Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome

Pediatr Nephrol. 2021 Sep;36(9):2719-2730. doi: 10.1007/s00467-021-05040-9. Epub 2021 Mar 27.


Background: Autosomal recessive Alport syndrome (ARAS) is caused by pathogenic variants in both alleles of either COL4A3 or COL4A4 genes. Reports on ARAS are rare due to small patient numbers and there are no reports on renin-angiotensin-aldosterone system (RAAS) inhibition therapy in ARAS.

Methods: Retrospective study in 101 patients with ARAS from Chinese Registry Database of Hereditary Kidney Diseases and European Alport Registry. Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in ARAS were evaluated.

Results: Median age was 15 years (range 1.5-46 years). Twelve patients progressed to stage 5 chronic kidney disease (CKD5) at median age 20.5 years. Patients without missense variants had both higher prevalence and earlier onset age of hearing loss, nephrotic-range proteinuria, more rapid decline of eGFR, and earlier onset age of CKD5 compared to patients with 1 or 2 missense variants. Most patients (79/101, 78%) currently are treated with RAAS inhibitors; median age at therapy initiation was 10 years and mean duration 6.5 ± 6.0 years. Median age at CKD5 for untreated patients was 24 years. RAAS inhibition therapy delayed CKD5 onset in those with impaired kidney function (T-III) to median age 35 years, but is undefined in treated patients with proteinuria (T-II) due to low number of events. No treated patients with microalbuminuria (T-I) progressed to CKD5. ARAS patients with 1 or 2 missense variants showed better response to treatment than patients with non-missense-variants.

Conclusions: Our study provides the first evidence for early use of RAAS inhibition therapy in patients with ARAS. Furthermore, genotype in ARAS correlates with response to therapy in favor of missense variants.

Keywords: Alport syndrome; Autosomal recessive inheritance; COL4A3 gene; COL4A4 gene; Nephroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Angiotensin-Converting Enzyme Inhibitors* / therapeutic use
  • Child
  • Child, Preschool
  • Genotype
  • Humans
  • Infant
  • Middle Aged
  • Nephritis, Hereditary* / drug therapy
  • Nephritis, Hereditary* / genetics
  • Phenotype
  • Protective Agents / therapeutic use
  • Renin-Angiotensin System / drug effects
  • Retrospective Studies
  • Young Adult


  • Angiotensin-Converting Enzyme Inhibitors
  • Protective Agents