Bose et al. BMC Nephrology 2012, 13:104 http://www.biomedcentral.com/1471-2369/13/104
RESEARCH ARTICLE
Open Access
Dysglycemia but not lipids is associated with abnormal urinary albumin excretion in diabetic kidney disease: a report from the Kidney Early Evaluation Program (KEEP) Subhasish Bose1*, Andrew S Bomback2, Nehal N Mehta3, Shu-Cheng Chen4, Suying Li4, Adam Whaley-Connell5, Joseph Benjamin1 and Peter A McCullough6 KEEP investigators
Abstract Background: The relationship between glycemic control and lipid abnormalities with urinary albumin-creatinine ratio (ACR) in chronic kidney disease (CKD) patients with diabetes mellitus (DM) is unknown. We sought to investigate the association of dyslipidemia and glycemic control with levels of albuminuria in the National Kidney Foundation (NKF) Kidney Early Evaluation Program (KEEP) participants with DM and CKD stage 3 or higher. Methods: We performed a cross-sectional study of 6639 eligible KEEP patients with DM and CKD Stage 3 to 5 from June 2008 to December 2009. Multivariate logistic regression was used to evaluate the association of lipid parameters (per 10 mg/dl change in serum level) and glycosylated hemoglobin (HbA1c) values with three degrees of albuminuria normo (300 mg⁄g). Results: 2141 KEEP participants were included. HbA1c levels were strongly associated with micro-albuminuria (compared to normo-albuminuria) and macro-albuminuria (compared to normo-albuminuria and microalbuminuria). Each 1.0% increase in HbA1c increased the odds of micro-albuminuria by 32% (OR 1.32, 95% CI 1.231.42) and the odds of macro-albuminuria (vs. microalbuminuria) by 16% (OR 1.16, 95% CI 1.05-1.28). Only increases in serum HDL were associated with decreased odds of micro-albuminuria; otherwise, the association between other components of the serum lipid profile with urinary ACR did not reach statistical significance. Conclusion: In this cross-sectional study of 2141 KEEP participants with DM and CKD stages 3–5, overall glycemic control but not lipids were associated with abnormal urinary albumin excretion, a marker of increased risk for progressive disease. Keywords: Chronic Kidney Disease, Diabetes Mellitus, Proteinuria, Dyslipidemia, Glycosylated hemoglobin
Background Prevalence of chronic kidney disease (CKD) is increasing in the United States from approximately 12.7% reported in the National Health and Nutrition Examination Survey (NHANES) III (1988–1994) to 15.1% reported in the 2009 United States Renal Data System (USRDS) Annual Data Report, based on NHANES (2003–2006) data. CKD is a major cause of cardiovascular disease (CVD) morbidity and mortality worldwide and is now widely recognized as an * Correspondence:
[email protected] 1 Department of Nephrology, Temple University Hospital, Philadelphia, PA, USA Full list of author information is available at the end of the article
independent risk for the development of CVD [1]. The relationship between CKD and CVD is complex but appears to be bidirectional, where therapy directed at improving natural history of one generally improves prognosis of the other. Specifically, CVD outcomes have been shown to improve with the treatment of risk factors commonly found in association with CKD progression including hypertension, diabetes mellitus (DM), and dyslipidemia [2]. Increasing albuminuria is a recognized predictor for CVD. Even mild elevations in the range of microalbuminuria (30–299 mg/day) are associated with atherogenic lipoprotein abnormalities that promote
© 2012 Bose et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bose et al. BMC Nephrology 2012, 13:104 http://www.biomedcentral.com/1471-2369/13/104
endothelial dysfunction and CVD [3-5]. Serum lipid abnormalities have been established as a strong risk factor for CVD in the general population and are associated with advanced DM-related CKD and nephrotic range proteinuria. There is evidence that lipid abnormalities are associated with urinary albumin excretion (UAE) in patients with diabetes [6,7]. Increased UAE was found to be associated with ApoB-containing lipoproteins in patients with diabetes and the phenotype of hypertriglycerides/hyper-ApoB [6]. Our understanding of the lipid abnormalities associated with CKD and proteinuria are limited to correlative studies and targeting reductions in LDL. In this context, the relationship between dyslipidemia and diabetic kidney disease is derived from studies on HMG-coA reductase inhibition reducing proteinuria. However, limited data suggest that elevations in triglycerides have been implicated as a potential risk factor for progression of diabetic kidney disease [7]. Even less attention has been paid to the role of low versus high HDL parameters. We hypothesized that increasing levels of proteinuria would be associated with alterations in dyslipidemia and dysglycemia in patients with DM and CKD. We thus investigated the relationship between proteinuria, dyslipidemia, and dysglycemia in participants in the National Kidney Foundation (NKF)-Kidney Early Evaluation Program (KEEP).
Page 2 of 7
Definitions
Estimated glomerular filtration rate GFR (eGFR) was calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) study equation, and serum creatinine was calibrated by the Cleveland Clinic Research Laboratory [13]. We would like to re-emphasize that CKD stage 3 was defined using KDOQI/KDIGO criteria as an NKF initiative with an estimated GFR 60 with an albumin to creatinine ratio >30mg /g. ACR were calculated from urine samples and recorded as 300 mg⁄g. Microalbuminuria was defined as ACR of 30–300 mg/g, and macroalbuminuria, as ACR >300 mg/g. CKD was defined by an eGFR 60 with an ACR >30 mg/g. Other definitions included (1) hypertension: average systolic blood pressure >129 mm Hg or diastolic blood pressure >84 mm Hg (as per ATP III criteria for hypertension in association with dyslipidemia, glucose intolerance and abdominal obesity in metabolic syndrome) or a self-reported history of hypertension or patients taking blood pressure–lowering medication; and (2) dyslipidemia: triglyceride level >150 mg⁄dL or total cholesterol >200 mg⁄dL; (3) Diabetes mellitus: selfreported diabetes mellitus, retinopathy, and taking diabetic medications (including insulin). Other measures, including education level, tobacco and alcohol uses, and family history of diseases, were self-reported. Blood pressure, height, weight, and waist circumference were directly measured for all participants.
Methods NKF-KEEP
Statistical Analysis
KEEP is a free community-based health-screening program that targets populations aged ≥18 years at high risk of kidney disease, defined as history of diabetes or hypertension or a first order relative with diabetes, hypertension, or kidney disease, as has been described previously. Screening methods have been reported previously [8]. Since August 2000, the program has screened ≥128,000 participants from 50 states and the District of Colombia. The KEEP database has been fully described in previous reports [9-12]. The Human Subjects Committees at the University of Minnesota approved this study. All procedures were in accordance with the Helsinki Declaration of 1975 as revised in 1983 and Title 45, U.S. Code of Federal Regulations, Part 46, Protection of Human Subjects, Revised November 13, 2001. Prior to enrollment, participants provided written informed consent. All authors were granted free access to the database. This study included a total of 6639 eligible KEEP patients from June 2008 to December 2009 with HbA1c values. After excluding non-diabetic patients, non-CKD patients, and patients with missing values of urinary albumin-creatinine ratio (ACR), the total sample size was 2141.
Demographic and baseline characteristics of the study population based on quartiles of glycosylated hemoglobin (HbA1c) were compared. Values were expressed as frequency (percent) unless noted otherwise. KEEP health screening results for the participants were also categorized by HbA1c values. We performed multivariate logistic regression analyses to evaluate individual association of lipid parameters (per 10 mg/dl change in serum level) and HbA1c values with ACR, adjusting for risk factors such as age, gender, race, status of hypertension and smoking. These associations were compared across different degrees of ACR: normo-albuminuria (300 mg⁄g).
Results The final eligible sample size included 2141 KEEP participants with diabetes and CKD stage 3–5 (Table 1). Participants were grouped into 4 quartiles of glycemic control delineated by HbA1c values: ≤6.2%, 6.3-6.9%, 7.0-8.1%, and ≥8.2%. The participants were predominantly female (65%) and non-hispanic white (57.5%) with a median age of 66 years (range 58–75). Participants
Bose et al. BMC Nephrology 2012, 13:104 http://www.biomedcentral.com/1471-2369/13/104
Page 3 of 7
Table 1 Clinical Characteristics of KEEP Participants, 2008–2009, by Level of Glycemic Control as Evident by HbA1c
2141 (100)
Q1 [4.5 to 6.2] 576 (26.9)
Quartiles of Glycosylated Hemoglobin (HbA1c) Q2 [6.3 to 6.9] 564 (26.3)
Q3 [7.0 to 8.1] 482 (22.5)
Q4 [8.2 to 18.0] 519 (24.2)
Compare Q1 & Q4 (p value) }
66 (58–75)
69 (61–77)
72 (63–78)
67 (60–75)
59 (50–68)
