The Significance of Stone Culture in the Incidence of Sepsis: Results from a Prospective,Multicenter Study on Infections Post Flexible UreteroreNescopy (I-FUN) and Laser Lithotripsy for Renal Stones

Abstract

Objective:

Sepsis is the most serious complication of flexible ureteroscopy (F-URS) and laser lithotripsy. We assessed the influence of positive stone culture (SC) on major infectious complications (sepsis, septic shock).

Methods:

This prospective study enrolled adult patients deemed suitable for F-URS and laser lithotripsy from nine centers (January 2022–August 2023). Inclusion criteria were as follows: kidney stone(s), preoperative midstream urine culture (MSUC), stone(s) assessed at computed tomography scan, and SC. Exclusion criteria were as follows: bilateral procedures, ureteral stones, and children. Group 1 included patients with sterile SC. Group 2 included patients with positive SC. Data are presented as median (interquartile range). A multivariable logistic regression analysis was performed to evaluate factors associated with having a positive SC.

Results:

In total, 293 patients were included. Median age was 51.0 (24) years. There were 167 (57.0%) males. Group 2 included 32 (2.5%) patients. Group 2 patients were significantly older [75.0 (14) vs 51.0 (23) years, p = 0.02]. Stone features were similar. Major infectious complications were higher in Group 2 (15.6% vs 0.4%). One patient died because of sepsis in Group 2. Two out of 6 (33.3%) patients with major infectious complications had the same pathogen in MSUC and SC. In the multivariable regression analysis, diabetes (OR 3.23), symptomatic urinary infections within 3 months before operation (OR 4.82) and preoperative stent/nephrostomy (OR 2.92) were factors significantly associated with higher odds of positive SC.

Conclusions:

Patients with positive SC have a higher incidence of major infectious complications after F-URS lithotripsy. SC should be performed whenever feasible because there is a poor correlation between MSUC and SC.

Introduction

Flexible ureteroscopy (F-URS) with laser lithotripsy has gained popularity in the treatment of kidney stones worldwide,¹ being among the first-line options for stones up to 2 cm in diameter.^2,3 By virtue of technological advancements, the utilization of F-URS is gaining momentum as a choice even for large stone burden.⁴ However, F-URS is not devoid of serious complications such as sepsis, septic shock, and even sepsis-related death.^5
–7 The sepsis rate varies in the literature between 0.5% and 11.1%, whereas the rate of septic shock ranges from 0.3% to 4.6%.⁶

It is common practice to obtain a preoperative midstream urine culture (MSUC) before any stone surgical intervention and adequately treat preoperative infections if present. Nevertheless, MSUC is a poor predictor for major postoperative infectious complications after both ureteral and percutaneous lithotripsy.⁸ To the best of our knowledge, there is only one prospective study assessing the correlation between stone culture (SC) and sepsis and this included a series of patients undergoing either percutaneous or ureteral lithotripsy.⁹

This study aimed to evaluate the influence of a positive SC obtained by laser lithotripsy during F-URS for kidney stones on the occurrence of postoperative sepsis. The secondary outcome was to assess predictors of having a positive SC.

Materials and Methods

Study design

All consecutive patients with renal stone(s) scheduled for F-URS and laser lithotripsy were prospectively assessed from January 2022 to August 2023 and eventually included in the study across nine centers. Inclusion criteria were ≥18 years of age, renal stone(s) judged suitable for F-URS by the treating physician, a computed tomography (CT) scan performed within 3 months of operation, an MSUC performed within 10 days of operation, and an SC collected during operation. Exclusion criteria were concomitant ureteral stone, bilateral procedures, unavailable preoperative CT scan, MSUC, and SC.

We collected the following data: gender, age, comorbidity, body mass index, American Society of Anesthesiology score, age-adjusted Charlson comorbidity index, presence of symptomatic urinary infections 3 months before operation, stone features at CT scan (i.e., stone size and location, Hounsfield units), presence of indwelling catheters at surgery (i.e., ureteral stent, nephrostomy, urethral, suprapubic), previous stone operation on the affected kidney, and MSUC. Stone volume was assessed at CT scan by measuring the stone diameter in three axes and using the ellipsoid formula (length × width × depth × π × 0.167).²

In instances of symptomatic infection or asymptomatic bacteriuria detected during preoperative MSUC, patients received a 6-day course of antibiotics based on susceptibility profiles. There was no repetition of MSUC before the surgical procedure. Intraoperative and perioperative data were also gathered: use and size of ureteral access sheath, type of irrigation, lasing and total surgical time (from cystoscopy to bladder catheter positioning), exit strategy, SC results, and postoperative complications. Antiplatelets/anticoagulants were discontinued 3–7 days before operation as per practices followed at each center. The SC was conducted by crushing the largest stone fragments in saline with a sterile mortar and pestle and subsequently streaking it on agar plates.¹⁰ Bacterial growth on the agar plates was then examined after 24 to 48 hours.

Complications were characterized as any adverse event occurring within the first 30 days postprocedure, and their severity was assessed based on the Clavien classification system. Infectious complications were divided into minor (steadily or intermittently 38°C body temperature for a minimum of 24 hours) and major (sepsis, septic shock, and death related to sepsis). The definitions of sepsis and septic shock adhered to the guidelines outlined in the Third International Consensus Definitions (sepsis-3) by the presence of at least two clinical criteria that constitute the quick Sequential Organ Failure Assessment (SOFA) score.¹¹

The study was approved by the ethical board of the leading center (Comitato Etico Regione Marche, #378/2021) and other centers obtained approval from their institutional review board. All patients signed an informed consent form.

Surgical procedure

All patients received antibiotic prophylaxis 30 minutes before anesthesia with II- to III-generation cephalosporins, penicillin, or aminoglycosides, guided by local guidelines and resistance patterns. There were no specific criteria for performing F-URS, and the operation adhered to the standard of care and surgical practices of each participant center. Laser lithotripsy was performed using either holmium or Thulium fiber laser, depending on the availability and preference of each center.

Statistical analysis

Patients were divided into two groups according to the growth of pathogens at SC. Group 1 included patients with sterile culture, whereas Group 2 included patients who had a positive SC.

Continuous variables are presented as median (interquartile range). Categorical variables are reported as absolute frequency and percentage. Chi-square test was employed to evaluate differences in categorical variables between the two groups. Mann–Whitney U-test was used for continuous variables. A multivariable logistic regression analysis was performed to evaluate factors associated with having a positive SC. Variables that have been suggested in previous literature to impact sepsis after F-URS were entered into the model to assess their significance as independent predictors.^6,8 Data are presented as odds ratio (OR), 95% confidence interval (CI), and p-value. Statistical significance was set at a two-tailed p-value <0.05. All statistical tests were conducted using SPSS software package version 25.0 (IBM Corp., Armonk, NY).

Results

During the study period, 737 patients underwent F-URS and laser lithotripsy for kidney stone(s) only. SC was not performed in 444 patients, leaving 293 for the analysis. Table 1 shows patient baseline characteristics. Median age was 51.0 (24) years. There were 167 (57.0%) males. Among the included patients, 32 (2.5%) had a positive SC (Group 2). Group 2 patients were significantly older [median age 75.0 (14) years] than Group 1 patients [median age 51.0 (23) years, p = 0.02]. There was a significantly higher proportion of diabetic, ischemic heart disease, and hypertension patients in Group 2. Median age-adjusted Charlson comorbidity index was significantly higher in Group 2 [4 (3) vs 1 (2), p = 0.002]. There was also a significantly higher proportion of patients having a nephrostomy tube/ureteral stent in Group 2 (75.1%) compared to Group 1 (48.7%, p = 0.003). There was a significantly higher proportion of patients having symptomatic urine infections within 3 months before operation in Group 2 (40.6% vs 10.3%, p ≤ 0.001). Overall, 65 (69.9%) patients had a positive MSUC, and Escherichia coli was the most common isolated pathogen (Table 2). There was a significantly higher proportion of patients having asymptomatic bacteriuria or symptomatic infection at preoperative MSUC in Group 2 (p = 0.025).

Table 1.

Patient Baseline Characteristics

	Overall population (n = 293)	Negative stone culture (n = 261)	Positive stone culture (n = 32)	p value
Age, years, median (IQR)	51.0 (24)	51.0 (23)	75.0 (14)	0.001
Gender				0.22
Male, n (%)	167 (57.0)	152 (58.2)	15 (46.9)
Female, n (%)	126 (43.0)	109 (41.8)	17 (53.1)
BMI, median (IQR)	26.8 (5)	26.4 (15.8)	26.3 (6.4)	0.875
Age-adjusted Charlson comorbidity index, median (IQR)	1 (2)	1 (2)	4 (3)	0.008
Motility, n (%)				0.496
Normal	282 (96.2)	250 (95.8)	32 (100)
Wheelchair bound	9 (3.1)	9 (3.4)	0
Bed bound	2 (0.7)	2 (0.8)	0
Neurogenic bladder, n (%)	7 (2.4)	7 (2.7)	0	0.348
Multiple sclerosis, n (%)	3 (0.9)	3 (1.5)	0	0.542
Ischemic heart disease, n (%)	20 (6.8)	12 (4.6)	8 (25.0)	<0.001
Hypertension, n (%)	98 (33.4)	78 (29.9)	20 (62.5)	<0.001
COPD, n (%)	11 (3.8)	8 (3.1)	3 (9.4)	0.076
Indwelling bladder catheter, n (%)				0.900
Urethral	12 (4.1)	11 (4.2)	1 (3.1)
Suprapubic	1 (0.3)	1 (0.4)	0
Diabetes, n (%)				0.002
Type 1	7 (2.4)	5 (1.9)	2 (6.3)
Type 2	29 (9.9)	21 (8.0)	8 (25.0)
ASA score, n (%)				0.013
1	88 (30.0)	86 (33.0)	2 (6.3)
2	143 (48.8)	124 (47.5)	19 (59.3)
3	58 (19.8)	48 (18.4)	10 (31.3)
4	4 (1.4)	3 (1.1)	1 (3.1)
Symptomatic urinary infections within 3 months before operation, n (%)	40 (13.7)	27 (10.3)	13 (40.6)	<0.001
Preoperative urine culture, n (%)				0.025
Sterile	228 (77.8)	209 (80.1)	19 (59.4)
Asymptomatic bacteriuria	48 (16.4)	39 (14.9)	9 (28.1)
Infection	17 (5.8)	13 (5.0)	4 (12.5)
Affected kidney, n (%)				0.728
Left	155 (52.9)	139 (53.3)	16 (50.0)
Right	138 (47.1)	122 (46.7)	16 (50.0)
Stone volume, mm³, median (IQR)	629.0 (725.5)	629 (836)	835 (1373)	0.095
HU, median (IQR)	997.0 (424)	950 (400)	1013 (280)	0.266
Stone(s) location, n (%)				0.503
Pelvis	110 (37.6)	100 (38.3)	10 (31.3)
Lower pole	69 (23.5)	61 (23.4)	8 (25.0)
Interpolar	32 (10.9)	30 (11.5)	2 (6.2)
Upper pole	30 (10.2)	27 (10.3)	3 (9.4)
Multiple sites	52 (17.8)	43 (16.5)	9 (28.1)
Multiple stones, n (%)	116 (39.6)	103 (39.5)	13 (40.6)	0.899
Number of stones, n (%)				0.435
1	177 (60.4)	158 (60.6)	19 (59.4)
2	73 (24.9)	65 (24.9)	8 (25.0)
3	20 (6.8)	16 (6.1)	4 (12.5)
4	17 (5.8)	17 (6.5)	0
5	2 (0.7)	2 (0.8)	0
6	4 (1.4)	3 (1.1)	1 (3.1)
Hydronephrosis, n (%)				0.624
No	183 (62.5)	163 (62.5)	20 (62.5)
Mild	74 (25.3)	66 (25.3)	8 (25.0)
Moderate	26 (8.9)	22 (8.4)	4 (12.5)
Severe	10 (3.3)	10 (3.8)	0
Preoperative stent or nephrostomy, n (%)	151 (51.5)	127 (48.7)	24 (75.1)	0.005
Previous treatment for stone in the same kidney, n (%)				0.057
None	160 (54.6)	140 (53.6)	20 (62.5)
SWL	48 (16.4)	42 (16.1)	6 (18.7)
RIRS	73 (24.9)	70 (26.8)	3 (9.4)
PCNL	6 (2.0)	5 (1.9)	1 (3.1)
Open procedure	2 (0.7)	2 (0.8)	0
More than one	4 (1.4)	2 (0.8)	2 (6.3)
Anomalous kidney, n (%)^a		25 (9.6)	1 (3.1)	0.226
Duplex system	1 (0.3)	1 (0.4)	0
Ureteropelvic junction obstruction	20 (6.8)	20 (7.7)	0
Horseshoe kidney	1 (0.3)	1 (0.4)	0
Malrotated kidney	5 (1.7)	4 (1.5)	1 (100)
Ectopic kidney	2 (0.7)	2 (0.8)	0

Mann–Whitney U-test per continuous variables.

Chi-square test for categorical variables. Bold text indicates significant p value.

More than one possible.

Table 2.

Isolated Bacteria in Preoperative Urine Culture in 63 Out of 293 Patients

	n = 293
Negative	230 (78.5)
E. coli	18 (6.3)
Contaminated	13 (4.5)
Klebsiella pneumoniae	7 (2.4)
Enterococcus faecalis	5 (1.8)
Proteus mirabilis	5 (1.8)
Pseudomonas aeruginosa	4 (1.4)
Staphylococcus epidermidis	3 (0.7)
Polymicrobic	2 (0.7)
E.coli ESBL	2 (0.7)
Candida albicans	1 (0.3)
Klebsiella aerogenes	1 (0.3)
Stenotrophomonas maltophilia	1 (0.3)
Klebsiella ozaenae	1 (03)

Data are presented as absolute number (%).

Lasing time, use, and caliber of ureteral access sheath, placement of postoperative ureteral stent, and stone composition were similar among the groups (Table 3). Median total surgical time was significantly longer in Group 2 [90.0 (50) minutes vs 65 (35) minutes, p = 0.032]. There was also a significant difference in the type of irrigation, where intermittent flushing with a syringe was more prevalent in Group 2 (12.7% vs 2.7%), whereas Traxer’s flow was in Group 1 (27.2% vs 12.5%). Escherichia coli and Enterococcus faecalis were the most prevalent isolated pathogens in SC (2.1% for each one) (Table 4).

Table 3.

Intraoperative and Postoperative Outcomes

	Overall population (n = 293)	Negative stone culture (n = 261)	Positive stone culture (n = 32)	p value
Total surgical time, minutes, median (IQR)	65.0 (39)	65 (35)	90.0 (50)	0.032
Lasing time, minutes, median (IQR)	20.0 (20)	20 (20)	30.0 (22)	0.513
Postoperative stay, days, median (IQR)	1 (2)	1 (2)	3.0 (4)	<0.001
Type of irrigation during lithotripsy, n (%)				<0.001
Gravity	0	0	0
Pump	205 (70.0)	183 (70.1)	22 (68.8)
Intermittent with syringe	13 (4.4)	7 (2.7)	6 (12.7)
Traxer’s flow	75 (25.6)	71 (27.2)	4 (12.5)
Use of UAS, n (%)				0.067
No	25 (8.5)	25 (9.6)	0
Yes	268 (91.5)	236 (90.4)	32 (100)
Caliber of UAS, n (%)				0.336
Sheathless	26 (8.9)	26 (10.0)	0
9/11 Fr	3 (0.9)	3 (1.1)	0
10/12 Fr	67 (22.9)	62 (23.8)	5 (15.7)
9.5/11.5 Fr	6 (2.0)	5 (1.9)	1 (3.1)
11/13 Fr	146 (49.8)	125 (47.9)	21 (65.6)
12/14 Fr	40 (13.8)	36 (13.8)	4 (12.5)
12/14 Fr vacuum assisted	5 (1.7)	4 (1.5)	1 (3.1)
Placement of a postoperative ureteral stent, n (%)	262 (89.4)	230 (88.1)	32 (100)	0.039
Stone biochemistry, n (%)				0.007
Not performed	163 (55.6)	135 (51.7)	28 (87.5)
Calcium oxalate dihydrate	53 (18.1)	53 (20.3)	0
Calcium oxalate monohydrate	44 (15.0)	42 (19.0)	2 (6.3)
Uric acid	9 (3.1)	8 (3.1)	1 (3.1)
Struvite	1 (0.3)	1 (0.4)	0
Calcium phosphate	23 (7.8)	22 (8.4)	1 (3.1)
Postoperative complications,^b n (%)				<0.001
None	219 (74.7)	208 (79.7)	11 (34.4)
Clavien grade 1
Loin/abdominal pain (pain killer)	16 (5.5)	15 (5.7)	1 (3.1)
Clavien grade 2
Acute urinary retention (catheterization)	1 (0.3)	1 (0.4)	0
Hematuria (prolonged catheterization)	6 (2.1)	6 (2.3)	0
Prolonged fever^a/UTI (antibiotics)	25 (8.6)	14 (5.4)	9 (28.1)
Postdischarge UTI (antibiotics)	17 (5.8)	5 (1.9)	12 (37.5)
Clavien 3a
Perirenal hematoma (embolization)	1 (0.3)	1 (0.4)	0
Clavien 3b
Stent displacement (stent repositioning)	6 (2.1)	6 (2.3)	0
Steinstrasse (ureterolithotripsy)	1 (0.3)	1 (0.4)	0
Clavien 4b
Sepsis (antibiotics, fluids, noradrenaline)	4 (1.4)	1 (0.4)	3 (9.4)
Septic shock (ICU admission)	1 (0.3)	0	1 (3.1)
Clavien 5
Death because of sepsis	1 (0.3)	0	1 (3.1)
Type of postoperative infection, n (%)				<0.001
None	262 (89.5)	246 (94.3)	16 (50.0)
Minor
Fever^a (Clavien 2)	25 (8.6)	14 (5.4)	11 (34.4)
Major
Sepsis (Clavien 4b)	2 (0.7)	1 (0.4)	1 (3.1)
Septic shock with ICU admission (Clavien 4b)	3 (0.9)	0	3 (9.4)
Death (Clavien 5)	1 (0.3)	0	1 (3.1)

Mann–Whitney U-test per continuous variables.

Chi-square test for categorical variables. Bold text indicates significant p value.

UAS, ureteral access sheath; ICU, intensive care unit; UTI, urinary tract infection.

Temperature >38°C for a minimum of 24 hours (steadily or intermittently).

More than one possible.

Table 4.

Isolated Bacteria in Stone Culture in 32 Out of 293 Patients

	n = 293
Negative	261 (89.1)
Escherichia coli	6 (2.1)
Enterococcus faecalis	6 (2.1)
Polymicrobic	3 (1.2)
Candida albicans	2 (0.7)
Pseudomonas aeruginosa	2 (0.7)
Proteus mirabilis	2 (0.7)
Staphylococcus epidermidis	2 (0.7)
Serratia marcescens	1 (0.3)
Acinetobacter baumannii	1 (0.3)
Klebsiella pneumoniae	1 (0.3)
Staphylococcus aureus	1 (0.3)
Kluyveromyces spp.	1 (0.3)
Pseudomonas stutzeri	1 (0.3)
Trichosporon asahii	1 (0.3)
Enterococcus faecium MDR	1 (0.3)
Enterococcus faecium	1 (0.3)

Data are presented as absolute number (%).

MDR, multidrug resistant.

Nineteen patients out of 228 (8.3%) with negative preoperative MSUC had a positive SC, whereas 52 patients out of 65 (80%) with positive MSUC had a negative SC (Table 5). Among 13 patients who had both positive cultures, only 6 patients were harboring the same pathogen, namely, Escherichia coli (n = 2), Pseudomonas aeruginosa (n = 2), Enterococcus faecalis, and Proteus mirabilis.

Table 5.

Results of Preoperative Midstream Urine and Stone Cultures

	Negative stone culture	Positive stone culture	Total
Negative urine culture	209	19	228
Positive urine culture	52	13	65
Total	261	32	293

Regarding complications, there was a significant difference among the groups where only 34.4% of Group 2 patients had no complication compared to 79.7% in Group 1 (p < 0.001).

Concerning infectious complications, there was a significantly higher incidence in Group 2 (p < 0.001), with 5.4% cases of prolonged fever requiring antibiotics (Clavien grade 2) in Group 1 and 34.4% in Group 2. The sepsis rate was 0.4% in Group 1 vs 3.1% in Group 2 (Clavien grade 4 b). Septic shock rate was 9.4% (Clavien grade 4 b) in Group 2, where there was also one sepsis-related death (3.1%) (Clavien grade 5). No case of septic shock and death occurred in Group 1. Only two patients out of the six patients with major infectious complications had the same pathogen in MSUC and SC (i.e., Escherichia coli). The patient who died harbored Escherichia coli in MSUC and Kluyveromyces spp. in SC. This difference in complication rate converted to a significantly longer postoperative stay in Group 2 [3.0 (4) days vs 1 (2) days, p < 0.001].

In the multivariable regression analysis, diabetes (OR, 3.23; 95% CI 1.2–8.66; p = 0.02), symptomatic urinary infections within 3 months before operation (OR, 4.82; 95% CI, 1.89–12.23; p = 0.001), and preoperative stent/nephrostomy (OR, 2.92; 95% CI, 1.16–7.34, p = 0.03) were factors significantly associated with higher odds of having a positive SC (Table 6).

Table 6.

Multivariable Analysis of Predictive Factors of Having a Positive Stone Culture

	Or (95% CI)	p-value
Female gender	1.51 (0.66–3.47)	0.33
Diabetes	3.23 (1.2–8.66)	0.02
Symptomatic urinary infections within 3 months before operation	4.82 (1.89–12.23)	0.001
Preoperative stent/nephrostomy	2.92 (1.16–7.34)	0.03
Preoperative positive urine culture	1.20 (0.47–3.10)	0.71

Bold text indicates significant p value.

Discussion

Despite being a current practice worldwide, MSUC is showed to have a poor correlation with the occurrence of systemic inflammatory response syndrome after endourological stone procedures, whereas SC demonstrated better diagnostic accuracy.⁸ However, there was, in the past, a misconception and overemphasis on inflammation with the misleading hypothesis that there is a continuum from systemic inflammatory response syndrome through severe sepsis to shock.¹¹ Therefore, in the modern era, only sepsis should be considered as the endpoint in clinical trials for postoperative major infections.

In this study, we evaluated the importance of performing an SC collected during F-URS lithotripsy. Our results pointed out several important findings.

First, we found that patients harboring SC pathogens had a significantly higher incidence of major postoperative infectious events compared to those with negative SC. This highlights the importance of performing an SC in every patient undergoing F-URS whenever possible. Nevertheless, absence of stone for culture is a common limitation often seen when lasers are preferentially used for dusting, and perhaps surgeons attempted dusting in most cases in our study. Indeed, SC was feasible in only 39.8% of patients in our series. This could also be related to the fact that dusting, fragmenting, and extraction or their combination can be applied during F-URS with similar outcomes in terms of efficacy and safety.¹²

In addition, SC could undoubtedly play a crucial role in selecting postoperative antibiotics, especially in cases of sepsis, and this is particularly important in patients with negative MSUC. The need to change antibiotics based on SC results varied widely after endourological procedures, ranging from 1.3% to 64%.⁸ To reinforce this, several studies also found that the pathogens identified in blood cultures of patients with sepsis following endourological stone surgery were concordant with those isolated from SC.^13
–15

As shown in a recent systematic review,⁸ MSUC showed discordance between pathogens detected by MSUC and SC, supporting the feeling that relying on MSUC alone is a remarkably inadequate predictor for postoperative major infectious events. As an example, De Lorenzis et al. evaluated the concordance of pathogens isolated in MSUC, pelvic urine culture, and SC in a series of 107 patients undergoing F-URS or percutaneous nephrolithotripsy.¹⁶ They found that the concordance between MSUC and SC and between pelvic urine culture and SC was 54.5% and 65.4%, respectively. Notably, the concordance increased to 94.1% between SC and urine culture derived from stone fragmentation. In our study too, there was a low concordance of isolated pathogens in MSUC and SC, with only 6 of 13 (46.2%) patients harboring the same pathogen. Therefore, a pelvic urine culture collected during lithotripsy is a practical and reasonable compromise in daily practice when a stone sample is inadequate for culture.

Another important finding is the reflection that pathogens can be present around the stone even when the MSUC is negative and appropriate preoperative antibiotic treatment has been administered. This could particularly be the case in the presence of obstruction or an indwelling ureteral stent/nephrostomy tube because of colonization. This hypothesis is reinforced by the results of our regression analysis where a preoperative stent/nephrostomy tube was associated with almost threefold odds of having a positive SC. To support this, several studies show the increased risk of postoperative sepsis in patients undergoing ureteroscopy with a ureteral stent inserted before operation, particularly when dwelling time exceeds 30 days.⁶ Unfortunately, we did not gather these data and were not able to confirm a correlation between stent dwelling time and positive SC.

In addition, renal stone itself can serve as a potential source of infection. Pathogens may reside inside stones as demonstrated by the presence of 16S rRNA gene sequencing of multiple bacteria in stones, not only struvite but also calcium oxalate and calcium phosphate stones.¹⁷ Pathogens can be released during lithotripsy, with the possibility of entering the bloodstream because of high intrarenal pressure during F-URS and consequent pyelovenous and pyelolymphatic backflow. This assumption could be another reason why Group 2 patients had a higher incidence of major infectious events in our series. In Group 2, there was a significantly higher use of flush manual irrigation with syringe, which was demonstrated to be associated with the highest rise in pressure in an ex vivo model compared with other irrigation systems,¹⁸ and this could have had a role in the higher incidence of sepsis in Group 2 patients.

Of note, microbiological characteristics of isolated pathogens in our study reveal that the most frequent pathogens identified in MSUC were gram positive, whereas gram-positive and uncommon urinary pathogens were the most common agents isolated in SC. This finding is in line with previous reports^9,19 and is another supporting reason to routinely perform SC.

A further important finding of our study is that patients with diabetes had a threefold risk of having a positive SC. It is well known that diabetes mellitus is associated with a higher risk of infections. A recent meta-analysis based on 345 studies demonstrated that diabetes was associated with an increased risk of multiple types of infections and a stronger association with urinary infections (OR 2.59) was observed in case–control studies.²⁰ The elevated risk of urinary tract infections in patients with diabetes may be attributed to several unique mechanisms. Increased susceptibility in patients with diabetes is positively associated with increased duration and severity of diabetes.²¹ This, in part, explains why patients were significantly older in Group 2 and there was a significantly higher incidence of patients with diabetes in Group 2 (31.3% vs 9.9%). Moreover, elevated glucose concentrations in urine²² and renal parenchyma²³ among diabetic individuals can create an environment conducive to the growth of pathogens, which might convert into the colonization of kidney stones. In addition, chronic hyperglycemia raises the risk of developing kidney stone disease²⁴ making a vicious circle in patients with diabetes between stone formations, pathogen colonization of stones, and urinary infections.

Finally, we found that symptomatic urinary infections within 3 months of operation were associated with the highest risk of positive SC. This observation is supported by the evidence that patients suffering from renal stones frequently present with recurrent urinary tract infections and surgical clearance of stones often results in the resolution of infections.²⁵ However, we are still far from fully clarifying the correlation between kidney stone disease and urinary tract infections, and the “chicken and egg dilemma” still exists.

This study has some limitations. First, we were not able to assess why SC was not performed in all cases despite being a common practice in the involved centers. However, we argue that this was mostly related to insufficient samples. Second, we did not gather data on stent/nephrostomy tube-dwelling time and long term would potentially influence positive SC. Third, stone composition was not performed in more than half of patients, making it difficult to evaluate its influence on positive SC. Yet, 45.4% of included patients had a previous treatment in the affected kidney and this might also influence stone colonization. Moreover, total surgical time was significantly longer in Group 2 patients, and there was a significant difference in the type of irrigation employed between the groups with a potentially higher intrarenal pressure using intermittent irrigation with a syringe, which was employed more commonly in Group 2 patients. These differences could have had a role in postoperative sepsis incidence in Group 2 patients. Finally, we acknowledge that we did not have blood cultures of our patients with sepsis and positive SC to make further correlations.

Conclusion

Our study shows that patients with a positive SC have a significantly higher incidence of sepsis after F-URS lithotripsy. Yet, we demonstrated a poor pathogen concordance between preoperative MSUC and SC, highlighting the need to perform the latter in all patients whenever feasible.

Footnotes

Authors’ Contributions

Conception and design: D.C., G.M., A.V.F., T.M., S.F. Acquisition of data: C.B., V.D.S., G.M., A.C., A.B., G.B., E.A., R.R., A.V.F., T.M., Y.T., T.E.S., S.C., A.P., N.P., A.S. Statistics: D.C. Drafting of the article: D.C., V.G. Critical revision of important intellectual content: S.F., L.C., A.B.G., and V.G. Supervision: S.M. and A.B.G. All authors participated in article writing, review, and approval of the final version of the article for submission.

Author Disclosure Statement

The authors declare no conflict of interest.

Funding Information

No funding was received for this article.

Abbreviations Used

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