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Online Concise Clinical Science Review

Acute Kidney Injury After Pediatric Cardiac Surgery

Neumayr, Tara M. MD1; Alge, Joseph L. MD2; Afonso, Natasha S. MD, MPH3; Akcan-Arikan, Ayse MD2,3

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Pediatric Critical Care Medicine: May 2022 - Volume 23 - Issue 5 - p e249-e256
doi: 10.1097/PCC.0000000000002933
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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.

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Figure 1.:
Risk factors for cardiac surgery-associated acute kidney injury (AKI). Children in the pediatric cardiac ICU are at high risk of developing AKI due to the confluence of preoperative, intraoperative, and postoperative factors. Prior to undergoing surgery, patients are subject to a number of renal insults, and many patients have decreased renal reserve due to age, congenital or genetic factors, or prior history of AKI. Renal injury during pediatric cardiac surgery and cardiopulmonary bypass is mediated by aortic cross-clamping, circulatory arrest, hemodilution, altered blood flow dynamics, hemolysis, inflammation, oxidative stress, and resulting microvascular endothelial dysfunction. Ongoing renal insults in the postoperative phase, including cardiac dysfunction, hypoxemia, and intravascular volume depletion, can further contribute to renal injury and compromise renal recovery. Nephrotoxin exposure can add to risk throughout the perioperative course.

PATHOGENESIS

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.

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Figure 2.:
Mechanisms of renal injury and recovery in acute kidney injury (AKI). Renal outcomes after AKI are driven by repair mechanisms that lead to recovery of function in damaged tissues alongside maladaptive processes that perpetuate injury. (1) Surviving renal tubular epithelial cells dedifferentiate and undergo partial epithelial-to-mesenchymal transition, acquiring a proliferative, migratory, and phagocytic phenotype. Kidney injury molecule-1 (KIM-1) plays an important “clean up” role, enhancing phagocytic clearance of apoptotic debris. Renal progenitor cells may also take part in regeneration of tubular epithelium. (2a) Microvascular endothelial dysfunction in AKI further impairs renal perfusion. (2b) Mitochondrial dysfunction leads to oxidative stress and increased apoptosis, while the release of damage-associated molecular patterns (2c) activates an inflammatory cascade with activation of resident macrophages and tissue infiltration by neutrophils and lymphocytes. In contrast, maladaptive repair, including nonresolution of inflammation and prolonged mitochondrial dysfunction, can lead to (3) cellular senescence and (4) myofibroblast transformation, ultimately culminating in renal fibrosis and chronic kidney disease (CKD).

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.

CONCLUSIONS

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.

F3
Figure 3.:
Priorities for future investigation for acute kidney injury in the pediatric cardiac ICU. FST = furosemide stress test, KPMP = Kidney Precision Medicine Project, KRT = kidney replacement therapy.

REFERENCES

1. Kellum JA, Lameire N, Aspelin P, et al.: Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012; 2:1–138
2. Selewski DT, Cornell TT, Heung M, et al.: Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population. Intensive Care Med. 2014; 40:1481–1488
3. Selewski DT, Charlton JR, Jetton JG, et al.: Neonatal acute kidney injury. Pediatrics. 2015; 136:e463–e473
4. Zappitelli M, Ambalavanan N, Askenazi DJ, et al.: Developing a neonatal acute kidney injury research definition: A report from the NIDDK neonatal AKI workshop. Pediatr Res. 2017; 82:569–573
5. Kwiatkowski DM, Krawczeski CD: Acute kidney injury and fluid overload in infants and children after cardiac surgery. Pediatr Nephrol. 2017; 32:1509–1517
6. Zappitelli M, Bernier PL, Saczkowski RS, et al.: A small post-operative rise in serum creatinine predicts acute kidney injury in children undergoing cardiac surgery. Kidney Int. 2009; 76:885–892
7. Jefferies JL, Devarajan P: Early detection of acute kidney injury after pediatric cardiac surgery. Prog Pediatr Cardiol. 2016; 41:9–16
8. Ueno K, Shiokawa N, Takahashi Y, et al.: Kidney disease: Improving global outcomes in neonates with acute kidney injury after cardiac surgery. Clin Exp Nephrol. 2020; 24:167–173
9. Sethi SK, Goyal D, Yadav DK, et al.: Predictors of acute kidney injury post-cardiopulmonary bypass in children. Clin Exp Nephrol. 2011; 15:529–534
10. Alabbas A, Campbell A, Skippen P, et al.: Epidemiology of cardiac surgery-associated acute kidney injury in neonates: A retrospective study. Pediatr Nephrol. 2013; 28:1127–1134
11. Park SK, Hur M, Kim E, et al.: Risk factors for acute kidney injury after congenital cardiac surgery in infants and children: A retrospective observational study. PLoS One. 2016; 11:e0166328
12. Thiele RH, Isbell JM, Rosner MH: AKI associated with cardiac surgery. Clin J Am Soc Nephrol. 2015; 10:500–514
13. Squiccimarro E, Labriola C, Malvindi PG, et al.: Prevalence and clinical impact of systemic inflammatory reaction after cardiac surgery. J Cardiothorac Vasc Anesth. 2019; 33:1682–1690
14. Jiang M, Bai M, Lei J, et al.: Mitochondrial dysfunction and the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2020; 319:F1105–F1116
15. Tang C, Cai J, Yin XM, et al.: Mitochondrial quality control in kidney injury and repair. Nat Rev Nephrol. 2021; 17:299–318
16. Sato Y, Yanagita M: Immune cells and inflammation in AKI to CKD progression. Am J Physiol Renal Physiol. 2018; 315:F1501–F1512
17. Webb TN, Goldstein SL: Congenital heart surgery and acute kidney injury. Curr Opin Anaesthesiol. 2017; 30:105–112
18. Ranucci M, Aloisio T, Carboni G, et al.; Surgical and Clinical Outcome REsearch (SCORE) Group: Acute kidney injury and hemodilution during cardiopulmonary bypass: A changing scenario. Ann Thorac Surg. 2015; 100:95–100
19. Qureshi SH, Patel NN, Murphy GJ: Vascular endothelial cell changes in postcardiac surgery acute kidney injury. Am J Physiol Renal Physiol. 2018; 314:F726–F735
20. Lankadeva YR, Cochrane AD, Marino B, et al.: Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury. Kidney Int. 2019; 95:1338–1346
21. Evans RG, Iguchi N, Cochrane AD, et al.: Renal hemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep under total intravenous anesthesia. Am J Physiol Regul Integr Comp Physiol. 2020; 318:R206–R213
22. Little MH, Kairath P: Does renal repair recapitulate kidney development? J Am Soc Nephrol. 2017; 28:34–46
23. Kashani K, Al-Khafaji A, Ardiles T, et al.: Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013; 17:R25
24. Yang L, Besschetnova TY, Brooks CR, et al.: Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010; 16:535–543, 1p following 143
25. Black LM, Lever JM, Agarwal A: Renal inflammation and fibrosis: A double-edged sword. J Histochem Cytochem. 2019; 67:663–681
26. Jang HR, Rabb H: Immune cells in experimental acute kidney injury. Nat Rev Nephrol. 2015; 11:88–101
27. Andres-Hernando A, Dursun B, Altmann C, et al.: Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy. Nephrol Dial Transplant. 2012; 27:4339–4347
28. Yabuuchi N, Sagata M, Saigo C, et al.: Indoxyl sulfate as a mediator involved in dysregulation of pulmonary aquaporin-5 in acute lung injury caused by acute kidney injury. Int J Mol Sci. 2017; 18:1–9
29. Rabb H, Wang Z, Nemoto T, et al.: Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int. 2003; 63:600–606
30. Ravikumar P, Li L, Ye J, et al.: αKlotho deficiency in acute kidney injury contributes to lung damage. J Appl Physiol (1985). 2016; 120:723–732
31. Fox BM, Gil HW, Kirkbride-Romeo L, et al.: Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice. Kidney Int. 2019; 95:590–610
32. Soranno DE, Kirkbride-Romeo L, Wennersten SA, et al.: Acute kidney injury results in long-term diastolic dysfunction that is prevented by histone deacetylase inhibition. JACC Basic Transl Sci. 2021; 6:119–133
33. de Boer IH, Alpers CE, Azeloglu EU, et al.; Kidney Precision Medicine Project: Rationale and design of the Kidney Precision Medicine Project. Kidney Int. 2021; 99:498–510
34. Svensson AS, Kvitting JP, Kovesdy CP, et al.: Changes in serum cystatin C, creatinine, and C-reactive protein after cardiopulmonary bypass in patients with normal preoperative kidney function. Nephrology (Carlton). 2016; 21:519–525
35. Chawla LS, Davison DL, Brasha-Mitchell E, et al.: Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care. 2013; 17:8–10
36. Price JF, Younan S, Cabrera AG, et al.: Diuretic responsiveness and its prognostic significance in children with heart failure. J Card Fail. 2019; 25:941–947
37. Alge JL, Arthur JM: Biomarkers of AKI: A review of mechanistic relevance and potential therapeutic implications. Clin J Am Soc Nephrol. 2015; 10:147–155
38. Charlton JR, Portilla D, Okusa MD: A basic science view of acute kidney injury biomarkers. Nephrol Dial Transplant. 2014; 29:1301–1311
39. Parikh CR, Thiessen-Philbrook H, Garg AX, et al.; TRIBE-AKI Consortium: Performance of kidney injury molecule-1 and liver fatty acid-binding protein and combined biomarkers of AKI after cardiac surgery. Clin J Am Soc Nephrol. 2013; 8:1079–1088
40. Jia HM, Huang LF, Zheng Y, et al.: Diagnostic value of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 for acute kidney injury: A meta-analysis. Crit Care. 2017; 21:77
41. Gist KM, Goldstein SL, Wrona J, et al.: Kinetics of the cell cycle arrest biomarkers (TIMP-2*IGFBP-7) for prediction of acute kidney injury in infants after cardiac surgery. Pediatr Nephrol. 2017; 32:1611–1619
42. Bojan M, Pieroni L, Semeraro M, et al.: Cell-cycle arrest biomarkers: Usefulness for cardiac surgery-related acute kidney injury in neonates and infants. Pediatr Crit Care Med. 2020; 21:563–570
43. Alge JL, Karakala N, Neely BA, et al.; SAKInet Investigators: Urinary angiotensinogen and risk of severe AKI. Clin J Am Soc Nephrol. 2013; 8:184–193
44. Chen C, Yang X, Lei Y, et al.: Urinary biomarkers at the time of AKI diagnosis as predictors of progression of AKI among patients with acute cardiorenal syndrome. Clin J Am Soc Nephrol. 2016; 11:1536–1544
45. Cui S, Wu L, Feng X, et al.: Urinary angiotensinogen predicts progressive chronic kidney disease after an episode of experimental acute kidney injury. Clin Sci (Lond). 2018; 132:2121–2133
46. Efrati S, Berman S, Hamad RA, et al.: Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury. Nephrol Dial Transplant. 2012; 27:136–145
47. Wang Z, Liu Y, Han Y, et al.: Protective effects of aliskiren on ischemia-reperfusion-induced renal injury in rats. Eur J Pharmacol. 2013; 718:160–166
48. Gleeson PJ, Crippa IA, Mongkolpun W, et al.: Renin as a marker of tissue-perfusion and prognosis in critically ill patients. Crit Care Med. 2019; 47:152–158
49. Meersch M, Schmidt C, Hoffmeier A, et al.: Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: The PrevAKI randomized controlled trial. Intensive Care Med. 2017; 43:1551–1561
50. Bellos I, Iliopoulos DC, Perrea DN: Pharmacological interventions for the prevention of acute kidney injury after pediatric cardiac surgery: A network meta-analysis. Clin Exp Nephrol. 2019; 23:782–791
51. Goldstein SL, Dahale D, Kirkendall ES, et al.: A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children. Kidney Int. 2020; 97:580–588
52. Adams PS, Vargas D, Baust T, et al.: Associations of perioperative renal oximetry via near-infrared spectroscopy, urinary biomarkers, and postoperative acute kidney injury in infants after congenital heart surgery: Should creatinine continue to be the gold standard? Pediatr Crit Care Med. 2019; 20:27–37
53. Onder AM, Rosen D, Mullett C, et al.: Comparison of intraoperative aminophylline versus furosemide in treatment of oliguria during pediatric cardiac surgery. Pediatr Crit Care Med. 2016; 17:753–763
54. Lei C, Berra L, Rezoagli E, et al.: Nitric oxide decreases acute kidney injury and stage 3 chronic kidney disease after cardiac surgery. Am J Respir Crit Care Med. 2018; 198:1279–1287
55. Schlapbach LJ, Horton SB, Long DA, et al.; NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), the Paediatric Critical Care Research group (PCCRG) and the ANZICS Paediatric Study Group (PSG): Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): A randomised controlled trial. BMJ Open. 2019; 9:e026664
56. Van Driest SL, Jooste EH, Shi Y, et al.: Association between early postoperative acetaminophen exposure and acute kidney injury in pediatric patients undergoing cardiac surgery. JAMA Pediatr. 2018; 172:655–663
57. Kakajiwala A, Kim JY, Hughes JZ, et al.: Lack of furosemide responsiveness predicts acute kidney injury in infants after cardiac surgery. Ann Thorac Surg. 2017; 104:1388–1394
58. Borasino S, Wall KM, Crawford JH, et al.: Furosemide response predicts acute kidney injury after cardiac surgery in infants and neonates. Pediatr Crit Care Med. 2018; 19:310–317
59. Penk J, Gist KM, Wald EL, et al.: Furosemide response predicts acute kidney injury in children after cardiac surgery. J Thorac Cardiovasc Surg. 2019; 157:2444–2451
60. Puthumana J, Thiessen-Philbrook H, Xu L, et al.: Biomarkers of inflammation and repair in kidney disease progression. J Clin Invest. 2021; 131:139927
61. Cooper DS, Claes D, Goldstein SL, et al.: Follow-up renal assessment of injury long-term after acute kidney injury (FRAIL-AKI). Clin J Am Soc Nephrol. 2016; 11:21–29
62. Wong JH, Selewski DT, Yu S, et al.: Severe acute kidney injury following stage 1 Norwood palliation: Effect on outcomes and risk of severe acute kidney injury at subsequent surgical stages. Pediatr Crit Care Med. 2016; 17:615–623
63. Hasson DC, Brinton JT, Cowherd E, et al.: Risk factors for recurrent acute kidney injury in children who undergo multiple cardiac surgeries: A retrospective analysis. Pediatr Crit Care Med. 2019; 20:614–620
64. Greenberg JH, McArthur E, Thiessen-Philbrook H, et al.: Long-term risk of hypertension after surgical repair of congenital heart disease in children. JAMA Netw Open. 2021; 4:e215237
65. Rodriguez-Lopez S, Huynh L, Benisty K, et al.: Paucity of renal follow-up by school age after neonatal cardiac surgery. Cardiol Young. 2020; 30:822–828
66. Huynh L, Rodriguez-Lopez S, Benisty K, et al.: Follow-up after neonatal heart disease repair: Watch out for chronic kidney disease and hypertension! Pediatr Nephrol. 2020; 35:2137–2145
67. Pande C, Noll L, Serrano F, et al.: Association of acute kidney injury with neurodevelopmental outcomes in infants undergoing surgery for congenital heart disease. J Am Coll Cardiol. 2020; 75:631
Keywords:

acute kidney injury; cardiac surgery; cardiopulmonary bypass; children

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