Clinical applications of urine proteomics to lupus nephritis

摘要 狼疮性肾炎(LN)是通过肾脏活检确诊的，患者的蛋白尿为0.5g/24小时，但 蛋白尿的存在意味着肾脏损害已经发生。据估计，30%的 随着LN的每一次耀斑，肾素都会永久消失。肾损害前狼疮性肾炎的鉴别 使用尿蛋白质组生物标志物可以将LN的管理策略转变为预防， 有可能导致更早、更有效、毒性更低的治疗。三个具体目标将是 在这份R01的基础上提出了霍普金斯狼疮队列的工作(35年，2855 SLE 纵向队列，其中患者每3个月接受一次方案跟踪)，尤其是在 NIH RA/SLE加速药物伙伴关系(AMP)发现的尿液生物标记物。 目的1-建立尿液生物标记物，在蛋白尿前识别新的狼疮性肾炎。 以往的AMP尿蛋白组学研究显示，尿IL-16、CD163和中性粒细胞 含量表示肾内层粘连蛋白活性。这些生物标志物将在收集的尿样中进行定量 狼疮患者在蛋白尿发病前3个月内，最终被诊断为 通过肾活检来确定与没有升高的患者相比，生物标志物是否升高 发展LN。还将对完整的尿蛋白组学图谱进行评估，以发现其他生物标志物 可能有助于在蛋白尿之前预测LN的发病。 目的2-开发一种尿液生物标记物以指导治疗中免疫抑制的逐渐减少 在病人身上。重复活检时组织学NIH活动指数为2的患者发生 在一项研究中，随着免疫抑制的逐渐减少，蛋白尿发作和死亡率增加。四 AMP患者尿中与NIH活动指数和GT；2相关的生物标志物(IL-16、CD163、Galectin-1和 PRTN3)将在12份尿样中进行定量(分析1200个额外的尿蛋白) 临床明显缓解的LN患者因逐渐减少免疫抑制而发作，而LN患者为12 LN 患者在逐渐缩小时没有出现红肿。最具预测性的生物标志物将被组合成10个- Plex面板将在60名患者的前瞻性队列中进行验证，逐步减少免疫抑制。 目的3-建立检测LN早期慢性肾脏病(CKD)的生物标志物。尿液 对参加AMP187例患者的蛋白质组研究证实转化生长因子-β介导的纤维化和肿瘤坏死因子 在检测早期CKD方面，信号相关蛋白可能优于单独的蛋白尿。这些 将对AMP患者进行至少五年的临床跟踪，以确定他们的肾脏轨迹。 并找出尿蛋白组学(和其他组学)图谱的差异 保持稳定的肾功能与不稳定的人相比。

Abstract Lupus nephritis (LN) is diagnosed by kidney biopsy in patients with proteinuria > 0.5g/24h, but the presence of proteinuria means that kidney damage has already occurred. It is estimated that 30% of nephrons are permanently lost with each flare of LN. The identification of LN before kidney damage using urine proteomic biomarkers could shift the management strategy of LN to prevention, potentially leading to earlier, more effective, and less toxic treatment. Three specific aims will be addressed in this R01 building on the work of the Hopkins Lupus Cohort (a 35 year, 2855 SLE longitudinal cohort in which patients are followed by protocol every 3 months) and in particular on the urine biomarker discoveries from the NIH RA/SLE Accelerated Medicines Partnership (AMP). Aim 1 - Develop a urine biomarker panel to identify new lupus nephritis BEFORE proteinuria. Previous AMP urine proteomic studies revealed that urinary IL-16, CD163, and neutrophil granule content indicate intrarenal LN activity. These biomarkers will be quantitated in urine samples collected within 3 months before the onset of proteinuria in lupus patients who ultimately were diagnosed with LN by renal biopsy to determine if the biomarkers are elevated compared to patients who do not develop LN. A full urine proteomic profile will also be assessed to discover additional biomarkers that could contribute to a robust panel for predicting onset of LN before proteinuria. Aim 2 - Develop a urine biomarker panel to guide tapering of immunosuppression in treated LN patients. Patients with a histological NIH activity index >2 on repeat biopsy developed a proteinuria flare and increased mortality upon tapering of immunosuppression in one study. Four urinary biomarkers associated with NIH activity index >2 in AMP (IL-16, CD163, Galectin-1, and PRTN3) will be quantitated ( with analysis of 1200 additional urine proteins) in urine samples from 12 LN patients in apparent clinical remission who flared upon tapering immunosuppression versus 12 LN patients who did not flare upon tapering. The most predictive biomarkers will be combined into a 10- plex panel to be validated in a prospective cohort of 60 patients tapering immunosuppression. Aim 3 - Develop a biomarker for detection of early chronic kidney disease (CKD) in LN. Urine proteomic studies on 187 patients enrolled in AMP identified TGF-β-mediated fibrosis and TNF signaling related proteins that may be superior to proteinuria alone in detecting early CKD. These AMP patients will be followed clinically for at least five years to determine the trajectory of their kidney disease and to find differences in urine proteomic (and other omic) profiles between those who maintain stable renal function versus those who do not.