RECOMBINANT HUMAN INSULINLIKE GROWTH FACTOR

这项建议旨在阐明人类缺血后急性肾功能衰竭(ARF)的病理生理学机制并评估新的治疗方法。身体同种异体肾移植的延迟功能(DF)将作为ARF的原型模型。我们将检查140名连续接受TX治疗的患者，其中一半预计会出现DF和严重的低滤过。另一半将表现为即时功能(PF)和正常滤过，作为对照。我们希望检验四个主要假设。假说1是DF患者的缺血后损伤主要通过抑制跨毛细血管的水压梯度来降低GFR。GFR(胰岛素清除量)及其其余四个决定因素将在TX再灌流后1-3小时和7天进行评估。肾血浆流量(RPF)最初将由多普勒血流计测定，并在第7天通过一种基于相位对比的新的非侵入性技术-电影-MRI再次测定。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形态计量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是超滤净压力消散的结果。假说2是接受DF和PF的TX受者的抑郁与肾小管-肾小球反馈的激活和随之而来的传入血管收缩有关。部分Li+的排泄将作为Na+输送到致密黄斑的替代物。近端Na+重吸收受损将与肾血管阻力和系列活检中近端小管细胞的极性有关。细胞的极性将通过共聚焦显微镜下质膜上Na+/K+-ATPase和各种细胞骨架蛋白的分布来确定。假设3是，通过受损小管的细胞旁血流增强，允许滤液泄漏回间质，从而进一步降低分级大小的右旋糖苷的清除，以计算漏回的过滤胰岛素的比例。这将与肾小管基底膜剥脱和间质扩张的结构变化有关。最后，我们将在所有TX受试者中进行胰岛素样生长因子(IGF-1)与安慰剂的对照试验，预计在1-3小时的研究中，GFR&lt；15ml/min将出现DF和ARF。Rh-IGF-1在第7天恢复GFR将归因于胰岛素渗透性近端肾单位的再生，内衬有反漏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 recipients 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 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, 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 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.