Biological Variation of Plasma and Urinary Markers of Acute Kidney Injury in Patients with Chronic Kidney Disease

Abstract

BACKGROUND Identification of acute kidney injury (AKI) is predominantly based on changes in plasma creatinine concentration, an insensitive marker. Alternative biomarkers have been proposed. The reference change value (RCV), the point at which biomarker change can be inferred to have occurred with statistical certainty, provides an objective assessment of change in serial tests results in an individual. METHODS In 80 patients with chronic kidney disease, weekly measurements of blood and urinary biomarker concentrations were undertaken over 6 weeks. Variability was determined and compared before and after adjustment for urinary creatinine and across subgroups stratified by level of kidney function, proteinuria, and presence or absence of diabetes. RESULTS RCVs were determined for whole blood, plasma, and urinary neutrophil gelatinase-associated lipocalin (111%, 59%, and 693%, respectively), plasma cystatin C (14%), creatinine (17%), and urinary kidney injury molecule 1 (497%), tissue inhibitor of metalloproteinases 2 (454%), N-acetyl-β-d-glucosaminidase (361%), interleukin-18 (819%), albumin (430%), and α1-microglobulin (216%). Blood biomarkers exhibited lower variability than urinary biomarkers. Generally, adjusting urinary biomarker concentrations for creatinine reduced (P < 0.05) within-subject biological variability (CVI). For some markers, variation differed (P < 0.05) between subgroups. CONCLUSIONS These data can form a basis for application of these tests in clinical practice and research studies and are applicable across different levels of kidney function and proteinuria and in the presence or absence of diabetes. Most of the studied biomarkers have relatively high CVI (noise) but also have reported large concentration changes in response to renal insult (signal); thus progressive change should be detectable (high signal-to-noise ratio) when baseline data are available.

Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease

“…In an uncontrolled operational clinical environment, it is likely that biological and analytical variation, and hence RCVs, would increase. The within-subject biological variation of serum creatinine we have observed (4.4%) is in broad agreement with values reported in other studies in both healthy (4.1% to 7.6%, 16,[21][22][23][24][25][26][27][28] ) and diseased (5.7% to 9.9% 23,[29][30][31] ) cohorts. Enzymatic creatinine methods are less prone to interference than Jaffe methods and the use of an enzymatic assay in the present study improves confidence in the estimate of biological variation we have reported.…”

24-hour Serum Creatinine Variation Associates with Short- and Long-Term All-Cause Mortality: A Real-World Insight into Early Detection of Acute Kidney Injury

“…Reinhard et al found that the analytical variation of S-Cre was stable at less than 2% across a wide range of kidney functions; however, the within-person biological variation (CV I ) could vary from 4.7% to 8.9% for individuals with and without impaired renal function 9 . Similar observations were also made by Carter et al, who found a low CV A of 0.6% and a CV I from 5.1% to above 6% in patients with impaired kidney function (eGFR<60 mL/min/1.73 m 2 ) and proteinuria 10 . Moreover, previous studies suggested that a low index of individuality (II) for S-Cre supports stable S-Cre levels within an individual over time 10,11 .…”

“…Similar observations were also made by Carter et al, who found a low CV A of 0.6% and a CV I from 5.1% to above 6% in patients with impaired kidney function (eGFR<60 mL/min/1.73 m 2 ) and proteinuria 10 . Moreover, previous studies suggested that a low index of individuality (II) for S-Cre supports stable S-Cre levels within an individual over time 10,11 . However, few studies have associated S-Cre variability, particularly within 24 or 48 hours, with mortality using real-world data.…”

New Criterion to Evaluate Acute-on-Chronic Kidney Injury Based on the Creatinine Reference Change

“…Our study suggested that cROCK might be a more sensitive criterion for ACKI to better identify high-risk patients, for whom additional workup and evaluation might be warranted. RCV of SCr in adults have been previously reported to be between 14 and 25% [27][28][29], though these studies tend to be of small sample size and have not investigated the factors that might have an impact on RCV. Unlike the previous studies, we derived the RCV of SCr from a large sample of hospitalized patients without known risk of AKI other than CKD, instead of from "healthy" adults.…”

“…We have previously demonstrated the superiority of RCV-based criterion for pediatric AKI [26] and hypothesized that a RCV-based definition of ACKI may improve the reliability of detecting ACKI in adult. The RCV of SCr in adults is estimated at 14-25% [27][28][29], but the potential impact factors on RCV, particularly the baseline SCr level, have not been well studied.…”