Alport Syndrome

Order a molecular panel that includes COL4A3, COL4A4, and COL4A5 for persistent glomerular hematuria with any of the following: a family history of hematuria, CKD, kidney failure, sensorineural hearing loss, anterior lenticonus, or maculopathy. Absence of hearing, ocular, or family-history clues does not exclude a collagen IV disorder and should not defer testing when isolated glomerular hematuria persists. Wiley+1WileyGenetic testing and glomerular hematuria—A nephrologist's perspective - Kashtan - 2022 - American Journal of Medical Genetics Part C: Seminars in Medical Genetics - Wiley Online LibraryPubMedAlport Syndrome - GeneReviews® - NCBI Bookshelf

A pathogenic variant or variants in COL4A3, COL4A4, or COL4A5 in a patient with suggestive findings establishes a molecular diagnosis. A multigene kidney-disease panel is preferable when the phenotype is not definitive because it simultaneously evaluates the three collagen IV genes and competing inherited causes of glomerular hematuria. PubMedPubMedAlport Syndrome - GeneReviews® - NCBI Bookshelf

Use kidney biopsy selectively rather than as the default confirmation test. Electron microscopy and collagen IV alpha-chain immunostaining can support diagnosis when genetic testing is unavailable or uninformative; skin alpha5(IV) immunostaining is an additional option in selected X-linked cases. Biopsy remains particularly useful when the clinical course suggests a superimposed glomerular disease. Wiley+2WileyGenetic testing and glomerular hematuria—A nephrologist's perspective - Kashtan - 2022 - American Journal of Medical Genetics Part C: Seminars in Medical Genetics - Wiley Online LibraryPubMedAlport Syndrome - GeneReviews® - NCBI BookshelfPubMedDiagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN - PMC

Classify disease as X-linked COL4A5-related, autosomal recessive biallelic COL4A3/COL4A4-related, autosomal dominant monoallelic COL4A3/COL4A4-related, or digenic disease. For double heterozygous COL4A3/COL4A4 variants, determine whether variants are in cis or in trans: cis inheritance behaves as autosomal dominant, whereas trans inheritance is autosomal recessive. Nature+2NatureThe 2019 and 2021 International Workshops on Alport Syndrome | European Journal of Human GeneticsScienceDirectAlport SyndromeScienceDirectAlport Syndrome: Clinical Spectrum and Therapeutic Advances

Counsel males with X-linked Alport syndrome and males and females with autosomal recessive disease that untreated renal disease commonly progresses through proteinuria and renal insufficiency to ESKD. Females with X-linked disease and individuals with autosomal dominant disease have more variable courses, with kidney failure often delayed into later adulthood; hearing loss is relatively later and ocular involvement less common in these groups. ScienceDirect+1ScienceDirectAlport Syndrome: Clinical Spectrum and Therapeutic AdvancesPubMedAlport Syndrome - PubMed

Interpret monoallelic COL4A3/COL4A4 results in the clinical context. Labels including thin basement membrane nephropathy, autosomal dominant Alport syndrome, type IV collagen-associated kidney disease, and Alport spectrum nephropathy have been used; the absolute risk of kidney failure from a heterozygous pathogenic or likely pathogenic autosomal variant remains poorly defined. Oxford Academic+1Oxford AcademicDiagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN | Nephrology Dialysis Transplantation | Oxford AcademicPubMedDiagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN - PMC

Use an ACE inhibitor or ARB to reduce proteinuria and manage hypertension in proteinuric Alport syndrome; RAAS blockade is established standard management. In a prospective pediatric trial, ramipril delayed onset of proteinuria, an early marker of progressive kidney disease. Nature+3NatureThe 2019 and 2021 International Workshops on Alport Syndrome | European Journal of Human GeneticsWileyGenetic testing and glomerular hematuria—A nephrologist's perspective - Kashtan - 2022 - American Journal of Medical Genetics Part C: Seminars in Medical Genetics - Wiley Online LibraryWolters KluwerStudy Design and Baseline Characteristics of the... : American Journal of NephrologyPubMedAlport Syndrome - StatPearls - NCBI Bookshelf

For a heterozygous pathogenic or likely pathogenic COL4A3/COL4A4 variant, initiate RAAS blockade when albuminuria or additional risk factors for progression are present. Do not use the historically reassuring label “benign familial hematuria” to substitute for surveillance of albuminuria, blood pressure, and kidney function. Nature+2NatureThe 2019 and 2021 International Workshops on Alport Syndrome | European Journal of Human GeneticsOxford AcademicDiagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN | Nephrology Dialysis Transplantation | Oxford AcademicPubMedDiagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN - PMC

Monitor serial urine albumin or protein excretion, blood pressure, serum creatinine, and estimated GFR after RAAS-blockade initiation and during dose adjustment. If kidney function progresses to kidney failure, plan dialysis or kidney transplantation; many affected patients ultimately require kidney replacement therapy despite delayed progression with current measures. PubMedPubMedAlport Syndrome - StatPearls - NCBI Bookshelf

Arrange audiology and ophthalmology assessment because bilateral high-frequency sensorineural hearing loss, anterior lenticonus, and perimacular flecks are clinically informative manifestations of collagen IV disease. Their presence supports the diagnosis, but their absence does not rule it out. Nature+2NatureThe 2019 and 2021 International Workshops on Alport Syndrome | European Journal of Human GeneticsScienceDirectAlport SyndromeWileyGenetic testing and glomerular hematuria—A nephrologist's perspective - Kashtan - 2022 - American Journal of Medical Genetics Part C: Seminars in Medical Genetics - Wiley Online Library

Offer targeted molecular testing to at-risk relatives when the familial pathogenic variant is known. If it is not known, use urinalysis and blood-pressure evaluation to identify relatives requiring further assessment. Earlier identification is intended to permit surveillance and timely intervention before proteinuria and progressive renal disease emerge. PubMed+1PubMedAlport Syndrome - GeneReviews® - NCBI BookshelfPubMedAlport Syndrome - PubMed

Refer affected individuals and families for genetic counseling after a pathogenic result. Counseling should cover inheritance pattern, reproductive transmission risk, variable expression in females with X-linked disease and monoallelic autosomal disease, and the implications of testing relatives who may have isolated hematuria. Nature+2NatureThe 2019 and 2021 International Workshops on Alport Syndrome | European Journal of Human GeneticsPubMedAlport Syndrome - GeneReviews® - NCBI BookshelfPubMedAlport Syndrome - PubMed