A Urine-Based Biomarker for Chronic Prostatitis/Chronic Pelvic Pain Syndrome

A Retrospective Multi-Center Study

Weining Liang; Zhigang Wu; Guowei Zhang; Weikang Chen; Xiangnong Hu; Jianjun Yang; Jie Meng; Yan Zeng; Hongjun Li; Xuejun Shang


Transl Androl Urol. 2020;9(5):2218-2226. 

In This Article


CP/CPPS is caused by the interaction between immune, neurological and endocrine systems and psychological factors.[22] The theories behind the disease include stress-induced dysfunction of the hypothalamic-pituitary-adrenal axis,[23] abnormal adrenal cortex hormones (endocrine),[24] neurogenic inflammation[25] and muscle fascia pain syndrome.[26] In the latter two categories, local nervous system disorders are caused by past trauma, infection or anxious personality. Chronic unconscious tightening of the pelvis (regulated by the release of substances from nerve cells, such as substance P can also lead to inflammation. The prostate and other parts of the urogenital tract: bladder, urethra, testis can also be inflamed by long-term activation of mast cells at the ends of the pelvic nerves. Similar stress-induced genitourinary inflammation has been found in experiments of other mammals.[27] However, there is no correlation between the histological examination of prostatitis and the chronic prostatitis symptom index of the NIH-CPSI.[28]

CP/CPPS is a frustrating clinical condition for both practitioners and patients. In developing countries, the situation is worse because often CP/CPPS is not correctly diagnosed using a combination of multiple methodologies, including NIH-CPSI, EPS, 2- and 4 cup tests, and so on.[29] Instead, clinician experience sometimes dictates the treatment of self-described abdominal and urinary discomfort with a frequent prescription of antibiotics to observe treatment response to the anticipated CP/CPPS.

At present, there is no uniform standard and "gold standard" for the diagnosis of CP/CPPS, and laboratory diagnosis lacks widely accepted biomarkers, and the methodology that can be used in clinical research is very limited. There is no doubt that CP changes the local microenvironment of the prostate, and the corresponding biomarker changes will inevitably occur. Quick et al.[30] found CCL-2 and CCL-3 of CP/CPPS patients has a key inflammatory mediator effect. The results of Paulis et al.[31] showed that IL-6 in EPS of CP/CPPS patients was significantly higher than that in healthy controls, and its increased level was related to CP/CPPS symptom score (NIH-CPSI). Hochreiter et al.[32] found that IL-8 in EPS of type IIIA patients was significantly higher than type IIIB group and the control group, it is believed that IL-8 can be used to distinguish type IIIA and IIIB CP/CPPS. Miller et al.[33] measured NGF, IL-6, IL-8, and IL-10 in semen of CP/CPPS patients, and found that the level of NGF in semen was related to the severity of pain. These findings are consistent with the findings of Watanabe et al.[34] that the NGF in EPS is related to the NIH-CPSI pain score, and the level of NGF is significantly reduced after successful treatment. As a new member of the costimulatory molecule family, B7-H3 plays an important role in regulating the immune system. Wei et al.[35] reported that the B7-H3 in EPS of the control group was significantly higher than other subtypes group, and the B7-H3 level of CP/CPPS III B patients was higher than that of CP/CPPS IIIA patients. Traditional routine testing methods, including EPS and urine routine diagnostic examination are challenged. It has limited significance for clinical guidance. Therefore, we need to find a new biomarker to guide the diagnosis and treatment of CP/CPPS.

The available PSEP–ELISA assay as a simple, objective and non-invasive urine test supplies the clinician as a biological surrogate to aid in the diagnosis of CP/CPPS. In the past couple of years, the PSEP test became adopted in hospitals and clinics in China and received some positive responses. However, the correlation of urine PSEP level with EPS and/or NIH-CPSI was only described in meetings and conferences anecdotally. Therefore, the current study is the first to confirm that the PSEP level is associated with the increasing WBC counts and NIH-CPSI scores. Thus, an increasing PSEP level in the urine can be a sign of the severity of CP/CPPS and may guide the best treatment plan. However, it is a pilot study that only elaborates on the correlation of urine PSEP level with EPS and/or NIH-CPSI. Therefore, further study should focus on the cut-off point of PSEP to distinguish between IIIa and IIIb categories avoiding prostatic massage.

During the chronic prostatic process, leukocytes exudate and swarm to the inflammation region; leukocytes engulf lecithin, causing lecithin bodies to decrease.

In our current study, we do not find a strong correlation between urine PSEP level and density of EPS-lecithin corpuscles. We noticed this result and had extensive discussions with other clinicians. We believe that further study may be needed to test this relationship more closely in a study with a larger sample size.

There is intense research ongoing to find better and more practical biomarkers for CP/CPPS. Studies have shown that inflammatory cytokines in seminal plasma of CP/CPPS patients are increased significantly, including IL-1, IL-6, IL-8, IL-10, and TNF-a.[36] Polymorph nuclear (PMN) elastase in EPS was significantly higher in IIIa compared to IIIb.[37,38] Other pathogens than bacteria, including chlamydia, are associated with increased WBC counts and pain severity in men with CP/CPPS. Perhaps the most thorough survey of the protein biomarkers came from mass spectrometry of seminal plasma proteomes of prostatitis patients.[39] This study identified 418 proteins associated with prostatitis versus 280 present in healthy individuals with 1,662 proteins present in both populations. While these are encouraging steps towards the development of vial biomarkers for CP/CPPS, they are derived from EPS or require sophisticated equipment to perform analysis. Therefore, they are not of practical value for general clinical application at this moment.

While PSEP-ELISA assay is simple to perform on voided urine, much still is to be learned. For example, it would be essential to confirm our study by more independent hospitals and clinics around the world for different ethnic backgrounds. There are reports that in some regions, pathogens may be more closely related to CP/CPPS. Also, the mechanism of PSEP involvement in CP/CPPS is entirely unknown. It would be essential to understand why PSEP is elevated in CP/CPPS and whether it is causative, or it is a mere biomarker surrogate. The understanding of PSEP biology would also be necessary for drug development. For example, many animal models are currently being used to investigate the etiology and drug response of experimental prostatitis in animal models.[40] PSEP may be used to monitor the disease course and drug treatment outcomes. There are still some shortcomings in this study. There is no NIH classification of CP. The correlation between PSEP in urine of CP patients with different types and WBC, SPL counts in EPS, and NIH-CPSI score needs further study. We are preparing to carry out a multidisciplinary, multi-center, prospective, large-sample clinical study of evidence-based medicine. Moreover, CP/CPPS is often clinically associated with symptoms of urinary dysfunction. Currently, research on PSEP only confirms that it is related to the severity of symptoms, but cannot locate the cause. It may be necessary to combine UDS examinations, which is more conducive to accurate treatment of patients. UDS examination can identify specific types of lower urinary tract dysfunction in patients with CP/CPPS,[41] and then take targeted treatment.