The Level Of Urine Dipstick Proteinuria And Its Relation To The Risk Of Incident Cholelithiasis Ⅱ

RESULTS

During 904,360 person-years of follow-up, 2,919 (1.41%) incident cases of cholelithiasis developed from 2009 through 2013. Table 1 describes the baseline characteristics of the study participants in three groups of urine protein levels. There were significant differences between the three groups in all baseline characteristics except LDL-cholesterol and physical activity. The groups with more proteinuria tended to have worse clinical conditions than those without proteinuria, which was more prominent in the mean values of fasting glucose, triglyceride, eGFR, and SCr than other variables. However, despite the statistically significant difference in the P-for trend, some variables did not show clinically important differences among groups. In particular, this finding was distinct in the variables related to obesity and liver function, including BMI, AST, ALT, and GGT, which were within normal ranges in all groups. There were 2,919 cases of incident cholelithiasis during follow-up, and the characteristics of these individuals compared with the remainder of the cohort are presented in Table 2. In contrast to participants without incident cholelithiasis, those with incident cholelithiasis were older (60.8 [SD, 9.4] vs 57.7 [SD, 8.6] years) and had less favorable baseline characteristics in BMI, systolic BP, TG, HDL-cholesterol, eGFR, AST, ALT, GGT, and smoking amount. In particular, a group with incident cholelithiasis had higher levels in baseline characteristics related to obesity and liver function like BMI, AST, ALT, and GGT. However, all variables did not show the specific direction, and the group without chocholelithiasis had higher mean levels in diastolic BP, total cholesterol, LDL-cholesterol, SCr, alcohol intake, and physical activity. Table 3 shows the HRs and 95% CIs for cholelithiasis according to the three groups. In the unadjusted model, the HRs for cholelithiasis comparing mild and heavy proteinuria group versus the negative group were 1.12 (95% CI, 0.87–1.45) and 1.77 (95% CI, 1.33–2.34), respectively (P for trend <0.001). Adjustment for covariates attenuated this association, but statistical significance was maintained in the heavy proteinuria group (HR 1.46; 95% CI, 1.09–1.96). After adjusting for covariates, cholelithiasis was significantly associated with BMI, age, alcohol intake, smoking, and GGT. Gender subgroup analysis indicated that heavy proteinuria in women was significantly associated with an increased risk of incident cholelithiasis (HR 1.68; 95% CI, 1.06–2.65) even after adjusting for covariates (table 1). Men also showed a significant association in the unadjusted model (HR 1.65; 95% CI, 1.15–2.37), which disappeared after adjustment for covariates (HR 1.31; 95% CI, 0.89–1.92). In age subgroup analysis (table 2), the group age ≥56 years showed a significant association between heavy proteinuria and incident cholelithiasis (HR 1.44; 95% CI, 1.01–2.03), but the group age ≤55 years did not show a significant association after adjustment for covariates (HR 1.47; 95% CI, 0.85–2.55).

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AST, aspartate aminotransferase; ALT, alanine aminotransferase; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SCr, serum creatinine. Data are means (standard deviation), medians (interquartile range), or percentages. a P-value by ANOVA-test for continuous variables and a Chi-square test for categorical variables.

BP, TG, HDL-cholesterol, eGFR, AST, ALT, GGT, and smoking amount. In particular, a group with incident cholelithiasis had higher levels in baseline characteristics related to obesity and liver function like BMI, AST, ALT, and GGT. However, all variables did not show the specific direction, and the group without chocholelithiasis had higher mean levels in diastolic BP, total cholesterol, LDL-cholesterol, SCr, alcohol intake, and physical activity. Table 3 shows the HRs and 95% CIs for cholelithiasis according to the three groups. In the unadjusted model, the HRs for cholelithiasis comparing mild and heavy proteinuria group versus the negative group were 1.12 (95% CI, 0.87–1.45) and 1.77 (95% CI, 1.33–2.34), respectively (P for trend <0.001). Adjustment for covariates attenuated this association, but statistical significance was maintained in the heavy proteinuria group (HR 1.46; 95% CI, 1.09–1.96). After adjusting for covariates, cholelithiasis was significantly associated with BMI, age, alcohol intake, smoking, and GGT. Gender subgroup analysis indicated that heavy proteinuria in women was significantly associated with an increased risk of incident cholelithiasis (HR 1.68; 95% CI, 1.06–2.65) even after adjusting for covariates (table 1). Men also showed a significant association in the unadjusted model (HR 1.65; 95% CI, 1.15–2.37), which disappeared after adjustment for covariates (HR 1.31; 95% CI, 0.89–1.92). In age subgroup analysis (table 2), the group age ≥56 years showed a significant association between heavy proteinuria and incident cholelithiasis (HR 1.44; 95% CI, 1.01–2.03), but the group age ≤55 years did not show a significant association after adjustment for covariates (HR 1.47; 95% CI, 0.85–2.55).

AST, aspartate aminotransferase; ALT, alanine aminotransferase; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SCr, serum creatinine. Data are expressed as means (standard deviation) or percentages. a P-value by t-test for continuous variables and a Chi-square test for categorical variables.

DISCUSSION

In a longitudinal analysis of nationwide data, we evaluated the risk of incident cholelithiasis according to the levels of urine dipstick proteinuria. Our result indicated that urine dipstick proteinuria of 2+ or greater was significantly associated with an increased risk of cholelithiasis. The analysis of baseline characteristics of study subjects provides a potential mechanism for this finding. The subjects with higher urine dipstick proteinuria tended to have worse metabolic and renal conditions, which were similarly observed in subjects with incident cholelithiasis. These findings suggest that unfavorable clinical conditions had a role in the development of gallstones. This inference is supported by the previous studies displaying the role of metabolic derangements like insulin resistance, obesity, and dyslipidemia on the development of gallstones, proteinuria, and CKD.14–16 Thus, it is speculated that the metabolic milieu contributing to proteinuria triggers the pathophysiological processes involved in the development of gallstones. However, it is interesting that our results were statistically significant even after adjusting for covariates, including conventional risk factors for gallstones like age, gender, BMI, systolic BP, fasting glucose, total cholesterol, GGT, alcohol intake, and physical activity. This result indicates that proteinuria may be an independent risk factor for gallstones. Previous studies have also demonstrated that renal diseases related to proteinuria are potentially associated with gallstones. In a cross-sectional study of 2,686 men and 2,087 women in Taiwan,11 the prevalence of gallstones was 13.1% in the group of patients with CKD, and 4.9% in the group of patients without CKD (P < 0.001). Additionally, it has been demonstrated that the prevalence of gallstones was significantly higher in patients with end-stage renal disease (ESRD) treated with dialysis compared with a non-uremic group.17,18 Observational studies have shown a significant association between gallstones and renal stones.19,20 These results give rise to a hypothesis that considerable overlap may exist between pathophysiological mechanisms of renal diseases and gallstone disease. Moreover, considering that proteinuria is a clinical manifestation of renal diseases, including CKD and renal stones, these results may link proteinuria to gallstones. However, previous studies are limited in presenting the direct influence of proteinuria on incident gallstones. Their limitations are attributable to the cross-sectional design,10,11 less generalizability of results derived only from ESRD patients,17,18 and weak causative relationship between renal stone and proteinuria.19,20 Furthermore, several studies have reported that the prevalence of gallstones did not differ between dialysis patients and healthy controls.21–23 In contrast, we analyzed the longitudinal relationship between the level of urine dipstick proteinuria and the risk of incident gallstone, which may be an advantage in identifying the clinical implication of renal disease related to proteinuria as a risk factor for gallstone.

In our analysis, heavy proteinuria (≥2+) was significantly associated with the increased risk of gallstone, whereas mild proteinuria (1+) did not show a statistically significant association with gallstone. Previous studies have demonstrated that the level of proteinuria was a reliable baseline factor deeply correlated with the rate of eGFR decline and progressive CKD.24,25 Thus, it is postulated that the heavy proteinuria group had a higher proportion of advanced CKD with uremia than the mild proteinuria group over the follow-up period. A uremic state can derange the complex process of neural and hormonal factors controlling gallbladder motility.26–28 The neural and hormonal imbalance may alter gallbladder motility, promoting gallstone formation via the stasis of gallbladder in CKD patients.26–28 However, we cannot guarantee that the uremic state induced by CKD is a major mechanism for the association between proteinuria and cholelithiasis in our study. We could not evaluate the variation of renal function during follow-up due to not performing follow-up measurements of SCr and eGFR. Further studies should investigate the long-term association among baseline proteinuria, variation of renal function, and risk of cholelithiasis. The merits of the study are the robust number of study subjects, well-organized medical records (including diagnosis of cholelithiasis), and laboratory measurements based on credible nationwide data. These advantages enable us to quantify the risk of incident cholelithiasis according to the levels of urine dipstick proteinuria. Nonetheless, we acknowledge the limitation of the study. First, the level of proteinuria was evaluated only using a urine dipstick test. Although the urine dipstick test is widely available in screening proteinuria, it is insufficient to precisely quantify proteinuria. Second, the follow-up period of 4.36 years on average was relatively short. The cumulative incidence of cholelithiasis was 2.5% in our study, but longer follow-up might lead to both a lower incidence rate and higher cumulative incidence for cholelithiasis. Third, our study was conducted only for relatively elderly Koreans with a mean age of 57.8 (SD, 8.6) years. Our study showed that the prevalence of +1 proteinuria and ≥2+ proteinuria is 1.8% and 1.0%, respectively. However, in a cohort study of 18,201,275 Koreans with a mean age of 45.3 (SD, 14.6) years based on NHID, the prevalence of 1+ proteinuria and ≥2+ proteinuria was 1.18% (n = 214,883) and 0.56% (n = 103,745), respectively.29 The higher prevalence of proteinuria in our study may be attributable to the older age of our subjects. Fourth, we could not verify the validity of the incidence of cholelithiasis in the study due to a lack of validation on the incidence of cholelithiasis from previous analyses through NHID. Fifth, despite the possibility of loss to follow-up during follow-up, we could not conduct sensitivity analysis due to the limitation of our raw data. NHID was not designed for research, but rather for investigation of the health status of Koreans. Therefore, we could not identify the information needed for sensitivity analysis. 

These limitations warrant the necessity of further studies with more precise modalities quantifying proteinuria, longer follow-up, and a large number of subjects, including younger age groups. In conclusion, individuals with more proteinuria had a higher incidence of cholelithiasis, and urine dipstick proteinuria of 2+ or greater was significantly associated with an increased risk of cholelithiasis. These results add to the evidence for a hypothesis that the presence of renal disease reflected by proteinuria is an independent risk factor for gallstone disease.

ACKNOWLEDGEMENTS

We used the National Health Insurance Service–National Sample Cohort database and the dataset was obtained from the National Health Insurance Service. Our study findings were not related to the National Health Insurance Service. Author contribution: Jae-Hong Ryoo is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Sung Keun Park contributed to study design, manuscript preparation, and manuscript editing and wrote a manuscript as a first author. Chang-Mo Oh contributed to the study design and manuscript preparation. Dong-Young Lee and JungWook Kim participated in data analysis interpretation and manuscript review. Min-Ho Kim and Hee Yong Kang contributed to data acquisition, quality control of data and algorithms, data analysis and interpretation, and statistical analysis. Eunhee Ha contributed to data acquisition and manuscript review. Ju Young Jung contributed to manuscript editing. Conflicts of interest: None declared.

APPENDIX A. SUPPLEMENTARY DATA 

Supplementary data related to this article can be found at https:== doi.org=10.2188=jea.JE20190223. 

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