Alport syndrome: our knowledge update
https://doi.org/10.36485/1561-6274-2021-25-3-75-83
Abstract
Alport syndrome is a progressive multisystem disease associated with variants in genes COL4A3, COL4A4, COL4A5.The syndrome is an important genetic cause of kidney failure, including women with X-linked disease. Given the unfavorable natural history of Alport nephropathy and benefit from early treatment with angiotensin-converting enzyme inhibition, it is necessary to change our diagnostic approach in patients with persistent glomerular hematuria and management of patients with Alport syndrome. This review presents the ethiology, pathogenesis, genotype and phenotype heterogeneity of the syndrome and expert clinical practice recommendations to enhancing early diagnosis and achieving optimal outcomes in Alport syndrome.
About the Author
M. E. Aksenova
Department of Hereditary and Acquired Kidney Diseases named after Professor M.S. Ignatova, Scientific Research Institute of Pediatrics named after Academician Yu.E. Veltischev, Russian National Research Medical University named after N.I. Pirogov
Russian Federation
Russian Federation
Marina E. Aksenova, MD, PhD, Leading Researcher
125412 Moscow, Taldomskaya str., 2
Tel.: 8 495 4832183, 89166148139
References
1. Guthrie LG. Idiopathic or congenital, hereditary and family hematuria. Lancet1992;1:1243–1246. doi: 10.1001/jama.1902.02480220032009
2. Eason J, Smith GLM, Buchanan G. Hereditary and familial nephritis. Lancet1924;2:639–646
3. Hurst AF. Hereditary familial congenital hemorrhagic nephritis occurring in 16 individuals in three operations. Guy Hosp Rep1923;73:368–370
4. Alport AC. Hereditary familial congenital haemorrhagic nephritis. Br Med J1927;1:504–506. doi: 10.1136/bmj.1.3454.504
5. Gast C, Pengelly RJ, Lyon M et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 2016;31(6):961–970. doi: 10.1093/ndt/gfv325
6. Groopman EE, Marasa M, Cameron-Christie S et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med2019;10;380(2):142–151. doi: 10.1056/NEJMoa1806891
7. Neild GH. Primary renal disease in young adults with renal failure. Nephrol Dial Transplant2010;25(4):1025–1032. doi:10.1093/ndt/gfp653
8. Zhai Y, Liu X, Yang Q et al. IPDN-China promotes the development of pediatric dialysis in China. Pediatr Nephrol 2020;35(11):2163–2171. doi: 10.1007/s00467-020-04630-3
9. Abrahamson D, Hudson B, Stroganova L et al. Cellular origins of type IV collagen networks in developing glomeruli. JASN 2009;20:1471–1479. doi: 10.1681/ASN.2008101086
10. Gosgrove D, Liu S. Collagen IV diseases: a focus on the glomerular basement membrane in Alport syndrome. Matrix Biol 2017;57–58:45–54. doi:10.1016/j.matbio.2016.08.005
11. Tsuji K, Suleiman H, Miner JH et al. Ultrastructural Characterization of the Glomerulopathy in Alport Mice by Helium Ion Scanning Microscopy (HIM). Sci Rep2017;7(1):11696. doi: 10.1038/s41598-017-12064-5
12. Lin X, Suh JH, Go G, Miner JH. Feasibility of repairing glomerular basement membrane defects in Alport syndrome. J Am Soc Nephrol2014;25(4):687–692. doi: 10.1681/ASN.2013070798
13. Zeisberg M, Neilson E. Mechanisms of tubulointerstitial fibrosis. JASN2010; 21:1819–1834. doi: 10.1681/ASN.2010080793
14. Wickman L, Hodgin JB, Wang SQ et al. Podocyte depletion in thin GBM and Alport syndrome. PLoS One 2016;11(5):e0155255. doi: 10.1371/journal.pone.0155255
15. D’Agati VD. Podocyte growing pains in adaptive FSGS. JASN2017;28(10): 2825–2827. doi: 10.1681/ASN.2017060612
16. Aksenova M, Konkova N, Shagam L, Povilaitite P. Clinical significance of renal tissue ultrastructal cahanges in children wirh X-linked Alport syndrome Pediatriya – Zhurnal im G.N. Speranskogo. 2019; 98(5):14–19 (In Russ.)
17. Kashtan CE. Long-term management of Alport syndrome in pediatric patients.Pediatric Health Med Ther2013;4:41–45. doi:10.2147/PHMT.S35667
18. Meehan DT, Delimont D, Dufek B et al. Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice.Hear Res2016;341:100–108. doi: 10.1016/j.heares.2016.08.003
19. Choi J, Na K, Bae S, Roh G. Anterior lens capsule abnormalities in Alport syndrome. Korean J Ophthalmol2005;19:84–89. doi: 10.3341/kjo.2005.19.1.84
20. Tan R, Colville D, Wang Y et al. Alport retinopathy results from “severe” COL4A5 mutations and predicts early renal failure. CJASN 2010; 5:34–38. doi: 10.2215/CJN.01030209
21. Citirik M, Batman C, Men G et al. Electron microscopic examination of the anterior lens capsule in a case of Alport’s syndrome.Clin Exp Optom 2007; 90:367–370. doi: 10.1111/j.1444-0938.2007.00134.x
22. Colville D, Savige J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet 1997;18:161–173. PMID: 9457747
23. Wilson M, Trivedi R, Biber J, Golub R. Anterior capsule rupture and subsequent cataract formation in Alport syndrome. J AAPOS2006; 10:182–183. doi:10.1016/j.jaapos.2005.09.008
24. Díez-del Hoyo F, Sanz-Ruiz R, Díez-Villanueva P et al. A novel cardiovascular presentation of Alport Syndrome: spontaneous coronary artery dissection. Int J Cardiol2014;177(3):e133–134. doi: 10.1016/j.ijcard.2014.09.065
25. Kashtan C, Segal Y, Flinter F et al. Aortic abnormalities in males with Alport syndrome. Nephrol Dial Transplant 2010;25(11):3554–3560. doi: 10.1093/ndt/gfq271
26. Earl T, Khan L, Hagau D, Fernandez A. The spectrum of aortic pathology in Alport syndrome: a case report and review of the literature. Am J Kidney Dis2012;60(5):821–822. doi: 10.1053/j.ajkd.2012.06.024
27. Zhang Y, Ding J, Zhang H et al. Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X-linked Alport syndrome. Mol Genet Genomic Med 2019;7:e647. doi: 10.1002/mgg3.647
28. Mencarelli MA, Heidet L, Storey H et al. Evidence of digenic inheritance in Alport syndrome. J Med Genet 2015;52(3):163–174. doi: 10.1136/jmedgenet-2014-102822
29. Kashtan CE, Ding J, Garosi G 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 Int2018;93(5):1045–1051. doi: 10.1016/j.kint.2017.12.018
30. Jais JP, Knebelmann B, Giatras I et al. X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. J Am Soc Nephrol2003;14(10):2603–2610. doi: 10.1097/01.asn.0000090034.71205.74
31. Savige J, Colville D, Rheault M et al. Alport Syndrome in Women and Girls. Clin J Am Soc Nephrol2016 Sep 7;11(9):1713–1720. doi: 10.2215/CJN.00580116.
32. Aksenova M, Shagam L, Konkova N, Dlin V. X-linked Alport syndrome in females: experience of one center. Pediatr Nephrol 2018;33:1913. doi:10.1007/s00467-018-4028-x
33. Savige J, Storey H, Il Cheong H et al. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.PLoS One 2016;11(9):e0161802. doi: 10.1371/journal.pone.0161802
34. Kamiyoshi N, Nozu K, Fu XJ et al. Genetic, clinical and pathologic backgrounds of patients with autosomal dominant Alport syndrome.Clin J Am Soc Nephrol2016;11(8):1441–1449. doi: 10.2215/CJN.01000116
35. Fallerini C, Baldassarri M, Trevisson E et al. Alport syndrome: impact of digenic inheritance in patients management. Clin Genet2017;92(1):34–44. doi: 10.1111/cge.12919
36. Bekheirnia MR, Reed B, Gregory MC et al. GenotypePhenotype correlation in X-linked Alport Syndrome. J Am Soc Nephrol2010(21):876–883. doi:10.1681/ASN.2009070784
37. Kashtan CE. Alport syndrome and the X chromosome: implications of a diagnosis of Alport syndrome in females. Nephrol Dial Transplant 2007;22(6):1499–1505. doi: 10.1093/ndt/gfm024
38. Żurowska AM, Bielska O, Daca-Roszak P et al. Mild Xlinked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife. Kidney Int 2020;10:S0085–2538(20)31410-1. doi: 10.1016/j.kint.2020.10.040
39. Gao E, Yang X, Si N et al. Novel COL4A5 Splicing Mutation Causes Skipping of Exon 14 in a Chinese Family with Alport Syndrome. Kidney Dis2020;6(1):43–49. doi:10.1159/000502798
40. Bu L, Chen J, Nelson AC et al. Somatic Mosaicism in a Male Patient With X-linked Alport Syndrome. Kidney Int Rep 2019;4(7):1031–1035. doi: 10.1016/j.ekir.2019.03.005
41. Kamura M, Yamamura T, Omachi K et al. Trimerization and Genotype-Phenotype Correlation of COL4A5 Mutants in Alport Syndrome. Kidney Int Rep 2020;5(5):718–726. doi:10.1016/j.ekir.2020.01.008
42. Daga S, Fallerini C, Furini S et al. Non-collagene genes role in digenic Alport syndrome. BMC Nephrol2019;20(1):70. doi:10.1186/s12882-019-1258-5
43. Mohammad M, Nanra R, Colville D et al. A female with X-linked Alport syndrome and compound heterozygous COL4A5 mutations. Pediatr Nephrol2014;29(3):481–485. doi: 10.1007/s00467-013-2682-6
44. Li Y, Groopman EE, D'Agati V et al. Type IV Collagen Mutations in Familial IgA Nephropathy. Kidney Int Rep2020;5(7):1075–1078. doi:10.1016/j.ekir.2020.04.011
45. Tishler PV, Rosner B. The genetics of Alport syndrome. Birth Defects1974(10):93. PMID: 4470916
46. Flinter FA, Cameron JS, Chantler C et al. Genetics of classic Alport’s syndrome. Lancet1988;2:1005–1007. doi: 10.1016/s0140-6736(88)90753-2
47. Hanson H, Storey H, Pagan J, Flinter F. The Value of Clinical Criteria in Identifying Patients with X-Linked Alport Syndrome. Clin J Am Soc Nephrol2011;6(1):198–203. doi: 10.2215/CJN.00200110
48. Savige J, Gregory M, Gross O et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol2013;24(3):364–375. doi: 10.1681/ASN.2012020148J
49. Ohtsubo H, Morisada N, Kaito H et al. Alport-like glomerular basement membrane changes with renal-coloboma syndrome. Pediatr Nephrol2012;27(7):1189–1192. doi: 10.1007/s00467-012-2125-9
50. Han KH, Lee H, Kang HG et al. Renal manifestations of patients with MYH9-related disorders. Pediatr Nephrol 2011;26(4):549–555. doi: 10.1007/s00467-010-1735-3
51. Gross O, Licht C, Anders HJ et al. Early angiotensinconverting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int2012(5):494–501. doi: 10.1038/ki.2011.407
52. Yamamura T, Horinouchi T, Nagano C et al. Genotype-phenotype correlations influence the response to angiotensin-targeting drugs in Japanese patients with male X-linked Alport syndrome. Kidney Int2020(6):1605–1614. doi: 10.1016/j.kint.2020.06.038
53. Weinstock BA, Feldman DL, Fornoni A et al. Workshop Participants. Clinical trial recommendations for potential Alport syndrome therapies. Kidney Int 2020(6):1109–1116. doi: 10.1016/j.kint.2020.02.029
54. Kashtan CE, Gross O. Clinical practice recommendation for the diagnosis and management of Alport syndrome in children, adolescents, and young adults – an update for 2020.Pediatr Nephrol2021(3):711–719. doi:10.1007/s00467-020-04819-6
55. Kashtan CE, Ding J, Gregory M et al. Clinical practice recommendations for the treatment of Alport Syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol 2013;28(1):5–11. doi: 10.1007/s00467-012-2138-4
56. Gross O, Tönshoff B, Weber LT et al. German Pediatric Nephrology (GPN) Study Group and EARLY PRO-TECT Alport Investigators. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int2020(6):1275–1286. doi: 10.1016/j.kint.2019.12.015
57. Gross O, Beirowski B, Koepke ML et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int2003 Feb;63(2):438–446. doi: 10.1046/j.1523-1755.2003.00779.x
58. Aksenova ME, Konkova NE, Tutelman KM. Blood pressure level and progression of renal disease in children with Х-linked Alport syndrome. Nephrology (Saint-Petersburg)2020;24(6):78–84. (In Russ.). doi:10.36485/1561-6274-2020-24-6-78-84
59. Yamamura T, Horinouchi T, Adachi T et al. Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. Nat Commun2020;2;11(1):2777. doi: 10.1038/s41467-020-16605-x
60. Guo J, Song W, Boulanger J 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(7):865–881. doi: 10.1089/hum.2018.205
61. A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome – CARDINAL (CARDINAL). [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT03019185
62. Mabillard H, Sayer JA. SGLT2 inhibitors – a potential treatment for Alport syndrome. Clin Sci (Lond) 2020;28;134(4):379–388. doi: 10.1042/CS20191276
63. Davenport AP, Kuc RE, Southan C, Maguire JJ. New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res2018;67(Suppl 1):S37–S54. doi: 10.33549/physiolres.933872
64. Torra R, Furlano M. New therapeutic options for Alport syndrome. Nephrol Dial Transplant2019;34(8):1272–1279. doi:10.1093/ndt/gfz131
65. Omachi K, Miner JH. Alport Syndrome Therapeutics: Ready for Prime-Time Players. Trends Pharmacol Sci2019; 40(11): 803–806. doi: 10.1016/j.tips.2019.07.012
Review
For citations:
Aksenova M.E. Alport syndrome: our knowledge update. Nephrology (Saint-Petersburg). 2021;25(3):75-83. (In Russ.) https://doi.org/10.36485/1561-6274-2021-25-3-75-83
Views:
4517
Email this article 