Flexible ureteroscopy combined with potassium sodium hydrogen citrate(PSHC) intervention improves the stone-free rate(SFR) for 20–30 mm uric acid renal stones

Abstract

Objective

To evaluate the efficacy and safety of combining flexible ureteroscopy (FURS) with potassium sodium hydrogen citrate(PSHC) for the treatment of 20–30 mm uric acid renal stones.

Methods

A retrospective analysis of outcomes of patients with 20–30 mm uric acid renal stones who were treated with FURS and holmium lithotripsy was conducted between July 2021 and May 2024. Of them, 60 patients accepted FURS combined potassium sodium hydrogen citrate(PSHC) therapy while 70 patients underwent the FURS procedure alone. The demographic data, stone characteristics, surgical details, and perioperative outcomes of the patients were assessed retrospectively. Stone-free status was defined as the complete absence of stones on computed tomography.

Results

Totally 130 patients were enrolled and analyzed in this study. No significant differences were found between the two groups in terms of gender, age, body mass index, comorbidities, stone burden, stone density, number of stones, or laterality. The mean operation time, American Society of Anesthesiologists (ASA) score, postoperative stay, and complication rate were also similar between the groups. The combined group incurred higher costs (p < 0.01),but it achieved significantly higher stone-free rate and Wisconsin Stone Quality of Life Questionnaire score at 4 weeks post-operatively (96.7% vs. 85.7%,p = 0.029;124.63 vs. 114.44,p < 0.01). Additionally, the combined group had a significantly higher urine pH at 4 weeks postoperatively compared to the non-combined group (6.63 vs. 5.50, p < 0.01).

Conclusion

Compared to a single procedure, FURS combined with PSHC therapy is an effective and safe treatment for 20–30 mm uric acid renal stones.

Introduction

Nephrolithiasis is a widespread urological condition with a high incidence and recurrence rate [1]. Uric acid stones, which account for approximately 5-15% of all stone diseases, are the second most common type after calcium stones [2]. The incidence of uric acid stones varies significantly from 5 to 40% among different regions. This variation may be attributed to factors such as genetics, climate changes, and dietary habits [3–4]. Currently, the main treatments for nephrolithiasis, beyond conservative management, include extracorporeal shock wave lithotripsy (ESWL), flexible ureteroscopy (FURS), and percutaneous nephrolithotripsy (PCNL). Both the European Association of Urology (EAU) and the American Urological Association (AUA) guidelines recommend PCNL as the first-line treatment for renal stones larger than 20 mm [5–6]. Nevertheless, with advancements in technology, FURS has gained attention for managing stones larger than 20 mm owing to its faster recovery and lower complication risk, particularly for stones within 20–30 mm [7,8,9].Despite these advancements, FURS often does not fully clear all stone fragments, even with the use of a suctioning ureteral access sheath. Many patients spend extra time to passively discharge residual fragments. Additionally, the narrow infundibular-pelvic angle can limit the flexible scope to reach the appropriate calyx, which may contribute to residual stone fragments. These factors may all lead to the stone recurrence. A complete stone-free status after FURS procedure remains to be a challenge for urologists.

Oral dissolution therapy(ODT) for renal stones has been widely utilized over the past decades. Uric acid stones have been certificated as the only type of renal stones that can be dissolved via oral alkaline medications [10]. The reason is that the uric acid solubility significantly increases from 7 to 15 mg/dL at pH 5 to 200 mg/dL at pH 7 [11]. Though various alkali therapies have been employed, potassium sodium hydrogen citrate (PSHC) is demonstrated as the most effective for urine alkalization, with minimal side effects and high dissolution rates from 73–100% [12–13]. However, for uric acid renal stones larger than 20 mm, the dissolution process with PSHC often takes much long time and may not achieve a satisfactory stone-free rate (SFR). In this cases, surgical intervention is typically required to achieve the optimal outcome.

Thus, we hypothesize that combining FURS with PSHC intervention may improve SFR and reduce the recurrence of uric acid renal stones. However, data evaluating the combination of FURS and PSHC are lacking. Therefore, a retrospective controlled analysis was designed to assess the efficacy and safety of combining FURS with PSHC for treatment of 20–30 mm uric acid renal stones.

Methods and materials

This retrospective analysis was conducted with patients who underwent FURS for 20–30 mm renal stones between July 2021 and May 2024. Preoperative diagnostic procedures included a review of medical history, urine tests, sterile urine culture, serum creatinine and electrolytes, 24-hour urine electrolytes, and parathyroid hormone levels. Renal stones and kidney characteristics were assessed using plain X-rays of the kidneys, ureters, and bladder, and low-dose abdominal non-contrast computed tomography (NCCT). Stone composition was analyzed using automatic infrared spectrophotometry. Patients with abnormal renal anatomy, any relative or absolute contraindication to first-stage FURS, or hyperparathyroidism were excluded. In total, 130 cases were identified as uric acid stones and included in the analysis. Data analysis encompassed patient demographics, stone characteristics, surgical details, and perioperative outcomes. Every patient signed a consent form and the study protocol was approved by the Institutional Review Board of the Ninth People’s Hospital Affiliated to Soochow University(Approval Number KY2024-056-01).

FURS procedure and PSHC therapy

All surgeries were performed by Dr.Xu using a 7.5-Fr single-use flexible ureteroscope (Pusen 3033 A, China). Each patient was operated in the dorsal lithotomy position under general anesthesia, and administered at 30 min preoperatively with intravenous antibiotics that were tailored according to sterile urine culture results. Before FURS, routine ureteroscopy was performed using a semi-rigid ureteroscope (8–9.8 F, Richard Wolf GmbH, Knittlingen, Germany) to place a guidewire (Sensor, Boston Scientific) into the target renal pelvis of each patient. A hydrophilic-coated ureteral access sheath (11–13 Fr, Boston Scientific) was then inserted alongside the guidewire under direct vision. In cases where it was difficult to place the ureteral access sheath, the patients underwent either a mini-PCNL procedure or a second-stage FURS and were excluded. Renal stones were fragmented using a 200-µm holmium laser fiber with a pulse energy of 0.8–1.0 J and a frequency of 20–30 Hz, depending on stone volume and hardness. Stone fragments larger than 2 mm were retrieved using a basket extractor (TIPLESS Stone-Extractor Nitinol, reusable handle), while fragments ≤ 2 mm were left for spontaneous passage. A 4.7-Fr double-J stent was placed in each case, and its placement was confirmed using an X-ray at the end of the FURS procedure. Stone fragments were collected and analyzed immediately to determine the stone composition within 3 h postoperatively. All patients received CT scan 4 weeks postoperatively, and then the double-J stent was removed using flexible cystoscopy under local anesthesia.

Once the patients were diagnosed with uric acid stones, a combined PSHC therapy was administered one day postoperatively. The chosen medication was UrolytU^® (Martin Bauer GmbH&Co.KG, Germany), which includes dipstick pH indicators. The patients were instructed to take the medication three times daily, with a double dose in the evening. Urine pH was monitored and maintained between 6.5 and 7.2 using pH-sensitive strips. Additionally, an endocrinologist was consulted to manage serum uric acid levels in patients with hyperuricemia.

Blood pressure, urine pH level, serum uric acid level, creatinine, and electrolyte levels (mainly K⁺ and Na⁺) as well as patient tolerance to any side effect of the medication were monitored at days 3, 7, 15, and 28 postoperatively. The combined oral treatment was discontinued if any of the following phenomena were observed at the scheduled follow-up visits: persistent abnormal blood pressure, abnormal creatinine or electrolyte levels, or severe intolerable side effects. A NCCT scan was performed four weeks postoperatively to assess the SFR of the combined therapy. The continuation of PSHC treatment was decided on basis of the CT result. Stone-free data was classified into three grades: Grade A (no stones on CT scan), absolute stone free, Grade B (≤ 2 mm fragments) relative stone free, and Grade C (2.1–4 mm) fragments relative stone-free [14]. The stone-free status was defined as complete dissolution of stones with no residual fragments visible on the CT scan(Grade A).

Statistical analysis

Statistical analysis was accomplished via SPSS 27.0. Data were expressed as mean ± standard deviation (SD). Statistical analysis was carried out using Chi-square test for categorical variables and independent-samples t-test for continuous variables. A p-value < 0.05 was considered statistically significant.

Results

A total of 130 patients were enrolled in the study. PSHC was used in 60 patients, while the remaining 70 cases accepted a FURS procedure without PSHC therapy postoperatively. No significant difference was observed between the two groups in the baseline data (age, gender, body mass index (BMI), urine culture or pH, comorbidities, serum creatinine and electrolyte, and history of stone surgery). The stone characteristics were also similar in terms of cumulative stone burden, stone density, stone number and stone laterality (Table 1).

Table 1 Comparison of patients^, demographic and stone characteristics

The perioperative characteristics and outcomes were displayed in Table 2. No significant differences were found in perioperative parameters, including American Society of Anesthesiologists (ASA) score, operation time and post-operative duration(p = 0.720;p = 0.458;p = 0.627). The serum uric acid levels were similar between the two groups (p = 0.340), as we recommended an experienced endocrinologist to help adjust the uric acid levels for those with hyperuricemia. The overall cost in the combined group was significantly higher with the use of PSHC(3044.39US dollar vs. 2714.42US dollar, p < 0.01). Meanwhile, the urine pH also differed between the two groups at 4 weeks postoperatively (6.63 vs. 5.50,p < 0.01). NCCT scans performed at 4 weeks postoperatively revealed an SFR of 96.7%(58/60) in the combined group and 85.7%(60/70) in the none-combined group retrospectively (p = 0.029). Therefore, the Wisconsin Stone Quality of Life Questionnaire (WisQOL) scores were significantly different between the two groups, which was attributed to the perfect SFR in the combined group (124.63 vs. 114.44,p < 0.01).

Table 2 Comparison of perioperative parameters and outcomes between the groups

Complications were assessed according to the Clavien-Dindo modified system [15]. The overall complication rate was 18.46%, with 16.7% in the combined group and 20.0% in the non-combined group. No intraoperative complications including minimal ureteral perforation occurred in either group. The most common complication was postoperative fever in both groups. 5 patients were administered with non-steroidal anti-inflammatory drugs and recovered soon, while another 8 patients required additional antibiotic therapy according to the urine or blood culture. 2 patients experienced stomach discomfort after using PSHC, but recovered within 24 h after discontinuation of the medication. The incidence rates of persistent hematuria were comparable (p = 0.597). One patient experienced lumbago and had a slight subcapsular hematoma on the CT scan. Postoperative sepsis shock was observed in one patient of the non-combined group. He had a high fever of 39.8℃, with an increased procalcitonin level of > 99 ng/L and a decreased blood pressure of 90/60 mmHg. The patient recovered five days later with a decrease in infection indices.

Discussion

The treatment of nephrolithiasis has indeed evolved significantly over the past 60 years, particularly with advancements in surgical techniques and instruments. Currently, ESWL, FURS with lase lithotripsy, and PCNL are the main non-conservative options for renal stone removal. Both the EAU and AUA guidelines recommend PCNL as the first-line treatment for adults with renal stones larger than 20 mm [5–6]. PCNL offers a high SFR of up to 95%, but is also associated with a higher complication rate [16]. Studies indicate the puncture and dilation processes in PCNL carry an increased risk of bleeding and injury to adjacent organs [17,18,19]. ESWL is another suggested option for stones ≥ 20 mm, though the success rate declines with larger stones, as SFR drops to around 50% for stones exceeding 20 mm [20]. In comparison, FURS has gained worldwide popularity for treating renal stones because this less invasive procedure performed through natural body orifices, resulting in less direct damage to the kidneys and faster recovery. FURS is often performed as a day-operation, which contributes to its global acceptance. Several researchers have extended its use to renal stones larger than 20 mm, and obtained reasonable SFRs with lower complication rates. However, multiple procedures are sometimes needed to achieve the optimal results, especially for stones larger than 30 mm [21,22,23]. Additionally, completely removing small stone fragments during FURS can be challenging, even with basket retrieval or suctioning ureteral access sheath. Residual stone fragments may need to be cleared by patients through physical activities such as jumping and handstands, which are quite difficult for older adults or obese individuals. While the residual fragments are not effectively discharged, they can accumulate and eventually lead to stone recurrence.

Uric acid stones have become increasingly prevalent, known for its high recurrence rate. Individuals may potentially form multiple uric acid stones within three months. The rising prevalence of obesity and metabolic syndrome in recent years, which are closely associated with insulin resistance and lead to a decrease in urinary pH, is thought to contribute to the increasing incidence of uric acid stones [3]. A low urinary pH is identified as the most significant risk factor for uric acid stone formation. Nevertheless, uric acid stones can be dissolved when urinary pH is maintained above 6.5 [24], making stone dissolution therapy a viable treatment option.

ODT of uric acid stones has been used for several decades. Both the EAU and AUA guidelines on urolithiasis recommend it as a favorable treatment option [6, 24]. Salem et al. reported an overall response rate of 64.8% for ODT in treating uric acid stones [13]. Julia et al. demonstrated that theobromine significantly enhanced the dissolution of uric acid stones, suggesting that adding theobromine to a basifying therapy may be a new strategy for oral chemolysis of these stones [25]. However, the effectiveness of dissolution therapy depends on factors such as stone size and density, as treatment of larger and denser stones is more likely to fail [13]. Additionally, oral consumption of high-dose citrate or a combination of citrate and bicarbonate is associated with stomach discomfort in some cases. Prolonged use can potentially lead to the formation of sodium urate shells on the stone surface [26]. Though ODT has obvious advantages, the dissolution rate of stones larger than 20 mm decreases significantly. Combining ODT with appropriate surgical interventions may improve the final SFR of larger stones. Mokhless et al. combined ESWL and ODT to treat stones in 24 children with stone burden from 12 to 65 mm, and reported a perfect SFR of 100% [27]. In our study, we combined ODT(PSHC) with FURS to treat 20–30 mm uric acid renal stones, and evaluated the SFR at 4 weeks postoperatively using NCCT instead of X-ray or B-ultrasound. We defined stone-free status with no residual fragments visible on the CT scan. The final SFR of the combined group was excellent (96.7%) and significantly higher than that of the non-combined group (85.7%). We hypothesize the reason for this superior outcome is that the large stones during the FURS were fragmented into smaller pieces that can be more easily dissolved by PSHC. Some researchers adopted an average 3-month period of ODT, especially for larger stones, which was likely because they used ODT without any additional interventions. In contrast, we shortened the follow-up time to 4 weeks by combining ODT with FURS. Nevertheless, we were still concerned about potential side effects from long-term use of PSHC.

WisQOL is widely used to evaluate the quality of life in patients with renal stones [28–29]. In our study, patients in the combined group had significantly higher WisQOL scores compared to the non-combined group, which was likely attributed to the higher SFR in the combined group. Although the total cost was slightly higher in the combined group, patients were willing to pay because of the satisfactory SFR. Additionally, the use of PSHC can help prevent stone formation, which may also reduce future medical costs associated with stone recurrence. The mean urine pH remained low in the non-combined group at four weeks postoperatively, which may contribute to the comparatively lower SFR and the increased risk of stone recurrence.

The overall complication rate in the present series was 18.46%, which is comparable to some published data on FURS. Postoperative fever was the most common complication, while septic shock was the most dangerous, though both were treated successfully. Hematuria was also observed in our study and was associated with the placement of the double-J stent. The hematuria resolved within two days after stent removal. Infectious complications were the most frequent in our study, and were believed to be due to a high proportion of patients with diabetes mellitus, who are more likely to develop uric acid stones and suffer infection. Retrospectively, diabetes was identified as a contributing factor to this higher infection risk. The use of a suctioning access sheath may help reduce the risk of infection. Zhu et al. reported a 5.5% rate of infectious complications with the use of a suctioning sheath [30]. Qian et al. also noted a lower incidence of postoperative fever and systemic inflammatory response syndrome (SIRS) in patients using the sheath [31]. Furthermore, the suctioning sheath may reduce the need for stone baskets and improve the primary SFR postoperatively.

Our study has several limitations. First, as a retrospective study with a limited number of cases, the possibility of patient selection bias cannot be entirely excluded. Second, we measured stone size using the cumulative length of the stones rather than the stone surface area, which may impact the accuracy of size assessment. Lastly, the follow-up period may be relatively short, and thus longer-term follow-up is likely needed to more accurately assess the SFRs and stone recurrence rates in both groups.

Conclusions

The final SFR in the combined group is significantly higher with an acceptable low complication rate compared to the non-combined group. Hence, FURS combined with PSHC therapy is both effective and safe for treatment of 20–30 mm uric acid renal stones.