AGEs and sRAGE Variations at Different Timepoints in Patients with Chronic Kidney Disease

Patients with chronic kidney disease (CKD) are affected by enhanced oxidative stress and chronic inflammation, and these factors may contribute to increase advanced glycation end-products (AGEs). In this study we quantified AGEs and soluble receptors for AGE (sRAGE) isoforms and evaluated the association between their variations and eGFR at baseline and after 12 months. We evaluated 64 patients. AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer, and sRAGE by ELISA. Median age was 81 years, male patients accounted for 70%, 63% were diabetic, and eGFR was 27 ± 10 mL/min/1.73 m2. At follow up, sRAGE isoforms underwent a significant decrement (1679 [1393;2038] vs. 1442 [1117;2102], p < 0.0001), while AGEs/sRAGE ratios were increased (1.77 ± 0.92 vs. 2.24 ± 1.34, p = 0.004). Although AGEs and AGEs/sRAGE ratios were inversely related with eGFR, their basal values as well their variations did not show a significant association with eGFR changes. In a cohort of patients with a stable clinical condition at 1 year follow-up, AGEs/sRAGE was associated with renal function. The lack of association with eGFR suggests that other factors can influence its increase. In conclusion, AGEs/sRAGE can be an additional risk factor for CKD progression over a longer time, but its role as a prognostic tool needs further investigation.

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MO025ADVANCED GLYCATION END PRODUCTS (AGES) AND SOLUBLE RECEPTOR FOR AGES (SRAGE): ASSOCIATION WITH RISK OF MORTALITY IN CHRONIC KIDNEY DISEASE PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa140.mo025 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Elena Dozio ◽

Lara Caldiroli ◽

Silvia Nerini ◽

Elena Vianello ◽

Federico Ambrogi ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Total Protein ◽

Soluble Receptor ◽

Prognostic Role ◽

Decoy Receptor ◽

Glycation End Products ◽

End Products

Abstract Background and Aims In chronic kidney disease patients (CKD), excessive oxidative stress, uremia and chronic inflammation may increase the production of advanced glycation end-products (AGEs) which in turn promote CKD-related morbidities and mortality. Much attention has recently been paid to the soluble receptor for AGEs (sRAGE), as a marker of inflammation, oxidative stress, atherosclerosis and heart failure. sRAGE is a decoy receptor that prevents AGEs binding to RAGE, the cell membrane form of the receptor, and RAGE-related detrimental effects. Both AGEs and sRAGE accumulate in CKD due to the increased production and reduced kidney filtration. Recently, we reported an association between higher levels of sRAGE and mortality in hemodialysis and peritoneal dialysis patients. Whether AGEs, sRAGE and its different isoforms, namely the membrane-cleaved receptor cRAGE and the endogenous secretory form esRAGE, may also work as prognostic factors for mortality in non-dialysis CKD patients is not known. Method We quantified plasma sRAGE and esRAGE levels in 111 CKD patients (mean±SD age: 77.71±10.24 years, eGFR: 24.86±11.06 ml/min, male gender: 74.86%) by ELISA. Florescent AGEs and glycated albumin (GA) were quantified by AGEs-specific fluorescence (excitation: 365 nm, emission: 414-445 nm) and the quantILab assay (Werfen, Italy), respectively. The cRAGE form was estimated by subtracting esRAGE from sRAGE and the ratio cRAGE/esRAGE was calculated. AGEs were normalized against total proteins. Patients were screened for malnutrition and malnutrition-inflammation score (MIS) was calculated (4-8: risk of malnutrition, >8: malnutrition). The Cox proportional-hazards model was used for investigating the association between variables and survival time. Median follow-up time was 40 months. Results Mean levels of sRAGE, esRAGE and cRAGE were 2317±1224 pg/ml, 648±453 pg/ml and 1669±901 pg/ml, respectively. The mean value of cRAGE/esRAGE ratio was 2.82±0.96. AGEs/total protein content was 433.2 A.U., GA was 21.3±7.5 % and MIS 5.98 ±4.67. During the follow up, 28 patients died. Univariate Cox regression indicated a prognostic role for mortality for age (HR: 1.100, 95%CI: 1.041-1.163, p < 0.001), AGEs/total protein (HR: 1.004, 95%CI: 1.000-1.007, p < 0.05), esRAGE (HR: 1.001, 95%CI: 1.041-1.001, p < 0.01), cRAGE/esRAGE (HR: 0.5390, 95%CI: 0.331-0.888, p < 0.05) and MIS (HR: 1.079, 95%CI: 1.025-1.137, p < 0.01). After adjusting for age and MIS, the associations were still significant for esRAGE (HR: 1.001, 95%CI: 1.0002-1.001, p < 0.01) and cRAGE/esRAGE ratio (HR: 0.572, 95%CI: 0.347-0.943, p < 0.05), with AGEs/total protein at the margin of statistical significance (HR: 1.004, 95%CI: 0.9997-1.007, p = 0.0726). Conclusion In CKD higher levels of esRAGE and lower cRAGE/esRAGE ratio may have a prognostic role for mortality. Since esRAGE acts as a decoy receptor for AGEs and thus has a cytoprotective effect, from a pathological point of view the observed association with esRAGE but not cRAGE was quite surprisingly. One potential explanation is that AGEs increases all sRAGE isoforms, but esRAGE accumulation was greater than that of cRAGE due to a different synthesis/catabolism that needs further investigations. In conclusion, in CKD patients esRAGE and cRAGE/esRAGE seem to be useful supportive tools to identify high risk patients.

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Sex modulates the association of radial artery augmentation index with renal function decline in individuals without chronic kidney disease

International Urology and Nephrology ◽

10.1007/s11255-020-02776-5 ◽

2021 ◽

Author(s):

Qiao Qin ◽

Fangfang Fan ◽

Jia Jia ◽

Yan Zhang ◽

Bo Zheng

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Arterial Stiffness ◽

Confidence Interval ◽

Odds Ratio ◽

Adjusted Odds Ratio ◽

Augmentation Index ◽

Renal Function Decline

Abstract Purpose An increase in arterial stiffness is associated with rapid renal function decline (RFD) in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether the radial augmentation index (rAI), a surrogate marker of arterial stiffness, affects RFD in individuals without CKD. Methods A total of 3165 Chinese participants from an atherosclerosis cohort with estimated glomerular filtration rates (eGFR) of ≥ 60 mL/min/1.73 m2 were included in this study. The baseline rAI normalized to a heart rate of 75 beats/min (rAIp75) was obtained using an arterial applanation tonometry probe. The eGFRs at both baseline and follow-up were calculated using the equation derived from the Chronic Kidney Disease Epidemiology Collaboration. The association of the rAIp75 with RFD (defined as a drop in the eGFR category accompanied by a ≥ 25% drop in eGFR from baseline or a sustained decline in eGFR of > 5 mL/min/1.73 m2/year) was evaluated using the multivariate regression model. Results During the 2.35-year follow-up, the incidence of RFD was 7.30%. The rAIp75 had no statistically independent association with RFD after adjustment for possible confounders (adjusted odds ratio = 1.12, 95% confidence interval: 0.99–1.27, p = 0.074). When stratified according to sex, the rAIp75 was significantly associated with RFD in women, but not in men (adjusted odds ratio and 95% confidence interval: 1.23[1.06–1.43], p = 0.007 for women, 0.94[0.76–1.16], p = 0.542 for men; p for interaction = 0.038). Conclusion The rAI might help screen for those at high risk of early rapid RFD in women without CKD.

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Chronic kidney disease progression among patients with type 2 diabetes identified in US administrative claims: a population cohort study

Clinical Kidney Journal ◽

10.1093/ckj/sfaa200 ◽

2020 ◽

Author(s):

Csaba P Kovesdy ◽

Danielle Isaman ◽

Natalia Petruski-Ivleva ◽

Linda Fried ◽

Michael Blankenburg ◽

...

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Cohort Study ◽

Kidney Disease ◽

Disease Progression ◽

Administrative Claims ◽

Short Period ◽

Ckd Stage

Abstract Background Chronic kidney disease (CKD), one of the most common complications of type 2 diabetes (T2D), is associated with poor health outcomes and high healthcare expenditures. As the CKD population increases, a better understanding of the prevalence and progression of CKD is critical. However, few contemporary studies have explored the progression of CKD relative to its onset in T2D patients using established markers derived from real-world care settings. Methods This retrospective, population-based cohort study assessed CKD progression among adults with T2D and with newly recognized CKD identified from US administrative claims data between 1 January 2008 and 30 September 2018. Included were patients with T2D and laboratory evidence of CKD as indicated by the established estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) criteria. Disease progression was described as transitions across the eGFR- and UACR-based stages. Results A total of 65 731 and 23 035 patients with T2D contributed to the analysis of eGFR- and UACR-based CKD stage progression, respectively. CKD worsening was observed in approximately 10–17% of patients over a median follow-up of 2 years. Approximately one-third of patients experienced an increase in eGFR values or a decrease in UACR values during follow-up. Conclusions A relatively high proportion of patients were observed with disease progression over a short period of time, highlighting the need for better identification of patients at risk of rapidly progressive CKD. Future studies are needed to determine the clinical characteristics of these patients to inform earlier diagnostic and therapeutic interventions aimed at slowing disease progression.

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Plasma natriuretic peptide level is an independent determinant of major clinical outcomes in atrial fibrillation patients without heart failure: the Fushimi AF Registry

European Heart Journal ◽

10.1093/ehjci/ehaa946.0673 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

Y Hamatani ◽

M Iguchi ◽

Y Aono ◽

K Ishigami ◽

S Ikeda ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Clinical Outcomes ◽

Prognostic Marker ◽

Oral Anticoagulants ◽

Systemic Embolism ◽

The Mean

Abstract Background Atrial fibrillation (AF) increases the risk of death, stroke/systemic embolism and heart failure (HF). Plasma natriuretic peptide (NP) level is an important prognostic marker in HF patients. However, little is known regarding the prognostic significance of plasma NP level in AF patients without HF. Purpose The aim of this study is to investigate the relationship between plasma NP level and clinical outcomes such as all-cause death, stroke/systemic embolism and HF hospitalization during follow-up period in AF patients without HF. Methods The Fushimi AF Registry is a community-based prospective survey of AF patients in our city. The inclusion criterion of the registry is the documentation of AF at 12-lead electrocardiogram or Holter monitoring at any time, and there are no exclusion criteria. We started to enroll patients from March 2011, and follow-up data were available for 4,466 patients by the end of November 2019. From the registry, we excluded 1,220 patients without a pre-existing HF (defined as having one of the following; prior hospitalization for HF, New York Heart Association class ≥2, or left ventricular ejection fraction <40%). Among 3,246 AF patients without HF, we investigated 1,189 patients with the data of plasma BNP (n=401) or N-terminal pro-BNP (n=788) level at the enrollment. We divided the patients according to the quartile of each plasma BNP or NT-pro BNP level and compared the backgrounds and outcomes between these 4 groups stratified by plasma NP level. Results Of 1,189 patients, the mean age was 72.1±10.2 years, 454 (38%) were female and 684 (58%) were paroxysmal AF. The mean CHADS2 and CHA2DS2-VASc score were 1.6±1.1 and 2.9±1.5, respectively. Oral anticoagulants were prescribed in 671 (56%) at baseline. The median (interquartile range) BNP and N-terminal pro-BNP level were 84 (38, 176) and 500 (155, 984) pg/ml, respectively. Patients with high plasma NP level were older, and demonstrated lower prevalence of paroxysmal AF, higher CHADS2 and CHA2DS2-VASc scores and higher prevalence of chronic kidney disease and oral anticoagulants prescription (all P<0.01). A total of 165 all-cause death, 114 stroke/systemic embolism and 103 HF hospitalization occurred during the median follow-up period of 5.0 years. Kaplan-Meier curves demonstrated that higher plasma NP level was significantly associated with the incidences of all-cause death, stroke/systemic embolism and HF hospitalization in AF patients without HF (Figure 1A). Multivariable Cox regression analysis revealed that plasma NP level could stratify the risk of clinical outcomes even after adjustment by type of AF, CHA2DS2-VASc score, chronic kidney disease and oral anticoagulant prescription (Figure 1B). Conclusion Plasma NP level is a significant prognostic marker for all-cause death, stroke/systemic embolism and HF hospitalization in AF patients without HF, suggesting the importance of measuring plasma NP level in AF patients even without HF. Figure 1 Funding Acknowledgement Type of funding source: None

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Dietary Micronutrients and Risk of Chronic Kidney Disease: A Cohort Study with 12 Year Follow-Up

Nutrients ◽

10.3390/nu13051517 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1517

Author(s):

Juyeon Lee ◽

Kook-Hwan Oh ◽

Sue-Kyung Park

Keyword(s):

Chronic Kidney Disease ◽

Cohort Study ◽

Kidney Disease ◽

Epidemiologic Study ◽

Population Based ◽

Dietary Guidelines ◽

Dietary Intakes ◽

Increased Risk ◽

Ckd Stage

We investigated the association between dietary micronutrient intakes and the risk of chronic kidney disease (CKD) in the Ansan-Ansung study of the Korean Genome and Epidemiologic Study (KoGES), a population-based prospective cohort study. Of 9079 cohort participants with a baseline estimate glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and a urine albumin to creatinine ratio (UACR) <300 mg/g and who were not diagnosed with CKD, we ascertained 1392 new CKD cases over 12 year follow-up periods. The risk of CKD according to dietary micronutrient intakes was presented using hazard ratios (HRs) and 95% confidence intervals (95% CIs) in a full multivariable Cox proportional hazard models, adjusted for multiple micronutrients and important clinico-epidemiological risk factors. Low dietary intakes of phosphorus (<400 mg/day), vitamin B2 (<0.7 mg/day) and high dietary intake of vitamin B6 (≥1.6 mg/day) and C (≥100 mg/day) were associated with an increased risk of CKD stage 3B and over, compared with the intake at recommended levels (HR = 6.78 [95%CI = 2.18–21.11]; HR = 2.90 [95%CI = 1.01–8.33]; HR = 2.71 [95%CI = 1.26–5.81]; HR = 1.83 [95%CI = 1.00–3.33], respectively). In the restricted population, excluding new CKD cases defined within 2 years, an additional association with low folate levels (<100 µg/day) in higher risk of CKD stage 3B and over was observed (HR = 6.72 [95%CI = 1.40–32.16]). None of the micronutrients showed a significant association with the risk of developing CKD stage 3A. Adequate intake of micronutrients may lower the risk of CKD stage 3B and over, suggesting that dietary guidelines are needed in the general population to prevent CKD.

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Association of Dyskalemias with Ischemic Stroke in Advanced Chronic Kidney Disease Patients Transitioning to Dialysis

American Journal of Nephrology ◽

10.1159/000516902 ◽

2021 ◽

pp. 1-9

Author(s):

Ankur A. Dashputre ◽

Keiichi Sumida ◽

Fridtjof Thomas ◽

Justin Gatwood ◽

Oguz Akbilgic ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Ischemic Stroke ◽

Kidney Disease ◽

Lower Risk ◽

Chronic Exposure ◽

Cox Regression ◽

Acute Exposure ◽

Continuous Exposure ◽

Advanced Chronic Kidney Disease

Introduction: Hypo- and hyperkalemia are associated with a higher risk of ischemic stroke. However, this association has not been examined in an advanced chronic kidney disease (CKD) population. Methods: From among 102,477 US veterans transitioning to dialysis between 2007 and 2015, 21,357 patients with 2 pre-dialysis outpatient estimated glomerular filtration rates <30 mL/min/1.73 m2 90–365 days apart and at least 1 potassium (K) each in the baseline and follow-up period were identified. We separately examined the association of both baseline time-averaged K (chronic exposure) and time-updated K (acute exposure) treated as categorized (hypokalemia [K <3.5 mEq/L] and hyperkalemia [K >5.5 mEq/L] vs. referent [3.5–5.5 mEq/L]) and continuous exposure with time to the first ischemic stroke event prior to dialysis initiation using multivariable-adjusted Cox regression models. Results: A total of 2,638 (12.4%) ischemic stroke events (crude event rate 41.9 per 1,000 patient years; 95% confidence interval [CI] 40.4–43.6) over a median (Q1–Q3) follow-up time of 2.56 (1.59–3.89) years were observed. The baseline time-averaged K category of hypokalemia (adjusted hazard ratio [aHR], 95% CI: 1.35, 1.01–1.81) was marginally associated with a significantly higher risk of ischemic stroke. However, time-updated hyperkalemia was associated with a significantly lower risk of ischemic stroke (aHR, 95% CI: 0.82, 0.68–0.98). The exposure-outcome relationship remained consistent when using continuous K levels for both the exposures. Discussion/Conclusion: In patients with advanced CKD, hypokalemia (chronic exposure) was associated with a higher risk of ischemic stroke, whereas hyperkalemia (acute exposure) was associated with a lower risk of ischemic stroke. Further studies in this population are needed to explore the mechanisms underlying these associations.

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Osteoprotegerin is a marker of cardiovascular mortality in patients with chronic kidney disease stages 3–5

Scientific Reports ◽

10.1038/s41598-021-82072-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gustavo Lenci Marques ◽

Shirley Hayashi ◽

Anna Bjällmark ◽

Matilda Larsson ◽

Miguel Riella ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Multivariate Analysis ◽

Kidney Disease ◽

Cardiovascular Mortality ◽

Osteoclast Differentiation ◽

Survival Rates ◽

Elevated Serum ◽

High Sensitivity ◽

Intima Media Thickness

AbstractCardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG), known to regulate bone mass by inhibiting osteoclast differentiation and activation, might also play a role in vascular calcification. Increased circulating OPG levels in patients with CKD are associated with aortic calcification and increased mortality. We assessed the predictive role of OPG for all-cause and cardiovascular mortality in patients with CKD stages 3–5 over a 5-year follow-up period. We evaluated the relationship between OPG and all-cause and cardiovascular mortality in 145 CKD patients (stages 3–5) in a prospective observational follow-up study. Inflammation markers, including high-sensitivity C-reactive protein, standard echocardiography, and estimation of intima-media thickness in the common carotid artery, were assessed at baseline, and correlations with OPG levels were determined. The cutoff values for OPG were defined using ROC curves for cardiovascular mortality. Survival was assessed during follow up lasting for up to 5.5 years using Fine and Gray model. A total of 145 (89 men; age 58.9 ± 15.0 years) were followed up. The cutoff value for OPG determined using ROC was 10 pmol/L for general causes mortality and 10.08 pmol/L for CV causes mortality. Patients with higher serum OPG levels presented with higher mortality rates compared to patients with lower levels. Aalen–Johansen cumulative incidence curve analysis demonstrated significantly worse survival rates in individuals with higher baseline OPG levels for all-cause and cardiovascular mortality (p < 0.001). In multivariate analysis, OPG was a marker of general and cardiovascular mortality independent of sex, age, CVD, diabetes, and CRP levels. When CKD stages were included in the multivariate analysis, OPG was an independent marker of all-cause mortality but not cardiovascular mortality. Elevated serum OPG levels were associated with higher all-cause and cardiovascular mortality risk, independent of age, CVD, diabetes, and inflammatory markers, in patients with CKD.

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