Skip to main content

Advertisement

SpringerLink
Log in

Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults–an update for 2020

  • Guidelines
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

A Correction to this article was published on 12 January 2021

This article has been updated

Abstract

In 2013, we published a set of clinical practice recommendations for the treatment of Alport syndrome in this journal. We recommended delaying the initiation of angiotensin-converting enzyme inhibition until the onset of overt proteinuria or, in some cases, microalbuminuria. Developments that have occurred over the past 7 years have prompted us to revise these recommendations. We now recommend the initiation of treatment at the time of diagnosis in males with X-linked Alport syndrome and in males and females with autosomal recessive Alport syndrome. We further recommend starting treatment at the onset of microalbuminuria in females with X-linked Alport syndrome and in males and females with autosomal dominant Alport syndrome. This article presents the rationale for these revisions as well as recommendations for diagnostic tactics intended to ensure the early diagnosis of Alport syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Change history

  • 12 January 2021

    A Correction to this paper has been published: https://doi.org/10.1007/s00467-020-04892-x

References

  1. Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelmann B, Rheault M, Licht C (2013) Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport syndrome research collaborative. Pediatr Nephrol 28:5–11

    PubMed  Google Scholar 

  2. Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tönshoff B, Hocker B, Wydoga S, Ehrich JH, Pape L, Konrad M, Rasher W, Dotsch J, Muller-Wierfel DE, Hoyer P, Knebelmann B, Pirson Y, Grunfeld JP, Niaudet P, Cochat P, Heidet L, Lebbah S, Torra R, Friede T, Lange K, Muller GA, Weber M, Study Group Members of the Gesellschart fur Padiatrische Nephrologie (2012) Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int 81:494–501

    CAS  PubMed  Google Scholar 

  3. Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227

    CAS  PubMed  Google Scholar 

  4. Boye E, Mollet G, Forestier L, Cohen-Solal L, Heidet L, Cochat P, Grunfeld JP, Palcoux JB, Gubler MC, Antignac C (1998) Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet 63:1329–1340

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12:97–106

    CAS  PubMed  Google Scholar 

  6. Miner JH, Sanes JR (1996) Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol 135:1403–1413

    CAS  PubMed  Google Scholar 

  7. Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R, Hunter WJ, Samuelson GC (1996) Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev 10:2981–2992

    CAS  PubMed  Google Scholar 

  8. Rheault MN, Kren SM, Thielen BK, Mesa HA, Crosson JT, Thomas W, Sado Y, Kashtan CE, Segal Y (2004) Mouse model of X-linked Alport syndrome. J Am Soc Nephrol 15:1466–1474

    PubMed  Google Scholar 

  9. Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K, Smyth N, Schulze-Lohoff E, Weber M (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446

    CAS  PubMed  Google Scholar 

  10. Gross O, Schulze-Lohoff E, Koepke ML, Beirowski B, Addicks K, Bloch W, Smyth N, Weber M (2004) Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis. Nephrol Dial Transplant 19:1716–1723

    CAS  PubMed  Google Scholar 

  11. Gross O, Perin L, Deltas C (2014) Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol Dial Transplant 229 Suppl 4:iv124-130

  12. Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Muller GA, Gross O (2012) Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int 81:779–783

    CAS  PubMed  Google Scholar 

  13. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2000) X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 11:649–657

    CAS  PubMed  Google Scholar 

  14. Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz AA, Masoumi A, Schrier RW (2010) Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 21:876–883

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Horinouchi T, Nozu K, Yamamura T, Minamikawa S, Omori T, Nakanishi K, Fujimura J, Ashida A, Kitamura M, Kawano M, Shimabukuro W, Kitabayashi C, Imafuku A, Tamagaki K, Kamei K, Okamoto K, Fujinaga S, Oka M, Igarashi T, Miyazono A, Sawanobori E, Fujimaru R, Shima Y, Matsuo M, Ye MJ, Nozu Y, Morisada N, Kaito H, Ijima K (2018) Detection of splicing abnormalities and genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 29:2244–2254

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Yamamura T, Horinouchi T, Nagano C, Omori T, Sakakibara N, Aoto Y, Ishiko S, Nakanishi N, Shima Y, Nagase H, Takeda H, Rossanti R, Ye M, Nozu Y, Ishimori S, Ninchoji T, Kaito H, Morisada N, Iijima K, Nozu K (2020) Genotype-phenotype correlation and the effects of treatment with angiotensin-targeting drugs in Japanese patients with male X-linked Alport syndrome. Kidney Int. https://doi.org/10.1016/j.kint.2020.06.038

  17. Gross O, Tönshoff B, Weber LT, Pape L, Latta K, Fehrenbach H, Lange-Sperandio B, Zappel H, Hoyer P, Staude H, Konig S, John U, Gellermann J, Hoppe B, Gallano M, Hoecker B, Ehren R, Lerch C, Kashtan CE, Harden M, Boeckhaus J, Friede T, German Pediatric Nephrology (GPN) Study Group and EARLY PRO-TECT Alport Investigators (2020) 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 97:1275–1286

    CAS  PubMed  Google Scholar 

  18. Kashtan CE, Ding J, Garosi G, Heidet L, Massella L, Nakanishi K, Nozu K, Renieri A, Rheault M, Wang F, Gross O (2018) Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int 93:1045–1051

    PubMed  Google Scholar 

  19. Savige J (2018) Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep 3:1239–1241

    PubMed  PubMed Central  Google Scholar 

  20. Gast C, Pengelly RJ, Lyon M, Bunyan DJ, Seaby EG, Graham N, Venkat-Raman G, Ennis S (2016) Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 31:961–970

    CAS  PubMed  Google Scholar 

  21. Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Li Y, Zhang J, Nestor J, Krithivasan P, Lam WY, Mitrotti A, Piva S, Kil BH, Chatterjee D, Reingold R, Bradbury D, DiVecchia M, Snyder H, Mu X, Mehl K, Balderes O, Fasel DA, Weng C, Radharishnan J, Canetta P, Appel GB, Bomback AS, Ahn W, Uy NS, Alam S, Cohen DJ, Crew RJ, Dube GK, Rao MK, Kamalakaran S, Copeland B, Ren Z, Bridgers J, Malone CD, Mebane CM, Dagaonkar N, Fellstrom BC, Haefliger C, Mohan S, Sanna-Cherchi S, Kiryluk K, Fleckner J, March R, Platt A, Goldstein DB, Gharavi AG (2019) Diagnostic utility of exome sequencing for kidney disease. N Engl J Med 380:142–151

    CAS  PubMed  Google Scholar 

  22. Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Moller K, Wigger M, Peruzzi L, Mehls O, Schaefer F, ESCAPE Trial Group (2009) Strict blood-pressure control and progression of renal failure in children. N Engl J Med 361:1639–1650

    PubMed  Google Scholar 

  23. Nakanishi K, Iijima K, Ishikura K, Hataya H, Awazu M, Sako M, Honda M, Yoshikawa N, Japanese Pediatric IgA Nephropathy Study Group (2009) Efficacy and safety of lisinopril for mild childhood IgA nephropathy: a pilot study. Pediatr Nephrol 24:845–849

    PubMed  Google Scholar 

  24. Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, Moxey-Mims MM, Hogg RJ, Watkins SL, Fine RN, Hogan SL, Middleton JP, Vehaskari VM, Flynn PA, Powell LM, Vento S, McMahan JL, Siegel N, D'Agati VD, Frideman AL (2011) Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int 80:868–878

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jarad G, Knutsen RH, Mecham RP, Miner JH (2016) Albumin contributes to kidney disease progression in Alport syndrome. Am J Physiol Renal Physiol 311:F120–F130

    CAS  PubMed  PubMed Central  Google Scholar 

  26. van den Belt SM, HJL H, Gracchi V, de Zeeuw D, Wühl E, Schaefer F, ESCAPE Trial Group (2018) Early proteinuria lowering by angiotensin-converting enzyme inhibition predicts renal survival in children with CKD. J Am Soc Nephrol 29:2225–2233

    PubMed  PubMed Central  Google Scholar 

  27. Seeman T, Pohl M, Misselwitz J, John U (2009) Angiotensin receptor blocker reduces proteinuria independently of blood pressure in children already treated with angiotensin-converting enzyme inhibitors. Kidney Blood Press Res 32:440–444

    CAS  PubMed  Google Scholar 

  28. Giani M, Mastrangelo A, Villa R, Turolo S, Marra G, Tirelli AS, Hopfer H, Edefonti A (2013) Alport syndrome: the effects of spironolactone on proteinuria and urinary TGF-β1. Pediatr Nephrol 28:1837–1842

    PubMed  Google Scholar 

  29. Kaito H, Nozu K, Iijima K, Nakanishi K, Yoshiya K, Kanda K, Przybyslaw Kroi R, Yoshikawa N, Matsuo M (2006) The effect of aldosterone blockade in patients with Alport syndrome. Pediatr Nephrol 21:1824–1829

    PubMed  Google Scholar 

  30. Charbit M, Gubler MC, Dechaux M, Gagnadoux MF, Grünfeld JP, Niaudet P (2007) Cyclosporin therapy in patients with Alport syndrome. Pediatr Nephrol 22:57–63

    PubMed  Google Scholar 

  31. Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K (2014) Natural history of genetically proven autosomal recessive Alport syndrome. Pediatr Nephrol 29:1535–1544

    PubMed  Google Scholar 

  32. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander K, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2003) 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 Nephrol 14:2603–2610

    PubMed  Google Scholar 

  33. Kamiyoshi N, Nozu K, Fu XJ, Morisada N, Nozu Y, Ye MJ, Imafuku A, Miura K, Yamamura T, Minamikawa S, Shono A, Ninchoji T, Morioka I, Nakanishi K, Yoshikawa N, Kaito H, Iijima K (2016) Genetic, clinical, and pathologic backgrounds of patients with autosomal dominant Alport syndrome. Clin J Am Soc Nephrol 11:1441–1449

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Marcocci E, Uliana V, Bruttini M, Artuso R, Silengo MC, Zerial M, Bergesio F, Amoroso A, Savoldi S, Pennesi M, Giachino D, Rombola G, Fogazzi GB, Rosatelli C, Martinhago CD, Carmellini M, Mancini R, Di Costanzo G, Longo I, Renieri A, Mari F (2009) Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome. Nephrol Dial Transplant 24:1464–1471

    CAS  PubMed  Google Scholar 

  35. Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D (2015) Ocular features in Alport syndrome: pathogenesis and clinical significance. Clin J Am Soc Nephrol 10:703–709

    PubMed  PubMed Central  Google Scholar 

  36. Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA (2013) COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. J Am Soc Nephrol 24:1945–1954

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Temme J, Kramer A, Jager KJ, Lange K, Peters F, Müller GA, Kramar R, Heaf JG, Finne P, Palsson R, Reisaeter AV, Hoitsma AJ, Metcalfe W, Postorino M, Zurriaga O, Santos JP, Ravani P, Jarraya F, Verrina E, Dekker FW, Gross O (2012) Outcomes of male patients with Alport syndrome undergoing renal replacement therapy. Clin J Am Soc Nephrol 7:1969–1976

    PubMed  PubMed Central  Google Scholar 

  38. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM, BEACON Trial Investigators (2013) Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 369:2492–2503

    PubMed  PubMed Central  Google Scholar 

  39. Gomez IG, MacKenna DA, Johnson BG, Kaimal V, Roach AM, Ren S, Nakagawa N, Xin C, Newitt R, Pandya S, Xia TH, Liu X, Borza DB, Grafals M, Shankland SJ, Himmelfarb J, Portilla D, Liu S, Chau BN, Duffield JS (2015) Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest 125:141–156

    PubMed  Google Scholar 

  40. Guo J, Song W, Boulanger J, Xu EY, Wang F, Zhang Y, He Q, Wang S, Yang L, Pryce C, Phillips L, MacKenna D, Leberer E, Ibraghimov-Beskrovnaya O, Ding J, Liu S (2019) Dysregulated expression of microRNA-21 and disease-related genes in human patients and in a mouse model of Alport syndrome. Hum Gene Ther 30:865–881

    CAS  PubMed  Google Scholar 

  41. Kashtan CE, Gubler MC, Sisson-Ross S, Mauer M (1998) Chronology of renal scarring in males with Alport syndrome. Pediatr Nephrol 12:269–274

    CAS  PubMed  Google Scholar 

  42. Mabillard H, Sayer JA (2020) SGLT2 inhibitors - a potential treatment for Alport syndrome. Clin Sci (Lond) 134:379–388

    CAS  Google Scholar 

  43. Yamamura T, Horinouchi T, Adachi T, Terakawa M, Takaoka Y, Omachi K, Takasato M, Takaishi K, Shoji T, Onishi Y, Kanazawa Y, Koizumi M, Tomono Y, Sugano A, Shono A, Minamikawa S, Nagano C, Sakakibara N, Ishiko S, Aoto Y, Kamura M, Harita Y, Miura K, Kanda S, Morisada N, Rossanti R, Ye MJ, Nozu Y, Matsuo M, Kai H, Iijima K, Nozu K (2020) Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. Nat Commun 11:2777

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

CEK is the Executive Director of the Alport Syndrome Treatments and Outcomes Registry (alportregistry.org) (clinicaltrials.gov identifier NCT00481130), which receives funding from the Alport Syndrome Foundation (alportsyndrome.org) and private donors. CEK is a site investigator for the CARDINAL trial (clinicaltrials.gov identifier NCT03019185) sponsored by Reata Pharmaceuticals and the HERA trial (clinicaltrials.gov identifier NCT02855268) sponsored by Sanofi-Genzyme. CEK has consulting relationships with Retrophin, ONO Pharmaceuticals and Daiichi Sankyo and recent research funding from the Novartis Institute for Biomedical Research. None of the listed organizations or companies had input into the content of this manuscript.

OG is the initiator and principle investigator of the European Alport registry (clinicaltrials.gov identifier NCT02378805), which has received funding from the Association pour l’Information et la Recherche sur les Maladies Rénales Génétiques (AIRG) and the KfH Foundation Preventive Medicine (Fritz-Scheler Stipendium of the German Society of Nephrology). OG is initiator and principle investigator of the EARLY PRO-TECT Alport trial (clinicaltrials.gov identifier NCT01485978), which was funded by the German Federal Ministry of Education and Research (01KG1104). OG is national principle investigator for the CARDINAL trial (clinicaltrials.gov identifier NCT03019185) sponsored by Reata Pharmaceuticals and site investigator of the HERA trial (clinicaltrials.gov identifier NCT02855268) sponsored by Sanofi-Genzyme. OG has consulting relationships with Boehringer Ingelheim, ONO Pharmaceuticals, Reata Pharmaceuticals, Retrophin and Daiichi Sankyo. None of the listed organizations or companies had input into the content of this manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Medical School, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA

    Clifford E. Kashtan

  2. Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany

    Oliver Gross

Authors
  1. Clifford E. Kashtan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clifford E. Kashtan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest. Neither the authors nor their immediate family members have any financial relationships or holdings that influenced the writing of this manuscript or that will be affected by the content of the manuscript if published.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: "In the previous version of this article, the definition of microalbuminuria was misstated as a urine microalbumin-creatinine ratio of 30 mg/mg. The value was corrected to 30 mg/g.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kashtan, C.E., 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 36, 711–719 (2021). https://doi.org/10.1007/s00467-020-04819-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-020-04819-6

Keywords

Search

Navigation