Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Drugs. 2023 Nov;83(16):1475-1499. doi: 10.1007/s40265-023-01940-2. Epub 2023 Sep 25.
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a frequent cause of kidney failure. Currently, the diagnosis necessitates a kidney biopsy, with routine immunofluorescence microscopy revealing IgA as the dominant or co-dominant immunoglobulin in the glomerular immuno-deposits, often with IgG and sometimes IgM or both. Complement protein C3 is observed in most cases. IgAN leads to kidney failure in 20-40% of patients within 20 years of diagnosis and reduces average life expectancy by about 10 years. There is increasing clinical, biochemical, and genetic evidence that the complement system plays a paramount role in the pathogenesis of IgAN. The presence of C3 in the kidney immuno-deposits differentiates the diagnosis of IgAN from subclinical glomerular mesangial IgA deposition. Markers of complement activation via the lectin and alternative pathways in kidney-biopsy specimens are associated with disease activity and are predictive of poor outcome. Levels of select complement proteins in the circulation have also been assessed in patients with IgAN and found to be of prognostic value. Ongoing genetic studies have identified at least 30 loci associated with IgAN. Genes within some of these loci encode complement-system regulating proteins that can interact with immune complexes. The growing appreciation for the central role of complement components in IgAN pathogenesis highlighted these pathways as potential treatment targets and sparked great interest in pharmacological agents targeting the complement cascade for the treatment of IgAN, as evidenced by the plethora of ongoing clinical trials.
免疫球蛋白 A 肾病（IgAN）是全球最常见的原发性肾小球肾炎，也是肾衰竭的常见原因。目前，诊断需要进行肾活检，常规免疫荧光显微镜检查显示 IgA 是肾小球免疫沉积物中的主要或共同免疫球蛋白，常伴有 IgG，有时伴有 IgM 或两者兼有。大多数情况下可观察到补体蛋白 C3。在诊断后 20 年内，IgAN 导致 20-40%的患者发生肾衰竭，并使平均预期寿命缩短约 10 年。越来越多的临床、生化和遗传证据表明，补体系统在 IgAN 的发病机制中起着至关重要的作用。肾脏免疫沉积物中 C3 的存在将 IgAN 的诊断与亚临床肾小球系膜 IgA 沉积区分开来。肾活检标本中通过凝集素和替代途径激活补体的标志物与疾病活动相关，并可预测不良预后。循环中某些补体蛋白的水平也在 IgAN 患者中进行了评估，发现具有预后价值。正在进行的遗传研究已经确定了至少 30 个与 IgAN 相关的位点。这些位点中的一些基因编码补体系统调节蛋白，这些蛋白可以与免疫复合物相互作用。补体成分在 IgAN 发病机制中的核心作用日益受到重视，这突显了这些途径作为潜在治疗靶点的重要性，并激发了人们对靶向补体级联治疗 IgAN 的药理学药物的极大兴趣，这从大量正在进行的临床试验中可见一斑。
