Subclinical Viral Infection and Renal Allograft Injury

亚临床病毒感染和同种异体移植肾损伤

基本信息

批准号：
8665411
负责人：
Jodi M Smith
金额：
$ 33.36万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665411
关键词：
Acute Allografting Antiviral Therapy Atrophic Biopsy Blood CD8B1 gene Cells Childhood Chronic Cross-Sectional Studies Cytomegalovirus Data Development Dose Failure Fibrosis Funding Graft Survival Herpesviridae Histologic Human Herpesvirus 4 Immune response Immunohistochemistry Incidence Infection Injury Intervention Investigation Iohexol Kidney Kidney Transplantation Lead Link Measurable Measures Monitor National Institute of Diabetes and Digestive and Kidney Diseases Observational Study Oral Plasma Population Prevention Prophylactic treatment Prospective Studies Renal function Satellite Viruses Staining method Stains T-Lymphocyte Therapeutic immunosuppression Time Tissues Transplant Recipients Transplantation Tubular formation Viral Viral Load result Viremia Virus Virus Diseases Waiting Lists base immune activation interstitial kidney allograft mortality prospective response treatment strategy young adult

项目摘要

DESCRIPTION (provided by applicant): Chronic allograft injury is the leading cause of graft loss in renal transplantation. The shortage of available kidneys for transplantation has reached crisis levels with increasing numbers of waiting list mortalities. Strategies to prolong graft survival are urgently needed. The pediatric and young adult transplant population is one in which repeat transplantation is inevitable and therefore, this group is one who will especially benefit from intervention to prolong graft survival. Chronic allograft injury has replaced acute rejection as the major cause of graft loss. The potent immunosuppressive therapy that successfully reduced acute rejection rates has resulted in a higher incidence of infection due to herpes viruses, such as cytomegalovirus (CMV) and Epstein- Barr virus (EBV). Our prospective observational study in pediatric renal transplant patients demonstrated that subclinical CMV and EBV viral infection are associated with chronic allograft injury. We demonstrated that both high titers and prolonged episodes of subclinical CMV and EBV viremia are common despite oral antiviral therapy, and are independently and quantitatively associated with decreased GFR and histologic evidence of chronic allograft injury at two years' post-transplantation. These findings suggest that prevention, prophylaxis and/or treatment strategies targeting subclinical viral infection may be able to reduce the burden of allograft injury and associated graft loss in renal transplant patients. However, to guide such strategies the underlying link between subclinical viral infection and renal allograft injury must first be determined - including whether subclinical viral infection directly or indirectly contributes to allograft injury. To answer this question, we propose in Specific Aim 1 to prospectively determine the association of subclinical viral infection with renal allograft injury determined by; 1) measured GFR (iohexol), 2) quantification of allograft fibrosis and 3) innate immune activation in the renal allograft. In Specific Aim 2, we propose to determine whether the presence of viral specific T cell immune responses - which are able to modify either mechanism of virus-associated injury - alter the time course of viremia and/or allograft viral infection, and allograft injury.

描述（由申请人提供）：慢性同种异体移植物损伤是肾移植中移植物丢失的主要原因。随着等待名单上的死亡人数不断增加，可供移植的肾脏短缺已达到危机程度。迫切需要延长移植物存活的策略。儿科和年轻成人移植人群是重复移植不可避免的人群，因此，这一群体将特别受益于延长移植物存活的干预措施。慢性同种异体移植物损伤已取代急性排斥反应成为移植物丢失的主要原因。有效的免疫抑制疗法成功降低了急性排斥反应率，但导致疱疹病毒（例如巨细胞病毒（CMV）和EB病毒（EBV））感染的发生率更高。我们对儿童肾移植患者的前瞻性观察研究表明，亚临床 CMV 和 EBV 病毒感染与慢性同种异体移植物损伤相关。我们证明，尽管口服抗病毒治疗，亚临床 CMV 和 EBV 病毒血症的高滴度和长期发作仍然很常见，并且与移植后两年的 GFR 下降和慢性同种异体移植损伤的组织学证据独立且定量地相关。这些发现表明，针对亚临床病毒感染的预防、预防和/或治疗策略可能能够减轻肾移植患者同种异体移植物损伤和相关移植物丢失的负担。然而，为了指导此类策略，必须首先确定亚临床病毒感染与肾同种异体移植物损伤之间的潜在联系，包括亚临床病毒感染是否直接或间接导致同种异体移植物损伤。为了回答这个问题，我们在具体目标 1 中建议前瞻性地确定亚临床病毒感染与肾同种异体移植损伤之间的关联，具体确定如下： 1) 测量 GFR（碘海醇），2) 同种异体移植物纤维化的量化和 3) 同种异体肾移植物中的先天免疫激活。在具体目标 2 中，我们建议确定病毒特异性 T 细胞免疫反应的存在（能够改变病毒相关损伤的任一机制）是否会改变病毒血症和/或同种异体移植物病毒感染以及同种异体移植物损伤的时间进程。