Nephrology and Kidney Transplant Department, National Reference Center for Complex Glomerular Diseases, Hospital Clínic, Barcelona University, Barcelona; Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona; RICORS2040, Universidad Autónoma de Madrid, Madrid.
IIS-La Princesa, Servicio de Nefrología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid; RICORS2040, Universidad Autónoma de Madrid, Madrid.
Am J Kidney Dis. 2024 Dec;84(6):719-730.e1. doi: 10.1053/j.ajkd.2024.04.021. Epub 2024 Jul 6.
RATIONALE & OBJECTIVE: Chronic kidney disease of unknown etiology (CKDUE) is one of the main global causes of kidney failure. Genetic studies may identify an etiology in these patients, but few studies have implemented genetic testing of CKDUE in a population-based series of patients, which was the focus of the GENSEN Study.
Case series.
SETTINGS & PARTICIPANTS: 818 patients aged≤45 years at 51 Spanish centers with CKDUE, and either an estimated glomerular filtration rate of<15mL/min/1.73m or treatment with maintenance dialysis or transplantation.
Genetic testing for 529 genes associated with inherited nephropathies using high-throughput sequencing (HTS). Pathogenic and/or likely pathogenic (P/LP) gene variants concordant with the inheritance pattern were detected in 203 patients (24.8%). Variants in type IV collagen genes were the most frequent (COL4A5, COL4A4, COL4A3; 35% of total gene variants), followed by NPHP1, PAX2, UMOD, MUC1, and INF2 (7.3%, 5.9%, 2.5%, 2.5%, and 2.5%, respectively). Overall, 87 novel variants classified as P/LP were identified. The top 5 most common previously undiagnosed diseases were Alport syndrome spectrum (35% of total positive reports), genetic podocytopathies (19%), nephronophthisis (11%), autosomal dominant tubulointerstitial kidney disease (7%), and congenital anomalies of the kidney and urinary tract (CAKUT, 5%). A family history of kidney disease was reported by 191 participants (23.3%) and by 65 of 203 patients (32.0%) with P/LP variants.
Missing data, and selection bias resulting from voluntary enrollment.
Genomic testing with HTS identified a genetic cause of kidney disease in approximately one quarter of young patients with CKDUE and advanced kidney disease. These findings suggest that genetic studies are a potentially useful tool for the evaluation of people with CKDUE.
PLAIN-LANGUAGE SUMMARY: The cause of kidney disease is unknown for 1 in 5 patients requiring kidney replacement therapy, reflecting possible prior missed treatment opportunities. We assessed the diagnostic utility of genetic testing in children and adults aged≤45 years with either an estimated glomerular filtration rate of<15mL/min/1.73m or treatment with maintenance dialysis or transplantation. Genetic testing identified the cause of kidney disease in approximately 1 in 4 patients without a previously known cause of kidney disease, suggesting that genetic studies are a potentially useful tool for the evaluation of these patients.
不明原因的慢性肾脏病（CKDUE）是全球主要的肾衰竭病因之一。遗传研究可能会确定这些患者的病因，但很少有研究对基于人群的一系列患者进行 CKDUE 的遗传检测，这正是 GENSEN 研究的重点。
病例系列。
51 家西班牙中心的 818 名年龄≤45 岁的 CKDUE 患者，肾小球滤过率估计值<15mL/min/1.73m 或接受维持性透析或移植治疗。
使用高通量测序（HTS）对 529 个与遗传性肾病相关的基因进行基因检测。在 203 名患者（24.8%）中检测到与遗传模式一致的致病性和/或可能致病性（P/LP）基因突变。IV 型胶原蛋白基因的变异最为常见（COL4A5、COL4A4、COL4A3；占总基因突变的 35%），其次是 NPHP1、PAX2、UMOD、MUC1 和 INF2（分别为 7.3%、5.9%、2.5%、2.5%和 2.5%）。总体而言，共发现 87 种新的分类为 P/LP 的变异。前 5 种最常见的未确诊疾病是 Alport 综合征谱（占总阳性报告的 35%）、遗传性足细胞病（19%）、肾单位间质性肾病（11%）、常染色体显性肾小管间质性肾病（7%）和先天性肾和泌尿道异常（CAKUT，5%）。191 名参与者（23.3%）和 203 名 P/LP 变异患者中的 65 名（32.0%）报告有肾脏疾病家族史。
数据缺失，以及由于自愿参与而导致的选择偏倚。
使用 HTS 的基因组检测在约四分之一患有 CKDUE 和晚期肾病的年轻患者中确定了肾脏疾病的遗传原因。这些发现表明，遗传研究可能是评估 CKDUE 患者的有用工具。
