Torra Roser, Lipska-Zietkiewicz Beata, Acke Frederic, Antignac Corinne, Becker Jan Ulrich, Cornec-Le Gall Emilie, van Eerde Albertien M, Feltgen Nicolas, Ferrari Rossella, Gale Daniel P, Gear Susie, Gross Oliver, Haeberle Stefanie, Heidet Laurence, Lennon Rachel, Massella Laura, Pfau Kristina, Pizarro Maria Del Prado Venegas, Topaloglu Rezan, Wlodkowski Tanja, Zealey Heidi
Nephrology Department, Fundació Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), Departament de Medicina, Universitat Autònoma de Barcelona, RICORS2040, Barcelona, Spain.
Clinical Genetics Unit, Department of Biology and Medical Genetics, Medical University of Gdańsk, Gdańsk, Poland.
Nephrol Dial Transplant. 2025 May 30;40(6):1091-1106. doi: 10.1093/ndt/gfae265.
Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies. Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children. As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world. Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation. This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes.
由COL4A3/4/5基因的遗传缺陷导致的肾小球肾病，包括经典的阿尔波特综合征，是第二常见的遗传性肾病，其特征为持续性血尿，最终发展到需要进行肾脏替代治疗，常伴有感音神经性耳聋，偶尔伴有眼部异常。由于COL4A3/4/5肾小球病的表型异质性、多种遗传模式、可变的表达性、个体变异的疾病外显率，以及不完善的预后和病情进展因素，再加上临床试验稀缺且有限，尤其是在儿童中，因此对其进行诊断和管理极具挑战性。作为欧洲罕见肾病参考网络（ERKNet）、欧洲肾脏协会（ERA Genes&Kidney）和欧洲儿科肾脏病学会（ESPN）遗传性肾脏疾病工作组的联合倡议，一个由成人和儿童肾脏病学家、肾脏遗传学家、听力学家、眼科医生和肾脏病理学家组成的专家团队被挑选出来，对21个临床相关的PICO（患者或人群、干预措施、对照、结局）问题进行系统的文献综述。专家们制定了建议，并在一次共识会议上根据患者代表和代表世界所有地区的肾脏病学家投票小组的意见对这些建议进行了正式分级。在对出现持续性血尿、蛋白尿、不明原因的肾衰竭、不明原因的局灶节段性肾小球硬化以及可能的多囊肾病的个体进行初始评估时，对COL4A3/4/5基因进行联合分析的基因诊断已经是关键的诊断测试。早期肾素-血管紧张素系统阻断是标准的治疗方法；对于患有蛋白尿和慢性肾脏病的成年人，可加用钠-葡萄糖协同转运蛋白-2抑制剂。携带COL4A3/4/5杂合变异的亲属仅应被视为活体肾捐赠的最后可能来源。本指南为COL4A3/4/5基因致病性变异个体的诊断和管理提供了指导。
