Childhood Kidney Diseases

Korean Society of Pediatric Nephrology (대한소아신장학회)
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Biomarkers for the early diagnosis of Alport syndrome and associated kidney damage

  • Hong Duc Thi Nguyen (Department of Biomedical Science, Graduate School, Kyungpook National University) ;
  • Min Hyun Cho (Department of Pediatrics, School of Medicine, Kyungpook National University)
  • Received : 2025.01.01
  • Accepted : 2025.02.03
  • Published : 2025.02.28
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Abstract

Alport syndrome (AS) is a hereditary nephropathy characterized by progressive kidney damage that commonly leads to end-stage kidney disease. Early diagnosis is critical, as preemptive nephroprotective therapy, such as angiotensin-converting enzyme inhibitors, can significantly delay disease progression. However, the early diagnosis of AS remains challenging due to the lack of reliable preclinical or screening biomarkers, particularly before the onset of proteinuria. Although nonspecific microhematuria is oftenpresent, itis insufficientfor definitive early detection.Recent studies have identified potential early cellular alterations as candidate biomarkers for the preclinical detection of AS, but none have been widely implemented in clinical practice. This review presents the current knowledge on early biomarkers of kidney damage for AS, highlights promising avenues for future research, and emphasizes the importance of developing effective diagnostic tools to enable timely intervention and improve patient outcomes.

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References

  1. Kim JH. Alport syndrome: new advances in the last decade. Child Kidney Dis 2022;26:31-9. https://doi.org/10.3339/ckd.22.022
  2. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol 2021;36:711-9. https://doi.org/10.1007/s00467-020-04819-6
  3. Gunwar S, Ballester F, Noelken ME, Sado Y, Ninomiya Y, Hudson BG. Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem 1998;273:8767-75. https://doi.org/10.1074/jbc.273.15.8767
  4. Nozu K, Nakanishi K, Abe Y, Udagawa T, Okada S, Okamoto T, et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. Clin Exp Nephrol 2019;23:158-68. https://doi.org/10.1007/s10157-018-1629-4
  5. Kashtan CE, Ding J, Garosi G, Heidet L, Massella L, Nakanishi K, et al. Alport syndrome: aunified classificationof genetic disorders of collagen IV α345: a position paper of the Alport syndrome classification working group. Kidney Int 2018;93:1045-51. https://doi.org/10.1016/j.kint.2017.12.018
  6. Jais JP, Knebelmann B, Giatras I, Marchi M, Rizzoni G, Renieri A, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 2000;11:649-57. https://doi.org/10.1681/ASN.V114649
  7. Gross O, Friede T, Hilgers R, Gorlitz A, Gavenis K, Ahmed R, et al. Safety and efficacy of the ACE-inhibitor ramipril in Alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr 2012;2012:436046. https://doi.org/10.5402/2012/436046
  8. Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tonshoff B, et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int 2012;81:494-501. https://doi.org/10.1038/ki.2011.407
  9. Rhode H, Luse A, Tautkus B, Nabity M, John-Kroegel U, Weigel F, et al. Urinary protein-biomarkers reliably indicate very early kidney damage in children with Alport syndrome independently of albuminuria and inflammation. Kidney Int Rep 2023;8:2778-93. https://doi.org/10.1016/j.ekir.2023.09.028
  10. Muckova P, Wendler S, Rubel D, Buchler R, Alert M, Gross O, et al. Preclinical alterations in the serum of COL(IV)A3(-)/(-) mice as early biomarkers of Alport syndrome. J Proteome Res 2015;14:5202-14. https://doi.org/10.1021/acs.jproteome.5b00814
  11. Dennis J, Meehan DT, Delimont D, Zallocchi M, Perry GA, O'Brien S, et al. Collagen XIII induced in vascular endothelium mediates alpha-1beta1 integrin-dependent transmigration of monocytes in renal fibrosis.AmJPathol 2010;177:2527-40.
  12. Mambetsariev N, Mirzapoiazova T, Mambetsariev B, Sammani S, Lennon FE, Garcia JG, et al. Hyaluronic acid binding protein 2 is a novel regulator of vascular integrity. Arterioscler Thromb Vasc Biol 2010;30:483-90. https://doi.org/10.1161/ATVBAHA.109.200451
  13. Lhotta K, Schlogl A, Kronenberg F, Joannidis M, Konig P. Glomerular deposition of the complement C4 isotypes C4A and C4B in glomerulonephritis. Nephrol Dial Transplant 1996;11:1024-8. https://doi.org/10.1093/oxfordjournals.ndt.a027450
  14. Chimenz R, Chirico V, Basile P, Carcione A, Conti G, Monardo P, et al. HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome. J Nephrol 2021;34:1915-24. https://doi.org/10.1007/s40620-021-01015-z
  15. Yu CJ, Damaiyanti DW, Yan SJ, Wu CH, Tang MJ, Shieh DB, et al. The pathophysiologic role of gelsolin in chronic kidney disease: focus on podocytes. Int J Mol Sci 2021;22:13281. https://doi.org/10.3390/ijms222413281
  16. Jia W, Li H, He YW. The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment. Blood 2005;106:3854-9. https://doi.org/10.1182/blood-2005-04-1658
  17. Naudin C, Smith B, Bond DR, Dun MD, Scott RJ, Ashman LK, et al. Characterization of the early molecular changes in the glomeruli of Cd151 -/- mice highlights induction of mindin and MMP-10. Sci Rep 2017;7:15987. https://doi.org/10.1038/s41598-017-15993-3
  18. Dufek B, Meehan DT, Delimont D, Cheung L, Gratton MA, Phillips G, et al. Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. Kidney Int 2016;90:300-10. https://doi.org/10.1016/j.kint.2016.02.018
  19. Schiffrin EL, Pollock DM. Endothelin system in hypertension and chronic kidney disease. Hypertension 2024;81:691-701. https://doi.org/10.1161/HYPERTENSIONAHA.123.21716
  20. Husain S. Role of podocyte in kidney disease. Front Biosci (Landmark Ed) 2024;29:250. https://doi.org/10.31083/j.fbl2907250
  21. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 1998;54:687-97. https://doi.org/10.1046/j.1523-1755.1998.00044.x
  22. Ding F, Wickman L, Wang SQ, Zhang Y, Wang F, Afshinnia F, et al. Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport syndrome. Kidney Int 2017;92:1515-25. https://doi.org/10.1016/j.kint.2017.05.017
  23. Frank CN, Hou X, Petrosyan A, Villani V, Zhao R, Hansen JR, et al. Effect of disease progression on the podocyte cell cycle in Alport syndrome. Kidney Int 2022;101:106-18. https://doi.org/10.1016/j.kint.2021.08.026
  24. Tong J, Zheng Q, Gu X, Weng Q, Yu S, Fang Z, et al. COL4A3 mutation induced podocyte apoptosis by dysregulation of NADPH oxidase 4 and MMP-2. Kidney Int Rep 2023;8:1864-74. https://doi.org/10.1016/j.ekir.2023.06.007
  25. Kim JJ, David JM, Wilbon SS, Santos JV, Patel DM, Ahmad A, et al. Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome. EBioMedicine 2021;63:103162. https://doi.org/10.1016/j.ebiom.2020.103162
  26. Randles MJ, Lausecker F, Kong Q, Suleiman H, Reid G, Kolatsi-Joannou M, et al. Identification of an Altered matrix signature in kidney aging and disease. J Am Soc Nephrol 2021;32:1713-32. https://doi.org/10.1681/ASN.2020101442
  27. Soloyan H, Thornton M, Villani V, Khatchadourian P, Cravedi P, Angeletti A, et al. Glomerular endothelial cell heterogeneity in Alport syndrome. Sci Rep 2020;10:11414. https://doi.org/10.1038/s41598-020-67588-0
  28. Nyimanu D, Chapman FA, Gallacher PJ, Kuc RE, Williams TL, Newby DE, et al. Apelin is expressed throughout the human kidney, is elevated in chronic kidney disease & associates independently with decline in kidney function. Br J Clin Pharmacol 2022;88:5295-306. https://doi.org/10.1111/bcp.15446
  29. Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PX, et al. Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci Transl Med 2015;7:316ra193.
  30. Li B, Zhang Y, Wang F, Nair V, Ding F, Xiao H, et al. Urinary epidermal growth factor as a prognostic marker for the progression of Alport syndrome in children. Pediatr Nephrol 2018;33:1731-9. https://doi.org/10.1007/s00467-018-3988-1
  31. Tam FW, Ong AC. Renal monocyte chemoattractant protein-1: an emerging universal biomarker and therapeutic target for kidney diseases? Nephrol Dial Transplant 2020;35:198-203. https://doi.org/10.1093/ndt/gfz082
  32. Kashtan C, Schachter A, Klickstein L, Liu X, Jennings L, Finkel N. Urinary monocyte chemoattractant protein-1 in patients with Alport syndrome. Kidney Int Rep 2022;7:1112-4. https://doi.org/10.1016/j.ekir.2022.01.1052
  33. Guo J, Song W, Boulanger J, Xu EY, Wang F, Zhang Y, et al. Dysregulated expression of microRNA-21 and disease-related genes in human patients and in a mouse model of Alport syndrome. Hum Gene Ther 2019;30:865-81. https://doi.org/10.1089/hum.2018.205
  34. Cao J, Li C, Cui Z, Deng S, Lei T, Liu W, et al. Spatial transcriptomics: a powerful tool in disease understanding and drug discovery. Theranostics 2024;14:2946-68. https://doi.org/10.7150/thno.95908
  35. Clair G, Soloyan H, Cravedi P, Angeletti A, Salem F, Al-Rabadi L, et al. The spatially resolved transcriptome signatures of glomeruli in chronic kidney disease. JCI Insight 2024;9:e165515. https://doi.org/10.1172/jci.insight.165515