Soluble RAGE further stratifies risk of coronary artery and end-stage kidney disease in high-risk individuals with type 1 diabetes and treatment-resistant hypertension

TL;DR

Higher levels of sRAGE are linked to increased risk of heart and kidney disease in people with type 1 diabetes and hard-to-control high blood pressure.

Contribution

sRAGE provides additional risk stratification for CAD and ESKD beyond clinical variables in high-risk type 1 diabetes patients.

Findings

Higher sRAGE levels are associated with increased odds of treatment-resistant hypertension in type 1 diabetes patients.

sRAGE is linked to higher risk of coronary artery disease and end-stage kidney disease in those with treatment-resistant hypertension.

The association between sRAGE and disease risk is reduced after adjusting for estimated glomerular filtration rate.

Abstract

Soluble receptor for advanced glycation end-products (sRAGE) modulates RAGE-mediated inflammation and oxidative stress. We investigated if sRAGE stratifies cardiovascular and kidney disease risk in individuals with type 1 diabetes and baseline treatment-resistant hypertension (TRH).

This study included 1262 adults with type 1 diabetes from the FinnDiane study who were on antihypertensive therapy and whose sRAGE concentration was measured at baseline. Participants were divided into groups: controlled blood pressure (BP) (n = 295), uncontrolled BP (n = 730) or TRH (n = 237). Prospective analyses were performed in those with baseline TRH. Of them, 62 developed coronary artery disease (CAD) and 38 stroke (median follow-up 12 years), while 99 progressed to end-stage kidney disease (ESKD) (median follow-up 9.2 years).

Every 100 units increase in baseline sRAGE was associated with 4% higher odds for TRH, compared to those with uncontrolled BP (P = 0.003), and 6% higher odds than those with controlled BP (P = 0.0006). Associations attenuated after adjusting for kidney markers. In the competing risk analysis, higher sRAGE was associated with greater risk of CAD (SHR 1.05, P = 0.01) in those with TRH. After adjusting for eGFR, the association attenuated (SHR 1.04, P = 0.052), but the same trend remained. sRAGE was not associated with stroke. Furthermore, sRAGE was associated with higher risk of ESKD (SHR 1.06, P < 0.0001), but no longer after adjusting for eGFR (P = 0.4).

Elevated sRAGE is associated with increased odds of TRH in individuals with type 1 diabetes. sRAGE further stratifies high risk of incident CAD and ESKD, even after accounting for clinical variables. Along with eGFR, sRAGE may help to identify individuals at the highest risk of adverse cardiovascular and kidney outcomes.

The online version contains supplementary material available at 10.1186/s12933-025-03017-8.

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