In this multicenter study of children undergoing cardiac surgery, higher CysC concentrations obtained within the first 6 h of surgery strongly predicted stage 2 (more severe) AKI development in the subsequent days, as well as longer duration of mechanical ventilation and longer length of stay. We found that preoperative CysC did not predict the development of postoperative AKI. However, higher pre-operative eGFR and percent SCr change in the first 6 h after surgery predicted the development of postoperative stage 1 (or mild) AKI. This is the first study to directly compare two markers of GFR, SCr and CysC, for early prediction of AKI in children.
Preoperative CysC concentrations were not associated with development of postoperative AKI, when adjusted for other clinical factors, such as cardiopulmonary bypass time, demographics, and surgical severity score. Interestingly, we found that higher and not lower preoperative eGFR was associated with the development of AKI, even when we meticulously adjusted for age-associated differences in GFR by deriving GFR percentile values and adjusting for age in multivariate analyses. These two findings appear to refute our underlying hypothesis that preoperative CKD is a risk factor for AKI, as has been suggested by adult studies11
and in one study of AKI in children treated with aminoglycosides.17
A potential explanation is that children who are malnourished with lower muscle mass and consequently lower SCr concentrations (resulting in higher eGFR), are at increased risk for AKI development. This highlights the limitations of using SCr for GFR estimations. However, it is also possible that because few subjects had preoperative CKD, we may not have been able to detect a CKD–AKI association. Another possible confounding factor is that the Schwartz formula, which was derived from children greater than 2 years of age with established CKD,18
overestimates GFR, particularly in infants or children with fairly preserved renal function. This is supported by the fact that the median preoperative eGFR percentile value for children under 2 years old was the 81st percentile, compared with the 41st percentile in older children (shown in , for children less than 2 years old), suggesting that eGFR is overestimated in younger children. We did not estimate GFR using published CysC equations, as none of them have been validated in infants. These results provide a serendipitous indicator that future studies should attempt to derive equations from SCr and CysC specific to younger children, as well as to children with GFR approaching the normal range, which may help better identify mild CKD as a risk factor for postoperative AKI. Finally, it is possible that the use of a SCr-based AKI definition is an imperfect, yet only available, reference standard, which is currently a challenge for all AKI studies.
From our previous work, we discovered that almost all postoperative cardiac surgery-associated AKI occurs within the first 3 days after surgery.3
Therefore, AKI therapeutic trials in this population will need to provide an intervention as early as possible during or after surgery. We found that postoperative serum CysC concentrations in the 5th quintile (>1.01 mg/dl), obtained very early after surgery, independently predicted development of stage 2 AKI. The cut-point of 1.16 mg/dl from a recent single-centre study was strongly associated with AKI severity.16
Thus, early postoperative CysC may be helpful for future clinical trials aimed at reducing the incidence of SCr doubling and dialysis need or other clinical outcomes such as duration of ventilation. We also found that clinical variables that are easily determinable immediately after surgery provided fairly good prediction of postoperative AKI development. It is likely that using a combination of clinical and early postoperative biomarker data will provide the best method for determining eligibility into future AKI clinical trials in children undergoing cardiac surgery, to optimize sensitivity and specificity.
Although we have demonstrated that CysC may have a role in early stage 2 AKI identification for trials, it is still unclear to what extent CysC should be used in clinical care. CysC currently costs significantly more to measure than SCr does, though cost will hopefully become less of a hindrance in time. Second, as we currently do not have specific treatments for AKI in children, whether or not incorporating CysC into clinical care will improve outcome will remain unknown until trials are performed. Therefore, we propose that future AKI clinical trials should incorporate measurement of CysC and cost analyses as outcomes. Trials examining currently available measures of managing AKI (such as early dialysis initiation or early goal-directed fluid management) should examine if knowledge of early postoperative CysC concentrations would lead to changes in outcomes such as duration of mechanical ventilation or management of fluid balance and oxygenation. The results of our study justify thorough evaluations of incorporating CysC into clinical care of this population.
Our study had several unique strengths. This is the first multicenter study of AKI and new AKI biomarkers in children, and to our knowledge the first study to examine specifically the role of preoperative renal function for AKI prediction in children. Because the timing of the most likely renal injurious event was known (cardiopulmonary bypass surgery), we were able to identify a clinically reproducible time point on which to evaluate CysC for early AKI prediction. Our use of eGFR percentiles for expressing preoperative renal function is novel and likely more valid for expressing renal function in younger children who are known to have an expected age- and development-associated lower raw eGFR value compared with older children. Another strength was our careful exclusion of subjects who already had clear evidence of AKI immediately postoperatively, when evaluating the ability of CysC to truly predict AKI earlier than SCr can. We evaluated doubling of SCr or need for dialysis (stage 2 AKI) as one of our primary outcomes. Thus, our findings will be useful for future clinical trials for AKI, which are likely to use a similar clinically meaningful outcome.
A limitation of this study was the somewhat restricted sample size, which did not allow us to adequately evaluate for effect modification and led to poor precision around some estimates, with wide CIs. Although the low prevalence of significant preoperative CKD was a limitation in being able to assess the CKD–AKI relation, our finding that few children having complex heart surgery have baseline CKD was important to demonstrate for future studies and understanding this population. Our study was limited to children undergoing cardiac surgery; therefore, the findings may not be immediately generalizable to all other hospitalized children and similarly rigorous studies in other non-cardiac pediatric populations are warranted.
In conclusion, the use of clinical risk factors may have an important role in predicting postoperative AKI in children who have had cardiac surgery. Early postoperative CysC is a useful marker to predict development of AKI but preoperative CysC does not contribute significantly. More research is required to better understand how to estimate preoperative renal function in young children and in children with GFR in the normal to mildly low range.