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Article of the Month: Identification of non-invasive biomarkers of UCPPS: findings from the MAPP Research Network

Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

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

Adelle Dagher*, Adam Curatolo*, Monisha Sachdev*, Alisa J. Stephens, Chris Mullins§, J. Richard Landis, Adrie van Bokhoven, Andrew El-Hayek*, John W. Froehlich**, Andrew C. Briscoe**, Roopali Roy*,††, Jiang Yang*,††, Michel A. Pontari‡‡David Zurakowski††§§, Richard S. Lee**††, Marsha A. Moses*,†† for the MAPP Research Network 
*Vascular Biology Program, Department of Surgery, Boston Childrens Hospital, Boston, MA,

 

Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, §National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, **Department of Urology, Boston Childrens Hospital, Boston, MA, ††Department of Surgery, Harvard Medical School, Boston, MA, ‡‡Lewis Katz School of Medicine at Temple University, Philadelphia, PA, and §§Department of Anesthesia, Boston Childrens Hospital, Boston, MA, USA

 

How to Cite

Dagher, A., Curatolo, A., Sachdev, M., Stephens, A. J., Mullins, C., Landis, J. R., van Bokhoven, A., El-Hayek, A., Froehlich, J. W., Briscoe, A. C., Roy, R., Yang, J., Pontari, M. A., Zurakowski, D., Lee, R. S., Moses, M. A. and the MAPP Research Network (2017), 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. BJU International, 120: 130–142. doi: 10.1111/bju.13832

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.

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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.

Editorial: Biomarkers for UCPPS: is there light at the end of the tunnel?

Management of urological disease begins with an accurate diagnosis. For this purpose, urologists have PSA and biopsy for prostate cancer, bacterial culture for UTI, CT scan for urolithiasis, cytology, cystoscopy and biopsies for bladder cancer, semen analysis for infertility and the list goes on. We have been able to use these accurate diagnostic markers to kill, maim, remove, fragment or burn our way to therapeutic success. Unfortunately, this has not been true in the case of urological chronic pelvic pain syndrome (UCPPS), where specific diagnoses and therapeutic strategies continue to elude us. Urologists managing patients with UCPPS need something concrete and quantifiable to move the field and improve patient care. A validated and reliable biomarker might fit the bill.

As Dagher et al. [1] 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. The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) developed the MAPP Research Network to provide a comprehensive, multidisciplinary research approach for UCPPS [2, 3]. A major goal of this novel initiative is to better understand UCPPS pathophysiology allowing improved diagnoses and patient stratification that informs identification of therapeutic targets and ultimately improves clinical management.

In the present study, candidate biomarkers were initially selected based on their proposed involvement in underlying processes implicated in UCPPS. The authors showed marginal biomarker discrimination between patients with UCPPS and healthy control subjects. Furthermore, they observed provocative biomarker patterns correlating with pain and urinary symptom severity. None of these observations were conclusive enough, however, to allow a clinically applicable differentiation between patients with UCPPS and control subjects with no UCPPS symptoms. The patterns associated with pain and urinary severity were also not sufficiently robust to provide clinical direction. The underlying reason for these results is probably related to our recent understanding that UCPPS is not a clearly defined disease, but rather a complicated syndrome consisting of a confusing myriad of clinical conditions involving the bladder, prostate and/or pelvic floor and probably systemic contributions from other systems, including the nervous system. Indeed, the chronic pelvic pain and urinary symptoms appear as a result of interrelated, but variable, pathophysiology incorporating inflammatory, microbial, endocrine, neuromuscular, peripheral and CNS and even psychological pathways. The systemic characterization of UCPPS in the MAPP Network supports the idea that each patient with a UCPPS diagnosis represents an individual clinical picture and symptom profile. The promise of well-powered and carefully controlled biomarker research, such as described in the present study, will probably be realized when fully integrated into a systemic clinical profile using phenotypic insights (biological and symptom) still evolving from the MAPP Network and other studies. This is expected to yield a better understanding of specific mechanisms and symptom profiles operative in individual patients or patient subgroups. Identification of biomarker patterns that inform the clinical picture has the promise to allow us, in future, to make individualized diagnoses leading to individualized mechanistically (not only phenotypically) directed prognostic and therapeutic strategies. Success in such efforts will lead to UCPPS becoming less of a urological mystery. Then this enigmatic condition might join other urological diseases for which we have accurate diagnostic algorithms and successful therapeutic interventions.

The ongoing MAPP-2 Research Network’s Symptom Patterns Study is using state-of-the-art approaches to examine closely the interrelationships between the inflammatory, endocrine, microbial, neurological and psychological systems and how these interactions influence patients’ symptoms over a 2–3-year time period. This includes correlations with diverse biological markers over time. It is hoped that MAPP-2 will unravel the tangled web of these mechanistic pathways, allowing better diagnosis and ultimately, better therapy for our patients with UCPPS. That is our promise of the light at the end of a very long urological tunnel.

J. Curtis Nickel *

 

*Queens University, Kingston, ON, Canada and Urology, Canada Research Chair in Urologic Pain and Inammation, Queens University, Kingston, ON, Canada

 

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