Genetics and Immune Predictors for Recurrent Glomerular Diseases in the Kidney Allograft
同种异体移植肾中复发性肾小球疾病的遗传学和免疫预测因子
基本信息
- 批准号:10637158
- 负责人:
- 金额:$ 37.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAllograftingAntibodiesBiopsyClinical DataDNADataDevelopmentDiffuseDiseaseDonor SelectionEnsureFailureFc ReceptorFocal and Segmental GlomerulosclerosisFutureGalactoseGene Expression ProfilingGeneticGenetic ModelsGenetic Predisposition to DiseaseGenetic RiskGenomicsGenotypeGoalsHealthIGA GlomerulonephritisIgA1ImmuneImmune TargetingImmune signalingImmunoglobulin GImmunologic FactorsImmunologic MonitoringImmunotherapyIncidenceIndividualInheritedKidneyKidney DiseasesKidney FailureKidney TransplantationMediatingMembranous GlomerulonephritisMicroanatomyPathogenesisPatient MonitoringPatientsPhospholipase A2PolysaccharidesPrognosisRecurrenceRecurrent diseaseRegimenRenal glomerular diseaseRequest for ApplicationsResearchResearch PersonnelRiskRisk FactorsRoleSNP arraySecondary toSerologySerumSignal TransductionSteroid-resistant idiopathic nephrotic syndromeSteroidsTechnologyTestingTransplant RecipientsTransplantationTumor Necrosis Factor Superfamily LigandsUp-Regulationclinically relevantcohortdesigndisorder controleffective therapyfollow-upgenome wide association studygenome-wideimprovedkidney allograftmembernano-stringnephrinnovelpost-transplantprecision medicinerisk varianttranscriptomic profilingtransplant centers
项目摘要
PROJECT SUMMARY/ABSTRACT
The recent development of potent immunosuppressive regimens has led to decreased incidence of acute
rejection and increased incidence of non-rejection complications, including recurrent immune-mediated
glomerular diseases (GD) which have emerged as leading causes of kidney allograft failure.
IgA nephropathy (IgAN), membranous nephropathy (MN), and diffuse podocytopathy (DP) are the most common
causes of primary GD in the native kidney and these same GD can recur after transplantation. In the native
kidney, it is apparent that immune and genetic factors are important contributors to each of these GD.
Although little is known about the pathogenesis of recurrent GD after transplantation, few studies have shown
that rigorous donor-recipient HLA matching and steroid-free immunosuppressive regimens are risk factors for
recurrent GD. Therefore, we hypothesized that, similar to GD in the native kidney, recurrent GD are mediated
by genomic and immune factors. To define the role of genomic and immune factors in recurrent IgAN, MN, and
DP, we have begun collecting clinical data, DNA from donor-recipient pairs, recipients’ sera, and kidney allograft
biopsies from multiple transplant centers to assemble the largest cohort of transplant patients with recurrent and
non-recurrent GD (n=1,035 at least). To ensure adequate power and eliminate the need for replication studies,
we are using genetic risk scores (GRS) and serologic studies that has been previously validated in the native
kidney. Hence, we developed a research plan composed of three aims that follow parallel approaches.
In Specific Aim-1, we will (1) use genome wide SNP arrays to genotype donor-recipient pairs in patients with
recurrent and non-recurrent IgAN, generate individual 30-SNP IgAN GRS, and test these GRS as predictors of
recurrent disease, (2) test the values of pre-transplant serum levels of galactose-deficient IgA1, IgG anti-glycan
antibodies (Ab), and combined IgAN risk scores (which integrate the IgAN GRS with the above pre-transplant
serum levels) as predictors for recurrent disease, and (3) compare transcriptomic profiling of different post-
transplantation GD to identify immune signals specific for recurrent IgAN.
In Specific Aim-2, we will test donor and recipient MN GRS, anti-phospholipase A2 receptor Ab, and combined
MN risk scores as predictors for recurrent MN, and identify intra-graft immune signals specific for recurrent MN.
In Specific Aim-3, we will test the values of donor and recipient DP GRS and anti-nephrin Ab as predictors for
recurrent DP, and use transcriptomic profiling to identify immune signals specific for recurrent disease.
Health relatedness of the project: The proposed project will integrate the field of transplantation with novel donor
screening technologies and immune monitoring. In the short-term, this proposal promises to define predictors of
these relatively rare but clinically relevant recurrent GD. In the long-term, this project has the potential to
introduce novel genomic donor-recipient matching and immune monitoring for patients with kidney failure
secondary to GD to decrease incidence of recurrent GD, and improve the health of kidney transplant recipients.
项目摘要/摘要
最近有效的免疫抑制方案的发展已经导致急性
排斥和非排斥并发症发生率增加,包括免疫介导的复发
肾小球疾病(GD)已成为肾移植失败的主要原因。
IgA肾病(IgAN)、膜性肾病(MN)和弥漫性足细胞病变(DP)是最常见的
原发于肾的原发GD和相同的GD在移植后可复发。在美国本土
肾脏,很明显,免疫和遗传因素是这些GD的重要因素。
尽管对移植后复发的GD的发病机制知之甚少,但很少有研究表明
严格的供受者人类白细胞抗原配型和非类固醇免疫抑制方案是
复发性GD。因此,我们假设,类似于天然肾脏中的GD,复发的GD是由
由基因组和免疫因素决定。明确基因组和免疫因素在复发的IgAN、MN和
我们已经开始收集临床数据、供受者对的DNA、受者血清和同种异体肾移植。
从多个移植中心进行活检,以汇集最大的移植患者队列,这些患者的复发和
未复发的GD(至少1035例)。为了确保足够的功率并消除复制研究的需要,
我们使用的是遗传风险评分(GRS)和血清学研究,这些研究以前已经在本地得到验证
肾脏。因此,我们制定了一个由三个目标组成的研究计划,这些目标遵循平行方法。
在特定的Aim-1中,我们将(1)使用全基因组SNP阵列来对患者的供受者对进行分型
复发和非复发免疫球蛋白肾病,生成个体30-SNP免疫球蛋白肾病GR,并测试这些GR作为预测因子
复发性疾病,(2)检测移植前血清半乳糖缺乏性IgA1、Ig G抗糖值
抗体(Ab)和联合的IgAN风险评分(将IgAN GRS与移植前的上述指标相结合
血清水平)作为复发疾病的预测因子,以及(3)比较不同治疗后的转录图谱。
Gd移植以识别针对复发IgAN的免疫信号。
在特定的AIM-2中,我们将检测供体和受体的MN GRS、抗磷脂酶A2受体抗体,并结合
MN风险评分可作为复发MN的预测因子,并识别复发MN的移植物内免疫信号。
在特定的目标-3中,我们将测试供体和受体的DP GRS和抗neparin Ab的值作为预测
复发性DP,并使用转录图谱来识别针对复发性疾病的免疫信号。
项目的健康相关性:拟议的项目将把移植领域与新的捐赠者结合起来
筛查技术和免疫监测。在短期内,这项提案承诺定义
这些相对罕见但临床相关的复发GD。从长远来看,这个项目有可能
介绍肾功能衰竭患者的新型基因组供受者配型和免疫监测
继发于GD,可降低GD复发,改善肾移植患者的健康状况。
项目成果
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