Abstract
Rationale & Objective: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. Study Design: A multicenter, prospective, cohort study. Setting & Participants: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. Exposures: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Outcomes: Incident heart failure, myocardial infarction, and stroke events. Analytical Approach: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. Results: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. Limitations: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. Conclusions: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 226-235.e1 |
| Journal | American Journal of Kidney Diseases |
| Volume | 78 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 2021 |
Funding
Aside from authors Feldman, Go, and Lash, the CRIC Study Investigators include Lawrence J. Appel, MD, MPH, Jiang He, MD, PhD, Panduranga S. Rao, MD, Mahboob Rahman, MD, and Raymond R. Townsend, MD. Yan Chen, PhD, Leila R. Zelnick, PhD, Matthew P. Huber, MD, Ke Wang, MD, Nisha Bansal, MD MAS, Andrew N. Hoofnagle, MD, PhD, Rajan K. Paranji, PhD, Susan R. Heckbert, MD, PhD, Noel S. Weiss, MD, DrPH, Alan S. Go, MD, Chi-yuan Hsu, MD, Harold I. Feldman, MD, Sushrut S. Waikar, MD, Rupal C. Mehta, MD, Anand Srivastava, MD, MPH, Stephen L. Seliger, MD, MS, James P. Lash, MD, Anna C. Porter, MD, MS, Dominic S. Raj, MD, and Bryan R. Kestenbaum, MD, MS. Designed study: BRK, HIF, ASG, JPL; conducted literature search: YC, MPH, KW, BRK; collected data: ANH, BRK; analyzed data: YC, LRZ, MPH, KW, ANH, BRK; interpreted data: all authors. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. This work was supported by US National Institutes of Health (NIH) grant R01 DK107931. Funding for the CRIC Study was obtained under a cooperative agreement of National Institute of Diabetes and Digestive and Kidney Diseases grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902; Perelman School of Medicine, University of Pennsylvania Clinical and Translational Science award NIH/National Center for Advancing Translational Sciences (NCATS) (UL1TR000003; Johns Hopkins University grant UL1 TR-000424; University of Maryland award GCRC M01 RR-16500; Clinical and Translational Science Collaborative of Cleveland; NCATS grant UL1TR000439, a 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 COBRE for Clinical and Translational Research in Cardiometabolic Diseases grant P20 GM109036; and a Kaiser Permanente NIH/ National Center for Research Resources grant UCSF-CT SI UL1 RR-024131. Funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors declare that they have no relevant financial interests. Aspects of this work have been published in the doctoral thesis Proximal Tubular Secretion, Cardiovascular Events, and Kidney Clearance of Medications by Dr Chen (University of Washington, 2020), http://hdl.handle.net/1773/46467 (currently accessible in abstract form only). Received September 12, 2020. Evaluated by 3 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Steven Fishbane, MD). Accepted in revised form December 11, 2020. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. This work was supported by US National Institutes of Health ( NIH ) grant R01 DK107931. Funding for the CRIC Study was obtained under a cooperative agreement of National Institute of Diabetes and Digestive and Kidney Diseases grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902; Perelman School of Medicine, University of Pennsylvania Clinical and Translational Science award NIH / National Center for Advancing Translational Sciences ( NCATS ) (UL1TR000003; Johns Hopkins University grant UL1 TR-000424; University of Maryland award GCRC M01 RR-16500; Clinical and Translational Science Collaborative of Cleveland; NCATS grant UL1TR000439, a 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 COBRE for Clinical and Translational Research in Cardiometabolic Diseases grant P20 GM109036; and a Kaiser Permanente NIH / National Center for Research Resources grant UCSF- CT SI UL1 RR-024131. Funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication.
Keywords
- cardiovascular disease (CVD)
- chronic kidney disease (CKD)
- cinnamoylglycine
- glomerular filtration rate (GFR)
- heart failure (HF)
- indoxyl sulfate
- isovalerylglycine
- kynurenic acid
- myocardial infarction (MI)
- p-cresol sulfate
- protein-bound
- proximal tubule
- pyridoxic acid
- renal function
- secretory solute clearance
- stroke
- tiglylglycine
- tubular secretion
- tubular secretory clearance
- uremic toxins
- xanthosine
ASJC Scopus subject areas
- Nephrology
