nidНефрология и диализNephrology and Dialysis1680-44222618-9801Российское диализное общество10.28996/2618-9801-2023-4-554-563nid-132Research ArticleШКОЛА НЕФРОЛОГАEDUCATIONAL MATERIALSБолезнь тонких базальных мембран и аутосомно-доминантный синдром Альпорта - единство противоположностей. Современные представления и нерешённые проблемыThin basement membrane disease and autosomal dominant Alport syndrome are a unity of opposites. Modern ideas and unsolved problemsКаганМ. Ю.KaganM. Yu.mkaganorenburg@yahoo.comБервинаН. Н.BervinaN. N.nbervina@mail.ruПовилайтитеП. Е.PovilaititeP. E.povpe@yandex.ruГАУЗ Областная детская клиническая больницаРоссия"Regional Children's Clinical Hospital"Russian FederationГБУ Ростовской области «Патолого-анатомическое бюро»РоссияRostov Region Pathoanatomical BureauRussian Federation202321062024254554563Copyright © Каган М.Ю., Бервина Н.Н., Повилайтите П.Е., 20242024Каган М.Ю., Бервина Н.Н., Повилайтите П.Е.Kagan M.Y., Bervina N.N., Povilaitite P.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephro.ru/jour/article/view/132

Болезнь тонких базальных мембран (БТБМ) и аутосомно-доминантный синдром Альпорта (АДСА) являются наследственными заболеваниями почек, которые обусловлены структурными аномалиями α-3 и α-4 цепей коллагена 4 типа. Изначально концепция двух отдельных состояний была предложена на основании предполагаемых клинико-морфологических различий. У большинства пациентов с БТБМ отмечаются гематурия с незначительной протеинурией или без нее, нормальная функция почек и диффузное истончение гломерулярной базальной мембраны (ГБМ) при электронной микроскопии. Однако встречаются пациенты с БТБМ, у которых во взрослом возрасте развивается терминальная стадия хронической болезни почек (тХБП). Напротив, синдром Альпорта (СА) определяется как прогрессирующая нефропатия, сопровождающаяся потерей слуха и глазными аномалиями, с неравномерным утолщением и расслоением ГБМ. Тем не менее, у многих пациентов с АДСА отсутствуют экстраренальные проявления, тХБП развивается только в пожилом и старческом возрасте, а единственным изменением ГБМ является её истончение. Генетические исследования доказали, что и БТБМ, и АДСА обусловлены гетерозиготными патогенными вариантами в генах COL4A3 и COL4A4. В связи с чем возникают сложности в разграничении этих двух состояний и напрашивается вопрос о необходимости пересмотра старой концепции двух разных заболеваний. Диагностика СА имеет большое значение, поскольку способствует тщательному наблюдению и раннему лечению пациентов, в то время как диагноз БТБМ может приводить к недооценке риска развития тХБП. Хотя долгое время АДСА считался крайне редким заболеванием, последние исследования с использованием секвенирования нового поколения продемонстрировали, что число таких пациентов гораздо больше, чем предполагалось ранее, что привело к многочисленным дискуссиям по поводу диагностики этого состояния. Мы приводим обзор имеющихся публикаций, посвященных БТБМ и АДСА, и собственное клиническое наблюдение, которое демонстрирует трудности, возникающие при диагностике патологии коллагена 4 типа.

Thin basement membrane disease (TBMD) and autosomal dominant Alport syndrome (ADAS) are inherited renal diseases caused by structural abnormalities of α-3 and α-4 chains of collagen type 4. The concept that TBMD and ADAS are distinct conditions was initially proposed based on supposed clinical and morphologic differences. Most patients with TBMD have hematuria with little or no proteinuria, normal renal function, and diffuse thinning of the glomerular basement membrane (GBM) on electron microscopy. However, there are patients with TBMD who develop end-stage chronic kidney disease (ESKD) in adulthood. In contrast, Alport syndrome (AS) is defined as progressive nephropathy accompanied by hearing loss and ocular abnormalities, with irregular thickening and lamellation of the GBM. However, many patients with ADAS have no extrarenal manifestations, ESKD does not develop until old age, and the only change in the GBM is thinning. Genetic studies have proven that both TBMD and ADAS are caused by heterozygous pathogenic variants in the COL4A3 and COL4A4 genes. There are difficulties in differentiating between these two conditions and the old concept of two different diseases should be reconsidered. The diagnosis of AS is important because it facilitates close follow-up and early treatment of patients, whereas the diagnosis of TBMD may lead to an underestimation of the risk of developing ESKD. Although ADAS has long been considered an extremely rare condition, recent studies using next-generation sequencing have demonstrated that the number of these patients is much larger than previously thought, leading to much debate over the diagnosis of this condition. We present a review of available publications on TBMD and ADAS and our clinical observation demonstrating the difficulties encountered in diagnosing collagen type 4 pathology.

заболевание тонкой базальной мембраныаутосомно-доминантный синдром Альпортагетерозиготный вариант COL4A3 или COL4A4thin basement membrane diseaseautosomal dominant Alport syndromeheterozygous COL4A3 or COL4A4 variantReferencesMoriniеre V., Dahan K., Hilbert P. et al. Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol. 2014. 25(12):2740-51. doi: 10.1681/ASN.2013080912Moriniеre V., Dahan K., Hilbert P. et al. Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol. 2014. 25(12):2740-51. doi: 10.1681/ASN.2013080912Gibson J., Fieldhouse R., Chan M. M. et al. Prevalence estimates of predicted pathogenic COL4A3-COL4A5 variants in a population sequencing database and their implications for Alport syndrome. J Am Soc Nephrol. 2021. 32:2273-2290. doi: 10.1681/ASN.2020071065Gibson J., Fieldhouse R., Chan M. M. et al. Prevalence estimates of predicted pathogenic COL4A3-COL4A5 variants in a population sequencing database and their implications for Alport syndrome. J Am Soc Nephrol. 2021. 32:2273-2290. doi: 10.1681/ASN.2020071065Savige J., Lipska-Zietkiewicz B.S., Watson E. et al. Guidelines for Genetic Testing and Management of Alport Syndrome. Clin J Am Soc Nephrol. 2022. 17(1):143-154. doi: 10.2215/CJN.04230321Savige J., Lipska-Zietkiewicz B.S., Watson E. et al. Guidelines for Genetic Testing and Management of Alport Syndrome. Clin J Am Soc Nephrol. 2022. 17(1):143-154. doi: 10.2215/CJN.04230321Alport A.C. Hereditary familial congenital haemorrhagic nephritis. Br Med J. 1927. 1:504-506. doi: 10.1136/bmj.1.3454.504Alport A.C. Hereditary familial congenital haemorrhagic nephritis. Br Med J. 1927. 1:504-506. doi: 10.1136/bmj.1.3454.504Williamson D.A. Alport’s syndrome of hereditary nephritis with deafness. Lancet. 1961. 2(7216):1321-23. doi: 10.1016/s0140-6736(61)90899-6Williamson D.A. Alport’s syndrome of hereditary nephritis with deafness. Lancet. 1961. 2(7216):1321-23. doi: 10.1016/s0140-6736(61)90899-6Gauthier B., Trachtman H., Frank R. et al. Familial thin basement membrane nephropathy in children with asymptomatic microhematuria. Nephron. 1989. 51(4):502-8. doi: 10.1159/000185384Gauthier B., Trachtman H., Frank R. et al. Familial thin basement membrane nephropathy in children with asymptomatic microhematuria. Nephron. 1989. 51(4):502-8. doi: 10.1159/000185384Spear G.S., Slusser R.J. Alport’s syndrome: emphasizing electron microscopic studies of the glomerulus. Am J Pathol. 1972. 69(2):213-224. PMC2032644Spear G.S., Slusser R.J. Alport’s syndrome: emphasizing electron microscopic studies of the glomerulus. Am J Pathol. 1972. 69(2):213-224. PMC2032644Kashtan C., Fish A.J., Kleppel M. et al. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis. J Clin Invest. 1986. 78(4):1035-1044. doi: 10.1172/JCI112658Kashtan C., Fish A.J., Kleppel M. et al. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis. J Clin Invest. 1986. 78(4):1035-1044. doi: 10.1172/JCI112658Hostikka S.L., Eddy R.L., Byers M.G. et al. Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci U S A. 1990. 87(4):1606-10. doi: 10.1073/pnas.87.4.1606Hostikka S.L., Eddy R.L., Byers M.G. et al. Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci U S A. 1990. 87(4):1606-10. doi: 10.1073/pnas.87.4.1606Barker D.F., Hostikka S.L., Zhou J. et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science. 1990. 248(4960):1224-1227. doi: 10.1126/science.2349482Barker D.F., Hostikka S.L., Zhou J. et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science. 1990. 248(4960):1224-1227. doi: 10.1126/science.2349482Miner J.H., Sanes J.R. Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol. 1996. 135(5):1403-1413. doi: 10.1083/jcb.135.5.1403Miner J.H., Sanes J.R. Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol. 1996. 135(5):1403-1413. doi: 10.1083/jcb.135.5.1403Boye E., Mollet G., Forestier L. et al. Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet. 1998. 63(5):1329-1340. doi: 10.1086/302106Boye E., Mollet G., Forestier L. et al. Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet. 1998. 63(5):1329-1340. doi: 10.1086/302106Heidet L., Arrondel C., Forestier L. et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol. 2001. 12(1):97-106. doi: 10.1681/ASN.V12197Heidet L., Arrondel C., Forestier L. et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol. 2001. 12(1):97-106. doi: 10.1681/ASN.V12197Gross O., Beirowski B., Koepke M.L. et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int. 2003. 63(2):438-446. doi: 10.1046/j.1523-1755.2003.00779.xGross O., Beirowski B., Koepke M.L. et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int. 2003. 63(2):438-446. doi: 10.1046/j.1523-1755.2003.00779.xGross O., Licht C., Anders H.J. et al. Early angiotensinconverting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012. (5):494-501. doi: 10.1038/ki.2011.407Gross O., Licht C., Anders H.J. et al. Early angiotensinconverting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012. (5):494-501. doi: 10.1038/ki.2011.407Yamamura 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 Int. 2020. (6):1605-1614. doi: 10.1016/j.kint.2020.06.038Yamamura 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 Int. 2020. (6):1605-1614. doi: 10.1016/j.kint.2020.06.038Gross O., Tönshoff B., Weber L.T. 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 Int. 2020. (6):1275-1286. doi: 10.1016/j.kint.2019.12.015Gross O., Tönshoff B., Weber L.T. 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 Int. 2020. (6):1275-1286. doi: 10.1016/j.kint.2019.12.015Kashtan C.E., 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/s00467-012-2138-4Kashtan C.E., 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/s00467-012-2138-4Kashtan C.E., Gross O. Clinical practice recommendation for the diagnosis and management of Alport syndrome in children, adolescents, and young adults - an update for 2020. Pediatr Nephrol. 2021. (3):711-719. doi:10.1007/s00467-020-04819-6Kashtan C.E., Gross O. Clinical practice recommendation for the diagnosis and management of Alport syndrome in children, adolescents, and young adults - an update for 2020. Pediatr Nephrol. 2021. (3):711-719. doi:10.1007/s00467-020-04819-6Kashtan C.E. Genetic testing and glomerular hematuria-A nephrologist's perspective. Am J Med Genet C Semin Med Genet. 2022. 190(3):399-403. doi: 10.1002/ajmg.c.31987Kashtan C.E. Genetic testing and glomerular hematuria-A nephrologist's perspective. Am J Med Genet C Semin Med Genet. 2022. 190(3):399-403. doi: 10.1002/ajmg.c.31987McConville J.M., McAdams A.J. Familial and nonfamilial benign hematuria. J Pediatr. 1966. 69(2):207-14. doi: 10.1016/s0022-3476(66)80321-9McConville J.M., McAdams A.J. Familial and nonfamilial benign hematuria. J Pediatr. 1966. 69(2):207-14. doi: 10.1016/s0022-3476(66)80321-9Rogers P.W., Kurtzman N.A., Bunn S.M.Jr., White MG. Familial benign essential hematuria. Arch Intern Med. 1973. 131(2):257-62. doi:10.1001/archinte.1973.00320080093013Rogers P.W., Kurtzman N.A., Bunn S.M.Jr., White MG. Familial benign essential hematuria. Arch Intern Med. 1973. 131(2):257-62. doi:10.1001/archinte.1973.00320080093013Savige J., Rana K., Tonna S. et al. Thin basement membrane nephropathy. Kidney Int. 2003. 64(4):1169-78. doi: 10.1046/j.1523-1755.2003.00234.xSavige J., Rana K., Tonna S. et al. Thin basement membrane nephropathy. Kidney Int. 2003. 64(4):1169-78. doi: 10.1046/j.1523-1755.2003.00234.xNogueira M., Cartwright J.Jr., Horn K. et al. Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation. Am J Kidney Dis. 2000. 35(4):E15. doi: 10.1016/s0272-6386(00)70033-3Nogueira M., Cartwright J.Jr., Horn K. et al. Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation. Am J Kidney Dis. 2000. 35(4):E15. doi: 10.1016/s0272-6386(00)70033-3Dische F.E., Weston M.J., Parsons V. Abnormally thin glomerular basement membranes associated with hematuria, proteinuria or renal failure in adults. Am J Nephrol. 1985. 5(2):103-9. doi: 10.1159/000166914Dische F.E., Weston M.J., Parsons V. Abnormally thin glomerular basement membranes associated with hematuria, proteinuria or renal failure in adults. Am J Nephrol. 1985. 5(2):103-9. doi: 10.1159/000166914Mochizuki T., Lemmink H.H., Mariyama M. et al. Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet. 1994. 8(1):77-81. doi: 10.1038/ng0994-77Mochizuki T., Lemmink H.H., Mariyama M. et al. Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet. 1994. 8(1):77-81. doi: 10.1038/ng0994-77Lemmink H.H., Nillesen W.N., Mochizuki T. et al. Benign familial hematuria due to mutation of the type IV collagen alpha4 gene. J Clin Invest. 1996. 98(5):1114-8. doi: 10.1172/JCI118893Lemmink H.H., Nillesen W.N., Mochizuki T. et al. Benign familial hematuria due to mutation of the type IV collagen alpha4 gene. J Clin Invest. 1996. 98(5):1114-8. doi: 10.1172/JCI118893Deltas C., Savva I., Voskarides K. et al. Carriers of autosomal recessive Alport syndrome with thin basement membrane nephropathy presenting as focal segmental glomerulosclerosis in later life. Nephron. 2015. 130(4):271-80. doi: 10.1159/000435789Deltas C., Savva I., Voskarides K. et al. Carriers of autosomal recessive Alport syndrome with thin basement membrane nephropathy presenting as focal segmental glomerulosclerosis in later life. Nephron. 2015. 130(4):271-80. doi: 10.1159/000435789Jefferson J.A., Lemmink H.H., Hughes A.E. et al. Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4). Nephrol Dial Transplant. 1997. 12(8):1595-9. doi: 10.1093/ndt/12.8.1595Jefferson J.A., Lemmink H.H., Hughes A.E. et al. Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4). Nephrol Dial Transplant. 1997. 12(8):1595-9. doi: 10.1093/ndt/12.8.1595Longo I., Porcedda P., Mari F. et al. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int. 2002. 61(6):1947-56. doi: 10.1046/j.1523-1755.2002.00379.xLongo I., Porcedda P., Mari F. et al. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int. 2002. 61(6):1947-56. doi: 10.1046/j.1523-1755.2002.00379.xKamiyoshi N., Nozu K., Fu X.J. et al. Genetic, clinical, and pathologic backgrounds of patients with autosomal dominant Alport syndrome. Clin J Am Soc Nephrol. 2016. 11(8):1441-9. doi: 10.2215/CJN.01000116Kamiyoshi N., Nozu K., Fu X.J. et al. Genetic, clinical, and pathologic backgrounds of patients with autosomal dominant Alport syndrome. Clin J Am Soc Nephrol. 2016. 11(8):1441-9. doi: 10.2215/CJN.01000116Yamamura T., Nozu K., Minamikawa S. et al. Comparison between conventional and comprehensive sequencing approaches for genetic diagnosis of Alport syndrome. Mol Genet Genomic Med. 2019. 7(9):e883. doi: 10.1002/mgg3.883Yamamura T., Nozu K., Minamikawa S. et al. Comparison between conventional and comprehensive sequencing approaches for genetic diagnosis of Alport syndrome. Mol Genet Genomic Med. 2019. 7(9):e883. doi: 10.1002/mgg3.883Savige J. Should we diagnose autosomal dominant Alport syndrome when There Is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018. 3:1239-41. doi: 10.1016/j.ekir.2018.08.002Savige J. Should we diagnose autosomal dominant Alport syndrome when There Is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018. 3:1239-41. doi: 10.1016/j.ekir.2018.08.002Savige J., Ariani F., Mari F. et al. Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatr Nephrol. 2019. 34(7):1175-89. doi: 10.1007/s00467-018-3985-4Savige J., Ariani F., Mari F. et al. Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatr Nephrol. 2019. 34(7):1175-89. doi: 10.1007/s00467-018-3985-4Kashtan C. Alport syndrome: facts and opinions. F100Res. 2017. 6:50. doi: 10.12688/f1000research.9636.1Kashtan C. Alport syndrome: facts and opinions. F100Res. 2017. 6:50. doi: 10.12688/f1000research.9636.1Kashtan C.E., Ding J., Garosi G. et al. Alport syndrome: a unified classification of genetic disorders of collagen IV alpha345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int. 2018. 93(5):1045-51. doi: 10.1016/j.kint.2017.12.018Kashtan C.E., Ding J., Garosi G. et al. Alport syndrome: a unified classification of genetic disorders of collagen IV alpha345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int. 2018. 93(5):1045-51. doi: 10.1016/j.kint.2017.12.018Papazachariou L., Papagregoriou G., Hadjipanagi D. et al. Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis. Clin Genet. 2017. 92(5):517-27. doi: 10.1111/cge.13077Papazachariou L., Papagregoriou G., Hadjipanagi D. et al. Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis. Clin Genet. 2017. 92(5):517-27. doi: 10.1111/cge.13077Malone A.F., Phelan P.J., Hall G. et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014. 86(6):1253-9. doi: 10.1038/ki.2014.305Malone A.F., Phelan P.J., Hall G. et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014. 86(6):1253-9. doi: 10.1038/ki.2014.305Nabais Sa M.J., Storey H. et al. Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families. Clin Genet. 2015. 88(5):456-61. doi: 10.1111/cge.12521Nabais Sa M.J., Storey H. et al. Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families. Clin Genet. 2015. 88(5):456-61. doi: 10.1111/cge.12521Frese J., Kettwig M., Zappel H. et al. Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis. Int J Mol Sci. 2019. 20(3):519. doi: 10.3390/ijms20030519Frese J., Kettwig M., Zappel H. et al. Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis. Int J Mol Sci. 2019. 20(3):519. doi: 10.3390/ijms20030519Voskarides K., Arsali M., Athanasiou Y.et al. Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria. Pediatr Nephrol. 2012. 27(4):675-9. doi: 10.1007/s00467-011-2084-6Voskarides K., Arsali M., Athanasiou Y.et al. Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria. Pediatr Nephrol. 2012. 27(4):675-9. doi: 10.1007/s00467-011-2084-6Voskarides K., Stefanou C., Pieri M. et al. A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population. PLoS One. 2017. 12(3):e0174274. doi: 10.1371/journal.pone.0174274Voskarides K., Stefanou C., Pieri M. et al. A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population. PLoS One. 2017. 12(3):e0174274. doi: 10.1371/journal.pone.0174274Deltas C., Papagregoriou G., Louka S.F. et al. Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice. Genes (Basel). 2023. 25;14(9):1686. doi: 10.3390/genes14091686Deltas C., Papagregoriou G., Louka S.F. et al. Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice. Genes (Basel). 2023. 25;14(9):1686. doi: 10.3390/genes14091686Savige J., Renieri A., Ars E. et al. Digenic Alport Syndrome. Clin J Am Soc Nephrol. 2022. 17(11):1697-1706. doi: 10.2215/CJN.03120322Savige J., Renieri A., Ars E. et al. Digenic Alport Syndrome. Clin J Am Soc Nephrol. 2022. 17(11):1697-1706. doi: 10.2215/CJN.03120322Аксенова М.Е. Синдром Альпорта: современные представления. Нефрология. 2021. 25(3):75-83. https://doi.org/10.36485/1561-6274-2021-25-3-75-83Аксенова М.Е. Синдром Альпорта: современные представления. Нефрология. 2021. 25(3):75-83. https://doi.org/10.36485/1561-6274-2021-25-3-75-83Torra R., Furlano M. New therapeutic options for Alport syndrome. Nephrol Dial Transplant. 2019. 34(8):1272-1279. doi: 10.1093/ndt/gfz131Torra R., Furlano M. New therapeutic options for Alport syndrome. Nephrol Dial Transplant. 2019. 34(8):1272-1279. doi: 10.1093/ndt/gfz131

The authors declare that there are no conflicts of interest present.