Current and Novel Biomarkers of Progression Risk in Children with Chronic Kidney Disease

Abstract

Background: Due to the complexity of chronic kidney disease (CKD) pathophysiology, biomarkers representing different mechanistic pathways have been targeted for the study and development of novel biomarkers. The discovery of clinically useful CKD biomarkers would allow for the identification of those children at the highest risk of kidney function decline for timely interventions and enrollment in clinical trials.

Summary: Glomerular filtration rate and proteinuria are traditional biomarkers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and an improved knowledge of CKD pathophysiology. This review highlights promising biomarkers associated with the progression of CKD that could potentially serve as future prognostic markers in children with CKD.

Key messages: Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management.

Keywords: Biomarker; Children; Chronic kidney disease; Metabolomics; MicroRNA.

Fig. 1.

Novel plasma and urine biomarkers of chronic kidney disease progression. EGF, epidermal growth factor; HDL, high-density lipoprotein; KIM-1, kidney injury molecule-1; Kyn, kynurenine; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein-1; suPAR, soluble urokinase plasminogen activator receptor; TNFR1, TNF-α receptor type 1; TNFR2, TNF-α receptor type 2; Trp, tryptophan; VLDL, very-low-density lipoprotein; YKL-40, chitinase-3-like protein 1.

Fig. 2.

Fully adjusted hazard ratio with 95% confidence interval for CKD progression per doubling of plasma biomarkers in selected cohorts. eGFR unit is mL/min per 1.73 m². * sign indicates statistically significant association. CKiD, Chronic Kidney Disease in Children cohort study; CRIC, Chronic Renal Insufficiency Cohort study; KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1; MESA, Multi-Ethnic Study of Atherosclerosis study; REGARDS, Reasons for Geographic and Racial Differences in Stroke study; suPAR, soluble urokinase plasminogen activator receptor; TNFR1, TNF-a receptor type 1; TNFR2, TNF-a receptor type 2; YKL-40, chitinase-3-like protein-1.

Fig. 3.

Biomarker prognostic enrichment tool of trials application on selected plasma biomarkers for chronic kidney disease (CKD) progression in children. Based on the rate of events (CKD progression) observed in the Chronic Kidney Disease in Children (CKiD) study and the associations of biomarkers with CKD progression (adjusted hazard ratio per doubling of biomarker), we demonstrate the time in years to develop CKD progression and number of participants needed, based on the level of enrichment. Clinical trial enrichment is an enrollment strategy to enroll participants that are more likely to develop the outcome of interest based on their characteristics. This strategy allows for enrolling fewer patients, not enrolling patients who are unlikely to develop the primary outcome, and reducing the cost of a clinical trial. Parameters used in the biomarker prognostic enrichment tool for survival outcomes: simulated sample size 1,000, 5 years observation period, survival rate 0.66 (34% of children developed CKD progression within 5 years), effect size (hazard ratio per doubling of plasma biomarker), enrichment levels 0.25 steps between 0 and 0.75, trial length of 5 years, treatment hazard ratio for sample size calculation of 0.8.Using TNFR-1 as an example, with a 75% level of enrichment, 1,500 participants would be enrolled and 60% would have reached CKD progression by 5 years compared to 40% of 2,500 participants without enrichment. Using MCP-1 as an example, we are unable to increase the percentage of participants who reach the primary outcome and we are unable to reduce the sample size of the clinical trial. The prognostic enrichment tools can be accessed at prognosticenrichment.com. KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1; TNFR1, TNF-a receptor type 1; TNFR2, TNF-a receptor type 2.