Protein Biomarkers in Chronic Kidney Disease in Children—What Do We Know So Far?
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Protocol
2.2. Data Analysis
3. Results
4. Discussion
4.1. Biomarkers of Tubular Injury
4.1.1. Neutrophil Gelatinase Associated Lipocalin (NGAL)
4.1.2. Interleukin 18 (IL-18)
4.1.3. Kidney Injury Molecule—1 (KIM-1)
4.1.4. Epidermal Growth Factor (EGF)
4.1.5. α1-Microglobulin
4.2. Biomarkers of Inflammation
4.2.1. Tumor Necrosis Receptor 1 and 2 (TNFR1 and TNFR2)
4.2.2. Blood Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR)
4.2.3. Monocyte Chemoattractant Protein-1 (MCP-1)
4.2.4. Chitinase-3-like Protein 1 (YKL-40)
4.3. Biomarkers of Fibrosis
4.3.1. Blood Transforming Growth Factor β1 (TGF-β1)
4.3.2. Blood Bone Morphogenic Protein-7 (BMP-7)
4.3.3. Blood Matrix Metalloproteinase-2 and 9 (MMP-2, MMP-9)
4.3.4. Urinary procollagen III N-terminal peptide (PIIINP)
4.4. Miscellaneous
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
AKI | Acute Kidney Injury |
ALL | Acute lymphoblastic leukaemia |
BMP-7 | Blood bone morphogenic protein-7 |
CAKUT | Congenital anomalies of the kidneys and the urinary tract |
CKD | Chronic Kidney Disease |
CKiD | Chronic Kidney Disease in Children (CKiD) cohort from 54 North American centres |
ESKD | End-stage kidney disease |
FGF23 | Fibroblast growth factor 23 |
GFR | Glomerular Filtration Rate |
HN | Hydronephrosis |
HSP | Heat Shock Protein |
IL-18 | Interleukin—18 |
IL-6 | Interleukin—6 |
KDIGO | Kidney Disease: Improving Global Outcomes |
KIM-1 | Kidney Injury Molecule—1 |
L-FABP | Liver-type Fatty Acid-Binding Protein |
MCP-1 | Monocyte Chemotactic Protein—1 |
MMP | Matrix Metaloproteinase |
NAG | N-Acetyl-β-d-amino Glycosidase |
NGAL | Neutrophil Gelatinase-Associated Lipocalin |
PIIINP | procollagen III N-terminal peptide |
RBP4 | Retinol-binding Protein 4 |
SLE | Systemic lupus erythematosus |
suPAR | Blood soluble urokinase-type plasminogen activator receptor |
TFF3 | Treofil Factor 3TGF-β1—Blood transforming growth factor β1 |
TIMP | Tissue Inhibitor of Metaloproteinase |
TNFR 1, 2 | Tumor Necrosis Receptor 1 and 2 |
VDBP | Vitamin D-binding Protein |
YKL-40 | Chitinase-3-like protein 1 |
References
- Greenbaum, L.A.; Warady, B.A.; Furth, S.L. Current advances in chronic kidney disease in children: Growth, cardiovascular, and neurocognitive risk factors. Semin. Nephrol. 2009, 29, 425–434. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Harshman, L.A.; Johnson, R.J.; Matheson, M.B.; Kogon, A.J.; Shinnar, S.; Gerson, A.C.; Warady, B.A.; Furth, S.L.; Hooper, S.R. Academic achievement in children with chronic kidney disease: A report from the CKiD cohort. Pediatr. Nephrol. 2019, 34, 689–696. [Google Scholar] [CrossRef] [PubMed]
- Harambat, J.; van Stralen, K.J.; Kim, J.J.; Tizard, E.J. Epidemiology of chronic kidney disease in children. Pediatr. Nephrol. 2012, 27, 363–373, Erratum in Pediatr. Nephrol. 2012, 27, 507 . [Google Scholar] [CrossRef] [PubMed] [Green Version]
- van Amstel, S.P.; Noordzij, M.; Warady, B.A.; Cano, F.; Craig, J.C.; Groothoff, J.W.; Ishikura, K.; Neu, A.; Safouh, H.; Xu, H.; et al. Renal replacement therapy for children throughout the world: The need for a global registry. Pediatr. Nephrol. 2018, 33, 863–871. [Google Scholar] [CrossRef] [Green Version]
- Harambat, J.; Madden, I. What is the true burden of chronic kidney disease in children worldwide? Pediatr. Nephrol. 2022, 38, 1389–1393. [Google Scholar] [CrossRef]
- Tasic, V.; Janchevska, A.; Emini, N.; Sahpazova, E.; Gucev, Z.; Polenakovic, M. Chronic kidney disease—Pediatric risk factors. Prilozi 2016, 37, 9–13. [Google Scholar] [CrossRef] [Green Version]
- Ahn, S.Y.; Moxey-Mims, M. CKD in Children: The Importance of a National Epidemiologic Study. Am. J. Kidney Dis. 2018, 72, 628–630. [Google Scholar] [CrossRef] [Green Version]
- Helal, I.; Fick-Brosnahan, G.M.; Reed-Gitomer, B.; Schrier, R.W. Glomerular hyperfiltration: Definitions, mechanisms and clinical implications. Nat. Rev. Nephrol. 2012, 8, 293–300. [Google Scholar] [CrossRef]
- Hogg, R.J.; Furth, S.; Lemley, K.V.; Portman, R.; Schwartz, G.J.; Coresh, J.; Balk, E.; Lau, J.; Levin, A.; Kausz, A.T.; et al. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: Evaluation, classification, and stratification. Pediatrics 2003, 111, 1416–1421. [Google Scholar] [CrossRef] [Green Version]
- Levin, A.; Stevens, P.E. Summary of KDIGO 2012 CKD Guideline: Behind the scenes, need for guidance, and a framework for moving forward. Kidney Int. 2014, 85, 49–61. [Google Scholar] [CrossRef] [Green Version]
- Levey, A.S.; Cattran, D.; Friedman, A.; Miller, W.G.; Sedor, J.; Tuttle, K.; Kasiske, B.; Hostetter, T. Proteinuria as a surrogate outcome in CKD: Report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am. J. Kidney Dis. 2009, 54, 205–226. [Google Scholar] [CrossRef] [Green Version]
- Perrone, R.D.; Madias, N.E.; Levey, A.S. Serum creatinine as an index of renal function: New insights into old concepts. Clin. Chem. 1992, 38, 1933–1953. [Google Scholar] [CrossRef] [PubMed]
- Greenberg, J.H.; Parikh, C.R. Biomarkers for Diagnosis and Prognosis of AKI in Children: One Size Does Not Fit All. Clin. J. Am. Soc. Nephrol. 2017, 12, 1551–1557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Parikh, C.R.; Lu, J.C.; Coca, S.G.; Devarajan, P. Tubular proteinuria in acute kidney injury: A critical evaluation of current status and future promise. Ann. Clin. Biochem. 2010, 47, 301–312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Greenberg, J.H.; Kakajiwala, A.; Parikh, C.R.; Furth, S. Emerging biomarkers of chronic kidney disease in children. Pediatr. Nephrol. 2018, 33, 925–933. [Google Scholar] [CrossRef] [PubMed]
- Fathallah-Shaykh, S.A. Proteinuria and progression of pediatric chronic kidney disease: Lessons from recent clinical studies. Pediatr. Nephrol. 2017, 32, 743–751. [Google Scholar] [CrossRef] [PubMed]
- Wong, C.S.; Pierce, C.B.; Cole, S.R.; Warady, B.A.; Mak, R.H.; Benador, N.M.; Kaskel, F.; Furth, S.L.; Schwartz, G.J.; CKiD Investigators. Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the chronic kidney disease in children study. Clin. J. Am. Soc. Nephrol. 2009, 4, 812–819. [Google Scholar] [CrossRef] [Green Version]
- Warady, B.A.; Abraham, A.G.; Schwartz, G.J.; Wong, C.S.; Muñoz, A.; Betoko, A.; Mitsnefes, M.; Kaskel, F.; Greenbaum, L.A.; Mak, R.H.; et al. Predictors of Rapid Progression of Glomerular and Nonglomerular Kidney Disease in Children and Adolescents: The Chronic Kidney Disease in Children (CKiD) Cohort. Am. J. Kidney Dis. 2015, 65, 878–888. [Google Scholar] [CrossRef] [Green Version]
- Ruiz-Ortega, M.; Rayego-Mateos, S.; Lamas, S.; Ortiz, A.; Rodrigues-Diez, R.R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol. 2020, 16, 269–288. [Google Scholar] [CrossRef]
- Zhong, J.; Yang, H.C.; Fogo, A.B. A perspective on chronic kidney disease progression. Am. J. Physiol. Renal. Physiol. 2017, 312, F375–F384. [Google Scholar] [CrossRef] [Green Version]
- Tesch, G.H. Review: Serum and urine biomarkers of kidney disease: A pathophysiological perspective. Nephrology 2010, 15, 609–616. [Google Scholar] [CrossRef] [PubMed]
- Devarajan, P. The use of targeted biomarkers for chronic kidney disease. Adv. Chronic Kidney Dis. 2010, 17, 469–479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cagney, D.N.; Sul, J.; Huang, R.Y.; Ligon, K.L.; Wen, P.Y.; Alexander, B.M. The FDA NIH Biomarkers, EndpointS, and other Tools (BEST) resource in neuro-oncology. Neuro-Oncology 2018, 20, 1162–1172. [Google Scholar] [CrossRef] [PubMed]
- Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
- Musiał, K.; Zwolińska, D. Fractional excretion as a new marker of tubular damage in children with chronic kidney disease. Clin. Chim. Acta Int. J. Clin. Chem. 2018, 480, 99–106. [Google Scholar] [CrossRef]
- Greenberg, J.H.; Devarajan, P.; Thiessen-Philbrook, H.R.; Krawczeski, C.; Parikh, C.R.; Zappitelli, M.; TRIBE-AKI Consortium. Kidney injury biomarkers 5 years after AKI due to pediatric cardiac surgery. Pediatr. Nephrol. 2018, 33, 1069–1077. [Google Scholar] [CrossRef]
- Bieniaś, B.; Sikora, P. Potential Novel Biomarkers of Obstructive Nephropathy in Children with Hydronephrosis. Dis. Markers 2018, 2018, 1015726. [Google Scholar] [CrossRef]
- Wu, C.Y.; Yang, H.Y.; Chien, H.P.; Tseng, M.H.; Huang, J.L. Urinary clusterin-a novel urinary biomarker associated with pediatric lupus renal histopathologic features and renal survival. Pediatr. Nephrol. 2018, 33, 1189–1198. [Google Scholar] [CrossRef]
- Lipiec, K.; Adamczyk, P.; Świętochowska, E.; Ziora, K.; Szczepańska, M. L-FABP and IL-6 as markers of chronic kidney damage in children after hemolytic uremic syndrome. Adv. Clin. Exp. Med. 2018, 27, 955–962. [Google Scholar] [CrossRef]
- Bartoli, F.; Pastore, V.; Calè, I.; Aceto, G.; Campanella, V.; Lasalandra, C.; Magaldi, S.; Niglio, F.; Basile, A.; Cocomazzi, R. Prospective Study on Several Urinary Biomarkers as Indicators of Renal Damage in Children with CAKUT. Eur. J. Pediatr. Surg. 2019, 29, 215–222. [Google Scholar]
- Azukaitis, K.; Ju, W.; Kirchner, M.; Nair, V.; Smith, M.; Fang, Z.; Thurn-Valsassina, D.; Bayazit, A.; Niemirska, A.; Canpolat, N. Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children. Kidney Int. 2019, 96, 214–221. [Google Scholar] [CrossRef] [PubMed]
- Musiał, K.; Zwolińska, D. New markers of cell migration and inflammation in children with chronic kidney disease. Biomarkers 2019, 24, 295–302. [Google Scholar] [CrossRef] [PubMed]
- Taranta-Janusz, K.; Moczulska, A.; Nosek, H.; Michaluk-Skutnik, J.; Klukowski, M.; Wasilewska, A. Urinary procollagen III aminoterminal propeptide and β-catenin—New diagnostic biomarkers in solitary functioning kidney? Adv. Med. Sci. 2019, 64, 189–194. [Google Scholar] [CrossRef] [PubMed]
- Nickavar, A.; Valavi, E.; Safaeian, B.; Moosavian, M. Validity of urine neutrophile gelatinase-associated lipocalin in children with primary vesicoureteral reflux. Int. Urol. Nephrol. 2020, 52, 599–602. [Google Scholar] [CrossRef]
- Staub, E.; Urfer-Maurer, N.; Lemola, S.; Risch, L.; Evers, K.S.; Welzel, T.; Pfister, M. Comparison of Blood Pressure and Kidney Markers between Adolescent Former Preterm Infants and Term Controls. Children 2020, 7, 141. [Google Scholar] [CrossRef]
- Latoch, E.; Konończuk, K.; Taranta-Janusz, K.; Muszyńska-Rosłan, K.; Szymczak, E.; Wasilewska, A.; Krawczuk-Rybak, M. Urine NGAL and KIM-1: Tubular injury markers in acute lymphoblastic leukemia survivors. Cancer Chemother. Pharmacol. 2020, 86, 741–749. [Google Scholar] [CrossRef]
- Gul, A.; Yilmaz, R.; Ozmen, Z.C.; Gumuser, R.; Demir, O.; Unsal, V. Assessment of renal function in obese and overweight children with NGAL and KIM-1 biomarkers. Valoración de la función renal en niños con sobrepeso y obesidad con las moléculas NGAL y KIM-1. Nutr. Hosp. 2020, 34, 436–442. [Google Scholar]
- McLeod, D.J.; Sebastião, Y.V.; Ching, C.B.; Greenberg, J.H.; Furth, S.L.; Becknell, B. Longitudinal kidney injury biomarker trajectories in children with obstructive uropathy. Pediatr. Nephrol. 2020, 35, 1907–1914. [Google Scholar] [CrossRef]
- Greenberg, J.H.; Abraham, A.G.; Xu, Y.; Schelling, J.R.; Feldman, H.I.; Sabbisetti, V.S.; Gonzalez, M.C.; Coca, S.; Schrauben, S.J.; Waikar, S.S.; et al. Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children. J. Am. Soc. Nephrol. 2020, 31, 1067–1077. [Google Scholar] [CrossRef]
- Weidemann, D.K.; Abraham, A.G.; Roem, J.L.; Furth, S.L.; Warady, B.A. Plasma Soluble Urokinase Plasminogen Activator Receptor (suPAR) and CKD Progression in Children. Am. J. Kidney Dis. 2020, 76, 194–202. [Google Scholar] [CrossRef]
- Musiał, K.; Zwolińska, D. Monocyte chemoattractant protein-1, macrophage colony stimulating factor, survivin, and tissue inhibitor of matrix metalloproteinases-2 in analysis of damage and repair related to pediatric chronic kidney injury. Adv. Clin. Exp. Med. 2020, 29, 1083–1090. [Google Scholar] [CrossRef] [PubMed]
- Stabouli, S.; Kotsis, V.; Maliachova, O.; Printza, N.; Chainoglou, A.; Christoforidis, A.; Taparkou, A.; Dotis, J.; Farmaki, E.; Zafeiriou, D. Matrix metalloproteinase-2, -9 and arterial stiffness in children and adolescents: The role of chronic kidney disease, diabetes, and hypertension. Int. J. Cardiol. Hypertens. 2020, 4, 100025. [Google Scholar] [CrossRef] [PubMed]
- Anand, S.; Bajpai, M.; Khanna, T.; Kumar, A. Urinary biomarkers as point-of-care tests for predicting progressive deterioration of kidney function in congenital anomalies of kidney and urinary tract: Trefoil family factors (TFFs) as the emerging biomarkers. Pediatr. Nephrol. 2021, 36, 1465–1472. [Google Scholar] [CrossRef] [PubMed]
- Leibler, J.H.; Ramirez-Rubio, O.; Velázquez, J.J.A. Biomarkers of kidney injury among children in a high-risk region for chronic kidney disease of uncertain etiology. Pediatr. Nephrol. 2021, 36, 387–396. [Google Scholar] [CrossRef]
- Będzichowska, A.; Jobs, K.; Kloc, M.; Bujnowska, A.; Kalicki, B. The Assessment of the Usefulness of Selected Markers in the Diagnosis of Chronic Kidney Disease in Children. Biomark. Insights 2021, 16, 11772719211011173. [Google Scholar] [CrossRef]
- Jacobson, M.H.; Wu, Y.; Liu, M. Organophosphate pesticides and progression of chronic kidney disease among children: A prospective cohort study. Environ. Int. 2021, 155, 106597. [Google Scholar] [CrossRef]
- Sethi, S.K.; Sharma, R.; Gupta, A.; Tibrewal, A.; Akole, R.; Dhir, R.; Soni, K.; Bansal, S.B.; Jha, P.K.; Bhan, A.; et al. Long-Term Renal Outcomes in Children with Acute Kidney Injury Post Cardiac Surgery. Kidney Int. Rep. 2021, 6, 1850–1857. [Google Scholar] [CrossRef]
- Ahn, M.B.; Cho, K.S.; Kim, S.K.; Kim, S.H.; Cho, W.K.; Jung, M.H.; Suh, J.S.; Suh, B.K. Poor Glycemic Control Can Increase the Plasma Kidney Injury Molecule-1 Concentration in Normoalbuminuric Children and Adolescents with Diabetes Mellitus. Children 2021, 8, 417. [Google Scholar] [CrossRef]
- Williams, C.E.C.; Toner, A.; Wright, R.D.; Oni, L. A systematic review of urine biomarkers in children with IgA vasculitis nephritis. Pediatr. Nephrol. 2021, 36, 3033–3044. [Google Scholar] [CrossRef]
- Nosek, H.; Jankowska, D.; Brzozowska, K.; Kazberuk, K.; Wasilewska, A.; Taranta-Janusz, K. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis and Selected Cytokines-Potential Biomarkers in Children with Solitary Functioning Kidney. J. Clin. Med. 2021, 10, 497. [Google Scholar] [CrossRef]
- Sandokji, I.; Greenberg, J.H. Plasma and Urine Biomarkers of CKD: A Review of Findings in the CKiD Study. Semin. Nephrol. 2021, 41, 416–426. [Google Scholar] [CrossRef] [PubMed]
- Turczyn, A.; Pańczyk-Tomaszewska, M.; Krzemień, G.; Górska, E.; Demkow, U. The Usefulness of Urinary Periostin, Cytokeratin-18, and Endoglin for Diagnosing Renal Fibrosis in Children with Congenital Obstructive Nephropathy. J. Clin. Med. 2021, 10, 4899. [Google Scholar] [CrossRef] [PubMed]
- Tunçay, S.C.; Doğan, E.; Hakverdi, G.; Tutar, Z.Ü.; Mir, S. Interleukin-8 is increased in chronic kidney disease in children, but not related to cardiovascular disease. J. Bras. Nefrol. 2021, 43, 359–364. [Google Scholar] [CrossRef] [PubMed]
- Denburg, M.R.; Xu, Y.; Abraham, A.G.; Coresh, J.; Chen, J.; Grams, M.E.; Feldman, H.I.; Kimmel, P.L.; Rebholz, C.M.; Rhee, E.P.; et al. Metabolite Biomarkers of CKD Progression in Children. Clin. J. Am. Soc. Nephrol. 2021, 16, 1178–1189. [Google Scholar] [CrossRef]
- Johnson, M.J.; Tommerdahl, K.L.; Vinovskis, C.; Waikar, S.; Reinicke, T.; Parikh, C.R.; Obeid, W.; Nelson, R.G.; van Raalte, D.H.; Pyle, L.; et al. Relationship between biomarkers of tubular injury and intrarenal hemodynamic dysfunction in youth with type 1 diabetes. Pediatr. Nephrol. 2022, 37, 3085–3092. [Google Scholar] [CrossRef]
- Gunasekara, T.D.K.S.C.; De Silva, P.M.C.S.; Ekanayake, E.M.D.V.; Thakshila, W.A.K.G.; Pinipa, R.A.I.; Sandamini, P.M.M.A.; Gunarathna, S.D.; Chandana, E.P.S.; Jayasinghe, S.S.; Herath, C.; et al. Urinary biomarkers indicate pediatric renal injury among rural farming communities in Sri Lanka. Sci. Rep. 2022, 12, 8040. [Google Scholar] [CrossRef]
- Alderson, H.V.; Ritchie, J.P.; Pagano, S.; Middleton, R.J.; Pruijm, M.; Vuilleumier, N.; Kalra, P.A. The Associations of Blood Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin with Progression from CKD to ESRD. Clin. J. Am. Soc. Nephrol. 2016, 11, 2141–2149. [Google Scholar] [CrossRef] [Green Version]
- Gowda, S.; Desai, P.B.; Kulkarni, S.S.; Hull, V.V.; Math, A.A.; Vernekar, S.N. Markers of renal function tests. N. Am. J. Med. Sci. 2010, 2, 170–173. [Google Scholar]
- Ferguson, M.A.; Waikar, S.S. Established and emerging markers of kidney function. Clin. Chem. 2012, 58, 680–689. [Google Scholar] [CrossRef] [Green Version]
- Mårtensson, J.; Xu, S.; Bell, M.; Martling, C.R.; Venge, P. Immunoassays distinguishing between HNL/NGAL released in urine from kidney epithelial cells and neutrophils. Clin. Chim. Acta 2012, 413, 1661–1667. [Google Scholar] [CrossRef]
- Brunner, H.I.; Mueller, M.; Rutherford, C.; Passo, M.H.; Witte, D.; Grom, A.; Mishra, J.; Devarajan, P. Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2006, 54, 2577–2584. [Google Scholar] [CrossRef] [PubMed]
- Trachtman, H.; Christen, E.; Cnaan, A.; Patrick, J.; Mai, V.; Mishra, J.; Jain, A.; Bullington, N.; Devarajan, P. Investigators of the HUS-SYNSORB Pk Multicenter Clinical Trial. Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: A novel marker of renal injury. Pediatr. Nephrol. 2006, 21, 989–994. [Google Scholar] [CrossRef] [PubMed]
- Smith, E.R.; Lee, D.; Cai, M.M.; Tomlinson, L.A.; Ford, M.L.; McMahon, L.P.; Holt, S.G. Urinary neutrophil gelatinase-associated lipocalin may aid prediction of renal decline in patients with non-proteinuric Stages 3 and 4 chronic kidney disease (CKD). Nephrol. Dial. Transplant. 2013, 28, 1569–1579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, K.D.; Yang, W.; Go, A.S.; Anderson, A.H.; Feldman, H.I.; Fischer, M.J.; He, J.; Kallem, R.R.; Kusek, J.W.; Master, S.R.; et al. Urine neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease and death in CKD: Results from the Chronic Renal Insufficiency Cohort (CRIC) Study. Am. J. Kidney Dis. 2015, 65, 267–274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kasahara, M.; Mori, K.; Satoh, N.; Kuwabara, T.; Yokoi, H.; Shimatsu, A.; Sugawara, A.; Mukoyama, M.; Nakao, K. Reduction in urinary excretion of neutrophil gelatinase-associated lipocalin by angiotensin receptor blockers in hypertensive patients. Nephrol. Dial. Transplant. 2009, 24, 2608–2610. [Google Scholar] [CrossRef] [Green Version]
- Kuwabara, T.; Mori, K.; Mukoyama, M.; Kasahara, M.; Yokoi, H.; Saito, Y.; Yoshioka, T.; Ogawa, Y.; Imamaki, H.; Kusakabe, T.; et al. Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int. 2009, 75, 285–294. [Google Scholar] [CrossRef] [Green Version]
- Gracie, J.A.; Robertson, S.E.; McInnes, I.B. Interleukin-18. J. Leukoc. Biol. 2003, 73, 213–224. [Google Scholar] [CrossRef] [Green Version]
- Liu, X.; Guan, Y.; Xu, S.; Li, Q.; Sun, Y.; Han, R.; Jiang, C. Early Predictors of Acute Kidney Injury: A Narrative Review. Kidney Blood Press Res. 2016, 41, 680–700. [Google Scholar] [CrossRef]
- Zubowska, M.; Wyka, K.; Fendler, W.; Młynarski, W.; Zalewska-Szewczyk, B. Interleukin 18 as a marker of chronic nephropathy in children after anticancer treatment. Dis. Markers 2013, 35, 811–818. [Google Scholar] [CrossRef] [Green Version]
- Hall, I.E.; Doshi, M.D.; Reese, P.P.; Marcus, R.J.; Thiessen-Philbrook, H.; Parikh, C.R. Association between peritransplant kidney injury biomarkers and 1-year allograft outcomes. Clin. J. Am. Soc. Nephrol. 2012, 7, 1224–1233. [Google Scholar] [CrossRef] [Green Version]
- Shlipak, M.G.; Scherzer, R.; Abraham, A.; Tien, P.C.; Grunfeld, C.; Peralta, C.A.; Devarajan, P.; Bennett, M.; Butch, A.W.; Anastos, K.; et al. Urinary markers of kidney injury and kidney function decline in HIV-infected women. J. Acquir. Immune. Defic. Syndr. 2012, 61, 565–573. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Peralta, C.; Scherzer, R.; Grunfeld, C.; Abraham, A.; Tien, P.; Devarajan, P.; Bennett, M.; Butch, A.; Anastos, K.; Cohen, M.; et al. Urinary biomarkers of kidney injury are associated with all-cause mortality in the Women’s Interagency HIV Study (WIHS). HIV Med. 2014, 15, 291–300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yin, C.; Wang, N. Kidney injury molecule-1 in kidney disease. Ren. Fail. 2016, 38, 1567–1573. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sandokji, I.; Greenberg, J.H. Novel biomarkers of acute kidney injury in children: An update on recent findings. Curr. Opin. Pediatr. 2020, 32, 354–359. [Google Scholar] [CrossRef]
- Han, W.K.; Bailly, V.; Abichandani, R.; Thadhani, R.; Bonventre, J.V. Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int. 2002, 62, 237–244. [Google Scholar] [CrossRef] [Green Version]
- Bieniaś, B.; Zajączkowska, M.; Borzęcka, H.; Sikora, P.; Wieczorkiewicz-Płaza, A.; Wilczyńska, B. Early Markers of Tubulointerstitial Fibrosis in Children With Idiopathic Nephrotic Syndrome: Preliminary Report. Medicine 2015, 94, e1746. [Google Scholar] [CrossRef]
- Ucakturk, A.; Avci, B.; Genc, G.; Ozkaya, O.; Aydin, M. Kidney injury molecule-1 and neutrophil gelatinase associated lipocalin in normoalbuminuric diabetic children. J. Pediatr. Endocrinol. Metab. 2016, 29, 145–151. [Google Scholar] [CrossRef]
- Tang, J.; Liu, N.; Zhuang, S. Role of epidermal growth factor receptor in acute and chronic kidney injury. Kidney Int. 2013, 83, 804–810. [Google Scholar] [CrossRef] [Green Version]
- Norman, J.; Tsau, Y.K.; Bacay, A.; Fine, L.G. Epidermal growth factor accelerates functional recovery from ischaemic acute tubular necrosis in the rat: Role of the epidermal growth factor receptor. Clin. Sci. 1990, 78, 445–450. [Google Scholar] [CrossRef]
- Ju, W.; Nair, V.; Smith, S.; Zhu, L.; Shedden, K.; Song, P.X.K.; Mariani, L.H.; Eichinger, F.H.; Berthier, C.C.; Randolph, A.; et al. Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci. Transl. Med. 2015, 7, 316ra193. [Google Scholar] [CrossRef] [Green Version]
- Penders, J.; Delanghe, J.R. Alpha 1-microglobulin: Clinical laboratory aspects and applications. Clin. Chim, Act. 2004, 346, 107–118. [Google Scholar] [CrossRef] [PubMed]
- O’Seaghdha, C.M.; Hwang, S.J.; Larson, M.G.; Meigs, J.B.; Vasan, R.S.; Fox, C.S. Analysis of a urinary biomarker panel for incident kidney disease and clinical outcomes. J. Am. Soc. Nephrol. 2013, 24, 1880–1888. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jotwani, V.; Scherzer, R.; Abraham, A. Association of urine α1-microglobulin with kidney function decline and mortality in HIV-infected women. Clin. J. Am. Soc. Nephrol. 2015, 10, 63–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Al-Lamki, R.S.; Mayadas, T.N. TNF receptors: Signaling pathways and contribution to renal dysfunction. Kidney Int. 2015, 87, 281–296. [Google Scholar] [CrossRef] [Green Version]
- Mehaffey, E.; Majid, D.S.A. Tumor necrosis factor-α, kidney function, and hypertension. Am. J. Physiol. Renal Physiol. 2017, 313, F1005–F1008. [Google Scholar] [CrossRef] [Green Version]
- Guo, G.; Morrissey, J.; McCracken, R.; Tolley, T.; Klahr, S. Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy. Am. J. Physiol. 1999, 277, F766–F772. [Google Scholar] [CrossRef]
- Ernandez, T.; Mayadas, T.N. Immunoregulatory role of TNF alpha in inflammatory kidney diseases. Kidney Int. 2009, 76, 262–276. [Google Scholar] [CrossRef] [Green Version]
- Shankar, A.; Sun, L.; Klein, B.E.; Lee, K.E.; Muntner, P.; Nieto, F.J.; Tsai, M.Y.; Cruickshanks, K.J.; Schubert, C.R.; Brazy, P.C.; et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: A population-based cohort study. Kidney Int. 2011, 80, 1231–1238. [Google Scholar] [CrossRef] [Green Version]
- Jutley, R.S.; Youngson, G.G.; Eremin, O.; Ninan, G.K. Serum cytokine profile in reflux nephropathy. Pediatr. Surg. Int. 2000, 16, 64–68. [Google Scholar] [CrossRef]
- Moreira, J.M.; da Silva, A.N.; Marciano Vieira, É.L.; Teixeira, A.L.; Kummer, A.M.; Simões, E.; Silva, A.C. Soluble tumor necrosis factor receptors are associated with severity of kidney dysfunction in pediatric chronic kidney disease. Pediatr. Nephrol. 2019, 34, 349–352. [Google Scholar] [CrossRef]
- Hayek, S.S.; Sever, S.; Ko, Y.A.; Trachtman, H.; Awad, M.; Wadhwani, S.; Altintas, M.M.; Wei, C.; Hotton, A.L.; French, A.L.; et al. Soluble Urokinase Receptor and Chronic Kidney Disease. N. Engl. J. Med. 2015, 373, 1916–1925. [Google Scholar] [CrossRef] [PubMed]
- Wei, C.; El Hindi, S.; Li, J.; Fornoni, A.; Goes, N.; Sageshima, J.; Maiguel, D.; Karumanchi, S.A.; Yap, H.K.; Saleem, M.; et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 2011, 17, 952–960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wei, C.; Trachtman, H.; Li, J.; Dong, C.; Friedman, A.L.; Gassman, J.J.; McMahan, J.L.; Radeva, M.; Heil, K.M.; Trautmann, A.; et al. Circulating suPAR in two cohorts of primary FSGS. J. Am. Soc. Nephrol. 2012, 23, 2051–2059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schaefer, F.; Trachtman, H.; Wühl, E.; Kirchner, M.; Hayek, S.S.; Anarat, A.; Duzova, A.; Mir, S.; Paripovic, D.; Yilmaz, A.; et al. Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children. JAMA Pediatr. 2017, 171, e172914, Erratum in JAMA Pediatr. 2017, 171, 1127. [Google Scholar] [CrossRef] [PubMed]
- Kim, M.J.; Tam, F.W. Urinary monocyte chemoattractant protein-1 in renal disease. Clin. Chim. Acta 2011, 412, 2022–2030. [Google Scholar] [CrossRef]
- Ghobrial, E.E.; El Hamshary, A.A.; Mohamed, A.G.; Abd El Raheim, Y.A.; Talaat, A.A. Urinary monocyte chemoattractant protein-1 as a biomarker of lupus nephritis activity in children. Saudi J. Kidney Dis. Transpl. 2015, 26, 507–515. [Google Scholar] [CrossRef]
- Vianna, H.R.; Soares, C.M.; Silveira, K.D.; Elmiro, G.S.; Mendes, P.M.; de Sousa Tavares, M.; Teixeira, M.M.; Miranda, D.M.; Simões E Silva, A.C. Cytokines in chronic kidney disease: Potential link of MCP-1 and dyslipidemia in glomerular diseases. Pediatr. Nephrol. 2013, 28, 463–469. [Google Scholar] [CrossRef]
- Schmidt, I.M.; Hall, I.E.; Kale, S. Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function. J. Am. Soc. Nephrol. 2013, 24, 309–319. [Google Scholar] [CrossRef] [Green Version]
- Tsakas, S.; Goumenos, D.S. Accurate measurement and clinical significance of urinary transforming growth factor-beta1. Am. J. Nephrol. 2006, 26, 186–193. [Google Scholar] [CrossRef]
- Cheng, O.; Thuillier, R.; Sampson, E. Connective tissue growth factor is a biomarker and mediator of kidney allograft fibrosis. Am. J. Transplant. 2006, 6, 2292–2306. [Google Scholar] [CrossRef]
- Woroniecki, R.P.; Shatat, I.F.; Supe, K.; Du, Z.; Kaskel, F.J. Urinary cytokines and steroid responsiveness in idiopathic nephrotic syndrome of childhood. Am. J. Nephrol. 2008, 28, 83–90. [Google Scholar] [CrossRef] [PubMed]
- Zieg, J.; Blahova, K.; Seeman, T.; Bronsky, J.; Dvorakova, H.; Pechova, M.; Janda, J.; Matousovic, K. Urinary transforming growth factor-β1 in children with obstructive uropathy. Nephrology 2011, 16, 595–598. [Google Scholar] [CrossRef] [PubMed]
- Musiał, K.; Fornalczyk, K.; Zwolińska, D. Osteopontin (OPN), PDGF-BB (platelet-derived growth factor) and BMP-7 (bone morphogenetic protein) as markers of atherogenesis in children with chronic kidney disease (CKD) treated conservatively--preliminary results. Pol. Merkur. Lek. 2008, 24 (Suppl. 4), 25–27. [Google Scholar]
- Hruska, K.A.; Guo, G.; Wozniak, M. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol.-Renal Physiol. 2000, 279, F130–F143. [Google Scholar] [CrossRef] [PubMed]
- Zeisberg, M.; Hanai, J.; Sugimoto, H.; Mammoto, T.; Charytan, D.; Strutz, F.; Kalluri, R. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 2003, 9, 964–968. [Google Scholar] [CrossRef]
- Wiercinska, E.; Naber, H.P.H.; Pardali, E.; Pluijm, G.V.D.; Dam, H.V.; Dijke, P.T. The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res. Treat. 2011, 128, 657–666. [Google Scholar] [CrossRef] [Green Version]
- Musiał, K.; Zwolińska, D. Matrix metalloproteinases (MMP-2,9) and their tissue inhibitors (TIMP-1,2) as novel markers of stress response and atherogenesis in children with chronic kidney disease (CKD) on conservative treatment. Cell Stress Chaperones 2011, 16, 97–103. [Google Scholar] [CrossRef] [Green Version]
- Korzeniecka-Kozerska, A.; Wasilewska, A.; Tenderenda, E.; Sulik, A.; Cybulski, K. Urinary MMP-9/NGAL ratio as a potential marker of FSGS in nephrotic children. Dis. Markers 2013, 34, 357–362. [Google Scholar] [CrossRef]
- Ghoul, B.E.; Squalli, T.; Servais, A.; Elie, C.; Meas-Yedid, V.; Trivint, C.; Vanmassenhove, J.; Grünfeld, J.P.; Olivo-Marin, J.C.; Thervet, E.; et al. Urinary procollagen III aminoterminal propeptide (PIIINP): A fibrotest for the nephrologist. Clin. J. Am. Soc. Nephrol. 2010, 5, 205–210. [Google Scholar] [CrossRef] [Green Version]
- Teppo, A.M.; Törnroth, T.; Honkanen, E.; Grönhagen-Riska, C. Urinary amino-terminal propeptide of type III procollagen (PIIINP) as a marker of interstitial fibrosis in renal transplant recipients. Transplantation 2003, 75, 2113–2119. [Google Scholar] [CrossRef]
- Portale, A.A.; Wolf, M.; Jüppner, H.; Messinger, S.; Kumar, J.; Wesseling-Perry, K.; Schwartz, G.J.; Furth, S.L.; Warady, B.A.; Salusky, I.B. Disordered FGF23 and mineral metabolism in children with CKD. Clin. J. Am. Soc. Nephrol. 2014, 9, 344–353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Portale, A.A.; Wolf, M.S.; Messinger, S.; Perwad, F.; Jüppner, H.; Warady, B.A.; Furth, S.L.; Salusky, I.B. Fibroblast Growth Factor 23 and Risk of CKD Progression in Children. Clin. J. Am. Soc. Nephrol. 2016, 11, 1989–1998. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kamijo-Ikemori, A.; Sugaya, T.; Obama, A.; Hiroi, J.; Miura, H.; Watanabe, M.; Kumai, T.; Ohtani-Kaneko, R.; Hirata, K.; Kimura, K. Liver-type fatty acid-binding protein attenuates renal injury induced by unilateral ureteral obstruction. Am. J. Pathol. 2006, 169, 1107–1117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kamijo, A.; Sugaya, T.; Hikawa, A.; Yamanouchi, M.; Hirata, Y.; Ishimitsu, T.; Numabe, A.; Takagi, M.; Hayakawa, H.; Tabei, F.; et al. Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease. Mol. Cell Biochem. 2006, 284, 175–182. [Google Scholar] [CrossRef] [PubMed]
- Jaconi, S.; Rose, K.; Hughes, G.J.; Saurat, J.H.; Siegenthaler, G. Characterization of two post-translationally processed forms of human serum retinol-binding protein: Altered ratios in chronic renal failure. J. Lipid Res. 1995, 36, 1247–1253. [Google Scholar] [CrossRef]
- Fathallah-Shaykh, S.A.; Flynn, J.T.; Pierce, C.B.; Abraham, A.G.; Blydt-Hansen, T.D.; Massengill, S.F.; Moxey-Mims, M.M.; Warady, B.A.; Furth, S.L.; Wong, C.S. Progression of Pediatric CKD of Nonglomerular Origin in the CKiD Cohort. Clin. J. Am. Soc. Nephrol. 2015, 10, 571–577. [Google Scholar] [CrossRef] [Green Version]
Year | Author | Study Design | Results |
---|---|---|---|
NGAL | |||
2018 | Greenberg et al. [26] | - Prospective cohort of children 5 years after cardiac surgery, with a 49% rate of AKI because of surgery with cardiopulmonary bypass and with potential risk for long-term CKD. - From the total of 305 participants, 110 took part in the 5-year follow-up. - Age of participants during cardiac surgery: 1 month—18 years old. - measurement of urinary: NGAL, IL-18, KIM-1, MCP-1, YKL-40. - Biomarkers levels were compared between patients who had postoperative AKI and those without this complication. - Cross-sectional analysis between the biomarkers and hypertension or CKD was performed. | - None of the biomarkers was associated with CKD or hypertension in 5 years follow-up. - Values of assessed markers after 5 years of follow-up in the overall group of participants were as follows, with no significant differences between patients with or without postoperative AKI (expressed as median with interquartile range): uNGAL 4.4 (2.1–10.2) ng/mL; uIL-18 14.7 (8.6–23.4) pg/mL; uKIM-1 250.6 (157.6–568.5) pg/mL; uMCP-1 109.9 (46.4–169.4) pg/mL; uYKL-40 336 (157.1–615.1)pg/mL. - There was no significant difference in eGFR between patients with or without postoperative AKI, and overall was 113 (103–126) mL/min/1.73 m2; however, CKD and hypertension were present in 18 (17%) and 20 (18%) children, respectively. - Only uNGAL was elevated in children with CKD and with hypertension after 5 years of observation. |
2018 | Bienias et al. [27] | - 45 children with congenital unilateral hydronephrosis (HN) due to ureteropelvic junction obstruction and 21 healthy controls - Assessment of new kidney biomarkers including urinary: glutathione S-transferases (GST) alpha-GST, pi-GST, NGAL, KIM-1 (expressed as ratio to creatinine) and serum sNGAL. | - Patients with the highest grade of (HN) showed significantly increased values of all urinary and serum biomarkers, whereas those with the lowest grade HN showed only significant elevation of sNGAL; values below, patients with the highest grade of HN (n = 25) vs. control group (expressed as median with interquartile range). Urinary: alpha-GST (ng/mg cr.) 4.51 (0.54–17.3) vs. 1.11 (0.26–3.5); pi–GST (ng/mg cr.) 30.4 (17.5–24.9) vs. 14.6 (7.4–28.5); NGAL (ng/mg cr.) 1.73 (0.17–10) vs. 0.83 (0.04–9.5); KIM–1 (ng/mg cr.) 2.4 (0.2–5.1) vs. 0.28(0.06–1.06). Serum: NGAL (ng/mL) 59.9 (45.2–85.3) vs. 4.8 (2.1–10.4). - uNGAL positively correlated with a percentage loss of relative function of an obstructed kidney in renal scintigraphy (r = 0.5, p < 0.05). - ROC curve analysis showed the best diagnostic profile for uNGAL/cr and alpha-GST/cr in the detection of obstructive nephropathy. |
2018 | Wu et al. [28] | - 60 pediatric cases with SLE and LN, 29 without LN and 22 healthy controls. - Assessment of urinary biomarkers: b2-microglobulin, cystatin C, KIM-1, MCP-1 clusterin, calbindin, IL-18, NGAL, TFF3, osteopontin and glutathione S-transferase for their ability to predict renal histopathologic findings and progression to end-stage kidney disease. | - Urinary albumin and clusterin were elevated in patients with tubulointerstitial lesions (p = 0.035 and 0.048, respectively). - Urinary clusterin performed best at predicting end-stage kidney disease with cutoff of 0.61 × 104 (AUC 0.804, p = 0.002). |
2018 | Musiał et al. [25] | - 70 children with CKD stages 1–5 treated conservatively, and 12 age-matched healthy peers. - Assessment of the usefulness of fractional excretion (FE) of vitamin D-binding protein (VDBP), retinol-binding protein (RBP4) and heat shock proteins (hsp). | - FE values of all parameters exceeded 1% in CKD st. 2 and raised significantly versus control group: in stage 2—RBP4 and HSF1; stage 3—VDBP; stage 4—Hsp27. |
2018 | Lipiec et al. [29] | - 29 children with a history of HUS endangered with risk of CKD compared to healthy peers. - Assessment of L-FABP and interleukin 6 (IL-6) in serum and urine. | - Children after HUS had significantly higher L-FABP and IL-6 in both serum and urine when compared to healthy peers Values below: group after HUS vs. healthy peers (expressed as a mean and SD): sIL-6 (ng/mL) 79.96 ± 26.68 vs. 7.34 ± 1.43; uIL-6 (ng/mL) 97.64 ± 15.46 vs. 36.87 ± 12.01; sL-FABP (ng/mL) 72.49 ± 18.53 vs. 2.65 ± 0.75; uL-FABP (ng/mL) 11.54 ± 4.32 vs. 2.76 ± 0.63. |
2019 | Bartoli F. et al. [30] | - 80 children with CAKUT (40 hypodysplasia, 22 agenesic, 10 multicystic, 8 nephrectomy) after extensive urological and nephrological workups below 14 years old and without recent urinary tract infection or hypertension and compared to 30 healthy controls. - Evaluation urinary levels of MCP-1, EGF, b2-microglobulin, FAS-ligand. - Assessment of urinary ratios uEGF/uMCP-1 (regenerative versus inflammatory response) and uEGF/ub2-microglobulin (regeneration versus tubular damage). | - uEGF values (pg/mL, mean, SD) were significantly lower in controls (515 ± 168) and nephrectomy children (408 ± 201) in comparison to multidysplastic (794 ± 243), hypodysplastic (754 ± 435) and agenesic (628 ± 252) patients. - Urinary levels of MCP-1 (pg/mL, mean, SD) were highest in multicystic patients (3.3 ± 1.3), but hypodysplastic, agenesic and multicystic participants also had uMCP-1 up-regulated in comparison to controls (2.2 ± 1.6). - Both ratios, uEGF/uMCP-1 and u EGF/ub2-microglobulin, were downregulated in all CAKUT children when compared to healthy participants. |
2019 | Azukaitis et al. [31] | - Children with CKD from 4C study (Cardiovascular Comorbidity in Children with CKD) with baseline eGFR 10–60 mL/min/1.73 m2. - CAKUT were the most common cause of CKD, while glomerular disease accounted for less than 10% of cases. - Urinary EGF (uEGF) measured 6 months after enrolment. | - In a Cox proportional hazards model, higher uEGF/cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69–0.84). |
2019 | Musiał et al. [32] | - 41 CKD children (19 patients on haemodialysis, 22 children on automated peritoneal dialysis) and 23 healthy controls. - Assessment of serum concentration of MCP-1, MCSF and neopterin. | - serum MCP-1, MCSF and neopterin were significantly elevated in all patients versus controls, and the highest values were obtained in hemodialyzed children. - Single hemodialysis sessions lowered the concentrations of all markers; however, they rose before the next procedure. |
2019 | Taranta-Janusz et al. [33] | - 98 children with solitary functioning kidney (SFK) with a median age of 8 years compared to matched 54 healthy peers. - Assessment of PIIINP and beta-catenin in urine. | - uPIIINP in SFK children was statistically higher compared to controls. - No difference in median urinary beta-catenin between the two groups. |
2020 | Nickavar et al. [34] | - 32 children with primary vesicoureteral reflux (mean age 36.84 ± 28.16 months) and 37 healthy peers (mean age 32.32 ± 29.08 months) were evaluated. - Comparison of uNGAL and uNGAL/cr between children with and without VUR. - Kidney parenchymal function assessed using DMSA scans. | - Mean uNGAL and uNGAL/cr were higher in patients with VUR. - The optimal predicting cutoff value for uNGAL/cr with the highest sensitivity and specificity was 0.88 ng/mg (sensitivity 84%, specificity 81%). - uNGAL/cr significantly increased in patients with decreased parenchymal function according to DMSA scans (16.89 ± 32.34 vs. 3.74 ± 10.8 ng/mg, p = 0.041). |
2020 | Staub et al. [35] | - A group of 51 former preterm infants, aged 10–15 years old, were assessed for blood pressure and kidney markers measured in serum and urine (creatinine, NGAL, uromodulin) and only serum (cystatin C, beta-2-microglobulin, beta trace protein) and compared to 82 term-born controls. | - Serum: creatinine and NGAL were significantly higher in the preterm group. - No association between the term of birth and other biomarkers was found. |
2020 | Latoch et al. [36] | - 60 patients previously treated for acute lymphoblastic leukemia (ALL) compared to 53 healthy peers. - Median time after cessation of treatment was 6.55 years, with a median age of 12 years. - Assessment of uNGAL and uKIM-1 and expressed as a ratio to creatinine (uNGAL/cr, uKIM-1/cr) in the study group with consideration of time after the end of treatment, eGFR and cumulative doses of methotrexate and cyclophosphamide. | - Median levels of both uNGAL and uNGAL/cr were significantly higher in ALL survivors than healthy children (uNGAL 3.98; 1.48–11.45 vs. 0.004; 0.001–0.005 ng/mL, p < 0.0001; uNGAL/cr 31.37, 14.23–84.67 vs. 0.004, 0.002–0.007 mg/mg, p < 0.0001; data given as median with interquartile range). - uNGAL seemed to be the best predictor of decreased eGFR (AUC = 0.67). - uKIM-1/cr was significantly higher in ALL survivors than in healthy children (uKIM-1/cr 6.16; 3.29–9.98 vs. 0.93, 0.44–1.48 ng/mg, p < 0.0001; data given as median with interquartile range). - ALL survivors had statistically higher uKIM-1 and eGFR 5 years after the end of treatment when compared to those with an observation period of fewer than 5 years. - Cumulative doses of methotrexate and cyclophosphamide did not predict the values of uNGAL and uKIM-1. |
2020 | Gul et al. [37] | - 50 obese and 26 overweight adolescents aged 10–16 years old compared to 26 normal body weight children in the control group. - Assessment of uNGAL and uKIM-1 in examined children and expressed as a ratio to creatinine. | - No significant differences in uNGAL and uNGAL/cr were found between obese, overweight and normal body weight participants. - uNGAL was higher in overweight or obese children with LDL dyslipidemia as compared to those with LDL within reference values (64.12, 30.98–114.32 vs. 39.51, 25.59–56.37 ng/mL; p = 0.024, data presented as median, Q1–Q3). - There was a correlation between insulin levels (insulin resistance) and uNGAL/cr in overweight participants (r = 0.515, p = 0.008) but not in the obese group. - No significant differences in uKIM-1 were found between obese, overweight and normal body weight participants. |
2020 | Nickavar et al. [34] | - Comparison of uNGAL between children with and without VUR. - Kidney parenchymal function assessed using DMSA scans. | - Mean uNGAL and uNGAL/cr were higher in patients with VUR. - uNGAL/cr significantly increased in patients with decreased parenchymal function according to DMSA scans |
2020 | McLeod et al. [38] | - 22 children with obstructive uropathy were identified in the CKiD cohort receiving KRT and compared to 22 KRT-free controls. - Measurement of urinary and plasma NGAL, IL-18 and L-FAB at enrolment and annually during 5 years of follow-up and comparison between cases and controls. | - No difference between examined biomarkers between KRT children and controls at baseline. - Mean pNGAL and uL-FABP/cr increased throughout the study period in cases (15.38 ng/mL per year and 0.2 ng/mL per mg/dl per year, respectively, p = 0.01 for both) while remaining stable in controls. |
2020 | Greenberg et al. [39] | - 651 participants from the CKiD cohort with eGFR 30–90 mL/min/1.73 m2 with its further assessment annually. - 195 had a glomerular and 456 nonglomerular cause of CKD. - Median age of study participants was 11 years, with the diagnosis of CKD at a median of 8.2 years, and the median follow-up time was 5.7 years. - Assessment of kidney biomarkers in serum: KIM-1, YKL-40, MCP-1, suPAR and TNFR-1/TNFR-2 in relation to eGFR decline in subgroups (glomerular versus nonglomerular cause of CKD) twice: a) baseline (5 months after study enrolment); b) in the primary endpoint (CKD progression defined as 50% decline in EGFR or ESKD). | - All biomarkers were inversely correlated with eGFR, with the strongest relationship between eGFR and TNFR-1 (r = −0.74) - After multivariable adjustment, children with a plasma KIM-1, TNFR-1 and TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration of the respective marker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). - Plasma MCP-1, suPAR and YKL-40 were not independently associated with CKD progression. |
2020 | Weidemann et al. [40] | - 565 participants (age 1–16 years) enrolled from the CKiD cohort. - Assessment of plasma suPAR concentration and categorized by quartiles, measured at study entry and after a 6-month follow-up interval. - Outcome was CKD progression, defined as the need for KRT or more than a 50% decline in eGFR. | - Participants in the highest quartile of plasma suPAR concentration had 54% faster progression of CKD in comparison to those in the lowest quartile. - Plasma suPAR levels showed little change over 6 months. |
2020 | Musiał et al. [41] | - 70 children with conservatively treated CKD stages 1–5 and 12 healthy controls. - Assessment of serum and urine concentration of MCP-1, MCSF, TIMP-2 and survivin. | - Serum concentrations of all parameters were significantly elevated at CKD stage 1 compared to controls - Urinary MCP-1 and MCSF (stages 1–2) rose earlier than TIMP-2 or survivin |
2020 | Stabouli et al. [42] | - 33 CKD participants, 18 T1D patients, 24 healthy controls. - Assessment of MMP-2 and MMP-9 between studied groups. - Measurements of office BP, pulse wave analysis and carotid–femoral pulse wave velocity. | - MMP-2 values were higher in the CKD compared to diabetes patients and healthy participants. - MMP-9 values did not differ between these groups. - Only MMP-2 correlated positively with creatinine in CKD patients and negatively in diabetic participants. - MMP-2 was associated with arterial stiffness indicators in the presence of hypertension. |
2021 | Anand et al. [43] | - 50 children with CAKUT, aged <14 years old, were divided into group 1 (without CKD) or group 2 (with CKD) compared to healthy peers. - Measurement of NGAL; trefoil family factors (TFF) 1, 3; and albuminuria in the urine at the beginning and after 1 year of follow-up. Kidney function was assessed using DTPA, DMSA scans and GFR at baseline and after 1 year of observation (assessed using Schwartz formula). | - Median concentrations of uNGAL (281.2 mcg/g cr.), TFF 1 (44.5 mcg/gcr.) and TFF 3 (176.5 mcg/g cr.) were significantly higher in CAKUT patients in comparison to controls (p < 0.05). - Children with progressive deterioration of kidney function (group 2) had higher uNGAL than those from group 1 (without CKD progression). - TFF 3 was found to have the highest AUC (0.919) on the ROC curve for predicting progressive kidney functional deterioration. |
2021 | Leiber et al. [44] | - Cross-sectional study of 210 children living in a MeN endemic region of Nicaragua. - Evaluation of urinary kidney biomarkers: NGAL, KIM-1, IL-18, MCP-1, YKL-40 and its association with eGFR. - Comparison of the levels of the above markers between the study group and healthy children from other countries. | - Median uNGAL, uIL-18 and uKIM-1 were significantly higher in the study group. - A one-year increase in age was associated with a 40% increase in odds of being in the highest quartile of uNGAL. - Children with dysuria had 2.5 times the odds of having uNGAL in the highest quartile. |
2021 | Będzichowska et al. [45] | - 59 children with kidney disorders that had indications for renoscintigraphy were divided into two groups with renal scarring and with normal kidney pictures. - Assessment of eGFR calculated by Schwartz formula (children with glomerular hyperfiltration defined as EGFR ≥ 130 mL/min/1.73 m2 versus normal filtration with eGFR <130 mL/min/1.73 m2) and new kidney biomarkers, including serum: KIM-1, FGF-23, NAG, NGAL and uromodulin, and urinary: NGAL and uromodulin. | - Children with hyperfiltration had higher sNGAL and FGF-23. - No significant differences were found between the children with hyperfiltration and normal filtration in terms of blood levels of KIM-1, FGF-23, NAG, NGAL and uromodulin, and urinary NGAL and uromodulin. |
2021 | Jacobson et al. [46] | - 618 participants from the CKiD cohort (pediatric CKD patients from the US and Canada) were enrolled to assess whether exposure to environmental chemicals, such as pesticides, impacts renal function and chronic kidney disease (CKD). - Children were followed over an average of 3 years. - In serially collected urine samples over time, six nonspecific dialkyl phosphate (DAP) metabolites of pesticides were measured together with kidney biomarkers: NGAL, KIM-1. - Assessment of eGFR and proteinuria was performed annually. | - There was no relation between DAPs and uNGAL or other clinical renal outcomes: proteinuria and blood pressure. - Although DAPs were associated with lower eGFR at baseline, there was a tendency of higher eGFR over follow-up that seemed to be inconsistent. - DAPs were associated with increased KIM-1 urinary excretion over time, suggesting the presence of subclinical kidney injury. |
2021 | Sethi et al. [47] | - 44 children after cardiac surgery with cardiopulmonary bypass who had postoperative AKI in comparison to 49 healthy peers. - Median follow-up of 41 months. - Assessment of urinary: NGAL, IL-18, KIM-1 with adjusting for creatinine concentration. | - The cases had significantly higher uNGAL, uIL-18 and uKIM-1 on follow-up, and values remained higher after adjusting for urine creatinine, - None of the patients had proteinuria or hypertension, |
2021 | Ahn et al. [48] | - 55 children and adolescents with T1D and T2D were divided into two subgroups with normal and high albuminuria. - 44 healthy controls. - Evaluation of KIM-1 in urine and plasma. | - pKIM-1 concentration was significantly higher in diabetic children compared to controls. - Similarly, pKIM-1 was higher in high albuminuric than normoalbuminuric participants. - HbA1c was identified as an important risk factor for increased pKIM-1. |
2021 | Williams et al. [49] | - Systematic review of urine biomarkers in children with IgA vasculitis nephritis in terms of clinical and pre-clinical ability to predict the presence of nephritis and subsequent CKD. - 13 eligible studies with a total of 2446 pediatric patients: 1236 children with IgAV-N, 449 children with IgAV without nephritis and 761 healthy controls - Assessment of severity of nephritis with “old” indicators: 24-hour protein excretion in urine, protein/creatinine ratio in urine, urinary albumin concentration. | - Most promising urinary biomarkers in predicting the presence of nephritis were: KIM-1 (AUC 0.93), MCP-1 (AUC 0.83), NAG (0.76). - They appeared to correlate with disease severity |
2021 | Nosek et al. [50] | - 80 children with congenital or acquired SFK compared to healthy controls. - Serum TWEAK and urinary MCP-1 and RANTES were assessed in relation to kidney function (serum creatinine, eGFR, albuminuria, hypertension) | - Serum TWEAK and urinary MCP-1 and RANTES levels were higher in SFK patients |
2021 | Sandokij et al. [51] | - participants from the CKiD cohort, the group from the previous study of Greenberg et al. [38]. - uMCP-1 assessment of baseline (5 months after study enrolment) and in the primary endpoint (CKD progression defined as 50% decline in EGFR or ESKD). - Children with different causes of CKD (glomerular versus nonglomerular) | - In the CKiD cohort, uMCP-1 was related to CKD progression. - After adjustment for eGFR, hypertension and proteinuria, children with uMCP-1 in the fourth quartile had a significantly higher risk of CKD progression in comparison with those having uMCP-1 in the lowest quartile. - It was evident in patients with autosomal recessive polycystic kidney disease (ARPKD). - uMCP-1 was highly correlated with uKIM-1 (r = 0.7, p < 0.01). |
2021 | Turczyn et al. [52] | - 81 children with congenital obstructive nephropathy and 60 healthy controls. - Assessing the severity of renal fibrosis based on 99mTC-ethylenedicysteine scintigraphy scans: severe, moderate and borderline lesions. - Investigation of predictive value if urinary endoglin, periostin, cytokeratin-18, TGF- β1. | - Urinary: periostin, periostin/cr and cytokeratin-18 levels were higher in the study group when compared to controls. - Children with severe scars had higher urinary periostin/cr than those with borderline changes. - Periostin and cytokeratin-18 were independently related to the presence of severe and moderate scarring. - TGF- β1 demonstrated low utility for assessing renal fibrosis in children with obstructive nephropathy. |
2021 | Tuncay et al. [53] | - 50 patients diagnosed with pre-dialytic CKD and 30 healthy controls. -Measurement of serum: IL-8, IL-10, IL-13 and TGF- β1. - Assessment of carotid–femoral pulse wave velocity, carotid intima-media thickness and left ventricular mass index as markers of cardiovascular disease. | - Only serum IL-8 was higher in CKD patients. - No difference in levels of IL-8, IL-10, IL-13, TGF- β1 in CKD patients with and without cardiovascular disease. |
2021 | Denburg et al. [54] | - Metabolomics quantification of plasma samples from 645 children (median age 12 years) with chronic kidney disease (CKiD cohort participants). - Metabolites were standardized and logarithmically transformed. - Assessing the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% decline of eGFR adjusting for age, sex, race, body mass index, hypertension, glomerular vs. nonglomerular diagnosis, proteinuria and baseline eGFR. - Median time of follow-up was 4.8 years. | - Among participants with baseline eGFR ≥ 60 mL/min/1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three of purine or pyrimidine metabolism (N6-carbamoylthreonyladenosine, dihydrouridine, pseudouridine), two amino acids (C-glycosyltryptophan, lanthionine), the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate and gulonate. - In those with baseline eGFR < 60 mL/min/1.73 m2, a higher level of tetrahydrocortisol sulfate was associated with a lower risk of progression of CKD. |
2022 | Johnson et al. [55] | - 50 adolescents with T1D were examined and compared to 20 healthy BMI- and age-matched controls. - Assessment of the relationship between intrarenal hemodynamic function (assessed with intraglomerular pressure, efferent arteriole resistance, afferent arteriolar resistance or renal plasma flow, GFR, albumin/creatinine ratio) and kidney biomarkers in urine (NGAL, IL-18, KIM-1, YKL-40, MCP-1 and copeptin). | - YKL-40 and KIM-1 concentrations were positively associated with GFR, renal plasma flow, albumin/creatinine ratio, and intraglomerular pressure in T1D adolescents. - No significant association between NGAL, IL-18, MCP-1, and intrarenal hemodynamic function indicators was found. |
2022 | Guansekara et al. [56] | - School students (10–18 years old) from endemic areas are endangered with CKD compared to children from non-endemic regions. - Assessment of the utility of kidney biomarkers in urine as early detectors of the disease (uNGAL, uKIM-1) and in relation to albuminuria. | - Endemic participants reported no difference in the uNGAL levels. - Children from endemic regions had higher uKIM-1 expression compared to those from other regions - Albuminuric participants reported elevated uKIM-1 levels compared to normoalbuminuric |
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Rybi Szumińska, A.; Wasilewska, A.; Kamianowska, M. Protein Biomarkers in Chronic Kidney Disease in Children—What Do We Know So Far? J. Clin. Med. 2023, 12, 3934. https://doi.org/10.3390/jcm12123934
Rybi Szumińska A, Wasilewska A, Kamianowska M. Protein Biomarkers in Chronic Kidney Disease in Children—What Do We Know So Far? Journal of Clinical Medicine. 2023; 12(12):3934. https://doi.org/10.3390/jcm12123934
Chicago/Turabian StyleRybi Szumińska, Agnieszka, Anna Wasilewska, and Monika Kamianowska. 2023. "Protein Biomarkers in Chronic Kidney Disease in Children—What Do We Know So Far?" Journal of Clinical Medicine 12, no. 12: 3934. https://doi.org/10.3390/jcm12123934
APA StyleRybi Szumińska, A., Wasilewska, A., & Kamianowska, M. (2023). Protein Biomarkers in Chronic Kidney Disease in Children—What Do We Know So Far? Journal of Clinical Medicine, 12(12), 3934. https://doi.org/10.3390/jcm12123934