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

Abstract

Objective To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies. Methods Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)‐2, MMP‐9, MMP‐9/neutrophil gelatinase‐associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF‐R1) and NGAL were assayed and quantitated using mono‐specific enzyme‐linked immunosorbent assays for each protein. Log‐transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t‐test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver‐operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with 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 men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP‐9 and MMP‐9/NGAL complex, and urinary severity was significantly positively associated with MMP‐9, MMP‐9/NGAL complex and VEGF‐R1. In women with UCPPS, 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 women with UCPPS 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 men, and all biomarkers in women, 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 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.

Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome

“…In addition, systemic anti‐VEGF neutralizing antibody pretreatment significantly reduced the pelvic nociceptive response to cyclophosphamide‐induced cystitis compared with controls in rats . Furthermore, it has recently been reported that VEGF was thought to be one of the crucial urine markers to discriminate IC/BPS patients from OAB patients, and that urinary symptom and pain severity was significantly correlated with urinary VEGF levels in female IC/BPS patients . Taken together, these findings suggest that the increased VEGF levels in bladder tissues or urine, which could be correlated with angiogenesis, may provide new insights into the pathophysiological basis of IC/BPS.…”

Anti‐vascular endothelial growth factor treatment decreases bladder pain in cyclophosphamide cystitis: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network animal model study

“…VEGF receptors (VEGF‐R1, VEGF‐R2) and their co‐receptors, the neuropilins (Nrp‐1, Nrp‐2) are expressed at high levels in the human bladder urothelium . Recent clinical studies showed that tissue and urinary VEGF levels are elevated among patients with IC/BPS, and VEGF levels are positively correlated to the severity of bladder pain in patients . Intravesical instillation of VEGF resulted in an increase in bladder sensory fibre density, upregulation of voltage‐gated sodium channels in lumbosacral dorsal root ganglia, and development of pelvic hypersensitivity in mice .…”

“…VEGF is a pleiotropic cytokine traditionally known for its angiogenic activity . Recent clinical studies showed that bladder and urinary VEGF expression is elevated among patients with IC/BPS , and that bladder and urinary expression levels correlated to the severity of pain . VEGF expression was reduced after onabotulinumtoxinA (Botox) injection into the bladder and improvement of the pain .…”

Biomarkers for urological chronic pelvic pain: is there light at the end of the tunnel?

“…As Dagher et al. clearly show in their study, this is not going to be as easy as we had hoped. The research group analysed urine samples for candidate biological markers from both patients with UCPPS and healthy controls recruited for the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.…”