RECOMBINANT HUMAN INSULINLIKE GROWTH FACTOR

该提案旨在阐明的病理生理学和评估 新的治疗缺血后，急性肾功能衰竭（ARF）的人。 尸体肾同种异体移植物（Tx）的延迟功能（DF）将作为 ARF的原型模型。我们将检查140个连续的Tx 其中一半的人被预测会表现出DF和严重的 低滤过剩下的一半，谁会体现提示功能 (PF)正常滤过作为对照。我们希望测试四个 主要假设 假设#1是DF患者的缺血后损伤降低了 GFR主要通过降低跨毛细血管液压梯度。 GFR（胰岛素清除率）及其其余四个决定因素将被 在Tx再灌注后1-3小时和7天进行评价。肾血浆 最初将通过多普勒流量计确定流量（RPF）， 在第7天通过基于相位对比的新型非侵入性技术， 电影核磁共振成像。将通过膜渗透压测定法测定起始压。 每次通过活检获得的肾小球将接受 形态分析和粘性流的水动力学模型， 确定过滤表面积（s）和水力渗透率（k）。 将使用超滤模型。我们想确认 人类持续性ARF是蚊帐消散的结果 超滤压力。 假设#2是DF与PF的Tx接受者中的抑郁是 与肾小管-肾小球反馈（TGF）激活相关， 随之而来的传入血管收缩。Li+排泄分数 将用作Na+递送至致密斑的替代物。 近端Na+重吸收受损与肾血管 阻力和极性的近端小管细胞在系列 活组织检查细胞极性将由细胞的分布来确定。 Na ~+/K ~+-ATP酶与质膜各种细胞骨架蛋白 使用共聚焦显微镜。 假设#3是通过受损小管的增强的细胞旁流 允许滤液漏回到氚中，从而进一步 降低分级大小的葡聚糖的清除率以计算 过滤后的胰岛素部分泄漏回来。这将与 肾小管基底膜剥脱的结构改变， 他们的氚膨胀。最后，我们将进行一个受控的 胰岛素样生长因子（IGF-1）与安慰剂在所有治疗中的试验 在1-3岁时，GFR<15 ml/min，预测受试者将出现DF和ARF。 人力资源研究。rh-IGF-1在第7天恢复GFR的作用将归因于 胰岛素可渗透近端肾单位的再生 和TGF介导的传入收缩。

This proposal seeks to elucidate the pathophysiology of and evaluate novel therapy for postischemic, acute renal failure (ARF) in humans. Delayed function (DF) of a cadaveric renal allograft (Tx) will serve as a prototypic model of ARF. We will examine 140 consecutive Tx recipietns of whom half are predicted to manifest DF and severe hypofiltration. The remaining half, who will manifest prompt function (PF) and normofiltration will serve as controls. We wish to test four main hypotheses. Hypothesis #1 is that postischemic injury in those with DF lowers the GFR mainly by depressing the transcapillary hydraulic pressure gradient. GFR (insulin clearance) and its remaining four determinants will be evaluated 1-3 hr and 7 days after reperfusion of the Tx. Renal plasma flow (RPF) will be determined initially by Doppler flow meter and again on day 7 by a novel, non-invasive technique based on phase contrast, cine-MRI. Oncotic pressure will be determined by membrane osmometry. Glomeruli obtained by biopsy on each occasion will be subjected to a morphometric analysis and a hydrodynamic model of viscous flow to determine filtration surface area (s) and hydraulic permeability (k). A model of ultrafiltration will be used. We seek to confirm that sustained ARF in humans is a consequence of dissipation of the net pressure for ultrafiltration. Hypothesis #2 is that depression in Tx recipients with DF vs PF is associated with activation of tubulo-glomerular feedback (TGF) and consequent afferent vasoconstriction. the fractional excretion of Li+ will be used as a surrogate for Na+ delivery to the macula densa. Impaired proximal Na+ reabsorption will be realted to renovascular resistance and to polarity of proximal tubule cells in the serial biopsies. Cell polarity will be determined from the distribution of Na+/K+- ATPase and various cytoskeletal proteins of the plasma membrane using confocal microscopy. Hypothesis #3 is that enhanced paracellular flow through damaged tubules allows filtrate to leak back into the interstitium, thereby further lowering the clearance of dextrans of graded size to calculate the fraction of filtered insulin that leaks back. This will then be related to structural alterations in denudation of tubular basement membrane and expansion of their interstitium. Finally, we eill conduct a controlled trial of insulin-like growth factor (IGF-1) vs placebo in all Tx recipients predicted to exhibit DF and ARF by a GFR<15 ml/min at the 1-3 hr study. rh-IGF-1 in restoring GFR by day 7 will be attributable to regeneration of an insulin-permeable proximal nephron lined by backleak and TGF-mediated afferent constriction.