Focal Segmental Glomerulosclerosis Pathogenesis

局灶节段性肾小球硬化发病机制

• 批准号: 6983888
• 负责人: Jeffrey Burnett Kopp
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6983888
• 关键词: ACE inhibitors; African American; HIV infections; antifibrinolytic agents; antihypertensive agents; clinical trials; dexamethasone; dosage; genetically modified animals; glomerular filtration rate; glomerulosclerosis; hormone therapy; human immunodeficiency virus 1; human subject; human therapy evaluation; kidney disorder chemotherapy; laboratory mouse; molecular pathology; patient oriented research; sirolimus

Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndrome characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, HIV-associated FSGS, hyperfiltration FSGS (due to reduced renal mass, renal toxins, or obesity), and genetic causes. In order to define the molecular mechanisms responsible for HIV-associated FSGS, we have established a line of mice in which transgene expression can be regulated in the glomerular podocyte using an tetracycline-regulated system. We have shown that expression is tightly regulated and is restricted to the podocyte. We have used this system to express the HIV-1 accessory protein Vpr in the podocyte. These mice develop proteinuria beginning 4 weeks after treatment with tetracycline and with 95% of mice developing proteinuria by 20 weeks. FSGS appears at 8 weeks, progressing to global glomerulosclerosis and end-stage kidney disease. Podocyte phenotype is abnormal, with reduced expression of the differentiation marker synaptopodin and de novo expression of the injury marker desmin. Increased cell proliferation is present in the glomerular tuft, parietal epithelum, and tubular epithelium. These results demonstrate that Vpr is sufficient to induce HIV-associated FSGS in transgenic mice. We have recently generated mutant Vpr mice, either bearing the R80A mutation that abrogates the cell cycle arrest function of Vpr, or the L64-67-68A triple mutation that abrogates nuclear receptor binding. We are characterizing the phenotype of these mice Pirfenidone is an orally-active, small molecule inhibitor of fibrosis, whose mechanism of action has not been well-defined but might involve inhibiting production of TGF-beta. We have carried out an open label, phase II study for FSGS patients with declining renal function. The study design compares the rate of glomerular filtration rate (GFR) decline during a baseline period in which blood pressure is controlled and the patient receives angiotensin antagonist medication (ACE inhibitor or angiotensin receptor blocker) with the rate of GFR decline while on pirfenidone therapy plus angiotensin antagonist medication. We have enrolled 20 patients, who receive treatment for at least one year but may continue pirfenidone thereafter. In 16 patients who have received at least 4 months of therapy, after a mean follow-up of 19 months, the GFR decline rate improved from 0.81 +/- 0.46 (mean, SD) ml/min/mo during the baseline period to 0.55 +/- 0.40 ml/min/mo while receiving pirfenidone (P=0.03). This represents an improvement of 32%, an effect size comparable to that of ACE inhibitors in patients with diabetic nephropathy (another disease characterized by glomerulosclerosis). We are discussing with collaborator plans to carry out a multi-center, randomized, placebo-controlled phase III study to confirm efficacy. Building on our results with intermittent oral pulse dexamethasone, we have initiated a new trial comparing a more intensive steroid regimen for children and adults with minimal change disease and FSGS. We have increased the dexamethasone dose in three ways: increased duration (48 weeks versus 32 weeks), increased dose during the first 3 months (50 mg/m2 for the weeks 1-16 and 25 mg/m2 for weeks 17-48) and randomized patients to 2 doses every 2 weeks and 4 doses every 4 weeks (all patients receive 48 doses over 48 weeks). Five patients have been enrolled in this study.

局灶性节段性肾小球硬化症（FSGS）是一种临床病理综合征，其特征在于纤维化蛋白在肾小球中的积累，最初仅涉及一些受影响肾小球的肾小球（局灶性）（局灶性）（局灶性）（焦点）（段）。 FSG可以分类如下：特发性FSG，与HIV相关的FSG，过滤过滤FSG（由于肾脏质量减少，肾脏毒素或肥胖）以及遗传原因。 为了定义负责HIV相关FSG的分子机制，我们已经建立了一系列小鼠，其中可以使用四环素调控的系统在肾小球足细胞中调节转基因表达。我们已经表明表达受到严格调节，并且仅限于足细胞。我们已经使用该系统在足细胞中表达HIV-1辅助蛋白VPR。这些小鼠在用四环素治疗后4周开始发育蛋白尿，而95％的小鼠在20周内产生蛋白尿。 FSG出现在8周时，发展为全球肾小球硬化和末期肾脏疾病。足细胞表型异常，分化标记突触素的表达降低，并从头表达损伤标志物脱敏蛋白。细胞增殖增加存在于肾小球簇，顶层上皮和管状上皮中。这些结果表明，VPR足以诱导转基因小鼠中与HIV相关的FSG。我们最近产生了突变的VPR小鼠，它具有废除VPR细胞周期停滞函数的R80A突变，或者是消除核受体结合的L64-67-68A三重突变。我们正在表征这些小鼠的表型 Pirfenidone是一种口服活性的小分子纤维化分子抑制剂，其作用机理尚未明确定义，但可能涉及抑制TGF-beta的产生。我们已经针对肾功能下降的FSGS患者进行了开放标签，II期研究。该研究设计比较了控制血压的基线周期的肾小球滤过率（GFR）降低的速率，并且患者接受血管紧张素拮抗剂药物（ACE抑制剂或血管紧张素受体阻滞剂）与GFR的降低，而GFR的速率下降，而Pirfenidone疗法加上Pirfenidone疗法加血管紧张素蛋白疗法。我们已经招募了20名患者，他们至少接受了一年的治疗，但此后可能会继续进行pirfenidone。在接受至少4个月治疗的16例患者中，平均随访19个月后，GFR下降率从基线期间的0.81 +/- 0.46（平均，SD）ML/min/mo提高到0.55 +/- 0.40 mL/min/min/mo，同时接受Pirfenidone（P = 0.03）。这是32％的改善，其作用大小与糖尿病性肾病患者（另一种以肾小球硬化症为特征）患者的ACE抑制剂相当。我们正在与合作者计划进行讨论，以进行多中心，随机，安慰剂对照的III期研究以确认功效。 基于间歇性口服脉冲地塞米松的结果，我们开始了一项新的试验，比较了更密集的类固醇方案对儿童和成人的疾病和FSG的最小变化。我们以三种方式增加了地塞米松剂量：持续时间增加（48周对32周），在前3个月内增加剂量（17-48周的1-16周的50 mg/m2和25 mg/m2周），随机患者随机患者每2周每2周和4剂接受每48剂48剂的剂量（每2周一次）。这项研究已入学五名患者。