Yan Chen1,2, Leila R Zelnick2,3, Ke Wang2,3, Andrew N Hoofnagle2,4, Jessica O Becker4, Chi-Yuan Hsu5, Harold I Feldman6,7, Rupal C Mehta8, James P Lash9, Sushrut S Waikar10, Tariq Shafi11, Stephen L Seliger12, Michael G Shlipak13, Mahboob Rahman14,15, Bryan R Kestenbaum16,3. 1. Department of Epidemiology, University of Washington, Seattle, Washington. 2. Kidney Research Institute, Seattle, Washington. 3. Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington. 4. Department of Laboratory Medicine, University of Washington, Seattle, Washington. 5. Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California. 6. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. 7. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania. 8. Division of Nephrology and Hypertension, Department of Medicine, Jesse Brown Veterans Administration Medical Center and Northwestern University, Chicago, Illinois. 9. Division of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. 10. Brigham and Women's Hospital, Renal Division, Boston, Massachusetts. 11. Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi. 12. Division of Nephrology, School of Medicine, University of Maryland, Baltimore, Maryland. 13. Division of Nephrology, Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California. 14. Division of Nephrology and Hypertension, Department of Medicine, Case Western Reserve University, Cleveland, Ohio; and. 15. Louis Stokes Cleveland Veterans Affairs Medical Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio. 16. Kidney Research Institute, Seattle, Washington; brk@uw.edu.
Abstract
BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.
BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.
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