Investigation of risk factors in the development of recurrent urethral stricture after internal urethrotomy

Abstract

BACKGROUND

Urethral stricture is a condition that often develops with trauma and results in narrowing of the urethral lumen. Although endoscopic methods are mostly used in its treatment, it has high recurrence rates. Therefore, open urethroplasty is recommended after unsuccessful endoscopic treatments.

AIM

To investigate the risk factors associated with urethral stricture recurrence.

METHODS

The data of male patients who underwent internal urethrotomy for urethral stricture between January 2017 and January 2023 were retrospectively analyzed. Demographic data, comorbidities, preoperative haemogram, and biochemical values obtained from peripheral blood and operative data were recorded. Patients were divided into two groups in terms of recurrence development; recurrence and non-recurrence. Initially recorded data were compared between the two groups.

RESULTS

A total of 303 patients were included in the study. The mean age of the patients was 66.6 ± 13.6 years. The mean duration of recurrence development was 9.63 ± 9.84 (min-max: 1-39) months in the recurrence group. Recurrence did not occur in non-recurrence group throughout the follow-up period with an average time of 44.15 ± 24.07 (min-max: 12-84) months. In the comparison of both groups, the presence of diabetes mellitus (DM), hypertension (HT), and multiple comorbidities were significantly higher in the recurrence (+) group (P = 0.038, P = 0.012, P = 0.013). Blood group, postoperative use of non-steroidal anti-inflammatory drugs, preoperative cystostomy, cause of stricture, iatrogenic cause of stricture, location and length of stricture, indwelling urinary cathater size and day of catheter removal did not differ between the two groups. No statistically significant difference was observed between the two groups in terms of age, uroflowmetric maximum flow rate value, hemogram parameters, aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting blood sugar, creatinine, glomerular filtration rate, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, monocyte-lymphocyte ratio and AST/ALT ratios.

CONCLUSION

In patients with urethral stricture recurrence, only the frequency of DM and HT was high, while inflammation marker levels and stricture-related parameters were similar between the groups.

Key Words: Inflammation; Internal urethrotomy; Recurrence; Urethral stricture; Urethra

Core Tip: In our study, we aimed to investigate whether there are inflammation markers in peripheral blood that can predict urethral stricture recurrence after internal urethrotomy and whether other etiological factors have a place in predicting stricture recurrence. According to our results, no inflammation marker was found to predict urethral stricture recurrence. The possibility of recurrence in patients with comorbidities such as diabetes mellitus and hypertension should be taken into consideration and the patient should be informed that more curative methods may be needed.

INTRODUCTION

Urethral stricture is defined as the narrowing of the relevant segment of the urethra due to fibrosis of the urethral mucosa and surrounding spongiose tissue due to various causes[1]. The incidence is generally accepted as 229-627 per 100000. The anterior urethra is the most commonly affected part, with the bulbar urethra being the most common. Although the known causes are sexually transmitted infections, external urethral trauma, iatrogenic urethral trauma, and previous prostate surgery, inflammation also plays an important role in the etiology[2].

The underlying cause of the pathophysiology of urethral stricture is still unclear[3,4]. The most commonly proposed hypothesis is inflammation of the mucosa and submucosal connective tissue resulting in scar formation. The spogiofibrotic process is induced by inflammatory mediators. The search for a marker to predict this inflammation is ongoing but has not yet been found[5].

Internal urethrotomy under direct vision is the most common endoscopic surgical method for bulbar and short-segment urethral strictures. Urethral patency rates vary between 8% and 77% after internal urethrotomy[1]. These inadequate patency rates, i.e. high recurrence rates, significantly impair patient quality of life. Current guidelines recommend open urethroplasty if an endoscopic treatment has failed or in patients at high risk for recurrence of the stricture[6]. According to studies, patients who have undergone two or more internal urethrotomies have more complex strictures and the need for grafts for urethroplasty is higher than those who have undergone one internal urethrotomy[7].

In this study, we have aimed to investigate whether there are inflammation markers in peripheral blood that can predict urethral stricture recurrence after internal urethrotomy and whether other etiological factors have a place in predicting stricture recurrence.

MATERIALS AND METHODS

After obtaining ethical approval numbered 2011-KAEK-25/11-17 from the ethics committee of Health Sciences University Bursa Yuksek Ihtisas Training and Research Hospital, we retrospectively accessed the data of patients who underwent internal urethrotomy for urethral stricture between January 2017 and January 2023 from the hospital computer system. Patients' comorbidities [diabetes mellitus (DM), hypertension (HT), coronary artery disease, pulmonary pathologies], possible causes of stricture, stricture segment from the operative notes, estimated stricture length measured endoscopically, catheter diameter used, and catheter withdrawal day were recorded. In patients with postoperative recurrence, the time of recurrence and the number of recurrences were recorded. Having more than one comorbidity was defined as at least having 2 or more diseases, including DM and HT. Postoperative use of intravenous and/or oral non-steroidal anti-inflammatory drugs was recorded. Preoperative haemogram, neutrophil, lymphocyte, platelet, aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting blood sugar (FBSG), creatinine, and glomerular filtration rate (GFR) values from peripheral blood were also recorded. Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, lymphocyte-monocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and AST/ALT (De ritis ratio) rates were calculated.

No recurrence was defined as patients who did not develop stricture after the first internal urethrotomy throughout the follow-up period. The time to recurrence was defined as the time from the first operation to the first clinical sign of recurrence (symptoms and uroflowmetric evaluation) or the date of the next reoperation.

Patients with a history of malignancy, diseases that may affect inflammation markers and biochemical parameters (liver diseases, renal diseases, hematological diseases, etc.), and patients who had undergone open urethral surgery were excluded from the study.

Patients were divided into two groups as with and without recurrence after the first internal urethrotomy. The data were compared between the two groups.

Statistical analysis

Data were presented as mean, standard deviation, median, IQR, number, and percentage. The Kolmogorow-Smirnov test was applied to determine whether the data were suitable for normal distribution. Between the 2 groups, numerical data were compared by the Mann-Whitney U test, while non-parametric data were compared by the Chi-square test. Variables predicting recurrence were investigated by regression analysis. P < 0.05 was considered statistically significant and the SPSS 21.0 program was used.

RESULTS

After the exclusion criteria were applied, a total of 303 patients were included in the study. The mean age of the patients was 66.6 ± 13.6 years. The cause of stenosis was iatrogenic in 113 (37.2%) patients, trauma in 17 (5.7%), inflammatory in 4 (1.3%), and idiopathic in 169 (55.8%). During the follow-up period, a total of 51 (16.8%) patients developed recurrence, while 252 (83.2%) patients did not develop recurrence. The mean duration of recurrence development was 9.63 ± 9.84 (min-max: 1-39) months in patients with recurrence. Recurrence did not occur in non-recurrence group throughout the follow-up period with an average time of 44.15 ± 24.07 (min-max: 12-84) months.

The median number of recurrence was 1 (min-max 1-6) in 51 patients with recurrence. There were 36 patients with 1 recurrence, 8 patients with 2 recurrences, 2 patients with 3 recurrences, 2 patients with 4 recurrences, 2 patients with 5 recurrences, and 1 patient with 6 recurrences. In 15 patients with 2 or more recurrences, endoscopic treatment was continued because the patients did not want open surgery. When the strictures recurred during the follow-up period, 8 of these 15 patients accepted the urethroplasty option and urethroplasty was performed, 5 patients wanted to be treated with clean intermittent catheterization, and 2 patients underwent urethral stenting.

In the comparison of both groups, DM, HT, and having more than one comorbid disease was found to be statistically significantly higher in the recurrence group (P = 0.038, P = 0.012, P = 0.013). In multivariate analysis, Exp (B): 0.514 (95%CI: 0.265-0.998, P = 0.008) for HT and Exp (B): 0.625 (95%CI: 0.289-1.349, P = 0.026) for DM were found as risk factors for urethral stricture recurrence. There was no difference between the two groups in terms of blood group, post-operative non-steroidal anti-inflammatory use, pre-operative cystostomy, cause of stricture, iatrogenic cause of stricture, location of stricture, length of stricture, catheter diameter and catheter withdrawal day (Table 1).

Table 1 Comparison of demographic data between the groups, n (%).

Variables	No recurrent, n = 252	Recurrent, n = 51	P value
DM			0.038
Absence	215 (85.3)	37 (72.5)
Presence	37 (14.7)	14 (27.5)
HT			0.012
Absence	159 (63)	22 (43.1)
Presence	93 (37)	29 (56.9)
KAD			0.707
Absence	200 (79.3)	39 (76.5)
Presence	52 (20.7)	12 (23)
Lung pathologies			0.211
Absence	228 (90.4)	43 (84.3)
Presence	24 (9.6)	8 (15.7)
Comorbidity			0.013
Absence	121 (48)	15 (29.5)
One comorbidity	59 (23.4)	11 (21.5)
More than one comorbidity	72 (28.6)	25 (49)
Primary cause			0.071
Iatrogenic	87 (34.6)	26 (60)
Trauma	13 (5.1)	4 (7.9)
Post-inflamatuar	4 (1.6)	0 (0)
Idiopatic	148 (58.7)	21 (41.1)
Cause of iatrojenic			0.488
RP	12 (13.8)	5 (19.3)
RT	12 (13.8)	4 (15.3)
Others	53 (60.9)	12 (46.1)
RP+RT	10 (11.5)	5 (19.3)
Stricture localization			0.707
Penile	25 (10)	6 (11.8)
Bulbar	136 (54)	29 (56.9)
Bulbomembranous	18 (7.2)	2 (3.9)
Membranous	8 (3.1)	0 (0)
Prostatic urethra	7 (2.7)	0 (0)
Bladder neck	23 (9.1)	8 (15.6)
Panurethral	8 (3.2)	1 (2)
More than one	27 (10.7)	5 (9.8)
Postoperative NSAII administration			0.758
Absence	140 (55.5)	30 (58.8)
Presence	112 (44.5)	21 (41.2)
Preoperative cystostomy			0.764
Absence	235 (93.2)	47 (92.1)
Presence	17 (6.8)	4 (7.9)
Blood group			0.405
A+	110 (43.7)	23 (45)
A-	18 (7.1)	1 (2)
B+	22 (8.8)	3 (5.9)
B-	6 (2.3)	1 (2)
AB+	21 (8.4)	3 (5.9)
AB-	3 (1.2)	3 (5.9)
0+	66 (26.2)	16 (31.3)
0-	6 (2.3)	1 (2)
Scricture lenght			0.196
< 1 cm	76 (30.1)	9 (17.7)
1-2 cm	154 (61.1)	39 (76.4)
2-4 cm	10 (4)	2 (3.9)
> 4 cm	12 (4.8)	1 (2)
Postoperative inserted indwelling urinary catheter size			0.809
16 Fr	25 (10)	4 (7.8)
18 Fr	105(41.6)	24 (47.1)
20 Fr	122 (48.4)	23 (45.1)
Catheter removal day			0.765
< 3 d	10 (4)	2 (4)
3-5 d	61 (24.2)	10 (19.6)
> 5 d	181 (71.8)	39 (76.4)

DM: Diabetes mellitus; HT: Hypertension; CAD: Coronary artery disease; RP: Radical prostatectomy; RT: Radiotherapy; NSAII: Non-steroidal anti-inflammatory drug.

No statistically significant difference was observed between the two groups in terms of age, Q max value on uroflowmetry, haemogram parameters, AST, ALT, FBSG, creatinine, GFR, NLR, PLR, Lymphocyte monocyte ratio (LMR), MLR, and De ritis rates (Table 2).

Table 2 Comparison of data between groups.

Variables (median-IQR)	No recurrent, n = 252	Recurrent, n = 51	P value
Age (yr)	70 (62-75)	68 (61-71)	0.109
Qmax (mL/sn)	6 (4-7)	6 (3.5-8)	0.800
Hgb (g/dL)	13.8 (12.4-14.7)	13.8 (12.8-14.7)	0.987
Hct	41.7 (37.7-44.4)	41 (38.8-43.8)	0.769
Leukocyte (103/µL)	7.4 (6.2-9.3)	7.1 (6.3-8.6)	0.501
Neutrophil (103/µL)	4.7 (3.7-6)	4.5 (3.6-5.6)	0.444
Lymphocyte (103/µL)	1.9 (1.5-2.4)	1.7 (1.4-2.3)	0.558
Platelet (103/µL)	251 (207-303)	241 (214-297)	0.789
Monocyte (103/µL)	0.5 (0.4-0.6)	0.5 (0.3-0.7)	0.509
AST (U/L)	17 (14-20)	17 (13-21)	0.421
ALT (U/L)	15 (11-21)	16 (12-22)	0.467
Glucose (mg/dL)	101 (89-118)	98 (84-116)	0.369
Creatinine (mg/dL)	0.9 (0.8-1.1)	1 (0.9-1.1)	0.209
GFR (mL/mn)	82 (64-93)	80 (71-89)	0.613
NLR	2.4 (1.8-3.4)	2.3 (1.7-3.6)	0.743
PLR	126 (99-173)	131(96-183)	0.711
LMR	3.8 (2.9-4.7)	3.4 (2.4-4.8)	0.393
MLR	0.2 (0.2-0.3)	0.2 (0.2-0.4)	0.393
De ritis ratio	1 (0.8-1.4)	1 (0.8-1.2)	0.259

Qmax: Maximum flow rate; Hgb: Hemoglobin; Hct: Hematocrit; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GFR: Glomerular filtration rate; NLR: Neutrophil lymphocyte ratio; PLR: Platelet lymphocyte ratio; LMR: Lymphocyte monocyte ratio; MLR: Monocyte lymphocyte ratio.

DISCUSSION

In the management of urethral stricture, the location, length, and degree of stricture are taken into consideration. Endoscopic methods are often preferred by urologists[8,9]. Easy application, faster recovery, and being more economical can be counted among the reasons for preference. However, urethral stricture tends to recur due to the nature of the disease. In case of recurrence, more curative methods such as open urethroplasty are preferred for the benefit of the patient in appropriate patients. In our study, we investigated the usability of various data to predict urethral stricture recurrence after endoscopic intervention and found that inflammation markers have no place in the prediction of recurrence.

According to our study results, the presence of DM and HT was significantly higher in the group with recurrence of urethral stricture. This relationship may probably be attributed to the fact that these diseases develop on the background of inflammation[10,11]. From a surgical perspective, diseases such as DM and obesity are known to contribute to numerous perioperative complications, including relative vascular insufficiency, chronic low-grade inflammation, impaired collagen synthesis, and micro- and macromolecular deficiency[12]. A similar relationship is observed in patients with lichen sclerosis, which is a serious risk factor in patients with urethral stricture. These patients are more likely to have DM and HT[13,14]. In support of our study results, Breyer et al[15] found DM as a predictive factor in the development of recurrence after open urethroplasty according to multivariate analysis.

In infectious conditions developing in the body, neutrophilia or neutropenia with monocytosis and lymphopenia are expected[16]. Changes in neutrophil, lymphocyte, and monocyte ratios reflect the systemic inflammatory response. These ratios are associated with cancer-related prognosis in many cancer types[17-21]. In our study, we investigated the relationship between these rates and urethral stricture, but we did not find a relationship between inflammation markers and urethral stricture recurrence. There are studies in the literature with opposite results. Venugopalan et al[22] investigated the role of inflammation markers in the development of stricture after transurethral prostate resection surgery. According to the results, preoperative NLR and PLR were found to be statistically significantly higher in the group with stenosis compared to the group without stenosis. In a study of 512 patients, Urkmez et al[23] found that neutrophil count and neutrophil-to-lymphocyte ratio were higher in the group with recurrence than in the group without recurrence. Topaktaş et al[24] investigated whether inflammation markers can be used to predict recurrence after urethroplasty. Similar to our results, neutrophil, lymphocyte, and NLR values were similar between recurrence and non-recurrence groups in 117 patients. We think that the different results in some literature and our study may be due to patient-related factors (stricture length, degree of stricture, etc.) and different methodological designs.

The increased likelihood of recurrence in patients with multiple comorbidities is another result of our study. The literature supports this conclusion. Chapman et al[12] investigated the factors affecting the development of recurrence after urethroplasty. According to multivariate results, infectious etiology, stenosis length, increased patient comorbidity, and obesity were found to be independent predictors of recurrence. The mentioned study included patients after urethroplasty. However, it is thought that the stenosis that develops after urethroplasty develops on a similar basis as after endoscopic methods, that is, based on inflammation[25]. Therefore, although the study population is different, it supports our results in this respect.

Urethral trauma is an important factor in the development of urethral stricture[26]. A few days after transurethral surgery, isolated erythematous areas on the urethral mucosa can be visualized. In addition, leakage of urine into the subepithelial space causes increased inflammation and subsequent scar formation[27]. This process can be progressive, with urethral stenosis resulting from edema and subsequent stenosis formation leading to increased intramural voiding pressure, leading to further leakage across the mucosal barrier. Myofibroblasts are probably responsible for the formation of the stricture and giant cells may play a role in the continuation of collagen synthesis[28]. In the literature, studies are showing that the use of anti-inflammatory or steroid drugs may prevent the development and recurrence of urethral stricture. Sciarra et al[29] investigated the effect of cyclooxygenase-2 inhibitor use on the development of urethral stricture in patients undergoing transurethral prostate resection. According to the results, the Q max value of the cyclooxygenase-2 inhibitor group in the first postoperative month was significantly higher. Kurt et al[30] investigated the effect of triamnisolone and mitomycin-C on urethral stricture recurrence in 24 rabbits. As a result, decreased recurrence rates were found in both treatment groups compared to the control group. In our study, contrary to the mentioned studies, we concluded that the use of post-operative non-steroidal anti-inflammatory drugs did not affect the development of recurrence. In the European Urology Guidelines, it is emphasized that the experience of the use of anti-inflammatory drugs is limited[1]. More detailed studies are needed to address the precise pathophysiology of scar development, remodeling, and epithelialization stages to define new therapeutic targets.

One of the limitations of our study is that our study was performed in a retrospective design with a relatively small number of patients. The fact that internal urethrotomy operations were performed not by a single surgeon but by different surgeons may have caused minimal differences in the information given about the stenosis and the surgical method applied. In addition, the absence of retrograde urethrography, which would have allowed a more objective assessment of stricture, in most patients may be considered another limitation.

CONCLUSION

According to our results, no inflammation marker was found to predict urethral stricture recurrence. The possibility of recurrence in patients with comorbidities such as DM and HT should be taken into consideration and the patient should be informed that more curative methods may be needed.