背景:常染色体显性多囊肾病(ADPKD)是一种单基因疾病,其特征是肾脏中充满液体的囊肿积聚,导致肾脏体积增大和进行性肾功能损害。疾病严重程度,虽然,可能由于等位基因和遗传异质性而有所不同。本研究旨在确定PKD1截断和非截断突变与ADPKD患者肾功能下降之间的基因型-表型相关性。
方法:我们在科威特建立了一项单中心回顾性队列研究,在临床和遗传上随访了每位确诊为PKD1-ADPKD的患者。每年进行肾功能检查。我们为每个个体拟合了具有随机截距的广义加性混合效应模型,以分析跨突变类型的肾功能的重复测量。然后,我们在cox比例风险模型中计算了肾衰竭的生存时间。模型根据性别进行了调整,访问年龄和出生年份。
结果:该研究包括22名截断和20名非截断(共42名)患者,平均随访6.6年(范围:1至12年)。与PKD1非截断突变患者(每年-3.5ml/min/1.73m2;95CI-4.0,-3.1)相比,PKD1截断突变患者的eGFR下降速度更快(每年-4.7ml/min/1.73m2;95CI-5.0,-4.4)(相互作用P<0.001)。肾衰竭时间的Kaplan-Meier生存分析显示,PKD1截断突变患者的肾脏生存时间(中位数51年)比非截断突变患者(中位数56年)短(Pforlog-rank=0.008)。
结论:在纵向和生存分析中,与PKD1非截断突变患者相比,PKD1截断突变患者的肾功能下降更快.早期识别PKD1截断突变的患者可以,充其量,告知早期临床干预措施或,至少,帮助建议积极的监测。
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disease characterized by the accumulation of fluid-filled cysts in the kidneys, leading to renal volume enlargement and progressive kidney function impairment. Disease severity, though, may vary due to allelic and genetic heterogeneity. This study aimed to determine genotype-phenotype correlations between
PKD1 truncating and non-truncating mutations and kidney function decline in ADPKD patients.
METHODS: We established a single-center retrospective cohort study in Kuwait where we followed every patient with a confirmed
PKD1-ADPKD diagnosis clinically and genetically. Renal function tests were performed annually. We fitted generalized additive mixed effects models with random intercepts for each individual to analyze repeated measures of kidney function across mutation type. We then calculated survival time to kidney failure in a cox proportional hazards model. Models were adjusted for sex, age at visit, and birth year.
RESULTS: The study included 22 truncating and 20 non-truncating (42 total) patients followed for an average of 6.6 years (range: 1-12 years). Those with PKD1 truncating mutations had a more rapid rate of eGFR decline (-4.7 mL/min/1.73 m2 per year; 95% CI: -5.0, -4.4) compared to patients with
PKD1 non-truncating mutations (-3.5 mL/min/1.73 m2 per year; 95% CI: -4.0, -3.1) (p for interaction <0.001). Kaplan-Meier survival analysis of time to kidney failure showed that patients with PKD1 truncating mutations had a shorter renal survival time (median 51 years) compared to those with non-truncating mutations (median 56 years) (P for log-rank = 0.008).
CONCLUSIONS: In longitudinal and survival analyses, patients with
PKD1 truncating mutations showed a faster decline in kidney function compared to patients
PKD1 non-truncating mutations. Early identification of patients with PKD1 truncating mutations can, at best, inform early clinical interventions or, at least, help suggest aggressive monitoring.