HHS Public Access Author manuscript Author Manuscript
J Diabetes Complications. Author manuscript; available in PMC 2017 August 01. Published in final edited form as: J Diabetes Complications. 2016 August ; 30(6): 1093–1096. doi:10.1016/j.jdiacomp.2016.04.012.
Elevated copeptin is associated with atherosclerosis and diabetic kidney disease in adults with type 1 diabetes Petter Bjornstad, M.D.1,2, David M. Maahs, M.D., Ph.D.1,2,3, Thomas Jensen, M.D.4, Miguel A. Lanaspa, Ph.D3, Richard J. Johnson, M.D.3, Marian Rewers, M.D., Ph.D.1,2, and Janet K. Snell-Bergeon, Ph.D., M.P.H.1,2 1Department
Author Manuscript
2Barbara
of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO
Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
3Department
of Nephrology, University of Colorado Denver, Aurora, CO
4Department
of Adult Endocrinology, University of Colorado School of Medicine, Aurora, CO
Abstract Background—Vasopressin exerts important cardio-renal effects, but remains problematic to measure. Copeptin is a more stable peptide derived from the same precursor molecule. We examined the associations between copeptin, coronary artery calcium (CAC), albuminuria and impaired glomerular filtration rate (GFR) in adults with type 1 diabetes (T1D).
Author Manuscript
Methods—Participants with (n=209) and without T1D (n=244) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, CAC measured using 128-slice spiral CT, urinary albumin-to-creatinine ratio (UACR) and eGFR calculated by CKD-EPI creatinine. Impaired GFR was defined as eGFR 13pmol/L (>97.5th percentile for healthy adults). Unadjusted and adjusted (age, sex, HbA1c, SBP and LDL-C) logistic models were applied to examine the relationships. Results—Participants with T1D had greater ultrasensitive copeptin concentrations than nondiabetics (3.5 [95% CI 2.3–3.8] vs. 2.8 [2.7–3.1], p=0.003). In participants with T1D, elevated copeptin was associated with greater odds of impaired eGFR (OR: 18.52, 95% CI 4.03–85.02), albuminuria (10.55, 2.24–49.62), high CAC (6.61, 1.39–31.31) and very high CAC (6.24, 1.51–
Author Manuscript
Address all correspondence to: Petter Bjornstad, M.D., Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, 1775 Aurora Court, Aurora, CO 80045, Phone: 720.579.1048, Fax: 303.724.6779, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: PB researched, wrote, contributed to discussion, analyzed data and reviewed/edited the manuscript; DMM researched, contributed to discussion, and reviewed/edited the manuscript; MR designed the CACTI Study, researched, contributed to the discussion and reviewed/edited the manuscript; TJ contributed to the discussion and reviewed/edited the manuscript; ML contributed to the discussion and reviewed/edited the manuscript; RJJ contributed to the discussion and reviewed/edited the manuscript; JKSB researched, wrote, analyzed data, contributed to the discussion, reviewed/edited the manuscript.
Bjornstad et al.
Page 2
Author Manuscript
25.90) in multivariable models. Similar linear relationships were obtained with ultrasensitive copeptin, eGFR, UACR, CAC volume and CAC score in adjusted models. Conclusion—In this cross-sectional analysis, copeptin was strongly associated with diabetic kidney disease and coronary atherosclerosis in adults with T1D. Further research is needed to determine whether these relationships hold true longitudinally in people with T1D.
Introduction Cardio-renal complications are the major causes of mortality in type 1 diabetes (T1D) [1], with diabetic kidney disease (DKD) being the single most important cause of renal failure in the Western world [2]. Coronary artery calcification (CAC), a marker of coronary artery plaque burden, predicts coronary events in T1D [2]. The presence and progression of CAC are useful surrogate CAD end points in evaluating novel CAD risk factors [2].
Author Manuscript
Arginine vasopressin (AVP) plays an essential role in regulation of volume status and exerts important renal and cardiovascular effects [3]. Measuring AVP is unfortunately associated with technical difficulties, due to its relatively small size and short half-life. Copeptin is a more stable peptide derived from the same precursor molecule as AVP, and is recognized as a surrogate marker for AVP useful in the assessment of fluid and osmosis status in various diseases [3].
Author Manuscript
AVP concentrations are higher in people with diabetes compared with healthy counterparts [4], and people with T1D are thought to have an exaggerated response to AVP [5]. High concentrations of plasma AVP are known to stimulate V1a receptors preferentially [5], which may contribute to the cardiovascular complications associated with diabetes. Associations between copeptin, CAD and DKD have been demonstrated in adults with type 2 diabetes (T2D) [6, 7], but these relationships have to our knowledge not yet been examined in adults with T1D. Accordingly, we sought to examine the associations between copeptin, elevated coronary artery calcium (CAC), albuminuria and impaired GFR (13pmol/L, which is >97.5th percentile for healthy adults [8]. The ultrasensitive copeptin assay has a lower limit of detection of 0.9 pmol/L and a functional assay sensitivity of 13pmol/L. We applied multivariable logistic regression models, adjusted for age, sex, HbA1c, SBP and LDL-C (American Diabetes’ Association ABC risk factors) to evaluate the relationships between US copeptin, elevated copeptin, albuminuria, impaired GFR and high and very high CAC. Unadjusted and adjusted generalized linear models were also applied to examine the relationships between US copeptin, UACR, eGFR and CAC score. Finally, we stratified participants according to tertiles of US copeptin (high: ≥4.34, mid: 2.73–4.34, low:
J Diabetes Complications. Author manuscript; available in PMC 2017 August 01. Published in final edited form as: J Diabetes Complications. 2016 August ; 30(6): 1093–1096. doi:10.1016/j.jdiacomp.2016.04.012.
Elevated copeptin is associated with atherosclerosis and diabetic kidney disease in adults with type 1 diabetes Petter Bjornstad, M.D.1,2, David M. Maahs, M.D., Ph.D.1,2,3, Thomas Jensen, M.D.4, Miguel A. Lanaspa, Ph.D3, Richard J. Johnson, M.D.3, Marian Rewers, M.D., Ph.D.1,2, and Janet K. Snell-Bergeon, Ph.D., M.P.H.1,2 1Department
Author Manuscript
2Barbara
of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO
Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
3Department
of Nephrology, University of Colorado Denver, Aurora, CO
4Department
of Adult Endocrinology, University of Colorado School of Medicine, Aurora, CO
Abstract Background—Vasopressin exerts important cardio-renal effects, but remains problematic to measure. Copeptin is a more stable peptide derived from the same precursor molecule. We examined the associations between copeptin, coronary artery calcium (CAC), albuminuria and impaired glomerular filtration rate (GFR) in adults with type 1 diabetes (T1D).
Author Manuscript
Methods—Participants with (n=209) and without T1D (n=244) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, CAC measured using 128-slice spiral CT, urinary albumin-to-creatinine ratio (UACR) and eGFR calculated by CKD-EPI creatinine. Impaired GFR was defined as eGFR 13pmol/L (>97.5th percentile for healthy adults). Unadjusted and adjusted (age, sex, HbA1c, SBP and LDL-C) logistic models were applied to examine the relationships. Results—Participants with T1D had greater ultrasensitive copeptin concentrations than nondiabetics (3.5 [95% CI 2.3–3.8] vs. 2.8 [2.7–3.1], p=0.003). In participants with T1D, elevated copeptin was associated with greater odds of impaired eGFR (OR: 18.52, 95% CI 4.03–85.02), albuminuria (10.55, 2.24–49.62), high CAC (6.61, 1.39–31.31) and very high CAC (6.24, 1.51–
Author Manuscript
Address all correspondence to: Petter Bjornstad, M.D., Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, 1775 Aurora Court, Aurora, CO 80045, Phone: 720.579.1048, Fax: 303.724.6779, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: PB researched, wrote, contributed to discussion, analyzed data and reviewed/edited the manuscript; DMM researched, contributed to discussion, and reviewed/edited the manuscript; MR designed the CACTI Study, researched, contributed to the discussion and reviewed/edited the manuscript; TJ contributed to the discussion and reviewed/edited the manuscript; ML contributed to the discussion and reviewed/edited the manuscript; RJJ contributed to the discussion and reviewed/edited the manuscript; JKSB researched, wrote, analyzed data, contributed to the discussion, reviewed/edited the manuscript.
Bjornstad et al.
Page 2
Author Manuscript
25.90) in multivariable models. Similar linear relationships were obtained with ultrasensitive copeptin, eGFR, UACR, CAC volume and CAC score in adjusted models. Conclusion—In this cross-sectional analysis, copeptin was strongly associated with diabetic kidney disease and coronary atherosclerosis in adults with T1D. Further research is needed to determine whether these relationships hold true longitudinally in people with T1D.
Introduction Cardio-renal complications are the major causes of mortality in type 1 diabetes (T1D) [1], with diabetic kidney disease (DKD) being the single most important cause of renal failure in the Western world [2]. Coronary artery calcification (CAC), a marker of coronary artery plaque burden, predicts coronary events in T1D [2]. The presence and progression of CAC are useful surrogate CAD end points in evaluating novel CAD risk factors [2].
Author Manuscript
Arginine vasopressin (AVP) plays an essential role in regulation of volume status and exerts important renal and cardiovascular effects [3]. Measuring AVP is unfortunately associated with technical difficulties, due to its relatively small size and short half-life. Copeptin is a more stable peptide derived from the same precursor molecule as AVP, and is recognized as a surrogate marker for AVP useful in the assessment of fluid and osmosis status in various diseases [3].
Author Manuscript
AVP concentrations are higher in people with diabetes compared with healthy counterparts [4], and people with T1D are thought to have an exaggerated response to AVP [5]. High concentrations of plasma AVP are known to stimulate V1a receptors preferentially [5], which may contribute to the cardiovascular complications associated with diabetes. Associations between copeptin, CAD and DKD have been demonstrated in adults with type 2 diabetes (T2D) [6, 7], but these relationships have to our knowledge not yet been examined in adults with T1D. Accordingly, we sought to examine the associations between copeptin, elevated coronary artery calcium (CAC), albuminuria and impaired GFR (13pmol/L, which is >97.5th percentile for healthy adults [8]. The ultrasensitive copeptin assay has a lower limit of detection of 0.9 pmol/L and a functional assay sensitivity of 13pmol/L. We applied multivariable logistic regression models, adjusted for age, sex, HbA1c, SBP and LDL-C (American Diabetes’ Association ABC risk factors) to evaluate the relationships between US copeptin, elevated copeptin, albuminuria, impaired GFR and high and very high CAC. Unadjusted and adjusted generalized linear models were also applied to examine the relationships between US copeptin, UACR, eGFR and CAC score. Finally, we stratified participants according to tertiles of US copeptin (high: ≥4.34, mid: 2.73–4.34, low:
