Identification of novel non‐invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network

Objective To date, no definitive, broadly accepted biomarkers for UCPPS have been identified. The present study examines a series of candidate markers for UCPPS selected based on proposed involvement in underlying biological processes and is intended to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies. Methods Baseline urine samples from MAPP Research Network study participants with UCPPS (n=259), positive controls (PC) (chronic pain without pelvic pain, n=107), and healthy controls (HC) (n=125) were analyzed for the presence of proteins suggested in the literature to be associated with UCPPS. MMP-2 (Matrix Metalloproteinase-2), MMP-9, MMP-9/NGAL complex (Neutrophil gelatinase-associated lipocalin, also known as Lipocalin-2), VEGF (Vascular Endothelial Growth Factor), VEGF-R1 (VEGF Receptor 1) and NGAL were assayed and quantitated using mono-specific ELISAs for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) were compared among UCPPS, PC, and HC participants within sex using the Student's t-test, with p-values adjusted for multiple comparisons. Multivariable logistic regression and ROC curves assessed biomarkers’ utility in distinguishing UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression. Results Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF-R1, and MMP-9 in males and VEGF concentration (pg/mL) in females were associated with UCPPS versus HC. These proteins provided only marginal discrimination between UCPPS participants and HC. In UCCPS males, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex and urinary severity with MMP-9, MMP-9/NGAL complex, and VEGF-R1. In UCPPS females, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in UCPPS females was significantly positively associated with concentrations of all biomarkers except NGAL and urinary severity with all concentrations except VEGF-R1. Conclusion Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in males, and all biomarkers in females, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 in males and VEGF in females may provide potential new insights into the pathophysiology of UCPPS. This article is protected by copyright. All rights reserved.