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Diagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN

ERKNet/ERA/ESPN · 2024 · Europe

Source and licence

Authors
Roser Torra, Beata Lipska-Zietkiewicz, Frederic Acke et al.
Title
Diagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN
Journal
Nephrology Dialysis Transplantation, 2024
DOI
10.1093/ndt/gfae265
Licence
CC BY 4.0
Changes
Verbatim excerpts; formatting adapted

Full text retrieved 2026-10-27 from Europe PMC · PMC12209846

Licence statement of the original publication

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

This page reproduces excerpts of the original publication; the original is authoritative. It has not been reviewed by a physician, does not state a recommendation of Medelix and does not replace medical advice. The guideline may have been updated since.

Open the original publication →Full text on Europe PMC

Recommendations

Verbatim, with grade of recommendation or strength of consensus where given.

Q1: XLAS AND ARAS: WHAT ARE THE DIFFERENCES AMONG THEM AND WHAT IS THEIR PREVALENCE?

  • 1-Statement: XLAS is much more prevalent than ARAS and affects males and females differently.Grade A, strong

Q2: WHAT ARE THE PENETRANCE AND PREVALENCE OF HETEROZYGOUS COL4A3/COL4A4 SINGLE PATHOGENIC VARIANTS?

  • 2-Recommendation: Single pathogenic variants in COL4A3/COL4A4 are relatively frequent in the general population and therefore their presence should not be regarded as the only cause of the kidney disease and other/additional diagnoses (e.g. IgA nephropathy) should be considered.Grade B, strong

Q3: IS THE TERM ‘DIGENIC’ JUSTIFIED IN AS?

  • 3-Statement: The presence of pathogenic variants in more than one of COL4A3/4/5, sometimes called ‘digenic’, may lead to an age at onset of KF that is intermediate between that reported for XLAS or ARAS and monoallelic autosomal disease.Grade D, expert opinon

Q4: WHEN TO ORDER ALPORT GENE TESTING? WHAT IS THE LIST OF CLINICAL AND/OR HISTOLOGICAL FINDINGS THAT REQUIRE EXCLUDING ALPORT DIAGNOSIS IN DIFFERENTIAL DIAGNOSTICS AND WHAT SHOULD BE DONE IN MINORS?

  • When genetic testing is done to investigate proteinuric kidney disease, cystic kidney disease, unexplained KF, or hearing loss, COL4A3/4/5 gene testing should be included (Box 2).Grade B, strong
  • 4.2-Recommendation: The experts support the need for genetic testing in minors presenting signs of renal and/or extra-renal impairment belonging to Alport spectrum but refrain from proposing genetic testing in an asymptomatic child (including absence of haematuria), without the family having received genetic counselling.Grade B, strong

Q5: SHOULD GENETIC TESTING IN RELATIVES BE ENCOURAGED? SHOULD IT BE LIMITED TO (FAMILY) VARIANT TESTING OR RATHER COVER ALL THREE GENES? SHOULD PARTNERS BE TESTED WHEN WISHING TO CREATE A FAMILY?

  • 5.1-Suggestion: Where the molecular diagnosis of AS is established in an index case, genetic testing for that variant could be offered to all adult relatives at risk of inheriting the disease.Grade D, expert opinon

Q6: SHOULD ALPORT GENE TESTING BE INCLUDED IN GENE PANELS DESIGNED FOR KIDNEY DISEASES?

  • 6-Recommendation: Where genetic testing is done to investigate proteinuric kidney disease, unexplained KF or possibly cystic kidney disease, COL4A3/4/5 gene testing should be included.Grade B, strong

Q7: SHOULD ALPORT GENE TESTING BE INCLUDED ON THE LIST OF SECONDARY FINDINGS/ACTIONABLE FINDINGS?

  • 7-Suggestion: Where genomic testing was performed for an indication other than to investigate kidney disease, a secondary finding of pathogenic variants in the COL4A5 gene and cases with two or more pathogenic variants in COL4A3/COL4A4 should be reported.Grade C, moderate

Q8: GIVEN THE RELATIVELY HIGH FREQUENCY OF INDIVIDUALS WITH HETEROZYGOUS COL4A3/4 VARIANTS IN THE GENERAL POPULATION AND THEIR POTENTIALLY DETERIORATING EFFECT ON THE PHENOTYPE, SHOULD PATIENTS WITH PATHOGENIC COL4A3/4 VARIANTS BE SCREENED FOR OTHER KIDNEY DISEASES IN THE CLINICAL PRACTICE?

  • 8-Suggestion: Caution should be exercised before asserting that a heterozygous P/LP COL4A3/COL4A4 variant fully explains the phenotype. This may require exclusion of an additional genetic or acquired kidney diseases.Grade C, moderate

Q9: WHAT IS THE SENSITIVITY OF CURRENT GENETIC TESTS FOR AS? WHAT ARE THE POTENTIAL DIAGNOSTIC TOOLS IF NEXT-GENERATION SEQUENCING (NGS)-BASED GENETIC TESTING IS NEGATIVE?

  • 9-Statement: No targeted gene panel is 100% sensitive for the different types of genetic changes that can cause AS. In well-designed gene panels the sensitivity of COL4A3/4/5 gene analysis to detect pathogenic variants is estimated to exceed 85%.Grade D, expert opinon

Q10: WHAT IS THE ESTIMATED LIFELONG RELATIVE RISK OF STAGE 5 CKD IN INDIVIDUALS WITH HETEROZYGOUS COL4A3/COL4A4 VARIANTS VERSUS THAT IN THE GENERAL POPULATION?

  • 10.1-Statement: The risk of reaching KF at advanced age is higher for individuals with heterozygous P/LP COL4A3/COL4A4 variants compared with the general population.Grade B, strong
  • 10.2-Statement: Nephroprotective therapy can significantly reduce this risk.Grade B, strong

Q11: WHAT IS THE ESTIMATED LIFELONG RELATIVE RISK AND AGE-RELATED RISK OF STAGE 5 CKD DEPENDING ON PATTERN OF INHERITANCE AND SEX?

  • 11.1-Statement: The majority of untreated XLAS males will reach KF in the second to fifth decade of life.Grade A, strong
  • 11.2-Statement: The vast majority of XLAS males progress to CKD G5 with a variable speed of progression influenced by genotype, timing of nephroprotective therapy, and other environmental factors.Grade B, strong
  • 11.3-Statement: XLAS females have a variable kidney outcome.Grade A, strong
  • 11.4-Statement: This is probably mostly influenced by variable chromosome X inactivation, early start of nephroprotective therapy, and other environmental factors.Grade C, moderate
  • 11.5-Statement: There is currently no evidence that there are sex differences in clinical symptoms and incidence for individuals with heterozygous P/LP COL4A3 or COL4A4 variants and individuals with ARAS.Grade B, strong
  • 11.6-Statement: ARAS patients all progress to KF with a variable speed of progression influenced by genotype, early start of nephroprotective therapy, and other environmental factors. The majority of untreated ARAS patients will require kidney replacement therapy (KRT) in the second to third decade of life.Grade B, strong

Q12: WHAT IS THE SUGGESTED FOLLOW-UP FOR INDIVIDUALS WITH HETEROZYGOUS P/LP COL4A3/COL4A4 VARIANTS?

  • 12.1-Suggestion: In asymptomatic adults with heterozygous P/LP COL4A3/COL4A4 variants, we suggest performing regular screenings (1- to 2-year intervals) for microhaematuria and microalbuminuria (employing UACR), along with annual blood pressure monitoring. The interval of screening should be individualized based on age, familial history, and comorbidities.Grade D, expert opinion
  • 12.2-Suggestion: In individuals with microalbuminuria (defined by UACR > 30 mg/g on two distinct urine samples) and after initiation of renin-angiotensin-aldosterone system (RAS) blockers, we suggest monitoring eGFR and microalbuminuria every 6 months to 1 year. In individuals with CKD G2–G5, the interval for eGFR and UACR/UPCR monitoring should be adjusted to CKD stage and treatments.Grade D, expert opinion
  • 12.3-Suggestion: In at-risk children and in children diagnosed with heterozygous P/LP COL4A3/COL4A4 variants (for instance diagnosed in the setting of persistent haematuria), we suggest monitoring urinalysis every 1–4 years from 4–6 years old.Grade D, expert opinion

Q13: TO WHOM, WHEN, AND HOW SHOULD HEARING BE ASSESSED?

  • 13.1-Suggestion: In patients with ARAS and males with XLAS, we suggest a first hearing evaluation at 4 years of age, followed by a hearing evaluation every year until adulthood. In adulthood, we suggest a hearing evaluation every 3 years. We recommend hearing screening until the age of 50 and testing based on symptoms afterwards.Grade D, expert opinion
  • 13.2-Suggestion: We do not recommend regular hearing evaluation in individuals with a heterozygous P/LP COL4A3/COL4A4 variant and only suggest testing in patients with subjective hearing loss.Grade D, expert opinion
  • 13.3-Suggestion: In female patients with XLAS we suggest hearing evaluation at diagnosis or when reaching adulthood and then every 5 years in the absence of hearing loss symptoms.Grade D, expert opinion
  • 13.4-Suggestion: We suggest pure tone audiometry as a standard hearing test.Grade D, expert opinion
  • We recommend pure tone audiometry in all patients. If hearing loss is present, additional speech audiometry quantifying speech intelligibility could be considered. In very young patients with unreliable pure tone audiometric thresholds, transient evoked otoacoustic emissions (TEOAE) can be considered if the middle ear status is normal, as well as auditory brainstem potentials (ABR).

Q14: TO WHOM, WHEN AND HOW SHOULD OPHTHALMOLOGIC EXAM BE PERFORMED?

  • 14-Suggestion: A full ophthalmologic examination should be performed at the time of diagnosis, including dilated fundoscopy. Periodical eye examinations could be performed from the time of diagnosis for XLAS and ARAS.Grade D, expert opinion

Q16: WHAT IS THE ROLE OF KIDNEY BIOPSY IN PATIENTS WHO ALREADY HAVE A GENETIC DIAGNOSIS OF (OR FAMILY HISTORY OF CONFIRMED) AS?

  • 16.1-Suggestion: A kidney biopsy is not needed in individuals with a genetic diagnosis of XLAS or ARAS.Grade D, expert opinion
  • 16.2-Suggestion: A kidney biopsy can sometimes be useful in individuals with heterozygous P/LP COL4A3/COL4A4 variants because other aetiologies of glomerular diseases may coexist.Grade D, expert opinion
  • 16.3-Suggestion: In individuals with heterozygous P/LP COL4A3/COL4A4 variants and no microalbuminuria, over 40 years of age, who have been informed about the risk of subsequent development of CKD and want to donate a kidney, a kidney biopsy with electron microscopy should be discussed to evaluate the risk of developing severe CKD post-donation.Grade D, expert opinion

Q17: WHEN (CONSIDERING BOTH AGE AND CLINICAL SITUATION) SHOULD RAS BLOCKERS BE STARTED IN A PATIENT WITH A COL4A3/4/5 VARIANT?

  • 17.1-Recommendation: Early initiation of RAS blockade treatment is recommended in AS, with the most extensive evidence for ramipril due to the most abundant preclinical and clinical studies on safety and efficacy.Grade B, strong
  • 17.2-Recommendation: RAS blockers should be initiated and titrated to maximum dose when microalbuminuria is detected irrespective of the genetic subgroup.Grade B, strong
  • 17.3-Suggestion: In males with XLAS and in both sexes with ARAS, after 2 years of age, we suggest initiating RAS blockers as soon as microscopic haematuria is detected.Grade C, moderate
  • 17.4-Suggestion: In heterozygous individuals with autosomal AS or females with heterozygous XLAS, we suggest not to start RAS blockers if they only show isolated microscopic haematuria.Grade D, expert opinion

Q18: SHOULD SGLT2-INHIBITORS BE USED IN AS? IF SO, WHEN SHOULD THEY BE PRESCRIBED?

  • 18.1-Statement: Existing evidence supports the use of SGLT2-inhibitors (SGLT2i) in adults with proteinuria and CKD and this benefit is likely to apply to individuals with AS.Grade D, expert opinion
  • 18.2-Suggestion: In adults with AS and CKD G2A3 or higher (G3A1–3 and G4A1–3) with albuminuria, despite RAS blockers, the addition of a SGLT2i should be considered.Grade D, expert opinion
  • 18.3-Statement: SGLT2i have not been trialled in children with CKD (no data available) and therefore a recommendation cannot be made on their use in children.Grade D, expert opinion
  • 18.4-Suggestion: We suggest not to use SGLT2i as monotherapy without underlying RAS blockade.Grade C, moderate

Q19: SHOULD FURTHER STUDIES BE PERFORMED IN A PATIENT PRESENTING AT DIAGNOSIS WITH NEPHROTIC SYNDROME IN WHOM A COL4A3/4/5 PATHOGENIC VARIANT IS IDENTIFIED?

  • 19.1-Suggestion: A kidney biopsy is suggested in an individual with a P/LP COL4A3/4/5 variant if the onset of nephrotic syndrome is abrupt or the degree of proteinuria does not match the expected clinical presentation of the disease.Grade D, expert opinion
  • 19.2-Suggestion: In the presence of an unexpected nephrotic syndrome and a non-specific kidney biopsy, we suggest expanding genetic testing by using a genetic panel test that includes all genes associated with inherited kidney disease or exome sequencing.Grade D, expert opinion

Q20: COULD INDIVIDUALS WITH HETEROZYGOUS COL4A3/COL4A4/COL4A5 PATHOGENIC VARIANTS BE CONSIDERED AS LIVING DONORS?

  • 20.1-Recommendation: We recommend determining the exact genotype in all possible donors.Grade B, strong
  • 20.2-Suggestion: All relatives with heterozygous AS variants (males or females with heterozygous P/LP variants in COL4A3/COL4A4 or females with a variant in COL4A5) should only be considered as the last possible resource for living kidney donation.Grade D, expert opinion
  • 20.3-Suggestion: Living kidney donation is not advisable in individuals heterozygous for a single P/LP variant in COL4A3, COL4A4, or COL4A5 aged under 40 years, or at any age if there is clinical or histological evidence of kidney damage (e.g. albuminuria, reduced eGFR or interstitial fibrosis/tubular atrophy greater than what would be normal for their age).Grade D, expert opinion
  • 20.4-Suggestion: Where kidney donation is considered by an individual heterozygous for a single P/LP variant in COL4A3, COL4A4, or COL4A5 aged over 40 years, in the absence of albuminuria or reduced eGFR, a kidney biopsy could be performed to detect evidence of subclinical kidney damage (i.e. scarring greater than what would be normal for their age) that would preclude donation. A decision to proceed with donation should only be made after careful consideration of the risks and benefits for that individual/family.Grade D, expert opinion
  • 20.5-Suggestion: Lifelong monitoring (with prompt nephroprotective RAS blockade therapy if microalbuminuria or hypertension develop) could be offered to individuals heterozygous for a single P/LP variant in COL4A3 or COL4A4 or COL4A5 who have donated a kidney, as for all living kidney donors.Grade D, expert opinion

Q21: WHAT IS THE PREVALENCE AND THE MANAGEMENT OF ALPORT POST-TRANSPLANT NEPHRITIS OR DE NOVO GBM DISEASE?

  • 21-Statement: While the risk of anti-GBM disease following a kidney transplant for AS without immunosuppressive therapy may be significant, current immunosuppressive treatments reduce this risk to less than 3%.Grade D, expert opinion

Abstract

Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies.

Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children.

As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were

selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world.

Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation.

This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes.

Contents of the original publication

The section headings of the original.

  • INTRODUCTION
  • MATERIALS AND METHODS
  • Q1: XLAS AND ARAS: WHAT ARE THE DIFFERENCES AMONG THEM AND WHAT IS THEIR PREVALENCE?
  • Q2: WHAT ARE THE PENETRANCE AND PREVALENCE OF HETEROZYGOUS COL4A3/COL4A4 SINGLE PATHOGENIC VARIANTS?
  • Q3: IS THE TERM ‘DIGENIC’ JUSTIFIED IN AS?
  • Q4: WHEN TO ORDER ALPORT GENE TESTING? WHAT IS THE LIST OF CLINICAL AND/OR HISTOLOGICAL FINDINGS THAT REQUIRE EXCLUDING ALPORT DIAGNOSIS IN DIFFERENTIAL DIAGNOSTICS AND WHAT SHOULD BE DONE IN MINORS?
  • Q5: SHOULD GENETIC TESTING IN RELATIVES BE ENCOURAGED? SHOULD IT BE LIMITED TO (FAMILY) VARIANT TESTING OR RATHER COVER ALL THREE GENES? SHOULD PARTNERS BE TESTED WHEN WISHING TO CREATE A FAMILY?
  • Q6: SHOULD ALPORT GENE TESTING BE INCLUDED IN GENE PANELS DESIGNED FOR KIDNEY DISEASES?
  • Q7: SHOULD ALPORT GENE TESTING BE INCLUDED ON THE LIST OF SECONDARY FINDINGS/ACTIONABLE FINDINGS?
  • Q8: GIVEN THE RELATIVELY HIGH FREQUENCY OF INDIVIDUALS WITH HETEROZYGOUS COL4A3/4 VARIANTS IN THE GENERAL POPULATION AND THEIR POTENTIALLY DETERIORATING EFFECT ON THE PHENOTYPE, SHOULD PATIENTS WITH PATHOGENIC COL4A3/4 VARIANTS BE SCREENED FOR OTHER KIDNEY DISEASES IN THE CLINICAL PRACTICE?
  • Q9: WHAT IS THE SENSITIVITY OF CURRENT GENETIC TESTS FOR AS? WHAT ARE THE POTENTIAL DIAGNOSTIC TOOLS IF NEXT-GENERATION SEQUENCING (NGS)-BASED GENETIC TESTING IS NEGATIVE?
  • Q10: WHAT IS THE ESTIMATED LIFELONG RELATIVE RISK OF STAGE 5 CKD IN INDIVIDUALS WITH HETEROZYGOUS COL4A3/COL4A4 VARIANTS VERSUS THAT IN THE GENERAL POPULATION?
  • Q11: WHAT IS THE ESTIMATED LIFELONG RELATIVE RISK AND AGE-RELATED RISK OF STAGE 5 CKD DEPENDING ON PATTERN OF INHERITANCE AND SEX?
  • XLAS—Male
  • XLAS—Female
  • ARAS—both genders
  • Individuals with a heterozygous P/LP COL4A3/COL4A4 variant
  • Q12: WHAT IS THE SUGGESTED FOLLOW-UP FOR INDIVIDUALS WITH HETEROZYGOUS P/LP COL4A3/COL4A4 VARIANTS?
  • Q13: TO WHOM, WHEN, AND HOW SHOULD HEARING BE ASSESSED?
  • Q14: TO WHOM, WHEN AND HOW SHOULD OPHTHALMOLOGIC EXAM BE PERFORMED?
  • Q15: WHAT ARE THE PROGRESSION FACTORS IN AS?
  • Q16: WHAT IS THE ROLE OF KIDNEY BIOPSY IN PATIENTS WHO ALREADY HAVE A GENETIC DIAGNOSIS OF (OR FAMILY HISTORY OF CONFIRMED) AS?
  • Q17: WHEN (CONSIDERING BOTH AGE AND CLINICAL SITUATION) SHOULD RAS BLOCKERS BE STARTED IN A PATIENT WITH A COL4A3/4/5 VARIANT?
  • Efficacy and dosing of RAS blockade
  • Safety of RAS-blockade and off-label use in children
  • Research objective RAS blockade in AS
  • Q18: SHOULD SGLT2-INHIBITORS BE USED IN AS? IF SO, WHEN SHOULD THEY BE PRESCRIBED?
  • Efficacy of SGLT2i in AS
  • Safety of SGLT2i and off-label use in children
  • Research objective SGLT2i in AS
  • Q19: SHOULD FURTHER STUDIES BE PERFORMED IN A PATIENT PRESENTING AT DIAGNOSIS WITH NEPHROTIC SYNDROME IN WHOM A COL4A3/4/5 PATHOGENIC VARIANT IS IDENTIFIED?
  • Q20: COULD INDIVIDUALS WITH HETEROZYGOUS COL4A3/COL4A4/COL4A5 PATHOGENIC VARIANTS BE CONSIDERED AS LIVING DONORS?
  • Q21: WHAT IS THE PREVALENCE AND THE MANAGEMENT OF ALPORT POST-TRANSPLANT NEPHRITIS OR DE NOVO GBM DISEASE?
  • PATIENT NEEDS FOR PEOPLE WITH AS
  • CLOSING REMARKS AND FUTURE PERSPECTIVES

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