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Pediatric Nephrology
Published in:

14-03-2024 | Urinary Tract Infection in Pediatrics | Review

Biomarkers for urinary tract infection: present and future perspectives

Authors: Tej K. Mattoo, John David Spencer

Published in: Pediatric Nephrology | Issue 10/2024

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Abstract

A prompt diagnosis of urinary tract infection (UTI) is necessary to minimize its symptoms and limit sequelae. The current UTI screening by urine test strip analysis and microscopic examination has suboptimal diagnostic accuracy. A definitive diagnosis of UTI by urine culture takes two to three days for the results. These limitations necessitate a need for better biomarkers for the diagnosis and subsequent management of UTI in children. Here, we review the value of currently available UTI biomarkers and highlight the potential of emerging biomarkers that can facilitate a more rapid and accurate UTI diagnosis. Of the newer UTI biomarkers, the most promising are blood procalcitonin (PCT) and urinary neutrophil gelatinase-associated lipocalin (NGAL). PCT can provide diagnostic benefits and should be considered in patients who have a blood test for other reasons. NGAL, which is on the threshold of clinical care, needs more research to address its scope and utilization, including point-of-care application. Employment of these and other biomarkers may ultimately improve UTI diagnosis, guide UTI therapy, reduce antibiotic use, and mitigate UTI complications.

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Literature
1.
Zorc JJ, Levine DA, Platt SL, Dayan PS, Macias CG, Krief W et al (2005) Clinical and demographic factors associated with urinary tract infection in young febrile infants. Pediatrics 116:644–648PubMed
2.
Shaikh N, Morone NE, Bost JE, Farrell MH (2008) Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J 27:302–308PubMed
3.
Kanellopoulos TA, Salakos C, Spiliopoulou I, Ellina A, Nikolakopoulou NM, Papanastasiou DA (2006) First urinary tract infection in neonates, infants and young children: a comparative study. Pediatr Nephrol 21:1131–1137PubMed
4.
Peters CA, Skoog SJ, Arant BS Jr, Copp HL, Elder JS, Hudson RG et al (2010) Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol 184:1134–1144PubMed
5.
Shaikh N, Ewing AL, Bhatnagar S, Hoberman A (2010) Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics 126:1084–1091PubMed
6.
Bensman A, Dunand O, Ulinski T Urinary Tract Infections. In: Avner E, Harmon W, Niaudet P, Yoshikawa N (eds). Pediatric Nephrology, 6th edn. Springer, Berlin Heidelberg, pp 1299–1309
7.
Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R (2007) Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA 298:179–186PubMed
8.
Akram M, Shahid M, Khan AU (2007) Etiology and antibiotic resistance patterns of community-acquired urinary tract infections in J N M C Hospital Aligarh. India Ann Clin Microbiol Antimicrob 6:4PubMed
9.
Chakupurakal R, Ahmed M, Sobithadevi DN, Chinnappan S, Reynolds T (2010) Urinary tract pathogens and resistance pattern. J Clin Pathol 63:652–654PubMed
10.
Lutter SA, Currie ML, Mitz LB, Greenbaum LA (2005) Antibiotic resistance patterns in children hospitalized for urinary tract infections. Arch Pediatr Adolesc Med 159:924–928PubMed
11.
Bell LE, Mattoo TK (2009) Update on childhood urinary tract infection and vesicoureteral reflux. Semin Nephrol 29:349–359PubMed
12.
Mattoo TK, Shaikh N, Nelson CP (2021) Contemporary management of urinary tract infection in children. Pediatrics 147:e2020012138PubMed
13.
Biggi A, Dardanelli L, Pomero G, Cussino P, Noello C, Sernia O et al (2001) Acute renal cortical scintigraphy in children with a first urinary tract infection. Pediatr Nephrol 16:733–738PubMed
14.
Garin EH, Olavarria F, Araya C, Broussain M, Barrera C, Young L (2007) Diagnostic significance of clinical and laboratory findings to localize site of urinary infection. Pediatr Nephrol 22:1002–1006PubMed
15.
16.
Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24:971–983PubMed
17.
Davenport M, Mach KE, Shortliffe LMD, Banaei N, Wang TH, Liao JC (2017) New and developing diagnostic technologies for urinary tract infections. Nat Rev Urol 14:296–310PubMedPubMedCentral
18.
Sequeira-Antunes B, Ferreira HA (2023) Urinary biomarkers and point-of-care urinalysis devices for early diagnosis and management of disease: a review. Biomedicines 11:1051PubMedPubMedCentral
19.
Santucci L, Bruschi M, Candiano G, Lugani F, Petretto A, Bonanni A et al (2016) Urine proteome biomarkers in kidney diseases. I. Limits, perspectives, and first focus on normal urine. Biomark Insights 11:41–48PubMedPubMedCentral
20.
Urinary tract infections in infants and children older than one month: clinical features and diagnosis (2021) Shaikh N, Hoberman A. Wolters Kluwer, Philadelphia
21.
Nadeem S, Manuel MM, Oke OK, Patel V, Filkins LM, Badawy MK et al (2022) Association of pyuria with uropathogens in young children. J Pediatr 245:208-212.e2PubMed
22.
Ünsal H, Kaman A, Tanır G (2019) Relationship between urinalysis findings and responsible pathogens in children with urinary tract infections. J Pediatr Urol 15:606.e1-e6PubMed
23.
Shaikh N, Shope TR, Hoberman A, Vigliotti A, Kurs-Lasky M, Martin JM (2016) Association between uropathogen and pyuria. Pediatrics 138:e20160087PubMed
24.
Nadeem S, Badawy M, Oke OK, Filkins LM, Park JY, Hennes HM (2021) Pyuria and urine concentration for identifying urinary tract infection in young children. Pediatrics 147:e2020014068PubMed
25.
Shaikh N, Osio VA, Wessel CB, Jeong JH (2020) Prevalence of asymptomatic bacteriuria in children: a meta-analysis. J Pediatr 217:110-117.e4PubMed
26.
Fogazzi GB (2019) Urinalysis. In: Johnson RJ, Floege J, Tonelli M (eds) Comprehensive clinical nephrology. Elsevier, New York, pp 39–52
27.
American Academy of Pediatrics (1999) Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 103:843–852
28.
Whiting P, Westwood M, Watt I, Cooper J, Kleijnen J (2005) Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: a systematic review. BMC Pediatr 5:4PubMedPubMedCentral
29.
Downs SM (1999) Technical report: urinary tract infections in febrile infants and young children The Urinary Tract Subcommittee of the American Academy of Pediatrics Committee on Quality Improvement. Pediatrics 103:e54PubMed
30.
Gorelick MH, Shaw KN (1999) Screening tests for urinary tract infection in children: a meta-analysis. Pediatrics 104:e54PubMed
31.
Kazi BA, Buffone GJ, Revell PA, Chandramohan L, Dowlin MD, Cruz AT (2013) Performance characteristics of urinalyses for the diagnosis of pediatric urinary tract infection. Am J Emerg Med 31:1405–1407PubMed
32.
Williams GJ, Macaskill P, Chan SF, Turner RM, Hodson E, Craig JC (2010) Absolute and relative accuracy of rapid urine tests for urinary tract infection in children: a meta-analysis. Lancet Infect Dis 10:240–250PubMed
33.
Montini G, Spencer JD, Hewitt IK (2022) Urinary tract infections in children. In: Emma F, Goldstein SL, Bagga A, Bates CM, Shroff R (eds) Pediatric Nephrology. Springer, Cham, pp 1323–1342
34.
Coulthard MG (2019) Using urine nitrite sticks to test for urinary tract infection in children aged < 2 years: a meta-analysis. Pediatr Nephrol 34:1283–1288PubMedPubMedCentral
35.
Benador N, Siegrist CA, Gendrel D, Greder C, Benador D, Assicot M et al (1998) Procalcitonin is a marker of severity of renal lesions in pyelonephritis. Pediatrics 102:1422–1425PubMed
36.
Kotoula A, Gardikis S, Tsalkidis A, Mantadakis E, Zissimopoulos A, Deftereos S et al (2009) Comparative efficacies of procalcitonin and conventional inflammatory markers for prediction of renal parenchymal inflammation in pediatric first urinary tract infection. Urology 73:782–786PubMed
37.
Bressan S, Andreola B, Zucchetta P, Montini G, Burei M, Perilongo G et al (2009) Procalcitonin as a predictor of renal scarring in infants and young children. Pediatr Nephrol 24:1199–1204PubMed
38.
Sheu J-N, Chang H-M, Chen S-M, Hung T-W, Lue K-H (2011) The role of procalcitonin for acute pyelonephritis and subsequent renal scarring in infants and young children. J Urol 186:2002–2008
39.
Leroy S, Fernandez-Lopez A, Nikfar R, Romanello C, Bouissou F, Gervaix A et al (2013) Association of procalcitonin with acute pyelonephritis and renal scars in pediatric UTI. Pediatrics 131:870–879PubMed
40.
Zhang H, Yang J, Lin L, Huo B, Dai H, He Y (2016) Diagnostic value of serum procalcitonin for acute pyelonephritis in infants and children with urinary tract infections: an updated meta-analysis. World J Urol 34:431–441PubMed
41.
Shaikh KJ, Osio VA, Leeflang MM, Shaikh N (2020) Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children. Cochrane Database Syst Rev 9:CD009185PubMed
42.
Kjeldsen L, Bainton DF, Sengelov H, Borregaard N (1994) Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. Blood 83:799–807PubMed
43.
Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432PubMed
44.
Paragas N, Kulkarni R, Werth M, Schmidt-Ott KM, Forster C, Deng R et al (2014) alpha-Intercalated cells defend the urinary system from bacterial infection. J Clin Invest 124:2963–2976PubMedPubMedCentral
45.
Paragas N, Qiu A, Zhang Q, Samstein B, Deng SX, Schmidt-Ott KM et al (2011) The NGAL reporter mouse detects the response of the kidney to injury in real time. Nat Med 17:216–222PubMedPubMedCentral
46.
Steigedal M, Marstad A, Haug M, Damas JK, Strong RK, Roberts PL et al (2014) Lipocalin 2 imparts selective pressure on bacterial growth in the bladder and is elevated in women with urinary tract infection. J Immunol 193:6081–6089PubMedPubMedCentral
47.
Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK et al (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921PubMed
48.
Yamamoto A, Nakayama S, Wakabayashi Y, Yoshino Y, Kitazawa T (2023) Urine neutrophil gelatinase-associated lipocalin as a biomarker of adult pyelonephritis. J Infect Chemother 29:508–512PubMed
49.
Abbasi A, Nabizadeh F, Gardeh M, Mohamed Ali K, Yousefifard M, Hosseini M (2020) Discriminatory precision of neutrophil gelatinase-associated lipocalin in detection of urinary tract infection in children: a systematic review and meta-analysis. Arch Acad Emerg Med 8:e56PubMedPubMedCentral
50.
Shaikh K, Rajakumar V, Osio VA, Shaikh N (2021) Neutrophil gelatinase-associated lipocalin for urinary tract infection and pyelonephritis: a systematic review. Pediatr Nephrol 36:1481–1487PubMed
51.
Forster CS, Lubell TR, Dayan PS, Shaikh N (2023) Accuracy of NGAL as a biomarker for urinary tract infection in young febrile children: an individual patient data meta-analysis. J Pediatr 258:113394PubMed
52.
Forster CS, Devarajan P (2017) Neutrophil gelatinase-associated lipocalin: utility in urologic conditions. Pediatr Nephrol 32:377–381PubMed
53.
Martensson J, Xu S, Bell M, Martling CR, Venge P (2012) Immunoassays distinguishing between HNL/NGAL released in urine from kidney epithelial cells and neutrophils. Clin Chim Acta 413:1661–1667PubMed
54.
Cai L, Rubin J, Han W, Venge P, Xu S (2010) The origin of multiple molecular forms in urine of HNL/NGAL. Clin J Am Soc Nephrol 5:2229–2235PubMedPubMedCentral
55.
Lubell TR, Barasch JM, King B, Ochs JB, Fan W, Duong J et al (2022) Urinary tract infections in children: testing a novel, noninvasive, point-of-care diagnostic marker. Acad Emerg Med 29:326–333PubMed
56.
Kowalewski NN, Forster CS (2021) Collection, processing, and storage consideration for urinary biomarker research. J Vis Exp 176
57.
Singer E, Elger A, Elitok S, Kettritz R, Nickolas TL, Barasch J et al (2011) Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes. Kidney Int 80:405–414PubMed
58.
Valdimarsson S, Jodal U, Barregard L, Hansson S (2017) Urine neutrophil gelatinase-associated lipocalin and other biomarkers in infants with urinary tract infection and in febrile controls. Pediatr Nephrol 32:2079–2087PubMed
59.
Proverbio D, Spada E, Baggiani L, Bagnagatti De Giorgi G, Ferro E, Martino PA et al (2015) Short communication: relationship between urinary neutrophil gelatinase-associated lipocalin and noninfectious pyuria in dogs. Dis Markers 2015:387825PubMedPubMedCentral
60.
Kim DY, Yim HE, Son MH, Yoo KH (2023) Urine specific gravity, pyuria, and neutrophil gelatinase-associated lipocalin for identifying urinary tract infection in young children. Pediatr Nephrol 38:3337–3346PubMed
61.
Nickavar A, Valavi E, Safaeian B, Moosavian M (2020) Validity of urine neutrophile gelatinase-associated lipocalin in children with primary vesicoureteral reflux. Int Urol Nephrol 52:599–602PubMed
62.
Amiri R, Faradmal J, Rezaie B, Sedighi I, Sanaei Z, Solgi G (2020) Evaluation of urinary neutrophil gelatinase-associated lipocalin as a biomarker in pediatric vesicoureteral reflux assessment. Iran J Kidney Dis 14:373–379PubMed
63.
Gavrilovici C, Dusa CP, Iliescu Halitchi C, Lupu VV, Spoiala EL, Bogos RA et al (2023) The role of urinary NGAL in the management of primary vesicoureteral reflux in children. Int J Mol Sci 24:7904PubMedPubMedCentral
64.
Gupta S, Preece J, Haynes A, Becknell B, Ching C (2019) Differentiating asymptomatic bacteriuria from urinary tract infection in the pediatric neurogenic bladder population: NGAL as a promising biomarker. Top Spinal Cord Inj Rehabil 25:214–221PubMedPubMedCentral
65.
Schwartz L, de Dios R-R, Stonebrook E, Becknell B, Spencer JD (2023) Uropathogen and host responses in pyelonephritis. Nat Rev Nephrol 19:658–671PubMedPubMedCentral
66.
Mobley HL, Donnenberg MS, Hagan EC (2009) Uropathogenic Escherichia coli. EcoSal Plus 3
67.
Forster CS, Lamanna OK, Rounds A, Sprague BM, Ljungberg I, Groah SL (2021) The association between urine neutrophil gelatinase-associated lipocalin and UTI in people with neurogenic lower urinary tract dysfunction. Spinal Cord 59:959–966PubMed
68.
Forster CS, Jackson E, Ma Q, Bennett M, Shah SS, Goldstein SL (2018) Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders. Pediatr Nephrol 33:1365–1374PubMedPubMedCentral
69.
Forster CS, Johnson K, Patel V, Wax R, Rodig N, Barasch J et al (2017) Urinary NGAL deficiency in recurrent urinary tract infections. Pediatr Nephrol 32:1077–1080PubMedPubMedCentral
70.
Nanda N, Juthani-Mehta M (2009) Novel biomarkers for the diagnosis of urinary tract infection-a systematic review. Biomark Insights 4:111–121PubMedPubMedCentral
71.
Hosseini M, Ahmadzadeh H, Toloui A, Ahmadzadeh K, Madani Neishaboori A, Rafiei Alavi SN et al (2022) The value of interleukin levels in the diagnosis of febrile urinary tract infections in children and adolescents; a systematic review and meta-analysis. J Pediatr Urol 18:211–223PubMed
72.
Edwards G, Seeley A, Carter A, Patrick Smith M, Cross E, Hughes K et al (2023) What is the diagnostic accuracy of novel urine biomarkers for urinary tract infection? Biomark Insights 18:11772719221144460PubMedPubMedCentral
73.
Shaikh N, Kurs-Lasky M, Liu H, Rajakumar V, Qureini H, Conway IO et al (2023) Biomarkers for febrile urinary tract infection in children. Front Pediatr 11:1163546PubMedPubMedCentral
74.
Otto G, Burdick M, Strieter R, Godaly G (2005) Chemokine response to febrile urinary tract infection. Kidney Int 68:62–70PubMed
75.
Spencer JD, Hains DS, Porter E, Bevins CL, Dirosario J, Becknell B et al (2012) Human alpha defensin 5 expression in the human kidney and urinary tract. PLoS One 7:e31712PubMedPubMedCentral
76.
Becknell B, Schwaderer A, Hains DS, Spencer JD (2015) Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis. Nat Rev Nephrol 11:642–655PubMed
77.
Watson JR, Hains DS, Cohen DM, Spencer JD, Kline JM, Yin H et al (2016) Evaluation of novel urinary tract infection biomarkers in children. Pediatr Res 79:934–939PubMedPubMedCentral
78.
Davies EL, Bacelar MM, Marshall MJ, Johnson E, Wardle TD, Andrew SM et al (2006) Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL. Clin Exp Immunol 145:183–189PubMedPubMedCentral
79.
Yilmaz A, Yildirim ZY, Emre S, Gedikbasi A, Yildirim T, Dirican A et al (2016) Urine heat shock protein 70 levels as a marker of urinary tract infection in children. Pediatr Nephrol 31:1469–1476PubMed
80.
Yilmaz A, Afonso AC, Akil I, Aksu B, Alpay H, Atmis B et al (2023) Urinary HSP70 improves diagnostic accuracy for urinary tract infection in children: UTILISE study. Pediatr Nephrol 38:791–799PubMed
81.
Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N et al (2004) Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 65:791–797PubMed
82.
Mo L, Huang HY, Zhu XH, Shapiro E, Hasty DL, Wu XR (2004) Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int 66:1159–1166PubMed
83.
Reinhart HH, Spencer JR, Zaki NF, Sobel JD (1992) Quantitation of urinary Tamm-Horsfall protein in children with urinary tract infection. Eur Urol 22:194–199PubMed
84.
Everaert K, Oostra C, Delanghe J, Vande Walle J, Van Laere M, Oosterlinck W (1998) Diagnosis and localization of a complicated urinary tract infection in neurogenic bladder disease by tubular proteinuria and serum prostate specific antigen. Spinal Cord 36:33–38PubMed
85.
Golovanova OE, Reznikov IuP, Maksimov NA, Pankrat’ev LM, Balkarov IM, (1986) Beta 2-microglobulin in the blood serum and urine of patients with interstitial kidney lesions. Ter Arkh 58:27–29PubMed
86.
Kenneally C, Murphy CP, Sleator RD, Culligan EP (2022) The urinary microbiome and biological therapeutics: novel therapies for urinary tract infections. Microbiol Res 259:127010PubMed
87.
Almas S, Carpenter RE, Rowan C, Tamrakar VK, Bishop J, Sharma R (2023) Advantage of precision metagenomics for urinary tract infection diagnostics. Front Cell Infect Microbiol 13:1221289PubMedPubMedCentral
88.
Shaikh N, Martin JM, Hoberman A, Skae M, Milkovich L, McElheny C et al (2020) Biomarkers that differentiate false positive urinalyses from true urinary tract infection. Pediatr Nephrol 35:321–329PubMed
89.
Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S, Brincat C et al (2016) The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J Clin Microbiol 54:1216–1222PubMedPubMedCentral
90.
Huang T, Yang J, Zhou W, Liu X, Pan Y, Song Y (2019) Rapid identification of urinary tract infections based on ultrasensitive bacteria detection using volumetric bar-chart chip. Sens Actuators B Chem 298:126885
91.
Herberg JA, Kaforou M, Wright VJ, Shailes H, Eleftherohorinou H, Hoggart CJ et al (2016) Diagnostic test accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children. JAMA 316:835–845PubMedPubMedCentral
92.
Butler D, Ambite I, Wan MLY, Tran TH, Wullt B, Svanborg C (2022) Immunomodulation therapy offers new molecular strategies to treat UTI. Nat Rev Urol 19:419–437PubMedPubMedCentral
Metadata
Title
Biomarkers for urinary tract infection: present and future perspectives
Authors
Tej K. Mattoo
John David Spencer
Publication date
14-03-2024
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 10/2024
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-024-06321-9

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