Author + information
- †Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Texas
- ‡The Heart Hospital, Plano, Texas
- ↵∗Reprint requests and correspondence:
Dr. Peter A. McCullough, Baylor Heart and Vascular Institute, 621 North Hall Street, H030, Dallas, Texas 75226.
Cardiac surgery in children has markedly advanced and is a mainstay for the treatment of serious congenital cardiac malformations. Because the heart, great vessels, and total blood volume are much smaller in children than in adults, the cardiopulmonary bypass procedure is challenging with respect to maintaining organ perfusion during cardiac surgery. Most pediatric surgeries involves cross-clamping major vessels, greater degrees of vascular repair, and operations that, overall, are more complicated than common coronary artery bypass graft surgeries in adults. Another major difference between cardiac surgeries in children and those in adults is that children undergoing cardiac surgery are largely free of diabetes and hypertension and, thus, have normal renal function and a full complement of functioning nephrons capable of dramatically up-regulating response and repair proteins after injury. Thus, children undergoing cardiac surgery and cardiopulmonary bypass are ideal for the study of ischemia and reperfusion injury (cardiac surgery-associated acute kidney injury [CSA-AKI]) to the normal human kidney (1).
In this issue of the Journal, Basu et al. (2) report the proteomic signals that are measurable in urine from 345 children who underwent cardiac surgery. Of note, children who developed AKI had much longer (42% greater) periods of cardiopulmonary bypass (135 vs. 95 min) than those who did not. Using a different but established serum marker of renal filtration, cystatin-C, and a urinary biomarker, neutrophil gelatinase-associated lipocalin (NGAL), which is both constitutively and inducibly produced in the distal nephron, the investigators were better able to detect AKI (3). NGAL is a siderophore that works to mop up unbound iron, which is released in low levels during autophagy and normal cellular housekeeping and in much larger quantities in the setting of AKI. Thus, the release of unbound catalytic iron due to hemolysis in cardiopulmonary bypass and from renal tubular cells in AKI results in rapid up-regulation of NGAL, which can be easily measured in the urine (4). As shown in Figure 1, Basu et al. (2) demonstrated that AKI, defined by the Kidney Disease Global Outcomes Initiative (KDIGO) as a more severe and sustained rise in serum creatinine and reduction in urine output, is more readily anticipated by use of a composite of plasma cystatin-C (to indicate changes in renal filtration) and urine NGAL (to indicate renal tubular epithelial cell response to injury) (5).
Because transient changes in serum creatinine and urine output are common in children after coming off cardiopulmonary bypass, there is a great need for increased specificity for AKI in order to anticipate the postoperative course. If this new approach indicates AKI before elevation of serum creatinine, instead of the usual postoperative care pathway, avoidance of nephrotoxins, alerts for renal drug dosing, close hemodynamic monitoring, and nephrology consultation would all come into play. Although plasma and urine NGAL are commercially available in Europe, and another urine AKI marker, L-type fatty acid-binding protein, is available in Japan, we await the commercial availability of the first U.S. Food and Drug Administration-approved urine AKI assay (cell cycle arrest proteins, insulin growth factor-binding protein-7x tissue inhibitor of metalloproteinase-2) (6). Deployment of this novel detection approach for CSA-AKI in children and probably also in adults holds great promise, not only for changes in clinical care but for development of improved forms of cardiopulmonary bypass, which may include therapeutic aspects of ultrafiltration or modification of plasma (free iron removal, cytokine modulation, and others) (7). Although we believe that cardiopulmonary bypass for children undergoing cardiac surgery will continue to be used in most cases, the implementation of novel biomarkers represents a clear improvement on the decades-old approach of serum creatinine monitoring and hopefully will be an important developmental step toward the future prevention and treatment of CSA-AKI.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation