Use of non-conventional biomarkers in the early diagnosis of acute kidney injury in preterm newborns with sepsis

Barbosa, Joycilene da Silva; Silva Júnior, Geraldo Bezerra da; Meneses, Gdayllon Cavalcante; Martins, Alice Maria Costa; Daher, Elizabeth De Francesco; Machado, Rosângela Pinheiro Gonçalves; Lemes, Romélia Pinheiro Gonçalves

doi:10.1590/2175-8239-JBN-2020-0222

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Brazilian Journal of Nephrology

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Review Articles • Braz. J. Nephrol. 44 (1) • Jan-Mar 2022 • https://doi.org/10.1590/2175-8239-JBN-2020-0222 copy

Use of non-conventional biomarkers in the early diagnosis of acute kidney injury in preterm newborns with sepsis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Acute kidney injury (AKI) is a common finding in Neotatal Intensive Care Units (NICU). Sepsis is one the main causes of AKI in preterm newborns. AKI has been associated with significant death rates. Early detection of the condition is the first step to improving prevention, treatment, and outcomes, while decreasing length of hospitalization, care costs, and morbimortality. AKI may progress to chronic kidney disease (CKD), a condition linked with dialysis and greater risk of cardiovascular disease. This review article aims to discuss cases of AKI in preterm newborns with sepsis, the use of biomarkers in lab workup, and the use of non-conventional biomarkers for the early identification of AKI.

Keywords:
Acute Kidney Injury; Sepsis; Infant, Premature; Biomarkers

Stage	Serum creatinine	Urine output
0	No change or increase < 0.3 mg/dL	≥ 0.5 mL/kg/h
1	Increase ≥ 0.3 mg/dL in 48 hours or ≥1.5 to 1.9 times the reference value^* *()** Reference value: lowest previous creatinine level. SCr: serum creatinine. Source: Adapted from Alconcher et al., 202020. ≤ 7 days	< 0.5 mL/kg/h for 6 to 12 hours
2	≥ 2 to 2.9 times the reference value	< 0.5 mL/kg/h for ≥12 hours
3	≥ 3 times the reference value or SCr ≥ 2.5 mg/dL or need for dialysis	< 0.3 mL/kg/h for ≥ 24 hours or anuria for ≥ 12 hours

Biomarker	Origin in the kidney	Pros	Cons
Serum creatinine	Glomerulus²¹21 Freire KMS, Bersolin NL, Farah ACF, Carvalho FLC, Góes JEC. Acute kidney injury in children: incidence and prognostic factors in critically ill patients. Rev Bras Ter Intensiva [Internet]. 2010 Jun; [citado 2019 Nov 17]; 22(2):166-74. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103507X2010000200011&lng=en&nrm=iso http://www.scielo.br/scielo.php?script=s...	SCr is the standard serum marker for the detection of AKI; very inexpensive and offers good chemical stability in clinical practice²⁴24 Peres LAB, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, et al. Biomarkers of acute kidney injury. J Bras Nefrol [Internet]. 2013 Set; [citado 2019 Nov 16]; 35(3):229-36. Available from: http://www.scielo.br/pdf/jbn/v35n3/en_ v35n3a10.pdf http://www.scielo.br/pdf/jbn/v35n3/en_ v... .	It is a late marker of kidney involvement²¹21 Freire KMS, Bersolin NL, Farah ACF, Carvalho FLC, Góes JEC. Acute kidney injury in children: incidence and prognostic factors in critically ill patients. Rev Bras Ter Intensiva [Internet]. 2010 Jun; [citado 2019 Nov 17]; 22(2):166-74. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103507X2010000200011&lng=en&nrm=iso http://www.scielo.br/scielo.php?script=s... affected by age, sex, nutrition, muscle mass, medication²²22 Ciccia E, Devarajan P. Pediatric acute kidney injury: prevalence, impact and management challenges. Int J Nephrol Renovasc Dis [Internet]. 2017; [citado 2019 Nov 15]; 10:77-84. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386613/pdf/ijnrd-10-077.pdf https://www.ncbi.nlm.nih.gov/pmc/article... , and, after birth, neonatal SCr reflects serum creatinine levels present in the mother²³23 Jetton JG, Askenazi DJ. Update on acute kidney injury in the neonate. Curr Opin Pediatr [Internet]. 2012 Abr; [citado 2019 Nov 14]; 24(2):191-6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545784/ https://www.ncbi.nlm.nih.gov/pmc/article... .
Cystatin C	Glomeruus²⁴24 Peres LAB, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, et al. Biomarkers of acute kidney injury. J Bras Nefrol [Internet]. 2013 Set; [citado 2019 Nov 16]; 35(3):229-36. Available from: http://www.scielo.br/pdf/jbn/v35n3/en_ v35n3a10.pdf http://www.scielo.br/pdf/jbn/v35n3/en_ v... and proximal tubule⁵²52 Ghys L, Paepe D, Smets P, Lefebvre H, Delanghe J, Daminet S. Cystatin C: a new renal marker and its potential use in small animal medicine. J Vet Intern Med [Internet]. 2014; [citado 2021 Ago 13]; 28:1152-64. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857948/pdf/JVIM-281152.pdf https://www.ncbi.nlm.nih.gov/pmc/article...	It is completely reabsorbed, not secreted, and is not significantly affected by age, sex, ethnicity, or muscle mass²⁴24 Peres LAB, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, et al. Biomarkers of acute kidney injury. J Bras Nefrol [Internet]. 2013 Set; [citado 2019 Nov 16]; 35(3):229-36. Available from: http://www.scielo.br/pdf/jbn/v35n3/en_ v35n3a10.pdf http://www.scielo.br/pdf/jbn/v35n3/en_ v... .	CysC is not specific enough to distinguish AKI from CKD; its levels increase in a delayed manner; it is considered more as a marker of GFR instead of primary AKI²⁴24 Peres LAB, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, et al. Biomarkers of acute kidney injury. J Bras Nefrol [Internet]. 2013 Set; [citado 2019 Nov 16]; 35(3):229-36. Available from: http://www.scielo.br/pdf/jbn/v35n3/en_ v35n3a10.pdf http://www.scielo.br/pdf/jbn/v35n3/en_ v... ^,⁴⁰40 Slocum JL, Heung M, Pennathur S. Marking renal injury: can we move beyond serum creatinine? Transl Res [Internet]. 2012 Abr; [citado 2021 Ago 13]; 159(4):277-89. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308350/pdf/nihms360231.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .
NGAL	Distal tubule³⁴34 Devarajan P. NGAL for the detection of acute kidney injury in the emergency room. Biomark Med [Internet]. 2014 Fev; [citado 2020 Out 10]; 8(2):217-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106139/pdf/nihms-613137.pdf https://www.ncbi.nlm.nih.gov/pmc/article... ^,³⁵35 Zappitelli M, Greenberg JH, Coca SG, Krawczeski CD, Li S, Thiessen-Philbrook HR, et al. Association of definition of acute kidney injury by cystatin C rise with biomarkers and clinical outcomes in children undergoing cardiac surgery. JAMA Pediatr [Internet]. 2015; [citado 2020 Out 10]; 169(6):583-91. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506750/ https://www.ncbi.nlm.nih.gov/pmc/article...	Noninvasive; sensitive for accurate early detection; a precise predictor; good for risk stratification; NGAL increases are proportional to the severity of AKI³⁴34 Devarajan P. NGAL for the detection of acute kidney injury in the emergency room. Biomark Med [Internet]. 2014 Fev; [citado 2020 Out 10]; 8(2):217-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106139/pdf/nihms-613137.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .	Plasma levels include production in organs other than the kidneys; uNGAL is affected by dehydration, difficulty obtaining samples, excessive hydration, and diuretics³⁰30 Dusse LMS, Rios DRA, Sousa LPN, Moraes RMMS, Domingueti CP, Gomes KB. Biomarkers of renal function: what is currently available? RBAC [Internet]. 2017; [citado 2019 Nov 19]; 49(1):41-51. Available from: http://www.rbac.org.br/wp-content/uploads/2017/06/RBAC-1-2017-ref.-427.pdf http://www.rbac.org.br/wp-content/upload... .
IL-6	Podocytes⁵³53 Su H, Lei C, Zhang C. Interleukin-6 signaling pathway and its role in kidney disease: an update. Front Immunol [Internet]. 2017; [citado 2021 Ago 14]; 8:405. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2017.00405/full https://www.frontiersin.org/articles/10....	This cytokine is a marker of early host infection response; its levels increase before CRP increases; it is produced by numerous cells³⁷37 Fan Y, Yu JL. Umbilical blood biomarkers for predicting early-onset neonatal sepsis. World J Pediatr [Internet]. 2012; [citado 2019 Nov 17]; 8(2):101-8. Available from: https://link-springer-com.ez11.periodicos.capes.gov.br/content/pdf/10.1007%2Fs12519-012-0347-3.pdf https://link-springer-com.ez11.periodico... .	Supporting evidence adjusted to the current KDIGO criteria is still lacking⁵⁴54 Shimazui T, Nakada T, Tateishi Y, Oshima T, Aizimu T, Oda S. Association between serum levels of interleukin-6 on ICU admission and subsequent outcomes in critically ill patients with acute kidney injury. BMC Nephrol [Internet]. 2019; [citado 2021 Ago 13]; 20:74. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397495/pdf/12882_2019_Article_1265.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .
IL-18	Proximal⁴⁰40 Slocum JL, Heung M, Pennathur S. Marking renal injury: can we move beyond serum creatinine? Transl Res [Internet]. 2012 Abr; [citado 2021 Ago 13]; 159(4):277-89. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308350/pdf/nihms360231.pdf https://www.ncbi.nlm.nih.gov/pmc/article... and distal⁵⁵55 Gauer S, Sichler O, Obermuller N, Holzmann Y, Kiss E, Sobkowiak E, et al. IL-18 is expressed in the intercalated cell of human kidney. Kidney Int [Internet]. 2007; [citado 2021 Ago 13]; 72:1081-7. Available from: https://www.kidney-international.org/action/showPdf?pii=S00852538%2815%2952796-8 https://www.kidney-international.org/act... tubules	IL-18 is a biomarker of ischemic AKI⁵⁶56 Edelstein CL. Biomarkers of acute kidney injury. Adv Chronic Kidney Dis [Internet]. 2008 Jul; [citado 2021 Ago 13]; 15(3):222-34. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287955/pdf/nihms-200858.pdf https://www.ncbi.nlm.nih.gov/pmc/article... ; its levels increase before SCr increases²⁴24 Peres LAB, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, et al. Biomarkers of acute kidney injury. J Bras Nefrol [Internet]. 2013 Set; [citado 2019 Nov 16]; 35(3):229-36. Available from: http://www.scielo.br/pdf/jbn/v35n3/en_ v35n3a10.pdf http://www.scielo.br/pdf/jbn/v35n3/en_ v... .	Expensive; also derived from myocardial ischemia, lung injury; the entire center may be required to use IL-18 so that cutoff values are established⁵⁷57 Lin X, Yuan J, Zhao Y, Zhao Y. Urine interleukin-18 in prediction of acute kidney injury: a systemic review and meta-analysis. J Nephrol [Internet]. 2015; [citado 2021 Ago 13]; 28:7-16. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322238/pdf/40620_2014_Article_113.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .
KIM-1	Proximal tubule⁵⁸58 Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. Nephrol Dial Transplant [Internet]. 2009 Mar; [citado 2021 Ago 13]; 24(11):3265-8. Available from: https://academic.oup.com/ndt/article/24/11/3265/1942806 https://academic.oup.com/ndt/article/24/...	An early indicator or poor kidney outcome, KIM-1 cannot be detected in healthy kidneys and urine; it is a sensitive predictor of kidney outcome in AKI⁴¹41 Xie Y, Wang Q, Wang C, Qi C, Ni Z, Mou S. High urinary excretion of kidney injury molecule-1 predicts adverse outcomes in acute kidney injury: a case control study. Crit Care [Internet]. 2016; [citado 2019 Nov 17]; 20:1-12. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018198/pdf/130542016_Article_1455.pdf https://www.ncbi.nlm.nih.gov/pmc/article... ^,⁴²42 Tu Y, Wang H, Sun R, Ni Y, Ma L, Xv F, et al. Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury. Ren Fail [Internet]. 2014 Nov; [citado 2019 Nov 16]; 36(10):1559-63. Available from: https://www.tandfonline.com/doi/full/10.3109/0886022X.2014.949764 https://www.tandfonline.com/doi/full/10.... .	It is used inly in research and presents limitations in the early diagnosis of AKI and recovery monitoring after kidney injury²⁴24 Peres LAB, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, et al. Biomarkers of acute kidney injury. J Bras Nefrol [Internet]. 2013 Set; [citado 2019 Nov 16]; 35(3):229-36. Available from: http://www.scielo.br/pdf/jbn/v35n3/en_ v35n3a10.pdf http://www.scielo.br/pdf/jbn/v35n3/en_ v... ^,⁴⁰40 Slocum JL, Heung M, Pennathur S. Marking renal injury: can we move beyond serum creatinine? Transl Res [Internet]. 2012 Abr; [citado 2021 Ago 13]; 159(4):277-89. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308350/pdf/nihms360231.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .
L-FABP	Proximal tubule⁴³43 Noiri E, Doi K, Negishi K, Tanaka T, Hamasaki Y, Fujita T, et al. Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury. Am J Physiol Renal Physiol [Internet]. 2009 Nov; [citado 2021 Ago 13]; 296:F669-F79. Available from: https://journals.physiology.org/doi/pdf/10.1152/ajprenal.90513.2008 https://journals.physiology.org/doi/pdf/...	L-FABP is expressed only in proximal tubule epithelial cells; tubular injury by hypoxia increases the synthesis of this biomarker, making it a promising tool to monitor tubulointerstitial injury⁴³43 Noiri E, Doi K, Negishi K, Tanaka T, Hamasaki Y, Fujita T, et al. Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury. Am J Physiol Renal Physiol [Internet]. 2009 Nov; [citado 2021 Ago 13]; 296:F669-F79. Available from: https://journals.physiology.org/doi/pdf/10.1152/ajprenal.90513.2008 https://journals.physiology.org/doi/pdf/... .	There is no standardized assay that allows widespread clinical use of L-FABP⁴⁰40 Slocum JL, Heung M, Pennathur S. Marking renal injury: can we move beyond serum creatinine? Transl Res [Internet]. 2012 Abr; [citado 2021 Ago 13]; 159(4):277-89. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308350/pdf/nihms360231.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .
TIMP-2	Proximal tubule⁵⁹59 Knafl D, Müller M, Pajenda S, Genc Z, Hecking M, Wagner L. The urine biomarker panel [IGFBP7]x[TIMP-2] (NephroCheck((r)) parameter) does not correlate with IGFBP7 and TIMP-2 gene expression in urinary sediment. PloS One. 2017;12(11):e0188316. DOI: https://doi.org/10.1371/journal.pone.0188316 https://doi.org/10.1371/journal.pone.018...	Outperforms all other biomarkers and has produced great results in sepsis-induced AKI³²32 Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care [Internet]. 2013; [citado 2021 Ago 12]; 17(1):R25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057242/pdf/cc12503.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .	The current method is time consuming and the biomarker has not been approved for individuals aged less than 21 years; false positive results may lead to unnecessary, expensive testing⁴⁵45 Vijayan A, Faubel S, Askenazi DJ, Cerda J, Fissell WH, Heung M, et al. Clinical use of the urine biomarker [TIMP-2] × [IGFBP7] for acute kidney injury risk assessment. Am J Kidney Dis [Internet]. 2016 Jul; [citado 2021 Ago 13]; 68(1):19-28. Available from: https://pubmed.ncbi.nlm.nih.gov/26948834/ https://pubmed.ncbi.nlm.nih.gov/26948834... .
IGFBP7	Proximal tubule⁶⁰60 Emlet DR, Pastor-Soler N, Marciszyn A, Wen X, Gomez H, Humphries WH, et al. Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells. Am J Physiol Renal Physiol [Internet]. 2017 FEv; [citado 2021 Ago 13]; 312(2):F284-F96. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336590/?report=printable https://www.ncbi.nlm.nih.gov/pmc/article...	It has outperformed existing biomarkers as a predictor of AKI; it offers great outcomes for surgery patients³²32 Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care [Internet]. 2013; [citado 2021 Ago 12]; 17(1):R25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057242/pdf/cc12503.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .	Not approved for individuals aged less than 21 years; false positive results may lead to unnecessary, expensive testing; the current method is time consuming⁴⁵45 Vijayan A, Faubel S, Askenazi DJ, Cerda J, Fissell WH, Heung M, et al. Clinical use of the urine biomarker [TIMP-2] × [IGFBP7] for acute kidney injury risk assessment. Am J Kidney Dis [Internet]. 2016 Jul; [citado 2021 Ago 13]; 68(1):19-28. Available from: https://pubmed.ncbi.nlm.nih.gov/26948834/ https://pubmed.ncbi.nlm.nih.gov/26948834... .
Syndecan-1	Endothelial glycocalyx⁴⁹49 Neves FMO, Araújo CB, Freitas DF, Arruda BFT, Filho LJMM, Salles VB, et al. Fibroblast growth factor 23, endothelium biomarkers and acute kidney injury in critically-ill patients. J Transl Med [Internet]. 2019; [citado 2019 Nov 17]; 17(1):121. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458699/pdf/12967_2019_Article_1875.pdf https://www.ncbi.nlm.nih.gov/pmc/article...	This biomarker of endothelial glycocalyx injury61 can be used in the diagnostic and prognostic evaluation of sepsis⁶²62 Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care [Internet]. 2019; [citado 2019 Nov 17]; 23:16. Available from: https://ccforum.biomedcentral.com/track/pdf/10.1186/s13054-018-2292-6 https://ccforum.biomedcentral.com/track/... ^,⁶³63 Becker BF, Jacob M, Leipert S, Salmon AHJ, Chappell D. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin Pharmacol [Internet]. 2015; [citado 2019 Nov 17]; 80(3):389-402. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574825/pdf/bcp0080-0389.pdf https://www.ncbi.nlm.nih.gov/pmc/article... .	Its mechanism in AKI has not been entirely elucidated⁶⁴64 Qin L, Xue F, Yin F, Zhao J, Zhang K. Expression of syndecan-1, PKC and VEGF in rats with acute kidney injury and correlation between syndecan-1 and renal function. Eur Rev Med Pharmacol Sci [Internet]. 2020; [citado 2021 Ago 13]; 24:12794-801. Available from: https://www.europeanreview.org/wp/wp-content/uploads/12794-12801.pdf https://www.europeanreview.org/wp/wp-con... .
Nephrin	Podocytes⁵⁰50 Kandasamy Y, Smith R, Lumbers ER, Rudd D. Nephrin - a biomarker of early glomerular injury. Biomark Res [Internet]. 2014; [citado 2019 Nov 17]; 2:21. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363192/ https://www.ncbi.nlm.nih.gov/pmc/article...	Nephrin may become an important biomarker of early glomerular injury⁵⁰50 Kandasamy Y, Smith R, Lumbers ER, Rudd D. Nephrin - a biomarker of early glomerular injury. Biomark Res [Internet]. 2014; [citado 2019 Nov 17]; 2:21. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363192/ https://www.ncbi.nlm.nih.gov/pmc/article... and AKI in NICU settings, particularly for preterm newborns⁵¹51 Chen J, Li G, Wang S, Hu X, Sun Y, Dai X, et al. Urinary nephrin as a biomarker of glomerular maturation and injury is associated with acute kidney injury and mortality in critically ill neonates. Neonatology [Internet]. 2019; [citado 2019 Nov 15]; 116:58-66. Available from: https://relaped.com/wp-content/uploads/2019/07/CHEN-2019.pdf https://relaped.com/wp-content/uploads/2... .	Additional clinical studies are needed to assess and monitor potential uses in the prognostic evaluation of pediatric patients with kidney disease⁵⁰50 Kandasamy Y, Smith R, Lumbers ER, Rudd D. Nephrin - a biomarker of early glomerular injury. Biomark Res [Internet]. 2014; [citado 2019 Nov 17]; 2:21. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363192/ https://www.ncbi.nlm.nih.gov/pmc/article... .

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[1] Correspondence to: Joycilene da Silva Barbosa. E-mail: joycileneacarau@gmail.com