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Using Serum Cystatin C to Predict Acute Kidney Injury Following Infant Cardiac Surgery

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Abstract

Acute kidney injury (AKI) following cardiopulmonary bypass (CPB) is associated with increased morbidity and mortality. Serum Cystatin C (CysC) is a novel biomarker synthesized by all nucleated cells that may act as an early indicator of AKI following infant CPB. Prospective observational study of infants (< 1 year) requiring CPB during cardiac surgery. CysC was measured at baseline and 12, 24, 48, and 72 h following CPB initiation. Each post-op percent difference in CysC (e.g. %CysC12h) from baseline was calculated. Clinical variables along with urine output (UOP) and serum creatinine (SCr) were followed. Subjects were divided into two groups: AKI and non-AKI based upon the Kidney Disease Improving Global Outcomes (KDIGO) classification. AKI occurred in 41.9% (18) of the 43 infants enrolled. Patient demographics and baseline CysC levels were similar between groups. CysC levels were 0.97 ± 0.28 mg/L over the study period, and directly correlated with SCr (R = 0.71, p < 0.0001). Although absolute CysC levels were not significant between groups, the %CysC12h was significantly greater in the AKI group (AKI: − 16% ± 22% vs. Non-AKI − 28% ± 9% mg/L; p = 0.003). However, multivariate analysis demonstrated that a lower UOP (Odds Ratio:0.298; 95% CI 0.073, 0.850; p = 0.02) but not %CysC12h was independently associated with AKI. Despite a significant difference in the %CysC12h, only UOP was independently associated with AKI. Larger studies of a more homogenous population are needed to understand these results and to explore the variability in this biomarker seen across institutions.

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Acknowledgements

We thank the Pediatric Cardiac Care Center Staff for their hard work in making this a success: (1) Nursing Staff for excellent communication and timely sample collection, (2) PICU and NICU Fellows, Attending Physicians and Advanced Practice Providers for their enthusiasm and dedication to all aspects of the project, (3) Partial financial support was awarded by: Clausen and Bradford Fellowship Award. University of Rochester Medical Center. Abadeer M, Cholette J. October 16, 2020. Status: Awarded. Amount: $25,000.

Funding

Partial funding for the study was provided by the Clausen and Bradford Fellowship Award. University of Rochester Medical Center. Abadeer M, Cholette J. October 16, 2020. Status: Awarded. Amount: $25,000.

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Authors and Affiliations

  1. Department of Pediatrics, Golisano Children’s Hospital, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA

    Maher Abadeer, Susan D. Martin, Angela M. Groves, Alison L. Kent, George J. Schwartz, Patrick Brophy & Jill M. Cholette

  2. Department of Surgery, Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, NY, USA

    Michael F. Swartz & George M. Alfieris

  3. College of Health and Medicine, Australian National University, Canberra, ACT, Australia

    Alison L. Kent

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Contributions

MA drafted/submitted the IRB proposal, organized, implemented and collected samples and data for the research study, applied for funding via the Clausen and Bradford Award, helped with data analysis and wrote the main manuscript text. MFS helped with editing several versions of the manuscript and performed the majority of complex data analysis, and created Figs. 1, 2, 3, 4, S1, S2, and S4, and Tables 5, S1, and S2. SDM helped with sample processing and revision of IRB proposal, and troubleshooting logistics for the study. AMG helped with establishing the study protocol, running sample analysis and troubleshooting logistical issues ALK was formerly the principal investigator, helped with editing the IRB proposal and manuscript, and supplied the laboratory space and freezer for sample processing. GJS helped with manuscript editing, and supplied the laboratory personnel and equipment for running serum cystatin C. He supplied expertise on the interpretation of serum cystatin C values and was an invaluable resource. PB helped with editing the IRB proposal, troubleshooting logistics and helped supply institutional funding for the study. GMA was the principal CT surgeon operating on subjects included in the study, and permitted study sample collection in the OR JMC is the current principal investigator, helped with multiple abstract and manuscript revisions, and troubleshooting logistics

Corresponding author

Correspondence to Jill M. Cholette.

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The individual authors listed have no relevant financial disclosures or conflicts of interest in relation to the content of this research. This study did receive financial funding as outlined above.

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Informed written consent was obtained from all parent guardians along with written assent or script assent from pediatric subjects when age-appropriate.

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Study approval was obtained from the Research Subjects Review Board to ensure that rights and welfare of human subjects is protected

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Supplementary Information

246_2022_3080_MOESM1_ESM.jpeg

Fig. S1: Flow diagram of children who underwent a prospective observational trial to examine serum Cystatin C as a marker for Acute Kidney Injury (AKI). Abbreviations: ECMO-Extra-corporeal membrane oxygenation; CPB-Cardiopulmonary bypass. (JPEG 299 kb)

246_2022_3080_MOESM2_ESM.jpeg

Fig. S2: Box and Whisker Plots between infants that developed acute kidney injury (AKI-grey) and those who did not (no-AKI-white) demonstrate: S2a) The glomerular filtration rate (GFR) as estimated by Cystatin C (CysC), S2b) The percent change in GFR from baseline as estimated by CysC, S2c) The GFR as estimated by the serum creatinine (SCr), S2d) The percent change in GFR from baseline as estimated by SCr. *Denotes P value < 0.05. **Denotes P value of < 0.01 (JPEG 577 kb)

246_2022_3080_MOESM3_ESM.jpeg

Fig. S3 S3a) Linear regression (solid line) between 12 hour percent change in CysC (12hr-%CysC) and intra-operative net fluid balance (%), S3b) Linear regression (solid line) between %CysC12hr and hemofiltration volume towards end of cardiopulmonary bypass, S3c) Linear regression (solid line) between %CysC and net fluid balance for each subject during post-operative days (POD) 0 – 3, S3d) Linear regression (solid line) between mediastinal tube output and urine output on POD 0 – 2. Dotted lines reflect the 95% confidence intervals. (JPEG 542 kb)

246_2022_3080_MOESM4_ESM.jpeg

Fig. S4 Receiver operator characteristics curve utilizing the combination of urine output (UOP) and percent change of CysC at 12 hrs (12 hr %CysC) to predict AKI. Abbreviation: AUC-Area Under the Curve (JPEG 248 kb)

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Abadeer, M., Swartz, M.F., Martin, S.D. et al. Using Serum Cystatin C to Predict Acute Kidney Injury Following Infant Cardiac Surgery. Pediatr Cardiol 44, 855–866 (2023). https://doi.org/10.1007/s00246-022-03080-y

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