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.

慢性肾脏病 (CKD) 患者出现认知障碍和进行性认知能力下降的风险很高。据推测，通常通过肾小管分泌去除的蛋白质结合有机溶质的滞留会导致 CKD 中的认知障碍。

我们在前瞻性慢性肾功能不全队列 (CRIC) 研究中对 2362 名最初没有认知障碍和中风的参与者进行了追踪。我们通过 8 种内源性溶质的 24 小时肾脏清除率来估计肾小管分泌清除率，这些溶质主要通过肾小管分泌消除。CRIC 研究人员每年使用改良简易精神状态（3MS）检查评估参与者的认知功能。认知能力下降被定义为 3MS 评分较基线持续下降超过 5 分。使用针对潜在混杂因素进行调整的 Cox 回归模型，我们分析了分泌性溶质清除率、血清溶质浓度和认知能力下降之间的关联。

每个参与者后续 3MS 检查的中位数为 6 次。在平均 9.1 年的随访中，发生了 247 起认知衰退事件。调整基线 eGFR、蛋白尿和其他混杂变量后，八种分泌性溶质中的五种（肉桂酰甘氨酸、异戊酰甘氨酸、犬尿酸、吡哆酸和替甘甘氨酸）的肾脏清除率较低与认知能力下降相关。清除率每降低 50%，认知能力下降的风险就会增加 17% 到 34%。相反，溶质的血清浓度与认知能力下降无关。

在一项 CKD 前瞻性研究中，肾脏对分泌溶质的清除率降低与整体认知能力下降有关，与 eGFR 无关。需要进一步的工作来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。