Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators.
OBJECTIVE
Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients.


METHODS
We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA.


RESULTS
Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.


CONCLUSIONS
Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.
Department of Medicine, Division of Nephrology, Johns Hopkins University, Baltimore, Maryland, United States of America; Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, United States of America.
Tariq
T
Shafi
Department of Medicine, Division of Nephrology, Veterans Administration Palo Alto Health Care System and Stanford University, Palo Alto, California, United States of America.
Timothy W
TW
Meyer
Department of Medicine, Case Western University School of Medicine, Cleveland, Ohio, United States of America.
Thomas H
TH
Hostetter
Departments of Medicine and Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Michal L
ML
Melamed
Departments of Medicine and Pediatrics, University of Toronto, Toronto, Canada.
Rulan S
RS
Parekh
Department of Medicine, Division of Nephrology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Seungyoung
S
Hwang
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Tanushree
T
Banerjee
Department of Medicine, Division of Nephrology, Johns Hopkins University, Baltimore, Maryland, United States of America; Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, United States of America; Departments of Epidemiology and Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Josef
J
Coresh
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Neil R
NR
Powe
D000328:Adult; D000368:Aged; D015415:Biomarkers; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality*; D002423:Cause of Death; D003408:Cresols; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives; D006626:Hippurates; D006801:Humans; D007200:Indican; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000453:epidemiology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D009026:Mortality; D063868:Patient Outcome Assessment; D006435:Renal Dialysis / Q000009:adverse effects*; D013463:Sulfuric Acid Esters; D014481:United States / Q000453:epidemiology
D015415:Biomarkers; D003408:Cresols; D006626:Hippurates; D013463:Sulfuric Acid Esters; D005973:Glutamine; C408690:4-cresol sulfate; C003089:phenylacetylglutamine; D007200:Indican; C030514:hippuric acid