Introduction
Urolithiasis represents a prevalent pathology that urologists encounter in everyday practice. Its significance stems from the high volume of cases, costly and painful renal colic episodes, and the requirements for updated healthcare facilities. One important aspect of urinary stones is the high rate of recurrence in both the pediatric and adult populations [
1,
2]. The recurrence rates were 11, 20, 31, and 39% at 2, 5, 10, and 15 years, respectively [
3]. Various definitions have been proposed for stone recurrence that can be classified as either symptomatic or radiological recurrence [
4]. Stone recurrence is a worthy investigation as it adds to the burden of repeated emergency and outpatient visits, frequent imaging, various interventions, and the need for continuous follow-up [
5].
Risk factors and prevention of stone recurrence have been the focus of a plethora of published articles. Identified potential risk factors included younger age, male sex, higher body mass index (BMI), positive family history, pregnancy, a history of uric acid, struvite or brushite stones, non-calcium oxalate monohydrate stones, urine pH, and the presence of diabetes mellitus [
6,
7]. A nomogram has been previously developed to predict the recurrence risk based on a group of clinical factors [
3].
While 24 h urinary metabolic evaluation has been recommended to guide the therapy to prevent stone recurrence [
8,
9], recent reports questioned its role [
5,
10‐
12]. In addition, another unforeseen parameter that might potentially affect stone recurrence is the presence of urinary tract infection (UTI) particularly in staghorn stones [
13,
14]. Bacterial infection has been shown to promote the growth and aggregation of calcium oxalate crystals [
15]. In this context, this study was designed to evaluate the association between the recurrent stone status and the presence of active UTI represented by positive midstream urine culture (MSU-C), renal pelvis culture (RP-C), or stone culture (S-C).
Materials and methods
Study design
A prospective evaluation of patients who underwent percutaneous nephrolithotomy (PCNL) in a tertiary referral center was performed between November 2019 and November 2021. Informed consent was taken before enrollment in the study. The study protocol has been reviewed and approved by the local ethical committee and the institutional review board. Patients with stents or indwelling catheters or those who fail to provide a 24 h urine collection were excluded from the study. Other exclusion criteria included the presence of medical conditions that contribute to stone formation (hyperparathyroidism or renal tubular acidosis), or anatomical abnormalities (UPJ stenosis or horseshoe kidney).
Measurements and intervention
Upon admission, patients' demographic data were recorded, including gender, associated comorbidities, and BMI. Serum tests included creatinine, sodium, potassium, magnesium, calcium, phosphorus, and albumin. Patients were asked to provide 24 h urinary collection to undergo a full metabolic workup that included 24 h urinary calcium, phosphorus, oxalate, citrate, and uric acid. In addition, urine pH was measured, and the glomerular filtration rate (GFR) was calculated using the 24 h urine volume, serum, and urinary creatinine. Urinary constituents were analyzed based on raw numbers and by laboratory standards. The cut-off values of hypercalciuria, hyperuricosuria, hyperoxaluria and hypocitraturia were 200 mg/day, 750 mg/day, 45 mg/day, and 320 mg/day, respectively.
According to our protocol, any patient with positive pre-operative MSU-C receives the appropriate antibiotic 3–7 days before PCNL to prevent postoperative infectious complications. A routine third-generation cephalosporin was administered one hour before the surgery if MSU-C was negative. All patients underwent PCNL in the prone position after a ureteral catheter fixation. The caliceal puncture was done under fluoroscopic guidance and mechanical dilatation was done using Alkene’s metal dilators. Stone disintegration was accomplished using mechanical or laser disintegration. Postoperative nephrostomy tube placement and ureteral versus JJ stent placement were left to the discretion of the surgeon. Before stone disintegration, a renal pelvis urine sample was obtained and sent separately for culture (RP-C). In addition, fragments of stones were sent for stone culture (S-C) according to Tavichakorntrakool et al. method [
16] and biochemical analysis with infrared spectrophotometry (Fourier-transform infrared spectroscopy (FTIR) 2000, Perkin-Elmer Co., U.S.A
).
Outcome
The primary outcome of the study was to identify the relationship between ipsilateral renal stone intervention history and both the metabolic workup, and results of MSU-C, RP-C, and S-C. Any patient with a previous history of PCNL or retrograde intrarenal surgery either in our hospital or elsewhere with documented stone-free status or the presence of clinically insignificant residual fragments (< 3 mm) at the time of hospital discharge and completed at least 6 months free period was considered a recurrent stone former. In addition, patients with no history of any stone intervention were considered primary stone formers. Cohen’s Kappa was used to describe the level of agreement between each pair of RP-C, S-C, and MSU-C. The level of agreement is considered excellent, fair to good, and poor for Kappa levels more than 0.75, 0.4–0.75, and less than 0.4, respectively.
Statistical analysis
Numeric data were displayed as mean ± SD or median (IQR) according to parametric distribution and the significance level was calculated using the Student t or Mann–Whitney U tests, respectively. Categorical variables were presented as percentages in each category and were compared using the Chi-square test. Factors with a significance level of < 0.05 on univariate analysis were entered into a multivariate logistic regression model to identify the independent predictors of stone recurrence. To avoid multicollinearity in logistic regression model covariates, 3 distinct models were constructed using MSU-C, RP-C, and S-C separately. The area under the curve (AUC) was calculated for each model and compared to select the final model with the best performance. The statistical analysis was performed using R programming language version 4.1.2.
Discussion
The hallmark findings of the current study are that positive S-C was the only independent significant factor associated with recurrent stone formation and that no metabolic stone workup parameter was significantly associated with stone recurrence. In addition, there was a discrepancy between the leading organism in S-C and RP-C (gram-positive S. aureus) compared to gram-negative E. coli in MSU-C.
The role of gram-positive and negative bacteria in promoting stone crystallization has been previously explored. Chutipongtanate and associates have shown that
E. coli,
S. aureus,
K. pneumoniae, and
S. pneumoniae dramatically promoted calcium oxalate crystal aggregation and growth to a diameter greater than the lumen of the distal tubules [
15]. The authors noticed that this effect is specific to bacterial viability and is dose-dependent. In another report about PCNL for staghorn stones, recurrent episodes of UTIs were an independent predictor of stone recurrence or residual stone enlargement [
14]. Likewise, the
Staphylococcus spp. has been linked to staghorn stone recurrence [
13].
In this report, S-C has achieved the most significant association with stone recurrence when compared to MSU-C or RP-C. To the best of our knowledge, the comparative effect of MSU-C, RP-C, and S-C has not been explored in the context of stone recurrence. The correlation between MSU-C, RP-C, and S-C has been extensively studied in evaluating postoperative sepsis with S-C being considered the most accurate tool [
17]. MSU-C does not represent the infection status of the upper tract, especially in the presence of obstruction [
18]. In addition, a weak correlation has been found between the lower urinary tract (MSU-C) and upper urinary tract (RP-C and S-C) [
19]. Similarly, as a predictor of post-PCNL sepsis, S-C and RP-C have shown superior outcomes in the prediction of infectious complications in a recent meta-analysis [
17].
The pivotal role of 24 h metabolic stone evaluation is to identify patients with urinary abnormalities that could specifically benefit from specific dietary recommendations and targeted medical therapy. This is why metabolic evaluation is recommended by the American Urological Association (AUA) as well as the European Association of Urology (EAU) [
20]. On the other hand, contradictory results questioning this approach are emerging in concordance with our study. In a recent study using a propensity score matching analysis, 61.2% of patients who completed 24 h metabolic testing developed recurrent stone events compared to 54% who had not any metabolic evaluation (p < 0.001) [
5]. Further analysis of patients with the recurrent stone disease showed that 57.1% of patients with metabolic evaluation developed a third stone-related episode compared to 53.3% of patients who had no metabolic evaluation (p < 0.001). More interestingly, testing the hypothesis of the significance of metabolic evaluation revealed that patients who had performed the metabolic evaluation and consequently received a new prescription of thiazide or alkali salt were more likely to develop another stone event compared to those who did not undergo metabolic evaluation or receive a prescription. In another report, Samson et al. examined the association between 24 h urine and stone recurrence in a large population of patients [
10]. The authors reported that there was an annual decline in the usage of 24 h testing and that there was no significant association between performing the test and stone recurrence in either the total population or the high-risk groups.
Several factors could help interpret these results. Initially, problems related to the completion and accuracy of performing 24 h urine collection were cumbersome and exhausting, and some patients might not exhibit urinary abnormalities during the period of collection. In addition, there is no consensus on how clinicians interpret and treat the abnormalities if found. Furthermore, this metabolic evaluation should be followed by a strict diet regimen and a specific prescription which are less likely to be complied with by the patients [
5].
Although our study shed the light on a new parameter that might affect stone recurrence and lessens the importance of another well-known factor, several drawbacks need to be acknowledged. Initially, the retrospective nature of the history of stone disease with the inability to document the primary stone burden, the inaccurate determination of the number of previous episodes, and the inability to investigate the history of UTI are potential factors that could have affected the outcome. Obese females constituted the main portion of our study compared to obese males (73.5 vs 53.8%, p = 0.006) which might not reflect the higher incidence of stone formation in males. The possible cause of this might be related to the geographical origin of this work where obesity is likely predominant and that the population demographics are changing with the growing incidence of obesity and metabolic syndrome. In addition, the examined metabolic evaluation and culture analyses were at the endpoint of the study. Therefore, the conclusion is better described as an association rather than a prediction. Furthermore, our study is missing the initial stone composition, stone density, and the initial metabolic evaluation and cultures which could have a significant impact on stone recurrence.
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