Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 1 ORIGINAL PAPER 5% to 10% of the population, leading many individuals to seek medical care for stone-related problems in emer- gency and general outpatient departments. The lifetime possibility of experiencing urolithiasis is estimated to be around 13% for males and 7% for females. The incidence of urolithiasis is highest for males between the ages of 40 and 60, whereas for females, it peaks in the late 20s (1-3). A ureteric stone accounts for 20% of stones in the urinary tract, with 70% of these stones typically sit- uated in the distal part of the ureter (3). Major complaints such as urinary tract infection, vomit- ing, renal obstruction, nausea, hematuria (bloody urine), and abdominal or back pain in ureteral calculi can be noticed (4). A non-contrast computed tomography (NCCT) scan is the most preferred imaging technique for urolithi- asis diagnosis in symptomatic patients. The sensitivity and specificity of this diagnostic method were found to be approximately 100%, making it an extremely reliable diagnostic tool (4). Regarding the management of stone passage, a consider- able number of ureteral stones have the potential to pass on their own (5). Per the European Urological Association's and American Urological Association's recommendations, medical expulsive therapy (MET) is considered the primary treatment for ureteral stones measuring less than 10 mm (6). Not all patients taking MET can achieve spontaneous stone passage. The key factors influencing predictability include the stone's size and its location. As indicated by the American Urological Association, 68% of stones meas- uring less than 5 mm and 47% of stones exceeding 5 mm in size were noted to pass spontaneously (7). In cases where the stone cannot pass naturally, treatment alterna- tives such as extracorporeal shockwave lithotripsy (ESWL), ureteroscopy, and open surgery may be considered (4). Inflammatory markers are indicators of an inflammatory response in the human body. The level of inflammation can be detected by various markers, such as serum pro- calcitonin, C-reactive protein (CRP), and others (8). Elevated levels of these markers are observed in various conditions, including COVID-19, cancer, and inflamma- Introduction: In ureterolithiasis, the predic- tion of spontaneous passage poses a chal- lenge for urologists. Moreover, there is controversy surrounding the preferred management approach, whether medical or surgi- cal, as each approach has its disadvantages. Procalcitonin and other inflammatory markers were studied for predicting stone passage spontaneously, but their significance remains controver- sial. This study aims to assess the association between these markers, especially procalcitonin, and spontaneous ureteral stone passage. Materials and methods: In this multicenter prospective cohort study from March 2022 to October 2023, consecutive patients with a single unilateral distal ureteric stone less than 10 mm were enrolled. Exclusion criteria were specified. Patients under- went medical expulsive therapy (MET) and were monitored for stone passage. The significance level was set at p < 0.05. Results: Out of 94 patients enrolled, 72.3% were male and 27.7% were female, with a mean age of 38.84± 10.41 years. Stone sizes varied, with the most common range being 4 mm- 5.9 mm. Participants were categorized based on spontaneous stone passage as spontaneous stone passage (SSP) and non-SSP. No significant differences were observed in most demographic and laboratory variables. However, serum procalcitonin and C-reactive protein showed significant differences between the SSP and non-SSP groups. Conclusions: Although several inflammatory markers were stud- ied to predict the spontaneous passage of the ureteral stone, the current study concluded that only elevated procalcitonin, C-reactive protein, and large stone diameter decrease the chance of spontaneous ureteral stone passage. KEY WORDS: Nephrolithiasis; Spontaneous stone passage; Inflammatory marker; Procalcitonin level; Renal stone surgery. Submitted 1 September 2024; Accepted 9 September 2024 INTRODUCTION Nephrolithiasis is a common urinary tract disease, rank- ing third in terms of prevalence after urinary tract infec- tion and benign prostate obstruction. It affects around Role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm Ismaeel Aghaways 1, Rawa Bapir 2-4, Nabaz S. Siwaily 2, Ahmed Mohammed Abdalqadir 2, Shakhawan Hamaamin Said 1, Ayman M. Mustafa 3, Bryar Othman Muhammed 5, Hawbash M. Rahim 4, 6, Berun A. Abdalla 3, 4, Fahmi H. Kakamad 1, 3, 4, Shvan H. Mohammed 4 1 College of Medicine, University of Sulaimani, Madam Mitterrand Street, Sulaimani, Kurdistan, Iraq; 2 Department of Urology, Sulaymaniyah Surgical Teaching Hospital, Sulaymaniyah, Iraq; 3 Smart Health Tower, Madam Mitterrand Street, Sulaimani, Kurdistan, Iraq; 4 Kscien Organization, Hamdi Str, Azadi Mall, Sulaimani, Kurdistan, Iraq; 5 Smart Health Tower (Raparin Branch), Karukh Street, Ranya, Sulaymaniyah, Kurdistan, Iraq; 6 Medical Laboratory Science Department, College of Health Sciences, University of Human Development, Sulaymaniyah, Kurdistan Region, Iraq; DOI: 10.4081/aiua.2024.12997 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 I. Aghaways, R. Bapir, N.S. Siwaily, et al. 2 tory bowel disease (9). Newly conducted research has been released, demonstrating that biochemical indicators of inflammation can function as predictors for the spon- taneous passage of stones (10). The relevance of inflam- matory markers in the spontaneous passage of ureteral stones is a subject of debate among various studies (11). The current study aims to assess the association between serum procalcitonin, CRP, and other inflammatory mark- ers with the possibility of passing stones spontaneously. MATERIALS AND METHODS Study design and setting This prospective observational cohort study was conduct- ed from March 2022 to October 2023. Ethical approval was secured by the ethics committee with a degree No. 53. and both written and informed consent were obtained from each participant. Inclusion and exclusion criteria The study focused on patients aged between 18 and 64 years, including both genders. It only included patients diagnosed through a non-contrast-enhanced CT scan with single unilateral stones less than 10mm in size and located in the distal ureter below the lower border of the sacroiliac joint. Individuals with a single functioning kidney, more than 1 stone in the same ureter, bilateral ureteric and/or concur- rent renal stones, severe hydronephrosis [defined as Grade 4 hydronephrosis based on the Onen classification system- which characterizes severe hydronephrosis as greater than 50% loss of renal parenchyma or a cyst-like kidney with no significant visible renal parenchyma (12)], impaired renal function, congenital or acquired anatomical anomaly of the urinary tract, pregnant patients, history of ureteral stenosis or reconstructive ureteral surgery, previous intervention for a stone or any other operation (within 2 months of inclusion in the study), or individuals who had ESWL and stent or nephrostomy insertion for a stone in the same ureter were not included. Furthermore, exclusion criteria were patients with dia- betes, thyroid or hepatic disease, active malignancy, active inflammatory bowel disease, active infectious dis- ease, immunological diseases, active chronic inflammato- ry disease, or patients who used antibiotic, steroid, NSAIDS, or immune suppressant medicines (within 2 weeks of inclusion in the study) or patients with docu- mented infection clinically (fever > 38) or via investiga- tions (positive urine culture) or patients who were also unable to comply with MET or had contraindications to MET therapy or side effects of the medications or patients who preferred immediate active treatment of stones, or who were lost follow-up during the study. Sample and data collection Upon admission and throughout the acute phase, demo- graphic information such as age, gender, body weight, and height were obtained from all patients. This information was obtained as part of the initial assessment to character- ize the study population. Body mass index (BMI) was com- puted as the ratio of height in meter square to weight in kilogram and expressed as kg/m2. A medical history and thorough physical examination were conducted on each participant to assess their overall health and identify any clinical signs. As part of the initial assessment, inflamma- tory markers were measured, including complete blood count (white blood cells (WBCs), neutrophils (NCs), lym- phocytes, neutrophil-to-lymphocyte ratio (NLR), platelet-to- lymphocyte ratio (PLR), serum procalcitonin, C-reactive protein, and serum creatinine to evaluate disease severity. All patients underwent NCCT scans of the kidney, ureter, and bladder. Axial NCCT images with a slice thickness of 5 mm were obtained, utilizing specific imaging parame- ters such as a soft-tissue window with a width of 360, a pitch of 1.5, a tube voltage of 120 kV, and a tube current ranging from 70 to 90 mAs. Radiological findings includ- ed a detailed analysis of stone characteristics, determining stone side (right versus left), site (proximal, mid, and dis- tal), size (defined by the stone’s greatest diameter), and density measured in Hounsfield units. In terms of hydronephrosis grading, the study utilized the Onen clas- sification system. This system categorized grades 0 and 1 as indicating no-to-mild hydronephrosis. Conversely, grades 2, 3, and 4 were grouped to represent moderate- to-severe hydronephrosis. This classification allowed for a concise and clinically relevant assessment of the degree of hydronephrosis in the study population, providing a more detailed analysis of renal conditions and their impli- cations (12). Concerning the anatomical position, the dis- tal ureter was specified as the segment extending from the lower boundary of the sacroiliac joint to the bladder. Stone size calculations were performed using both coro- nal and axial images obtained through cross-sectional imaging. Finally, all the obtained data were recorded for further analysis. Follow-up Patients without indications for interventional treatment underwent observation and MET, which involved a pre- scription of diclofenac sodium (75 mg/day) and tamsu- losin (0.4 mg/day) for four weeks, along with a recom- mended daily fluid intake of 2-3 liters. Those on MET attended weekly outpatient controls, excluding emergen- cies. During these visits, patients were asked about the stone passage and any renal colic incidents. For those unable to pass the stone, confirmation was sought through ultrasound/plain kidney-ureter-bladder at weeks one, two, and three, and at the fourth week using non- contrast abdominal CT. Individuals failing to pass the stone were categorized as passage negative (NO SSP), while those successful were grouped as passage positive (SSP). Failure of passage was defined as the stone's pres- ence on NCCT after four weeks or urgent intervention within the period due to stone-related complications, such as drainage, shockwave lithotripsy, or ureteroscopy (URS). Inflammatory markers were not reassessed during the follow-up period; instead, the follow-up focused on monitoring stone passage and patient progress. Statistical analysis The acquired data were analyzed via Statistical Package for the Social Sciences software 25.0. Quantitative variables were analyzed by using an independent sample t-test and Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 3 Role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm chi-square; additionally, these data were presented in the form of means and standard deviations. Qualitative data were presented as proportions and percentages. In this study, a p-value of < 0.05 was considered significant. RESULTS Demographic characteristics Of the total patients enrolled in this study (n = 94), 68 (72.3%) were male and 26 (27.7%) were female. They had a mean age of 38.84 ± 10.41 years (19-64 years), with the majority of the patients (33%) being between 29 and 38 years old. The mean BMI of the participants was 26.3 ± 4.638, with the majority of participants falling within the normal range (18.5-24.9). Stone sizes were further classified into different classes; the most common stone size falls within the 4 mm-5.9 mm range, compris- ing the largest percentage of the sample (39.36%). Further characteristics of the enrolled participants are given in Table 1. Clinical characteristics and statistical analysis The individuals enrolled in this study were divided into two main groups depending on whether they experienced spontaneous passage of stones or non-spontaneous pas- sage of stones, with a mean age of 39.4 ± 10.8 and 37.78 ± 9.73, respectively. The mean stone size ± SD in SSP was 5.41 ± 1.6, while the size of the stone in non-SSP was 6.37 ± 1.76. Inflammatory markers are regarded as predictive factors for the evaluation of spontaneous stone passage. In this study, several demographics, laboratory, and radiological vari- ables were analyzed to investigate their association with spontaneous stone passage. No statistically significant dif- ferences among several variables between the NO SSP and SSP groups were found, includ- ing age, BMI, side (right or left) of the kidney stone, serum creatinine, PLR, white blood cells, granulocytes, and platelets. Regarding the association between inflam- matory markers and the possibility of stone passage spontaneously, a high statistically significant difference in serum procalcitonin levels was found between the NO SSP and SSP groups (p < 0.001), with the mean of procalcitonin being higher (0.14 ± 0.089) among the NO SSP groups compared to the SSP group (0.05 ± 0.027). CRP, as another inflammatory marker, was found to have sta- tistical significance between the NO SSP and SSP groups (p < 0.001), with the mean of CRP being lower among the SSP group (5.55 ± 5.06) compared to the NO SSP group (12.63 ± 11.03). Additionally, NLR and lym- phocytes were found to have statistical sig- nificance difference between the NO SSP and SSP groups with a p-value of (0.032, and 0.032), respectively (Table 2). Accordingly, the size of the stone also showed a statistically significant difference between the NO SSP and SSP groups (p-value = 0.009), with the mean stone size being higher among the NO SSP group (6.37 ± 1.76) compared to the SSP group (5.41 ± 1.6). Which indicated that larger stone sizes have less possibility of passing spontaneously. Additionally, stone sizes were grouped into 2 major groups and analyzed Table 1. Baseline characteristics. Variables Frequency Percentage (%) Gender Male 68 72.3 Female 26 27.7 Age 19-28 17 18.1 29-38 31 33 38-47 27 28.7 Above 47 19 20.2 Stone Size (Longest Diameter) 2 mm-3.9 mm 13 13.82 4 mm-5.9 mm 37 39.36 6 mm-7.9 mm 28 29.8 8 mm-9.9 mm 16 17.02 Side Right 48 51.06 Left 46 48.94 BMI < 18.5 3 3.2 18.5-24.9 33 35.1 25-29.9 41 43.6 > 30 17 18.1 Hydronephrosis grade Mild 68 72.3 Moderate 26 27.7 Table 2. Analyzing demographic, laboratory, and radiological variables for predicting passage of stones spontaneously. Variable Total NO SSP SSP P-value Age (Mean ± SD) 38.84 ± 10.41 37.78 ± 9.73 39.4 ± 10.8 0.474 Gender Male (n, %) 68 (72.3%) 19 (61.2%) 49 (77.8%) 0.018 Female (n, %) 26 (27.7%) 12 (38.7%) 14 (22.2%) BMI (Mean ± SD) 26.3 ± 4.638 26.05 ± 4.38 26.44 ± 4.8 0.695 Side Right (n, %) 48 (51.06%) 16 (48.48%) 32 (52.46%) 0.717 Left (n, %) 46 (48.94%) 17 (51.52%) 29 (47.54%) Size (Mean ± SD) 5.7 ± 1.7 6.37 ± 1.76 5.41 ± 1.6 0.009 Serum procalcitonin (Mean ± SD) 0.083 ± 0.072 0.14 ± 0.089 0.05 ± 0.027 < 0.001 CRP (Mean ± SD) 8.04 ± 8.36 12.63 ± 11.03 5.55 ± 5.06 < 0.001 Serum creatinine (Mean ± SD) 0.88 ± 0.22 0.92 ± 0.21 0.86 ± 0.22 0.197 NLR (Mean ± SD) 3.39 ± 2.186 2.74 ± 1.61 3.75 ± 2.37 0.032 PLR (Mean ± SD) 126.62 ± 86.66 112.78 ± 86.78 134.1 ± 86.38 0.257 White blood cells (Mean ± SD) 9.73 ± 2.9 9.01 ± 2.77 10.12 ± 2.92 0.078 Hydronephrosis grade Mild (n, %) 68 (72.3%) 19 (57.6%) 49 (80.3%) 0.018 Moderate (n, %) 26 (27.7%) 14 (42.4%) 12 (19.7%) Size group (n, %) < 6 mm 62 (65.96%) 17 (51.5%) 45 (73.77%) 0.022 > 6 mm 32 (34.04%) 16 (48.5%) 16 (26.23%) Granulocyte (Mean ± SD) 7.68 ± 2.51 7.26 ± 2.45 7.91 ± 2.53 0.233 Lymphocyte (Mean ± SD) 3.16 ± 3.38 4.17 ± 5.38 2.61 ± 1.20 0.032 Platelets (Mean ± SD) 276.21 ± 73.12 275.5 ± 71.3 276.59 ± 74.67 0.946 Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 I. Aghaways, R. Bapir, N.S. Siwaily, et al. 4 statistically to demonstrate their association with stone passage; a statistically significant difference was also found (p-value = 0.022). Hydronephrosis grade was determined for all the patients and further classified into mild and moderate to determine its association with the spontaneous passage of stones. This variable was also found statistically significant (p-value = 0.018). Another factor that should be taken into account in this study is the significant difference in gender distribution between the NO SSP and SSP groups (p = 0.018). The SSP group had a higher percentage of males (77.8%) (Table 2). Regarding the association between procalcitonin level at admission with the weeks of stone passage and hydronephrosis grade, it was found that procalcitonin levels vary significantly across different weeks of stone passage (p < 0.001). Procalcitonin levels were lowest at Week 0 (0.021 ± 0.002) and increased progressively in subsequent weeks: Week 1 (0.038 ± 0.016), Week 2 (0.049 ± 0.022), Week 3 (0.077 ± 0.013), and Week 4 (0.084 ± 0.059). However, no significant difference in procalcitonin levels between different hydronephrosis grades was found (p = 0.093) (Table 3). Receiver operating characteristic (ROC) for the association between procalcitonin and stone passage showed an area of 0.925 (%95 C.I. 0.866-0.984) with a cut-off value of 0.076, a sensitivity of 82%, a specificity of 88%, and a p-value < 0.001 (Figure 1) (Table 4). DISCUSSION Nephrolithiasis is a commonly occurring urinary tract condition, which is the third most prevalent disease after infections in the urinary tract and benign obstruction in the prostate (1). Various therapeutic approaches and treatment methods exist for the management of stones in the ureter, depending on factors such as the size of the stone, location, composition, and clinical aspects (11). These treatment options range from conservative treat- ment or non-surgical treatment (with analgesics with or without MET to assist spontaneous stone passage) to invasive treatments such as ESWL and ureteroscopy (URS-L) (flexible or semi-rigid) (6, 13, 14). Medical treat- ment is considered cost-effective, alleviating the need for surgical procedures and leading to minimal complica- tions. Potential disadvantages of MET may include recur- ring colic and urinary tract infections (11). Conversely, invasive procedures lead to a safer and more efficient stone removal rate, with a higher cost compared to med- ical treatment. Furthermore, potential complications in the urinary system, such as the formation of hematomas, urinary infections, and urinary extravasation, should be taken into account as adverse effects of this treatment approach (15). The success of ESWL and URS-L treatments depends on the stone's location and size, with reported success rates ranging from 68% to 90% for ESWL and 80% to 97% for URS-L (6). Likewise, delaying surgical intervention until medical therapy fails can be stressful for the patient and increase treatment costs compared to the immediate sur- gical removal of a stone (11). These controversies about choosing the management method have led many researchers to study inflammatory markers. These mark- ers can help clinicians decide on the most effective treat- ment method for patients. Medical expulsive therapy (MET) involves the administra- tion of medications to facilitate the expulsion of ureteric stones. Various drugs, including alpha-blockers, calcium channels blockers, corticosteroids, and phosphodi- esterase-5 inhibitors, have undergone thorough examina- tion. Recent guidelines recommend alpha-blockers as an effective standalone therapy for the medical removal of stones in the ureter. On the other hand, there isn't enough evidence to consider other drugs mentioned as Table 3. Association between procalcitonin level at admission and weeks of stone passage and Hydronephrosis grade. Parameters Procalcitonin level P value Week of stone passage (Mean ± SD) Week 0 0.021 ± 0.002 < 0.001 Week 1 0.038 ± 0.016 Week 2 0.049 ± 0.022 Week 3 0.077 ± 0.013 Week 4 0.084 ± 0.059 Hydronephrosis grade (Mean ± SD) Mild 0.075 ± 0.07 0.093 Moderate 0.103 ± 0.077 Table 4. Receiver operating characteristic (ROC) for the association between procalcitonin and stone passage. Parameters Area 95% confidence Cut off P-value under curve interval value Procalcitonin 0.925 0.866-0.984 0.076 < 0.001 ROC Sensitivity 82% Specificity 87.9% Figure 1. Receiver operator curve analysis for Association between serum procalcitonin and stone passage. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 5 Role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm standalone therapies (14). According to the recent guide- lines from the European Association of Urology (EAU), for distal ureteric stones larger than 5 mm, alpha-blockers are recommended as MET (15, 16). Most studies in the literature assess MET outcomes over a four-week dura- tion, and there is no data available to support other time intervals currently. In the present study, patients were given diclofenac sodium (75 mg/day,) as an analgesic to reduce pain and tamsulosin (0.4 mg/day) for four weeks, along with a daily fluid intake of 2-3 liters. The possibility of passing ureteral stones naturally is highly influenced by two crucial factors, its size and loca- tion. The relationship between stone size and spontaneous stone passage (SSP) is inversely proportional. Stones meas- uring less than 5 mm have a 75% chance of passing nat- urally, with the possibility of passage decreasing as the size increases. For ureteral stones between 5 and 10 mm, the chance of spontaneous passage ranges from 25 to 46%. Additionally, it has been reported that for stones less than 4mm, there is a 95% possibility of spontaneous passage within 40 days (1, 11, 17). The European Association of Urology and American Urological Association (EAU/AUA) panel examined spontaneous passage rates through a recent meta-analysis, revealing rates of 68% for stones smaller than 5 mm and 48% for stones ranging from 5 to 10 mm (18). One study by Demehri et al. clas- sified patients into 3 groups based on stone sizes, groups were less than or equal to 5 mm, between 5 and 10 mm, and greater than 10 mm. A spontaneous passage rate of 92% for stones less than 5 mm and 9.1% for stones larg- er than 10 mm was observed (19). The current study revealed an overall SSP rate of 67%; additionally, the mean size of the stone was 5.41 ± 1.6 among SSP groups and 6.37 ± 1.76 among NO SSP groups, with a p-value of 0.009, which indicates a statistically significant difference between the two groups in terms of stone size. Likewise, patients in this study were classified into two groups based on stone size, and statistical analysis showed a p- value of 0.022 with the highest rate of SSP (73.77%) for stones less than 6mm. Several studies have consistently demonstrated that demographic characteristics do not exert a significant influence on the probability of ureteral stones passage spontaneously. A study conducted by Mohammad et al. involving 73 patients with distal ureteric stones sized 4-8 mm revealed no significant difference in age, BMI, or gen- der between the SSP and non-SSP groups statistically (3). In another study, which was conducted on 54 patients with single ureteral stones, no significant difference was found in demographic characteristics between the SSP and NO SSP groups (1). However, according to a study conducted by Puntub et al., which included 139 patients with ureteral stones < 10 mm, demographic characteris- tics such as age and gender showed statistically significant differences between the SSP and NO SSP groups. The study found that individuals with SSP had a mean age of 44.53 years, while those with NO SSP had an average age of 52.62 years. The study also observed that males had a better chance of SSP than females. The statistical analysis showed a significant relationship between age, gender and stone passage with a p-value of 0.003 and 0.031, respectively (4). In the present study, considering various demographic characteristics, only gender exhibited a sta- tistically significant difference between the SSP and non- SSP groups. The incidence of SSP was significantly high- er among males (77.8%) compared to females (22.2%), and this was found to be statistically significant with a p- value of 0.018. Regarding the side of the stone, in one study by Jain et al. conducted on 185 patients with stones in the ureter, the side of the stone showed no significant difference among the SSP and NO SPP groups (20). In another study in which 156 patients enrolled, the side of the stone showed no statistically significant difference among the SSP and NO SSP groups with a p-value of 0.1 (7). In this study, statistical analysis showed no significant difference in the spontaneous passage of ureteral stones between left- and right-sided stones with a p-value of 0.717. Regarding the association between inflammatory markers and ureteral stone passage, several inflammatory markers have been studied. In a study involving 156 patients con- ducted by Sfoungaristos et al., elevated levels of WBCs and NC during the acute phase of renal colic were linked to an elevated possibility of ureteral stones passing sponta- neously (7). Likewise, in another study by Özcan et al., which was conducted on 251 renal colic patients, statis- tical analysis showed a significant difference in WBCs and neutrophils among groups that pass their stones sponta- neously and those that do not pass their stones, with the level being higher among NO SSP groups compared to SSP groups (21). In another study, which was performed on 192 patients, WBCs and NCs were decreased among SSP groups compared to NO SSP groups, with a p-value of 0.0005 for both markers (14). Additionally, in a study by Park et al., in which a total of 182 patients were enrolled, it was reported that an elevated level of NC per- centage leads to a spontaneous decrease in the rate of ureteral stone passage (22). A possible causation for this finding is that ureteral stone presence leads to swelling of the ureteral mucosa, ultimately resulting in obstruction. These interactions may contribute to increased inflamma- tory reactions and an elevated percentage of neutrophils and white blood cells (4). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to- lymphocyte ratio (PLR) are other markers that can be used as predictors of ureteral stone passage. Different studies suggested that elevated NLR and PLR are associated with a decreased possibility of spontaneous ureteral stone pas- sage. Statistical analysis showed that there is an inverse relationship between NLR and PLR levels and the sponta- neous passage of ureteral stones, as indicated by a p-value of less than 0.005 in various studies (5, 8, 11, 23). However, in contrast to the above-mentioned studies, according to a study by Ahmed et al., which was performed on 163 patients for spontaneous passage prediction of stones less than 10 mm, it was reported that serum WBCs did not show a significant difference between SSP and non-SSP groups (12). Likewise, in a retrospective study performed on 279 patients, it was found that inflammato- ry markers, particularly WBCs, NC, and NLR, do not serve as meaningful parameters for passage prediction of ureteral stones as they did not show any difference between both groups significantly (24). Additionally, in a prospective study that was performed Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 I. Aghaways, R. Bapir, N.S. Siwaily, et al. 6 to find the relationship between stone passage and inflammatory markers, in which 139 patients were enrolled, it was concluded that both WBCs and NCs did not play a role in predicting the passage of stones sponta- neously, with a p-value of 0.97 and 0.58, respectively (4). The current study findings are in contrast with these studies. We observed elevated NLR and decreased lym- phocyte count among patients who pass their stones spon- taneously (SSP), with mean values of 3.75 ± 2.37 and 2.61 ± 1.20, respectively, compared to NO SSP groups with mean values of 2.74 ± 1.61 and 4.17 ± 5.38, respective- ly. The statistical analysis of both variables showed a p- value of 0.032. Additionally, the current study findings did not show any statistically significant differences in WBCs, PLR, NCs, and platelets among the SSP and NO SSP groups. Another inflammatory parameter that serves as a mean- ingful parameter for predicting ureteral stone passage is CRP, which is primarily produced by the liver in response to tissue damage and serves as a sensitive indicator of inflammation (25). Previous studies have established associations between CRP and various inflammatory con- ditions, including diabetic nephropathy (26), subacute thyroiditis (27), and hepatitis (28). In numerous studies, the serum CRP level appeared as a significant predictor for the spontaneous passage of ureteral stones. These studies consistently observed a significant elevation in serum CRP levels among patients who did not experience spontaneous ureteral stone passage (2-4, 20-22). One potential explanation of the mentioned results could be that the rise in these levels reflects the extent of inflam- mation induced in the ureteral mucosa as a stone passes through. This is supported by the observation that the interaction between the mucosa of the ureter and the stone leads to inflammation at the site where the stone is located (29). However, in contrast to these findings, a study conduct- ed by Hassan et al., in which 195 patients were enrolled, reported that the spontaneous passage rate of ureteral stones among individuals with high CRP levels was high- er, with a statistically significant p-value of less than 0.05 (30). The current study reported that CRP is a strong inflammatory marker to predict spontaneous passage of ureteral stones, with the level being elevated among those who did not pass their stones spontaneously (12.63 ± 11.03), compared to SSP groups (5.55 ± 5.06) with a p-value of < 0.001. Apart from stone size, location, WBC indices, and CRP, to our knowledge, there are limited studies in genuine lit- erature that examine the effects of procalcitonin on stone passage (31). Procalcitonin is a peptide composed of 116 amino acids, possessing a molecular weight of approxi- mately 13 kilodaltons. Ghillani et al. initially characterized this hormone in 1989 as a precursor to calcitonin, a thy- roid gland-produced hormone consisting of 32 amino acids (32). The normal range for procalcitonin in the gen- eral population is recognized as being below 0.05 ng/mL. During systemic infections, it may elevate to levels of 2 ng/mL, and in cases of sepsis, it can reach levels higher than 10 ng/mL (33). Likewise, procalcitonin has been identified as useful in establishing a relationship between infections in the urinary tract and obstructed ureteral stones. According to Papa Giannopoulos et al., they found that procalcitonin levels exceeding 100 pg/ml (0.1 ng/ml) were observed in 18% of patients treated with medical expulsive therapy (MET), 45% of those had undergone procedures such as ureteroscopy with laser lithotripsy (URS- L) or the placement of a ureteral stent (34). In a study conducted by Cilesiz et al. to examine the role of procal- citonin in predicting the possibility of spontaneous pas- sage of ureteral stones, in which 54 patients were enrolled, it was reported that the procalcitonin levels were significantly elevated in groups that did not experi- ence spontaneous stone passage (0.207 ± 0.145 ng/ml) compared to those with successful spontaneous stone passage (0.133 ± 0.028 ng/ml) with a p-value of < 0.001 (1). In the current study, in which 94 patients were involved, it was found that procalcitonin levels were sig- nificantly higher among groups failing to pass their stones spontaneously (0.14 ± 0.089) compared to those who passed their stones spontaneously (0.05 ± 0.027), with a p-value of < 0.001. In this study, the determined cutoff value for procalcitonin in predicting stone passage was established at 0.076 ng/ml with an AUC of 0.925, a sen- sitivity of 82%, and a specificity of 88% (95% CI 0.866- 0.984). The possible explanation for elevated procalci- tonin among NO SSP groups is linked to an excess of mucosal inflammation. This excess mucosal inflamma- tion might have increased the possibility of stone impaction in the future, making their passage more chal- lenging (1). In this study, the association between procal- citonin levels and weeks of passage among SSP groups was examined at the time. Patients were classified based on weeks of stone passage into five groups. Statistical analysis showed that procalcitonin levels vary significant- ly across different weeks of stone passage (p < 0.001). Procalcitonin levels are lowest at Week 0 (0.021 ± 0.002) and increase progressively in subsequent weeks: Week 1 (0.038 ± 0.016), Week 2 (0.049 ± 0.022), Week 3 (0.077 ± 0.013), and Week 4 (0.084 ± 0.059). The association between stone passage and hydronephro- sis grade is a subject of controversy, yet individuals with no or mild hydronephrosis were more likely to pass their stones spontaneously than those with moderate hydronephrosis, according to a study conducted on 163 patients (13). In contrast, in a study by Jendeberg et al., which was performed on 392 patients retrospectively, it was reported that stones inducing moderate to significant hydronephrosis exhibited a greater likelihood of sponta- neous passage compared to stones causing either no hydronephrosis or only mild hydronephrosis, with a p- value of 0.002 (35). In the present study, hydronephrosis grade was significantly different among SSP and NO SSP groups. Statistical analysis showed an increased chance of SSP when dealing with mild hydronephrosis (80.3%) compared to moderate hydronephrosis (19.7%), with a p-value of 0.018. A notable limitation of this study is that we did not assess the time length from the onset of symptoms to the first admission. Consequently, we did not analyze how this time interval might relate to inflammatory markers. Future research should consider evaluating this aspect to provide further insights into the progression of inflam- mation and its impact on inflammatory indexes. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12997 7 Role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm CONCLUSIONS The findings suggest that elevated levels of procalcitonin may be a contributing factor in complicating the stone's passage and lengthening the duration of the stone passage. Likewise, elevated CRP and larger stones were found to decrease the chance of SSP. The validity and confirmation of the current findings require further studies. REFERENCES 1. Çilesiz NC, Arslan B, Balcı MB, et al. 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Size matters: The width and location of a ureteral stone accurately predict the chance of spontaneous passage. Eur Radiol. 2017; 27:4775-85. Correspondence Ismaeel Aghaways ismaeelagha@hotmail.com Shakhawan Hamaamin Said shakhwan.said@gmail.com College of Medicine, University of Sulaimani, Madam Mitterrand Street, Sulaimani, Kurdistan, Iraq Rawa Bapir Dr.rawa@yahoo.com Nabaz S. Siwaily nabaz@gmail.com Ahmed Mohammed Abdalqadir ahmed.abdalqadir@gmail.com Department of Urology, Sulaymaniyah Surgical Teaching Hospital, Sulaymaniyah, Iraq Ayman M. Mustafa aymanmajid75@gmail.com Berun A. Abdalla berun.anwer95@gmail.com Smart Health Tower, Madam Mitterrand Street, Sulaimani, Kurdistan, Iraq Bryar Othman Muhammed muhammed.ali@gmail.com Smart Health Tower/Raparin, Madam Mitterrand Street, Sulaimani, Kurdistan, Iraq Hawbash M. Rahim hawbash.mhamad96@gmail.com Shvan H. Mohammed shvanh80@gmail.com Kscien Organization, Hamdi Str, Azadi Mall, Sulaimani, Kurdistan, Iraq Fahmi Hussein Kakamad (Corresponding Author) fahmi.hussein@univsul.edu.iq Doctor City, Building 11, Apartment 50, Sulaimani, Kurdistan, Iraq Conflict of interest: The authors declare no potential conflict of interest.