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 andmortality, 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 1.73m2. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 817-827 |
| Number of pages | 11 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 31 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2020 |
Funding
Dr. Becker reports grants from the National Institutes of Health (NIH), during the conduct of the study. Dr. Feldman reports grants from NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK), during the conduct of the study; other from Kyowa Hakko Kirin Co., Ltd.; and other from American Journal of Kidney Disease, outside the submitted work. Dr. Hoofnagle reports grants from the NIH, during the conduct of the study; grants from Waters, Inc., outside the submitted work. Dr. Hsu reports grants from NIH-NIDDK, during the conduct of the study; and personal fees from EcoR1 Capital Fund, personal fees from Health Advances, personal fees from Ice Miller LLP, nonfinancial support from Microlife, personal fees and grants from Satellite Healthcare, and personal fees from UpToDate, outside the submitted work. Dr. Mehta reports other from Abbott Laboratories, other from AbbVie Inc., and other from Teva Pharmaceutical Industries, outside the submitted work. Dr. Lash reports grants from NIH, during the conduct of the study. Dr. Rahman reports grants from NIH, during the conduct of the study. Dr. Shafi reports personal fees from Hershey Medical Center, personal fees from Siemens, personal fees from University of California Irvine, personal fees from University of Mississippi Medical Center, and personal fees from University of Tennessee, outside the submitted work. Dr. Waikar reports grants and personal fees from Allena Pharmaceuticals, personal fees from Barron and Budd (versus Fresenius), personal fees from Bunch and James, personal fees from Cerus, personal fees from CVS, personal fees from GE Health Care, personal fees from GSK, personal fees from Harvard Clinical Research Institute (also known as Baim), personal fees from JNJ, personal fees from Kantum Pharma, personal fees from Mallinckrodt, personal fees from Mass Medical International, personal fees from Pfizer, personal fees from Public Health Advocacy Institute, personal fees from Roth Capital Partners, personal fees from Strataca, personal fees from Takeda, personal fees from Venbio, and personal fees from Wolters Kluewer, outside the submitted work. Dr. Zelnick reports grants from NIDDK, during the conduct of the study. This work was supported by NIH grant R01 DK107931. Funding for the CRIC study was obtained under a cooperative agreement from the NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine, University of Pennsylvania, Clinical and Translational Science Award NIH/ National Center for Advancing Translational Sciences (NCATS) grant UL1TR000003; Johns Hopkins University grant UL1 TR-000424; University of Maryland General Clinical Research Center grant M01 RR-16500; Clinical and Translational Science Collaborative of Cleveland, School of Medicine, CaseWestern Reserve University grant UL1TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research; Michigan Institute for Clinical and Health Research grant UL1TR000433; University of Illinois at Chicago grant CTSAUL1RR029879; Tulane University Centers of Biomedical Research Excellence (COBRE) award for Clinical and Translational Research in Cardiometabolic Diseases (P20 GM109036); and Kaiser Permanente NIH/National Center for Research Resources, Clinical and Translational Science Institute, University of California, San Francisco grant UL1 RR-024131. This work was supported by NIH grant R01 DK107931. Funding for the CRIC study was obtained under a cooperative agreement from the NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine, University of Pennsylvania, Clinical and Translational Science Award NIH/ National Center for Advancing Translational Sciences (NCATS) grant UL1TR000003; Johns Hopkins University grant UL1 TR-000424; University of Maryland General Clinical Research Center grant M01 RR-16500; Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University grant UL1TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research; Michigan Institute for Clinical and Health Research grant UL1TR000433; University of Illinois at Chicago grant CTSAUL1RR029879; Tulane University Centers of Biomedical Research Excellence (COBRE) award for Clinical and Translational Research in Cardiometabolic Diseases (P20 GM109036); and Kaiser Permanente NIH/National Center for Research Resources, Clinical and Translational Science Institute, University of California, San Francisco grant UL1 RR-024131.
ASJC Scopus subject areas
- General Medicine