawa et al.
reported that the kidneys of hyperoxaluric rats treated with
(2) (3)
Activation of Mitochondrial
Cyclophilin D injury
Renal tubular cell
(1)
COM crystal
Mitochondria
Fig. 1 Proposed pathway of kidney stone formation. In the proposed pathway, calcium oxalate monohydrate (COM) crystals attach to renal tubular cells (1), lead-
ing to activation of cyclophilin D (2). Subsequently, mitochondrial collapse (3) and oxidative stress occur (4). These events activate apoptosis, cell injury (5) and
osteopontin expression (6). Thereafter, collapsed mitochondria and fragmented microvilli drop off into the urine (7) and condense into kidney stones (8).
34
the angiotensin II type I receptor blocker, candesartan, had
fewer calcium oxalate crystal deposits, reduced OPN expres-
sion and reduced malondialdehyde levels compared with that
in untreated rats.44
OS caused by mitochondrial collapse is involved in the
early phase of kidney stone disease in mice.30,31 As mito-
chondria are the sites of aerobic metabolism, they are major
sources of intracellular ROS, and mitochondrial ROS produc-
tion increases in response to cell damage or increased
stress.44
We recently examined the pathogenesis of the early phase
of urinary stone formation in association with renal tubular
cell injury. Calcium oxalate crystals adhere to epithelial cells,
and NADPH oxidase generates superoxide, which activates
cyclophilin D in mitochondria. Acceleration of the MPT
resulted in mitochondrial collapse, OS, activation of the
apoptotic pathway, and strong expression of OPN in the ini-
tial process of renal calcium crystallization in both in vitro
and in vivo experiments (Fig. 1).45 Cyclosporin A and
NIM811, a novel selective inhibitor of cyclophilin D activa-
tion, successfully blocked the acceleration of MPT, expres-
sion of OPN and renal calcication.45,46 As NIM811 is a 4-
substituted cyclosporin that does not bind to cyclophilin A, it
lacks immunosuppressive and anti-inammatory activities.
NIM811 and cyclosporin A have identical constitution formu-
las, but different structural formulas.
Cyp D activation induced the acceleration of MPT, thereby
changing the mitochondrial transmembrane potential and induc-
ing mitochondrial collapse. Cytochrome c is an important pro-
tein that induces apoptosis. On mitochondrial collapse,
cytochrome c is released into the cytosol and binds to cytosolic
apoptotic protease-activating factor 1, thereby activating cas-
pase-9 and caspase-3, and initiating apoptosis. During this pro-
cess, ROS are also released from the intramembranous
(4) (5)
Oxidative Cell injury
stress
(6)
Expression of
Osteopontin
Stone
(7) (8)
Collapsed mitochondria and Stone formation
fragmented microvilli drop off
COM crystal Fragmented microvilli Osteopontin
2016 The Japanese Urological Association

compartment into the cytosol, further injuring renal tubular
cells.47 Inhibiting Cyp D activation prevented renal calcium
crystallization caused by mitochondrial collapse, OS and activa-
tion of the apoptosis pathway. Targeting Cyp D activation
through pharmacological and/or genetic approaches might offer
new therapeutic strategies for kidney stone disease.
Potential preventive approaches based
on the mechanism of stone formation
There are many common features between urolithiasis and
atherosclerosis. OPN, calcium and phosphate acid are com-
monly regarded as the components of calcication.48 Both
diseases develop at the highest frequency in middle-aged and
elderly males, and postmenopausal females,4952 and both
involve macrophages and cytokines as inducers.53 As the
incidence of urinary stones is high in developed countries,
Westernized diets have been implicated as the main cause;1
however, we recently showed that administration of animal
protein to rats did not cause urinary stones, although meta-
bolic acidosis occurred and urinary calcium excretion
increased. Thus, we considered that excess ingestion of
cholesterol, the main cause of atherosclerosis, could be the
cause of urinary stones. When rats were fed a 3% choles-
terol-loaded diet, OPN mRNA levels in renal tubular cells
and kidney increased, followed by urinary stone formation.54
In addition, administration of EPA, used to treat atherosclero-
sis, reduced OPN levels, and inhibited stone formation in
both humans and rats.5557 The mechanism of this cholesterol
load-induced OPN increase and subsequent stone formation
has not been claried. It has been assumed that excess
cholesterol ingestion causes binding of intestinal bile acid to
cholesterol; this process frees oxalic acid and increases its
absorption from the intestine, resulting in an increase in uri-
nary oxalic acid excretion. An increase in oxalic acid levels
is considered one of the mechanisms of excess cholesterol
ingestion-induced stone formation.54,58,59
Abnormal lipid metabolism has already been observed clin-
ically in urinary stone patients.7,15 These patients tend to
have signicantly elevated serum cholesterol levels. Further-
more, calcication of the aortic wall was observed by com-
puted tomography in just 5% of young, healthy Japanese
subjects, but in approximately 40% of stone patients.60 As
EPA administration is effective for the prevention of hyper-
lipidemia and atherosclerosis, EPA might be a possible
method of preventing calcium stone formation. Epidemiologi-
cal study cannot show the preventive effect against urolithia-
sis;15 however, clinical administration of EPA has shown a
preventive effect against urolithiasis.56,57 EPA might be one
such potential preventive therapy.
Adipocytokines secreted by adipocytes play an important
role in metabolic syndrome.61,62 We observed that adiponectin
expression was decreased in renal tubular cells in urolithiasis
model mice when OPN expression was enhanced, and that this
change resulted in urinary stone formation.28 Mice with a
knocked-out appetite center hormone, leptin, became obese,
and adiponectin levels decreased. OPN was markedly
expressed in the kidneys of leptin-decient mice, and urinary
stone formation was observed. Our epidemiological study
2016 The Japanese Urological Association
Pathophysiology of urolithiasis
recently showed the impact of insulin resistance, insulin and
adiponectin on patients with urinary stones in the Japanese
population.63 Administration of adiponectin, an adipose-
derived hormone, was shown to inhibit urinary stone formation
in these mice,28 as adiponectin prevents atherosclerotic vascu-
lar stenosis.61 Thus, adiponectin might be another preventive
therapy for urolithiasis. Furthermore, anti-obesity medications
might also have preventive effects against urolithiasis.
Pioglitazone, a PPAR-gamma activator used to treat dia-
betes, has anti-inammatory and anti-oxidative effects, and
can improve insulin sensitivity. Our recent epidemiological
study showed that homeostasis model assessment of insulin
resistance and serum insulin levels are associated with a his-
tory of kidney stones in Japanese women.63 Therefore, we
hypothesized that pioglitazone is a potential new therapy for
renal stone disease, and investigated its effects on stone for-
mation in rat models. Accordingly, we recently reported the
inhibitory effect of pioglitazone on calcium deposition
through renal tubular cell protection, and its anti-oxidative
and anti-inammatory effects in a urolithiasis model mouse.64
Signicantly fewer renal stones formed in rats treated with
pioglitazone than in the control group. Furthermore, the crys-
tals were smaller in rats treated with pioglitazone than in the
untreated control group. In pioglitazone-treated rats, MCP-1
levels were signicantly lower and superoxide dismutase
levels signicantly higher than those in the control group.
PPAR-gamma plays a repressive role in the inammatory
response. Thus, pioglitazone might suppress stone formation
by reducing OS and renal tubular cell injury. These results
suggest that PPAR-gamma agonists could be a potential new
treatment for renal stone formation.
Genetic factors of kidney stone disease
If a genetic predisposition to urolithiasis can be detected, pro-
phylaxis can be achieved. Environmental factors, such as life-
style, obesity, dietary habits and dehydration, have been
implicated in urolithiasis development,7 whereas hormonal,
genetic or anatomical factors might also inuence its patho-
genesis.8 In addition, a family history of the disease has been
reported to increase the disease risk in men by 2.57-fold,65
and the concordance rate of the disease in monozygotic twins
was found to be higher than that in dizygotic twins (32.4%
vs 17.3%),66 suggesting that genetic factors have a pivotal
role in the etiology of urolithiasis.
SNPs are used as tools for identifying genetic markers of
disease. Furthermore, they play an important role in determin-
ing the genetic risk of complex human diseases, such as can-
cer, cardiovascular disease, diabetes, mental illness and
autoimmune disease, with the ultimate goal of improving pre-
ventive strategies, diagnostic tools and therapies.67 Urinary
calcium stones are likely to be caused by both genetic and
non-genetic (environmental) factors. Recently, some genes
associated with urinary calcium stones, such as the vitamin D
receptor, E-cadherin, urokinase and vascular endothelial
growth factor, have been investigated in SNP studies.
Previous SNP analyses have shown that genetic polymor-
phisms of the genes encoding the calcium-sensing receptor,68
vitamin D receptor,69 OPN70,71 and matrix Gla protein72 are
35
T YASUI ET AL.

highly correlated with kidney stone formation (Table 1).71
These studies avoided candidate genes, which enabled identi-
cation of otherwise unpredictable loci involved in calcium
nephrolithiasis. GWAS represent a fundamental advance for
genetic research, but require specic bioinformatics software
for data analysis and a large number of patients to maintain
statistical power.73 Despite their importance, GWAS ndings
often explain a small proportion of the causes of complex
non-Mendelian diseases.74
Table 2 shows the genes identied by GWAS that were
found to be associated with calcium stone formation. Previ-
ous data from GWAS in Caucasian populations (from Iceland
and the Netherlands) showed that CLDN14 is associated with
urolithiasis, and revealed discovered common, synonymous
variants in the CLDN14 gene associated with kidney stone
formation (odds ratio 1.25 and P = 4.0 9 10
12 for
rs219780[C]).75 Approximately 62% of the general popula-
tion is homozygous for rs219780[C], and is estimated to have
a 1.64-fold greater risk of developing the disease compared
with non-carriers. The CLDN14 gene is expressed in the kid-
ney and regulates paracellular permeability at epithelial tight
junctions.
Furthermore, another genome-wide meta-analysis in
12 865 Caucasian and Indian Asian individuals showed that
calcium-sensing receptor variants are associated with serum
calcium levels.76 This meta-analysis reported that serum cal-
cium is associated with SNPs in or near the calcium-sensing
receptor gene on chromosome 3q13. The top hit, with a P-
value of 6.3 9 10
37, was rs1801725, a missense variant,
explaining 1.26% of the variance in serum calcium.
In 2012, a GWAS of urolithiasis in the Japanese popula-
tion, including 5796 patients with urolithiasis and 17 344
healthy controls, was carried out.77 This study identied three
novel loci for urolithiasis at 5q35.3 (RGS14-SLC34A1-PFN3-
F12), 7p14.3 (INMT-FAM188B-AQP1) and 13q14.1 (DGKH).
Furthermore, replication was carried out for these three loci
using independent samples in casecontrol studies.78 The loci
rs12654812 in 5q35.3, rs12669187 in 7p14.3 and rs7981733
in 13q14.1 were signicantly associated with urolithiasis, and
a meta-analysis of current and previous GWAS results also
showed a signicant association with urolithiasis (P = 1.42 9
10
13, 1.25 9 10
15 and 5.81 9 10
10, respectively). That
replication study observed a cumulative effect with these
three SNPs; individuals with three or more risk alleles had a
5.9-fold higher risk of urolithiasis development than those
with only one risk allele.
The three GWAS studies discussed above identied differ-
ent loci as the most important ones affecting urolithiasis. It
has been suggested that these differences might be the result
of GWAS limitations or heterogeneity in race or the sample
set. Many researchers hope to trace individual genetic proles
to dene calcium stone risk, response to treatment and pre-
ventive lifestyle. Modern high-throughput technology might
provide the information to full this hope. However, genetic
factors explain approximately 50% of predisposition to stone
formation, and the contribution of a particular gene to litho-
genesis might change as a function of genetic and environ-
mental context. In contrast, environmental factors and diet
explain the residual predisposition to stone formation, and
might modify gene expression at different biological levels.79
These factors might not only inuence the phenotypic effects
of gene products, but also modify gene transcription and
expression.
Conclusions
Various theories of human kidney stone pathogenesis sug-
gest that stone formation is a complex process. The patho-
genesis of calcium oxalate stone formation is a multistep
process that involves nucleation, crystal growth, crystal
aggregation and crystal retention. It appears that the process
of renal tubular cell injury is of key importance in renal

Table 1 Typical genes and SNPs associated with calcium urolithiasis

Gene Coded protein Locus Case/controls (n/n) SNP Region Ref.

CaSR Calcium-sensing receptor 3q21.1 167/214 rs7652589 50 -UTR [68]
rs1501899 Intron 1
VDR Vitamin D receptor 12q1214 110/127 rs10735810 Start codon [69]
rs1544410 Intron 8
rs7975232 Intron 8
spp1 Osteopontin 4q22.1 126/214 -145 and -144 Promoter [71]
MGP Matrix-gla protein 12p12.3 122/125 rs4236 Exon 4 [72]

Table 2 Genes identified by GWASs that are associated with calcium urolithiasis

Gene Protein Locus Case/controls (n/n) Markers, n Associated SNPs Ref.

CLDN14 Claudin-14 21q22.3 3773/42 510 (in 3 steps) 303 120 rs219780 [75]
rs219780
SLC34A1 NPT2a (type II sodium-phosphate co-transporter family) 5q35.3 5892/17 809 (in 3 steps) 712 726 rs11746443 [77]
AQP1 Aquaporin 1 7p14.3 5892/17 809 (in 3 steps) 712 726 rs1000597 [77]
DGKH Diacylglycerol kinase 13q14.1 5892/17 809 (in 3 steps) 712 726 rs4142110 [77]

36 2016 The Japanese Urological Association


stone formation. Though many aspects of the mechanism of
renal stone formation remain unclear, it is certain that ROS,
OS and renal tubular cell injury are important factors of
lithogenesis. Here, we have provided a detailed discussion
of several standpoints found to occur in stones that modulate
the process of stone formation, thereby leading to better
understanding of the pathophysiology and pathogenesis of
kidney stone disease. Many aspects of the mechanism under-
lying renal stone formation remain unclear at present; hence,
a better understanding of this intricate mechanism will lead
to the development of novel strategies for preventing this
disease.
Acknowledgments
This work was supported by Grants-in-Aid from the Ministry
of Education, Culture, Science and Technology (16790922,
18791132, 20591887, 23592375, 23249074, 24659716,
24592434, 25462520, 25670685, 15K10627); the Takeda
Science Foundation; and the Japanese Urological Association.
Conflict of interest
None declared.
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Editorial Comment
Editorial Comment to Pathophysiology-based treatment of urolithiasis
As we all know, urolithiasis is a complex multifactorial dis-
ease. Yasui, Kohri and their team have been carrying out a
number of approaches to identify the mechanism as well as
treatment strategy against urolithiasis for over 20 years. Their
38
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approach covered basic research, clinical research, genetic
analysis and epidemiology.
As described in the current article,1 the incidence of upper
urinary tract stones in Japan increased threefold in the
2016 The Japanese Urological Association