INJ
INTERNATIONAL NEUROUROLOGY JOURNAL
pISSN 2093-4777 eISSN 2093-6931
Original Article
Volume 19 | Number 2 | June 2015 pages 131-210
INTERNATIONAL NEUROUROLOGY JOURNAL
Int Neurourol J 2016;20:33-39 http://dx.doi.org/10.5213/inj.1630454.227 pISSN 2093-4777 · eISSN 2093-6931
Official Journal of Korean Continence Society / Korean Society of Urological Research / The Korean Children’s Continence and Enuresis Society / The Korean Association of Urogenital Tract Infection and Inflammation
einj.org Mobile Web
Lower Levels of Urinary Nerve Growth Factor Might Predict Recurrent Urinary Tract Infections in Women Fei-Chi Chuang1, Hsin-Tzu Liu2, Hann-Chorng Kuo2 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Department of Urology, Buddhist Tzu Chi General Hospital and Buddhist Tzu Chi University, Hualien, Taiwan
1 2
Purpose: To investigate the changes in urinary nerve growth factor (uNGF) levels after acute urinary tract infection (UTI) and to assess the role of uNGF in predicting UTI recurrence in women. Methods: Women with uncomplicated, symptomatic UTIs were enrolled. Cephalexin 500 mg (every 6 hours) was administered for 7–14 days to treat acute UTIs. Subsequently, the patients were randomized to receive either sulfamethoxazole/trimethoprim 800 mg/160 mg daily at bedtime, or celecoxib 200 mg daily for 3 months and were monitored for up to 12 months. NGF levels in the urine were determined at baseline, 1, 4, and 12 weeks after the initiation of prophylactic therapy, and were compared between women with first-time UTIs and recurrent UTIs, sulfamethoxazole/trimethoprim and celecoxib-treated women, and no UTI recurrence and UTI recurrence that occurred during the follow-up period. Twenty women free of UTIs served as controls. Results: A total of 139 women with UTI and 20 controls were enrolled in the study, which included 50 women with a firsttime UTI and 89 women with recurrent UTIs. Thirty-seven women completed the study. Women with recurrent UTIs (n=23) had a trend of lower uNGF levels than women with first-time UTIs (n=14). During follow-up, 9 women had UTI recurrence. The serial uNGF levels in women with UTI recurrence were significantly lower than those in women who did not have UTI recurrence during the follow-up period. Conclusions: The lower levels of uNGF in women with recurrent UTI and the incidence of UTI recurrence during follow-up suggest that lower uNGF might reflect the defective innate immunity in women with recurrent UTI. Keywords: Biomarkers; Inflammation; Immunity, Innate; Nerve Growth Factor; Urinary Tract Infection • Research Ethics: The study was approved by the Institutional Review Board and Ethics Committee of the Buddhist Tzu Chi General Hospital and was registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01800799). • Conflict of Interest: No potential conflict of interest relevant to this article was reported.
INTRODUCTION Urinary tract infections (UTIs) are common bacterial infections in women, and UTI recurrence occurs in one in four affected women [1]. Recurrent UTI is one of the most common diagnoses of pelvic floor dysfunction among women. AccordCorresponding author: Hann-Chorng Kuo http://orcid.org/0000-0001-7165-4771 Department of Urology, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chuang Yang Road, Hualien City, Taiwan E-mail: [email protected] / Tel: +886-3-8561825 / Fax: +886-3-8560794 Submitted: September 26, 2015 / Accepted after revision: December 4, 2015
ing to the International Urogynecological Association/ International Continence Society joint report on the terminology for female pelvic floor dysfunction, recurrent UTI is defined as at least 3 symptomatic and medically diagnosed UTIs in a 12month period [2]. The previous UTI should have resolved completely prior to another UTI being diagnosed. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright © 2016 Korean Continence Society
www.einj.org
INJ
Chuang, et al. • uNGF May Have an Innate Immunity Role in Recurrent UTI
Nerve growth factor (NGF) is a small, secreted protein that induces the differentiation and survival of specific target neurons. NGF has a potential role as a urinary biomarker of lower urinary tract dysfunction that has both, diagnostic and therapeutic implications [3-5]. NGF is produced by the urothelium and smooth muscle [6]. Clinical and experimental data directly link increased levels of NGF in the bladder tissue and urine to lower urinary tract disorders, including bladder outlet obstruction, overactive bladder, interstitial cystitis, and chronic prostatitis [7-9]. Increased levels of NGF have also been reported in the bladder tissue and urine of patients with sensory urgency and detrusor overactivity [10-13]. NGF is implicated as a chemical mediator of pathology-induced changes in C-fiber afferent nerve excitability and reflex bladder activity [14,15]. Previous studies have reported that patients with recurrent UTIs have elevated urinary NGF (uNGF), which suggests that chronic inflammation is present in the bladders of these patients after resolution of their UTIs [3]. Chronic inflammation of the bladder wall is associated with increased apoptosis and decreased expression of tight junction proteins of the urothelium [16]. Based on this evidence, we hypothesized that chronic inflammation exists in in the bladder wall after an acute UTI episode, which might potentiate UTI recurrence in these patients. To test this hypothesis, the changes in uNGF levels after acute UTI episodes were assessed. Additionally, we evaluated whether uNGF levels could be used as a biomarker in women to monitor chronic inflammation and predict UTI recurrence following the initial UTI episode.
MATERIALS AND METHODS From February 2013 through March 2014, women with uncomplicated, symptomatic, and urine analysis-proven UTI who consecutively visited the outpatient urologic clinic were prospectively enrolled in the study. Patients with previous bladder or urethral surgery, genital prolapse, and possible neurogenic lesions were excluded from the study cohort. The study was approved by the Institutional Review Board and Ethics Committee of the Buddhist Tzu Chi General Hospital and was registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT 01800799). All patients were informed about the study rationale and procedures, and written consent was obtained before enrollment in the study. The enrolled women also completed the Chinese version of the self-reported overactive bladder symptom score and visual
34 www.einj.org
analogue scale for pain at baseline. Cephalexin 500 mg every 6 hours was administered for 1 to 2 weeks to treat the acute UTIs. When the acute UTI symptoms subsided and a urine analysis was negative for infection, the women were randomized to receive either sulfamethoxazole/trimethoprim 800 mg/160 mg daily at bedtime, or celecoxib 200 mg once daily. The women administered antibiotics were treated prophylactically for 3 months while the remaining women were treated for chronic inflammation for 3 months. Uroflowmetry and postvoid residual (PVR) volume were measured before starting the prophylactic antibiotic or anti-inflammatory treatments. In addition, a 30-mL urine sample at full bladder capacity was obtained for the laboratory testing of uNGF levels at baseline (acute UTI), 1 week (after cephalexin treatment), 4 weeks, and 12 weeks (during and at the end of the prophylactic antibiotic or anti-inflammatory treatments). NGF levels in the urine were measured using an enzyme-linked immunosorbent assay. The changes in uNGF levels were compared between women with first-time UTIs and women with a history of recurrent UTIs, women treated with prophylactic antibiotic and women treated for inflammation after their acute UTI, and women who did not have a UTI recurrence and those that did during the follow-up period. Recurrent UTI was defined as at least 3 symptomatic and medically diagnosed UTIs in the previous 12 months at the time of patient enrollment. During the follow-up period, UTI recurrence was diagnosed if patient had one episode of UTI proven by urinalysis and urine culture. We also invited 20 women who had stress urinary incontinence and were free of UTIs to serve as controls. All calculations were performed using SPSS ver. 10.0 (SPSS Inc., Chicago, IL, USA). P
INTERNATIONAL NEUROUROLOGY JOURNAL
pISSN 2093-4777 eISSN 2093-6931
Original Article
Volume 19 | Number 2 | June 2015 pages 131-210
INTERNATIONAL NEUROUROLOGY JOURNAL
Int Neurourol J 2016;20:33-39 http://dx.doi.org/10.5213/inj.1630454.227 pISSN 2093-4777 · eISSN 2093-6931
Official Journal of Korean Continence Society / Korean Society of Urological Research / The Korean Children’s Continence and Enuresis Society / The Korean Association of Urogenital Tract Infection and Inflammation
einj.org Mobile Web
Lower Levels of Urinary Nerve Growth Factor Might Predict Recurrent Urinary Tract Infections in Women Fei-Chi Chuang1, Hsin-Tzu Liu2, Hann-Chorng Kuo2 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Department of Urology, Buddhist Tzu Chi General Hospital and Buddhist Tzu Chi University, Hualien, Taiwan
1 2
Purpose: To investigate the changes in urinary nerve growth factor (uNGF) levels after acute urinary tract infection (UTI) and to assess the role of uNGF in predicting UTI recurrence in women. Methods: Women with uncomplicated, symptomatic UTIs were enrolled. Cephalexin 500 mg (every 6 hours) was administered for 7–14 days to treat acute UTIs. Subsequently, the patients were randomized to receive either sulfamethoxazole/trimethoprim 800 mg/160 mg daily at bedtime, or celecoxib 200 mg daily for 3 months and were monitored for up to 12 months. NGF levels in the urine were determined at baseline, 1, 4, and 12 weeks after the initiation of prophylactic therapy, and were compared between women with first-time UTIs and recurrent UTIs, sulfamethoxazole/trimethoprim and celecoxib-treated women, and no UTI recurrence and UTI recurrence that occurred during the follow-up period. Twenty women free of UTIs served as controls. Results: A total of 139 women with UTI and 20 controls were enrolled in the study, which included 50 women with a firsttime UTI and 89 women with recurrent UTIs. Thirty-seven women completed the study. Women with recurrent UTIs (n=23) had a trend of lower uNGF levels than women with first-time UTIs (n=14). During follow-up, 9 women had UTI recurrence. The serial uNGF levels in women with UTI recurrence were significantly lower than those in women who did not have UTI recurrence during the follow-up period. Conclusions: The lower levels of uNGF in women with recurrent UTI and the incidence of UTI recurrence during follow-up suggest that lower uNGF might reflect the defective innate immunity in women with recurrent UTI. Keywords: Biomarkers; Inflammation; Immunity, Innate; Nerve Growth Factor; Urinary Tract Infection • Research Ethics: The study was approved by the Institutional Review Board and Ethics Committee of the Buddhist Tzu Chi General Hospital and was registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01800799). • Conflict of Interest: No potential conflict of interest relevant to this article was reported.
INTRODUCTION Urinary tract infections (UTIs) are common bacterial infections in women, and UTI recurrence occurs in one in four affected women [1]. Recurrent UTI is one of the most common diagnoses of pelvic floor dysfunction among women. AccordCorresponding author: Hann-Chorng Kuo http://orcid.org/0000-0001-7165-4771 Department of Urology, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chuang Yang Road, Hualien City, Taiwan E-mail: [email protected] / Tel: +886-3-8561825 / Fax: +886-3-8560794 Submitted: September 26, 2015 / Accepted after revision: December 4, 2015
ing to the International Urogynecological Association/ International Continence Society joint report on the terminology for female pelvic floor dysfunction, recurrent UTI is defined as at least 3 symptomatic and medically diagnosed UTIs in a 12month period [2]. The previous UTI should have resolved completely prior to another UTI being diagnosed. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright © 2016 Korean Continence Society
www.einj.org
INJ
Chuang, et al. • uNGF May Have an Innate Immunity Role in Recurrent UTI
Nerve growth factor (NGF) is a small, secreted protein that induces the differentiation and survival of specific target neurons. NGF has a potential role as a urinary biomarker of lower urinary tract dysfunction that has both, diagnostic and therapeutic implications [3-5]. NGF is produced by the urothelium and smooth muscle [6]. Clinical and experimental data directly link increased levels of NGF in the bladder tissue and urine to lower urinary tract disorders, including bladder outlet obstruction, overactive bladder, interstitial cystitis, and chronic prostatitis [7-9]. Increased levels of NGF have also been reported in the bladder tissue and urine of patients with sensory urgency and detrusor overactivity [10-13]. NGF is implicated as a chemical mediator of pathology-induced changes in C-fiber afferent nerve excitability and reflex bladder activity [14,15]. Previous studies have reported that patients with recurrent UTIs have elevated urinary NGF (uNGF), which suggests that chronic inflammation is present in the bladders of these patients after resolution of their UTIs [3]. Chronic inflammation of the bladder wall is associated with increased apoptosis and decreased expression of tight junction proteins of the urothelium [16]. Based on this evidence, we hypothesized that chronic inflammation exists in in the bladder wall after an acute UTI episode, which might potentiate UTI recurrence in these patients. To test this hypothesis, the changes in uNGF levels after acute UTI episodes were assessed. Additionally, we evaluated whether uNGF levels could be used as a biomarker in women to monitor chronic inflammation and predict UTI recurrence following the initial UTI episode.
MATERIALS AND METHODS From February 2013 through March 2014, women with uncomplicated, symptomatic, and urine analysis-proven UTI who consecutively visited the outpatient urologic clinic were prospectively enrolled in the study. Patients with previous bladder or urethral surgery, genital prolapse, and possible neurogenic lesions were excluded from the study cohort. The study was approved by the Institutional Review Board and Ethics Committee of the Buddhist Tzu Chi General Hospital and was registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT 01800799). All patients were informed about the study rationale and procedures, and written consent was obtained before enrollment in the study. The enrolled women also completed the Chinese version of the self-reported overactive bladder symptom score and visual
34 www.einj.org
analogue scale for pain at baseline. Cephalexin 500 mg every 6 hours was administered for 1 to 2 weeks to treat the acute UTIs. When the acute UTI symptoms subsided and a urine analysis was negative for infection, the women were randomized to receive either sulfamethoxazole/trimethoprim 800 mg/160 mg daily at bedtime, or celecoxib 200 mg once daily. The women administered antibiotics were treated prophylactically for 3 months while the remaining women were treated for chronic inflammation for 3 months. Uroflowmetry and postvoid residual (PVR) volume were measured before starting the prophylactic antibiotic or anti-inflammatory treatments. In addition, a 30-mL urine sample at full bladder capacity was obtained for the laboratory testing of uNGF levels at baseline (acute UTI), 1 week (after cephalexin treatment), 4 weeks, and 12 weeks (during and at the end of the prophylactic antibiotic or anti-inflammatory treatments). NGF levels in the urine were measured using an enzyme-linked immunosorbent assay. The changes in uNGF levels were compared between women with first-time UTIs and women with a history of recurrent UTIs, women treated with prophylactic antibiotic and women treated for inflammation after their acute UTI, and women who did not have a UTI recurrence and those that did during the follow-up period. Recurrent UTI was defined as at least 3 symptomatic and medically diagnosed UTIs in the previous 12 months at the time of patient enrollment. During the follow-up period, UTI recurrence was diagnosed if patient had one episode of UTI proven by urinalysis and urine culture. We also invited 20 women who had stress urinary incontinence and were free of UTIs to serve as controls. All calculations were performed using SPSS ver. 10.0 (SPSS Inc., Chicago, IL, USA). P
