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1.  Endogenous Secretory Receptor for Advanced Glycation End Products Is Associated With Low Serum Interleukin-1 Receptor Antagonist and Elevated IL-6 in Older Community-Dwelling Adults 
Background.
Advanced glycation end products (AGEs) are thought to cause inflammation through interaction with the receptor for AGEs (RAGE), therefore contributing to adverse aging-related processes. The relationship between AGEs, RAGE, and inflammation has not been well characterized.
Methods.
We examined the relationship of plasma endogenous secretory RAGE (esRAGE); carboxymethyl-lysine (CML), a circulating AGE; and inflammatory mediators in 1,298 adults, 20–97 years, who participated in the InCHIANTI study in Tuscany, Italy. Blood levels of esRAGE, CML, interleukin-1 receptor antagonist (IL-1RA), IL-1β, tumor necrosis factor-α (TNF-α), IL-6, IL-6 receptor (IL-6R), IL-18, C-reactive protein (CRP), transforming growth factor-β (TGF-β), and fibrinogen were measured.
Results.
Log plasma esRAGE was associated with log IL-1RA (β = −0.069, SE = 0.036, p = .05) and log IL-6 (β = 0.077, SE = 0.035, p = .03), respectively, in separate multivariable linear regression models, adjusting for potential confounders. Log plasma esRAGE was also negatively associated with log TGF-β but did not reach statistical significance (β = −0.091, SE = 0.053, p = .09). Log plasma esRAGE was not significantly associated with log IL-1β, log TNF-α, IL-6R, log IL-18, or CRP. Log plasma CML was not associated with any of the inflammatory mediators except for IL-6R (β = −14.10, SE = 5.94, p = .02) and fibrinogen (β = 13.95, SE = 7.21, p = .05) in separate multivariable models, adjusting for potential confounders.
Conclusions.
Plasma esRAGE is correlated with higher IL-6 and lower IL-1RA. These findings suggest that plasma esRAGE plays a role in modulating inflammation, although the exact mechanisms remain to be elucidated.
doi:10.1093/gerona/glq225
PMCID: PMC3055279  PMID: 21357189
Advanced glycation end products; C-reactive protein; Endogenous secretory receptor for advanced glycation end products; Interleukin-1 receptor antagonist; Interleukin-6
2.  Advanced Glycation End Products and Their Circulating Receptors and Level of Kidney Function in Older Community-Dwelling Women 
Background
Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the pathogenesis of renal disease but their relation with level of kidney function has not been well characterized.
Study Design
Cross-sectional and prospective.
Setting and Participants
548 moderately to severely disabled community-dwelling women in the Women's Health and Aging Study I in Baltimore, Maryland.
Predictor
Serum L-carboxymethyl-lysine (CML), a dominant AGE, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE).
Outcomes & Measurements
Glomerular filtration rate (GFR), prevalent and incident reduced GFR (GFR <60 mL/min/1.73 m2). Serum CML, sRAGE, and esRAGE.
Results
Of 548 women, 283 (51.6%) had reduced GFR at baseline. Serum CML was associated with reduced GFR (Odds Ratios [O.R.; all expressed per 1 Standard Deviation], 1.98, 95% Confidence Interval [C.I.] 1.41-2.76, P <0.001) in a multivariate logistic regression model adjusting for age, race, hemoglobin A1c, and chronic diseases. Serum sRAGE (ng/mL) and esRAGE (ng/mL), respectively, were associated with reduced GFR (O.R. 1.42, 95% C.I. 1.12-1.79, P = 0.003; O.R. 1.42, 95% C.I. 1.14-1.77, P = 0.001) in separate multivariate logistic regression models, adjusting for potential confounders. Of 230 women without reduced GFR at baseline, 32 (13.9%) developed reduced GFR by the follow-up visit 12 months later. Serum CML (μg/mL), sRAGE (ng/mL), and esRAGE (ng/mL), respectively, at baseline was associated with the prevalence of reduced GFR 12 months later (O.R. 1.80, 95% C.I. 1.19-2.71, P = 0.005; O.R. 1.32, 95% C.I. 1.01-1.74, P = 0.05; O.R. 1.33, 95% C.I. 1.01-1.77, P = 0.05) in separate multivariate logistic regression models adjusting for potential confounders.
Limitations
Small number of incident cases, limited follow-up interval, creatinine not standardized.
Conclusions
AGEs and circulating RAGE are independently associated with reduced GFR and seem to predict reduced GFR. AGEs are amenable to interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
doi:10.1053/j.ajkd.2008.06.018
PMCID: PMC2637807  PMID: 18789567
advanced glycation end products; reduced glomerular filtration rate
3.  Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes 
Diabetes  2011;60(9):2379-2385.
OBJECTIVE
Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS).
RESEARCH DESIGN AND METHODS
We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates.
RESULTS
sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25–2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11–1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38–1.14). Atorvastatin, 10 mg daily, did not alter sRAGE.
CONCLUSIONS
Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.
doi:10.2337/db11-0291
PMCID: PMC3161327  PMID: 21771973
4.  Soluble RAGE but not endogenous secretory RAGE is associated with albuminuria in patients with type 2 diabetes 
Background
Total circulating soluble receptor for advanced glycation endproducts (sRAGE) and a more defined endogenous secretory splice variant of the receptor (esRAGE) were shown to be associated with different markers of cardiovascular risk in patients with diabetes. Since previous data were partly divergent, the aim of this study was to compare sRAGE and esRAGE in a head-to-head analysis in patients with type 2 diabetes (T2DM) with albuminuria.
Methods
sRAGE and esRAGE were studied in plasma of 110 T2DM patients using enzyme-linked immunosorbant assays (ELISA) detecting either sRAGE or esRAGE only. Both sRAGE and esRAGE were compared with regard to applicability as markers for vascular disease and glucose control in T2DM.
Results
In bivariate analysis, sRAGE correlated with age (R = 0.22, p = 0.02) and the 24 hour albumin excretion rate (R = 0.18, p = 0.05), while esRAGE correlated positively with age only (R = 0.23, p = 0.02). In contrast to previous reports, neither sRAGE nor esRAGE correlated with glucose control or intima-media-thickness (IMT) as a predictor of macrovascular disease. In multivariate regression models, the associations between sRAGE and albuminuria as well as esRAGE and age were shown to be independent of glucose control, diabetes duration, body-mass index, glomerular filtration rate, blood pressure and gender.
Conclusion
This is the first study comparing sRAGE and esRAGE as markers of vascular complications in patients with T2DM. sRAGE but not esRAGE is independently associated with albuminuria in these patients while neither sRAGE nor esRAGE are associated with markers of glucose control or macrovascular disease.
doi:10.1186/1475-2840-6-9
PMCID: PMC1821011  PMID: 17343760
5.  Endogenous Secretory RAGE as a Novel Biomarker for Metabolic Syndrome and Cardiovascular Diseases 
Biomarker Insights  2007;2:331-339.
Receptor for advanced glycation end-products (RAGE) is known to be involved in both micro- and macro-vascular complications in diabetes. Among numerous truncated forms of RAGE recently described, the C-terminally truncated form of RAGE has received much attention. This form of RAGE, carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains, is released outside from cells, binds ligands including AGEs, and is capable of neutralizing RAGE signaling on endothelial cells in culture. This form of RAGE is generated as a splice variant and is named endogenous secretory RAGE (esRAGE). Adenoviral overexpression of esRAGE reverses diabetic impairment of vascular dysfunction, suggesting that esRAGE may be an important inhibitor of RAGE signaling in vivo and potentially be useful for prevention of diabetic vascular complications. An ELISA system to measure plasma esRAGE was recently developed, and the pathophysiological roles of esRAGE have begun to be unveiled clinically. Plasma esRAGE levels are decreased in patients with several metabolic diseases including type 1 and type 2 diabetes, metabolic syndrome and hypertension. In cross-sectional analysis, plasma esRAGE levels are inversely correlated with carotid or femoral atherosclerosis. In an observational cohort of patients with end-stage renal disease, cumulative incidence of cardiovascular death was significantly higher in subjects with lower plasma esRAGE levels. These findings suggest that plasma esRAGE may act as a protective factor against and a novel biomarker for the occurrence of metabolic syndrome and cardiovascular diseases.
PMCID: PMC2717812  PMID: 19662215
receptor for advanced glycation end-products (RAGE); soluble RAGE (sRAGE); endogenous secretory RAGE (esRAGE); AGEs; atherosclerosis; metabolic syndrome; inflammation
6.  Low Serum Level of the Endogenous Secretory Receptor for Advanced Glycation End Products (esRAGE) Is a Risk Factor for Prevalent Vertebral Fractures Independent of Bone Mineral Density in Patients With Type 2 Diabetes 
Diabetes Care  2009;32(12):2263-2268.
OBJECTIVE
Patients with type 2 diabetes are known to have an increased risk for fracture compared with non–type 2 diabetic control subjects, despite having higher bone mineral density (BMD). We previously showed that serum pentosidine, one of the advanced glycation end products (AGEs), was associated with prevalent vertebral fractures (VFs) in those with type 2 diabetes. The involvement of the endogenous secretory receptor for AGEs (esRAGE) in VFs in those with type 2 diabetes, however, is still unknown.
RESEARCH DESIGN AND METHODS
We compared parameters including esRAGE, pentosidine, and BMD in Japanese type 2 diabetic patients (137 men >50 years old and 140 postmenopausal women) with and without VFs.
RESULTS
The esRAGE-to-pentosidine ratio in type 2 diabetic patients with VFs was significantly lower than in those without VFs (men: 7.1 ± 2.8 vs. 9.4 ± 6.2, P = 0.013, respectively; women: 4.7 ± 2.7 vs. 8.2 ± 5.4, P < 0.001, respectively). Multivariate logistic regression analysis adjusted for age, BMI, A1C, serum creatinine, duration of diabetes, therapeutic agents, diabetes complications, osteoporotic risk factors, and lumbar BMD identified the serum esRAGE level and esRAGE-to-pentosidine ratio as factors associated with the presence of VFs, independent of BMD in men (odds ratio [OR] 0.46 [95% CI 0.25–0.84], P = 0.012; and OR 0.34 [0.15–0.76], P = 0.009, respectively) and in women (OR 0.32 [0.16–0.67], P = 0.002; and OR 0.14 [0.04–0.43], P = 0.001, respectively).
CONCLUSIONS
These results show that serum esRAGE level and esRAGE-to-pentosidine ratio are more useful than BMD for assessing the risk of VFs in type 2 diabetic patients.
doi:10.2337/dc09-0901
PMCID: PMC2782988  PMID: 19752174
7.  Elevated serum advanced glycation end products and their circulating receptors are associated with anaemia in older community-dwelling women 
Age and Ageing  2009;38(3):283-289.
Objective: to determine whether serum carboxymethyl-lysine, a dominant advanced glycation end product (AGE), and circulating total receptor for AGEs (sRAGE) and endogenous secretory receptor for AGEs (esRAGE) are associated with anaemia.
Design: cross-sectional analysis.
Setting: moderately severely disabled women, ≥65 years, living in the community in Baltimore, MD (the Women's Health and Aging Study I).
Participants: 519 women with and without anaemia.
Main outcome measure: haemoglobin and anaemia (haemoglobin <12 g/dL).
Results: of 519 women, 128 (24.7%) had anaemia. All odds ratios (OR) were expressed per one standard deviation. Serum CML was associated with anaemia [OR 1.47, 95% confidence interval (CI) 1.11–1.95, P = 0.008] in a multivariate logistic regression model adjusting for age, race, smoking, education and chronic diseases. Serum sRAGE (ng/mL) and esRAGE (ng/mL) were associated with anaemia (OR 1.52, 95% CI 1.21–1.92, P = 0.0004; OR 1.49, 95% CI 1.18–1.87, P = 0.0006, respectively) in separate multivariate logistic regression models, adjusting for the same covariates mentioned above. Serum CML (P = 0.004), sRAGE (P < 0.0001) and esRAGE (P < 0.0001) were inversely and independently associated with haemoglobin concentrations.
Conclusion: AGEs and circulating RAGE are independently associated with haemoglobin and anaemia in older women. AGEs are amenable to interventions, as serum AGEs can be lowered by a change in dietary pattern and pharmacological treatment.
doi:10.1093/ageing/afp011
PMCID: PMC2724885  PMID: 19252206
advanced glycation end products; anaemia; haemoglobin; women; elderly
8.  Bone-Targeting Endogenous Secretory Receptor for Advanced Glycation End Products Rescues Rheumatoid Arthritis 
Molecular Medicine  2013;19(1):183-194.
Rheumatoid arthritis (RA) is a chronic inflammatory synovitis that leads to the destruction of bone and cartilage. The receptor for advanced glycation end products (RAGE) is a multiligand membrane-bound receptor for high-mobility group box-1 (HMGB1) associated with development of RA by inducing production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmembrane-bound form of RAGE (endogenous secretory RAGE [esRAGE]) functioning as a decoy receptor. We assessed its tissue distribution and therapeutic effectiveness in a murine model of collagen-induced arthritis (CIA). Acidic oligopeptide–tagged esRAGE (D6-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D6-esRAGE with a dose of 1 mg/kg to RA model mice significantly ameliorated inflammatory arthritis, synovial hyperplasia, cartilage destruction and bone destruction, while untagged esRAGE showed little effectiveness. Moreover, D6-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-α, IL-1 and IL-6, while esRAGE reduced the levels of IL-1 and IL-6 to a lesser extent, suggesting that production of IL-1 and IL-6 reduced along the blockade of HMGB1 receptor downstream signals by D6-esRAGE could be attributed to remission of CIA. These findings indicate that D6-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA.
doi:10.2119/molmed.2012.00309
PMCID: PMC3745595  PMID: 23821362
9.  Association of plasma sRAGE, but not esRAGE with lung function impairment in COPD 
Respiratory Research  2014;15(1):24.
Rationale
Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and DLCO, and with different circulating AGEs.
Methods
Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV1 (%predicted) and FEV1/VC (%) were measured in both groups; DLCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE Nϵ-(carboxymethyl) lysine (CML) was decreased, Nϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.
Results
Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV1 (r = 0.235, p = 0.032), FEV1/VC (r = 0.218, p = 0.047), and DLCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).
Conclusion
Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV1, FEV1/VC and DLCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.
doi:10.1186/1465-9921-15-24
PMCID: PMC3944004  PMID: 24564838
sRAGE; esRAGE; FEV1; COPD
10.  The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers 
Nephron Extra  2013;3(1):106-112.
Background
Fibroblast growth factor-23 (FGF-23) has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD), although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated.
Methods
We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP), endogenous soluble receptor of advanced glycation end products (esRAGE), advanced oxidation protein products (AOPP), parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI) was determined using non-contrast CT scans of the abdominal aorta.
Results
FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906) and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p < 0.001). In univariate analysis, ACI correlated with hsCRP, esRAGE, FGF-23, dialysis vintage, systolic blood pressure (BP) and serum cholesterol. In multiple regression analysis not including inflammation markers, ACI was associated with FGF-23. However, inclusion of inflammation markers in another multiple regression analyses showed that ACI correlated with hsCRP, BP, dialysis vintage and esRAGE but not with FGF-23 (R2 = 0.65, p < 0.001).
Conclusion
FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers.
doi:10.1159/000356118
PMCID: PMC3843931  PMID: 24348506
Fibroblast growth factor-23; Vascular calcification; Chronic kidney disease; Inflammation markers; Uremic toxins; Chronic kidney disease

11.  Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women 
Objective
To characterize the relationship between advanced glycation end products (AGEs) and circulating receptors for AGEs (RAGE) with cardiovascular disease mortality.
Methods
The relationships between serum AGEs, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, ≥65 years, in Baltimore, Maryland.
Results
During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGEs was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [H.R.] for highest versus lower three quartiles 1.94, 95% Confidence Interval [C.I.] 1.08-3.48, P = 0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (H.R. per 1 Standard Deviation [S.D.] 1.27, 95% C.I. 0.98-1.65, P = 0.07; H.R. 1.28, 95% C.I. 1.02-1.63, P = 0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (H.R. for highest versus lower three quartiles, 2.29, 95% C.I. 1.21-4.34, P = 0.01; H.R. per 1 S.D., 1.24, 95% C.I. 0.92-1.65, P = 0.16; H.R. per 1 S.D. 1.45, 95% C.I. 1.08-1.93, P = 0.01), after adjusting for the same covariates.
Conclusions
High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
PMCID: PMC2684987  PMID: 19448391
advanced glycation end products; aging; atherosclerosis; cardiovascular disease; mortality
12.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
13.  Carboxymethyl-lysine, an advanced glycation end product, and decline of renal function in older community-dwelling adults 
European journal of nutrition  2008;48(1):38-44.
Background
Advanced glycation end products (AGEs) are bioactive molecules found in greater concentrations in foods that have been processed at high temperatures. AGEs have been associated with impaired renal function in diabetes and in uremia. The relationship between AGEs and renal function in community-dwelling adults has not been well characterized.
Aim of the Study
The objective was to determine whether plasma AGEs are independently associated with chronic kidney disease (CKD) and predictive of renal function in older adults.
Methods
The relationship between plasma carboxymethyl-lysine (CML), an AGE, and CKD (≥stage 3 of National Kidney Foundation classification; estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) and eGFR at 3- and 6-years follow-up was examined in a population-based study of aging, the InCHIANTI study, in Tuscany, Italy.
Results
Of 1,008 adults, aged ≥65 years, 153 (15.2%) had CKD at enrollment. Mean (Standard Deviation [S.D.]) plasma CML was 365 (110) ng/mL. Plasma CML was associated with CKD (Odds Ratio [O.R.] expressed per 1 S.D., 1.53, 95% Confidence Interval [C.I.] 1.27-1.84, P <0.0001) in a multivariate logistic regression model, adjusting for potential confounders. Plasma CML was associated with eGFR (beta = -2.77, standard error [S.E.] = 0.51, P <0.0001) at baseline, 3-year (beta = -2.54, S.E. = 0.61, P <0.0001) and 6-year follow-up visits (beta = -1.21, S.E. = 0.70, P = 0.08) in multivariate linear regression models, adjusting for potential confounders. The associations between plasma CML and prevalent CKD, eGFR, and eGFR at 3- and 6-year follow-up were significant and nearly unchanged after exclusion of adults with diabetes.
Conclusion
Plasma CML is independently associated with CKD and is an independent predictor of decline in renal function in older community-dwelling adults.
doi:10.1007/s00394-008-0757-0
PMCID: PMC2637810  PMID: 19031098
advanced glycation end products; aging; carboxymethyl-lysine; chronic kidney disease; renal function
14.  Elevated serum advanced glycation end products and poor grip strength in older community-dwelling women 
Background
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes, heart disease, and kidney failure, and may potential affect skeletal muscle. Whether AGEs are associated with poor muscle strength is unknown.
Methods
Serum carboxymethyl-lysine (CML), a dominant AGE, circulating receptor for AGEs (sRAGE), and endogenous secretory RAGE (esRAGE) and grip strength were measured in 559 moderately to severely disabled women, age ≥65 years, in the Women’s Health and Aging Study I in Baltimore, Maryland.
Results
Mean (SD) grip strength among women in the highest quartile of serum CML compared with women in the lower three quartiles was 18.6 and 20.0 kg, respectively (P = 0.002), adjusting for age, race, body mass index, cognitive dysfunction, depression, and diabetes. Serum sRAGE and esRAGE were not significantly associated with grip strength.
Conclusion
Women with high serum AGEs have greater muscle weakness. Further studies are needed to determine whether AGEs, a potentially modifiable risk factor, are associated with physical performance and disability in older adults.
doi:10.1093/gerona/gln018
PMCID: PMC2645474  PMID: 19182228
advanced glycation end products; aging; inflammation; muscle; sarcopenia
15.  Serum Levels of Receptors for Advanced Glycation End Products in Normal-Weight and Obese Children Born Small and Large for Gestational Age 
Diabetes Care  2012;35(6):1361-1363.
OBJECTIVE
To assess potential alterations in soluble and endogenous secretory receptors for advanced glycation end products (sRAGE and esRAGE) in normal-weight (NW) and obese (Ob) children born small (SGA) and large (LGA) compared with appropriate for gestational age (AGA) subjects and to explore if birth weight (BW), insulin resistance (IR), and obesity represent independent risk factors.
RESEARCH DESIGN AND METHODS
We categorized 130 prepubertal children into six groups according to BW and obesity and evaluated sRAGE, esRAGE, and homeostasis model assessment of IR.
RESULTS
sRAGE and esRAGE were lower in Ob SGA and LGA children than Ob AGA subjects (all P < 0.05), and in NW SGA and LGA children than NW AGA subjects (all P < 0.05). Interestingly, BW and IR were significantly and independently related to RAGE.
CONCLUSIONS
sRAGE and esRAGE are decreased in SGA and LGA children, and BW and IR seem to play an important role in the reduction of RAGE.
doi:10.2337/dc11-2302
PMCID: PMC3357256  PMID: 22511256
16.  Association of Four Genetic Polymorphisms of AGER and Its Circulating Forms with Coronary Artery Disease: A Meta-Analysis 
PLoS ONE  2013;8(7):e70834.
Background
Considerable efforts have been devoted to evaluating the association of the receptor for advanced glycation end-products (gene AGER and protein: RAGE) genetic variants to coronary artery disease (CAD); the results, however, are often irreproducible. To generate more information, we sought to explore four common polymorphisms of AGER and its circulating forms associated with the risk of CAD via a meta-analysis.
Methodology/Principal Findings
Articles were identified by searching PubMed, EMBASE, Wanfang and CNKI databases before March 2013. Qualified articles had case-control designs and investigated AGER four polymorphisms (T-429C, T-374A, Gly82Ser, G1704A) or circulating soluble RAGE (sRAGE) or endogenous secretory RAGE (esRAGE) levels associated with CAD. Twenty-seven articles involving 39 independent groups fulfilled the predefined criteria. Overall, no significance was observed for all examined polymorphisms under allelic and dominant models. When restricting groups to CAD patients with diabetes mellitus or renal disease, deviations of risk estimates from the unity were stronger than overall estimates for all polymorphisms except for G1704A due to limited available studies. For example, under dominant model, having -429C allele increased the odds of developing CAD in diabetic patients by 1.22-fold (95% confidence interval (95% CI) 0.99–1.51; P = 0.06; I2 = 6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; P = 0.111; I2 = 18.0%). Circulating sRAGE levels were non-significantly lower in CAD patients than in controls, whereas this reduction was totally and significantly reversed in CAD patients with diabetes mellitus (weighted mean difference: 185.71 pg/ml; 95% CI: 106.82 to 264.61 pg/ml). Circulating esRAGE levels were remarkably lower in CAD patients, as well as in subgroups with or without diabetes mellitus and without renal disease.
Conclusions
Our findings demonstrated that association of AGER genetic polymorphisms with CAD was potentiated in patients with diabetes mellitus or renal disease. Practically, circulating esRAGE might be a powerful negative predictor for the development of CAD.
doi:10.1371/journal.pone.0070834
PMCID: PMC3722145  PMID: 23894685
17.  Serum Level of Endogenous Secretory Receptor for Advanced Glycation End Products and Other Factors in Type 2 Diabetic Patients With Mild Cognitive Impairment 
Diabetes Care  2011;34(12):2586-2590.
OBJECTIVE
Determine the serum levels of endogenous secretory receptor for advanced glycation end products (esRAGEs) in patients with type 2 diabetes and mild cognitive impairment (MCI) and in control patients with type 2 diabetes but no MCI, and examine the relationship of esRAGE and MCI with other clinical factors.
RESEARCH DESIGN AND METHODS
A total of 101 patients with type 2 diabetes who were hospitalized in the Department of Endocrinology at Fujian Provincial Hospital between January 2010 and January 2011 were enrolled. There were 58 patients with MCI and 43 patients without MCI (control). Serum levels of esRAGE were measured using an enzyme-linked immunosorbent assay (ELISA). Other clinical parameters were also measured.
RESULTS
Type 2 diabetic patients with MCI had a longer duration of diabetes; elevated HbA1c, total cholesterol (CHOL), LDL cholesterol (LDL-C), triglyceride (TG), intima-media thickness, C-reactive protein (CRP), and brachial-ankle pulse wave velocity (ba-PWV); and lower ankle brachial index (ABI) and esRAGE relative to the control group. Among patients with MCI, the Montreal Cognitive Assessment (MoCA) score was positively correlated with serum esRAGE but negatively correlated with CHOL. Spearman rank correlation analysis indicated that esRAGE was positively correlated with MoCA score and ABI but negatively correlated with ba-PWV, CHOL, TG, and CRP in all subjects.
CONCLUSIONS
Our results suggest that esRAGE may be a potential protective factor for dyslipidemia, atherosclerosis, and MCI in patients with type 2 diabetes.
doi:10.2337/dc11-0958
PMCID: PMC3220856  PMID: 22011410
18.  RAGE and Soluble RAGE: Potential Therapeutic Targets for Cardiovascular Diseases 
Molecular Medicine  2007;13(11-12):625-635.
Receptor for advanced glycation end-products (RAGE) is known to be involved in microvascular complications in diabetes. RAGE is also profoundly associated with macrovascular complications in diabetes through regulation of atherogenesis, angiogenic response, vascular injury, and inflammatory response. The potential significance of RAGE in the pathogenesis of cardiovascular disease appears not to be confined solely to nondiabetic rather than diabetic conditions. Numerous truncated forms of RAGE have recently been described, and the C-terminally truncated soluble form of RAGE has received much attention. Soluble RAGE consists of several forms, including endogenous secretory RAGE (esRAGE), which is a spliced variant of RAGE, and a shedded form derived from cell-surface RAGE. These heterogeneous forms of soluble RAGE, which carry all of the extracellular domains but are devoid of the transmembrane and intracytoplasmic domains, bind ligands including AGEs and can antagonize RAGE signaling in vitro and in vivo. ELISA systems have been developed to measure plasma esRAGE and total soluble RAGE, and the pathophysiological roles of soluble RAGE have begun to be unveiled clinically. In this review, we summarize recent findings regarding pathophysiological roles in cardiovascular disease of RAGE and soluble RAGE and discuss their potential usefulness as therapeutic targets and biomarkers for the disease.
doi:10.2119/2007-00087.Koyama
PMCID: PMC2017106  PMID: 17932553
19.  Clinical chorioamnionitis is characterized by increased expression of the alarmin HMGB1 and One of Its Receptors, sRAGE 
Objective
High-mobility group box-1 (HMGB1) protein is an alarmin, a normal cell constituent, which is released into the extracellular environment upon cellular stress/damage, and is capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines; this may be modulated the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objective of this study was to determine: 1) if clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) if the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age.
Methods
Amniotic fluid samples were collected from the following groups: 1) mid-trimester (MT) (n=45); 2) term with (n=48) and without labor (n=22) without intra-amniotic infection; and 3) term with clinical chorioamnionitis (n=46). Amniotic fluid concentrations of HMGB1, sRAGE and esRAGE concentrations were determined by ELISA.
Results
1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than that of those without this condition (clinical chorioamnionitis: median 3.8 ng/mL vs. term in labor: median 1.8 ng/mL, p=0.007; and vs. term not in labor median 1.1 ng/mL, p=0.003); 2) in contrast, patients with clinical chorioamnionitis had a lower median sRAGE concentration than those without this condition (clinical chorioamnionitis: median 9.3 ng/mL vs. term in labor: median 18.6 ng/mL, p=0.001; and vs. term not in labor median 28.4 ng/mL, p<0.001); 3) amniotic fluid concentrations of esRAGE did not significantly change in patients with clinical chorioamnionitis at term (clinical chorioamnionitis: median 5.4 ng/mL vs. term in labor: median 6.1 ng/mL, p=0.9; and vs. term not in labor median 9.5 ng/mL, p=0.06); and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor (p=0.4) and between women in the mid-trimester and those at term not in labor (mid-trimester: median 1.5 ng/mL; p=0.2).
Conclusion
An increase in the amniotic fluid HMGB1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis at term. This finding provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical chorioamnionitis at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations.
doi:10.3109/14767058.2011.599083
PMCID: PMC3914307  PMID: 22578261
danger signal; intra-amniotic inflammation; sterile inflammation; pregnancy; neuroinflammation; neuro-immune reflects; amniotic fluid; DAMPs; damage-associated molecular patterns; intra-amniotic infection; term labor
20.  Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats 
Objective: Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE). This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney. Methods: Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks). Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE (esRAGE), and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Results: Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up-regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in accumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased. Conclusions: Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney.
doi:10.1631/jzus.B1101004
PMCID: PMC3150719  PMID: 21796806
Receptor for advanced glycation end-product (RAGE); Endogenous secretory RAGE (esRAGE); Soluble RAGE (sRAGE); Diabetic nephropathy; Atorvastatin
21.  Elevated Serum Advanced Glycation End Products and Poor Grip Strength in Older Community-Dwelling Women 
Background
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes, heart disease, and kidney failure and may potentially affect skeletal muscle. Whether AGEs are associated with poor muscle strength is unknown.
Methods
Serum carboxymethyl-lysine (CML), a dominant AGE, circulating soluble form of receptor for advanced glycation end products (sRAGE), and endogenous secretory receptor for advanced glycation end product (esRAGE) and grip strength were measured in 559 moderately to severely disabled women, age 65 and older, in the Women's Health and Aging Study I in Baltimore, Md.
Results
Mean (standard deviation) grip strength among women in the highest quartile of serum CML compared with women in the lower three quartiles was 18.6 and 20.0 kg, respectively (p = .002), adjusting for age, race, body mass index, cognitive dysfunction, depression, and diabetes. Serum sRAGE and esRAGE were not significantly associated with grip strength.
Conclusions
Women with high serum AGEs have greater muscle weakness. Further studies are needed to determine whether AGEs, a potentially modifiable risk factor, are associated with physical performance and disability in older adults.
doi:10.1093/gerona/gln018
PMCID: PMC2645474  PMID: 19182228
Advanced glycation end products; Aging; Inflammation; Muscle; Sarcopenia
22.  Association Between Serum Endogenous Secretory Receptor for Advanced Glycation End Products and Risk of Type 2 Diabetes Mellitus with Combined Depression in the Chinese Population 
Diabetes Technology & Therapeutics  2012;14(10):936-942.
Abstract
Objective
The role of the endogenous secretory receptor for advanced glycation end products (esRAGE) in depression of diabetes patients and its clinical significance are unclear. This study investigated the role of serum esRAGE in patients with type 2 diabetes mellitus with depression in the Chinese population.
Patients and Methods
One hundred nineteen hospitalized patients with type 2 diabetes were recruited at Fujian Provincial Hospital (Fuzhou, China) from February 2010 to January 2011. All selected subjects were assessed with the Hamilton Rating Scale for Depression (HAMD). Among them, 71 patients with both type 2 diabetes and depression were included. All selected subjects were examined for the following: esRAGE concentration, glycosylated hemoglobin (HbA1c), blood lipids, C-reactive protein, trace of albumin in urine, and carotid artery intima-media thickness (IMT). Association between serum esRAGE levels and risk of type 2 diabetes mellitus with depression was also analyzed.
Results
There were statistically significant differences in gender, age, body mass index, waist circumference, and treatment methods between the group with depression and the group without depression (P<0.05). Multiple linear regression analysis showed that HAMD scores were negatively correlated with esRAGE levels (standard regression coefficient −0.270, P<0.01). HAMD-17 scores were positively correlated with IMT (standard regression coefficient 0.183, P<0.05) and with HbA1c (standard regression coefficient 0.314, P<0.01).
Conclusions
Female gender, younger age, obesity, poor glycemic control, complications, and insulin therapy are all risk factors of type 2 diabetes mellitus with combined depression in the Chinese population. Inflammation and atherosclerosis play an important role in the pathogenesis of depression. esRAGE is a protective factor of depression among patients who have type 2 diabetes.
doi:10.1089/dia.2012.0072
PMCID: PMC3458998  PMID: 22856651
23.  Placental growth factor, pregnancy-associated plasma protein-A, soluble receptor for advanced glycation end products, extracellular newly identified receptor for receptor for advanced glycation end products binding protein and high mobility group box 1 levels in patients with acute kidney injury: a cross sectional study 
BMC Nephrology  2013;14:245.
Background
Placental growth factor (PlGF), pregnancy-associated plasma protein-A (PAPP-A), soluble receptor for advanced glycation end products (sRAGE), extracellular newly identified receptor for RAGE binding protein (EN-RAGE) and high mobility group box 1 (HMGB-1) are novel biomarkers in chronic kidney disease (CKD). However, their clinical significance in acute kidney injury (AKI) is unknown. The aim of this cross-sectional study was to determine whether selected biomarkers are changed in AKI patients.
Methods
Serum PlGF, PAPP-A, sRAGE, EN-RAGE and HMGB-1 levels were assessed in 40 patients with AKI, 42 CKD 5 patients, 31 haemodialysis patients (HD) and 39 age-matched healthy controls.
Results
PAPP-A was elevated in AKI (20.6 ± 16.9 mIU/L) compared with controls (9.1 ± 2.3 mIU/L, p < 0.001). PlGF was not increased in AKI (11.7 ± 7.4 pg/mL) versus controls (8.5 ± 2.4 pg/mL, n.s.), as well as sRAGE was not elevated in AKI (2400 ± 1400 pg/mL) compared with controls (1760 ± 730 pg/mL, n.s), but was lower compared with CKD 5 (3200 ± 1500 pg/mL, p < 0.05); EN-RAGE was elevated in AKI 480 ± 450 ng/mL in comparison with controls (60 ± 62 ng/mL), CKD 5 (190 ± 120 ng/mL), and HD (120 ± 100 ng/mL), all p < 0.001. Similarly, HMGB-1 was increased in AKI (5.8 ± 7.5 ng/mL) versus controls (1.7 ± 1.4 ng/mL), CKD 5 (3.2 ± 3.1 ng/mL) and HD (2.5 ±2.1 ng/mL), all p < 0.001.
In AKI group, in multivariate regression analysis: PAPP–A levels were associated with transferrin (p <0.001), negatively with albumin (p < 0.01) and prealbumin (p < 0.05); PlGF levels were associated with C - reactive protein (p < 0.001). EN-RAGE levels were associated with ferritin (p < 0.01) and orosomucoid (p = 0.02), and HMGB-1 levels with leukocyte count (p < 0.01) and negatively with proteinuria (p = 0.02).
Conclusions
In AKI patients, PAPP-A, EN-RAGE and HMGB1 are elevated, but sRAGE and PlGF are not increased. Whereas PAPP-A correlates with markers of nutrition; PlGF, EN-RAGE and HMGB-1 are related to inflammatory parameters.
doi:10.1186/1471-2369-14-245
PMCID: PMC4228333  PMID: 24188108
Acute kidney injury; Biomarkers; Chronic kidney disease; Extracellular newly identified receptor for advanced glycation end products binding protein; Haemodialysis; Placental growth factor; Pregnancy-associated plasma protein-A; Soluble receptor for advanced glycation end products
24.  Increased serum myeloid-related protein 8/14 level is associated with atherosclerosis in type 2 diabetic patients 
Background
Myeloid-related protein 8/14 (MRP8/14) is a stable heterodimer formed by two different calcium-binding proteins (MRP8 and MRP14). Studies have identified that MRP8/14 regulates vascular inflammation and serves as a novel marker of acute coronary syndrome. In this study, we evaluated the correlation between serum levels of MRP8/14, hsCRP, endogenous secretory receptor for advanced glycation end-products (esRAGE) and the occurrence of coronary artery disease (CAD), or carotid intima-media thickness (IMT) when CAD was not yet developed in diabetic patients.
Methods
Serum levels of MRP8/14, esRAGE and hsCRP were measured in 375 diabetic patients. Then the results of those who had CAD were compared against who had not. Also, we investigated the associations between above-mentioned indicators and IMT of subjects without CAD in both diabetic group and non-diabetic one.
Results
Serum MRP8/14 was significantly higher in CAD than in non-CAD group (9.7 ± 3.6 ug/ml vs. 8.2 ± 3.0 ug/ml, P < 0.001). It was associated with severity of CAD (r = 0.16, P = 0.026). In non-CAD group, MRP8/14 was associated with IMT in patients with (r = 0.30, P < 0.001) or without diabetes (r = 0.26, P = 0.015). The areas under the curves of receiver operating characteristic for CAD were 0.63 (95% CI 0.57-0.68) for MRP8/14, 0.76 (95% CI 0.71-0.81) for hsCRP and 0.62 (95% CI 0.56 -0.67) for esRAGE.
Conclusion
In summary, we report that diabetic patients with CAD had elevated plasma MRP8/14 levels which were also positively correlated with the severity of CAD and carotid IMT in patients without clinically overt CAD.
doi:10.1186/1475-2840-10-41
PMCID: PMC3120649  PMID: 21592353
MRP8/14; Diabetes mellitus; Coronary artery disease; Intima media thickness
25.  -374 T/A RAGE Polymorphism Is Associated with Chronic Kidney Disease Progression in Subjects Affected by Nephrocardiovascular Disease 
PLoS ONE  2013;8(4):e60089.
Background
Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease.
Methods
174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6–9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease.
Results
Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline.
Conclusions
-374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.
doi:10.1371/journal.pone.0060089
PMCID: PMC3617170  PMID: 23593165

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