Hyperfiltration-mediated Injury in the Remaining Kidney of a Transplant Donor.
Hyperfiltration-mediated Injury in the Remaining Kidney of a Transplant Donor.
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DOI：
10.1097/tp.0000000000002304
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发表时间：
2018-10
期刊：
影响因子：
6.2
通讯作者：
Sharma M
中科院分区：
文献类型：
--
作者：
Srivastava T;Hariharan S;Alon US;McCarthy ET;Sharma R;El-Meanawy A;Savin VJ;Sharma M
肾脏捐赠者在捐献15-30年后面临着微小但明确的终末期肾病风险。手术切除1个肾后，供者发生蛋白尿、高血压，肾功能逐渐下降，其原因是高滤过。遗传变异、生理适应和合并症在捐献后的几年内加剧了高滤过引起的肾功能丧失。对肾小球血流动力学和毛细血管压力的关注导致了针对肾素-血管紧张素-醛固酮系统(RAAS)的药物的开发，但这些药物在移植受者和捐赠者中产生了喜忧参半的结果。最近关于肾小球生物机械力的研究突出了拉伸应力和流体流动剪切应力(FFSS)与超滤的不同影响。肾小球毛细血管压力引起的毛细血管壁伸展增加了覆盖毛细血管的足细胞足突的张应力。同时，由于单个肾单位肾小球滤过率导致的超滤液流量增加，足细胞胞体上的FFSS升高。当张应力激活RAAS时，FFSS主要激活COX2-PGE2-EP2轴。区分这两种机制至关重要，因为目前的治疗方法侧重于RAAS系统。更好地了解生物力学的作用可以引导新的治疗药物通过COX2-PGE2-EP2轴在高滤过介导的损伤中靶向FFSS。我们概述了对移植供者的风险的几个方面，并讨论了FFSS在足细胞损伤、肾小球屏障功能丧失导致蛋白尿和肾功能逐渐丧失中的相关性，以及减轻高滤过介导的剩余肾脏损伤的潜在治疗策略。
Kidney donors face a small but definite risk of end-stage renal disease 15-30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and co-morbidities exacerbate the hyperfiltration-induced loss of kidney function in the years following donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single nephron glomerular filtration rate elevates FFSS on the podocyte cell body. While tensile stress invokes the RAAS, FFSS predominantly activates the COX2-PGE2-EP2 axis. Distinguishing these 2 mechanisms is critical, as current therapeutic approaches focus on the RAAS system. A better understanding of the biomechanical forces can lead to novel therapeutic agents to target FFSS through the COX2-PGE2-EP2 axis in hyperfiltration-mediated injury. We present an overview of several aspects of the risk to transplant donors and discuss the relevance of FFSS in podocyte injury, loss of glomerular barrier function leading to albuminuria and gradual loss of renal function, and potential therapeutic strategies to mitigate hyperfiltration-mediated injury to the remaining kidney.