Age at disease onset and risk of chronic kidney disease in patients with heterozygous disease-causing variants in COL4A3 and COL4A4.

Background: A key goal in managing patients with heterozygous disease-causing COL4A3 and COL4A4 (COL4A3/4) variants, affecting individuals spanning a broad age range, is to slow the development of chronic kidney disease (CKD). Whether age of onset is associated with the risk of CKD has not been investigated. Methods: In 294 patients (118 males) with heterozygous disease-causing COL4A3/4 variants in the Shanghai Registry of Alport Syndrome, we made the comparison of risk of CKD between those showing disease onset before 18 years old (early onset) or from 18 years and older (late onset). CKD were defined as onset of persistent albuminuria (albumin-to-creatinine ratio ≥30 mg/g) or CKD G2 (estimated glomerular filtration rate <90 ml/min/1.73 m2). Results: 147 (50.0%) of patients had initial presentation of symptoms of kidney diseases when they were <18 years old [median age at onset, 5.0 years (IQR, 3.0-8.0 years)], and in the remainder when they were older [median age at onset, 30.0 years (IQR, 26.0-38.0 years)]. During a median follow-up of 3.0 years (IQR, 0-10.3 years), earlier disease onset showed significant associations with higher risk of albuminuria [hazard ratio (HR) 7.08, 95% confidence intervals (CI) 4.59-10.93] and CKD G2 (HR 3.49, 95%CI 1.57-7.75). Risk of albuminuria increased by 64%, and risk of CKD G2 increased by 34%, per 5-year step toward younger age at disease onset. Conclusions: Earlier onset of disease may predict higher risk of CKD in patients with heterozygous disease-causing COL4A3/4 variants. This association, if verified in large prospective studies, may help stratify patients by risk of worse prognosis, which can guide their management and preemptive nephroprotective treatment.