Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery

Katja M. Gist; David S. Cooper; Julia Wrona; Sarah Faubel; Christopher Altmann; Zhiqian Gao; Bradley Scott Marino; Jeffrey Alten; Kristal M. Hock; Tomoyuki Mizuno; Alexander A. Vinks; Melanie S. Joy; Michael F. Wempe; Michael R. Bennett; Stuart L. Goldstein

doi:10.1097/FTD.0000000000000496

Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery

Katja M. Gist^*, David S. Cooper, Julia Wrona, Sarah Faubel, Christopher Altmann, Zhiqian Gao, Bradley Scott Marino, Jeffrey Alten, Kristal M. Hock, Tomoyuki Mizuno, Alexander A. Vinks, Melanie S. Joy, Michael F. Wempe, Michael R. Bennett, Stuart L. Goldstein

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Background: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. Methods: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. Results: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2∗IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. Conclusions: In this pilot study, urine TIMP-2∗IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.

Original language	English (US)
Pages (from-to)	186-194
Number of pages	9
Journal	Therapeutic drug monitoring
Volume	40
Issue number	2
DOIs	https://doi.org/10.1097/FTD.0000000000000496
State	Published - Apr 1 2018

Funding

Supported by Thrasher Pediatric Research Foundation, Early Career award. K. M. Gist received grant funding from the E.W. Thrasher Foundation, The Center for Acute Care Nephrology, the Heart Institute Research Core, and the Division of Critical Care Medicine at Cincinnati Children’s Hos-pital Medical Center also provided internal grant support for the study. Urinary TIMP-2*IGFBP-7 processing was supported by a pilot grant from the Children’s Hospital Colorado Research Institute.

Keywords

acute kidney injury
biomarkers
cardiac surgery
infants
milrinone

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1097/FTD.0000000000000496

Cite this

Gist, K. M., Cooper, D. S., Wrona, J., Faubel, S., Altmann, C., Gao, Z., Marino, B. S., Alten, J., Hock, K. M., Mizuno, T., Vinks, A. A., Joy, M. S., Wempe, M. F., Bennett, M. R., & Goldstein, S. L. (2018). Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery. Therapeutic drug monitoring, 40(2), 186-194. https://doi.org/10.1097/FTD.0000000000000496

@article{538840219d224da48e96aea556549868,

title = "Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery",

abstract = "Background: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. Methods: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. Results: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2∗IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. Conclusions: In this pilot study, urine TIMP-2∗IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.",

keywords = "acute kidney injury, biomarkers, cardiac surgery, infants, milrinone",

author = "Gist, {Katja M.} and Cooper, {David S.} and Julia Wrona and Sarah Faubel and Christopher Altmann and Zhiqian Gao and Marino, {Bradley Scott} and Jeffrey Alten and Hock, {Kristal M.} and Tomoyuki Mizuno and Vinks, {Alexander A.} and Joy, {Melanie S.} and Wempe, {Michael F.} and Bennett, {Michael R.} and Goldstein, {Stuart L.}",

year = "2018",

month = apr,

day = "1",

doi = "10.1097/FTD.0000000000000496",

language = "English (US)",

volume = "40",

pages = "186--194",

journal = "Therapeutic drug monitoring",

issn = "0163-4356",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "2",

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Gist, KM, Cooper, DS, Wrona, J, Faubel, S, Altmann, C, Gao, Z, Marino, BS, Alten, J, Hock, KM, Mizuno, T, Vinks, AA, Joy, MS, Wempe, MF, Bennett, MR & Goldstein, SL 2018, 'Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery', Therapeutic drug monitoring, vol. 40, no. 2, pp. 186-194. https://doi.org/10.1097/FTD.0000000000000496

Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery. / Gist, Katja M.; Cooper, David S.; Wrona, Julia et al.
In: Therapeutic drug monitoring, Vol. 40, No. 2, 01.04.2018, p. 186-194.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery

AU - Gist, Katja M.

AU - Cooper, David S.

AU - Wrona, Julia

AU - Faubel, Sarah

AU - Altmann, Christopher

AU - Gao, Zhiqian

AU - Marino, Bradley Scott

AU - Alten, Jeffrey

AU - Hock, Kristal M.

AU - Mizuno, Tomoyuki

AU - Vinks, Alexander A.

AU - Joy, Melanie S.

AU - Wempe, Michael F.

AU - Bennett, Michael R.

AU - Goldstein, Stuart L.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Background: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. Methods: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. Results: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2∗IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. Conclusions: In this pilot study, urine TIMP-2∗IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.

AB - Background: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. Methods: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. Results: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2∗IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. Conclusions: In this pilot study, urine TIMP-2∗IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.

KW - acute kidney injury

KW - biomarkers

KW - cardiac surgery

KW - infants

KW - milrinone

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U2 - 10.1097/FTD.0000000000000496

DO - 10.1097/FTD.0000000000000496

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AN - SCOPUS:85053937090

SN - 0163-4356

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JO - Therapeutic drug monitoring

JF - Therapeutic drug monitoring

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ER -

Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants after Cardiac Surgery

Abstract

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UN SDGs

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