538-P: Copeptin and Renin Angiotensin Aldosterone System (RAAS) Activation in Long-Standing Type 1 Diabetes (T1D)
Authors: BJORNSTAD PETTER , LOVSHIN JULIE A. , LYTVYN YULIYA , WIROMRAT PATTARA , CHUNG LINH T. , VINOVSKIS CARISSA L. , LOVBLOM LEIF ERIK , BOULET GENEVIEVE , LAI VESTA S. , TSE JOSEPHINE M. , CHAM LESLIE , ORSZAG ANDREJ , WEISMAN ALANNA , KEENAN HILLARY A. , BRENT MICHAEL H. , PAUL NARINDER , BRIL VERA , PERKINS BRUCE A. , CHERNEY DAVID 
Published: June 2019

It remains unclear why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). Vasopressin and its surrogate copeptin have been implicated in the pathogenesis of DKD. We hypothesized that DKD resistors would be distinguished from those with DKD by copeptin concentrations.
Renal hemodynamic function, including renal vascular resistance (RVR), was measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II as a measure of RAAS activation in 75 participants (65±8 years, HbA1c 7.4±0.8%) with prolonged T1D durations (≥50 years) and in equal numbers of nondiabetic controls (66±8 years). Copeptin was measured by B·R·A·H·M·S proAVP copeptin KRYPTOR assay. Participants with T1D were categorized as DKD resistors (n=50) if they had eGFR ≥60 ml/min/1.73 m2 and 24-hour urine albumin excretion (UAE) &lt;30 mg/d, and as DKD (n=25) if they had eGFR &lt;60 ml/min/1.73 m2 or 24-hour UAE &gt;30 mg/d at their screening visit. Multivariable linear regression (adjusted for age, sex and HbA1c) was used to evaluate the relationships with copeptin.
DKD resistors had lower copeptin (least square geometric means, 95% CI: 4.0 [3.4-4.8] pmol/l) compared to those with DKD (5.8 [4.5-7.6] pmol/l, p=0.02) and the nondiabetic controls (4.8 [4.1-5.5] pmol/l, p=0.01) adjusting for age, sex and HbA1c. In T1D, copeptin inversely associated with GFR (adjusted β±SE: -8.0±3.2, p=0.02) and positively with renin concentration (50.3±24.9, p=0.049) after multivariable adjustments. These relationships were not evident in nondiabetic controls. Further, copeptin inversely associated with change in RVR following exogenous angiotensin II only in participants with T1D (adjusted β±SE: -6.9±3.4, p=0.04).
In longstanding T1D, copeptin associated with intrarenal RAAS activation and renal hemodynamic function, suggesting a possible interplay between vasopressin and RAAS in the pathogenesis of DKD.

Disclosure
P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Y. Lytvyn: None. P. Wiromrat: None. L.T. Chung: None. C.L. Vinovskis: None. L. Lovblom: None. G. Boulet: Other Relationship; Self; Medtronic. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi.

Funding
JDRF (17-2013-312, 2-SRA-2018-627-M-B)