Child Kidney Dis.  2025 Feb;29(1):12-18. 10.3339/ckd.25.004.

Biomarkers for the early diagnosis of Alport syndrome and associated kidney damage

• Nguyen HDT
• Cho MH

• KMID: 2565476
• DOI: http://doi.org/10.3339/ckd.25.004

Abstract

Alport syndrome (AS) is a hereditary nephropathy characterized by progressive kidney damage that commonly leads to endstage 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 often present, it is insufficient for 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.

Keyword

Alport syndrome; Biomarkers; Diagnosis; Proteinuria

Figure

• 

  Fig. 1. Biomarkers of kidney damage in Alport syndrome. PDlim2, PDZ and LIM domain 2; NOX4, NADPH oxidase 4; DDR1, discoidin domain receptor tyrosine kinase 1; MCP-1, monocyte chemoattractant protein-1; miR-21, microRNA-21; TNS1, tensin 1; CCND1, cyclin D1; GJA5, gap junction protein alpha-5; uEGF, urine epidermal growth factor.

Reference

References

1. Kim JH. Alport syndrome: new advances in the last decade. Child Kidney Dis. 2022; 26:31–9. DOI: 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. DOI: 10.1007/s00467-020-04819-6. PMID: 33159213.

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. DOI: 10.1074/jbc.273.15.8767. PMID: 9535854.

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. DOI: 10.1007/s10157-018-1629-4. PMID: 30128941.

5. Kashtan CE, Ding J, Garosi G, Heidet L, Massella L, Nakanishi K, et al. Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport syndrome classification working group. Kidney Int. 2018; 93:1045–51. DOI: 10.1016/j.kint.2017.12.018. PMID: 29551517.

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. DOI: 10.1681/asn.v114649. PMID: 10752524.

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. DOI: 10.5402/2012/436046. PMID: 22811928.

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. DOI: 10.1038/ki.2011.407. PMID: 22166847.

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. DOI: 10.1016/j.ekir.2023.09.028. PMID: 38106579.

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. DOI: 10.1021/acs.jproteome.5b00814. PMID: 26487288.

11. Dennis J, Meehan DT, Delimont D, Zallocchi M, Perry GA, O'Brien S, et al. Collagen XIII induced in vascular endothelium mediates alpha1beta1 integrin-dependent transmigration of monocytes in renal fibrosis. Am J Pathol. 2010; 177:2527–40. DOI: 10.2353/ajpath.2010.100017. PMID: 20864678.

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. DOI: 10.1161/atvbaha.109.200451. PMID: 20042707.

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. DOI: 10.1093/ndt/11.6.1024. PMID: 8671963.

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. DOI: 10.1007/s40620-021-01015-z. PMID: 33761123.

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. DOI: 10.3390/ijms222413281. PMID: 34948078.

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. DOI: 10.1182/blood-2005-04-1658. PMID: 16105980.

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. DOI: 10.1038/s41598-017-15993-3. PMID: 29167507.

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. DOI: 10.1016/j.kint.2016.02.018. PMID: 27165837.

19. Schiffrin EL, Pollock DM. Endothelin system in hypertension and chronic kidney disease. Hypertension. 2024; 81:691–701. DOI: 10.1161/hypertensionaha.123.21716. PMID: 38059359.

20. Husain S. Role of podocyte in kidney disease. Front Biosci (Landmark Ed). 2024; 29:250. DOI: 10.31083/j.fbl2907250. PMID: 39082335.

21. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 1998; 54:687–97. DOI: 10.1046/j.1523-1755.1998.00044.x. PMID: 9734594.

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. DOI: 10.1016/j.kint.2017.05.017. PMID: 28754557.

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. DOI: 10.1016/j.kint.2021.08.026. PMID: 34562503.

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. DOI: 10.1016/j.ekir.2023.06.007. PMID: 37705901.

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. DOI: 10.1016/j.ebiom.2020.103162. PMID: 33340991.

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. DOI: 10.1681/asn.2020101442. PMID: 34049963.

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. DOI: 10.1038/s41598-020-67588-0. PMID: 32651395.

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. DOI: 10.1111/bcp.15446. PMID: 35748053.

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. DOI: 10.3410/f.725982757.793522730. PMID: 26631632.

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. DOI: 10.1007/s00467-018-3988-1. PMID: 29948307.

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. DOI: 10.1093/ndt/gfz082. PMID: 31089695.

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. DOI: 10.1016/j.ekir.2022.01.1052. PMID: 35571002.

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. DOI: 10.1089/hum.2018.205. PMID: 30808234.

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. DOI: 10.7150/thno.95908. PMID: 38773973.

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. DOI: 10.1172/jci.insight.165515. PMID: 38516889.