The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: A prospective cohort study

Author summaryWhy was this study done? Advanced glycation end products (AGEs) are chemical compounds that play a role in health problems associated with aging, diabetes, and heart disease. The kidneys play a role in removing AGEs; therefore, people with kidney disease can develop accumulation of AGEs over time. The measurement of skin autofluorescence (SAF) is a noninvasive method to assess AGE accumulation. An important previous study found that people requiring dialysis have high SAF levels and that these are strong predictors of a higher risk of death from heart disease or any cause, but SAF has not been as well studied in people with milder forms of kidney disease who are also at higher risk of heart disease. What did the researchers do and find? A total of 1,707 people with relatively mild chronic kidney disease (CKD, stage 3) and average age of 73 years were enrolled into this study from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. During an observation period of 5 to 6 years, we found that a higher SAF level at enrolment was associated with a 12% higher risk of having a heart attack, heart failure, or stroke and a 16% higher risk of death from any cause. Additionally, an increase in SAF level over 1 year was associated with a 11% higher risk of having a heart attack, heart failure, or stroke and a 24% higher risk of death from any cause. What do these findings mean? Higher SAF levels are an independent risk factor for heart attacks, heart failure, stroke, or death from any cause in people with mild chronic kidney disease, though the risk seems lower than in people requiring dialysis. We should now explore ways to lower AGE levels in people with kidney disease, which may include adaptations to reduce the amount of AGEs in the diet. Because our study population was predominantly elderly and of white ethnicity, our findings may not be directly applicable to more ethnically diverse or younger populations. Background Tissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause mortality (ACM), but data at earlier stages of chronic kidney disease (CKD) are inconclusive. We investigated SAF as a risk factor for CVEs and ACM in a prospective study of persons with CKD stage 3. Methods and findings Participants with estimated glomerular filtration rate (eGFR) 59 to 30 mL/min/1.73 m(2)on two consecutive previous blood tests were recruited from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. SAF was measured in participants with CKD stage 3 at baseline, 1, and 5 years using an AGE reader (DiagnOptics). Data on hospital admissions with CVEs (based on international classification of diseases [ICD]-10 coding) and deaths were obtained from NHS Digital. Cox proportional hazards models were used to investigate baseline variables associated with CVEs and ACM. A total of 1,707 of 1,741 participants with SAF readings at baseline were included in this analysis: The mean (+/- SD) age was 72.9 +/- 9.0 years; 1,036 (60.7%) were female, 1,681 (98.5%) were of white ethnicity, and mean (+/- SD) eGFR was 53.5 +/- 11.9 mL/min/1.73 m(2). We observed 319 deaths and 590 CVEs during a mean of 6.0 +/- 1.5 and 5.1 +/- 2.2 years of observation, respectively. Higher baseline SAF was an independent risk factor for CVEs (hazard ratio [HR] 1.12 per SD, 95% CI 1.03-1.22,p= 0.01) and ACM (HR 1.16, 95% CI 1.03-1.30,p= 0.01). Additionally, increase in SAF over 1 year was independently associated with subsequent CVEs (HR 1.11 per SD, 95% CI 1.00-1.22;p= 0.04) and ACM (HR 1.24, 95% CI 1.09-1.41,p= 0.001). We relied on ICD-10 codes to identify hospital admissions with CVEs, and there may therefore have been some misclassification. Conclusions We have identified SAF as an independent risk factor for CVE and ACM in persons with early CKD. These findings suggest that interventions to reduce AGE accumulation, such as dietary AGE restriction, may reduce cardiovascular risk in CKD, but this requires testing in prospective randomised trials. Our findings may not be applicable to more ethnically diverse or younger populations.