Reference intervals for kidney tubular secretion markers in the general population: The HUNT3 study

BackgroundChronic kidney disease (CKD) prevalence and prognosis are currently based exclusively on glomerular functions, but the kidney tubule possesses numerous additional functions with pathophysiological and prognostic value. Tubular secretion is also critical for toxin and drug elimination but has not been well described in healthy individuals and corresponding reference ranges have not been established.Material and methodsAmong participants from the Norwegian population-based HUNT3 study we identified a healthy subset by excluding those reporting poor general health, or smoking, diabetes, cardiovascular disease, treated hypertension, severe, and CKD (eGFR <60 mL/min/1.73 m²). We measured 12 well-characterized markers of tubular secretion in blood and urine using liquid chromatography mass spectrometry (LC-MS). Tubular secretory function was reported for each marker as urine/plasma-ratio (UPR, with and without indexing to urine creatinine and osmolality), clearance, and fractional excretion.ResultsWe included 636 healthy participants (295 men) with mean age 47 years (SD 14). Less than 3.2% of participants in age and sex subgroups fell outside the upper and lower limits of a common reference interval, so partitioning for age and sex was not necessary. Median urine/plasma ratio indexed for creatinine (UPRcreat) ranged from 3 to 87 uM/uM·mmol, and plasma clearance ranged from 35 to 976 mL/min. Phenylacetylglutamine, isovalerylglycine, 2-methylsuccinic acid, and hippuric acid demonstrated the highest UPRcreat values (87, 75, 72, and 61 uM/uM·mmol, respectively). We also measured 1,7-dimethyluric acid, kynurenic acid, adipic acid, suberic acid, cinnamoylglycine, 1,2,7-trimethyluric acid, indoxyl sulfate, and p-cresol sulfate. Reference intervals based on 2.5th and 97.5th percentiles were similar across age and sex.ConclusionThis study quantifies reference ranges of endogenous tubular secretory solutes among a population of community dwelling healthy adults.