RECOMBINANT HUMAN INSULINLIKE GROWTH FACTOR

本研究旨在阐明人类急性肾衰竭（ARF）的病理生理学和评估新疗法。尸体移植肾（Tx）的延迟功能（DF）可作为ARF的原型模型。我们将检查140个连续的Tx受者，其中一半预测表现为DF和严重的低滤过。剩下的一半，谁将表现出提示功能（PF）和正常过滤将作为对照。我们希望检验四个主要假设。假设1:DF患者的缺血后损伤主要通过抑制经毛细血管水压梯度来降低GDR。GFR（胰岛素清除率）及其其余四个决定因素将在Tx再灌注后1 - 3小时和7天进行评估。肾血浆流量（RPF）将首先通过多普勒流量计进行测定，并在第7天再次通过基于相位对比，电影mri的新型无创技术进行测定。肿瘤压将通过膜渗透法测定。每次活检获得的肾小球将进行形态计量学分析和粘性流动的流体动力学模型，以确定过滤表面积(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是超滤净压力耗散的结果。假设2：与PF相比，DF受体的抑郁与小管-肾小球反馈（TFG）的激活和随之而来的传入血管收缩有关。Li+的部分排泄将被用作Na+递送到黄斑致密的替代品。在连续活检中，近端Na+重吸收受损将与肾血管阻力和近端小管细胞极性有关。利用共聚焦显微镜从Na+/K+- atp酶和质膜上各种细胞骨架蛋白的分布来确定细胞极性。假设#3是通过受损小管增强的细胞旁流动允许滤液渗漏回间质，从而进一步降低分级大小的右旋糖酐的清除率，以计算渗漏回的过滤胰岛素的比例。这将与管状基底膜的剥落和间质扩张的结构改变有关。最后，对于假设#4，我们将在所有在1 - 3小时研究中GFR < 15 ml/min预测出现DF和ARF的Tx受体中进行胰岛素样生长因子（IGF-1）与安慰剂的对照试验。Rh-IFG-1在第7天恢复GFR的作用可归因于胰岛素可渗透的近端肾元的再生，其中内衬有反漏和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 recipients of who 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 GDR mainly by depressing the transcapillary hydraulic pressure gradient. GFR (insulin clearance) and its remaining four determinants will be evaluated 1 - 3 hour 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 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 (TFG) 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 related 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, for Hypothesis #4, we will 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 hour study. Rh-IFG-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.