Subclinical Viral Infection and Renal Allograft Injury

亚临床病毒感染和同种异体移植肾损伤

• 批准号: 8450925
• 负责人: Jodi M Smith
• 金额: $ 32.26万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/8450925
• 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

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）：慢性同种异体移植损伤是肾移植中移植物丧失的主要原因。随着候补名单死亡率的增加，可用的肾脏缺乏移植的肾脏已达到危机水平。迫切需要延长延长移植物生存的策略。小儿和年轻的成人移植人群是不可避免的重复移植的人群，因此，该群体将特别受益于延长延长移植物生存的人。慢性同种异体移植损伤已取代急性排斥，这是移植物损失的主要原因。成功降低急性排斥率的有效免疫抑制疗法导致由于疱疹病毒（例如巨细胞病毒（CMV））和爱泼斯坦Barr病毒（EBV）引起的感染率更高。我们对小儿肾移植患者的前瞻性观察性研究表明，亚临床CMV和EBV病毒感染与慢性同种异体移植损伤有关。我们证明，尽管口服抗病毒药疗法，同时，在两年后两年的移植术后，高滴度和长时间的cmv病毒血症和EBV病毒血症很常见，并且与GFR的降低以及慢性同种异体移植物损伤的组织学证据是独立和定量相关的。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的同种异体移植损伤和相关移植物损失的负担。但是，为了指导这种策略，必须首先确定亚临床病毒感染与肾脏同种异体损伤之间的基本联系 - 包括亚临床病毒感染是直接还是间接导致同种异体移植损伤。为了回答这个问题，我们在特定目标1中提出了前瞻性确定亚临床病毒感染与由肾脏同种异体损伤的关联； 1）测量的GFR（IOHEXOL），2）定量同种异体移植纤维化和3）肾同种异体移植中的先天免疫激活。在特定目标2中，我们建议确定病毒特异性T细胞免疫反应的存在（能够修改病毒相关损伤机制）是否会改变病毒血症和/或同种异体移植病毒感染的时间过程以及同种异体移植损伤。