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

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.

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.