Gallstones increase the risk of developing
renal stones: a
nationwide population-based retrospective
cohort study
C.-H. LI
1,2, F.-C. SUNG
3,4, Y.-C. WANG
3, D. LIN
3and C.-H. KAO
4,5Introduction
Gallstones are common in the general population. The national prevalence of gallstones varies between 0.1% and 61.5% worldwide.1 The prevalence
in Taiwan was 10.7%.2 Incidence increases
with age and patients are predominantly female. Gallstones particularly affect premenopausal women.
Gallstones can be divided into two major types: cholesterol stones and pigment stones. Unlike in Western countries, pigment stones are prevalent in Asia.3,4 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% and 20%.6–8 In Asia, the prevalence of renal stones
varies between 1% and 5%.9 Unlike gallstones,
renal stones are more prevalent among men than women.10 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
public health issues and substantially increase the economic burden on national health insurance.
12,13 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 this study, we used a 13-year nationwide
population-based dataset to determine the relationship between gallstones and renal stones.
Materials and methods
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 1 million people randomly selected from the total population of insurant in the 1996–2010 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 (ICD-9-CM). 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 (CMU-REC-101-012).
Study population
Using the population-based claims data from 1996 to 2010, we identified 25 258 new gallstone
(ICD-9-CM code 574) patients the first-time gallstone diagnosis served as the index year from 1998 to 2008.
The gallstone patients (N= 25 258) are classified according to ICD-9-CM. If the ICD-9-CM is 574.0,
574.1, 574.3, 574.4, 574.6, 574.7 and 574.8 were classified in group with cholecystitis (n = 10 778, 42.7%) (symptomatic). The ICD-9-CM coding is 574.2, 574.5 and 574.9 were classified in group
without cholecystitis (n = 14 480, 57.3%) (asymptomatic). For comparison, we randomly selected
101 029 individuals without gallstones at a ratio of 1:4, frequency-matched by sex, age and index year. Gallstone diagnosis dates were designated as index dates to enable the measurement of follow-up person-years. The follow-up person-years 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 follow-up. People with a history of gallstones at the baseline were excluded from the study. Comorbidities that may have an association with renal stones (ICD-9-CM code 592) were also identified, including diabetes (ICD-9-CM codes 250),
hypertension (ICD-9-CM codes 401-405), hyperlipidemia (ICD-9-CM codes 272), hyperparathyroidism
(ICD-9-CM 252.0, 252.1, 252.2, 252.8), urinary tract infection (UTI; ICD-9-CM 599, 595.0, 595.2, 590.0, 590.1, 590.11, 590.8, 590.81), gout (ICD-9-CM 274), Crohn’s disease (ICD-9-(ICD-9-CM 555.0-555.2), liver cirrhosis CM 571) and obesity (ICD-9-CM 278.0).
Statistical analysis
We compared the distributions of age, sex and
comorbidities between the gallstone and nongallstone groups by using the Chi-squared 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 non-gallstone 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 < 0.05 in twotailed tests considered significant. We used R software
(R Foundation for Statistical Computing,
Vienna, Austria) to conduct a Kaplan–Meier analysis to measure the cumulative renal stone incidence for both study groups, and used the log-rank test to assess the differences between the two cumulative incidence curves.
Results
Table 1 compares the demographic characteristics and comorbidities of the gallstone (N= 25 258) and non-gallstone groups (N= 101 029). Both groups had similar distributions of sex and age, and were predominantly female (54.5%) and 35–65 years of age (54.8%). Mean age in gallstone group is 55.9 (SD: 16.9), and in non-gallstone 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 that only liver cirrhosis had the interaction with gallstone
(P = 0.0253). The overall incidence of renal stones was 1.79-fold higher in the gallstone group than in the non-gallstone group (13.03 vs. 7.29 per 1000
person-years). The corresponding adjusted HR was 1.68 (95% CI = 1.59–1.77), assessed using multivariable
(Table 3). The incidence was higher in men than in women. The age-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 35–65 years (adjusted HR= 1.59, 95% CI = 1.49– 1.70) and 65 years and older (adjusted HR= 1.76, 95% CI = 1.59–1.94). Renal stone incidence estimated for patients with liver cirrhosis was slightly
higher than that in patients without liver cirrhosis. By the end of the follow-up period, the cumulative incidence of renal stones was 5.0% higher in
the gallstone group than in the non-gallstone group (13.0% vs. 8.0%) (Figure 1). Table 4 shows that the incidence rate ratio of the gallstone group to the non-gallstone group declined slightly with time. The adjusted HR declined from 2.51 (95% CI = 2.25–2.80) at the 1-year follow-up to 1.42 (95% CI = 1.28–1.57) after 5 years or more.
Discussion
This nationwide population-based retrospective cohort study evaluated the relationship between gallstones and renal stones in Taiwan. In an early cross-sectional study, Akoudad et al.14 indicated
that kidney stone disease is related to gallstones in African-Americans. In another cross-sectional prospective study, Taylor et al.15 reported 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-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 Some conditions also contribute to the development,
including liver cirrhosis and Crohn’s disease.
1 The prevalence of renal stones is higher in
men than in women.16 The risk of renal stone development
can be averted by diet and lifestyle
changes.17 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 cholesterol.4,19,20 The risk
magnitude is greater in
women than in men and is high in patients with youth-onset obesity.1 The presence of central obesity
is more related to the risk of gallstones than
merely a high BMI.21 Diabetes influences cholelithiasis
but is not an independent factor.22
Hyperlipidemia is another risk that has been identified in Taiwan22 but not in Western countries.23
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 stones.17,24,25 Diabetes predicts
the formation of uric acid stones but not calcium stones.26,27 Renal stone formation in certain patients
may be explained by the effect of these conditions on the insulin-signaling pathway.26
We suggest that metabolic changes influence stone formation, both in the gallbladder and in the kidneys. Our study revealed that gallstone patients have a higher rate of metabolism-related comorbidities (e.g. diabetes, hyperlipidemia and hypertension). The role of hypertension has not been
identified by previous studies.
Gallbladder wall inflammation is a critical factor promoting the formation of stones.28 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 of the bile ducts.28 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 alkylation. The leading pathogens are Proteus and Staphylococcus aureus.29
These can influence the breakdown of urea and affect the acid-base status of urine. Based on these data, infection and inflammation might play a critical role in stone formation. However, the correlation between these two types of stone is unclear. Crohn’s disease has been associated with both stones.30,31 This is likely because the condition
interrupts bile acid absorption and disturbs the enterohepatic cycling of bilirubin, increasing the formation
of cholesterol stones and pigment
stones.28,32 It also facilitates an increase in urine
oxalate, promoting the formation of calciumcontaining stones.33 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 time-lag analysis
to prevent detection bias. Table 4 shows that prevalence was highest in the first year and decreases
gradually in the following years. Using
first year was 2.51 (95% CI = 2.25–2.80), 1.56 within 1–3 years, 1.54 within 3–5 years and 1.42 at the 5-year follow-up.
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
