Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa;
J Am Soc Nephrol. 2013 Nov;24(11):1820-9. doi: 10.1681/ASN.2013010045. Epub 2013 Aug 1.
Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Short-term use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN.
致密物沉积病（DDD）和 C3 肾小球肾炎（C3GN）是 C3 肾小球病广泛认可的亚型。这些超罕见的肾脏疾病的特点是补体替代途径的液相失调，导致补体蛋白在肾小球中沉积。疾病诱因未知，由于缺乏靶向治疗，进展为终末期肾衰竭是常见的最终结果。我们研究了可溶性 CR1，一种有效的补体活性调节剂，以测试其是否能恢复 C3 肾小球病的补体调节。使用 DDD 患者的血清进行的体外研究表明，可溶性 CR1 可防止替代途径 C3 转化酶的失调，即使存在 C3 肾炎因子也是如此。在补体因子 H 缺乏和人 CR1 转基因的小鼠中，可溶性 CR1 治疗可阻止替代途径的激活，导致血清 C3 水平正常化，以及 iC3b 从肾小球基底膜清除。在一名终末期肾衰竭的儿科患者中短期使用可溶性 CR1 证明了其安全性和使末端补体途径正常化的能力。总的来说，这些数据表明可溶性 CR1 重新建立了替代补体途径的调节，并为评估可溶性 CR1 作为 DDD 和 C3GN 的治疗方法的有限试验提供了支持。
