Julie A Lovshin1,2, Geneviève Boulet3, Yuliya Lytvyn2, Leif E Lovblom3, Petter Bjornstad2,4, Mohammed A Farooqi3, Vesta Lai2, Leslie Cham2, Josephine Tse2, Andrej Orszag3, Daniel Scarr3, Alanna Weisman1,3, Hillary A Keenan5, Michael H Brent6, Narinder Paul7, Vera Bril8, Bruce A Perkins1,3, David Zi Cherney2. 1. Division of Endocrinology and Metabolism and. 2. Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 3. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 4. Research Division, Barbara Davis Center for Diabetes, Aurora, Colorado, USA. 5. Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. 6. Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 7. Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network, Toronto, Ontario, Canada. 8. Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS: Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS: Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION: In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING: JDRF operating grant 17-2013-312.
BACKGROUND: In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS: Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS: Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION: In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING: JDRF operating grant 17-2013-312.
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Authors: Yuliya Lytvyn; Petter Bjornstad; Julie A Lovshin; Sunita K Singh; Genevieve Boulet; Mohammed A Farooqi; Vesta Lai; Josephine Tse; Leslie Cham; Leif E Lovblom; Alanna Weisman; Hillary A Keenan; Michael H Brent; Narinder Paul; Vera Bril; Andrew Advani; Etienne Sochett; Bruce A Perkins; David Z I Cherney Journal: Diabetes Obes Metab Date: 2019-03-28 Impact factor: 6.577
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Authors: Julie A Lovshin; Yuliya Lytvyn; Leif E Lovblom; Alexandra Katz; Geneviève Boulet; Petter Bjornstad; Vesta Lai; Leslie Cham; Josephine Tse; Andrej Orszag; Hillary A Keenan; Narinder Paul; Vera Bril; David T Wong; Kylen D McReelis; Michael H Brent; Bruce A Perkins; David Z I Cherney Journal: Diabetes Care Date: 2018-12-06 Impact factor: 19.112
Authors: Yuliya Lytvyn; Petter Bjornstad; Julie A Lovshin; Genevieve Boulet; Mohammed A Farooqi; Vesta Lai; Josephine Tse; Leslie Cham; Leif E Lovblom; Alanna Weisman; Hillary A Keenan; Michael H Brent; Narinder Paul; Vera Bril; Andrew Advani; Etienne Sochett; Bruce A Perkins; David Z I Cherney Journal: Am J Kidney Dis Date: 2019-02-22 Impact factor: 8.860
Authors: Julie A Lovshin; Petter Bjornstad; Leif E Lovblom; Johnny-Wei Bai; Yuliya Lytvyn; Geneviève Boulet; Mohammed A Farooqi; Sam Santiago; Andrej Orszag; Daniel Scarr; Alanna Weisman; Hillary A Keenan; Michael H Brent; Narinder Paul; Vera Bril; Bruce A Perkins; David Z I Cherney Journal: Diabetes Care Date: 2018-10-01 Impact factor: 19.112
Authors: Daniel Scarr; Petter Bjornstad; Leif E Lovblom; Julie A Lovshin; Genevieve Boulet; Yuliya Lytvyn; Mohammed A Farooqi; Vesta Lai; Andrej Orszag; Alanna Weisman; Hillary A Keenan; Michael H Brent; Narinder Paul; Vera Bril; David Z I Cherney; Bruce A Perkins Journal: Kidney Int Rep Date: 2019-02-21