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Observational Study
. 2021 May;35(5):107880.
doi: 10.1016/j.jdiacomp.2021.107880. Epub 2021 Feb 2.

Relationships between inflammation, hemodynamic function and RAAS in longstanding type 1 diabetes and diabetic kidney disease

Jaya Prakash Nath Ambinathan  1 , Vikas S Sridhar  1 , Yuliya Lytvyn  1 , Leif Erik Lovblom  2 , Hongyan Liu  1 , Petter Bjornstad  3 , Bruce A Perkins  4 , Julie A Lovshin  5 , David Z I Cherney  6
Affiliations
Observational Study

Relationships between inflammation, hemodynamic function and RAAS in longstanding type 1 diabetes and diabetic kidney disease

Jaya Prakash Nath Ambinathan et al. J Diabetes Complications. 2021 May.

Abstract

The renin angiotensin aldosterone system (RAAS) is associated with renal disease and inflammation in a diabetes setting, however, little is known about the implicated mechanisms in individuals with long standing diabetes. Accordingly, our aim was to perform an observational study to quantify urinary excretion of inflammatory biomarkers in participants with long standing type 1 diabetes (T1D) (with and without diabetic kidney disease [DKD]) and controls, at baseline and in response to RAAS activation. GFRINULIN, ERPFPAH, and 42 urine inflammatory biomarkers were measured in 74 participants with T1D for ≥50 years (21 with DKD and 44 without DKD [DKD resistors]) and 73 healthy controls. Additionally, inflammatory biomarkers were measured before and after an angiotensin II infusion (ANGII, 1 ng∙kg-1∙min-1). Significantly lower urinary excretion of cytokines (IL-18, IL-1RA, IL-8), chemokines (MCP1, RANTES) and growth factors (TGF-α, PDGFAA, PDGFBB, VEGF-A) was observed in participants with T1D at baseline compared to controls. Urinary IL-6 was higher in DKD than in DKD resistors in an exploratory analysis unadjusted for multiple comparisons. In T1D only, lower GFRINULIN correlated with greater excretion of proinflammatory biomarkers (IL-18, IP-10, & RANTES), growth factors (PDGF-AA & VEGFAA), and chemokines (eotaxin & MCP-1). ANGII increased 31 of 42 inflammatory biomarkers in T1D vs controls (p < 0.05), regardless of DKD resistor status. In conclusion, lower GFR and intra-renal RAAS activation were associated with increased inflammation even after longstanding T1D. The increased urinary IL-6 in patients with DKD requires further investigation to determine whether IL-6 is a candidate protective biomarker for prognostication or targeted therapy in DKD.

Keywords: Diabetic kidney disease; Nephropathy; Renin aldosterone angiotensin system; Type 1 diabetes.

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Conflict of interest statement

Declaration of competing interest J.P.A., Y.L., and H.L. have no conflicts of interest to declare. V.S.S. is supported by the Department of Medicine Eliot Phillipson Clinician Scientist Training Program and a Banting and Best Diabetes Centre Postdoctoral fellowship at the University of Toronto. L.E.L. received support from a CIHR Canada Graduate Scholarship Doctoral Award. P.B. has acted as a consultant for Bayer, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, Novo Nordisk and Horizon Pharma. PB serves on advisory boards for Boehringer Ingelheim and XORTX. B.A.P. has received speaker honoraria from Abbott, Medtronic, Insulet, and Novo-Nordisk; research support to his research institute from Boehringer Ingleheim and the Bank of Montreal (BMO), and has served as a consultant to Boehringer Ingelheim, Abbott, and Novo-Nordisk. J.A.L. has received either consulting fees or speaking honorarium or both from Novo Nordisk. D.Z.I.C. has received consulting fees or speaking honorarium or both from Janssen, Boehringer Ingelheim-Eli, Lilly, AstraZeneca, Merck, and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim-Eli, Lilly, AstraZeneca and Merck.

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