Benjamin Lidgard1, Nisha Bansal2, Leila R Zelnick2, Andrew Hoofnagle2, Jing Chen3, Derek Colaizzo4, Mirela Dobre5, Katherine T Mills3, Anna C Porter6, Sylvia E Rosas7,8, Mark J Sarnak9, Stephen Seliger10, James Sondheimer11, Manjula Kurella Tamura12, Kristine Yaffe13, Bryan Kestenbaum2. 1. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington blidgard@uw.edu. 2. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington. 3. Department of Medicine, Tulane University, New Orleans, Louisiana. 4. University of Pennsylvania, Philadelphia, Pennsylvania. 5. Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio. 6. Department of Medicine, Section of Nephrology, University of Illinois at Chicago, Chicago, Illinois. 7. Kidney and Hypertension Unit, Joslin Diabetes Center, Boston, Massachusetts. 8. Harvard Medical School, Boston, Massachusetts. 9. Department of Medicine, Tufts Medical Center, Boston, Massachusetts. 10. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. 11. Department of Medicine, Division of Nephrology, Wayne State University, Detroit, Michigan. 12. Department of Medicine, Stanford University and VA Palo Alto Health Care System, Palo Alto, California. 13. Departments of Psychiatry, Neurology, Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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