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Published ahead of print on August 2, 2006
J Am Soc Nephrol 17: 2599-2606, 2006
© 2006 American Society of Nephrology
doi: 10.1681/ASN.2006040331
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Epidemiology and Outcomes

Adiponectin and Mortality in Patients with Chronic Kidney Disease

Vandana Menon*, Lijun Li*, Xuelei Wang{dagger}, Tom Greene{dagger}, Vaidyanathapuram Balakrishnan*, Magdalena Madero*, Arema A. Pereira*, Gerald J. Beck{dagger}, John W. Kusek{ddagger}, Allan J. Collins§, Andrew S. Levey* and Mark J. Sarnak*

* Department of Medicine, Division of Nephrology, Tufts-New England Medical Center, Boston, Massachusetts; {dagger} Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio; {ddagger} National Institutes of Health, Bethesda, Maryland; and § Division of Nephrology, Hennepin County Medical Center, Minneapolis, Minnesota

Address correspondence to: Dr. Vandana Menon, Tufts-New England Medical Center, Division of Nephrology, 750 Washington Street, NEMC #391, Boston, MA 02111. Phone: 617-636-8791; Fax: 617-636-8329; E-mail: vmenon{at}tufts-nemc.org

Received for publication April 10, 2006. Accepted for publication June 29, 2006.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (N = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean ± SD age was 52 ± 12 yr, and mean ± SD glomerular filtration rate (GFR) rate was 33 ± 12 ml/min per 1.73 m2. Eighty-five percent of participants were white, and 60% were male. Mean ± SD adiponectin was 12.8 ± 8.0 µg/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-µg/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; P = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Adiponectin is an adipocyte-derived peptide that may possess antiatherogenic properties (1,2). Obesity (3), coronary artery disease (4–6), and diabetes (7) are characterized by low adiponectin levels, suggesting an inverse association with cardiovascular disease (CVD) risk. Whereas prospective studies in diabetic and nondiabetic men have demonstrated an inverse relationship between adiponectin levels and risk for CVD events (5,6), this association was not found in women (8) and in a population-based cohort of American Indians (9). On the contrary, in a few studies, high rather than low adiponectin levels were associated with adverse outcomes in patients with type 1 diabetes (10,11) and heart failure (12).

Kidney function is an important determinant of circulating levels of adiponectin (13,14), and levels of this protein are markedly elevated in kidney failure (15). Data on the relationship between adiponectin and outcomes in patients with chronic kidney disease (CKD) are sparse. Low adiponectin levels were associated with increased risk for CVD events in one study of hemodialysis patients (15). Similarly, there was an inverse correlation between adiponectin levels and incident CVD in univariate analyses in a small cohort of patients in the earlier stages of CKD (13). Using data from the randomized cohort of the Modification of Diet in Renal Disease (MDRD) Study, we therefore examined the association between adiponectin levels and all-cause and CVD mortality in a cohort of patients with CKD stages 3 to 4.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
The MDRD study, conducted from 1989 to 1993, was a randomized, controlled trial to study the effect of dietary protein restriction and strict BP control on the progression of kidney disease (16). A total of 585 patients with a baseline GFR of 25 to 55 ml/min per 1.73 m2 were randomly assigned in study A, and 255 patients with a baseline GFR of 13 to 24 ml/min per 1.73 m2 were randomly assigned in study B. Patients in study A and study B were combined for these analyses.

Adiponectin was measured in 820 frozen fasting serum samples that were drawn at baseline from the randomized cohort of the MDRD study using a commercially available enzyme immunoassay kit (R&D Systems, Minneapolis, MN). The coefficient of variation for intra- and interassay precision were <5 and <7%, respectively.

Survival status and date and cause of death were ascertained from the National Death Index. A death was ascribed to CVD when the primary cause of death was International Classification of Diseases, Ninth Revision codes 390 through 459 (n = 98) or when kidney disease or diabetes was listed as the primary cause of death and CVD was the secondary cause of death (n = 24). Survival time was defined as time from randomization to death or end of follow-up (December 31, 2000). Data collection procedures were approved by the Cleveland Clinic Foundation and Tufts-New England Medical Center Institutional Review Boards.

Statistical Analyses
Summary statistics according to tertiles of adiponectin are presented as percentages for categorical data, mean (±SD) for approximately normally distributed continuous variables and as median (interquartile range) for skewed continuous variables. Differences in baseline characteristics between the groups were tested using the {chi}2 test, one-way ANOVA, and the Kruskall-Wallis test as appropriate. Independent determinants of adiponectin were identified in a multivariable linear regression model. Differences in survival between the tertiles of adiponectin were compared using Kaplan-Meier survival plots and with survival curves adjusted for gender.

Cox proportional hazards models were used to evaluate the relationship between adiponectin and all-cause and CVD mortality initially without adjustment and subsequently adjusting for several groups of a priori defined confounding variables. Model 1 adjusted for randomization assignments to protein diets and BP strata, age, gender, and race. Model 2 adjusted for traditional CVD risk factors, including history of CVD and diabetes, smoking status, body mass index (BMI), systolic BP, HDL cholesterol, triglycerides, and natural log-transformed C-reactive protein (CRP) and glycosylated hemoglobin (HbA1c) in addition to the variables in model 1. Model 3 adjusted for variables in model 2 as well as kidney disease factors GFR and log-transformed proteinuria. Proportional hazards assumptions were tested using log minus log survival plots and plots of Schoenfeld residuals versus survival time. Hazard ratios (HR) are presented per 1-µg/ml increase in adiponectin, and 95% confidence intervals (CI) were calculated for the HR. We calculated R2 for multivariable linear regression models with adiponectin as the dependent variable and covariates from models 1, 2, and 3 as independent variables to quantify the correlation between adiponectin and covariates. P < 0.05 was considered significant for the primary outcomes of all-cause and CVD mortality.

Additional Analyses
We tested for nonlinearity by examining the functional form of the relationship of all-cause mortality risk and CVD mortality risk versus adiponectin as a continuous variable while controlling for the covariates by fitting a cubic smoothing spline with 5 degrees of freedom. Given the associations of albumin with both adiponectin and mortality (17), the final Cox model (model 3) was repeated with additional adjustment for serum albumin. Model 3 also was repeated replacing HbA1c with insulin or with homeostasis model assessment (HOMA) as an indicator of insulin resistance (18). Because both insulin and HOMA had skewed distributions, they were natural log transformed for these analyses.

Because adiponectin is inversely correlated with GFR, adiponectin may be related to progression of kidney disease, and kidney failure may modify the relationship between adiponectin and mortality outcomes. Therefore, Cox models (corresponding to model 3) were repeated using four additional outcomes: (1) Kidney failure, (2) all-cause or (3) CVD death before reaching kidney failure (need for renal replacement therapy with dialysis or transplantation) with censoring at kidney failure or end of follow-up, and (4) a composite outcome of death or kidney failure. For these four secondary outcomes, we report actual P values and consider P < 0.0127 significant (critical value based on the Bonferroni correction).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Baseline Characteristics
The study cohort had mean ± SD age of 52 ± 12 yr, GFR of 33 ± 12 ml/min per 1.73 m2, and adiponectin of 12.8 ± 8.0 µg/ml. The sample predominantly was white (85%), 60% were male, and 10% were current smokers. Higher adiponectin was associated with a favorable CVD risk profile, including female gender; lower BMI, triglycerides, and CRP; and higher HDL cholesterol (Table 1). Individuals in the highest tertile of adiponectin had a lower prevalence of diabetes and lower levels of glucose, HbA1c, insulin, and HOMA. Adiponectin was associated with more severe kidney disease; that is, with increasing tertiles of adiponectin, proteinuria increased and GFR decreased.


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  		Table 1. Baseline characteristics by tertiles of adiponectina

 
Determinants of Adiponectin
In a multivariable linear regression model, female gender; lower triglycerides, BMI, HOMA, GFR, albumin, and CRP; and higher HDL cholesterol, systolic BP, and proteinuria were associated with higher adiponectin levels (Table 2). This model explained 43% of the variability in adiponectin levels. Age and history of diabetes or CVD did not enter the model. When insulin, glucose, or HbA1c was entered instead of HOMA, each was significant (data not shown).


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  		Table 2. Multivariable linear regression for determinants of adiponectina

 
Outcomes
Median follow-up for analyses of survival was 10 yr. All-cause mortality was 25% (n = 201), and CVD mortality was 15% (n = 122). Kaplan-Meier survival curves for all-cause mortality by tertiles of adiponectin did not demonstrate a difference; however, higher tertiles of adiponectin seemed to be associated with worse survival after adjustment for gender (Figure 1). In unadjusted analysis, there was no association between adiponectin and all-cause mortality (Table 3). After adjustment for randomization assignments and demographic and CVD risk factors, there was a 3% increased risk for all-cause mortality for each 1-µg/ml increase in adiponectin (Table 3, model 2). This association persisted after adjustment for kidney disease factors (Table 3, model 3). With adjustment for gender alone, the HR was 1.02 (95% CI 1.01 to 1.04; P = 0.01). Therefore differences in gender distribution (fewer women in the highest adiponectin tertile) seems to account for the differences between the univariate and multivariable associations. In unadjusted analysis, a 1-µg/ml increase in adiponectin was associated with a 3% increase in the risk for CVD mortality (Table 3). This association persisted in multivariable Cox models adjusting for randomization assignments and demographic, CVD, and kidney disease risk factors (Table 3).


Figure 1
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  		Figure 1. Kaplan-Meier survival curves did not show an association between tertiles of adiponectin and all-cause mortality (A). However, gender-adjusted survival curves showed a graded relationship between increasing tertiles of adiponectin and all-cause mortality (B).

 

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  		Table 3. Relationship between adiponectin and all-cause and cardiovascular mortality

 
To quantify the correlation between adiponectin and covariates, we performed multivariable linear regression models with adiponectin as the dependent variable and models 1, 2, and 3 covariates as independent variables. The R2 was 0.15 for demographic factors and randomization assignments, 0.32 for CVD risk factors, and 0.10 for kidney disease factors.

Additional Analyses
In nonparametric regression analyses, the log-adjusted risk ratio had a linear relationship with adiponectin for all-cause (P = 0.826 for the nonlinearity test; P < 0.001 linear effect) and CVD mortality (P = 0.839 for the nonlinearity test; P < 0.001 linear effect; Figure 2).


Figure 2
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  		Figure 2. The functional form of the relationship of cardiovascular (CVD) mortality risk versus adiponectin as a continuous variable was examined while controlling for the covariates of model 2 by fitting a cubic smoothing spline with 5 degrees of freedom. The log-adjusted risk ratio had a linear relationship with adiponectin CVD mortality (P = 0.839 for the nonlinearity test; P < 0.001 linear effect).

 
The fully adjusted Cox model (Table 3, model 3) was repeated with the addition of serum albumin; the adjusted HR was 1.03 (95% CI 1.00 to 1.05; P = 0.03) for all-cause mortality and 1.06 (95% CI 1.03 to 1.08; P < 0.001) for CVD mortality. Replacing HbA1c with glucose, insulin or HOMA did not appreciably alter the results (data not shown).

A total of 544 patients reached kidney failure during follow-up. There was a significant association between adiponectin (per 1-µg/ml increase) and kidney failure in unadjusted analysis (HR 1.02; 95% CI 1.01 to 1.03; P < 0.001); however, adjustment for GFR attenuated this relationship, and it was no longer significant (HR 1.00; 95% CI 0.99 to 1.01; P = 0.55).

Sixty-six participants died from any cause and 35 from CVD before reaching kidney failure. In unadjusted analyses, the HR was 1.02 (95% CI 0.99 to 1.05; P = 0.25) for all-cause and 1.04 (95% CI 1.01 to 1.08; P = 0.02) for CVD mortality. The HR after adjustment for age, gender, and GFR was 1.03 (95% CI 1.00 to 1.07; P = 0.05) for all-cause and 1.07 (95% CI 1.03 to 1.11; P = 0.001) for CVD mortality. Given the limited number of events, we did not perform further multivariable adjustment.

A total of 610 participants died or reached kidney failure by December 31, 2000. There was no association between adiponectin and the composite outcome of kidney failure or death in Cox model adjusting for age, gender, race, diabetes, randomization assignments, systolic BP, BMI, proteinuria, GFR, and cause of kidney disease (HR 1.00; 95% CI 0.99 to 1.02; P = 0.55).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In this cohort of patients with CKD stages 3 to 4, high adiponectin was associated with increased risk for all-cause and CVD mortality. These findings are in contrast to previous studies in patients with kidney disease that have suggested a beneficial effect of high levels of adiponectin. We confirm previous findings that high adiponectin is associated with a more favorable CVD risk profile (19–21) and demonstrate that it is associated with more advanced kidney disease with lower GFR and higher degree of proteinuria.

Low levels of adiponectin were associated with higher risk for incident coronary heart disease events in men with and without diabetes in the Health Professionals Follow-Up Study (5,6). Similar results were obtained in a cohort of patients with type 2 diabetes (22). Therefore, data from cross-sectional and prospective studies suggest that high levels of this hormone may mitigate CVD risk. In contrast to these data, other studies have reported no association between adiponectin and CVD or even that higher levels of adiponectin may be associated with CVD. An Italian study of patients with type 2 diabetes failed to demonstrate a difference in adiponectin levels between participants with and without CVD (23). In cross-sectional studies in patients with type 1 diabetes, high rather than low adiponectin was associated with retinopathy and CVD (10,11,24). A case-control study did not find an association between adiponectin and angiographically confirmed coronary heart disease (25). Analysis of data from the Strong Heart Study failed to find an association between adiponectin and incident coronary heart disease (9), whereas in a population-based sample of women, low adiponectin did not predict CVD (8). In a recent prospective study of 195 patients with chronic heart failure, high rather than low adiponectin was an independent predictor of all-cause mortality (12). Therefore, despite the existence of strong experimental evidence, prospective epidemiologic studies have not demonstrated conclusively a relationship between adiponectin and reduced risk for CVD.

There is a correlation between kidney function and adiponectin, and levels of this protein are markedly elevated in kidney failure (26), inversely related to GFR and directly related to proteinuria (10,13,14,26,27). Adiponectin levels decreased after successful kidney transplantation, suggesting a role for the kidney in biodegradation and/or elimination of this protein (28).

Limited data on the relationship between adiponectin and CVD exist in patients with CKD. There was no difference in adiponectin levels between patients with and without history of CVD in a cross-sectional study of hemodialysis patients (29). High adiponectin was associated with a favorable CVD risk profile in patients with kidney failure as well as those in the earlier stages of CKD (13,15,29). Becker et al. (13) found an inverse association between adiponectin and prevalent CVD in cross-sectional analyses and a univariate association between low adiponectin and incident CVD in patients with nondiabetic kidney disease. Similarly, low adiponectin was an independent predictor of a composite outcome of fatal and nonfatal CVD events but not of all-cause mortality in 227 dialysis patients (15). Of note, in the study by Kistorp et al. (12), which demonstrated a direct relationship between adiponectin and mortality, creatinine clearance in the patients with the highest tertile of adiponectin was 58 ± 20 ml/min.

Differences in results between our study and those reported by Becker et al. (13) may be attributable to differences in the study population, differences in severity of kidney disease, and the variables that were adjusted for in multivariate analyses. In the study by Becker et al. (13), the patient population had better preserved kidney function with mean estimated GFR of 63 ml/min per 1.73 m2, compared with 32 ml/min per 1.73 m2 in the MDRD study cohort. Similarly, mean adiponectin was lower (6.1 µg/ml) compared with the MDRD study cohort (12.8 µg/ml), perhaps reflecting less advanced kidney disease. Becker et al. (13) demonstrated a significant univariate association between low adiponectin and incident CVD but were unable to perform multivariable analyses because of small numbers of events and limited statistical power.

There are several potential explanations for why adiponectin may be a maker of increased CVD risk in patients with CKD; however, it must be acknowledged that our study, although hypothesis generating, does not directly address any of them. First, the accumulation of adiponectin in CKD may reflect or mediate the wasting and malnutrition that characterize this disease state (30). Contrary to the general population, high BMI and increased adiposity seem to confer a survival advantage in dialysis patients (30,31) and in heart failure (32). There are some experimental data to suggest that adiponectin may be associated with weight loss secondary to increased energy expenditure (33,34). We and others have demonstrated an inverse relationship of adiponectin with BMI (35) and serum albumin (26). Therefore, it is possible that the high adiponectin levels in patients with CKD, similar to patients with heart failure (12), may reflect poor nutritional status and/or vulnerability to the wasting processes and therefore is a marker of poor prognosis. In our study, the relationship between adiponectin and mortality was independent of BMI and remained significant, especially for CVD mortality with adjustment for serum albumin. However, given the strong relationship between nutritional indices and outcomes in kidney disease, the observed associations may be the result of inadequate adjustment for the effect of malnutrition on outcomes. These data suggest that in the CKD population, unlike the general population and similar to patients with heart failure, high adiponectin may reflect other pathologic processes, including malnutrition.

Second, several studies have suggested an independent relationship between reduced kidney function and mortality (36,37). Therefore, given the close association between adiponectin and kidney function, the observed relationship between adiponectin and mortality may reflect either residual confounding as a result of decreased kidney function or confounding by parallel processes that accompany kidney disease and are not captured by adjustment for kidney function. We used iothalamate GFR and proteinuria as precise measures of kidney function. In addition, we did not find a relationship between adiponectin and kidney failure or with a composite outcome of death and kidney failure. Furthermore, the association between adiponectin and CVD mortality was present in patients who died before reaching kidney failure.

Third, although little is known regarding the kidney handling of adiponectin, one could speculate that in kidney disease, derangements in the metabolism of adiponectin could result in (1) an alteration of the ratio between different forms of this peptide, (2) disordered posttranslational modification leading to altered or decreased biologic activity, and/or (3) accumulation of an abnormal metabolite. Any or all of these processes could have deleterious consequences that counteract its beneficial insulin-sensitizing, anti-inflammatory, and antiatherogenic effects. There are some experimental data in support of this hypothesis. Circulating adiponectin exists in two discrete complexes (38); the ratio between these two forms seems to determine improvements in insulin sensitivity in response to thiazolidinedione treatment (39). Eight isomers that are formed as a result of posttranslational modifications have been identified, and these forms seem to differ in the signal transduction pathways that they activate and their degree of biologic activity and effects on target tissues (40).

Finally, the observed results may be unique to the this study population. The MDRD study represents a predominantly nondiabetic, relatively healthy CKD population. This cohort is different from the preponderance of patients with CKD in that a majority of the participants progress to kidney failure. However, the low prevalence of preexisting CVD, diabetes, and malnutrition reduces confounding by these powerful risk factors.

The strengths of this prospective study include the large number of patients, long-term follow-up, low prevalence of CVD at baseline, detailed ascertainment of potentially confounding variables, and precise measurement of GFR. The main limitations are lack of follow-up adiponectin measurements and the use of a single baseline measurement to predict events several years in the future. However, serum concentrations of adiponectin seem stable during a period of 1 yr, with minimal short-term variation and high degree of reproducibility (41). Another concern is the potential misclassification of causes of death; however, this should not influence the relationship between adiponectin and all-cause mortality. Finally, we acknowledge that there was no association between adiponectin and all-cause mortality in unadjusted analyses. However, we believe, as explained in our Results section, that this may be accounted for by the lower number of women in the higher adiponectin groups.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
High rather than low adiponectin is a predictor of all-cause and CVD mortality in this cohort of patients with CKD stages 3 to 4. We do not believe that these findings in any way negate the results from experimental and general population studies that suggest a cardioprotective role for adiponectin. Rather, as with the heart failure population, we believe that patients with CKD are very different from the general population. Further studies are required in this specific patient population to confirm this finding and to examine potential mechanisms underlying this relationship.


   Acknowledgments
 
This study was funded by National Institute of Diabetes and Digestive and Kidney Diseases grants K23 DK67303, K23 DK02904, and UO1 DK35073.


   Footnotes
 
Published online ahead of print. Publication date available at www.jasn.org.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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