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Biomarkers of acute kidney injury after pediatric cardiac surgery: a meta-analysis of diagnostic test accuracy

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Abstract

Acute kidney injury (AKI) occurs frequently after cardiac surgery in children. Although current diagnostic criteria rely on serum creatinine and urine output, changes occur only after considerable loss of kidney function. This meta-analysis aimed to synthesize the knowledge on novel biomarkers and compare their ability to predict AKI. PubMed/MEDLINE, Embase, Scopus, and reference lists were searched for relevant studies published by March 2021. Diagnostic accuracy parameters were extracted and analyzed using hierarchical summary receiver operating characteristic (HSROC) method. Pooled estimates of the area under the curve (AUC) were calculated using conventional random-effects meta-analysis. Fifty-six articles investigating 49 biomarkers in 8617 participants fulfilled our eligibility criteria. Data from 37 studies were available for meta-analysis. Of the 10 biomarkers suitable for HSROC analysis, urinary neutrophil gelatinase-associated lipocalin (uNGAL) to creatinine (Cr) ratio yielded the highest diagnostic odds ratio (91.0, 95% CI 90.1–91.9), with a sensitivity of 91.3% (95% CI 91.2–91.3%) and a specificity of 89.7% (95% CI 89.6–89.7%). These results were confirmed in pooled AUC analysis, as uNGAL-to-Cr ratio and uNGAL were the only elaborately studied biomarkers (> 5 observations) with pooled AUCs ≥ 0.800. Liver fatty acid-binding protein (L-FABP), serum cystatin C (sCysC), serum NGAL (sNGAL), and interleukin-18 (IL-18) all had AUCs ≥ 0.700.

Conclusion: A variety of biomarkers have been proposed as predictors of cardiac surgery-associated AKI in children, of which uNGAL was the most prominent with excellent diagnostic qualities. However, more consolidatory evidence will be required before these novel biomarkers may eventually help realize precision medicine in AKI management.

What is Known:

• Acute kidney injury (AKI) occurs in about 30–60% of children undergoing cardiac surgery and is associated with increased in-hospital mortality and adverse short-term outcomes. However, in current clinical practice, AKI definitions and detection often rely on changes in serum creatinine and urine output, which are late and insensitive markers of kidney injury.

• Although various novel biomarkers have been studied for the diagnosis of AKI in children after cardiac surgery, it remains unclear how these compare to one another in terms of diagnostic accuracy.

What is New:

• Pooled analyses suggest that for the diagnosis of AKI in children who underwent cardiac surgery, NGAL is the most accurate among the most frequently studied biomarkers.

• A number of other promising biomarkers have been reported, although they will require further research into their diagnostic accuracy and clinical applicability.

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Abbreviations

AKI:

Acute kidney injury

AKIN:

Acute Kidney Injury Network

AUC:

Area under the curve

CI:

Confidence interval

CPB:

Cardiopulmonary bypass

CysC:

Cystatin C

DOR:

Diagnostic odds ratio

FP:

False positives

FN:

False negatives

H-FABP:

Heart-type fatty acid-binding protein

HSROC:

Hierarchical summary receiver operating characteristic curve

HVA-SO4:

Homovanillic acid sulfate

IGFBP7:

Insulin-like growth factor-binding protein 7

IL-6:

Interleukin 6

IL-8:

Interleukin 18

KDIGO:

Kidney Disease Improving Global Outcomes

KIM-1:

Kidney injury molecule-1

KIU:

Kallikrein inhibiting units

L-FABP:

Liver fatty acid-binding protein

LR:

Likelihood ratio

MOOSE:

Meta-analysis Of Observational Studies in Epidemiology

NGAL:

Neutrophil gelatinase-associated lipocalin

NPV:

Negative predictive value

PPV:

Positive predictive value

PRISMA:

Preferred Reporting Items for Systematic reviews and Meta-Analyses

RIFLE:

Risk for renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage renal disease

SCr:

Serum creatinine

TIMP-2:

Tissue inhibitor of metalloproteinase 2

TP:

True positives

TN:

True negatives

UMOD:

Uromodulin

References

  1. Hoste EAJ, Kellum JA, Selby NM et al (2018) Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol 14:607–625

    Article  CAS  Google Scholar 

  2. Van den Eynde J, Delpire B, Jacquemyn X et al (2021) Risk factors for acute kidney injury after pediatric cardiac surgery: a meta-analysis. Pediatr Nephrol 1:1–11. https://doi.org/10.1007/S00467-021-05297-0/FIGURES/2

    Article  Google Scholar 

  3. Li S, Krawczeski CD, Zappitelli M et al (2011) Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery: a prospective multicenter study. Crit Care Med 39:1493–1499. https://doi.org/10.1097/CCM.0b013e31821201d3

    Article  PubMed  PubMed Central  Google Scholar 

  4. Blinder JJ, Goldstein SL, Lee V-V et al (2012) Congenital heart surgery in infants: Effects of acute kidney injury on outcomes. J Thorac Cardiovasc Surg 143:368–374. https://doi.org/10.1016/j.jtcvs.2011.06.021

    Article  PubMed  Google Scholar 

  5. Van den Eynde J, Rotbi H, Gewillig M et al (2021) In-hospital outcomes of acute kidney injury after pediatric cardiac surgery: a meta-analysis. Front Pediatr 9:941. https://doi.org/10.3389/FPED.2021.733744/BIBTEX

    Article  Google Scholar 

  6. Uchino S, Kellum JA, Bellomo R et al (2005) Acute renal failure in critically ill patients: a multinational, multicenter study. J Am Med Assoc 294:813–818. https://doi.org/10.1001/jama.294.7.813

    Article  CAS  Google Scholar 

  7. Singbartl K, Kellum JA (2012) AKI in the ICU: definition, epidemiology, risk stratification, and outcomes. Kidney Int 81:819–825. https://doi.org/10.1038/ki.2011.339

    Article  CAS  PubMed  Google Scholar 

  8. Kellum JA, Levin N, Bouman C, Lameire N (2002) Developing a consensus classification system for acute renal failure. In: Current Opinion in Critical Care. Curr Opin Crit Care, pp 509–514

  9. Bellomo R, Ronco C, Kellum JA et al (2004) Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. In: Critical care (London, England). BioMed Central, p R204

  10. Akcan-Arikan A, Zappitelli M, Loftis LL et al (2007) Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 71:1028–1035. https://doi.org/10.1038/sj.ki.5002231

    Article  CAS  PubMed  Google Scholar 

  11. Mehta RL, Kellum JA, Shah SV et al (2007) Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31. https://doi.org/10.1186/cc5713

    Article  PubMed  PubMed Central  Google Scholar 

  12. Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron 120:c179–c184. https://doi.org/10.1159/000339789

    Article  PubMed  Google Scholar 

  13. Mårtensson J, Martling CR, Bell M (2012) Novel biomarkers of acute kidney injury and failure: Clinical applicability. Br J Anaesth 109:843–850

    Article  Google Scholar 

  14. Coca SG, Yalavarthy R, Concato J, Parikh CR (2008) Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 73:1008–1016

    Article  CAS  Google Scholar 

  15. Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372

  16. Arends LR, Hamza TH, Van Houwelingen JC et al (2008) Bivariate random effects meta-analysis of ROC curves. Med Decis Mak 28:621–638. https://doi.org/10.1177/0272989X08319957

    Article  CAS  Google Scholar 

  17. Rutter CM, Gatsonis CA (2001) A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations. Stat Med 20:2865–2884. https://doi.org/10.1002/sim.942

    Article  CAS  PubMed  Google Scholar 

  18. DerSimonian R, Kacker R (2007) Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 28:105–114. https://doi.org/10.1016/j.cct.2006.04.004

    Article  PubMed  Google Scholar 

  19. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. Br Med J 327:557–560

    Article  Google Scholar 

  20. Brennan KG, Parravicini E, Lorenz JM, Bateman DA (2020) Patterns of urinary neutrophil gelatinase-associated lipocalin and acute kidney injury in neonates receiving cardiopulmonary bypass. Children 7:132. https://doi.org/10.3390/children7090132

    Article  PubMed Central  Google Scholar 

  21. Ricci Z, Netto R, Garisto C et al (2012) Whole blood assessment of neutrophil gelatinase-associated lipocalin versus pediatricRIFLE for acute kidney injury diagnosis and prognosis after pediatric cardiac surgery: cross-sectional study. Pediatr Crit Care Med 13:667–670. https://doi.org/10.1097/PCC.0b013e3182601167

    Article  PubMed  Google Scholar 

  22. Hazle MA, Gajarski RJ, Aiyagari R et al (2013) Urinary biomarkers and renal near-infrared spectroscopy predict intensive care unit outcomes after cardiac surgery in infants younger than 6 months of age. J Thorac Cardiovasc Surg 146:861-867.e1. https://doi.org/10.1016/j.jtcvs.2012.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gist KM, Cooper DS, Wrona J et al (2018) Acute kidney injury biomarkers predict an increase in serum milrinone concentration earlier than serum creatinine-defined acute kidney injury in infants after cardiac surgery. Ther Drug Monit 40:186–194. https://doi.org/10.1097/FTD.0000000000000496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bojan M, Vicca S, Lopez-Lopez V et al (2014) Predictive performance of urine neutrophil gelatinase- associated lipocalin for dialysis requirement and death following cardiac surgery in neonates and infants. Clin J Am Soc Nephrol 9:285–294. https://doi.org/10.2215/CJN.04730513

    Article  PubMed  Google Scholar 

  25. Herbert C, Patel M, Nugent A et al (2015) Serum cystatin C as an early marker of neutrophil gelatinase-associated lipocalin-positive acute kidney injury resulting from cardiopulmonary bypass in infants with congenital heart disease. Congenit Heart Dis 10:E180–E188. https://doi.org/10.1111/chd.12253

    Article  PubMed  Google Scholar 

  26. Nguyen MT, Dent CL, Ross GF et al (2008) Urinary aprotinin as a predictor of acute kidney injury after cardiac surgery in children receiving aprotinin therapy. Pediatr Nephrol 23:1317–1326. https://doi.org/10.1007/s00467-008-0827-9

    Article  PubMed  Google Scholar 

  27. Beger RD, Holland RD, Sun J et al (2008) Metabonomics of acute kidney injury in children after cardiac surgery. Pediatr Nephrol 23:977–984. https://doi.org/10.1007/s00467-008-0756-7

    Article  PubMed  Google Scholar 

  28. Dennen P, Altmann C, Kaufman J et al (2010) Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery. Crit Care 14:R181. https://doi.org/10.1186/cc9289

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bennett MR, Pyles O, Ma Q, Devarajan P (2018) Preoperative levels of urinary uromodulin predict acute kidney injury after pediatric cardiopulmonary bypass surgery. Pediatr Nephrol 33:521–526. https://doi.org/10.1007/s00467-017-3823-0

    Article  PubMed  Google Scholar 

  30. Nakhjavan-Shahraki B, Yousefifard M, Ataei N et al (2017) Accuracy of cystatin C in prediction of acute kidney injury in children; serum or urine levels: which one works better? A systematic review and meta-analysis. BMC Nephrol 18:1–13. https://doi.org/10.1186/s12882-017-0539-0

    Article  CAS  Google Scholar 

  31. Koyner JL, Garg AX, Shlipak MG et al (2013) Urinary cystatin C and acute kidney injury after cardiac surgery. Am J Kidney Dis 61:730–738. https://doi.org/10.1053/j.ajkd.2012.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Allegaert K, Mekahli D, Van den Anker J (2015) Cystatin C in newborns: a promising renal biomarker in search for standardization and validation. J Matern Neonatal Med 28:1833–1838

    Article  Google Scholar 

  33. Ho J, Tangri N, Komenda P et al (2015) Urinary, plasma, and serum biomarkers’ utility for predicting acute kidney injury associated with cardiac surgery in adults: a meta-analysis. Am J Kidney Dis 66:993–1005. https://doi.org/10.1053/j.ajkd.2015.06.018

    Article  CAS  PubMed  Google Scholar 

  34. Susantitaphong P, Siribamrungwong M, Doi K et al (2013) Performance of urinary liver-type fatty acid-binding protein in acute kidney injury: a meta-analysis. Am J Kidney Dis 61:430–439. https://doi.org/10.1053/j.ajkd.2012.10.016

    Article  CAS  PubMed  Google Scholar 

  35. Edelstein CL, Akcay A, Nguyen Q (2009) Mediators of inflammation in acute kidney injury. Mediators Inflamm 2009:12

    Google Scholar 

  36. Paparella D, Yau TM, Young E (2002) Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update Eur J Cardio-thoracic Surg 21:232–244

    Article  CAS  Google Scholar 

  37. Cai L, Borowiec J, Xu S et al (2009) Assays of urine levels of HNL/NGAL in patients undergoing cardiac surgery and the impact of antibody configuration on their clinical performances. Clin Chim Acta 403:121–125. https://doi.org/10.1016/j.cca.2009.01.030

    Article  CAS  PubMed  Google Scholar 

  38. Nauta FL, Boertien WE, Bakker SJL et al (2011) Glomerular and tubular damage markers are elevated in patients with diabetes. Diabetes Care 34:975–981. https://doi.org/10.2337/dc10-1545

    Article  PubMed  PubMed Central  Google Scholar 

  39. McIlroy DR, Wagener G, Lee HT (2010) Neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery: The effect of baseline renal function on diagnostic performance. Clin J Am Soc Nephrol 5:211–219. https://doi.org/10.2215/CJN.04240609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zheng J, Xiao Y, Yao Y et al (2012) Comparison of urinary biomarkers for early detection of acute kidney injury after cardiopulmonary bypass surgery in infants and young children. Pediatr Cardiol 344(34):880–886. https://doi.org/10.1007/S00246-012-0563-6

    Article  Google Scholar 

  41. Peco-Antić A, Ivanišević I, Vulićević I et al (2013) Biomarkers of acute kidney injury in pediatric cardiac surgery. Clin Biochem 46:1244–1251. https://doi.org/10.1016/J.CLINBIOCHEM.2013.07.008

    Article  PubMed  Google Scholar 

  42. Zheng J-Y, Xiao Y-Y, Yao Y, Han L (2013) Is serum cystatin C an early predictor for acute kidney injury following cardiopulmonary bypass surgery in infants and young children? Kaohsiung J Med Sci 29:494–499. https://doi.org/10.1016/J.KJMS.2013.01.004

    Article  PubMed  Google Scholar 

  43. Zappitelli M, Krawczeski CD, Devarajan P et al (2011) Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery. Kidney Int 80:655–662. https://doi.org/10.1038/KI.2011.123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. de Fontnouvelle CA, Greenberg JH, Thiessen-Philbrook HR et al (2017) Interleukin-8 and tumor necrosis factor predict acute kidney injury after pediatric cardiac surgery. Ann Thorac Surg 104:2072–2079. https://doi.org/10.1016/J.ATHORACSUR.2017.04.038

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bucholz EM, Whitlock RP, Zappitelli M et al (2015) Cardiac biomarkers and acute kidney injury after cardiac surgery. Pediatrics 135:e945–e956. https://doi.org/10.1542/PEDS.2014-2949

    Article  PubMed  PubMed Central  Google Scholar 

  46. Garimella PS, Jaber BL, Tighiouart H et al (2017) Association of preoperative urinary uromodulin with AKI after cardiac surgery. Clin J Am Soc Nephrol 12:10–18. https://doi.org/10.2215/CJN.02520316

    Article  PubMed  Google Scholar 

  47. Parikh A, Rizzo JA, Canetta P et al (2017) Does NGAL reduce costs? A cost analysis of urine NGAL (uNGAL) & serum creatinine (sCr) for acute kidney injury (AKI) diagnosis. PLoS ONE 12:e0178091. https://doi.org/10.1371/journal.pone.0178091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shaw AD, Chalfin DB, Kleintjens J (2011) The economic impact and cost-effectiveness of urinary neutrophil gelatinase-associated lipocalin after cardiac surgery. Clin Ther 33:1713–1725. https://doi.org/10.1016/j.clinthera.2011.09.014

    Article  CAS  PubMed  Google Scholar 

  49. Petrovic S, Bogavac-Stanojevic N, Lakic D et al (2015) Cost-effectiveness analysis of acute kidney injury biomarkers in pediatric cardiac surgery. Biochem Medica 25:262–271. https://doi.org/10.11613/BM.2015.027

  50. Goldstein SL (2011) Acute kidney injury biomarkers: renal angina and the need for a renal troponin I. BMC Med 9:1–5. https://doi.org/10.1186/1741-7015-9-135/PEER-REVIEW

    Article  Google Scholar 

  51. Van den Eynde J, Cloet N, Van Lerberghe R et al (2021) Strategies to prevent acute kidney injury after pediatric cardiac surgery a network meta-analysis. Clin J Am Soc Nephrol 16:1480–1490. https://doi.org/10.2215/CJN.05800421/-/DCSUPPLEMENTAL

    Article  PubMed  Google Scholar 

  52. Meersch M, Schmidt C, Hoffmeier A et al (2017) 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 43:1551–1561. https://doi.org/10.1007/S00134-016-4670-3/FIGURES/2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pozzoli S, Simonini M, Manunta P (2018) Predicting acute kidney injury: current status and future challenges. J Nephrol 31:209–223. https://doi.org/10.1007/s40620-017-0416-8

    Article  CAS  PubMed  Google Scholar 

  54. Huen SC, Parikh CR (2012) Predicting acute kidney injury after cardiac surgery: a systematic review. Ann Thorac Surg 93:337–347

    Article  Google Scholar 

  55. Basu RK, Zappitelli M, Brunner L et al (2014) Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children. Kidney Int 85:659. https://doi.org/10.1038/KI.2013.349

    Article  PubMed  Google Scholar 

  56. Menon S, Goldstein SL, Mottes T et al (2016) Urinary biomarker incorporation into the renal angina index early in intensive care unit admission optimizes acute kidney injury prediction in critically ill children: a prospective cohort study. Nephrol Dial Transplant 31:586–594. https://doi.org/10.1093/NDT/GFV457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thongprayoon C, Hansrivijit P, Bathini T et al (2020) Predicting acute kidney injury after cardiac surgery by machine learning approaches. J Clin Med 9:1767. https://doi.org/10.3390/jcm9061767

    Article  PubMed Central  Google Scholar 

  58. Park SK, Hur M, Kim E et al (2016) Risk factors for acute kidney injury after congenital cardiac surgery in infants and children: a retrospective observational study. PLoS ONE 11:1–15. https://doi.org/10.1371/journal.pone.0166328

    Article  CAS  Google Scholar 

  59. Kiryluk K, Bomback AS, Cheng YL et al (2018) Precision medicine for acute kidney injury (AKI): redefining AKI by agnostic kidney tissue interrogation and genetics. Semin Nephrol 38:40–51

    Article  Google Scholar 

  60. Schaub JA, Heung M (2019) Precision medicine in acute kidney injury: a promising future? Am J Respir Crit Care Med 199:814–816

    Article  CAS  Google Scholar 

  61. Ostermann M, Zarbock A, Goldstein S et al (2020) Recommendations on acute kidney injury biomarkers from the acute disease quality initiative consensus conference: a consensus statement. JAMA Netw Open 3:e2019209–e2019209. https://doi.org/10.1001/JAMANETWORKOPEN.2020.19209

    Article  PubMed  Google Scholar 

  62. Murray PT, Mehta RL, Shaw A et al (2014) Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference. Kidney Int 85:513–521. https://doi.org/10.1038/KI.2013.374/ATTACHMENT/AD74C145-383D-4990-9ECF-D8F342E4CB07/MMC1.DOC

    Article  PubMed  Google Scholar 

  63. Alten JA, Cooper DS, Blinder JJ et al (2021) Epidemiology of acute kidney injury after neonatal cardiac surgery: a report from the Multicenter Neonatal and Pediatric Heart and Renal Outcomes Network. Crit Care Med E941–E951. https://doi.org/10.1097/CCM.0000000000005165

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Acknowledgements

J. Van den Eynde was supported by the Belgian American Educational Foundation.

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Mr. Van den Eynde and Mr. Schuermans conceptualized and designed the study, collected data, carried out the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript. Profs. Verbakel, Gewillig, Kutty, Allegaert, and Mekahli conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Art Schuermans.

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Van den Eynde, J., Schuermans, A., Verbakel, J.Y. et al. Biomarkers of acute kidney injury after pediatric cardiac surgery: a meta-analysis of diagnostic test accuracy. Eur J Pediatr 181, 1909–1921 (2022). https://doi.org/10.1007/s00431-022-04380-4

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