Risk Factors for Upper Urinary Tract Stone Recurrence: A Retrospective Study of 247 Patients

Introduction

Urinary stones are one of the most common urological conditions, with a high prevalence rate in adults worldwide [1,2]. In the past 30 years, the global incidence rate of urolithiasis increased by 48.57% [3]. Studies showed that possible contributing factors include the increasing prevalence of obesity and diabetes, changes in dietary habits, and global warming [4–7]. The main symptoms of urinary stones are pain, hematuria, dysuria, fever, nausea, and vomiting [8,9]. CT is the first-line and the most important imaging modality for diagnosis of urolithiasis [9]. In recent years, with the development of minimally invasive surgeries such as ureteroscopic lithotripsy and percutaneous nephrolithotomy, the necessity for open surgical procedures like laparoscopic ureterolithotomy is largely reduced. However, some patients undergo a second surgery because of recurrence of urinary stones [10–13]. Rule et al reported that the recurrence rate is 20% in 5 years and 50% in 10 years [12]. The high recurrence rate of urinary stones causes enormous health care expenditures, excess illness, and reduced quality of life [14–16]. Thus, it is important to prevent the recurrence of urinary stones in clinical practice [17,18].

Some factors have been reported to be associated with recurrence of urinary stones, including climate, socioeconomic status, surgical methods, and use of drugs [12,14,19–21]. While strategies to prevent urinary calculi (eg, pharmacological interventions and lifestyle modifications) have been widely recommended, the incidence rate remains high and many patients require a second surgery due to recurrence.

The ROKS2014 nomogram was the first predictive model for stone recurrence [12], but it was focused more on renal calculi, and there is a lack of research specifically focusing on Asian populations.

In clinical studies, hematological indicators are frequently used to reflect patients’ inflammatory levels, nutrition status, and immune function. Some studies showed that inflammation, nutrition status, and immune function are associated with formation of urinary stones [22–27]. The C-reactive protein-albumin-lymphocyte (CALLY) index is a comprehensive biomarker that integrates C-reactive protein (CRP), albumin levels, and lymphocyte count to assess inflammation, immunological status, and nutrition status [28,29]. Dai et al reported that CALLY index values had an inverse association with formation of kidney stones [30], but the association with recurrence of upper urinary tract stones is unknown.

Few studies have assessed the relationship of patients’ characteristics during their first hospitalization for surgery due to upper urinary tract stones with recurrence. Therefore, we conducted this retrospective study and evaluated the laboratory and demographic factors of 247 patients during their first hospitalization for surgery due to upper urinary tract stones to explore the potential risk factors for recurrence.

Material and Methods

ETHICS APPROVAL:

This study received approval from the Medical Ethics Committee of Shanghai Tenth People’s Hospital of Tongji University (No. 25K69), and was conducted in strict adherence to the principles outlined in the Declaration of Helsinki. Given the retrospective characteristic of our study, we obtained a waiver of informed consent from the local institutional review board.

DATA SOURCE AND PARTICIPANTS:

We collected clinical data of patients with kidney or urinary calculi admitted to the Department of Urology, Shanghai Tenth People’s Hospital of Tongji University, China, from June 2019 to December 2021. All cases were diagnosed with urolithiasis by 1 or more imaging examinations such as urinary system color Doppler ultrasound, CT, or various endoscopies.

We enrolled patients with upper urinary tract stones who underwent first-time surgery using percutaneous nephrolithotomy (PCNL), ureteroscopic lithotripsy (URS), flexible ureteroscopic lithotripsy (fURSL), or laparoscopic ureterolithotomy (LU). An upper urinary tract stone was defined as a calculus located in the kidney and/or ureter (Figure 1 kidney stone and Figure 2 ureteral stone). The exclusion criteria were: (1) patients not diagnosis with urolithiasis for the first time; (2) age <18 years old; (3) patients without recurrence of urinary stones but the follow-up time was less than 3 years; and (4) patients with tumor, end-stage renal disease, congenital malformation of the kidneys or ureter.

OUTCOME DEFINITION:

Patients involved in this study were followed up at least once every 6 months to determine whether there was a recurrence of stones through clinical manifestations and imaging examinations. The study outcome was the recurrence of upper urinary tract stones within 3 years, confirmed by imaging examination. We additionally set an interval limit of the recurrence time for over 3 months. The recurrence criteria were defined as the existence of a new stone or the growth of a residual stone by more than 2 mm after surgery, diagnosed by imaging examination.

COVARIATE DEFINITION:

We collected data from the hospital information system on patient characteristics, including age, sex, body mass index (BMI), and diagnosis, as well as other covariates that may be associated with the recurrence of urinary stones: hypertension, diabetes mellitus, CRP (C-reactive protein), white blood cell count, platelet count, neutrophils count, lymphocyte count, monocyte count, serum albumin, serum creatinine, serum uric acid, serum calcium, serum magnesium, serum phosphorus, urine leukocyte esterase, urinary nitrite, urinary protein, urinary glucose, urine occult blood, ureteral stricture, and ureteral polyps. The neutrophil-to-lymphocyte ratio (NLR) was calculated using the formula: NLR=neutrophil count/lymphocyte count. The platelet-to-lymphocyte ratio (PLR) was calculated using the formula: PLR=platelet count/lymphocyte count. The lymphocyte-to-monocyte ratio (LMR) was calculated using the formula: LMR=lymphocyte count/monocyte count. The neutrophil-to-platelet ratio (NPR) was calculating using the formula: NPR=neutrophil count/platelet count. The systemic immune-inflammation index (SII) was calculated using the formula: SII=platelet count*neutrophil count/lymphocyte count. The systemic inflammation response index (SIRI) was calculated using the formula: SIRI=neutrophil count*monocyte count/lymphocyte count. The C-reactive protein-albumin-lymphocyte index (CALLY index) was determined as: serum albumin level (g/L) * absolute lymphocyte count (*109 cells/L)/(CRP *10) (mg/L) [29,31].

STATISTICAL ANALYSIS:

SPSS statistical software was used to analyze and process the research data. Data are expressed as percentages. Group comparisons were performed using the chi-squared test, as appropriate. Multivariate logistic regression analyses were performed to explore associations between these factors and recurrence. Multicollinearity among risk factors was assessed using the variance inflation factors (VIF), with a VIF value exceeding 10 indicating a multicollinearity concern. P<0.05 was considered statistically significant.

Results

BASELINE CHARACTERISTICS OF THE STUDY PARTICIPANTS:

We collected hospital records of 308 patients who were diagnosis with upper urinary stone and received surgical treatment in Shanghai Tenth People’s Hospital. According to the exclusion criteria, 61 were excluded. Finally, 247 patients with upper urinary tract stone were eligible for the present analysis, among whom 133 patients experienced at least 1 symptomatic recurrence of upper urinary stone within 3 years after the first surgery.

First, we divided patients into 2 or more groups for each factor. For BMI, we divided patients into 3 groups with a boundary of 24 and 28. For factors that could be detected in our hospital and provided a reference range, such as white blood cell count, platelet, CRP, serum calcium, serum potassium, serum phosphorus, and serum magnesium, the classification criteria were according to the reference range. For composite factors such as SII, NLR, PLR, LMR, NPR, SIRI, CALLY index, serum creatinine, and serum uric acid, the classification criteria were according to the optimal cut-off value derived from the ROC curve. The optimal cut-off value was identified according to the Youden index, which maximized the Youden index. The cut-off values of SII, NLR, PLR, LMR, NPR, SIRI, CALLY index, serum creatinine, and uric acid are listed in Table 1. As shown in Table 2, 163 male patients and 84 female patients were included in this study, and 98 male patients and 35 female patients had recurrence of upper urinary stones within 3 years. The results showed that the sex distribution was different between the 2 groups. The factors reflecting inflammation status such as SII and NLR were higher in the recurrence group. Then, we used chi-square analysis to screen out potential factors associated with recurrence, showing that sex, SII, NLR, LMR, NPR, SIRI, CALLY index, serum creatinine level, serum uric acid level, and ureter polyps were associated (P<0.05).

FACTORS ASSOCIATED WITH RECURRENCE OF UPPER URINARY STONES:

After collinearity testing, variables with P value less than 0.05 in the single-factor analysis were included in the multifactor analysis. The results (Table 3) showed that the VIF values of all factors were less than 10, suggesting that the collinearity between these variables was weak. Then, to find the independent influencing factors, we performed binary multifactor logistic regression, showing that CALLY index and serum creatinine level were the independent influencing factors (P<0.05) (Table 4).

Discussion

This retrospective cohort study investigated the association between clinically accessible biomarkers and 3-year recurrence rate of upper urinary tract stones. Multivariate analysis revealed that patients with lower CALLY index and higher serum creatinine levels results had significantly higher recurrence risks compared to those with higher CALLY index and normal serum creatinine levels results (P<0.05). Previous studies have reported the influence of stone composition and location on recurrence, and other studies have explored the role of drugs in preventing urinary stone recurrence [32–34]. The ROKS2014 nomogram focused on White people and there was a lack of laboratory data [12]. However, our study focused on Asians and mainly explored the relationship of laboratory test result data and recurrence.

The CALLY index is a comprehensive indictor that integrates nutritional status (albumin), systemic inflammatory response (CRP), and immune status (lymphocyte count). A few studies have reported that the CALLY index score is associated with the prognosis of diseases, including tumors, cardiovascular disease, and ulcerative colitis [29,35–38]. Some studies reported that inflammation may have a positive effect in the formation of urinary stones [22,39,40] However, factors reflecting the inflammation status, such as CRP, WBC, SII, and SIRI, were not independent influencing factors in our study, while the CALLY index was. In our study, patients with low CALLY index had a higher probability of recurrence. CALLY index components showed distinct patterns: hypoalbuminemia, lymphopenia, and elevated CRP in the recurrence group. This tripartite indicator may reflect persistent subclinical inflammation and an impaired mucosal defense mechanism, potentially facilitating stone formation. Consistent with our findings, Shoag et al found that CRP had a significant relationship with self-reported kidney stones [41].

Notably, serum creatinine, known as an indicator of renal function, is also an independent risk factor [42]. Keller et al found that patients with chronic kidney disease (CKD) had higher risk of urinary stones [43]. High serum creatinine can reflect worsening kidney function, with abnormal renal concentration and excretion, which can alter the balance between urinary stone formation and clearance.

However, there are some other potential indicators. Daudon et al explored the relationship between stone composition and recurrence, finding that uric acid stones had a higher recurrence rate than other types of stones [33]. They also found that the recurrence of phosphate stones was associated with infection, and the recurrence rate would be decreased if the infection was successfully treated [33]. Lifestyle may also be an important factor influencing the recurrence of urinary stones. Siener reported that changing the pH value of urine through diet was an important factor influencing the recurrence of urinary stones [44].

Our findings suggest that recurrence of upper urinary stones within 3 years after surgery is associated with renal function and inflammatory conditions, and CALLY index scores and serum creatinine levels are relative risk factors. Multicenter prospective clinical studies are needed to confirm whether CALLY index scores and serum creatinine levels are predictors of recurrence of upper urinary tract stones.

This study has some limitations. Firstly, as a retrospective study, some information came from the dictation and surgery records, such as hypertension, ureter stricture, and polyps, and these records may not be accurate, and the analytical method was rather simple and could not determine a causal relationship. Secondly, many patients had incomplete follow-up, reducing the sample size, and this could limit the validity of our conclusions. Thirdly, we did not assess all information possibly associated with the recurrence of upper urinary stones, such as details about stones.

Conclusions

Patients who underwent first-time surgery for upper urinary tract stones and who had a lower CALLY index scores and higher serum creatinine levels were at higher risk for recurrence of upper urinary tract stones at least once within 3 years.