Kidney Tubular Damage and Dysfunction Identify a Novel Axis of Chronic Kidney Disease

肾小管损伤和功能障碍确定了慢性肾脏病的新轴

• 批准号: 10683087
• 负责人: Joachim H Ix
• 金额: $ 59.19万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683087
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Adherence; Albuminuria; Ammonia; Ancillary Study; Arteriosclerosis; Atrophic; Award; Benign; Biological; Biological Markers; Blood; Blood Pressure; Blood flow; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Clinical; Clinical Trials; Clinical assessments; Collaborations; Communities; Creatinine; Diagnosis; Dimensions; Disease Progression; Energy Metabolism; Event; Factor Analysis; Fibrosis; Functional disorder; General Population; Glomerular Filtration Rate; Goals; Guidelines; Health; Histopathology; Immune; Individual; Inflammation; Injury; Injury to Kidney; Intervention Trial; Kidney; Life; Measurable; Measurement; Measures; Monitor; Nutrient; Outcome; Parents; Participant; Pathologic; Patient Care; Patients; Pattern; Persons; Physiological; Production; Randomized; Recommendation; Registries; Renal Mass; Renal function; Renal tubule structure; Reproducibility; Research; Risk; Risk Factors; Serum; Staging; Testing; Time; Tissues; Toxin; Translations; Tubular formation; Urine; Validation; Vertebral column; Work; absorption; adverse outcome; arm; base; blood pressure intervention; blood pressure reduction; cardiovascular disorder risk; clinical care; clinical practice; clinical risk; cohort; disease diagnosis; disease prognosis; follow-up; glomerular filtration; glomerulosclerosis; hemodynamics; hypertension treatment; improved; individual patient; interstitial; kidney biopsy; mortality; mortality risk; novel; novel strategies; parent grant; population based; predictive panel; prevent; prognostic; public health relevance; renal damage; response; success; tool; two-dimensional

PROJECT SUMMARY For over 50 years, clinicians have relied upon serum creatinine and albuminuria as the sole biomarkers to measure and monitor kidney health. These measures primarily mark the glomerular filtration rate (GFR) and glomerular damage, yet the kidney tubules are responsible for a myriad of functions critical to life, including toxin secretion, nutrient reabsorption, acid/base control, and immune defense. Currently, clinicians cannot evaluate tubule health except in rare instances when kidney biopsies are obtained. In our parent grant, R01DK098234, an ancillary study in the landmark Systolic Blood Pressure Intervention Trial (SPRINT), we found that non-invasive biomarkers that characterize health of the kidney tubules predict CKD progression and cardiovascular disease events, independent of creatinine, albuminuria, and other risk factors. We also made an important additional discovery that could challenge current paradigms, and will be a major focus of this renewal application. SPRINT found that while intensive blood pressure lowering reduced cardiovascular events and mortality, it also worsened serum creatinine. Yet, we found that participants in the intensive blood pressure lowering arm appeared to have reduced tubule injury. These findings indicate that rising serum creatinine levels in this setting typically reflect hemodynamic accommodation rather than intrinsic kidney injury; yet the concern for kidney damage in clinical care prevents many individuals from receiving life-extending, optimal hypertension treatment. Building on our successes in unlocking the prognostic potential of the kidney tubules in the parent grant, this renewal has the objective of building a Kidney Tubule Health Panel (KTHP) that can be applied to individual patients for eventual translation to clinical care. Our three major goals are: a) prediction of progressive CKD; b) prediction of cardiovascular disease; and c) differentiation of intrinsic tubule damage from benign hemodynamic accommodation within individuals who develop rising creatinine levels. To accomplish these prediction goals, we must explore several additional critical functions of the kidney tubules, including toxin secretion and ammonia production; and, we must explore more sensitive measures of kidney tubule injury, including biomarkers measured in blood as well as urine. We will evaluate, compare, and combine these new measures with existing measures from the parent award to identify a parsimonious set of measures that maximally achieves each of the afore-mentioned prediction goals, utilizing latent variable approaches to develop distinct and physiologically relevant axes of kidney tubule health that will comprise the KTHP. The KTHP will then be measured, evaluated and validated in the community-based Nord-TrØndelag Health (HUNT) Study and the Norwegian Kidney Biopsy Registry. This comprehensive work will allow us to advance the KTHP as a novel and useful clinical tool to improve prediction in CKD and to maximize adherence to life-saving therapies, moving beyond kidney measures that are exclusively glomerular focused.

项目总结 50多年来，临床医生一直依赖血清肌酐和蛋白尿作为唯一的生物标志物 测量和监测肾脏健康状况。这些措施主要标记肾小球滤过率(GFR)和 肾小球损伤，但肾小管对生命至关重要的无数功能负责，包括 毒素分泌、营养重吸收、酸碱控制和免疫防御。目前，临床医生不能 评估肾小管的健康状况，除非在极少数情况下进行肾活检。在我们的父母资助中， R01DK098234，具有里程碑意义的收缩压干预试验(Sprint)的辅助研究，我们 研究发现，表征肾小管健康状况的非侵入性生物标志物可以预测CKD的进展和 心血管疾病事件，与肌酐、蛋白尿和其他危险因素无关。我们还制作了 一项重要的额外发现，可能会挑战当前的范式，并将成为这一领域的主要焦点 续签申请。斯普林特发现，虽然紧张的血压降低会减少心血管事件 和死亡率，它还恶化了血清肌酐。然而，我们发现，参与者在密集的血压 手臂下垂似乎减轻了肾小管损伤。这些发现表明，升高的血清肌酐 这种情况下的水平通常反映的是血流动力学调节，而不是内在的肾脏损伤；然而 临床护理中对肾脏损害的关注使许多人无法获得延长生命、最佳的 高血压治疗。 在我们成功地释放了父母赠款中肾小管的预后潜力的基础上， 此次更新的目标是建立一个肾小管健康面板(KTHP)，可应用于 最终转化为临床护理的个别患者。我们的三个主要目标是：a)预测 进展性慢性肾脏病；b)心血管疾病的预测；以及c)固有肾小管损害的鉴别。 肌酐水平升高的个体内的良性血流动力学调节。要完成 为了达到这些预测目标，我们必须探索肾小管的几个额外的关键功能，包括 毒素分泌和氨的产生；以及，我们必须探索更敏感的肾小管措施 伤害，包括在血液和尿液中测量的生物标记物。我们将对它们进行评估、比较和组合 新措施和来自父奖项的现有措施，以确定一组节俭的措施，这些措施 最大限度地实现上述每个预测目标，利用潜变量方法 开发不同的和生理上相关的肾小管健康轴，这将构成KTHP。这个 KTHP随后将在以社区为基础的北树健康(Hunt)中进行测量、评估和验证 研究和挪威肾脏活组织检查登记处。这项全面的工作将使我们能够推进KTHP 作为一种新的有用的临床工具来改善慢性肾脏病的预测和最大限度地坚持救生 治疗，超越肾脏措施，完全专注于肾小球。

项目成果

Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial.

• DOI: 10.1016/j.xkme.2022.100546
• 发表时间: 2022-12
• 期刊: KIDNEY MEDICINE
• 影响因子: 3.9
• 作者: Ascher, Simon B.;Shlipak, Michael G.;Katz, Ronit;Bullen, Alexander L.;Scherzer, Rebecca;Hallan, Stein I.;Cheung, Alfred K.;Raphael, Kalani L.;Estrella, Michelle M.;Jotwani, Vasantha K.;Seegmiller, Jesse C.;Ix, Joachim H.;Garimella, Pranav S.
• 通讯作者: Garimella, Pranav S.

Variation of NT-proBNP and High-Sensitivity Cardiac Troponin T Across Levels of Estimated Glomerular Filtration Rate: The SPRINT Trial.

NT-proBNP 和高敏心肌肌钙蛋白 T 随估计肾小球滤过率水平的变化：SPRINT 试验。

• DOI: 10.1161/circulationaha.123.066377
• 发表时间: 2024
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Bansal,Nisha;Katz,Ronit;Seliger,Stephen;deFilippi,Christopher;Wettersten,Nicholas;deLemos,JamesA;Christenson,Robert;Killeen,AnthonyA;Berry,JarettD;Shlipak,MichaelG;Ix,JoachimH
• 通讯作者: Ix,JoachimH

Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial.

SPRINT 试验中 eGFR 降低的高血压成人肾小管生物标志物异常的临床危险因素。

• DOI: 10.1093/ajh/hpac102
• 发表时间: 2022
• 期刊: American journal of hypertension
• 影响因子: 3.2
• 作者: Ikeme,JesseC;Katz,Ronit;Muiru,AnthonyN;Estrella,MichelleM;Scherzer,Rebecca;Garimella,PranavS;Hallan,SteinI;Peralta,CarmenA;Ix,JoachimH;Shlipak,MichaelG
• 通讯作者: Shlipak,MichaelG