Dietary Acid Load, Subclinical Acidosis and Outcomes in Chronic Kidney Disease

描述（由申请人提供）：代谢性酸中毒是慢性肾脏疾病（CKD）进展的可改变危险因素。由于饮食营养代谢产生的非挥发性酸的日常负荷排泄受损，它在晚期CKD中发展。亚临床酸中毒发生在明显酸中毒之前，也可能对临床结果产生不利影响。在临床试验中，碱补充剂治疗显性和亚临床酸中毒可减缓肾脏疾病的进展，但在一些CKD患者中，碱补充剂的使用可能存在不可接受的风险。当存在亚临床但不明显的酸中毒时，通过控制饮食来降低非挥发性酸负荷可能是缓解酸中毒和改善早期CKD预后的补充策略。通过深入的以患者为导向的研究，我们将对伴有和不伴有糖尿病的早期3期CKD参与者以及健康对照者进行详细、直接的饮食摄入、肾酸排泄、肾小球滤过率和亚临床酸中毒的测量，以确定亚临床酸中毒的独立危险因素。利用这一丰富的数据来源，我们还将验证非挥发性酸负荷对金标准措施的估计，为未来的研究应用。最后，我们将直接测量来自慢性肾功能不全队列（CRIC）研究的1000名参与者的非挥发性酸负荷，这是一个不同的CKD队列，并在长期随访中检查其与硬临床结果的关系。我们预计这些研究的目的是将非挥发性酸负荷确定为CKD的一个可改变的危险因素，它可能通过直接导致亚临床酸中毒而产生不良影响，根据定义，亚临床酸中毒在绝大多数CKD患者中无法检测到。此外，本研究将为PI Julia Scialla博士在生理和流行病学研究方面提供丰富的培训经验。Scialla博士在约翰霍普金斯大学接受过临床肾脏病学和流行病学方面的培训，并在该领域发表过论文，这是她研究假设的基础。她将由Myles Wolf博士指导，他是一位经验丰富，资金充足的临床医生兼科学家，在患者方面拥有广泛的技能

DESCRIPTION (provided by applicant): Metabolic acidosis is a modifiable risk factor for chronic kidney disease (CKD) progression. It develops in advanced CKD due to impaired excretion of the daily load of nonvolatile acid that is generated from metabolism of dietary nutrients. Subclinical acidosis develops prior to overt acidosis and may also adversely affect clinical outcomes. Treatment of both overt and subclinical acidosis with alkali supplements slows renal disease progression in clinical trials, but use of alkali supplements may be associated with unacceptable risks in some CKD patients. Lowering nonvolatile acid load through dietary manipulation may be a complementary strategy to mitigate acidosis and improve outcomes earlier in CKD when subclinical, but not overt, acidosis is present. Using intensive patient-oriented research, we will perform detailed, direct measures of dietary intake, renal acid excretion, glomerular filtration rate and subclinical acidosis in participants with early stage 3 CKD with and without diabetes, and in healthy controls, to determine independent risk factors for subclinical acidosis. Using this rich source of data, we will also validate estimates of nonvolatile acid load against gold- standard measures for future research applications. Finally, we will directly measure nonvolatile acid load in 1000 participants from the Chronic Renal Insufficiency Cohort (CRIC) study, a diverse CKD cohort, and examine its association with hard clinical outcomes over long term follow-up. We anticipate that these research aims will establish nonvolatile acid load as a modifiable risk factor in CKD that may exert adverse effects by directly contributing to subclinical acidosis, which, by definition, escapes detection in the vast majority of patients with CKD. In addition, this research will provide a rich training experience fr the PI, Dr. Julia Scialla, in physiologic and epidemiologic research. Dr. Scialla has prior trainin in clinical nephrology and epidemiology at Johns Hopkins University and a record of publication in this field which formed the basis of her research hypotheses. She will be mentored by Dr. Myles Wolf, an experienced, well-funded clinician-scientist with a broad range of skills in patient oriented research, including physiologic and epidemiologic studies. The PI will also benefit from additional advising by experts in renal epidemiology, nutrition and translational research. This Mentored Patient-Oriented Research Career Development Award will help Dr. Scialla achieve her immediate and long term goals by supporting: (1) new training in physiologic research; (2) advanced training in epidemiology; (3) the development of scientific expertise in early abnormalities of acid-base homeostasis; and (4) the generation of critical preliminary data and scientific collaborations to facilitate her transition to research independence.