Department of Pediatrics, Peking University First Hospital, No. 1 Xi An Men Da Jie, Beijing, 100034, China.
Clinic of Nephrology and Rheumatology, University Medical Center Goettingen, Robert-Koch Str. 40, 37075, Goettingen, Germany.
Pediatr Nephrol. 2021 Sep;36(9):2719-2730. doi: 10.1007/s00467-021-05040-9. Epub 2021 Mar 27.
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.
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.
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.
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.
常染色体隐性遗传性 Alport 综合征（ARAS）是由 COL4A3 或 COL4A4 基因的两个等位基因中的致病性变异引起的。由于患者数量较少，ARAS 的报道很少，并且在 ARAS 中没有关于肾素-血管紧张素-醛固酮系统（RAAS）抑制治疗的报告。
对中国遗传性肾脏疾病登记数据库和欧洲 Alport 登记处的 101 例 ARAS 患者进行回顾性研究。评估 ARAS 中的基因型-表型相关性和 RAAS 抑制的肾保护作用。
中位年龄为 15 岁（范围 1.5-46 岁）。12 例患者在中位年龄 20.5 岁时进展为慢性肾脏病 5 期（CKD5）。与 1 或 2 个错义变异的患者相比，无错义变异的患者听力损失、肾病范围蛋白尿、eGFR 下降更快、CKD5 发病年龄更早的发生率更高。大多数患者（79/101，78%）目前正在接受 RAAS 抑制剂治疗；治疗开始的中位年龄为 10 岁，平均治疗时间为 6.5±6.0 年。未治疗患者的 CKD5 发病年龄为 24 岁。RAAS 抑制治疗使肾功能受损（T-III）患者的 CKD5 发病年龄延迟至 35 岁，但由于事件数量较少，蛋白尿（T-II）治疗患者的发病年龄尚不确定。无微量白蛋白尿（T-I）的治疗患者进展为 CKD5。与非错义变异患者相比，ARAS 患者的 1 或 2 个错义变异对治疗的反应更好。
本研究首次提供了 ARAS 患者早期使用 RAAS 抑制治疗的证据。此外，ARAS 中的基因型与治疗反应相关，有利于错义变异。
