The evolution of acute kidney injury (AKI) consensus criteria, culminating in the Kidney Disease Improving Global Outcomes (KDIGO) and neonatal KDIGO (nKDIGO) definitions (1–4) has meant that we are better able to identify and study this condition in pediatric cardiac disease. However, such case definition and knowledge about epidemiology has not had an impact on patient outcomes (5). Interventions that demonstrably alter the course of AKI are still lacking. In this Concise Clinical Science Review, we highlight the problem of cardiac surgery-associated AKI (CS-AKI) in the pediatric cardiac ICU (PCICU) and provide a context for future investigation that may yield innovations in our clinical approach to this syndrome.
EPIDEMIOLOGY AND FACTORS ASSOCIATED WITH CS-AKI
AKI is a spectrum wherein worse injury is associated with worse outcomes (6). Reports of incidence/prevalence of CS-AKI vary dramatically, in part due to center variability in surgical approaches, perfusion practices, case mix, changing surgical and PCICU management strategies over time, and inconsistent accounting for preoperative, surgical, and patient factors. The number of CS-AKI cases has increased as we have expanded the congenital lesions that are considered amenable to surgery (7). Even so, the nKDIGO definition, which takes into account the dynamic changes in renal function in early postnatal life, has yet to be widely applied in the neonatal cardiac population, contributing to a significant lag in our understanding of neonatal CS-AKI (8).
Accumulated data to date has produced a number of candidate “risk” or explanatory factors for CS-AKI (Fig. 1) (6,9–11). Going forward, iterative risk stratification tools incorporating both modifiable and nonmodifiable risk factors should be explored for their ability to favorably impact decisions on surgical planning and PCICU medical management.
Cardiac surgery (CS) and cardiopulmonary bypass (CPB) cause renal injury through many mechanisms (Fig. 2) (12–21). Once cellular respiration is impaired, particularly within the metabolically active renal tubular epithelial cells (RTECs), a cascade of events leads to cell death and compromises renal function. Postoperative cardiopulmonary dysfunction, cyanosis, reduced intravascular volume, and ongoing mechanical circulatory support can all perpetuate these stresses on renal perfusion and oxygen delivery.
Recovery from AKI is a multistep process, in which maladaptive repair may lead to incomplete healing and progression from AKI to chronic kidney disease (CKD) (Fig. 2) (14,15,22–26). Cell cycle arrest, identified as a marker of severe AKI, leads to early senescence, maladaptive repair, and development of renal fibrosis, suggesting an important role for surviving RTECs (23,24). Tubular regeneration is a highly energy-dependent process, and mitochondrial dysfunction, a prominent feature of AKI, leads to impaired renal recovery and progression to CKD if prolonged (14,15). Regeneration is characterized by transition to an anti-inflammatory state, and prolonged inflammation is implicated in nonrecovery of renal function and progression to CKD (25,26). Immunomodulators and therapies that improve mitochondrial function could enhance recovery from AKI. It is unknown if mechanisms of tubular regeneration differ between children and adults.
The ways in which AKI participates in organ crosstalk in PCICU patients is a fertile area of study. AKI is a systemic, pro-inflammatory condition with simultaneously impaired cytokine clearance (27). Bioaccumulation of uremic toxins in the lungs, with accompanying changes in expression of aquaporins and sodium channels in pulmonary epithelium, is implicated in impaired fluid handling and pulmonary edema (28,29). AKI is also associated with reduced expression of anti-oxidant genes in the lungs and a predisposition to lung injury from oxidative stress (30). Additionally, renal ischemia-reperfusion injury is associated with diastolic dysfunction and metabolomic changes in cardiac myocytes (31,32). Further elucidation of the molecular pathways involved in organ crosstalk is needed to stimulate the development of innovative therapies that mitigate the systemic effects of renal injury.
Many promising drugs have failed in CS-AKI trials, highlighting the challenges of AKI translational research in which animal models do not recapitulate the heterogeneous nature of AKI in humans. Recently, the Kidney Precision Medicine Project (KPMP) was launched to leverage the power of digital pathology, -omics technologies, and computational biology to analyze kidney biopsies from adult patients with AKI in order to identify pathways of injury and repair and facilitate the development of precision medicine (33). Unfortunately, pediatric patients are excluded, constituting a missed opportunity, but we should not leave it at that!
CLINICAL RISK ASSESSMENT TOOLS AND AKI BIOMARKERS
Anticipation of AKI risk, timely identification, and stratification of severity are vital steps in devising and implementing a targeted management strategy. Pragmatic clinical risk assessment tools, such as the Renal Angina Index and the Fluid Overload and Kidney Injury Score, have limited generalizability in the PCICU population: the AKI risk profile in congenital heart disease is different, and these algorithms do not consider the unique pathophysiology of CS-AKI. Additionally, both fluid overload and hemodilution after CPB artificially decrease serum creatinine, leading to under-diagnosis and down- or miss-staging of AKI (34). Oliguria may not be present due to prevalent diuretic use, and urine output (UOP) must be viewed through the lens of diuretic responsiveness and fluid balance. Impaired responsiveness to loop diuretics has been proposed as an early diagnostic marker of AKI and is a strong predictor of adverse outcomes in pediatric heart failure (35,36). Factors specific to cardiac pathophysiology should be incorporated into the designs of any future clinical risk assessment tool for the PCICU population.
A well-described limitation of the consensus AKI definitions is their reliance on serum creatinine. Creatinine is an index of kidney function rather than a marker of injury, and changes lag behind renal injury by about 24 hours. These limitations have driven the search for a “renal troponin,” leading to identification of several candidate early biomarkers. These have provided mechanistic insights into the pathophysiology of AKI in the areas: of iron metabolism, as in neutrophil gelatinase-associated lipocalin (NGAL); inflammation, as in interleukin-18; oxidative stress, as in human liver-type fatty acid-binding protein; and efferocytosis, as in kidney injury molecule-1 (37,38) However, the translational research investigating biomarker endpoints in AKI consortium study has failed to demonstrate sufficient accuracy to justify widespread clinical use (39).
Inclusion of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 in clinical risk assessment tools improves severe AKI prediction, and the assay (NephroCheck; Biomerieux, St. Louis, MO) is approved and validated as an early predictor of severe AKI in adults (23,40). Pediatric studies have found that these biomarkers rise 12 hours after CS and are predictive of AKI at the 24-hour time point, but measurements at earlier time points were not useful (41,42). A composite biomarker panel, such as with NGAL measured intraoperatively and NephroCheck measured at 12 hours, could be an attractive method for future interventional trials.
Angiotensinogen was first identified as a prognostic biomarker in the adult CS-AKI population, and it has since been validated as a biomarker of cardiorenal syndrome type 1 and as a predictor of AKI-to-CKD progression in adults (43–45). Urinary angiotensinogen correlates with serum renin concentration and is thought to reflect intrarenal renin-angiotensin system (RAS) activity (43). RAS antagonism ameliorates the severity of AKI in animal models (46,47), and measurements of plasma renin has prognostic value in a mixed population of critically ill adults (48), suggesting potential mechanistic and therapeutic links for future study.
PREVENTION AND THERAPY
The multicenter randomized trial of prevention of CS-AKI in adults demonstrated reduced frequency and severity of CS-AKI in high-risk patients with implementation of a “KDIGO bundle” of interventions, including: optimization of volume status and hemodynamics, avoidance of nephrotoxic drugs, and prevention of hyperglycemia (49). No such interventional trials exist in pediatric CS-AKI; a meta-analysis based on available observational data did not identify any effective candidate interventions (50). Electronic health record (EHR)-based systems for identification and prevention of nephrotoxin-associated AKI have not been evaluated in the PCICU population and presuppose that avoidance of the nephrotoxin is possible (51).
Strategies for perioperative AKI prevention include improved monitoring as well as trials of therapeutic agents. Intraoperative use of somatic (renal) near-infrared spectroscopy is an enhanced monitoring technique but correlates with other markers of severity of illness or hemodynamic instability (52). Trials of targeted intraoperative modification to improve systemic oxygen delivery and end-organ protection do not exist. Intraoperative aminophylline may increase UOP in the early postoperative period and reduce the need for kidney replacement therapy (KRT) in comparison to furosemide use (53). Intraoperative and postoperative nitric oxide (NO) in high-risk adult CS patients improved both AKI incidence and long-term renal outcomes (54); the ongoing NO during CPB to improve recovery in infants with congenital heart defects randomized controlled trial will assess the impact of entraining NO into the oxygenator during CPB, with the subsequent need for and duration of KRT included among planned secondary analyses (55). Early postoperative acetaminophen exposure demonstrated significantly reduced odds of AKI with optimized per-kilogram acetaminophen dosing in the first 48 hours of surgery (56). Further study of these and other preventive perioperative therapies is needed.
In patients who develop AKI despite our best efforts, the struggle to identify who will go on to develop severe AKI and who would benefit most from continuous KRT highlights the need for improved tools to assess renal reserve as well as the presence and rate of renal recovery. The furosemide stress test (FST) is a pragmatic instrument that fits well into the standard practices and clinical experience within the PCICU. The FST calls for a standardized-dose diuretic challenge with UOP responsiveness assessed at 2 and 6 hours. Lack of responsiveness is a good predictor of subsequent AKI, and responsiveness has strong negative predictive value for subsequent AKI in pediatric CS patients (57–59). Additional studies are needed, including prospective validation of FST and interpretation of diuretic responsiveness with continuous diuretic infusions in the PCICU population. The utility of recovery/repair biomarkers in predicting progressive AKI also requires further exploration (60). Similarly, the follow-up renal assessment of injury long-term after AKI study postulates that long-term follow-up of biomarkers may be helpful in identifying CKD risk (61).
Repeat AKI and loss of renal reserve is recognized in vulnerable populations such as staged single ventricle palliations, and severe AKI after the Norwood operation is a risk factor for severe AKI and longer duration of mechanical ventilation after subsequent stages as well as for chronic hypertension (62–64). Yet even in neonatal CS patients, who experience the highest rates of severe AKI, renal follow-up is incomplete or absent (65,66). Repeat episodes of severe CS-AKI are associated with lower cognitive, motor, and language scores in long-term follow-up (67). Further examination of global functional outcomes as well as longitudinal follow-up of renal function should be incorporated into the framework of successful cardiac programs.
AKI in critically ill pediatric patients with cardiac disease continues to pose a major challenge for clinicians. The seminal work to establish consensus definitions for AKI and neonatal AKI and to increase awareness of AKI risk factors and the potential utility of biomarkers has been foundational in the field, setting the stage for new approaches to clinical care. To ultimately realize our goal of improving outcomes, we suggest the following priorities (Fig. 3): 1) iterative risk stratification and clinical assessment tools geared toward pediatric cardiac patients, including those with cyanosis and those with decreased renal reserve (such as a history of prior AKI episodes); 2) preoperative and intraoperative risk mitigation strategies; 3) efforts by the pediatric cardiac and nephrology scientific communities to capitalize on the KPMP as a clarion call to collaborate on a similar effort to bring precision medicine to our patients; 4) delineation of the roles of the FST, diuretic escalation, and biomarker-guided goal-driven KRT in post-surgical and medical cardiac patients in whom fluid removal is required to improve cardiac performance and to allow for necessary steps in recovery such as delayed sternal closure; 5) basic science and translational research on the mechanisms of organ crosstalk, both acutely and chronically, building upon the cardiorenal syndromes; 6) the role of implementation science in removing barriers to seemingly straightforward interventions such as utilization of the KDIGO bundle and effective EHR alert systems; 7) leveraging existing collaborative efforts across PCICU centers to identify and implement best practices that impact key renal and clinical outcomes; and 8) discovery and utilization of biomarkers of renal repair and recovery that may guide decisions about risk assessment, KRT timing and use, and post-AKI follow-up care.
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