| |
Weight Gain Increases Risk for Kidney Disease
|
| |
| |
Changes in Body Weight Predict CKD in Healthy Men
Journal of American Society of Nephrology June 21, 2008
Seungho Ryu *1, Yoosoo Chang , Hee-Yeon Woo , Soo-Geun Kim *, Dong-Il Kim *, Won Sool Kim *, Byung-Seong Suh *, Nam-Kyong Choi , and Jong-Tae Lee
*Department of Occupational Medicine, Health Screening Center, and Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul National University Medical Research Center/Department of Preventive Medicine, Seoul National University College of Medicine, and ||Department of Public Health, Graduate School of Hanyang University, Hanyang University, Seoul, Korea
Gaining weight, even while remaining within the normal range, increases a patient's risk of chronic kidney disease, researchers here said. In a four-year prospective cohort study, men who gained more than 0.75 kilograms a year (about 1.65 pounds) were more than four times as likely to develop kidney disease as those who gained less than 0.25 kilograms, according to Seungho Ryu, M.D., of Kangbuk Samsung Hospital, and colleagues. The curve was actually U-shaped, the researchers said, with a loss of more than 0.75 kilograms a year also associated with an increased risk of kidney disease. But that finding "should be interpreted with caution," the researchers said, because it contradicts most other research. It's possible, they said, that participants who lost large amounts of weight were more overweight and less healthy to start with. Although obesity is associated with an increased risk of chronic kidney disease, the findings in this study held true whether participants were of normal weight, overweight, or obese, Dr. Ryu and colleagues reported
ABSTRACT
Several recent prospective studies have reported that obesity is associated with an increased risk for chronic kidney disease (CKD), but it is unknown whether weight gain increases the risk for CKD if one remains within the "normal" category of body mass index (BMI). We prospectively followed a cohort of 8792 healthy men who had no known risk factors for CKD and participated in a comprehensive health evaluation program at a large worksite. During 35,927 person-years of follow-up, 427 new incident cases of CKD (estimated GFR <64 ml/min per 1.73 m2) developed. Cox proportional hazards modeling revealed that in both the normal-weight and overweight groups, a U-shaped association between weight change categories and development of CKD was observed after adjustment for age, baseline GFR, baseline BMI, HDL, fasting blood glucose, uric acid, and exercise habits. The lowest risk for CKD was observed among those whose weight changed -0.25 to <0.25 kg/yr (P < 0.001 for quadratic term). Weight change as a time-dependent variable was significantly related to CKD incidence. These relationships remained significant even after further adjustment for Homeostasis Model Assessment of Insulin Resistance, high-sensitivity C-reactive protein, systolic BP, diastolic BP, metabolic syndrome, incident hypertension, or incident diabetes. In summary, increases in body weight are independently associated with an increased risk for CKD, even when the BMI remains within the normal range.
"In conclusion, weight gain in this study was significantly associated with an increased risk for development of CKD. The strength of this study was the large sample size, which allowed us to identify the effect among stratified subgroup analyses. Even in normal-weight participants, an increase in body weight of approximately >/=0.75 kg/yr predicted incident CKD.Our findings support that, even in a normal-weight population, a low initial BMI does not ameliorate the increase in risk for CKD with weight gain; therefore, avoidance of weight gain, even among lean individuals, is important to reduce the risk for this disease....
....The exact mechanisms by which weight gain over a relatively short period of time is associated with the development of CKD have yet to be elucidated, even though neither overweight nor obese individuals had an increased risk for developing CKD during the same period. Although BMI measures not only adiposity but also muscle mass, it is highly correlated with adiposity,24 and relatively small changes in weight could have a significant effect on body fat25 and influence cardiovascular or metabolic risk.26,27 There is increasing evidence that weight gain in adulthood increases the risk for chronic disease, such as hypertension, type 2 diabetes, and coronary heart diseases. 18,28-30 In addition, excessive adiposity may be associated with renal injury.21 As with obesity-induced hypertension and diabetes, the pathophysiology of obesity-related kidney disease may function through more subtle mechanisms, such as a variety of hormonal and cytokine influences.31,32 Further study is needed on the mechanisms by which weight gain increases CKD independent of obesity, hypertension, and diabetes...."
The number of patients with ESRD is increasing worldwide.1,2 Chronic kidney disease (CKD) is also an increasingly common and important condition3; however, at present, prospective data on risk factors for CKD are limited. Early identification and treatment of CKD is necessary to delay progression from CKD to ESRD.
Obesity is a major public health problem whose prevalence has been rising in developing countries as well as in developed countries.4 Overweight and obesity are well-established risk factors for cardiovascular disease, diabetes, and hypertension.5-10 Recently, several prospective studies have reported that obesity was associated with an increased risk for CKD or ESRD11-15; however, little research has been done to examine the effect of weight change within normal weight range and risk for CKD. The World Health Organization classification for healthy weight for Asians is a body mass index (BMI) of 18.5 to 23 kg/m2, for overweight as BMI of 23 to 25 kg/m2, and for obese as BMI >/=25 kg/m2.16 The healthy weight category spans a large range. Individuals at the lower end of healthy weight may, thus, believe that it is permissible to gain some weight as they age, as long as they remain within the healthy weight range; however, weight gain during adult life has been associated with adverse health outcomes.17,18 Previous studies have clearly shown a positive association between obesity and kidney disease11-15 and reported the role of obesity as a causative factor in glomerulomegaly and FSGS19-21; however, there is a paucity of data concerning the influence of the weight gain on CKD, especially in the normal-weight population without hypertension and diabetes. This prospective study examined the effect of weight change within the normal BMI on CKD in Korean male workers without hypertension and diabetes.
RESULTS
During 35,927.4 person-years of follow-up, 427 incident cases of CKD developed. At baseline, the mean age and BMI of the 8792 participants in the analytic cohort were 36.9 yr (SD 4.7; range 30 to 59 yr) and 23.8 kg/m2 (SD 2.7; range 15.1 to 37.3 kg/m2), respectively. Participants who were not included in the analytic cohort (n=2927) were on average 0.5 yr older and were more likely to be current smokers and current drinkers than those in the analytic cohort. During the follow-up, seven men died from non-renal diseases; six of them were not included in the analytic cohort. None of the other variables differed between two groups (data not shown).
Baseline characteristics of the study participants in relation to the weight change category are illustrated in Table 1. There were clear dosage-response relationships among all of the listed variables except high-sensitivity C-reactive protein (hsCRP), drinker, and regular exerciser with the weight change. Age, BMI, fasting blood glucose (FBG), systolic BP (SBP), diastolic BP (DBP), total cholesterol, triglyceride (TG), LDL cholesterol, y-glutamyltransferase (GGT), insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), uric acid, and creatinine were associated inversely with weight change, whereas HDL cholesterol, GFR, and current smoker were associated positively. The proportions of metabolic syndrome (MetS) and obesity (BMI 25 kg/m2) were also inversely associated with weight change. The overall prevalence of obesity was 33.4%.
Table 2 shows the risk for CKD incidence according to the baseline BMI categories. After adjustment for age, baseline GFR, HDL cholesterol, FBG, uric acid, regular exercise, and weight change over time, the baseline BMI categories were not significantly associated with the development of CKD.
Table 3 shows the risk for CKD incidence according to weight change over time. After adjustment for age, baseline GFR, baseline BMI, HDL cholesterol, FBG, uric acid, and regular exercise, weight change as a time-dependent variable was significantly related to CKD incidence. Non-time-dependent Cox regression models were also performed by using the weight change calculated from the slope of the regression model for each individual. CKD risk was significantly increased in the weight loss category of < -0.75 kg/yr and in the weight gain category of >/=0.75 kg/yr. A U-shaped association between weight change categories and development of CKD was observed with the lowest risk in the weight change category of -0.25 to <0.25 kg/yr (P =0.001 for quadratic term).
We further examined the association between weight change and incident CKD, stratified by BMI at baseline (Figure 1). In both the normal-weight and overweight groups, after adjustment for age, baseline GFR, baseline BMI, HDL cholesterol, FBG, uric acid, and regular exercise, a U-shaped association between weight change categories and development of CKD was observed with the lowest risk in the weight change category of -0.25 to <0.25 kg/yr (P <0.001 for quadratic
term). Weight change as a time-dependent variable was significantly related to CKD incidence. The relationship between weight change and incident CKD remained significant even after further adjustment for HOMA-IR, hsCRP, SBP, DBP, MetS, incident hypertension, and incident diabetes.
In sensitivity analysis, we also examined the association of weight change with incident CKD when the definition of incident CKD was limited to persistent CKD on follow-up or when we reclassified CKD as a GFR <60 ml/min per 1.73m2. Neither of these analyses qualitatively changed any of the observed associations
(data not shown).
Linear mixed-effect models were used to analyze the effect of weight change over time on longitudinal changes in GFR across the weight change groups. In all groups, after adjustment for age and baseline BMI, weight change over time was negatively associated with the longitudinal changes in GFR (P <0.001; data not shown).
DISCUSSION
In this prospective study of Korean men without hypertension and diabetes, weight gain was associated with the development of CKD, and this relationship was observed even in the normal-weight participants. The effect of weight change on incident CKD was maintained irrespective of various potential confounders, including age, baseline GFR, BMI, uric acid, HDL-cholesterol, and regular exercise. Moreover, this relationship remained even after adjustment for incident hypertension or incident diabetes.
A recent finding from the Physicians' Health Study (PHS) also showed that men with a BMI increase 10% had a significantly increased risk for CKD compared with those who maintained their BMI within 5% of their BMI at baseline.11 To our knowledge, however, this is the first study to demonstrate a relationship between weight change, even within normal-weight range, and CKD.
Few prospective studies have evaluated BMI as a potential risk factor in the development of CKD and subsequent ESRD. In longitudinal data from the PHS, the baseline BMI predicted subsequent CKD after a mean follow-up of 14.0 yr.11 The data from the Framingham Offspring Study showed that higher BMI was a risk factor for the development of new-onset kidney disease after a mean follow-up of 18.5 yr.12 Similarly, studies have demonstrated a significant positive relationship between BMI and ESRD risk13,14; however, no independent association between BMI and incident CKD was found in our study. Several possibilities may underlie this lack of relation. In a cross-sectional analysis of data from the National Health and Nutrition Examination Survey, only morbid obesity (defined as BMI >/=35 Kg/m2) was related to CKD,22 whereas only three individuals had BMI of 35 kg/m2 in our study. Another possibility is that the 4.1-yr follow-up period in this study may have been insufficient to establish any relationship between these factors. Iseki et al.23 suggested that BMI was not a major risk factor for the development of ESRD after their 10-yr follow-up period.
After extending this follow-up period to 17 yr, however, they found that BMI was associated with an increased risk for the development of ESRD in men.14 Finally, the difference may have arisen as a result of the restriction of our study to individuals without diabetes and hypertension, which are well-established mediators between obesity and kidney disease.22
The exact mechanisms by which weight gain over a relatively short period of time is associated with the development of CKD have yet to be elucidated, even though neither overweight nor obese individuals had an increased risk for developing CKD during the same period. Although BMI measures not only adiposity but also muscle mass, it is highly correlated with adiposity,24 and relatively small changes in weight could have a significant effect on body fat25 and influence cardiovascular or metabolic risk.26,27 There is increasing evidence that weight gain in adulthood increases the risk for chronic disease, such as hypertension, type 2 diabetes, and coronary heart diseases. 18,28-30 In addition, excessive adiposity may be associated with renal injury.21 As with obesity-induced hypertension and diabetes, the pathophysiology of obesity-related kidney disease may function through more subtle mechanisms, such as a variety of hormonal and cytokine influences.31,32 Further study is needed on the mechanisms by which weight gain increases CKD independent of obesity, hypertension, and diabetes.
Our finding of an increased risk for CKD associated with the weight loss category should be interpreted with caution. Few studies have examined the association between low body weight or weight loss and future risk for kidney disease. In a large cross-sectional population study, Ramirez et al.33 found a J-shaped relationship between BMI and the prevalence of proteinuria. A recent prospective study showed a J-shaped relationship between BMI and the risk for ESRD in China.34 In addition, all-cause mortality studies have reported U-shaped or J-shaped relationships between BMI and mortality.35-39 In this study, the underweight individuals (BMI <18.5 kg/m2) had NS increases in CKD risk compared with normal-weight men (18.5
Our study had several limitations. First, we used an estimated GFR instead of a directly measured GFR to define CKD. Arecent review article reported that current GFR estimates had a greater inaccuracy in populations without known CKD than in those with the disease.41 Nonetheless, current GFR estimates facilitate the detection, evaluation, and management of CKD, and many organizations recommend the use of equations that estimate GFR in epidemiologic studies and in clinical practice for the evaluation of renal function.41 Second, an abbreviated Modification of Diet in Renal Disease (MDRD) equation was not generated using longitudinal data within individuals;
therefore, if weight gain increases creatinine production, then a slight increase in serum creatinine (i.e., decrease in GFR) would be expected at the same true creatinine clearance. However, weight gain during adulthood is predominantly fat gain.42 In this study, weight changes were significantly associated with persistent CKD on follow-up. Third, we could not obtain information of family history of CKD, although family history is associated with the development of CKD.43 Fourth, bias from loss to follow-up may have influenced our results. The baseline characteristics of the participants who were not included in the analysis were not significantly different from those in the analytic cohort, with the exception of age, cigarette smoking, and alcohol consumption. It is likely, however, that loss to follow-up will be encountered, especially in those who are in poor health. This loss to follow-up of high-risk people would likely lead to a conservative bias and subsequent underestimation of risk. Fifth, these results may not be extrapolated to women. Finally, ethnic factors that are characteristic of the Asian population are not well established with respect to using equations that estimate GFR; therefore, these equations need to be validated in large Asian cohorts with additional studies.
In conclusion, weight gain in this study was significantly associated with an increased risk for development of CKD. The strength of this study was the large sample size, which allowed us to identify the effect among stratified subgroup analyses. Even in normal-weight participants, an increase in body weight of approximately >/=0.75 kg/yr predicted incident CKD.Our findings support that, even in a normal-weight population, a low initial BMI does not ameliorate the increase in risk for CKD with weight gain; therefore, avoidance of weight gain, even among lean individuals, is important to reduce the risk for this disease.
|
|
| |
| |
|
|
|
