American Journal of Kidney Diseases

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

Published:January 06, 2021DOI:

      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.


      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).


      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.


      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.


      Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.


      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.

      Graphical abstract

      Index Words

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        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.-y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-1305
        • Shlipak M.G.
        • Sarnak M.J.
        • Katz R.
        • et al.
        Cystatin C and the risk of death and cardiovascular events among elderly persons.
        N Engl J Med. 2005; 352: 2049-2060
        • Shlipak M.G.
        • Fried L.F.
        • Cushman M.
        • et al.
        Cardiovascular mortality risk in chronic kidney disease: comparison of conventional and novel risk factors.
        JAMA. 2005; 293: 1737-1745
        • Schwarz U.
        • Buzello M.
        • Ritz E.
        • et al.
        Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.
        Nephrol Dial Transplant. 2000; 15: 218-223
        • Tomiyama C.
        • Higa A.
        • Dalboni M.A.
        • et al.
        The impact of conventional and non-conventional risk factors on coronary calcification in pre-dialysis patients.
        Nephrol Dial Transplant. 2006; 21: 2464-2471
        • Koepsell H.
        • Lips K.
        • Volk C.
        Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications.
        Pharm Res. 2007; 24: 1227-1251
        • Vallon V.
        • Rieg T.
        • Ahn S.Y.
        • Wu W.
        • Eraly S.A.
        • Nigam S.K.
        Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics.
        Am J Physiol Renal Physiol. 2008; 294: F867-F873
        • Yacovino L.L.
        • Aleksunes L.M.
        Endocrine and metabolic regulation of renal drug transporters.
        J Biochem Mol Toxicol. 2012; 26: 407-421
        • Duranton F.
        • Cohen G.
        • De Smet R.
        • et al.
        Normal and pathologic concentrations of uremic toxins.
        J Am Soc Nephrol. 2012; 23: 1258-1270
        • Fujii H.
        • Nishijima F.
        • Goto S.
        • et al.
        Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress.
        Nephrol Dial Transplant. 2009; 24: 2089-2095
        • Yamamoto H.
        • Tsuruoka S.
        • Ioka T.
        • et al.
        Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells.
        Kidney Int. 2006; 69: 1780-1785
        • Lekawanvijit S.
        • Adrahtas A.
        • Kelly D.J.
        • Kompa A.R.
        • Wang B.H.
        • Krum H.
        Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes?.
        Eur Heart J. 2010; 31: 1771-1779
        • Baran H.
        • Staniek K.
        • Kepplinger B.
        • Gille L.
        • Stolze K.
        • Nohl H.
        Kynurenic acid influences the respiratory parameters of rat heart mitochondria.
        Pharmacology. 2001; 62: 119-123
        • Feldman H.I.
        • Appel L.J.
        • Chertow G.M.
        • et al.
        The chronic renal insufficiency cohort (CRIC) study: design and methods.
        J Am Soc Nephrol. 2003; 14: S148-S153
        • Bush K.T.
        • Wu W.
        • Lun C.
        • Nigam S.K.
        The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis.
        J Biol Chem. 2017; 292: 15789-15803
        • Rhee E.P.
        • Clish C.B.
        • Ghorbani A.
        • et al.
        A combined epidemiologic and metabolomic approach improves CKD prediction.
        J Am Soc Nephrol. 2013; 24: 1330-1338
        • Sirich T.L.
        • Aronov P.A.
        • Plummer N.S.
        • Hostetter T.H.
        • Meyer T.W.
        Numerous proteinbound solutes are cleared by the kidney with high efficiency.
        Kidney Int. 2013; 84: 585-590
        • Wang K.
        • Zelnick L.R.
        • Chen Y.
        • et al.
        Alterations of proximal tubular secretion in autosomal dominant polycystic kidney disease.
        Clin J Am Soc Nephrol. 2019; 15: 80-88
        • Wang K.
        • Zelnick L.R.
        • Hoofnagle A.N.
        • et al.
        Differences in proximal tubular solute clearance across common etiologies of chronic kidney disease.
        Nephrol Dial Transplant. 2019; 35: 1916-1923
        • Bansal N.
        • Anderson A.H.
        • Yang W.
        • et al.
        High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study.
        J Am Soc Nephrol. 2015; 26: 946-956
        • McKee P.A.
        • Castelli W.P.
        • McNamara P.M.
        • Kannel W.B.
        The natural history of congestive heart failure: the Framingham study.
        N Engl J Med. 1971; 285: 1441-1446
        • Einhorn P.T.
        • Davis B.R.
        • Massie B.M.
        • et al.
        The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) heart failure validation study: diagnosis and prognosis.
        Am Heart J. 2007; 153: 42-53
        • Thygesen K.
        • Alpert J.S.
        • White H.D.
        Universal definition of myocardial infarction.
        J Am Coll Cardiol. 2007; 50: 2173-2195
        • Liu K.D.
        • Yang W.
        • Go A.S.
        • et al.
        Urine neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease and death in CKD: results from the Chronic Renal Insufficiency Cohort (CRIC) Study.
        Am J Kidney Dis. 2015; 65: 267-274
        • Lash J.P.
        • Go A.S.
        • Appel L.J.
        • et al.
        Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
        Clinical J Am Soc Nephrol. 2009; 4: 1302-1311
        • Anderson A.H.
        • Yang W.
        • Hsu C.-y.
        • et al.
        Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) study.
        Am J Kidney Dis. 2012; 60: 250-261
        • Hsu C.-y.
        • Propert K.
        • Xie D.
        • et al.
        Measured GFR does not outperform estimated GFR in predicting CKD-related complications.
        J Am Soc Nephrol. 2011; 22: 1931-1937
        • Radulescu V.
        • Goyfman M.
        • Mohler III, E.R.
        • Gao Y.L.
        • Budoff M.J.
        • Investigators C.S.
        Prevalence and correlates of mitral annular calcification in adults with chronic kidney disease: Results from CRIC study.
        Atherosclerosis. 2015; 242: 117-122
        • Rahman M.
        • Yang W.
        • Akkina S.
        • et al.
        Relation of serum lipids and lipoproteins with progression of CKD: The CRIC study.
        Clinical J Am Soc Nephrol. 2014; 9: 1190-1198
        • Pfeffer M.A.
        • Burdmann E.A.
        • Chen C.-Y.
        • et al.
        A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.
        N Engl J Med. 2009; 361: 2019-2032
        • Bundy J.D.
        • Chen J.
        • Yang W.
        • et al.
        Risk factors for progression of coronary artery calcification in patients with chronic kidney disease: The CRIC study.
        Atherosclerosis. 2018; 271: 53-60
        • Chen Y.
        • Zelnick L.R.
        • Wang K.
        • et al.
        Kidney clearance of secretory solutes is associated with progression of CKD: the CRIC study.
        J Am Soc Nephrol. 2020; 31: 817-827
        • Bajaj A.
        • Xie D.
        • Cedillo-Couvert E.
        • et al.
        Lipids, apolipoproteins, and risk of atherosclerotic cardiovascular disease in persons with CKD.
        Am J Kidney Dis. 2019; 73: 827-836
        • Bansal N.
        • Zelnick L.
        • Go A.
        • et al.
        Cardiac Biomarkers and Risk of Incident Heart Failure in Chronic Kidney Disease: The CRIC (Chronic Renal Insufficiency Cohort) Study.
        J Am Heart Assoc. 2019; 8e012336
        • Fine J.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Hommel G.
        A stagewise rejective multiple test procedure based on a modified Bonferroni test.
        Biometrika. 1988; 75: 383-386
        • Dou L.
        • Cerini C.
        • Brunet P.
        • et al.
        P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines.
        Kidney Int. 2002; 62: 1999-2009
        • Faure V.
        • Cerini C.
        • Paul P.
        • Berland Y.
        • Dignat-George F.
        • Brunet P.
        The uremic solute p-cresol decreases leukocyte transendothelial migration in vitro.
        Int Immunol. 2006; 18: 1453-1459
        • Dou L.
        • Jourde-Chiche N.
        • Faure V.
        • et al.
        The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells.
        J Thromb Haemost. 2007; 5: 1302-1308
        • Vaziri N.D.
        • Zhao Y.-Y.
        • Pahl M.V.
        Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.
        Nephrol Dial Transplant. 2016; 31: 737-746
        • Moradi H.
        • Sica D.A.
        • Kalantar-Zadeh K.
        Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease.
        Am J Nephrol. 2013; 38: 136-148
        • Kharait S.
        • Haddad D.J.
        • Springer M.L.
        Nitric oxide counters the inhibitory effects of uremic toxin indoxyl sulfate on endothelial cells by governing ERK MAP kinase and myosin light chain activation.
        Biochem Biophys Res Commun. 2011; 409: 758-763
        • Addi T.
        • Dou L.
        • Burtey S.
        Tryptophan-derived uremic toxins and thrombosis in chronic kidney disease.
        Toxins. 2018; 10: 412
        • Gondouin B.
        • Cerini C.
        • Dou L.
        • et al.
        Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway.
        Kidney Int. 2013; 84: 733-744
        • Sallée M.
        • Dou L.
        • Cerini C.
        • Poitevin S.
        • Brunet P.
        • Burtey S.
        The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease.
        Toxins. 2014; 6: 934-949
        • Hsu C.-C.
        • Lu Y.-C.
        • Chiu C.-A.
        • et al.
        Levels of indoxyl sulfate are associated with severity of coronary atherosclerosis.
        Clin Invest Med. 2013; : E42-E49
        • DiNatale B.C.
        • Murray I.A.
        • Schroeder J.C.
        • et al.
        Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling.
        Toxicol Sci. 2010; 115: 89-97
        • Oshima N.
        • Onimaru H.
        • Matsubara H.
        • et al.
        Uric acid, indoxyl sulfate, and methylguanidine activate bulbospinal neurons in the RVLM via their specific transporters and by producing oxidative stress.
        Neuroscience. 2015; 304: 133-145
        • Wu I.-W.
        • Hsu K.-H.
        • Hsu H.-J.
        • et al.
        Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients—a prospective cohort study.
        Nephrol Dial Transplant. 2012; 27: 1169-1175
        • Meijers B.
        • Bammens B.
        • De Moor B.
        • Verbeke K.
        • Vanrenterghem Y.
        • Evenepoel P.
        Free p-cresol is associated with cardiovascular disease in hemodialysis patients.
        Kidney Int. 2008; 73: 1174-1180
        • Cao X.-S.
        • Chen J.
        • Zou J.-Z.
        • et al.
        Association of indoxyl sulfate with heart failure among patients on hemodialysis.
        Clinical J Am Soc Nephrol. 2015; 10: 111-119
        • Barreto F.C.
        • Barreto D.V.
        • Liabeuf S.
        • et al.
        Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients.
        Clinical J Am Soc Nephrol. 2009; 4: 1551-1558
        • Meijers B.K.
        • Claes K.
        • Bammens B.
        • et al.
        p-Cresol and cardiovascular risk in mild-to-moderate kidney disease.
        Clin J Am Soc Nephrol. 2010; 5: 1182-1189
        • Suchy-Dicey A.M.
        • Laha T.
        • Hoofnagle A.
        • et al.
        Tubular secretion in CKD.
        J Am Soc Nephrol. 2016; 27: 2148-2155
        • Thompson S.
        • James M.
        • Wiebe N.
        • et al.
        Cause of death in patients with reduced kidney function.
        J Am Soc Nephrol. 2015; 26: 2504-2511
        • Gansevoort R.T.
        • Correa-Rotter R.
        • Hemmelgarn B.R.
        • et al.
        Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention.
        Lancet. 2013; 382: 339-352
        • Russo P.
        End stage and chronic kidney disease: associations with renal cancer.
        Front Oncol. 2012; 2: 28
        • Cohen G.
        • Hörl W.H.
        Immune dysfunction in uremia—an update.
        Toxins. 2012; 4: 962-990