clinical investigation
www.kidney-international.org
Body mass index and causes of death in chronic kidney disease Sankar D. Navaneethan1,2, Jesse D. Schold3, Susana Arrigain3, John P. Kirwan4 and Joseph V. Nally, Jr5 1
Section of Nephrology, Department of Medicine, Selzman Institute for Kidney Health, Baylor College of Medicine, Houston, Texas, USA; Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA; 3Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA; 4Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; and 5Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
2
In chronic kidney disease (CKD), a higher body mass index (BMI) is associated with a lower risk for death, but causespecific death details are unknown across the BMI range. To define this, we studied 54,506 patients with CKD (stage 3 CKD- [91.5%]) from an institutional electronic medical record based–registry. We examined the associations among various causes of death (cardiovascular-, malignancy- and noncardiovascular/nonmalignancy–related deaths) across the BMI range using Cox proportional hazards and competing risks regression models. During a median followup of 3.7 years, 14,518 patients died. In the multivariable model, an inverted J-shaped association was noted between BMI and cardiovascular-related, malignancy-related, and noncardiovascular/nonmalignancy–related deaths. Similar associations were noted for BMI 25–29.9, 30–34.9, and 35–39.9 kg/m2 categories. A BMI >40 kg/m2 was not associated with cardiovascular-related and noncardiovascular/ nonmalignancy–related deaths in CKD. Sensitivity analyses yielded similar results even after adjusting for proteinuria and excluding diabetes and hypertension from the models. In CKD, compared with a BMI of 18.5–24.9 kg/m2, those who are overweight, with class 1 and 2 obesity have a lower risk for cardiovascularrelated, malignancy-related, and noncardiovascular/ nonmalignancy–related deaths. Future studies should examine the associations of other measures of adiposity with outcomes in CKD. Kidney International (2016) 89, 675–682; http://dx.doi.org/10.1016/ j.kint.2015.12.002 KEYWORDS: obesity; kidney disease; cardiovascular deaths and mortality Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
C
hronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease and mortality.1,2 More than two-thirds of patients with CKD are either overweight or obese, and both obesity and CKD contribute to a substantial public health burden.3 Obesity is an independent risk factor for the development of kidney disease in the general population.4 Although earlier studies report obesity as an independent risk factor for the development of end-stage renal disease, a recent large study that included the US Veteran population reported slower progression of kidney disease among those in the higher body mass index (BMI) categories.5,6 Similar to recent reports for type 2 diabetes, some groups have observed that obesity, assessed using BMI, in non–dialysis-dependent CKD is associated with a lower risk for all-cause mortality.7-11 Although there is some disagreement regarding the best predictor of obesity, BMI continues to be the mostly widely used metric.12-14 Cardiovascular disease and malignancy are leading causes of death in the general population.15 Recent reports from Canada and our group suggest that cardiovascular disease and malignancy accounts for the majority of deaths in the CKD population.16,17 Although obesity is associated with higher cardiovascular mortality in the general population, it is not associated with cancer and noncardiovascular/nonmalignancy– related deaths.18 The specific cause and biological mechanisms that explain the association between BMI and lower all-cause mortality are unclear, and whether overweight/obese patients with CKD sustain differential (higher or lower) rates of deaths from cardiovascular disease, malignancy, and other diseases is unknown. Such information would help us understand the relative contribution of various diseases to mortality rates in CKD and provide a platform for developing preventive and therapeutic strategies in this high-risk cohort. Therefore, we examined associations between various causes of death (cardiovascular-, malignancy-, and noncardiovascular/nonmalignancy–related deaths) in patients with CKD with a full range of obesity, as reflected in BMI values, who were followed in a large health care system and had cause-specific death data.
Correspondence: Sankar D. Navaneethan, Section of Nephrology, Baylor College of Medicine, One Baylor Plaza, Ste 100-37D, Houston, Texas 77030, USA. E-mail: [email protected]
RESULTS Patient characteristics
Received 26 May 2015; revised 15 September 2015; accepted 24 September 2015; published online 12 January 2016
The study population was composed of 54,506 patients with CKD who were not receiving dialysis or had
Kidney International (2016) 89, 675–682
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clinical investigation
SD Navaneethan et al.: BMI and cause-specific deaths
undergone renal transplantation. The mean age was 72.0 þ 11.7 years, with 44.2% men and 12.7% blacks. The mean BMI of the study cohort was 29.4 þ 6.6 kg/m2. The prevalence of diabetes, hypertension, malignancy, and coronary artery disease were 23.3%, 86.1%, 25%, and 20.7%, respectively. The mean estimated glomerular filtration rate (eGFR) was 47.8 ml/min/1.73 m2, with 67.9% of participants in stage 3a, 24.5% of participants in stage 3b, and 7.5% of participants in stage 4 CKD. Other details of the study population based on BMI categories are outlined in Table 1. Age- and sex-adjusted mortality rates and causes of death
During a median follow-up of 3.7 years (25th percentile, 1.8; 75th percentile, 5.8), 14,518 died. Figure 1 shows the proportion of various causes of death among those in different BMI categories. Table 2 and Figure 1 outline various causes of death in the cardiovascular and noncardiovascular/nonmalignancy–related categories. Overall, cardiovascular diseases (34.0%) and malignant neoplasms (28.9%) were the leading causes of death among the study population.
BMI and cause-specific death
In the models adjusting for relevant confounding variables, a BMI of 25 to 29.9 kg/m2 was associated with lower hazards for overall mortality (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.75–0.81; P < 0.001) and lower subhazards for cardiovascular (HR, 0.83; 95% CI, 0.77–0.89; P < 0.001), malignancy-related (HR, 0.84; 95% CI, 0.78–0.91; P < 0.001), and noncardiovascular/nonmalignancy–related deaths (HR, 0.81; 95% CI, 0.75–0.87; P < 0.001). A BMI of 30 to 34.9 kg/m2 was associated with lower hazards for overall mortality (HR, 0.73; 95% CI, 0.70–0.77; P < 0.001) and lower subhazards for cardiovascular (HR, 0.81; 95% CI, 0.74–0.89; P < 0.001), malignancy-related (HR, 0.80; 95% CI, 0.73–0.88; P < 0.001), and noncardiovascular/ nonmalignancy–related deaths (HR, 0.75; 95% CI, 0.69–0.82; P < 0.001). Similarly, a BMI of 35 to 39.9 kg/m2 was associated with lower hazards for overall mortality (HR, 0.73; 95% CI, 0.68– 0.78; P < 0.001) and lower subhazards for cardiovascular (HR, 0.80; 95% CI, 0.71–0.91; P < 0.001), malignancy-related (HR, 0.73; 95% CI, 0.64–0.83; P < 0.001), and noncardiovascular/nonmalignancy–related deaths (HR, 0.83; 95% CI, 0.74–0.93; P ¼ 0.001). However,
Table 1 | Characteristics of patients with CKD based on BMI levels 40 kg/m2 (n [ 3815)
74.4 153 24.9 19.2 17.4 0.99 7.2 28.0 82.1 55.9 12.7 8.9 10.1 6.1 48.2 34.6 52.1 45.6 11.3
75.1 12.5 39.6 10.6 22.7 1.7 13.2 27.2 81.9 71.5 18.8 8.2 10.1 3.4 54.9 49.4 55.1 47.3 10.5
73.4 11.0 51.3 11.1 27.5 1.4 19.8 26.9 86.5 79.2 22.5 7.2 10.0 3.3 62.5 59.5 58.0 48.1 10.0
70.5 10.8 46.8 13.5 32.2 1.4 28.0 23.8 88.5 81.7 21.8 7.5 9.0 2.8 68.5 63.0 60.6 48.3 10.0
68.0 10.5 37.9 16.6 37.2 1.4 37.1 20.9 88.7 81.6 20.4 8.7 6.6 2.5 74.1 63.7 63.1 47.7 10.2
64.2 10.6 27.8 18.7 45.2 5.0 44.4 17.0 87.9 79.9 16.7 10.3 4.8 1.8 75.7 60.7 60.3 47.1 10.4
67.9 24.5 7.5 4.1 0.79 12.8 1.8
60.4 28.3 11.3 4.0 0.55 12.2 1.9
65.8 25.5 8.7 4.1 1.4 12.6 1.8
68.8 24.2 7.0 4.1 0.45 13.0 1.8
69.9 23.5 6.6 4.1 0.45 13.0 1.8
68.1 24.2 7.7 4.1 0.44 12.8 1.8
65.4 26.3 8.3 4.0 0.46 12.5 1.7
Insurance (%) Medicaid Medicare Missing Other
0.7 78.5 2.8 17.9
1.7 78.7 3.4 16.2
0.7 82.1 2.6 14.7
0.5 81.0 2.4 16.1
0.7 76.9 2.9 19.4
0.8 73.1 3.4 22.6
1.5 66.7 4.5 27.3
Smoking (%) No Yes Missing
79.6 7.1 13.3
68.9 16.9 14.2
76.6 8.4 14.9
80.5 6.6 12.9
80.9 6.6 12.5
80.8 6.4 12.7
80.3 6.1 13.7
Variable
Summary N [ 54,506
Age (mean SD) 72.0 117 Male sex (%) 44.2 Black (%) 12.7 29.4 6.6 BMI (kg/m2) (mean SD) Diabetes (%) 23.3 Malignancy (%) 25.0 Hypertension (%) 86.1 Hyperlipidemia (%) 76.9 Coronary artery disease (%) 20.7 Congestive heart failure (%) 7.9 Cerebrovascular disease (%) 9.1 Peripheral vascular disease (%) 3.1 ACEI/ARB use (%) 63.9 Statin drug use (%) 58.1 Beta-blocker use (%) 58.5 47.8 10.2 eGFR (ml/min/1.73 m2) (mean SD) eGFR categories (%) 45–59 ml/min/1.73 m2 30–44 ml/min/1.73 m2 15–29 ml/min/1.73 m2 Albumin (g/dL) (mean SD) Hemoglobin (mg/dl) (mean SD)
ACEI/ARB, angiotensin-converting enzyme/angiotensin receptor blocker; BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.
676
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SD Navaneethan et al.: BMI and cause-specific deaths
weight change per year was a decrease of –0.3 kg/yr. The associations between BMI categories and all-cause mortality remained similar when adjusting for weight change per year (Supplementary Table S1 online). Sensitivity analyses
In a model with a BMI of 21.5 to 24.9 kg/m2 as the reference range, similar associations between BMI categories and various causes of death were noted (Supplementary Table S2 online). In a model with a BMI of 25 to 29.9 kg/m2 as the reference range, BMIs 40 kg/m2 for noncardiovascular/nonmalignancy–related causes of death (Supplementary Table S2 online). In a subgroup of patients who had proteinuria measurements, similar associations between BMI categories and various causes of death were noted (Supplementary Table S3 online). In the competing risk model in which diabetes and hypertension were not adjusted for, results similar to the primary analysis were noted (Supplementary Table S3 online). In the analysis in which we censored patients as of September 2009 (to exclude any patients who would have gone on to dialysis), results similar to the primary analysis were noted (Supplementary Table S3 online).
Figure 1 | Various causes of death among those in different body mass index (BMI) categories.
BMI > 40 kg/m2 was not associated with cardiovascular and noncardiovascular/nonmalignancy–related deaths (Tables 3 and 4). A lower BMI category (
www.kidney-international.org
Body mass index and causes of death in chronic kidney disease Sankar D. Navaneethan1,2, Jesse D. Schold3, Susana Arrigain3, John P. Kirwan4 and Joseph V. Nally, Jr5 1
Section of Nephrology, Department of Medicine, Selzman Institute for Kidney Health, Baylor College of Medicine, Houston, Texas, USA; Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA; 3Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA; 4Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; and 5Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
2
In chronic kidney disease (CKD), a higher body mass index (BMI) is associated with a lower risk for death, but causespecific death details are unknown across the BMI range. To define this, we studied 54,506 patients with CKD (stage 3 CKD- [91.5%]) from an institutional electronic medical record based–registry. We examined the associations among various causes of death (cardiovascular-, malignancy- and noncardiovascular/nonmalignancy–related deaths) across the BMI range using Cox proportional hazards and competing risks regression models. During a median followup of 3.7 years, 14,518 patients died. In the multivariable model, an inverted J-shaped association was noted between BMI and cardiovascular-related, malignancy-related, and noncardiovascular/nonmalignancy–related deaths. Similar associations were noted for BMI 25–29.9, 30–34.9, and 35–39.9 kg/m2 categories. A BMI >40 kg/m2 was not associated with cardiovascular-related and noncardiovascular/ nonmalignancy–related deaths in CKD. Sensitivity analyses yielded similar results even after adjusting for proteinuria and excluding diabetes and hypertension from the models. In CKD, compared with a BMI of 18.5–24.9 kg/m2, those who are overweight, with class 1 and 2 obesity have a lower risk for cardiovascularrelated, malignancy-related, and noncardiovascular/ nonmalignancy–related deaths. Future studies should examine the associations of other measures of adiposity with outcomes in CKD. Kidney International (2016) 89, 675–682; http://dx.doi.org/10.1016/ j.kint.2015.12.002 KEYWORDS: obesity; kidney disease; cardiovascular deaths and mortality Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
C
hronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease and mortality.1,2 More than two-thirds of patients with CKD are either overweight or obese, and both obesity and CKD contribute to a substantial public health burden.3 Obesity is an independent risk factor for the development of kidney disease in the general population.4 Although earlier studies report obesity as an independent risk factor for the development of end-stage renal disease, a recent large study that included the US Veteran population reported slower progression of kidney disease among those in the higher body mass index (BMI) categories.5,6 Similar to recent reports for type 2 diabetes, some groups have observed that obesity, assessed using BMI, in non–dialysis-dependent CKD is associated with a lower risk for all-cause mortality.7-11 Although there is some disagreement regarding the best predictor of obesity, BMI continues to be the mostly widely used metric.12-14 Cardiovascular disease and malignancy are leading causes of death in the general population.15 Recent reports from Canada and our group suggest that cardiovascular disease and malignancy accounts for the majority of deaths in the CKD population.16,17 Although obesity is associated with higher cardiovascular mortality in the general population, it is not associated with cancer and noncardiovascular/nonmalignancy– related deaths.18 The specific cause and biological mechanisms that explain the association between BMI and lower all-cause mortality are unclear, and whether overweight/obese patients with CKD sustain differential (higher or lower) rates of deaths from cardiovascular disease, malignancy, and other diseases is unknown. Such information would help us understand the relative contribution of various diseases to mortality rates in CKD and provide a platform for developing preventive and therapeutic strategies in this high-risk cohort. Therefore, we examined associations between various causes of death (cardiovascular-, malignancy-, and noncardiovascular/nonmalignancy–related deaths) in patients with CKD with a full range of obesity, as reflected in BMI values, who were followed in a large health care system and had cause-specific death data.
Correspondence: Sankar D. Navaneethan, Section of Nephrology, Baylor College of Medicine, One Baylor Plaza, Ste 100-37D, Houston, Texas 77030, USA. E-mail: [email protected]
RESULTS Patient characteristics
Received 26 May 2015; revised 15 September 2015; accepted 24 September 2015; published online 12 January 2016
The study population was composed of 54,506 patients with CKD who were not receiving dialysis or had
Kidney International (2016) 89, 675–682
675
clinical investigation
SD Navaneethan et al.: BMI and cause-specific deaths
undergone renal transplantation. The mean age was 72.0 þ 11.7 years, with 44.2% men and 12.7% blacks. The mean BMI of the study cohort was 29.4 þ 6.6 kg/m2. The prevalence of diabetes, hypertension, malignancy, and coronary artery disease were 23.3%, 86.1%, 25%, and 20.7%, respectively. The mean estimated glomerular filtration rate (eGFR) was 47.8 ml/min/1.73 m2, with 67.9% of participants in stage 3a, 24.5% of participants in stage 3b, and 7.5% of participants in stage 4 CKD. Other details of the study population based on BMI categories are outlined in Table 1. Age- and sex-adjusted mortality rates and causes of death
During a median follow-up of 3.7 years (25th percentile, 1.8; 75th percentile, 5.8), 14,518 died. Figure 1 shows the proportion of various causes of death among those in different BMI categories. Table 2 and Figure 1 outline various causes of death in the cardiovascular and noncardiovascular/nonmalignancy–related categories. Overall, cardiovascular diseases (34.0%) and malignant neoplasms (28.9%) were the leading causes of death among the study population.
BMI and cause-specific death
In the models adjusting for relevant confounding variables, a BMI of 25 to 29.9 kg/m2 was associated with lower hazards for overall mortality (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.75–0.81; P < 0.001) and lower subhazards for cardiovascular (HR, 0.83; 95% CI, 0.77–0.89; P < 0.001), malignancy-related (HR, 0.84; 95% CI, 0.78–0.91; P < 0.001), and noncardiovascular/nonmalignancy–related deaths (HR, 0.81; 95% CI, 0.75–0.87; P < 0.001). A BMI of 30 to 34.9 kg/m2 was associated with lower hazards for overall mortality (HR, 0.73; 95% CI, 0.70–0.77; P < 0.001) and lower subhazards for cardiovascular (HR, 0.81; 95% CI, 0.74–0.89; P < 0.001), malignancy-related (HR, 0.80; 95% CI, 0.73–0.88; P < 0.001), and noncardiovascular/ nonmalignancy–related deaths (HR, 0.75; 95% CI, 0.69–0.82; P < 0.001). Similarly, a BMI of 35 to 39.9 kg/m2 was associated with lower hazards for overall mortality (HR, 0.73; 95% CI, 0.68– 0.78; P < 0.001) and lower subhazards for cardiovascular (HR, 0.80; 95% CI, 0.71–0.91; P < 0.001), malignancy-related (HR, 0.73; 95% CI, 0.64–0.83; P < 0.001), and noncardiovascular/nonmalignancy–related deaths (HR, 0.83; 95% CI, 0.74–0.93; P ¼ 0.001). However,
Table 1 | Characteristics of patients with CKD based on BMI levels 40 kg/m2 (n [ 3815)
74.4 153 24.9 19.2 17.4 0.99 7.2 28.0 82.1 55.9 12.7 8.9 10.1 6.1 48.2 34.6 52.1 45.6 11.3
75.1 12.5 39.6 10.6 22.7 1.7 13.2 27.2 81.9 71.5 18.8 8.2 10.1 3.4 54.9 49.4 55.1 47.3 10.5
73.4 11.0 51.3 11.1 27.5 1.4 19.8 26.9 86.5 79.2 22.5 7.2 10.0 3.3 62.5 59.5 58.0 48.1 10.0
70.5 10.8 46.8 13.5 32.2 1.4 28.0 23.8 88.5 81.7 21.8 7.5 9.0 2.8 68.5 63.0 60.6 48.3 10.0
68.0 10.5 37.9 16.6 37.2 1.4 37.1 20.9 88.7 81.6 20.4 8.7 6.6 2.5 74.1 63.7 63.1 47.7 10.2
64.2 10.6 27.8 18.7 45.2 5.0 44.4 17.0 87.9 79.9 16.7 10.3 4.8 1.8 75.7 60.7 60.3 47.1 10.4
67.9 24.5 7.5 4.1 0.79 12.8 1.8
60.4 28.3 11.3 4.0 0.55 12.2 1.9
65.8 25.5 8.7 4.1 1.4 12.6 1.8
68.8 24.2 7.0 4.1 0.45 13.0 1.8
69.9 23.5 6.6 4.1 0.45 13.0 1.8
68.1 24.2 7.7 4.1 0.44 12.8 1.8
65.4 26.3 8.3 4.0 0.46 12.5 1.7
Insurance (%) Medicaid Medicare Missing Other
0.7 78.5 2.8 17.9
1.7 78.7 3.4 16.2
0.7 82.1 2.6 14.7
0.5 81.0 2.4 16.1
0.7 76.9 2.9 19.4
0.8 73.1 3.4 22.6
1.5 66.7 4.5 27.3
Smoking (%) No Yes Missing
79.6 7.1 13.3
68.9 16.9 14.2
76.6 8.4 14.9
80.5 6.6 12.9
80.9 6.6 12.5
80.8 6.4 12.7
80.3 6.1 13.7
Variable
Summary N [ 54,506
Age (mean SD) 72.0 117 Male sex (%) 44.2 Black (%) 12.7 29.4 6.6 BMI (kg/m2) (mean SD) Diabetes (%) 23.3 Malignancy (%) 25.0 Hypertension (%) 86.1 Hyperlipidemia (%) 76.9 Coronary artery disease (%) 20.7 Congestive heart failure (%) 7.9 Cerebrovascular disease (%) 9.1 Peripheral vascular disease (%) 3.1 ACEI/ARB use (%) 63.9 Statin drug use (%) 58.1 Beta-blocker use (%) 58.5 47.8 10.2 eGFR (ml/min/1.73 m2) (mean SD) eGFR categories (%) 45–59 ml/min/1.73 m2 30–44 ml/min/1.73 m2 15–29 ml/min/1.73 m2 Albumin (g/dL) (mean SD) Hemoglobin (mg/dl) (mean SD)
ACEI/ARB, angiotensin-converting enzyme/angiotensin receptor blocker; BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.
676
Kidney International (2016) 89, 675–682
clinical investigation
SD Navaneethan et al.: BMI and cause-specific deaths
weight change per year was a decrease of –0.3 kg/yr. The associations between BMI categories and all-cause mortality remained similar when adjusting for weight change per year (Supplementary Table S1 online). Sensitivity analyses
In a model with a BMI of 21.5 to 24.9 kg/m2 as the reference range, similar associations between BMI categories and various causes of death were noted (Supplementary Table S2 online). In a model with a BMI of 25 to 29.9 kg/m2 as the reference range, BMIs 40 kg/m2 for noncardiovascular/nonmalignancy–related causes of death (Supplementary Table S2 online). In a subgroup of patients who had proteinuria measurements, similar associations between BMI categories and various causes of death were noted (Supplementary Table S3 online). In the competing risk model in which diabetes and hypertension were not adjusted for, results similar to the primary analysis were noted (Supplementary Table S3 online). In the analysis in which we censored patients as of September 2009 (to exclude any patients who would have gone on to dialysis), results similar to the primary analysis were noted (Supplementary Table S3 online).
Figure 1 | Various causes of death among those in different body mass index (BMI) categories.
BMI > 40 kg/m2 was not associated with cardiovascular and noncardiovascular/nonmalignancy–related deaths (Tables 3 and 4). A lower BMI category (
