Abstract
BACKGROUNDSerum creatinine concentrations (SCrs) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the intensive care unit (ICU). Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults.METHODSWe collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured 7 endogenously produced secretory solutes using liquid chromatography–tandem mass spectrometry. We computed a composite secretion score incorporating all 7 solutes and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death.RESULTSThe urine-to-plasma ratios of 6 of 7 secretory solutes were lower in critically ill patients compared with healthy individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = –0.51 and r = –0.53, respectively). Each SD higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% to 38% lower) independent of severity of illness, SCr, and tubular injury markers. Higher urine-to-plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing.CONCLUSIONAmong critically ill adults, tubular secretory clearance is associated with adverse outcomes, and its measurement could improve assessment of kidney function and dosing of essential ICU medications.FUNDINGGrants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH) K23DK116967, the University of Washington Diabetes Research Center P30DK017047, an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers, and the Vanderbilt O’Brien Kidney Center (NIDDK 5P30 DK114809-03). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Highlights
Acute kidney injury (AKI) is the most common form of organ dysfunction in critically ill patients and is associated with prolonged hospitalization, requirement for acute dialysis, persistent kidney dysfunction, and death [1,2,3]
Tubular secretory clearance is associated with adverse outcomes, and its measurement could improve assessment of kidney function and dosing of essential intensive care unit (ICU) medications
To test the hypothesis that secretory solute urine-to-plasma (U/P) ratios are different between critically ill and healthy populations and that in critical illness secretory solute U/P ratios are associated with outcomes, matched plasma and urine samples were collected upon ICU admission from 170 participants enrolled in the Critical Illness Translational Research Cohort (CITRC) and 70 participants in the Healthy Kidney Study (HKS)
Summary
Acute kidney injury (AKI) is the most common form of organ dysfunction in critically ill patients and is associated with prolonged hospitalization, requirement for acute dialysis, persistent kidney dysfunction, and death [1,2,3]. Prognosis and recovery patterns in AKI vary substantially across individuals with similar creatinine measurements, suggesting incomplete assessment of kidney function by estimates of glomerular filtration alone [5,6,7,8]. The proximal tubules reabsorb filtered substances, synthesize vital hormones, maintain saltwater and acid-base homeostasis, and secrete retained organic solutes and drugs directly into the urine. Creating more inclusive measurements of kidney function that include tubular secretory clearance could enable more precise ICU drug dosing strategies and improve prognostic assessment. SCr is primarily eliminated by glomerular filtration; most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults
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