Protein Carbamylation and the Progression and Complications of CKD

蛋白质氨甲酰化与 CKD 的进展和并发症

• 批准号: 10368082
• 负责人: Sahir Kalim
• 金额: $ 25.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-14 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368082
• 关键词: Address; Adult; Albumins; Amino Acids; Atherosclerosis; Automobile Driving; Biochemical; Biochemical Process; Biological Assay; Biology; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Charge; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Cohort Analysis; Cohort Studies; Data; Diabetes Mellitus; Dialysis procedure; Dietary Intervention; Disease Outcome; Disease Progression; Dissociation; End stage renal failure; Epidemiology; Event; Exposure to; Functional disorder; Future; Glomerular Mesangial Cell; Goals; Heart failure; Hemodialysis; Individual; Investments; Ischemic Stroke; Kidney; Kidney Diseases; Kidney Failure; Life; Link; Longitudinal Studies; Measures; Mission; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Nutritional; Observational Study; Outcome; Participant; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral arterial disease; Persons; Phenotype; Plasma; Population; Post-Translational Protein Processing; Proteins; Public Health; Renal function; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Sampling; Serum Markers; Structure; Supplementation; Urea; Vulnerable Populations; Work; adjudicate; adverse outcome; biobank; cardiovascular risk factor; cohort; design; effective therapy; follow-up; indexing; inflammatory marker; insight; kidney fibrosis; modifiable risk; mortality; mortality risk; novel; novel therapeutic intervention; protein function; stem; targeted treatment; therapeutic target; treatment strategy

Project Summary/ Abstract 30 million US adults have chronic kidney disease (CKD) arising from diverse causes but commonly resulting in life-threatening complications such as cardiovascular disease (CVD) and progression to end stage renal disease (ESRD). Although we understand much about the epidemiology of CKD and its associations with CVD, the underlying mechanisms of CKD pathogenesis, progression, and complications remain less well understood. In this proposal we seek to comprehensively study a novel risk factor for the progression and complications of CKD known as protein carbamylation. Carbamylation describes a posttranslational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation increases with renal insufficiency and can change the charge, structure, and function of proteins, resulting in molecular and cellular dysfunction. Select carbamylated proteins have been shown to accelerate pathological biochemical processes such as atherosclerosis and renal fibrosis. We and others have characterized the associated morbidity and mortality risks of carbamylation in multiple ESRD cohorts, but the impact of carbamylation in the non-dialysis CKD population is unknown. The Chronic Renal Insufficiency Cohort (CRIC), an NIDDK- sponsored longitudinal study of 3,939 individuals with CKD that has stored biospecimens and adjudicated kidney and CV outcomes over an average of 6 years of follow-up, creates the ideal opportunity to meet our study's overall objective: we will rigorously quantify the impact of protein carbamylation (employing validated plasma markers of total body carbamylation burden such as carbamylated albumin, C-Alb) on key clinical outcomes in CKD using the CRIC biorepository. Our central hypothesis is that protein carbamylation independently associates with adverse renal and CV outcomes in people with CKD not yet on dialysis. In Aim 1 of the study we will quantify the association between carbamylation load and clinical outcomes in CKD including CKD progression (defined as 50% reduction in eGFR or progression to ESRD); all-cause mortality; and CV events (heart failure, myocardial infarction, ischemic stroke, or peripheral artery disease events). In Aim 2 we will classify which variables most significantly associate with carbamylation load, potentially identifying future therapeutic targets. Our approach includes assaying C-Alb in baseline samples from CRIC, analyzing outcomes in relation to these levels, and comparing various baseline covariates as predictors of C- Alb levels. The expected result of these studies is a comprehensive understanding of the pathophysiology of protein carbamylation in CKD and its relationship to important clinical outcomes. Such information could establish a modifiable risk factor in this vulnerable population. This proposal will boost the NIDDK's yield on its investment in CRIC while furthering its mission to understand the biology underlying CKD progression and its complications to ultimately advance effective treatment strategies.

项目总结/摘要 3000万美国成年人患有由各种原因引起的慢性肾病（CKD），但通常导致 危及生命的并发症，如心血管疾病（CVD）和进展为终末期肾功能衰竭 疾病（ESRD）。虽然我们对CKD的流行病学及其与CVD的关系了解很多， CKD发病机制、进展和并发症的潜在机制仍然不太清楚 明白在这项提案中，我们寻求全面研究一种新的进展风险因素， CKD的并发症称为蛋白质氨甲酰化。氨甲酰化描述了一种翻译后蛋白质 改性引起的，部分原因是暴露于尿素的解离产物氰酸盐。氨甲酰化增加， 肾功能不全，可以改变蛋白质的电荷，结构和功能，导致分子和 细胞功能障碍选择氨甲酰化蛋白质已被证明可以加速病理生化 如动脉粥样硬化和肾纤维化。我们和其他人已经描述了相关的 氨甲酰化在多个ESRD队列中的发病率和死亡率风险，但氨甲酰化在 非透析CKD人群未知。慢性肾功能不全队列（CRIC），NIDDK- 申办的3，939例CKD患者的纵向研究，已储存生物标本并判定 平均6年随访的肾脏和CV结局，为满足我们的 研究的总体目标：我们将严格量化蛋白质氨甲酰化的影响（采用经验证的 全身氨甲酰化负荷的血浆标志物，如氨甲酰化白蛋白，C-Alb）， 使用CRIC生物储存库的CKD结果。我们的中心假设是蛋白质氨甲酰化 与尚未接受透析的CKD患者的不良肾脏和CV结局独立相关。目标1 在本研究中，我们将量化氨甲酰化负荷与CKD临床结局之间的相关性 包括CKD进展（定义为eGFR降低50%或进展为ESRD）;全因死亡; 和CV事件（心力衰竭、心肌梗死、缺血性卒中或外周动脉疾病事件）。在 目的2我们将分类哪些变量与氨甲酰化负荷最显著相关， 确定未来的治疗目标。我们的方法包括测定CRIC基线样本中的C-Alb， 分析与这些水平相关的结果，并比较各种基线协变量作为C- 白蛋白水平。这些研究的预期结果是全面了解 蛋白氨甲酰化在CKD中的作用及其与重要临床结局的关系。此类信息可 在这一弱势群体中建立一个可改变的风险因素。这一提议将提高NIDDK的收益率， 投资于CRIC，同时推进其使命，以了解CKD进展的生物学基础及其 并发症，以最终推进有效的治疗策略。

项目成果

Response to Comment on Tang et al. The Impact of Carbamylation and Anemia on HbA1c's Association With Renal Outcomes in Patients With Diabetes and Chronic Kidney Disease. Diabetes Care 2023;46:130-137.

对 Tang 等人的评论的回应

• DOI: 10.2337/dci23-0011
• 发表时间: 2023
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Tang,Mengyao;Kalim,Sahir
• 通讯作者: Kalim,Sahir

The association between olfactory and gustatory dysfunction and chronic kidney disease.

• DOI: 10.1186/s12882-021-02659-6
• 发表时间: 2022-01-18
• 期刊: BMC nephrology
• 影响因子: 2.3
• 作者: Chewcharat A;Phipps EA;Bhatia K;Kalim S;Allegretti AS;Sise ME;Păunescu TG;Seethapathy R;Nigwekar SU
• 通讯作者: Nigwekar SU

Opioids in Hemodialysis Patients.

• DOI: 10.1016/j.semnephrol.2021.02.003
• 发表时间: 2021-01
• 期刊: Seminars in nephrology
• 影响因子: 3.3
• 作者: Kalim S;Lyons KS;Nigwekar SU
• 通讯作者: Nigwekar SU

Avenues for post-translational protein modification prevention and therapy.

• DOI: 10.1016/j.mam.2022.101083
• 发表时间: 2022-08
• 期刊: MOLECULAR ASPECTS OF MEDICINE
• 影响因子: 10.6
• 作者: Tang, Mengyao;Kalim, Sahir
• 通讯作者: Kalim, Sahir

Long-term Glycemic Variability: A Variable Glycemic Metric Entangled With Glycated Hemoglobin.

• DOI: 10.1053/j.ajkd.2023.06.001
• 发表时间: 2023-06
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Mengyao Tang;Sahir Kalim