Urinary Biomarkers for Steroid Resistant Nephrotic Syndr

描述(由申请人提供)： 目前治疗儿童特发性肾病综合征的初步方法是类固醇治疗试验，基于25年前的数据，数据显示，这些患者中有80%患有微小病变疾病，并对类固醇敏感(SS)。自那时以来，类固醇耐药(SR)的发生率显著增加。需要更好的生物标志物来促进适当的治疗选择，避免不必要的毒性，并为儿童特发性肾病综合征的发病机制和预后提供线索。我们假设，尿液生物标志物，以高分子质量(HMW)和低分子(LMW)蛋白的形式，比总或中分子(IMW)蛋白(如白蛋白)更能预测儿童特发性肾病综合征的自然病程、结果和治疗反应。HMW蛋白尿与节段性硬化有关，而LMW蛋白尿与肾活检的肾小管间质损害有关。在一项关于儿童肾病综合征的试验性横断面病例对照研究中，将对SR患者和SS患者进行比较。我们将使用最先进的蛋白质组学方法，为SR确定至少2个HMW范围的新尿蛋白生物标记物和2个LMW范围的新尿蛋白生物标记物。我们将确定SR和SS患者中新的和已知的尿液生物标志物排泄率的平均值和标准差。在R33阶段，我们将对儿童特发性肾病综合征进行前瞻性流行病学研究，以确定在R21阶段确定的SR生物标记物在首次出现肾病综合征的儿童的前瞻性研究中的预后价值。我们将与西方儿科肾病临床试验联盟的成员机构一起进行R33阶段。我们将SR生物标志物的排泄率与肾活检中肾小球和肾小管间质纤维化的程度相关联，这将通过一种新的定量计算机成像方法来测量。这些生物标志物将通过免疫组织化学和原位杂交在活检组织中进行定位。已确定的生物标志物将通过确定外源重组蛋白在足细胞、系膜细胞和近端肾小管细胞中过度表达或应用的影响来测试其致病意义。我们相信，来自当前研究的数据将改进我们的诊断和治疗策略，并可能为已识别的生物标记物的发病意义提供线索。

DESCRIPTION (provided by applicant): The current initial approach to idiopathic nephrotic syndrome in children is a therapeutic trial of steroids and was based on data from 25 years ago, which showed that 80% of these patients have minimal-change disease and are steroid-sensitive (SS). The incidence of steroid resistance (SR) has increased significantly since that time. Better biomarkers are needed to facilitate appropriate choices of therapy, to avoid unnecessary toxicity, and to provide clues to the pathogenesis and prognosis of idiopathic nephrotic syndrome in childhood. We hypothesize that urine biomarkers, in the form of high-molecular-weight (HMW) and low-molecular-weight (LMW) proteins, are better predictors of the natural course, outcome, and the response to treatment of idiopathic nephrotic syndrome of childhood than total or intermediate-molecular-weight (IMW) proteins such as albumin. HMW proteinuria is associated with segmental sclerosis, while LMW proteinuria is associated with tubulointerstitial damage on renal biopsy. SR patients will be compared with patients with SS patients in a pilot cross-sectional, case-control study of nephrotic syndrome in childhood. We will identify at least 2 novel urinary protein biomarkers in the HMW range and 2 novel urinary protein biomarkers in the LMW range for SR using cutting-edge proteomics methodology. We will determine the mean and standard deviation of the excretion rate of novel and known urinary biomarkers in SR versus SS patients. In the R33 phase, we will conduct a prospective epidemiologic study of idiopathic nephrotic syndrome in children in order to define the prognostic value of the SR biomarkers identified in the R21 phase in a prospective study of children who first presented with nephrotic syndrome. We will conduct the R33 phase with member institutions of the Western Consortium for Pediatric Nephrology Clinical Trials Group. We will correlate the excretion rate of SR biomarkers to the extent of glomerular and tubulointerstitial fibrosis on renal biopsy, which will be measured by a novel quantitative computer imaging methodology. These biomarkers will be localized in the biopsy by immunohistochemistry and in-situ hybridization. The biomarkers identified will be tested for pathogenetic significance by determining the effect of overexpression or application of exogenous recombinant protein in podocyte, mesangial cell and proximal tubular cell. We believe that data from the current study will improve our diagnostic and therapeutic strategy and may provide clues to the pathogenetic significance of the identified biomarkers.