Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2011 Mar 1.
Published in final edited form as: J Ren Nutr. 2009 Oct 22;20(2):74–81. doi: 10.1053/j.jrn.2009.08.001

Serum Carboxymethyl-lysine, a Dominant Advanced Glycation End Product, is Associated with Chronic Kidney Disease: the Baltimore Longitudinal Study of Aging

Richard D Semba *, Jeffrey C Fink †, Kai Sun *, B Gwen Windham, Luigi Ferrucci ‡
PMCID: PMC2829356  NIHMSID: NIHMS137361  PMID: 19853477

Abstract

Objective:

Advanced glycation end products (AGEs) are modifiable risk factors for renal disease that have been primarily studied in persons with diabetes or end-stage renal disease. The objective was to characterize the relationship between AGEs and renal function in community-dwelling adults.

Design:

Serum L-carboxymethyl-lysine (CML), a dominant AGE, was compared with renal function in a cross-sectional analysis.

Setting:

The Baltimore Longitudinal Study of Aging (BLSA) in Baltimore, Maryland.

Patients or Other Participants:

Community-dwelling men and women, aged 26-93 years, seen in a regular BLSA follow-up visit between 2002 and 2007.

Main outcome measure:

Chronic kidney disease (CKD), ≥stage 3 of National Kidney Foundation classification (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), and eGFR.

Results:

Of 750 adults, 121 (16.1%) had CKD. Serum CML was associated with CKD (Odds Ratio [O.R.] expressed per 1 Standard Deviation [S.D.], 1.37, 95% Confidence Interval [C.I.] 1.11-1.67, P = 0.003) in a multivariate logistic regression model adjusting for age, race, smoking, and chronic diseases. Serum CML was associated with eGFR (mL/min/1.73 m2) (beta = −2.21, standard error = 0.57, P = 0.0001) in multivariate linear regression model adjusting for age, race, smoking, and chronic diseases. After excluding patients with diabetes, serum CML was associated with CKD (O.R. per 1 S.D., 1.38, 95% C.I. 1.12-1.70, P = 0.003) and eGFR (beta = −2.09, standard error = 0.59, P = 0.0005), adjusting for the same covariates.

Conclusion:

Serum CML, a dominant AGE, is independently associated with CKD and eGFR.

Keywords: advanced glycation end products, aging, chronic kidney disease, glomerular filtration rate

Chronic kidney disease affects more than fifteen million people in the United States1 and is associated with high cardiovascular disease morbidity and mortality.2 The factors that affect the progression of chronic kidney disease and increase the risk of cardiovascular disease have been incompletely characterized. Advanced glycation end products (AGES) are bioactive molecules that are formed by the non-enzymatic glycation of proteins and other molecules, and AGEs are implicated in the pathogenesis of chronic kidney disease, diabetes, and atherosclerosis.3-5

Systemic AGEs are derived from two main sources: exogenous AGEs ingested in foods and endogenous AGEs formed in the body. AGEs accumulate in tissues, a process which is accelerated with aging.6 The western diet is rich in AGEs, as AGEs are formed when food is processed at elevated temperatures, i.e., deep frying, broiling, and grilling, and high concentrations of AGEs are found in foods such as French fries, potato chips, crackers, chicken nuggets, and cola drinks.7 About 10% of ingested AGEs are absorbed and two-thirds are retained in tissues.8 A reduced dietary intake of AGEs has been shown to lower serum AGEs, decrease inflammation, and improve vascular function in patients with diabetes or renal failure.9-11 AGE-breakers or inhibitors improve arterial compliance12 and cardiac function,13 and have been shown to improve renal function in patients with diabetes14,15 and in animal models.5,16-18

Chronic kidney disease and AGEs are involved in what has been termed a “vicious cycle”, as chronic kidney disease is associated with increased oxidative stress and carbonyl stress, i.e., the generation of reactive carbonyl compounds and AGEs. AGEs and other carbonyl-modified proteins, in turn, contribute to further decline of renal function.19 AGEs can damage the kidney through AGE-RAGE interaction, deposition of AGEs, and in situ glycation. AGEs are the focus of growing interest because experiments conducted in animal models have shown that blockage of AGEs reduces the complications of atherosclerosis and diabetes,20 and because of substantial improvement in measurement technology. AGEs have been primarily studied in patients with diabetes or end-stage renal disease, and less is known about AGEs and renal function in community-dwelling adults. We postulated that elevated levels of serum AGE were associated with chronic kidney disease and reduced renal function. To address this hypothesis, we studied the relationship between serum carboxymethyl-lysine (CML), a dominant AGE, and renal function in community-dwelling adults.

Materials and Methods

Study Population

The study subjects consisted of participants in the Baltimore Longitudinal Study of Aging (BLSA) who were seen between April 2002 and August 2007. The BLSA is a prospective open cohort study of community-dwelling volunteers, largely from the Baltimore/Washington area. The study was established in 1958 and is described in detail elsewhere.21 BLSA participants return every one to four years, depending upon age, to the National Institute on Aging Clinical Research Center in Baltimore, Maryland, for 2.5 days of medical, physiological, and psychological examinations.21 Height, weight, and waist circumference were determined for all participants. Body mass index (BMI) was determined as kg/m2. Smoking status was ascertained by a questionnaire that classified each subject as a non-smoker, former smoker, or current smoker. The BLSA has continuing approval from the Institutional Review Board (IRB) of the MedStar Research Institute, and the protocol for the present study was also approved by the IRB of the Johns Hopkins School of Medicine.

Laboratory Studies

Serum creatinine was measured using the Jaffe method. Blood samples were collected after an overnight fast and were stored continuously at −70° C until the time of analyses of serum AGEs. The measure of serum AGEs in this study was serum CML. CML is a dominant circulating AGE, the best characterized of all the AGEs, and a dominant AGE in tissue proteins.22 CML was measured using a competitive ELISA (AGE-CML ELISA, Microcoat, Penzberg, Germany).23 This assay has been validated,24 is specific, and shows no cross-reactivity with other compounds.23 Measurements were all performed in duplicate according to the protocol of the manufacturers, and the results were averaged. The within assay and between assay coefficients of variation for serum CML were both <5%.

Statistical Analysis

Continuous variables were compared using Wilcoxon rank-sum test. Categorical variables were compared using chi-square tests. BMI was categorized as underweight (<18.5 kg/m2), normal range (18.5-24.9 kg/m2), overweight (≥25-29.9 kg/m2) and obese (≥30 kg/m2).25 Kidney disease was classified as stage 1, 2, 3, 4, or 5, based upon an estimated glomerular filtration rate (eGFR) of ≥90, 60-89, 30-59, 15-29, and <15 mL/min/1.73 m2, respectively, using the 5 stage National Kidney Foundation classification26 and the 4-variable Modification of Diet in Renal Disease Study equation of Levey and colleagues.27 Chronic kidney disease was defined as stage 3 or worse. Logistic regression models were used to examine the relation between serum CML and other factors with chronic kidney disease. Linear regression models were used to examine the same cross-sectional relationships where the dependent variable was eGFR. Variables that were significantly associated with chronic kidney disease and eGFR in univariate analyses were entered into multivariate logistic and linear regression models. In linear and logistic regression models, one standard deviation in concentration of serum CML was used as the unit of change. In addition, serum CML levels were analyzed by use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and by use of statins and oral anti-diabetes drugs, since such drugs could have potential effects upon CML levels.28 The statistical program used was SAS (SAS Institute, Cary, NC), with data analysis conducted by Kai Sun. The level of significance used in this study was P <0.05.

Results

The demographic and health characteristics of 750 men and women with and without chronic kidney disease are shown in Table 1. Overall, mean (SD) serum CML was 0.47 (0.13) μg/mL. Of 750 adults, 121 (16.1%) had chronic kidney disease. Those with chronic kidney disease were more likely to be older, white, former smokers, and to have hypertension, angina, myocardial infarction, congestive heart failure, diabetes mellitus, and cancer. There were no significant differences in education, BMI, or stroke between those with and without chronic kidney disease. The prevalence of stroke was less than 1% (Table 1). The proportion of subjects with eGFR ≥90, 60-89, 30-59, 15-29, and <15 mL/min/1.73 m2 was 24.0%, 59.9%, 15.6%, 0.5%, and 0%, respectively.

Table 1.

Demographic and health characteristics of adult men and women with and without chronic kidney disease in the Baltimore Longitudinal Study of Aging

Characteristic* Chronic Kidney
Disease
N = 121		 No Chronic Kidney
Disease
N = 629		 P
N % or
Median
(25th, 75th
percentile)		 N % or
Median
(25th, 75th
percentile)
Age, years 121 74.8
(68.3, 80.9)		 629 61.9
(53.9, 71.8)		 <0.0001
Race White 106 87.6 384 61.0 <0.0001
Other 15 12.4 245 39.0
Sex Male 61 50.4 318 50.6 0.97
Female 60 49.6 311 49.4
Education <12 years 112 15.9 593 84.1 0.76
Smoking status Current 4 3.3 32 5.1 0.02
Former 67 55.4 263 41.8
Never 50 41.3 334 53.1
Body mass
index (kg/m2)		 <18.5 2 1.6 3 0.5 0.31
18.5-24.9 36 29.8 223 35.4
25.0-29.9 48 39.7 242 38.5
≥30 35 28.9 161 25.6
Serum creatinine (mg/dL) 121 1.30
(1.10, 1.50)		 629 0.90
(0.80, 1.10)		 <0.0001
Serum creatinine (μmol/L) 121 115 (97, 133) 628 80 (70, 97) <0.0001
Estimated glomerular filtration rate
(mL/min/1.73 m2)† 		121 53.5
(48.5, 57.1)		 629 79.6
(71.9, 91.1)		 <0.0001
Serum CML (μg/mL) 121 0.50
(0.41, 0.62)		 629 0.45
(0.37, 0.54)		 0.0004
Hypertension 56 46.3 179 28.4 0.0001
Angina 27 22.3 56 8.9 <0.0001
Myocardial infarction 12 9.9 17 2.7 0.0002
Congestive heart failure 3 2.5 2 0.3 0.03
Stroke 0 0 3 0.5 0.99
Diabetes mellitus 13 10.7 31 4.9 0.01
Cancer 19 15.7 60 9.5 0.04
Open in a new tab
*

Median (25th, 75th percentile) for continuous variables or percent of participants with specific characteristic as noted.

†

Estimated glomerular filtration rate calculated using the 4-variable Modification of Diet in Renal Disease Study equation of Levey and colleagues.26

Median (25th, 75th percentile) CML concentrations in participants with stage 1, 2, 3, and 4 kidney disease were 0.45 (0.37, 0.52), 0.46, (0.38, 0.54), 0.50 (0.41, 0.61), and 0.91(0.88, 0.94) μg/mL, respectively (P < 0.0001). There were 75 participants taking either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 62 participants taking statins, and 14 patients taking oral anti-diabetes drugs. Median (25th, 75th percentile) CML concentrations in participants taking: (i) angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, (ii) statins, (iii) oral anti-diabetes drugs, and (iv) none of the previous three groups of medications were 0.48 (0.41, 0.55), 0.46 (0.36, 0.57), 0.43 (0.37, 0.47), and 0.46 (0.38, 0.54) μg/mL, respectively (P = 0.54). When the analysis was restricted to those with chronic kidney disease only, the median (25th, 75th percentile) CML concentrations in the same four respective groups were 0.57 (0.43, 0.63), 0.55 (0.45, 0.63), 0.45 (0.45, 0.45), and 0.49 (0.41, 0.60) μg/mL, respectively (P = 0.68).

Separate multivariate logistic regression models were used to examine the cross-sectional relationship between serum CML and chronic kidney disease (Table 2). Serum CML was significantly associated with increased odds of chronic kidney disease in models adjusted for age and race and additionally for smoking and for hypertension, angina, myocardial infarction, congestive heart failure, diabetes, and cancer (Table 2). After excluding subjects with diabetes, serum CML was significantly associated with increased odds of chronic kidney disease in multivariate logistic regression models adjusting for the same covariates.

Table 2.

Multivariate logistic regression models of the relation of serum CML with chronic kidney disease in men and women in the Baltimore Longitudinal Study of Aging*

Model adjusted for age, race Model adjusted for age, race,
smoking		 Model adjusted for age, race,
smoking, and chronic diseases‡
OR 95% CI P OR 95% CI P OR 95%CI P
Serum
CML†
(μg/mL) 		All participants
(n = 750) 		1.36 1.11-1.66 0.003 1.36 1.11-1.66 0.003 1.37 1.11-1.67 0.003
Non-diabetic
participants
(n = 706) 		1.39 1.27-1.71 0.002 1.39 1.13-1.71 0.002 1.38 1.12-1.70 0.003
Open in a new tab
*

Separate logistic regression models shown for serum CML in which chronic kidney disease (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2) is the dependent variable.

†

Odds ratios expressed per 1 SD of serum CML (1 SD = 0.13 μg/mL).

‡

Chronic diseases were hypertension, angina, myocardial infarction, congestive heart failure, diabetes, and cancer.

The relation between serum CML and eGFR was examined in univariate linear regression analyses shown in Table 3. Age, race, former smoking, hypertension, angina, myocardial infarction, congestive heart failure, and cancer were associated with estimated GFR. Sex, education, stroke, diabetes, and BMI were not associated with eGFR. Serum CML was significantly associated with eGFR, in separate multivariate linear regression models adjusting for age and race, and adjusting additionally for smoking and for hypertension, angina, myocardial infarction, congestive heart failure, and cancer (Table 4). After excluding subjects with diabetes, serum CML was significantly associated with eGFR in multivariate linear regression models adjusting for the same covariates.

Table 3.

Relationships between demographic characteristics, serum CML, and other factors with estimated glomerular filtration rate in univariate linear regression models for men and women in the Baltimore Longitudinal Study of Aging

Characteristic* Beta SE P
Age, years −0.50 0.04 <0.0001
Sex, male −0.32 1.28 0.80
Race, white −10.60 1.29 <0.0001
Education <12 years 1.74 2.71 0.52
Smoking status Current −1.10 3.05 0.71
Former −3.95 1.31 0.003
Body mass index (kg/m2) <18.5 −1.43 7.97 0.86
25.0-29.9 −0.15 1.51 0.92
≥30 0.92 1.67 0.58
Serum CML (μg/mL), per 1 SD −3.05 0.65 <0.0001
Hypertension −3.22 1.38 0.02
Angina −8.00 2.03 <0.0001
Myocardial infarction −8.67 3.32 0.009
Congestive heart failure −8.34 1.91 <0.0001
Stroke 4.43 10.21 0.66
Diabetes mellitus −4.32 2.73 0.11
Cancer −5.10 2.09 0.01
Open in a new tab
*

Reference categories are sex (female), race (non-white), smoking status (never smoker), and body mass index (18.5-24.9 kg/m2).

Table 4.

Multivariate linear regression models of the relation of serum CML with estimated glomerular filtration rate in men and women in the Baltimore Longitudinal Study of Aging*

Model adjusted for age, race Model adjusted for age,
race, smoking		 Model adjusted for age, race,
smoking, and chronic
diseases‡
Beta SE P Beta SE P Beta SE P
Serum
CML†
(μg/mL) 		All
participants
(n = 750) 		−2.33 0.58 <0.0001 −2.33 0.59 <0.0001 −2.21 0.57 0.0001
Non-diabetic
participants
(n = 706) 		−2.10 0.59 0.0004 −2.11 0.59 0.0004 −2.09 0.59 0.0005
Open in a new tab
*

Separate linear regression models shown for serum CML in which estimated glomerular filtration rate (mL/min/1.73 m2) is the dependent variable.

†

Beta expressed per 1 SD of serum CML (1 SD = 0.13 μg/mL).

‡

Chronic diseases were hypertension, angina, myocardial infarction, congestive heart failure, and cancer.

Discussion

This study suggests that elevated serum CML is independently associated with chronic kidney disease in community-dwelling men and women. Elevated serum or plasma AGEs have been described in patients with diabetic nephropathy29,30 and end-stage renal disease.31,32 The present study shows that elevated serum CML was associated with chronic kidney disease and eGFR in men and women without diabetes. CML may be a promising biomarker for risk of cardiovascular and renal disease.33

AGEs are metabolized and removed by the kidney34,35 but the kidney is also a site for accumulation of AGEs and AGE-related damage.36 The serum concentrations of CML among adults with chronic kidney disease in this study were lower than CML concentrations described adults with diabetic nephropathy37 and diabetics with retinopathy.22 AGEs have been implicated in the pathogenesis of diabetic nephropathy and complications of end-stage renal disease.38 AGEs upregulate inflammation and the synthesis of fibronectin, laminin, and collagen IV in the kidney and promote glomerular sclerosis, fibrosis, and hypertrophy.5,38,39 The kidney is affected by AGEs, and declining renal function entails an increase in serum AGEs, thereby amplifying damage from AGEs.5 AGEs are not merely a marker of renal function, as treatment with AGE inhibitors improves renal function, suggesting a direct role of AGEs in the pathogenesis of chronic kidney disease.14,15 This is in contrast to what has been shown with hyperhomocysteinemia in kidney disease, where levels rise with declining renal function, but treatment has not been shown to be substantially beneficial.40,41

The study has some limitations. The serum creatinine measurements in the present study have not been standardized using standards traceable to isotope dilution mass spectrometry.42 Dietary intake of AGEs was not assessed in the present study, however, dietary intake of AGEs has been shown to correlate well with serum CML concentrations.10,43 Since the study design is cross-sectional, the direction of the association between elevated CML and chronic kidney disease cannot be inferred, however, it is established that pharmacological inhibition of AGE formation will improve renal function in animals16-18 and humans.14,15

The link between chronic kidney disease and cardiovascular disease has been largely attributed to endothelial dysfunction.2 An accumulation of AGEs in serum and tissues due to declining renal function may potentially exacerbate endothelial dysfunction and atherosclerosis.4 AGEs play a role in atherosclerosis by accumulating in arterial walls, increasing arterial stiffness by cross-linking collagen, contributing to the oxidation of low-density lipoprotein (LDL), crosslink with LDL and immunoglobulins in the subendothelium, initiating monocyte migration across endothelial cells, and upregulating inflammation via receptor for AGE (RAGE) and activation of transcription factor nuclear factor-κB.4

Dietary intake of AGEs contributes to a substantial portion of circulating AGEs,10 and dietary restriction of AGEs has been shown to reduce serum AGEs in patients with renal failure.40 However, during chronic kidney disease, increased blood AGE concentrations may be more related to endogenous glycoxidation than to AGEs in the diet. Diet is a major source of exogenous AGEs, and AGEs are especially high in Western diets where foods are processed under elevated temperatures such as by broiling, roasting, deep frying, oven frying, or grilling.7 The AGE content of the same food item can be increased 10-200 fold by increasing the temperature and conditions used in cooking.8 There still remain large gaps in knowledge regarding the AGE composition of foods that are common in the diets in different countries around the world, and the extent of AGE absorption from different foods and potential toxicities are incompletely characterized. Restriction of dietary AGE intake reduces the expression of C-reactive protein and adhesion molecules and improve endothelial function.9,11 Systemic levels of AGEs can potentially be modified by changes in dietary intake of AGEs, and such dietary modification could be evaluated to prevent onset as well as progression of chronic kidney disease. Such interventions could be particularly important in high risk groups such as the population studied here.

In conclusion, elevated CML, a dominant AGE, is independently associated with chronic kidney disease in community-dwelling men and women. Further studies are needed to determine whether elevated AGEs and circulating RAGE predict a decline in renal function and end-stage renal disease. The relationship between AGE and RAGE with cardiovascular disease in patients with chronic kidney disease has not been well characterized. AGEs are a potential target for interventions to prevent onset as well as progression of chronic kidney disease, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.

Acknowledgments

This work was supported by National Institute on Aging Grant R01 AG027012 and the Intramural Research Program of the NIH, National Institute on Aging.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038–2047. doi: 10.1001/jama.298.17.2038. [DOI] [PubMed] [Google Scholar]
  • 2.Schiffrin EL, Lipman ML, Mann JFE. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116:85–97. doi: 10.1161/CIRCULATIONAHA.106.678342. [DOI] [PubMed] [Google Scholar]
  • 3.Vlassara H, Striker G. Glycotoxins in the diet promote diabetes and diabetic complications. Curr Diabetes Rep. 2007;7:235–241. doi: 10.1007/s11892-007-0037-z. [DOI] [PubMed] [Google Scholar]
  • 4.Basta G, Schmidt AM, de Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63:582–592. doi: 10.1016/j.cardiores.2004.05.001. [DOI] [PubMed] [Google Scholar]
  • 5.Bohlender JM, Franke S, Stein G, et al. Advanced glycation end products and the kidney. Am J Renal Physiol. 2005;289:F645–F659. doi: 10.1152/ajprenal.00398.2004. [DOI] [PubMed] [Google Scholar]
  • 6.Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product Nε-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest. 1997;99:457–468. doi: 10.1172/JCI119180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Goldberg T, Cai W, Peppa M, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004;104:1287–1291. doi: 10.1016/j.jada.2004.05.214. [DOI] [PubMed] [Google Scholar]
  • 8.Koschinsky T, He CJ, Mitsuhashi T, et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci USA. 1997;94:6474–6479. doi: 10.1073/pnas.94.12.6474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Vlassara H, Cai W, Crandall J, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA. 2002;99:15596–15601. doi: 10.1073/pnas.242407999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Uribarri J, Peppa M, Cai W, et al. Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients. Am J Kidney Dis. 2003;42:532–538. doi: 10.1016/s0272-6386(03)00779-0. [DOI] [PubMed] [Google Scholar]
  • 11.Negrean M, Stirban A, Stratmann B, et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus. Am J Clin Nutr. 2007;85:1236–1243. doi: 10.1093/ajcn/85.5.1236. [DOI] [PubMed] [Google Scholar]
  • 12.Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001;104:1464–1470. doi: 10.1161/hc3801.097806. [DOI] [PubMed] [Google Scholar]
  • 13.Little WC, Zile MR, Kitzman DW, et al. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005;11:191–195. doi: 10.1016/j.cardfail.2004.09.010. [DOI] [PubMed] [Google Scholar]
  • 14.Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 2004;24:32–40. doi: 10.1159/000075627. [DOI] [PubMed] [Google Scholar]
  • 15.Williams ME, Bolton WK, Khalifah RG, et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol. 2007;27:605–614. doi: 10.1159/000108104. [DOI] [PubMed] [Google Scholar]
  • 16.Degenhardt TP, Alderson NL, Arrington DD, et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int. 2002;61:939–950. doi: 10.1046/j.1523-1755.2002.00207.x. [DOI] [PubMed] [Google Scholar]
  • 17.Forbes JM, Thallas V, Thomas MC, et al. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 2003;17:1762–1764. doi: 10.1096/fj.02-1102fje. [DOI] [PubMed] [Google Scholar]
  • 18.Susic D, Varagic J, Ahn J, et al. Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats. Am J Hypertens. 2004;17:328–333. doi: 10.1016/j.amjhyper.2003.12.015. [DOI] [PubMed] [Google Scholar]
  • 19.Miyata T, Kurokawa K, van Ypersele de Strihou C. Relevance of oxidative and carbonyl stress to long-term uremic complications. Kidney Int Suppl. 2000;76:S120–125. doi: 10.1046/j.1523-1755.2000.07615.x. [DOI] [PubMed] [Google Scholar]
  • 20.Basta G. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis. 2008;196:9–21. doi: 10.1016/j.atherosclerosis.2007.07.025. [DOI] [PubMed] [Google Scholar]
  • 21.Shock NW, Greulich RC, Andres RA, et al. Normal Human Aging: the Baltimore Longitudinal Study of Aging. U.S. Government Printing Office; Washington, D.C.: 1984. [Google Scholar]
  • 22.Reddy S, Bichler J, Wells-Knecht KJ, et al. N epsilon-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry. 1995;34:10872–10878. doi: 10.1021/bi00034a021. [DOI] [PubMed] [Google Scholar]
  • 23.Boehm BO, Schilling S, Rosinger S, et al. Elevated serum levels of Nε-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema. Diabetologia. 2004;47:1376–1379. doi: 10.1007/s00125-004-1455-y. [DOI] [PubMed] [Google Scholar]
  • 24.Zhang X, Frischmann M, Kientsch-Engel R, et al. Two immunochemical assays to measure advanced glycation end-products in serum from dialysis patients. Clin Chem Lab Med. 2005;43:503–511. doi: 10.1515/CCLM.2005.089. [DOI] [PubMed] [Google Scholar]
  • 25.James PT, Leach R, Kalamara E, et al. The worldwide obesity epidemic. Obes Res. 2001;9(suppl 4):228S–233S. doi: 10.1038/oby.2001.123. [DOI] [PubMed] [Google Scholar]
  • 26.Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139:137–147. doi: 10.7326/0003-4819-139-2-200307150-00013. [DOI] [PubMed] [Google Scholar]
  • 27.Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461–470. doi: 10.7326/0003-4819-130-6-199903160-00002. [DOI] [PubMed] [Google Scholar]
  • 28.Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. J Am Soc Nephrol. 2005;16:2363–2372. doi: 10.1681/ASN.2005010062. [DOI] [PubMed] [Google Scholar]
  • 29.Makita Z, Radoff S, Rayfield EJ, et al. Advanced glycosylation end-products in patients with diabetic nephropathy. N Engl J Med. 1991;325:836–842. doi: 10.1056/NEJM199109193251202. [DOI] [PubMed] [Google Scholar]
  • 30.Mostafa AA, Randell EW, Vasdev SC, et al. Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes. Mol Cell Biochem. 2007;302:35–42. doi: 10.1007/s11010-007-9422-9. [DOI] [PubMed] [Google Scholar]
  • 31.Miyata T, Ueda Y, Shinzato T, et al. Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: renal implications in the pathophysiology of pentosidine. J Am Soc Nephrol. 1996;7:1198–1206. doi: 10.1681/ASN.V781198. [DOI] [PubMed] [Google Scholar]
  • 32.Suliman ME, Heimbürger O, Bárány P, et al. Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy. J Am Soc Nephrol. 2003;14:1614–1422. doi: 10.1097/01.asn.0000067413.32377.cf. [DOI] [PubMed] [Google Scholar]
  • 33.Wautier MP, Boulanger E, Guillausseau PJ, Massin P, Wauter JL. AGEs, macrophage colony stimulating factor and vascular adhesion molecule blood levels are increased in patients with diabetic microangiopathy. Thromb Haemost. 2004;91:879–885. doi: 10.1160/TH03-07-0486. [DOI] [PubMed] [Google Scholar]
  • 34.Gugliucci A, Bendayan M. Renal fate of circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells. Diabetologia. 1996;39:149–160. doi: 10.1007/BF00403957. [DOI] [PubMed] [Google Scholar]
  • 35.Miyata T, Ueda Y, Horie K, et al. Renal catabolism of AGEs: the fate of pentosidine. Kidney Int. 1998;53:416–422. doi: 10.1046/j.1523-1755.1998.00756.x. [DOI] [PubMed] [Google Scholar]
  • 36.Schinzel R, Münch G, Heidland A, et al. Advanced glycation end products in end-stage renal disease and their removal. Nephron. 2001;87:295–303. doi: 10.1159/000045934. [DOI] [PubMed] [Google Scholar]
  • 37.Busch M, Franke S, Wolf G, et al. The advanced glycation end product Nε-carboxymethyllysine is not a predictor of cardiovascular events and renal outcomes in patients with type 2 diabetic kidney disease and hypertension. Am J Kidney Dis. 2006;48:571–579. doi: 10.1053/j.ajkd.2006.07.009. [DOI] [PubMed] [Google Scholar]
  • 38.Vlassara H, Striker LJ, Teichberg S, et al. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA. 1994;91:11704–11708. doi: 10.1073/pnas.91.24.11704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Yang CW, Vlassara H, Peten EP, et al. Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci USA. 1994;91:9436–9440. doi: 10.1073/pnas.91.20.9436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Bostom A. Homocysteine: “expensive creatinine” or important modifiable risk factor for arteriosclerotic outcomes in renal transplant recipients? J Am Soc Nephrol. 2000;11:149–151. doi: 10.1681/ASN.V111149. [DOI] [PubMed] [Google Scholar]
  • 41.Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007;298:1212–1214. doi: 10.1001/jama.298.10.1163. [DOI] [PubMed] [Google Scholar]
  • 42.Levey AS, Coresh J, Greene T, et al. Expressing the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem. 2007;53:766–772. doi: 10.1373/clinchem.2006.077180. [DOI] [PubMed] [Google Scholar]
  • 43.Uribarri J, Peppa M, Cai W, et al. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. J Am Soc Nephrol. 2003;14:728–731. doi: 10.1097/01.asn.0000051593.41395.b9. [DOI] [PubMed] [Google Scholar]

RESOURCES