The association of moderate renal dysfunction with impaired preference-based health-related quality of life: 3^rdKorean national health and nutritional examination survey

The data analyzed in this study were obtained from the 3^rd Korean National Health and Nutritional Examination Survey (KNHANES) 2005, which included a population-based random sampling of 34,145 individuals in households across 600 national districts. The survey was conducted with a stratified, multi-stage, clustered probability design in order to select a representative nationwide sample of the non-institutionalized Korean population. A total of 28,590 subjects were excluded from this study because they were age < 18 years (n = 8,292), did not complete either the EQ-5D questionnaire (n = 9,720) or blood test (n = 27,731), or had advanced renal dysfunction (n = 12). After the above exclusion criteria were applied, 5,555 individuals aged 18 years or older who had an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m² were included in this investigation. Because the analyzed survey data are publicly available, ethical approval was not required for this study.

HRQOL was measured using the EuroQol-5D (EQ-5D) questionnaire, a widely used generic preference-based instrument [17, 18]. The EQ-5D consists of five questions regarding current health status in terms of mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each question has three possible responses: "no problems", "some problems", and "extreme problems". The EQ-5D health states are defined as a combination of the responses for each item and the survey can therefore yield 3⁵ (= 243) possible combinations of responses. These responses were converted into weighted values according to the Korean value set [19], and the average was calculated as a quality adjustment weight for each health state. The EQ-5D instrument has been translated into Korean, and its validity (Spearman correlation coefficient with the first question of the Health Survey Short-Form 36:-0.51 in EQ-5D) and reliability (test-retest reliability) have been demonstrated previously [19, 20].

Blood samples were collected after a 12-hour overnight fast; they were properly processed, immediately refrigerated, and transported in cold storage to the central laboratory (Seoul Medical Science Institute, Seoul, Korea) within 24 hours. Serum creatinine, glucose, and lipid levels were measured using the ADVIA 1650 system (Bayer Health Care, Tarrytown, NY). The serum creatinine concentration was measured using the kinetic Jaffe method, and the inter-assay coefficient of variation was less than 5%. Because the creatinine assay was not calibrated to be traceable to an isotope dilution mass spectrometry (IDMS), eGFR was calculated using the original Modification of Diet in Renal Disease (MDRD) equation as follows: eGFR = 186.3 × (serum creatinine)^-1.154 × (age)^-0.203 × 0.742 (if female) [21]. Proteinuria was measured by the urine dipstick test.

Demographic characteristics included age, gender, marital status (living with/without a spouse), education level (no education or elementary school graduate/middle or high school graduate/university graduate or higher), occupational status (white collar/blue collar/student, soldier or housewife/no occupation), residential area (rural/urban), and monthly individual income (lowest quartile/2^nd and 3^rd quartile/highest quartile) in US dollars. Individuals who were legally married or cohabiting were considered to have a spouse; single, divorced, or separated individuals were categorized as not having a spouse. Information about various comorbidities was also collected. Hypertension was identified in individuals who met at least one of the following three criteria: physician diagnosis of hypertension, self-report of antihypertensive drug intake, and systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg. Blood pressure was measured manually twice at 30-second intervals after a minimum of five minutes of rest in a seated position, and the mean values were used to identify hypertensive participants. Diabetes was diagnosed in subjects with a fasting plasma glucose ≥ 126 mg/dL or those patients who were identified in the health interview survey as actively using an oral hypoglycemic agent or insulin. Diagnosis of metabolic syndrome was based on the presence of three or more of the following: (1) waist circumference ≥ 90 cm for men or ≥ 80 cm for women [22], (2) triglyceride levels ≥ 150 mg/dL, (3) high-density lipoprotein cholesterol levels < 40 mg/dL for men or < 50 mg/dL for women, (4) SBP ≥ 130 mmHg or DBP ≥ 85 mmHg or self-report of antihypertensive drug therapy, and (5) fasting plasma glucose level ≥ 100 mg/dL or self-report of ongoing treatment with an oral hypoglycemic agent or insulin. Anemia was defined as a hemoglobin level of < 13 g/dL for men and < 12 g/dL for women. Information regarding ischemic heart disease and cerebrovascular accidents was acquired from self-reported history. Ischemic heart disease included angina pectoris and myocardial infarction. Proteinuria was categorized into 3 groups according to the degree of proteinuria measured by the dipstick as negative, mild (trace to 1+), or heavy (2+ to 4+).

Information on health-related behaviors such as smoking status (life-time smoker/non-smoker), alcohol intake (less than once per month/more than once per month), and regular physical activity of moderate intensity (more/less than three times per week) was obtained from the health questionnaire. Life-time smokers included those adults who reported that they had smoked at least 100 cigarettes in their lifetime, and non-smokers included respondents who had smoked fewer than 100 cigarettes in their lifetime and did not smoke at the time of the survey. Moderate-intensity activities were defined as those lasting at least 10 minutes and causing a slight increase in the individual's heart rate compared with sedentary activities; table tennis, swimming, yoga and badminton were included as moderate-intensity activities, but walking was excluded. Psychological variables from questionnaires included self-reported stress (none or small amount/some or extreme) and sleep quality (sufficient/insufficient).

Data are presented as frequencies and percentages for categorical variables. Continuous variables are reported as means with standard deviations. Estimated GFR values were stratified into three categories (≥ 90.0, 60.0-89.9, and 30.0-59.9 mL/min/1.73 m²). Differences in demographic, socioeconomic, and psychological factors, as well as in health-related behavioral patterns and the EQ-5D utility scores across the eGFR categories were compared using the χ² test for trends (linear-by-linear association) for categorical variables. Similarly, a one-way analysis of variance was used to demonstrate the linearity of continuous variables across eGFR categories.

Univariate logistic regression analysis was performed to assess the relationship between impaired health utility (EQ-5D index score in lowest quartile) [23] and clinical or demographic data. Variables that showed significant association in the univariate analysis or that were of considerable theoretical relevance were entered into the multivariate logistic regression analysis using the backward conditional elimination method. To analyze the determinants of problems in each of the five EQ-5D dimensions, the three possible responses were dichotomized as "no problem" or "any problem", and a multivariate logistic regression analysis was performed with the presence of "any problem" as the dependent variable. Covariables that had co-linearity were excluded from the multivariate analyses. An analysis of covariance (ANCOVA) with the Bonferroni correction was used to estimate age-adjusted distributions of the EQ-5D utility score according to serum eGFR. All analyses were conducted using SPSS software (version 19.0, SPSS, IL), and P < 0.05 was considered to indicate statistical significance.

The demographic characteristics of the participants, stratified by eGFR, are shown in Table 1. The mean age of the study subjects was 46.5 ± 15.7 years, and 42.8% were male. A total of 716 participants had an eGFR of ≥ 90.0 mL/min/1.73 m², 4,353 had an eGFR of 60.0-89.9 mL/min/1.73 m², and 486 had an eGFR of 30.0-59.9 mL/min/1.73 m². The mean eGFR of each group was as follows: 96.7 mL/min/1.73 m² in the group with eGFRs of ≥ 90.0 mL/min/1.73 m²; 75.3 mL/min/1.73 m² in the group with eGFRs of 60.0-89.9 mL/min/1.73 m², and 55.9 mL/min/1.73 m² in the group with eGFRs of 30.0-59.9 mL/min/1.73 m². Subjects with a lower eGFR were older, predominantly women, and more likely to have comorbidities, including diabetes, hypertension, metabolic syndrome, anemia, ischemic heart disease and cerebrovascular accidents.

Table 2 shows the variables associated with health-related behaviors, socioeconomic status, and psychological variables. Subjects with a lower eGFR showed better health-related behavioral patterns, including lower rates of smoking and alcohol consumption. On the other hand, the proportion of subjects living in a rural area, having no occupation, or with less education was significantly higher as the eGFR decreased. In addition, household income also decreased with decreasing eGFR. Although the degree of stress did not differ between eGFR groups, the proportion of participants experiencing poor sleep quality increased significantly with decreasing eGFR and was particularly low in the group with eGFRs of 30.0-59.9 mL/min/1.73 m².

The proportions of participants reporting problems (some problem/extreme problem) in each dimension of the EQ-5D questionnaire are shown in Figure 1. There was a significant increase in reported problems in all dimensions of the EQ-5D with decreasing eGFR. In total, 46.1% of participants with eGFRs of 30.0-59.9 mL/min/1.73 m² had problems with mobility, 9.6% had problems with self-care, 32.6% had problems with usual activity, 70.5% had problems with pain/discomfort, and 37.8% had problems with anxiety/depression.

The crude EQ-5D utility score significantly decreased with decreasing eGFR (Figure 2A). The mean age-adjusted EQ-5D utility score for all participants was 0.845 ± 0.004 (standard error of the mean). The age-adjusted EQ-5D utility score was significantly lower among participants with an eGFR of 30.0-59.9 mL/min/1.73 m² (0.807 ± 0.009) compared with those participants with an eGFR of ≥ 90.0 mL/min/1.73 m² (0.857 ± 0.003) or 60.0-89.9 mL/min/1.73 m² (0.870 ± 0.003) (Figure 2B).

Figure 3 shows data from a nationally representative catalogue of age-adjusted mean EQ-5D utility scores for major chronic diseases, as derived from data from the 3^rd KNHANES [24]. When our results were integrated with the data from that catalogue, we found that individuals with an eGFR of 30.0-59.9 mL/min/1.73 m² had lower utility scores than those individuals with chronic obstructive pulmonary disease, asthma, hypertension, or diabetes.

A logistic regression model was built to assess factors that were significantly associated with impaired health utility, defined as an EQ-5D utility score in the lowest quartile. To perform logistic regression analysis, certain continuous values were transformed into categorical values, as previously described. Subjects were divided into three age groups, as follows: < 40 years old, 40-60 years old, and ≥ 60 years old. Body mass index and lipid levels were considered as components of metabolic syndrome. Table 3 displays the results of univariate and multivariate analyses for impaired HRQOL. In the univariate regression analysis, variables including age, gender, health-related behaviors (smoking, alcohol intake), socioeconomic factors (marital status, area of residence, occupation, education, and household income), psychological factors (stress, sleep quality), and other co-morbidities (e.g., hypertension, diabetes, metabolic syndrome, ischemic heart disease and cerebrovascular disease) showed significant association with impaired health utility. However, the degree of proteinuria failed to prove its association with health utility in the univariate regression analysis.

In the multivariate analysis, an eGFR of 30.0-59.9 mL/min/1.73 m² was one of the independent risk factors predicting impaired health utility (odds ratio (OR) 1.531; 95% confidence interval (CI) 1.077-2.176; P = 0.018) after adjustment for age, sex, comorbidities (diabetes, hypertension, metabolic syndrome, ischemic heart disease, and cerebrovascular accidents) health-related behaviors (alcohol intake, smoking, and physical activity), socioeconomic factors (marital status, occupation, education, rural residence, and income) and psychological factors (stress and sleep quality).

In the binary multivariate logistic regression on EQ-5D responses, an eGFR of 30.0-59.9 mL/min/1.73 m² was significantly associated with reported problems in the mobility (OR, 2.192; 95% CI, 1.178-4.077; P = 0.013) and pain/discomfort dimensions (OR, 1.574; 95% CI, 1.113-2.225; P = 0.010). Although impaired renal function was significantly associated with the self-care, usual activities, and anxiety/depression dimensions in the univariate analyses, these associations lost statistical significance after adjustment for covariates (Table 4).