Abstract
The current standard of care measures for kidney function, proteinuria, and serum creatinine (SCr) are poor predictors of early-stage kidney disease. Measures that can detect chronic kidney disease in its earlier stages are needed to enable therapeutic intervention and reduce adverse outcomes of chronic kidney disease. We have developed the Kidney Injury Test (KIT) and a novel KIT Score based on the composite measurement and validation of multiple biomarkers across a unique set of 397 urine samples. The test is performed on urine samples that require no processing at the site of collection and without target sequencing or amplification. We sought to verify that the pre-defined KIT test, KIT Score, and clinical thresholds correlate with established chronic kidney disease (CKD) and may provide predictive information on early kidney injury status above and beyond proteinuria and renal function measurements alone. Statistical analyses across six DNA, protein, and metabolite markers were performed on a subset of residual spot urine samples with CKD that met assay performance quality controls from patients attending the clinical labs at the University of California, San Francisco (UCSF) as part of an ongoing IRB-approved prospective study. Inclusion criteria included selection of patients with confirmed CKD and normal healthy controls; exclusion criteria included incomplete or missing information for sample classification, logistical delays in transport/processing of urine samples or low sample volume, and acute kidney injury. Multivariate logistic regression of kidney injury status and likelihood ratio statistics were used to assess the contribution of the KIT Score for prediction of kidney injury status and stage of CKD as well as assess the potential contribution of the KIT Score for detection of early-stage CKD above and beyond traditional measures of renal function. Urine samples were processed by a proprietary immunoprobe for measuring cell-free DNA (cfDNA), methylated cfDNA, clusterin, CXCL10, total protein, and creatinine. The KIT Score and stratified KIT Score Risk Group (high versus low) had a sensitivity and specificity for detection of kidney injury status (healthy or CKD) of 97.3% (95% CI: 94.6–99.3%) and 94.1% (95% CI: 82.3–100%). In addition, in patients with normal renal function (estimated glomerular filtration rate (eGFR) ≥ 90), the KIT Score clearly identifies those with predisposing risk factors for CKD, which could not be detected by eGFR or proteinuria (p < 0.001). The KIT Score uncovers a burden of kidney injury that may yet be incompletely recognized, opening the door for earlier detection, intervention and preservation of renal function.
Highlights
Chronic kidney disease (CKD) is a worldwide public health problem, with a global burden of 850 million people
Mo ecdo. 2r0r1e9la, 8t,ioxnFObRetPwEEeRenREtVhIeEWeGFR and the urinary protein/creatinine ratio (R2 = 0.0087) an5do,fa1s6 shown by other investigators [44], proteinuria was poor at categorizing stages of CKD (Figure 2)
Over a decade of transcriptional and LC–MS/MS-based urine proteomic studies [48,50,58,61,62,63,64] have resulted in a deeper biological understanding of kidney injury across different causes of CKD, which drove the selection of biomarkers for inclusion in the Kidney Injury Test (KIT) assay to represent injury across different intra-renal compartments
Summary
Chronic kidney disease (CKD) is a worldwide public health problem, with a global burden of 850 million people. CKD is defined as reduced renal reserve, persisting for ≥3 months and/or a prior diagnosis of a condition with known risk for kidney damage [1]. CKD is defined in a five-stage classification system for the assessment of kidney injury as patients advance towards the need for dialysis or transplantation [2]. The eGFR has poor sensitivity for early CKD detection, as the inherent redundancy of renal reserve masks the early rise in SCr. Kidney biopsies, often triggered with more advanced stages of CKD, have value to assess pathology, but are invasive, expensive [4], and cannot be utilized for serial monitoring of CKD progression
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