Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

ABSTRACT Rational & 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 eight 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 were characterized by a mean age of 56 years; 45% women; 41% Black; and a median eGFR of 43 mL/min/1.73m2. Lower 24-hour kidney clearances 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 The exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. Conclusions In a national cohort study of CKD, we found no clinically or statistically relevant associations between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, and 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.