RECOMBINANT HUMAN INSULINLIKE GROWTH FACTOR

这项建议试图阐明和评估的病理生理学。 人类缺血后急性肾功能衰竭(ARF)的新疗法。 身体同种异体肾移植延迟功能(DF)将作为 ARF的原型模型。我们将检查140个连续的TX 其中一半的接受者预计将表现为DF和严重 低滤过。剩下的一半，谁将表现出提示功能 (PF)和正常滤过作为对照。我们想测试四个 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管水力压力梯度来实现。 GFR(胰岛素清除量)及其其余四个决定因素将是 在TX再灌流后1-3小时和7天进行评估。肾血浆 流量(RPF)最初将由多普勒流量计确定，然后再次确定 在第7天，通过一种基于相位对比的新的非侵入性技术， 电影核磁共振。肿胀压力将通过膜渗透压计测定。 每次活检获得的肾小球将接受 粘性流动的形态分析和流体动力学模型 测定过滤表面积(S)和水力渗透率(K)。 将使用超滤模型。我们试图证实 人类持续的ARF是网络消散的结果 超滤压力。 假设2是DFVS PF的TX受者的抑郁 与激活肾小管肾小球反馈(TGF)和 随之而来的传入血管收缩。Li+的部分排泄 将作为Na+输送到致密黄斑的替代物。 近端Na+重吸收受损可能与肾血管有关 近曲小管细胞的抵抗力及对极性的影响 活组织检查。细胞的极性将根据以下分布确定 质膜Na+/K+-ATPase与多种细胞骨架蛋白 使用共聚焦显微镜。 假设3是通过受损小管的细胞旁血流增强 允许滤液回漏到间质中，从而进一步 降低分级尺寸的右旋转体的间隙以计算 过滤后的胰岛素漏回的部分。然后这将是相关的 肾小管基底膜剥脱的结构改变和 它们的间质扩张。最后，我们将进行一次受控 胰岛素样生长因子(IGF-1)与安慰剂在全德克萨斯的对比试验 预计受者在1-3岁时以15毫升/分钟的GFR/分钟出现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 反漏衬里的胰岛素渗透性近端肾单位的再生 和转化生长因子介导的传入收缩。

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.