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QJM: An
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Gallstones Increase the Risk
of Developing
Renal Stones: A Nationwide
Population-
based Retrospective
Cohort Study
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QJM: An International Journal of Medicine
QJM2013636.R1
Original Article
n/a
Li, ChiaHsiang; China Medical University Hospital, Department of Internal
Medicine Sung, FungChang; China Medical University Hospital,
Management Office for Health Data Wang, YuChiao; China Medical
University Hospital, Management Office for Health Data Lin, Dana; China
Medical University Hospital, Management Office for Health Data Kao, ChiaHung; China Medical University, School of Medicine
Epidemiology, Gastroenterology, Nephrology
Page 1 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
Revised Manuscript: ID QJM2013636
Gallstones Increase the Risk of Developing Renal Stones: A Nationwide Populationbased Retrospective Cohort
Study
Running title: Gallstones and Renal Stones
1,23,5 334,5*
ChiaHsiang Li, FungChang Sung, YuChiao Wang, Dana Lin, ChiaHung Kao
1
From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical
2
3
University Hospital, Taichung, Taiwan and China Medical University, Taichung, Taiwan; Management Office
4
for Health Data, China Medical University Hospital, Taichung, Taiwan; Department of Nuclear Medicine and
5
PET Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medicine
Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
*Corresponding author: ChiaHung Kao, MD, Graduate Institute of Clinical Medicine Science and School of
Medicine, College of Medicine, China Medical University, Taichung, Taiwan. No. 2, YuhDer Road, Taichung
404, Taiwan. Tel: 886422052121, ext. 7412, Fax: 886422336174, Email: d10040@mail.cmuh.org.tw.
Manuscripts submitted to QJM: An International Journal of Medicine Page 2 of 43
These authors’ individual contributions were as follows.
Conception and design: ChiaHsiang Li, Dana Lin, ChiaHung Kao. Administrative support: FungChang Sung.
Collection and assembly of data: All authors. Data analysis and interpretation: ChiaHsiang Li, YuChiao Wang,
ChiaHung Kao. Manuscript writing: All authors. Final approval of manuscript: All authors.
Funding
This work was supported by the study projects (DMR101036) in our hospital; Taiwan Department of Health
Clinical Trial and Research Center and for Excellence (DOH102TDB111004), Taiwan Department of Health
Cancer Research Center for Excellence (DOH102TDC111005); and International ResearchIntensive Centers of
Excellence in Taiwan (IRiCE) (NSC1012911I002303). The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for
this study.
Conflict of interest
The authors declare that they have no conflicts of interest.
Page 3 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
Abstract
Background: This study identifies the effects of gall stone on the risks of developing renal stone in a nationwide
cohort study. Aim: Studies on the association between gall stone and renal stone are scarce. Methods: We
identified patients with gallstones using the catastrophic illness registry of the Taiwan National Health Insurance
Research Database (NHIRD).We selected a comparison cohort, random frequencymatched by age, sex, and index
year, from the general population. We analyzed the risk of renal stones by using Cox proportional hazards
regression models for sex, age, and comorbidities. Results: Of the 23.74 million people in the database, we
followed 25 258 gallstone patients (54.5% female) and 101 029 control patients. The risk of developing renal
stones was 1.68fold greater in gallstone patients, compared with patients without gallstones after adjusting for
age, sex, and comorbidities. The substantially increased risk of renal stones was also significant in gallstone
patients regardless of comorbidities. In the followup period <1 year, the adjusted hazard ratios was 2.51 (95% CI
=2.252.80) compared to nongallstone group. The cumulative incidence of renal stone in the gallstone group was
higher than the nongallstone group (P < .0001, in the log rank test).
Conclusion: This nationwide cohort study demonstrates that the risk of renal stones is significantly higher in
gallstone patients, compared with the general population. This study provides information to enable physicians
to implement adequate prevention measures to decrease both stones formation.
Keywords: Gallstone; Renal stone; Cholelithiasis; Nephrolithiasis.
Manuscripts submitted to QJM: An International Journal of Medicine Page 4 of 43
Abbreviations
National Health Insurance (NHI) National Health Insurance Research Database (NHIRD) National Health
Research Institutes (NHRI)
What’s already known about this topic?
1. Both gallstone and renal stone are highly prevalent.
2. Whether they share a pathophysiological mechanism remains unclear.
What does this article add?
1. This nationwide cohort study demonstrates that the risk of renal stones is significantly higher in gallstone
patients.
2. To enable physicians to implement adequate prevention measures to decrease both stones formation.
Page 5 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
Introduction
Gallstones are common in the general population. The national prevalence of gallstones varies between
1
2
0.1% and 61.5% worldwide. The prevalence in Taiwan was 10.7%. Incidence increases with age and patients
are predominantly female. Gallstones particularly affect premenopausal women.
Gallstones can be divided into 2 major types: cholesterol stones and pigment stones. Unlike in Western
3, 4
countries, pigment stones are prevalent in Asia. Gallstones can be silent or accompanied by various clinical
problems, such as biliary colic, cholecystitis, obstructive jaundice, and pancreatitis. They are a leading cause of
emergency department visits and hospital admission for gastrointestinal problems.
4, 5
Renal stones are also common, and national prevalence varies globally between 2%
68 9
and 20%.In Asia, the prevalence of renal stones varies between 1% and 5%.Unlike gallstones, renal stones are
10
more prevalent among men than women. Recurrent stone formation is also a serious problem, and the incidence
of renal stone recurrence within 10 years has been found to be as high as 50%.
11
Both stones are highly prevalent. They are prominent public health issues and
12, 13
substantially increase the economic burden on national health insurance.Whether they share a
pathophysiological mechanism remains unclear.
Taiwan initiated its National Health Insurance (NHI) program in 1995, and the data available from this
program offer a unique opportunity for research. In the present study, we used a 13year nationwide populationbased dataset to determine the relationship between gallstones and renal stones.
Manuscripts submitted to QJM: An International Journal of Medicine Page 6 of 43
Methods and Materials Data source
The Taiwan Department of Health consolidated 13 insurance programs into the NHI program in March 1995.
More than 99% of the population of Taiwan has been covered by the program since 2000. We obtained a data
subset from the National Health Insurance Research Database (NHIRD) established by the National Health
Research Institutes (NHRI), which is authorized to manage the insurance data. This dataset consists of claims data
collected from one million people randomly selected from the total population of insurant in the 19962010 period.
Information on the demographic status of insured individuals and claims data for inpatient and outpatient care
were available in the dataset. Personal information was scrambled to protect privacy.
Patient diagnoses were coded using the International Classification of Diseases, 9th Revision, Clinical
Modification (ICD9CM). We ensured that all data were deidentified and analyzed anonymously. This study was
exempted from full ethical review by the institutional review board of China Medical University (CMUREC101012).
Study Population
Using the populationbased claims data from 19962010, we identified 25258 new gallstone (ICD9CM code 574)
patients the firsttime gallstone diagnosis served as the index year from 1998 to 2008. The gallstone patients
(N=25258) are classified according to ICD9CM. If the ICD9CM is 574.0, 574.1, 574.3, 574.4, 574.6, 574.7and
574.8 were classified in group with cholecystitis (n= 10778, %=42.7) (symptomatic). The ICD
Page 7 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
9CM coding is 574.2, 574.5 and 574.9 were classified in group without cholecystitis (n= 14480, %=57.3)
(asymptomatic). For comparison, we randomly selected 101 029 individuals without gallstones at a ratio of 1:4,
frequencymatched by sex, age, and index year. Gallstone diagnosis dates were designated as index dates to enable
the measurement of followup personyears. The followup personyears at the end of 2010 were calculated for each
participant until the diagnosis of renal stone, withdrawal from the insurance system, censored because of death, or
loss to followup. People with a history of gallstones at the baseline were excluded from the study. Comorbidities
that may have an association with renal stones (ICD9CM code 592) were also identified, including diabetes (ICD9CM codes 250), hypertension (ICD9CM codes 401405), hyperlipidemia (ICD9CM codes 272),
hyperparathyroidism (ICD9CM 252.0, 252.1, 252.2, 252.8), urinary tract infection (UTI; ICD9CM 599, 595.0,
595.2, 590.0, 590.1, 590.11, 590.8, 590.81), gout (ICD9CM 274), Crohn’s disease (ICD9CM 555.0555.2), liver
cirrhosis (ICD9CM 571) and obesity (ICD9CM 278.0).
Statistical analysis
We compared the distributions of age, sex, and comorbidities between the gallstone and nongallstone
groups by using the Chisquared test. The incidence of renal stones was estimated using age, sex, and
comorbidity for both cohorts. The incidence rate ratio of renal stones in the gallstone and nongallstone cohorts
was measured for these variables by using Poisson regression analysis.
Multivariable Cox proportional hazards model was used to compare the adjusted hazard ratios (HRs) of
renal stones between the gallstone cohort and the nongallstone
Manuscripts submitted to QJM: An International Journal of Medicine Page 8 of 43
cohort at a 95% confidence interval (CI), controlling for sex, age and comorbidities for adjustment. We
performed these statistical analyses by using the SAS 9.3 statistical package (SAS Institute Inc., NC, USA),
with P < .05 in 2tailed tests considered significant. We used R software (R Foundation for Statistical
Computing, Vienna, Austria) to conduct a KaplanMeier analysis to measure the cumulative renal stone
incidence for both study groups, and used the logrank test to assess the differences between the 2 cumulative
incidence curves.
Results
Table 1 compares the demographic characteristics and comorbidities of the gallstone (N = 25 258) and nongallstone groups (N = 101 029). Both groups had similar distributions of sex and age, and were predominantly
female (54.5%) and 3565 years of age (54.8%). Mean age in gallstone group is 55.9 (SD: 16.9), and in nongallstone group is 55.4 (SD: 17.1). Diabetes, hypertension, hyperlipidemia, hyperparathyroidism, UTI, gout,
Crohn’s disease, liver cirrhosis and obesity were more prevalent in the gallstone group at the baseline (P < 0.05).
In table 2, we analyzed the interaction between gallstone and comorbidity. We found only liver cirrhosis had
the interaction with gallstone (pvalue = 0.0253). The overall incidence of renal stones was 1.79fold higher in the
gallstone group than in the nongallstone group (13.03 vs 7.29 per 1000 personyears). The corresponding adjusted
HR was 1.68 (95% CI = 1.59–1.77), assessed using multivariable Cox proportional hazards regression analysis
(Table 3).The incidence was higher in men than in women. The age
Page 9 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
specific analysis showed that incidence of renal stones increased with age in both groups. However, the adjusted
HR was higher in gallstone patients aged < 35 years (adjusted HR = 2.01, 95% CI = 1.66–2.42) than in those
aged 3565 years (adjusted HR = 1.59, 95% CI = 1.491.70) and 65 years and older (adjusted HR = 1.76, 95% CI =
1.591.94). Renal stone incidence estimated for patients with liver cirrhosis was slightly higher than that in patients
without liver cirrhosis.
By the end of the followup period, the cumulative incidence of renal stones was 5.0% higher in the gallstone
group than in the nongallstone group (13.0% vs 8.0%) (Figure 1). Table 4 shows that the incidence rate ratio of
the gallstone group to the nongallstone group declined slightly with time. The adjusted HR declined from 2.51
(95% CI = 2.252.80) at the 1year followup to 1.42 (95% CI = 1.281.57) after 5 years or more.
Discussion
This nationwide populationbased retrospective cohort study evaluated the relationship between gallstones
and renal stones in Taiwan. In an early crosssectional study, Akoudad et al indicated that kidney stone disease
14
is related to gallstones in AfricanAmericans. In another crosssectional prospective study, Taylor et al reported
15
that both stone diseases are independently related in woman group and men group. Because we used data from
the NHI system, which covers more than 99% of the population of Taiwan, the results can be generalized. We
observed that the overall incidence rate of renal stones was 79% higher in the gallstone cohort than in the non
Manuscripts submitted to QJM: An International Journal of Medicine Page 10 of 43
gallstone cohort, with an adjusted HR of 1.68 in the following 13 years. We suggest, therefore, that
gallstones increase the risk of developing renal stones.
Gallstones are common and include inalterable risk factors, including age, sex, ethnicity, and gene factors.
1
1
Some conditions also contribute to the development, including liver cirrhosis and Crohn’s disease. The
16
prevalence of renal stones is higher in men than in women. The risk of renal stone development can be averted
17
by diet and lifestyle changes. Medical problems such as recurrent urinary tract infection, hyperparathyroidism
and metabolic disease also promote the formation of renal stone.
18
The reason gallstones predict the development of renal stones is not well documented,
but hypotheses have been proposed. Obesity is a critical risk factor for gallstone
formation because it influences the function of hepatic cells and affects the secretion of
4, 19, 20
cholesterol.The risk magnitude is greater in women than in men and is high in patients with youthonset
1
obesity. The presence of central obesity is more related to the risk of gallstones than merely a high BMI.
21
22
Diabetes influences cholelithiasis but is not an independent factor. Hyperlipidemia is another risk that has been
identified in
22 23
Taiwanbut not in Western countries.Recent studies have indicated that obesity exerts a systemic effect on the function
of the kidneys and promotes the formation of renal stones, mainly uric acid and infection
17, 24, 25 26,
27
stones.Diabetes predicts the formation of uric acid stones but not calcium stones. Renal stone formation in
certain patients may be explained by the effect of these conditions on the insulinsignaling pathway.
26
We suggest that metabolic changes influence stone formation, both in the gallbladder and the kidneys. Our
study revealed that gallstone patients have a higher rate of
Page 11 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
metabolismrelated comorbidities (eg, diabetes, hyperlipidemia, and hypertension). The role of hypertension has
not been identified by previous studies.
28
Gallbladder wall inflammation is a critical factor promoting the formation of stones. Infection by bacteria in
the genus Helicobacter may account for this, but the role infection plays must be identified. Brown pigment stones
containing calcium salts of unconjugated bilirubin and cholesterol are related to bacterial or parasitical infection
28
of the bile ducts. Bacteria release substances that increase levels of unconjugated bilirubin and bile acid, resulting
in stone formation. Infections also play a role in the formation of renal stones because they influence urine
29
alkylation. The leading pathogens are Proteus and Staphylococcus aureus. These can influence the breakdown of
urea and affect the acidbase status of urine. Based on these data, infection and inflammation might play a critical
role in stone formation. However, the correlation between these 2 types of stone is unclear.
30, 31
Crohn’s disease has been associated with both stones.This is likely because the condition interrupts bile
acid absorption and disturbs the enterohepatic cycling of
28, 32
bilirubin, increasing the formation of cholesterol stones and pigment stones.It also facilitates an increase in
33
urine oxalate, promoting the formation of calciumcontaining stones. The gastrointestinal system is a major
site for calorie, electrolyte, and fluid absorption. It is speculated that these factors influencing intestinal
absorption and circulation increase the risk of stone diseases.
To avoid falsely determining a high renal stone prevalence because of incidental image finding during
gallstone examination, we used timelag analysis to prevent detection bias. Table 4 shows that prevalence was
highest in the first year and decreases
Manuscripts submitted to QJM: An International Journal of Medicine Page 12 of 43
gradually in the following years. Using multivalent analysis, the adjusted HR within the first year was 2.51
(95% CI = 2.25–2.80), 1.56 within 1 to 3 years, 1.54 within 3 to 5 years, and 1.42 at the 5year followup.
This study has certain limitations. Because the data were obtained from the NHI system, we were unable to
evaluate the influence of lifestyle risk factors, including diet, lifestyle, and activity levels. We were also unable to
analyze family history or genetics. In addition, the database does not contain the data about BMI or waistline
measurements, stone components, major components of the metabolic syndrome, or urine samples for further
analysis. Finally, Gallstone disease is a frequent condition and gallbladder stones are clinically silent in the
majority of cases. Thus, at least theoretically, a critical amount of subjects included in the nongallstone cohort
group might have asymptomatic gallstones. Further study is required to evaluate the influence of these factors on
gallstones and renal stones.
Conclusion
In conclusion, our data provide evidence that the risk of developing renal stones is higher among people with
gallstones than among the general population. Because of the high recurrence rate of renal stones, being aware of
the appearance of early symptoms and signs is crucial. This study provides information to enable physicians to
implement adequate prevention measures to decrease stone formation.
Page 13 of 43 Manuscripts submitted to QJM: An International Journal of Medicine
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