Yuliya Lytvyn1, Petter Bjornstad2, Julie A Lovshin3, Genevieve Boulet3, Mohammed A Farooqi3, Vesta Lai4, Josephine Tse4, Leslie Cham4, Leif E Lovblom5, Alanna Weisman3, Hillary A Keenan6, Michael H Brent7, Narinder Paul8, Vera Bril9, Andrew Advani10, Etienne Sochett11, Bruce A Perkins3, David Z I Cherney4. 1. Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address: julia.lytvyn@mail.utoronto.ca. 2. Division of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO. 3. Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. 4. Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. 5. Lunenfeld-Tanenbaum Research Institute, Mount Sounai Hospital, University of Toronto, Toronto, Ontario, Canada. 6. Mount Sinai Hospital, Toronto, Ontario, Canada; Genzyme, Cambridge, MA. 7. Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada. 8. Division of Cardiothoracic Radiology, Joint Department of Medical Imaging, University Health Network, Toronto, Canada. 9. Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada; Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. 10. Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Ontario, Canada. 11. Division of Pediatric Endocrinology, Department of Pediatrics, University of Toronto, Ontario, Canada.
Abstract
RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.
RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.
Authors: Yuliya Lytvyn; Ronnie Har; Amy Locke; Vesta Lai; Derek Fong; Andrew Advani; Bruce A Perkins; David Z I Cherney Journal: Diabetes Date: 2017-04-13 Impact factor: 9.461
Authors: Aleksandar Denic; Jerry Mathew; Lilach O Lerman; John C Lieske; Joseph J Larson; Mariam P Alexander; Emilio Poggio; Richard J Glassock; Andrew D Rule Journal: N Engl J Med Date: 2017-06-15 Impact factor: 91.245
Authors: Dick de Zeeuw; Tadao Akizawa; Paul Audhya; George L Bakris; Melanie Chin; Heidi Christ-Schmidt; Angie Goldsberry; Mark Houser; Melissa Krauth; Hiddo J Lambers Heerspink; John J McMurray; Colin J Meyer; Hans-Henrik Parving; Giuseppe Remuzzi; Robert D Toto; Nosratola D Vaziri; Christoph Wanner; Janet Wittes; Danielle Wrolstad; Glenn M Chertow Journal: N Engl J Med Date: 2013-11-09 Impact factor: 91.245
Authors: David Z I Cherney; Heather N Reich; Judith A Miller; Vesta Lai; Bernard Zinman; Maria G Dekker; Timothy J Bradley; James W Scholey; Etienne B Sochett Journal: Am J Physiol Regul Integr Comp Physiol Date: 2010-04-21 Impact factor: 3.619
Authors: David M Nathan; Bernard Zinman; Patricia A Cleary; Jye-Yu C Backlund; Saul Genuth; Rachel Miller; Trevor J Orchard Journal: Arch Intern Med Date: 2009-07-27
Authors: Katherine R Tuttle; Janet B McGill; Douglas J Haney; Toni E Lin; Pamela W Anderson Journal: Clin J Am Soc Nephrol Date: 2007-05-30 Impact factor: 8.237
Authors: Y Lytvyn; M Škrtić; G K Yang; V Lai; J W Scholey; P M Yip; B A Perkins; D Z I Cherney Journal: Diabet Med Date: 2016-01-20 Impact factor: 4.359
Authors: David Z I Cherney; Heather N Reich; Shan Jiang; Ronnie Har; Rania Nasrallah; Richard L Hébert; Vesta Lai; James W Scholey; Etienne B Sochett Journal: Am J Physiol Regul Integr Comp Physiol Date: 2012-08-01 Impact factor: 3.619
Authors: Lennart Tonneijck; Mark M Smits; Marcel H A Muskiet; Trynke Hoekstra; Mark H H Kramer; A H Jan Danser; Michaela Diamant; Jaap A Joles; Daniël H van Raalte Journal: Diabetologia Date: 2016-04-01 Impact factor: 10.122
Authors: Melissa J Johnson; Kalie L Tommerdahl; Carissa Vinovskis; Sushrut Waikar; Trenton Reinicke; Chirag R Parikh; Wassim Obeid; Robert G Nelson; Daniel H van Raalte; Laura Pyle; Kristen J Nadeau; Petter Bjornstad Journal: Pediatr Nephrol Date: 2022-03-14 Impact factor: 3.651
Authors: Ivana Trutin; Zarko Bajic; Daniel Turudic; Andrea Cvitkovic-Roic; Danko Milosevic Journal: Front Pediatr Date: 2022-07-29 Impact factor: 3.569