Proteomic characterization of CKD progression a ‘step forward’ in drug targeting
The proteomic characterization of patients with chronic kidney disease allows for more generating mechanism-based hypotheses that could assist in future drug targeting, according to a speaker at American Society of Nephrology Kidney Week.
“Delaying or halting progression of CKD to established renal failure is a major goal of global health research,” Carlos Raul Ramirez Medina, a research associate in the division of cell matrix biology and regenerative medicine at University of Manchester, United Kingdom, said. “The mechanism of CKD progression among different CKD entities involves pro-fibrotic, pro-inflammatory and vascular pathways, but current treatments are nonspecific, with heterogeneity in terms of response and outcome. In-depth phenotypic and proteomic data can help investigate differences between patients with rapid disease progression and those who remain stable after diagnosis.”
Researchers used estimated glomerular filtration rate slope analysis to divide the discovery cohort of 414 patients with a range of kidney disease etiologies into fast progressors (change in GFR > -3 mL/min/yr; n=170) and stable patients (change in GFR > 0 mL/min/yr; n=244).
Plasma samples were investigated for novel proteomic signals using SWATH-MS, allowing a digitized proteomic profile to be created. The t-test identified differentially expressed proteins between the patient groups, and statistical analysis and machine learning approaches for discovery were executed using the computing environment R and other software provided by the Bioconductor project.
Researchers created a SWATH map on the 414 patients and 943 quantified proteins to be examined along with clinical data to determine potential progression biomarkers. A set of proteins were found to differentiate between patient groups (AUC=0.77), and baseline creatinine was not a viable predictor of CKD progression (AUC=0.51). Analyses revealed platelet degranulation to be statistically significant and potentially part of the development of CKD.
Potential protein biomarkers were afamin, T-complex protein 1 subunit delta, biglycan, AP-3 complex subunit beta-1 and IGHM. Complement C6 was determined to be a potential biomarker by all methods in this study.
“The in-depth proteomic characterization of this large-scale CKD cohort is a step forward in generating mechanism-based hypotheses that might then lend themselves to future drug targeting,” Medina said. “Candidate proteomic biomarkers will be validated in samples from selected patients in other large CKD cohorts such as the National Unified Renal Translational Research Enterprise (NURTuRE) using a targeted mass spectrometric analysis.”
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Medina CRR, et al. Paper SA-OR53. Presented at: ASN Kidney Week; Nov. 4-7, 2021 (virtual meeting).