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Clinical Chemistry 53: 71-77, 2007. First published November 16, 2006; 10.1373/clinchem.2006.078980
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2007;53:71-77.)
© 2007 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

{gamma}-Glutamyltransferase as a Predictor of Chronic Kidney Disease in Nonhypertensive and Nondiabetic Korean Men

Seungho Ryu1,a, Yoosoo Chang2, Dong-Il Kim1, Won Sool Kim1 and Byung-Seong Suh1

1 Department of Occupational Medicine and 2 Health Screening Center, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine. Seoul, Korea.

aAddress correspondence to this author at: Kangbuk Samsung Hospital, 108 Pyung dong, Jongro-Gu, Seoul, Korea 110-746. Fax 82-2-2001-2626; e-mail sh703.yoo{at}samsung.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Little research has been done to examine whether {gamma}-glutamyltransferase (GGT) is prospectively associated with the development of chronic kidney disease (CKD). We performed a prospective study to examine the association between GGT and the risk for the development of CKD.

Methods: The study cohort included a total of 10 337 healthy males with normal baseline kidney functions and no proteinuria. Participants were workers in a semiconductor manufacturing company and its 13 affiliates. CKD was defined as either the presence of proteinuria or a glomerular filtration rate (GFR) of <60 mL · min–1 · (1.732)–1. Cox proportional hazards models were used to calculate the adjusted hazard ratios in separate models for CKD.

Results: During a follow-up period of 25 774.4 person-years, 366 men developed CKD. After adjustments were made for age, baseline GFR, triglyceride, and HDL-C, the risk for CKD increased with an increasing quartile of serum GGT (p for trend <0.001). The top one fourth of serum GGT vs the bottom one fourth of relative risks for CKD was 1.90 (95% confidence interval, 1.37–2.63). These associations were also apparent in participants who consumed ≤20 g/day of alcohol and those with normal weight, with values of alanine aminotransferase within reference intervals, or with C-reactive protein <3.0 mg/L, and participants without metabolic syndrome.

Conclusions: Our findings, which were obtained from a large work-site cohort and excluded individuals with diabetes and hypertension, indicated that serum GGT may be an early predictor for the development of CKD, independent of baseline confounding factors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The number of patients with end-stage renal disease (ESRD)1 is increasing worldwide (1)(2). In 1999, the US Renal Data System documented a persistent increase in kidney failure that required dialysis therapy or transplantation in 340 000 patients and a projected increase to 651 000 patients by 2010 (3). In Korea, there has been a recent dramatic increase in the prevalence of ESRD patients requiring renal replacement therapy, from 303.6 per million population in 1994 to 854.0 per million population in 2004 (4).

Chronic kidney disease (CKD) often progresses to ESRD with its attendant complications; and the treatment of the earlier stages of CKD is effective in slowing the progression toward ESRD (5)(6). Thus, the identification of the precursors of CKD is very important. Few prospective studies, however, have provided data on the risk factors for the development of CKD among the population in Asia.

Serum {gamma}-glutamyltransferase (GGT) has been used widely as an index of alcohol intake or liver dysfunction (7)(8)(9). Serum GGT was proposed as a sensitive marker of oxidative stress (10) because it has dose–response associations with many cardiovascular disease risk factors, as well as future risk of diabetes; however, little research has been done to examine whether GGT is associated with the prospective development of CKD.

The goal of this study was to evaluate the association between GGT and the risk for CKD in nonhypertensive and nondiabetic male Korean workers.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study population
A prospective cohort study was conducted to examine the association between serum GGT and risk for CKD in nonhypertensive and nondiabetic male Korean workers who were employed at one of the biggest semiconductor manufacturing companies in Korea and its 13 affiliates. All employees participate in either annual or biennial health examination, as is required by Korea’s Industrial Safety and Health law. The study population included male workers ≥40 years of age who underwent an annual comprehensive health examination and workers 30 to 39 years of age who underwent a biennial comprehensive health examination. A total of 15 347 workers, 30 to 59 years of age, participated in the comprehensive health examinations at a university hospital in Seoul, Korea, between January and December of 2002. Among the 15 347 workers, 3532 (23.0%) were excluded for various reasons: 27 (0.7%) had a history of malignancy; 9 (0.3%) had a history of liver cirrhosis; 16 (0.5%) had a history of cardiovascular disease; 125 (3.5%) were receiving medical treatment for dyslipidemia; 11 (0.3%) were receiving medical treatment for hepatitis; 7 (0.2%) were receiving medical treatment for current kidney disease; 246 (7.0%) did not possess information about their past medical histories; 91 (2.6%) did not have a urinalysis performed; 279 (7.9%) were taking medication for diabetes or had fasting glucose concentrations ≥126 mg/dL; 2688 (76.1%) were taking medication for hypertension or had BPs ≥140/90 mmHg at their initial examinations; 260 (7.4%) had prevalent proteinuria; and 261 (7.4%) had glomerular filtration rates (GFRs) of <60 mL · min–1 · (1.732)–1 at the time of their initial examinations. Because some individuals had more than 1 exclusion criterion, the total number eligible for the study was 11 815. The study participants were reexamined at the same hospital annually, over a period of ~3.5 successive years, until May 2006. We excluded an additional 1478 individuals from our cohort who did not participate in consecutive annual or biennial health examinations during the follow-up period. Ultimately, 10 337 male workers were enrolled in the analysis and were observed for the development of CKD, and their mean (SD) follow-up periods were 2.49 (0.86) years. This study was approved by the Institutional Review Board at Kangbuk Samsung Hospital.

measurements
The initial health examinations that were performed in 2002 included a medical history, a physical examination, a questionnaire about health-related behavior, anthropometric measurements, and biochemical measurements. The medical history and history of prescription drug use were assessed by the examining physicians. All the participants were asked to respond to a questionnaire on health-related behavior. Questions about alcohol intake included the frequency of alcohol consumption on a weekly basis and the usual amount that was consumed on a daily basis. We considered persons reporting that they smoked to be current smokers. In addition, the participants were asked about their weekly frequency of physical activity, such as jogging, bicycling, and swimming that lasted long enough to produce perspiration.

Fasting blood samples were drawn from an antecubital vein from participants after they had fasted >12 h. The fasting serum glucose, total cholesterol, triglycerides, LDL cholesterol, HDL-cholesterol (HDL-C), uric acid, blood urea nitrogen, creatinine, {gamma}-glutamyltransferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) concentrations were measured enzymatically with an automatic analyzer (Advia 1650 AutoAnalyzer, Bayer Diagnostics). The fasting serum glucose was measured with the hexokinase method. Total cholesterol and serum triglycerides were measured with enzymatic colorimetric tests, low-density lipoprotein-cholesterol was measured with the homogeneous enzymatic colorimetric test, and HDL-C was measured with the selective inhibition method (Bayer Diagnostics). Insulin concentrations were measured with immunoradiometric assays (Biosource), with intra- and interassay CVs of 4.7% to 12.2%. We performed homeostasis model assessments of insulin resistance (HOMA-IR). High sensitivity-C reactive protein (CRP) was analyzed by performing particle-enhanced immunonephelomety with the BNTM System (Dade Behring). The result was presented as milligrams per liter, and the minimum detectable CRP concentration was 0.175 mg/L after performing 1:20 sample dilution. The serum creatinine was measured with the alkaline picrate (Jaffe) method. The coefficients of variation for the creatinine determinations were ≥3% from 2002 to 2005. The Korean Association of Quality Assurance for Clinical Laboratories assessed the quality control of the laboratory, both internally and externally, on a regular basis. The urine protein concentration was determined at each examination from the results of a single urine dipstick semiquantitative analysis (URiSCAN® Urine strip, YD Diagnostics). Dipstick urinalysis was performed on fresh, midstream urine samples that were collected in the morning. The results of the urine test were based on a scale that quantified proteinuria as absent, trace, 1+, 2+, 3+, and 4+. The dipstick results of 1+, 2+, 3+, and 4+ corresponded to protein concentrations of 30, 100, 300, and 1000 mg/dL, respectively. Kidney function was estimated by the GFR, which was calculated with the simplified Modification of Diet in Renal Disease Study equation that is defined as GFR = 186.3 x (serum creatinine)–1.154 x age–0.203 (17)(18). Proteinuria was defined as a finding of 1+ or greater. CKD was defined as either proteinuria or a GFR <60 mL · min–1 · (1.732)–1.

Trained nurses measured sitting blood pressure with a standard mercury sphygmomanometer. The 1st and 5th Korotkoff sounds were used to estimate the systolic blood pressure (SBP) and the diastolic blood pressure. Height and weight were measured after an overnight fast with study participants wearing a lightweight hospital gown and no shoes. The body mass index (BMI) was calculated as the patient’s weight (in kilograms) divided by the square of the patient’s height (in meters).

statistical analysis
The {chi}2-test and the one-way ANOVA were used to analyze the statistical differences among the characteristics of the study participants at the time of enrollment in relation to the serum GGT concentrations. Categories of serum GGT comprised the following quartiles: <18, 19–25, 26–39, and ≥40. The incidence density was expressed as the number of cases divided by the person-years from the baseline until the development of CKD, with the assumption of a date of diagnosis in the middle of the follow-up period or until the final physical examination. The incidence densities were compared by calculating the incidence density ratios with the 95% confidence interval (CI). We used the Cox proportional hazards model to calculate the adjusted hazard ratios in the model for CKD. The data were first adjusted for age alone, then for the multiple covariates. In the multivariate models, we included variables, which include age, baseline GFR, BMI, fasting glucose, SBP, total cholesterol, uric acid, HOMA-IR, CRP, smoking, alcohol consumption, incident diabetes, and incident hypertension, that might confound the relationship between the serum GGT and CKD. For the linear trends of risk, the number of quartiles was used as a continuous variable and tested on each model. The data were analyzed and the statistical analysis for the data was performed with SPSS version 12.0 software (SPSS Inc.). All the reported P values were 2-tailed, and those <0.05 were considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
At baseline, the 10 337 study participants had a mean (SD) age of 36.9 (4.8) years, 46.9% were current smokers, and 24.4% exercised regularly ≥1 time per week. The overall prevalence of overweight or obesity (BMI ≥25 kg/m2) was 34.0%. The participants who did not have follow-up measurements were, on average, 0.5 years older (P = 0.003) and had a fasting serum glucose ~0.03 mmol/L lower (P = 0.033) than those who were included in the analytic cohort; but there were no differences in the prevalence of metabolic syndrome and obesity, lipid profiles, uric acid concentrations, SBP, or baseline GFR.

The characteristics of the study participants in relation to the serum GGT concentrations are illustrated in Table 1 . For all of the listed variables there were clear dose–response relationships with serum GGT concentrations. Age, BMI, fasting serum glucose, systolic and diastolic blood pressures, total cholesterol, triglycerides, LDL-C, uric acid, creatinine, HOMA-IR, CRP, current smoking, and current alcohol drinking were associated positively, whereas HDL-C, GFR, and exercise were associated inversely. The percentage of those who had metabolic syndrome also increased in correlation with an increase in the serum GGT.


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  		Table 1. Baseline characteristics of the study participants by GGT concentration.

During 25 774.4 person-years of follow-up, 366 new incident cases of CKD developed (Table 2 ). After adjustments were made for age, baseline GFR, triglyceride, and HDL-C, GGT was significantly associated with the risk for CKD [adjusted relative risk (RR) 1.13 (95% CI, 1.06–1.20) per 1-SD increase in the natural log of GGT]. In the categorical analyses, the risk for CKD increased with increasing quartiles of serum GGT (P for trend <0.001), but the associations across quartiles of GGT seemed to be nonlinear. For study participants in the 4th quartile, CKD risk was significantly increased [adjusted RR, 1.90 (95% CI, 1.37–2.63)]. These results did not change after further adjustments for obesity, baseline HOMA-IR, or CRP.


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  		Table 2. Adjusted RR of incidence of CKD with explanatory factors.

To explore whether the risk for CKD with a serum GGT was mediated by the subsequent development of hypertension or diabetes, we fit additional models by adjusting for incident hypertension or diabetes at the time of follow-up. During 3 years of follow-up, 145 (1.4% of the cohort) developed incident diabetes and 1464 (14.2%) developed hypertension. After the inclusion of incident hypertension or diabetes, the risk for CKD still increased with increasing quartiles of serum GGT (for trend <0.001).

These associations were apparent in study participants who were alcohol drinkers of ≤20 g/day or were nonoverweight (BMI <25 kg/m2) or even lean (BMI <23 kg/m2), in participants with ALT concentrations within the reference interval or CRP <3.0 mg/L, and in those without the metabolic syndrome (Table 3 ).


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  		Table 3. Adjusted RR of incidence of CKD by quartile of GGT concentrations according to subgroups of alcohol consumption <20 g ethanol per day, BMI <25 kg/m2 or <23 kg/m2, ALT <35 U/L, CRP <3.0 mg/L, and nonmetabolic syndrome

In the unadjusted analyses, the quartiles of both ALT and AST were associated with a significantly increased risk for CKD (P for trend <0.001 and <0.001, respectively). After adjustments were made for potential confounders, however, neither ALT nor AST was related significantly to the incidence of CKD.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study demonstrated that the risk for CKD increased in correlation with an increase in the serum GGT in nonhypertensive and nondiabetic men. Other liver enzymes, such as ALT and AST, were not related significantly to the incidence of CKD. To the best of our knowledge, little research has been done to examine whether serum GGT is associated with the prospective development of CKD, so we were unable to compare our results with those of other studies.

The mechanisms by which the serum GGT increases the risk for CKD are not fully understood. In clinical practice, an increased concentration of serum GGT is conventionally interpreted as a marker of alcohol abuse or liver disease (7)(8)(9). In this study, the serum GGT predicted the incidence of CKD independently of the amount of alcohol consumed, as well as in drinkers of ≤20 g/day. The dose–response relationship between the serum GGT and the incidence of CKD was observed among individuals with ALT concentrations within the reference interval. Furthermore, neither ALT nor AST was related significantly to the incidence of CKD. Therefore, excessive alcohol consumption or liver diseases do not explain our results. Obesity could play a role in the association of serum GGT with the incidence of CKD, because obese adults have an increased risk for developing CKD (19). In this study, however, the serum GGT was predictive of CKD even among lean men with a BMI <23 kg/m2. Insulin resistance syndrome may explain the serum GGT–incident CKD relationship, because these conditions have been associated strongly with serum GGT (20), and several studies reported that insulin resistance was associated with an increased risk for CKD (21)(22). In this study, however, the risk for CKD increased with increasing quartiles of serum GGT independently of HOMA-IR, as well as in men without the metabolic syndrome. Systemic low-grade inflammation as assessed by CRP is another possible mechanism linking GGT with CKD development. A previous study showed that low-grade inflammation may be a predictor for a change in kidney function in the elderly (23), but our results, derived from apparently healthy persons, showed that CRP was not independently associated with incident CKD.

Recently, serum GGT has been proposed as a sensitive and reliable marker of oxidative stress (10). In the Coronary Artery Risk Development in Young Adults study, circulating concentrations of serum and dietary antioxidant vitamins, such as ß-carotene, {alpha}-carotene, ß-cryptoxanthin, zeaxanthin/lutein, and {alpha}-tocopherol, were related inversely in a dose–response manner to the serum GGT concentration within its reference interval (24). The same study also showed that serum GGT concentration predicted fibrinogen and C-reactive protein, which are markers of inflammation (25). These associations suggested that serum GGT may be a biological marker of oxidative stress. In addition, prospective cohort studies have shown that serum GGT predicted the development and outcomes of many diseases (10)(11)(12)(13)(14)(15)(16). On the basis of the findings of experimental and human studies, we attribute the association of serum GGT with CKD incidence in our study to a mechanism related to oxidative stress. Several experimental studies have demonstrated that O2–1 caused direct vasoconstriction of the renal cortical and medullary vessels and increased the intracellular calcium in the vascular smooth muscle and endothelial cells (26)(27)(28). These studies suggested that renal reactive oxygen species (ROS) caused renal vasoconstriction and sodium retention, and renal damage. Other studies reported that rats receiving a high sodium diet that caused increased arteriolar and venular O2–1 production exhibited severe renal damage, decreased GFR and renal plasma flow, and high renal superoxide production (29)(30). Furthermore, treatment with vitamin C and E decreased the production of renal superoxide and renal damage, and prevented the decrease in renal hemodynamics (31). Recent human studies indicated that individuals with essential hypertension have decreased antioxidant capacity and produce excessive amounts of ROS, and that more than half of these hypertensive patients were salt sensitive and had progressive renal damage (32)(33)(34). These experimental and human studies provided evidence to support the hypothesis that oxidative stress plays an important role in renal damage, but further interventional studies that target serum GGT are necessary to clarify the mechanisms of renal damage.

Our study had several limitations. First, we used an estimated GFR instead of a directly measured GFR to define CKD. A recent review article (35) reported that current GFR estimates had greater inaccuracy in populations without known CKD than in those with the disease. Nonetheless, current GFR estimates facilitate the detection, evaluation, and management of CKD, and many organizations recommend the use of equations that estimate GFR for the evaluation of renal function in epidemiologic studies and in clinical practice (35). Second, the dipstick urinalysis has imperfect sensitivity and specificity, but the number of false-positive results can be higher due to menstruation or comorbid illnesses in women and older persons, circumstances that did not affect our study population of healthy men, ages 30 to 59 years. In addition, the National Kidney Foundation Kidney Disease Outcome Quality Initiation Advisory Board recommended that under most circumstances spot urine samples rather than timed urine collection (overnight or 24-h) can be used for detection and monitoring proteinuria in adults, (18). Third, our findings may be biased by the healthy worker effect. However, although those participants who did not undergo follow-up measurements were, on average, 0.5 years older than those who were included in the analytic cohort, there were no differences between the 2 groups in the prevalence of metabolic syndrome or in obesity, lipid profiles, uric acid, SBP, or GFR concentrations at the baseline. Thus, the exclusion of participants without follow-up measurements would not be expected to bias our results. Finally, ethnic factors that are characteristic for the Asian population are not well established with respect to using equations that estimate GFR. Therefore, these equations need to be validated in additional studies with large Asian cohorts.

In conclusion, our findings, which were obtained from a large work-site cohort that excluded individuals with diabetes and hypertension, indicated that the serum GGT may be an early predictor for the development of CKD, independent of baseline confounding factors and the subsequent development of hypertension. In addition, our results supported previous studies that reported oxidative stress played an important role in the production of renal damage.


   Footnotes
 
1 Nonstandard abbreviations: ESRD, end-stage renal disease; CKD, chronic kidney disease; GGT, {gamma}-glutamyltransferase; GFR, glomerular filtration rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL-C, HDL-cholesterol; HOMA-IR, Homeostasis Model Assessment of insulin resistance; CRP, C reactive protein; SBP, systolic blood pressure; RR, relative risk; CI, confidence interval; BMI, body mass index; ROS, reactive oxygen species.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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D.-H. Lee, M. D. Gross, M. W. Steffes, and D. R. Jacobs Jr
Is Serum Gamma-Glutamyltransferase a Biomarker of Xenobiotics, Which Are Conjugated by Glutathione?
Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): e26 - e28.
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 Clin. Chem.Home page
Y. Chang, S. Ryu, E. Sung, and Y. Jang
Higher Concentrations of Alanine Aminotransferase within the Reference Interval Predict Nonalcoholic Fatty Liver Disease
Clin. Chem., April 1, 2007; 53(4): 686 - 692.
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 Clin. Chem.Home page
J. B. Whitfield
Serum {gamma}-Glutamyltransferase and Risk of Disease
Clin. Chem., January 1, 2007; 53(1): 1 - 2.
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