Yan Chen1, Leila R Zelnick2, Matthew P Huber3, Ke Wang2, Nisha Bansal2, Andrew N Hoofnagle4, Rajan K Paranji5, Susan R Heckbert6, Noel S Weiss6, Alan S Go7, Chi-Yuan Hsu8, Harold I Feldman9, Sushrut S Waikar10, Rupal C Mehta11, Anand Srivastava11, Stephen L Seliger12, James P Lash13, Anna C Porter13, Dominic S Raj14, Bryan R Kestenbaum15. 1. Department of Epidemiology, University of Washington, Seattle, WA; Kidney Research Institute, Seattle, WA. 2. Kidney Research Institute, Seattle, WA; Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA. 3. Department of Medicine, University of Washington, Seattle, WA. 4. Kidney Research Institute, Seattle, WA; Department of Laboratory Medicine, University of Washington, Seattle, WA. 5. Department of Chemistry, University of Washington, Seattle, WA. 6. Department of Epidemiology, University of Washington, Seattle, WA. 7. Division of Research, Kaiser Permanente Northern California, Oakland, CA. 8. Department of Medicine, Division of Nephrology, University of California San Francisco, San Francisco, CA. 9. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA. 10. Renal Division, Brigham and Women's Hospital, Boston, MA. 11. Department of Medicine, Division of Nephrology and Hypertension, Northwestern University, Chicago, IL. 12. Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD. 13. Department of Medicine, Division of Nephrology, University of Illinois at Chicago, Chicago, IL. 14. Department of Medicine, Division of Kidney Disease and Hypertension, George Washington University, Washington, DC. 15. Kidney Research Institute, Seattle, WA; Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA. Electronic address: brk@u.washington.edu.
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.
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.
Authors: Astrid M Suchy-Dicey; Thomas Laha; Andrew Hoofnagle; Rick Newitt; Tammy L Sirich; Timothy W Meyer; Ken E Thummel; N David Yanez; Jonathan Himmelfarb; Noel S Weiss; Bryan R Kestenbaum Journal: J Am Soc Nephrol Date: 2015-11-27 Impact factor: 10.121
Authors: Suree Lekawanvijit; Anastasia Adrahtas; Darren J Kelly; Andrew R Kompa; Bing H Wang; Henry Krum Journal: Eur Heart J Date: 2010-01-04 Impact factor: 29.983
Authors: James P Lash; Alan S Go; Lawrence J Appel; Jiang He; Akinlolu Ojo; Mahboob Rahman; Raymond R Townsend; Dawei Xie; Denise Cifelli; Janet Cohan; Jeffrey C Fink; Michael J Fischer; Crystal Gadegbeku; L Lee Hamm; John W Kusek; J Richard Landis; Andrew Narva; Nancy Robinson; Valerie Teal; Harold I Feldman Journal: Clin J Am Soc Nephrol Date: 2009-06-18 Impact factor: 8.237
Authors: Tammy L Sirich; Pavel A Aronov; Natalie S Plummer; Thomas H Hostetter; Timothy W Meyer Journal: Kidney Int Date: 2013-05-01 Impact factor: 10.612
Authors: Robert D Mair; Seolhyun Lee; Natalie S Plummer; Tammy L Sirich; Timothy W Meyer Journal: J Am Soc Nephrol Date: 2021-08-18 Impact factor: 10.121
Authors: Alexander L Bullen; Simon B Ascher; Rebecca Scherzer; Pranav S Garimella; Ronit Katz; Stein I Hallan; Alfred K Cheung; Kalani L Raphael; Michelle M Estrella; Vasantha K Jotwani; Rakesh Malhotra; Jesse C Seegmiller; Michael G Shlipak; Joachim H Ix Journal: J Am Soc Nephrol Date: 2022-08-16 Impact factor: 14.978