Modeling SLE Nephritis Through Urine MCP-1

描述（由申请人提供）：人类SLE累及肾脏是常见的，通常是严重的。虽然目前的免疫抑制药物可以控制肾性SLE，但如果能够预测狼疮肾耀斑的发病、严重程度或反应性，并相应地调整治疗方法，治疗将更有效，毒性更小。目前还没有临床验证的生物标志物可用于可靠地监测整个发作周期的SLE肾脏活动。然而，该实验室最近的数据显示，肾炎患者尿液中的趋化因子单核细胞趋化蛋白-1 （MCP-1）水平显著升高，这似乎反映了疾病的活动性和严重程度。因此，假设尿液MCP-1 （uMCP-1）是反映肾脏炎症水平的狼疮性肾炎生物标志物，可用于预测即将发生的耀斑、耀斑严重程度和耀斑预后。本研究的目的是验证uMCP-1作为SLE肾炎发作周期和肾脏炎症的生物标志物。研究目标将通过利用俄亥俄州立大学开发的俄亥俄SLE研究（OSS）数据库和标本库的两个具体目标来实现。OSS包含临床信息和一系列系统性红斑狼疮患者的尿液样本，这些患者在数年内每2个月前瞻性随访一次。在Aim 1中，在SLE肾脏耀斑发生之前、期间和之后获得的样本中，将通过ELISA检测uMCP-1水平，并与临床病程相关。将计算uMCP-1作为耀斑发作、严重程度和治疗反应预测因子的敏感性和特异性，并评估uMCP-1与SLE传统临床标志物的相互作用。在Aim 2中，肾活检测量的uMCP-1将与浸润性肾白细胞、肾小球新月形、肾小球硬化、间质纤维化和肾小管萎缩相关，以确定uMCP-1水平是否反映SLE肾炎中发现的可影响肾脏生存的特定肾脏病变。为了检验uMCP-1是否与肾脏炎症或纤维化有更好的相关性，我们将uMCP-1与肾脏炎症的关联强度与uMCP-1与肾脏纤维化的关联强度进行比较。总之，该项目有望证明uMCP-1是狼疮性肾炎及其耀斑的有效生物标志物，并可用于促进治疗决策。

DESCRIPTION (provided by applicant): Kidney involvement in human SLE is common and usually severe. Although current immunosuppressive drugs can control renal SLE, therapy would be more effective with less toxicity if the onset, severity, or responsiveness of lupus renal flares could be predicted, and treatment modified accordingly. Presently there are no clinically validated biomarkers that can be used to reliably monitor SLE renal activity throughout the flare cycle. However, recent data from this laboratory show that levels of the chemokine monocyte chemoattractant protein-1 (MCP-1) increase significantly in the urine of patients having a renal flare, and appear to reflect disease activity and severity. It was thus postulated that urine MCP-1 (uMCP-1) is a lupus nephritis biomarker that reflects the level of kidney inflammation, and that can be used to predict impending flare, flare severity, and flare prognosis. The purpose of this investigation is to validate uMCP-1 as a biomarker of SLE nephritis flare cycles and renal inflammation. The study goals will be addressed through two Specific Aims that utilize the Ohio SLE Study (OSS) database and specimen bank, developed at Ohio State University. The OSS contains clinical information and serial urine samples from a cohort of well-characterized SLE patients followed prospectively every 2 months over several years. In Aim 1, uMCP-1 levels will be measured by ELISA in samples obtained before, during, and after SLE renal flares, and correlated to clinical course. The sensitivity and specificity of uMCP-1 as a predictor of flare onset, severity, and response to therapy will be calculated, and the interaction of uMCP-1 with traditional clinical markers of SLE will be assessed. In Aim 2, uMCP-1 measured at kidney biopsy will be correlated with infiltrating renal leukocytes, glomerular crescents, glomerulosclerosis, interstitial fibrosis, and tubular atrophy, to determine whether uMCP-1 levels reflect specific renal lesions found in SLE nephritis that can affect kidney survival. To test whether uMCP-1 correlates better with renal inflammation or fibrosis, the strength of the association of uMCP-1 and renal inflammation will be compared to the strength of the association of uMCP-1 and renal fibrosis. In summary, this project is expected to demonstrate that uMCP-1 is a valid biomarker of lupus nephritis and its flare, and can be used to facilitate treatment decisions.