Evaluating the Complications and Risk of Urosepsis after Flexible Ureteroscopy in a Sodium-Glucose Co-transporter-2 Inhibitor Population with Heart Failure with Reduced Ejection Fraction

Abstract

Introduction

Recent guidelines highlight the significant role of sodium-glucose co-transporter-2 inhibitors (SGLT2is) in enhancing the overall condition of patients with heart failure with reduced ejection fraction (HFrEF), leading to their widespread use, but recent studies revealed an increased prevalence of urinary tract infections (UTIs) associated with this medication. The aim of the present study is to evaluate the risk of urosepsis after flexible ureteroscopy with flexible navigable vacuum assisted access sheath in patients diagnosed with renal stone disease who are using SGLT2i for HFrEF.

Materials and methods

This prospective comparative study included patients who were taking a SGLT2i (dapagliflozin 10 mg per day or empagliflozin 10 mg per day) for HFrEF and underwent flexible ureteroscopy in “Prof. Dr. Theodor Burghele” Clinical Hospital, Bucharest, Romania, between 01.01.2021 and 31.12.2024 for renal stone disease. All patients were completely assessed via imaging exam, complete blood count and urine analysis. The inclusion criteria were as follows: patients over 18 years old, established documented diagnosis of symptomatic HFrEF (Heart Failure New York Heart Association functional class II-IV), which has been present for at least two months and was optimally treated with pharmacological and/or device therapy, administration of SGLT2i, single-use flexible ureteroscopy, flexible and navigable vacuum-assisted ureteral access sheath (UAS) and the largest stone diameter less than 2 cm. The surgical technique met the same standard according to the recent recommendations of the International Alliance of Urolithiasis guideline on retrograde intrarenal surgery.

Results

Seventy-three patients who met the inclusion criteria were divided into two groups, according to previous SGLT2i administration, as follows: Group 1 (patients with SGLT2i) and Group 2 ( non-SGLT2i patients ). After analysing the demographic data, a slightly increased prevalence in female subjects was observed. There were no statistically different results regarding important pre-surgical data, such as mean stone dimension or density (HU), but there were preoperative differences regarding the prevalence of UTIs. After analyzing perioperative parameters such as mean previous JJ stented patients, mean surgical time and mean fluoroscopy time, the findings revealed no statistically significant differences. Regarding the main objective of the study, the present results revealed no differences in overall postoperative complications. There was a small number of postoperative urinary sepsis cases: three patients in Group 1 and two patients in Group 2.

Conclusion

Although SGLT2i administration may even increase the risk of developing UTIs, this does not influence the postoperative complications outcome after flexible ureteroscopy for renal stone disease. High-standard equipment such as single-use devices and suction ureteral access sheaths has a safe profile regarding sepsis occurrence even in UTIs, facilitating drug administration.

Keywords: SGLT2 inhibitors, heart failure with reduced ejection fraction, renal stone disease, flexible ureteroscopy.

INTRODUCTION

Urolithiasis has been always a major concern for urologists and is becoming a health issues¬ worldwide as a result of its increasing trends (1). Therefore, endourologists were very interested in developing new technologies and novel equipment to cope with this problem and offer personalized management for each patient. Flexible ureterorenoscopy (F-URS) represents one of the most selected procedures for renal stone disease nowadays and its continuous technical development is establishing new boundaries regarding stone dimension, stone-free rate and complications (2). Despite the great progresses in several aspects regarding scope dimension, visualization, laser power of fragmentation, ureteral access sheaths and single-use devices, the increased saline pressure during fragmentation procedure may lead to systemic absorption and dissemination of bacteria and cause life-threatening complications as sepsis (3, 4). Two of the game changers regarding the limitation of septic complications include the single-use F-URS development and the introduction of suction ureteral access sheaths (5).

Generally, sepsis is recognized as life-threatening organ failure resulting from bacterial aggression and dysregulated host response (6). Some reports show a global incidence around 48.9 million for these conditions, with more than 11 millions related deaths annually. Moreover, in the context of a global mortality of 19.7% and an increasing bacterial resistance, sepsis is one of the major threats of the modern era (7). Urosepsis in adults is more likely to be caused by an upper urinary tract obstruction in approximately 25% of people, but it may develop as a periprocedural complication (8). Proper management include urine drainage and intravenous antibiotic administration (9). Percutaneous nephrostomy (PCN) and ureteral stents (US) demonstrated their efficacy over time and are considered the main drainage options (10).

Even though, urosepsis is linked to several well-known risk factors and recent studies rises more and more concerns about a novel specific drug identified as sodium-glucose co-transporter-2 inhibitor (SGLT2i). There are still controversies about it, but many studies relate SGLT2i with an increased risk of urinary tract infections (UTIs) and sepsis (11, 12).

Sodium-glucose co-transporter-2 inhibitor is a relatively new class of medicine that already has proven good results in glycaemic level control, renal protection and management of heart failure (HF) (13). Since they show effectiveness beyond their primary role in glycaemic control for patients with type 2 diabetes mellitus (T2DM), SGLT2is have emerged as a major therapeutic option for the management of HF. Clinical evidence has demonstrated that, even in the absence of diabetes, empagliflozin and dapagliflozin, two of the most frequently prescribed SGLT2is, significantly lower the risk of hospitalisation and death related to HF. By lowering the renal threshold for glucose, SGLT2 inhibition interferes with tubular glucose reabsorption (13, 14).

There are still insufficient data of how this drug may induce the risk of UTIs, but most indicators are related to glycosuria and creating a proper environment for bacterial growth (12). Since it started to be largely utilized, there were many published reports on significant UTIs, pyelonephritis or even urosepsis related to this medical agent (11, 15).

Taking into account the impact of SGLT2is in recent guidelines and their key role in improving the general status of patients suffering from HF with reduced ejection fraction (HFrEF), they became largely utilized. It may be important for the future researches to evaluate the interactions between the potentially increased risk of developing UTIs when administering SGLT2is and endourologic procedures.

The aim of this study is to evaluate risk of urosepsis after F-URS with flexible navigable vacuum assisted ureteral access sheath (UAS) in patients with SGLT2i administration for HFrEF.

MATERIALS AND METHODS

This prospective comparative study included patients who were taking a SGLT2i (dapagliflozin 10 mg per day or empagliflozin 10 mg per day) for HFrEF and underwent flexible ureteroscopy in “Prof. Dr. Theodor Burghele” Clinical Hospital, Bucharest, Romania, between 01.01.2021 and 31.12.2024. The hospital profile includes two main important departments: urology and cardiology. Also, the urology department was recognized as Centre of Excellence by the European Association of Urology (16).

All patients taking SGLT2i for HFrEF under cardiologists’ care were evaluated as compensated at the intervention time. Stone disease was documented by computed tomography (CT) and the surgical indication (stone less than 2 cm) for F-URS was made according to the European Association of Urology guidelines (17).

Inclusion criteria comprised provision of signed informed consent prior to any study specific procedures; male or female patients aged ≥18 years at the time of consent; established documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV), which has been present for at least two months and was optimally treated with pharmacological and/or device therapy; left ventricular ejection fraction ≤40% (echocardiogram, radionuclide ventriculogram, contrast angiography or cardiac MRI) within the last 12 months prior to enrolment; single-use F-URS; flexible and navigable vacuum assisted UAS; and largest stone diameter less than 2 cm.

Exclusion criteria comprised patients under 18 years of age; recent use of or intolerable side effects related to an SGLT2i; presence of diabetes mellitus type 1 or 2; current acute decompensated HF or hospitalization due to decompensated HF < four weeks prior to enrolment; hypotension symptoms or a systolic blood pressure below 90 mm Hg; estimated glomerular filtration rate (eGFR) lower than 30 mL per minute per 1.73 m 2 of body surface area (or experiencing rapid decline in renal function); reusable F-URS; standard UAS; largest stone diameter more than 2 cm; and renal or ureteral abnormalties.

According to medication administration, study participants were assigned to two groups: Group 1, comprising SGLT2i patients diagnosed with renal stone disease, and Group 2, comprising non-SGLT2i patients who were randomly selected from the urology department, where they underwent F-URS on the same day.

All patients were primarily assessed using a complete blood count. Urine culture was always mandatory before surgical intervention according to the hospital policy for antimicrobial prevalence and antibiotic resistance. When positive urine culture was detected, patients received proper antibiotic treatment according to their test results for at least 72 hours before surgery. Antibiotic selection and administration was always commonly established with the Infectious Disease Department. All patients had a double J stent insertion at the end of the procedure as a standard technique.

The present study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of “Prof. Dr. Th. Burghele” Clinical Hospital, Bucharest, Romania (7056/21/07/2023).

The endourological procedures were performed by surgeons with over 10-year experience in F-URS under spinal anaesthesia. The surgical technique was following the general recommendations of the International Alliance of Urolithiasis guideline on retrograde intrarenal surgery (18).

The technical equipment consisted in 7.5 Fr. single-use F-URS (Pusen PU3033A), 10/12 Fr. flexible and navigable vacuum assisted UAS (ClearPetra® Welllead Flexi Ureteral Access Sheath) and Quanta System – Cyber Ho 150 Ultra High Power (Figures 1 and 2). The most frequently used settings were applied for dusting (0.5J/30 Hz).

The main objective of the present study was to analyze the differences regarding postoperative urosepsis rates between groups and to compare the prevalence of UTI. The secondary objective was to compare demographic data, several parameters such as intraoperative data (surgical time, fluoroscopy time), stone-free rate and overall complication rate.

The statistical analysis was made using IBM SPSS Statistics 21.0 software for data analysis. The rate was presented as percentage. P<0.05 indicated a significant statistical difference.

RESULTS

In total, 73 cases which met the criteria of inclusion. After analyzing individual patient characteristics, an increased prevalence of female sex was observed, unlike most studies, which reported exactly the opposite.

As expected, age distribution was higher in Group 1, which mostly happened because SGLT2i subjects diagnosed with renal stone disease were selected from a group of patients who were monitored for HFrEF in the Cardiology Department of our hospital.

Regarding stone characteristics, such as stone dimensions (the longest diameter measured in cm) or density [expressed in Hounsfield units (HU)], revealed no statistical significant differences. Patient baseline characteristics are shown in Table 1.

Important differences in prevalence of previous UTIs were observed. In Group 1, SGLT2i administration favored bacterial growth in 44.4% of cases. Even though there was a statistically significant difference, the small number of patients, the coexistence of other pathologies such as stone disease, urinary incontinence, or benign prostatic hyperplasia may have also influenced this characteristic because the mean age of patients assigned to Group 1 was higher than 15 years old. Irrespective of the group, all patients diagnosed with UTI prior to intervention received antibiotic treatment according to their antibiogram for at least three days before the endourological procedure.

Bacterial distribution identified E. coli as the main microbial agent in both study groups (Figure 3).

All surgical procedures were performed by experienced surgeons with more than ten years of experience in F-URS.

Despite several differences regarding presentation prior to intervention, there was only one case of failure to attempt the stone for the first time in Group 2. Usually, the 10/12 Fr. flexible and navigable vacuum-assisted UAS is the most frequently used device in daily practice. Surgical time and fluoroscopy time registered close values, which were anticipated due to the similarities found in stone characteristics (Table 2).

At the end of the procedure, all patients were standardly stented for a three-week period.

Maybe one of the most important outcomes after F-URS is represented by the stone-free rate. In this case, stone-free rates were comparable between the two study groups (Table 3). Moreover, the same pattern of similarities among postoperative complications and the risk of developing urosepsis were observed. Although there were more UTIs diagnosed in Group 1, according to the proper antibiotic treatment and the technical equipment (single-use F-URS and suction UAS), septic complications were maintained low even in SGLT2i patients.

Even though patients from Group 1 presented a significantly increased risk according to their medical history of HF and reduced ejection fraction, there were no Clavien III or IV complications registered in the present study (Figure 4). The similarities between groups regarding the postoperative outcome show that flexible ureteroscopy may be efficiently and safely performed in SGLT2i users.

DISCUSSION

Sodium-glucose co-transporter-2 inhibitors have already proven their efficacy in reducing cardiovascular deaths and hospitalization for HF, starting from EMPA-REG OUTCOME, and revealed even better results, a few years later, in the EMPEROR-Reduced trial by reducing hospitalization rates and improving the quality of life in HFrEF patients (ejection fraction <40%) (19). Taking into account the benefits of SGLT2is, the European Heart Failure Group included them among the first-line therapy in HF, irrespective of ejection fraction, as soon as possible. Despite their cardiological and glycaemic advantages and even though they are generally reported as safe drugs with only minor adverse effects, there are still debates about urogenital infections, pyelonephritis, or sepsis (20, 21). According to the pre-existing data, in the present study there were more asymptomatic UTIs in the SGLT2i group. Our analysis revealed no differences in bacterial prevalence from that reported in the general population, and E. coli was the most frequently isolated strain. Although Group 1 UTIs were registered more often, there was no statistically significant difference in sepsis incidence. Another important aspect for the safety of the procedure was that all cases of postoperative sepsis were registered in previously infected cases. Besides previous UTIs, prolonged surgical time also seemed to influence the risk of sepsis development.

Even though the number of patients was not very high, both groups had low-risk complications and especially reduced sepsis rate when employing single-use F-URS and flexible and navigable vacuum-aspirated UAS. Generally, complications were classified as Clavien I and II, and the present data are comparable to those reported in previous studies (22). Skolarikos et al found a 9% complication rate in their study, which was comparable to the results of both groups in our study (23).

Regarding sepsis occurrence secondary to postoperative pyelonephritis, our findings reveal low rates in the SGLT2 group. Some studies show a 2.4% risk of pyelonephritis after ureteroscopy (24). Even though we consider single-use devices more safe, earlier studies from 2017 already identified the presence of bacteria, haemoglobin and protein on the reusable devices, but after proper cleaning and hydrogen peroxide sterilisation they demonstrated that the use of single-use devices did not make the procedure safer nor did they decrease infectious complications (25). A more important aspect in preventing postoperative sepsis is to use UASs with a suction system. Normally, intrarenal pressure varies between 0 to 20 cm H 2 O (26). Classically, during F-URS, saline solution is continuously introduced in the pyelo-calyceal system to maintain a clear field, but on the other hand, this may increase the pressure up to 27.2 cm H 2 O. When it exceeds 27.2, fluid may return in the circulatory system following different pathways such as renal pelvis veins, tubules, or lymphatics (27). Maintaining low pressure during the endoscopic procedure seemed to show promising results in both groups.

The remaining parameters analyzed in the present study, that is operative characteristics (surgical time, fluoroscopy time), showed no differences between the two groups and also similarities with previously reported data. Using Pusen 3022TM, Salvado et al reported a mean operative time of 57 minutes and a mean fluoroscopy time of 74 minutes. These surgical results were also associated with a stone-free rate of 98% for calculi smaller than 10 mm, 95% for those between 10-20 mm and 78% for over 20 mm (28). Both operative parameters and stone-free rate obtained in the present study stay close to those already reported.

Urinary tract infections can cause difficulties even though the surgery, e.g. F-URS, is minimally invasive. According to a recent systematic study, the rates of sepsis varied from 0.3% to 4.6% and 0.5% to 11.1%, respectively (29). Comorbidities, age under 40, positive urine culture, urinary tract anatomical abnormalities, female sex, prolonged surgical time, larger stones, high irrigation pressure and placement of a double-J catheter following the procedure are risk factors for sepsis following F-URS (30-32). In the present study, the septic complication rate remained low. This may be the result of using flexible and navigable vacuum-aspired UASs, single-use devices and postoperative stent placement as standard procedure. Maybe the most important aspect of limiting the postoperative sepsis is the preoperative antibiotic administration according to correct determination whenever a UTI was observed.

Positive urine culture serves as an independent predictor for post-F-URS sepsis, and a nomogram has been developed to forecast the incidence of sepsis after F-URS (33). Uchinda et al and Blackmur et al investigated the significance of bladder urine culture in infectious complications and identified it as an independent risk factor that elevated the likelihood of such complications by 3.53 to 4.88 times. The high intrarenal pressure during F-URS may facilitate the entry of local infections and poisons into the bloodstream (34, 35). In the present study, only suction ureteral access systems were used in both groups. This seems to influence postoperative sepsis occurrence even when dealing with medical administration, such as SGLT2, which apparently increases the risk of developing UTIs.

This is the first study to evaluate postoperative complications after F-URS in non-diabetic SGLT2 patients. Even though the patients had a cardiological medical history of HFrEF, there was no postinterventional event regarding this baseline condition. One of the major strengths of the present study, beside the fact that it is a prospective study, is that all SGLT2i patients have been monitored over several years for their baseline pathology in an academic cardiology department. The decision regarding the surgical intervention was made after a thorough urological evaluation in the urology department of the same institution. Patients’ close monitoring in both cardiology and urology departments improved data accuracy and possibly postoperative outcomes. Another important strength is represented by the high standard of surgical equipment used in both groups.

The major limitation of the study is the small number of enrolled cases, but this has been mainly generated by the fact that SGLT2i is a relative new medication class for HFrEF. Another important limitation may appear from the inequivalent distribution between groups according to their baseline disease, but HFrEF did not influence the postoperative outcomes.

One of the main future directions for study participants is to determine the recurrence rates in SGLT2i groups. Even though the available data are are insufficient, recent studies have revealed an effect of SGLT2i on reducing the prevalence and incidence of renal stone disease (36). Several studies tried to exaplain the mechanism; their conclusion is that SGLT2 is located in the brush border membrane of proximal tubule cells in the kidney and reabsorbs approximately 90% of glucose filtered at the glomerulus. Sodium-glu- cose co-transporter-2 inhibitors, like empagliflozin, obstruct the normal reabsorption of glucose in the proximal tubule from glomerular filtrate, resulting in substantial glucosuria and a decrease in blood glucose levels. Also, SGLT2is promote weight and blood pressure reduction as well as urine volume elevation, the latter serving as an effective strategy to diminish stone recurrence (37-39).

CONCLUSIONS

Although SGLT2i administration may increase the risk of developing UTIs even in non-diabetic patients, it does not influence the postoperative complications outcome after F-URS for renal stone disease. High standard equipment, such as single-use devices and suction ureteral access sheaths, has a safe profile regarding sepsis occurrence, even UTIs, and facilitates drug administration. Further studies should be conducted to evaluate the renal stone recurrence rates after surgery in these patients. The present study also serves as a noteworthy example of interdisciplinary research bridging cardiology and urology – an intersection that remains underexplored in the current literature, despite its growing clinical relevance.

FIGURE 1.

Intraoperative images

FIGURE 2.

Laser setting for dusting

TABLE 1.

Bacterial distribution among study groups

FIGURE 3.

Bacterial distribution among study groups

TABLE 2.

Surgical characteristic

FIGURE 4.

Complication rate

TABLE 3.

Postoperative outcomes

Institutional Review Board

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of “Prof. Dr. Th. Burghele” Clinical Hospital, Bucharest, Romania (7056/21/07/2023).

Conflicts of Interest

None declared.

Financial Support

None declared.

Data availability

Data are contained within the article.

Informed consent

obtained from all patients included in the present study.