Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.
Department of Medicine, Tulane University, New Orleans, Louisiana.
J Am Soc Nephrol. 2022 Jul;33(7):1391-1401. doi: 10.1681/ASN.2021111435. Epub 2022 Apr 20.
People with chronic kidney disease (CKD) are at high risk for cognitive impairment and progressive cognitive decline. Retention of protein-bound organic solutes that are normally removed by tubular secretion is hypothesized to contribute to cognitive impairment in CKD.
We followed 2362 participants who were initially free of cognitive impairment and stroke in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study. We estimated tubular secretory clearance by the 24-hour kidney clearances of eight endogenous solutes that are primarily eliminated by tubular secretion. CRIC study investigators assessed participants' cognitive function annually using the Modified Mini-Mental State (3MS) Examination. Cognitive decline was defined as a sustained decrease of more than five points in the 3MS score from baseline. Using Cox regression models adjusted for potential confounders, we analyzed associations between secretory solute clearances, serum solute concentrations, and cognitive decline.
The median number of follow-up 3MS examinations was six per participant. There were 247 incident cognitive decline events over a median of 9.1 years of follow-up. Lower kidney clearances of five of the eight secretory solutes (cinnamoylglycine, isovalerylglycine, kynurenic acid, pyridoxic acid, and tiglylglycine) were associated with cognitive decline after adjustment for baseline eGFR, proteinuria, and other confounding variables. Effect sizes ranged from a 17% to a 34% higher risk of cognitive decline per 50% lower clearance. In contrast, serum concentrations of the solutes were not associated with cognitive decline.
Lower kidney clearances of secreted solutes are associated with incident global cognitive decline in a prospective study of CKD, independent of eGFR. Further work is needed to determine the domains of cognition most affected by decreased secretory clearance and the mechanisms of these associations.
患有慢性肾病（CKD）的人认知障碍和认知能力逐渐下降的风险很高。据推测，蛋白质结合的有机溶质的保留，这些溶质通常通过管状分泌被清除，这导致了 CKD 中的认知障碍。
我们对前瞻性慢性肾功能不全队列（CRIC）研究中最初无认知障碍和中风的 2362 名参与者进行了随访。我们通过 24 小时内 8 种主要通过管状分泌清除的内源性溶质的肾脏清除率来估计管状分泌清除率。CRIC 研究的调查人员每年使用改良的 Mini-Mental State（3MS）检查评估参与者的认知功能。认知下降定义为 3MS 评分从基线持续下降超过 5 分。使用 Cox 回归模型调整潜在的混杂因素后，我们分析了分泌溶质清除率、血清溶质浓度与认知下降之间的关系。
每位参与者的中位随访 3MS 检查次数为 6 次。在中位随访 9.1 年期间，发生了 247 例认知下降事件。在调整基线 eGFR、蛋白尿和其他混杂变量后，五种（肉桂酰甘氨酸、异缬草酸、犬尿氨酸、吡哆醛酸和丁烯甘氨酸）分泌溶质的肾脏清除率较低与认知下降有关。每种溶质的清除率每降低 50%，风险增加 17%至 34%。相比之下，溶质的血清浓度与认知下降无关。
在一项前瞻性 CKD 研究中，分泌溶质的肾脏清除率较低与新发的总体认知下降有关，与 eGFR 无关。需要进一步研究以确定受分泌清除率降低影响最大的认知领域以及这些关联的机制。
