Early or late intervention of upper urinary tract stone disease: What dictates it?

Abstract

Objective:

Urolithiasis is a multifactorial disease that causes symptomatology and needs to be managed depending on various clinical parameters. In this study, we aimed to investigate clinical factors for early operation in patients with uncomplicated symptomatic urolithiasis.

Materials and Methods:

Medical records of 148 patients who underwent ureterorenoscopic lithotripsy (URS) within 6 weeks of diagnosis of urolithiasis were retrospectively reviewed. The patients were divided into two groups: those operated early (≤3 days, n = 80) and those operated late (≥4 days, n = 68). Data, including age, sex, body mass index, degree of pain assessed with Visual Analog Scale (VAS), radiological and laboratory examinations at the time of admission, along with perioperative surgical data, were recorded.

Results:

110 (74.3%) males and 38 (25.7%) females with a median age of 38 years were operated on for uncomplicated ureteral stones. Median time from diagnosis to ureteroscopic intervention was 3 days. Among clinical factors, only the number of readmissions to the emergency room, the mean white blood cell count, the level of microscopic hematuria, and VAS scores of pain at the initial diagnosis were significantly higher in the early operated group (P < 0.05).

Conclusions:

Pain is a major clinical factor resulting in earlier URS in uncomplicated upper urinary tract stone disease. First admission to the emergency room due to renal colic with multiple readmissions after diagnosis, high level of microscopic hematuria, and white blood cell counts appear to be significant pain-related factors for earlier operation.

INTRODUCTION

Urolithiasis is a highly prevalent condition and, over the last decades, a progressive increase in its incidence has been reported all around the world.[1] Since the 1990s, the rate of emergency department (ED) visits with a diagnosis of upper urinary tract stones has shown a steady increase, nearly doubling from 178 to 340/100,000 population.[2] In contrast, total ED visit rates have increased by only 16% over the same time period.[3,4]

The selection of treatment modality for uncomplicated urolithiasis depends on several factors, including the physician’s preference based on the experience and training level of the urology team, status of the healthcare system (reimbursement issues) and cost, availability of medical technology, and concerns of the urologist regarding the patient discomfort.[5,6] However, none of these factors has been well proven to affect the treatment choice directly.[7]

With technological developments, ureteroscopic lithotripsy and stone removal (URS), one of the treatment options for urolithiasis, has been widely used over the last three decades.[8] Apart from its absolute indications, URS is the most viable optional treatment, particularly for uncomplicated mid-distal stones, among the existing treatment modalities.[9,10]

The fact that there are discrepancies between the clinics of individual patients and clinical uncertainties at the cutoff size of stones for choosing the treatment modality brings the reviewers or guidelines’ authors to a conclusion of a well-informed patient and surgeon-centered approach regarding the options and presumed unbiased clinical judgment and availability for every modality selected.[11] Both the European Association of Urology (EAU) and American Urological Association (AUA) guidelines recommend intervention for selected symptomatic patients, unless there are absolute indications; however, definitive recommendations and guidelines regarding their implementation are lacking due to inadequate evidence.[11] The EAU guidelines recommend stone removal for symptomatic patients as a feasible option for the first-line treatment in selected patients based on a Level 1b evidence, while the AUA guidelines recommend leaving the decision to the patient or clinician for sooner definitive stone treatment based on a shared decision-making approach with a Level C evidence only.[10,12] To what extent the conclusions or recommendations may affect the real-setting clinical practice is unknown; however, the necessity of creating more distinct criteria for the treatment modality decision is inevitable, since each treatment modality, despite the comparable success rates, can be associated with morbidity and economic burden. In cases of uncomplicated urolithiasis, the literature lacks clear criteria or predictive factors to guide clinicians in choosing among treatment modalities, particularly URS. In the present study, we aimed to investigate clinical factors for early operation in patients with uncomplicated symptomatic urolithiasis. This is the first and only study that may contribute to the decision-making process for early surgery by considering these clinical predictive factors.

MATERIALS AND METHODS

This retrospective study was conducted at Acibadem Kozyatagi Hospital between January and December 2023. The study was approved by the Acibadem Mehmet Ali Aydınlar University, School of Medicine (202027/12), Board of Ethics, and conducted in accordance with the principles of the Declaration of Helsinki. All precautions were taken to protect the patients’ privacy and confidentiality.

Medical records of 313 patients undergoing URS operations throughout the study period were retrospectively reviewed. A total of 148 patients who underwent URS within 6 weeks of the diagnosis of urolithiasis were included in the study. Patients aged <30 and >50 years and those having renal insufficiency and/or a solitary kidney, which are absolute indications for URS, were excluded. Age restriction was implemented because age may influence both the clinical presentation and outcomes of renal colic.[13] The optimal age range was determined based on published literature identifying age groups associated with stable clinical outcomes in renal colic without significant decreases or increases due to age.

Patients with asymptomatic stones that do not cause any degree of dilatation in the kidney and urinary infection, but operated after 6 weeks due to unlikely spontaneous passage were also excluded from the study. All patients were provided verbal and written information regarding the treatment modalities, including spontaneous passage, ESWL, and URS, by one of the two urologists of the study who are experienced in utilizing each modality, and the final decision was left to the patient’s preference. Written informed consent for URS was obtained from each patient. If the operation was not performed after the first diagnosis, the medical expulsive therapy (MET) consisting of alpha-blocker and/or analgesics was prescribed.

Data, including age, sex, body mass index (BMI), degree of pain as assessed with the Visual Analog Scale (VAS) at the time of first admission (10: most severe, 0: no pain), and all radiological and laboratory examinations at the time of admission, and perioperative surgical data were recorded. All patients underwent urinalysis, serum creatinine level, and white blood cell (WBC) count analysis. The presence of crystalluria, number of leukocytes and erythrocytes in urinalysis per high-power field, and leukocyte esterase along with hematuria on dipstick testing, were noted.

All patients underwent computed tomography (CT) using the Siemens Somatom Sensation-Syngo CT (Siemens Healthcare GmbH, Erlangen, Germany) device in accordance with the low-dose noncontrast CT protocol. The standard acquisition parameters were as follows: Tube voltage: 140 kV, tube current: 40 mA, pitch: 1,4, field of view: 455 mm, and slice thickness: 64 mm × 0.6 mm. Images were converted into 1.5-mm thin reconstructions in the abdominal soft-tissue kernel (B30f), automatically. Furthermore, 3-mm MIP images were created in coronal and sagittal plans to detect small calculi. Defined calculi through the urinary tracts were measured and recorded in three dimensions. These measurements were all achieved by MIP and MPR with Syngo. Via version B10 (Siemens Healthcare GmbH, Erlangen, Germany). The longest diameter of the stone in the CT scan was accepted as the size of the stone, as measured by two experienced radiologists. Stone locations were defined as the kidney and proximal ureter, mid ureter, and distal ureter only. The degree of hydronephrosis was graded 0–3 (0 = no, 1 = mild, 2 = moderate, 3 = severe).

The patients were divided into groups according to their first admissions to the department, which were either ED or outpatient clinics of urology. After the first diagnosis, readmission of the patients either to the ED or the urology clinics of the hospital were recorded in numbers.

The median time from the first diagnosis until the URS for all study groups was used for grouping, and two groups were created. The patients who were operated early (≤3 days, n = 80) constituted Group 1 and the patients who were operated late (≥4 days, n = 68) constituted Group 2. The factors that affected the operation holding time as of the time of the first diagnosis were evaluated between the groups.

Statistical analysis

Continuous variables

• The normality of distribution was assessed using the Shapiro–Wilk test

• Normally distributed continuous variables were presented as mean ± standard deviation and compared between groups using the Student’s t-test

• Nonnormally distributed continuous variables were presented as median (min–max) and compared using the Mann–Whitney U test.

Categorical variables

• Categorical variables were presented as counts and percentages

• Differences between groups were analyzed using the Chi-square test, or Fisher’s exact test when appropriate.

Statistical significance

• A P < 0.05 was considered statistically significant.

All analyses were performed using SPSS v25.0 (IBM Corp., Armonk, NY, USA).

RESULTS

Of the patients, 110 (74.3%) were male and 38 (25.7%) were female, with a median age of 38 (range, 30–49) years. None of the patients had an absolute indication of URS due to a solitary kidney. Demographic and clinical characteristics of the patients and radiological and laboratory data are shown in Table 1.

Table 1.

Demographic and clinical characteristics of patients

Variable	Minimum–maximum
Age (years)	30–50 (39.6±11.4)
Sex, number of patients (%)
Male	110 (74.3)
Female	38 (25.7)
Weight (kg)	44.0–124.0, (79.4±15.4)
Height (m)	1.6–1.9, (1.7±0.1)
BMI (kg/m2)	12.1–41.0, (26.4±4.8)
VAS score (1–10)	0.0–10.0, (6.2±2.3)
Time from the first diagnosis to operation (days)	0.0–42.0, (8.4±14.0)
Time from the first diagnosis to operation (days)
≤3	80 (54.1)
≥4	68 (45.9)
First admission
Emergency department	98 (66.2)
Outpatient clinic	50 (33.8)
Stone location
Proximal ureter and kidney	29 (19.6)
Mid-ureter	34 (23.0)
Distal ureter	90 (60.8)
Stone size (mm)
0–4	23 (15.5)
5–7	68 (45.9)
8–10	32 (21.6)
>10	25 (16.9)
Grade of hydronephrosis
Grade 0	5 (3.4)
Grade 1	69 (46.6)
Grade 2	60 (40.5)
Grade 3	14 (9.5)
Leukocyte in urine (per high power field at microscopy)
0–4	96 (64.9)
>4	36 (24.3)
Plenty	16 (10.8)
Leukocyte esterase positivity (dipstick)
0	99 (66.9)
I	22 (14.9)
II	16 (10.8)
III	7 (4.7)
IV	4 (2.7)
Erythrocytein urine (per high power field at microscopy)
0–4	60 (40.5)
>4–5	37 (25.0)
Plenty	51 (34.5)
Crystalluria
No	141 (95.3)
Yes	7 (4.7)
WBC (×103 uL) level (normal range: 4.06–10.6)
Normal	116 (78.4)
High	32 (21.6)
Creatinine (mg/mL) level (normal range: 0.7–1.3)
Normal	137 (92.6)
High	11 (7.4)
Number of Re-admissions after diagnosis
None	75 (50.7)
Once	49 (33.1)
Twice	22 (14.9)
Three times	2 (1.4)

Data are given in mean±SD, median (minimum–maximum) or number and frequency, where applicable. BMI: Body mass index, VAS: Visual Analog Scale, WBC: White blood cell, SD: Standard deviation

A comparison of the operation time after the first diagnosis (≤3 days and ≥4 days) is summarized in Table 2. There was no statistically significant difference in the age, sex, and BMI values between the two groups. Stone location, size, and hydronephrosis degrees did not significantly differ between the groups, either. However, the number of patients who were admitted to the ED at the time of first diagnosis was statistically significantly higher in the early operated group (Group 1) (P < 0.05). The number of readmissions was significantly higher in the late-operated group, primarily due to routine follow-up visits, and most of these readmissions occurred in outpatient clinics. In contrast, all readmissions in the early-operated group were to the ED due to severe colic symptoms.

Table 2.

Comparison of the operation time after the first diagnosis (≤3 days and ≥4 days)

Variable	Operated at ≤3 days after diagnosis	Operated at ≥4 days after diagnosis	P	Test
Sex, number of patients and (%)
Male	60 (75.0)	50 (73.5)	0.838	χ 2
Female	20 (25.0)	18 (26.5)
Age (years)	39.6±10.3	39.5±12.7	0.942	Mann–Whitney U
Weight (kg)	80.9±14.9	77.6±15.8	0.174	Mann–Whitney U
Height (m)	1.7±0.1	1.7±0.1	0.522	Mann–Whitney U
BMI (kg/m2)	26.7±4.5	26.0±5.0	0.327	Mann–Whitney U
VAS score (1–10)	7.2±1.8	5.0±2.3	0.000	Mann–Whitney U
First admission
Emergency department	62 (77.5)	36 (52.9)	0.002	χ 2
Outpatient clinic	18 (22.5)	32 (47.1)
Stone location
Proximal ureter and kidney	15 (20.1)	14 (20.6)	0.978	χ 2
Mid-ureter	16 (20.0)	18 (26.5)	0.447
Distal ureter	52 (65.0)	38 (55.9)	0.377
Stone size (mm)
0–4	14 (17.5)	9 (13.2)	0.094	χ 2
5–7	40 (50.0)	28 (41.2)
8–10	11 (13.8)	21 (30.9)
>10	15 (18.8)	10 (14.7)
Grade of hydro-nephrosis
Grade 0	1 (1.3)	4 (5.9)	0.136	χ 2
Grade 1	33 (41.3)	36 (52.9)
Grade 2	38 (47.5)	22 (32.4)
Grade 3	8 (10.0)	6 (8.8)
Leukocyte in urine (per high power field at microscopy)
0–4	51 (63.7)	45 (66.2)	0.817	χ 2
>4	21 (26.3)	15 (22.1)
Plenty	8 (10.0)	8 (11.8)
Leukocyte esterase positivity (dipstick)
0	57 (71.3)	42 (61.8)	0.295	χ 2
I	13 (16.3)	9 (13.2)
II	3 (3.8)	13 (19.1)
III	5 (6.3)	2 (2.9)
IV	2 (2.5)	2 (2.9)
Erythrocyte in urine (per high power field at microscopy)
0–4	25 (31.3)	35 (51.5)	0.032	χ 2
>4–5	25 (31.3)	12 (17.6)
Plenty	30 (7.5)	21 (30.9)
Crystalluria
No	75 (93.8)	66 (97.1)	0.345	χ 2
Yes	5 (6.3)	2 (2.9)
WBC (×103 uL) level (normal range: 4.06–10.6)
Normal	56 (70.0)	60 (88.2)	0.007	χ 2
High	24 (30.0)	8 (11.8)
Creatinine (mg/mL) level (Normal range: 0.7–1.3)
Normal	73 (91.3)	64 (94.1)	0.507	χ 2
High	7 (8.8)	4 (5.9)
Number of re-admissions after diagnosis
None	49 (61.3)	26 (38.2)	0.009	χ 2
Once	24 (30.0)	25 (36.8)
Twice	7 (8.8)	15 (22.1)
Three times	0	2 (2.9)

Data are given in mean±SD, median (minimum–maximum) or number and frequency where applicable. Statistically significant differences were written in bold characters. BMI: Body mass index, VAS: Visual Analog Scale, WBC: White blood cell, SD: Standard deviation

Urinalysis results of the early operation group showed a higher degree of hematuria, but no significant difference in leukocyturia or crystalluria (P < 0.05, P = 0.817, and P = 0.345, respectively). The mean WBC counts were significantly higher in the early operated group (P < 0.05), while the mean creatinine levels did not significantly differ (P > 0.05). Finally, the VAS scores at the time of diagnosis were significantly higher in the early operated group than the late operated group (P < 0.05).

DISCUSSION

To date, available modalities in the nonconservative management of urolithiasis include shock wave lithotripsy, percutaneous nephrolithotomy, and URS, including flexible and semirigid ureteroscopy.[9] The URS is accepted as an optional initial treatment modality, except for its absolute indications in urinary stone disease. However, the clinical factors affecting the optional initial decision of URS still remain unknown.

Among the factors examined in the literature, sex and BMI were used in our study due to their possible effects on pain sensation and stone passage. However, there is controversial data, particularly regarding the effect of BMI on pain. In a study, the authors reported that BMI had no impact on diagnosis, time to seek medical advice, or response to treatment in patients with renal colic exists, whereas another study showed that BMI had an adverse effect on the initial pain relief of renal colic by analgesics.[14,15] Of note, in the latter study, these findings can be attributed to the late absorption and metabolism of the drugs due to fatty liver. With a noteworthy interesting result, another study showed that lower BMI was associated with an increased severity of renal colic pain.[16] The authors proposed no explanation for this finding, except for a weak correlation with another study reporting that lower BMI increased the frequency of dysmenorrhea in women who were suspected of having pelvic pain.[17] Although some other studies demonstrated that BMI increased the severity of existing pain sensation, most of them focused on experimental dermal pain stimulation rather than visceral pain.[18,19] To the best of our knowledge, there is no study investigating the effect of BMI on the stone passage in the literature. In our study, BMI was considered because higher BMI may impair analgesic absorption, possibly due to fatty liver, and may also alter pain perception. However, neither sex nor BMI significantly affected the time to surgery.

Presence and level of leukocyturia or dipstick positivity of leukocyte esterase may be associated with the risk of a positive urine culture, while none of the patients with pyuria had growth in urine cultures in our study. Leukocyturia may be of clinical relevance, since it may be a sign of inflammation.[20] Thus, inflammation may prevent stone passage through edema or by disturbing the ureteral movement, forming a basis for the rationale of using anti-inflammatory drugs like corticosteroids or nonsteroidal anti-inflammatory drugs in medical stone expulsion.[15,21] However, pyuria was found to have no effect on the earlier operation time in our study (P = 0.817). Higher WBC counts in the early operated group may be another factor indicating higher inflammation in the urinary tract due to the stone, as leukocytosis has also been reported which might decrease spontaneous stone passage.[22] At our clinic, elevated WBC counts are initially evaluated as a potential indicator of infection, prompting urine culture testing along with checking body temperature and vital signs. If no evidence of infection is identified, the elevation is attributed to an inflammatory response, and no further follow-up is performed unless the patient’s clinical status changes over time. Patients are informed of this management approach and advised to monitor and report any changes in their condition.

Microscopic hematuria was investigated for stone disease in the literature and 10%–20% of patients with urolithiasis can present without microscopic hematuria.[23] However, researches were mostly focused on the predictability of hematuria for stone disease at emergency units.[23,24] Although the location of stone along with the degree of obstruction was found to be related to microscopic hematuria, there is paucity and heterogeneity of the literature to draw exact conclusions.[23] To the best of our knowledge, this is the first study indicating that microscopic hematuria may be related to early intervention in stone disease. Similar to leukocytes, erythrocytes in the urine tests may also be considered to be the possible sign of more active stone movements or more severe inflammatory reactions explaining a higher degree of microscopic hematuria in the early operated group. We believe that, in addition to elevated WBC and leukocyturia, these findings represent minor factors that may reflect increased inflammation caused by stone movement, which in turn leads to more pain. In our clinic, no specific follow-up is performed for microscopic hematuria detected in patients with urolithiasis.

One of our great interests at the beginning of the study was the possible stone size effect as a cause of earlier operation. In the current literature, the probability of spontaneous stone passage within 6 weeks is 98% for stones <5 mm and about 50% for all ureteric stones.[19,25] The fact that the size and location of the stone affect the spontaneous passage may be the main cause of the assumption that larger stones should be operated on first. However, severe pain may present in some cases, regardless of the stone size. The increased pressure in the renal pelvis due to obstruction stimulates local release of prostaglandins, which further induce diuresis and spasm of the ureter.[15] In their study, Shih et al. found that smaller stones yielded more severe pain, which could be attributed to the chronic condition of large stones, leading to chronic ureteral dilatation.[16] In chronic dilatation, the nociceptor is not sharply stretched, causing dull pain, unlike the smaller stones, which acutely cause a smaller surrounding ureteral lumen due to inflammatory edema around them and, thus, the ureteral lumen becomes totally obstructed, leading to more severe pain by triggering ureteral spasm.[26] Kuehhas et al. also found this correlation when they studied perception of colicky pain due to ureteral stones.[27] Regarding the relation of the stone size with the surgical intervention, most of the studies included patients admitted to the ED initially with renal colic and found that larger stones with more proximal location were more likely to be treated by a urological intervention. Moreover, specific criteria, known as the Papa criteria, were formed to predict the rate of intervention as described by Papa et al. including stone size, VAS-pain scores, and proximal location of the stone for the patients admitted to the ED with colicky pain.[28] Another prospective cohort study investigating the predictors of urological intervention for ED patients with suspected renal colic identified additional risk factors, including age, leukocyte esterase, WBC, history of renal colic, and tachycardia at triage.[14] However, Yan et al. could not validate the former study and concluded that the Papa criteria were not sufficiently accurate to identify which patients required an intervention or a subgroup not requiring urological follow-up.[29] Overall, the absence of correlation between stone size and time to operation in our study may be attributed to this unrevealed stone size-pain relation.

Hypothetically, the degree of hydronephrosis due to obstruction may have been associated with early surgical intervention. In our study, most of the patients had Grade 0 and Grade 2 hydronephrosis, which seems to be sufficient to analyze this effect. In a retrospective study, CT-confirmed obstruction was found not to be a predictor of urological intervention in patients with renal colic, unlike the other predictors, including stone size, proximal location, and severe pain.[30] However, one other study concluded that hydronephrosis was an effective factor for the probability of urological intervention at the initial diagnosis.[31] Based on previous study results and our findings, we consider that hydronephrosis may be a transient clinical phenomenon, and these inconclusive results may be the outcome of this fact, particularly for partial obstructions. These instantaneous detections of hydronephrosis may degrade or upgrade in degree during the stone’s journey, ending with either passage or intervention, and a single evaluation is insufficient to evaluate this factor in such research, unless it is followed in the short-term by multiple visualizations.

In the current study, the main factor affecting the decision of URS was the severity of pain at the initial diagnosis. Along with the number of readmissions related to the pain, this factor indicates the only clinical entity that the patient truly feels during the course of the illness. Moreover, the patients who were admitted to the ED due to the increased severity of renal colic pain were operated on earlier than those admitted to the urology clinics with less severe pain, indicating the considerable effect of pain on the timing of surgery. VAS pain scoring has certain limitations, such as potential misinterpretations in elderly patients and a ceiling effect, which may prevent patients from quantifying pain beyond the maximum score. In our study, however, no elderly patients were included due to the defined age range, and the ceiling effect was not observed, as no patient reported the maximum score. Although individual differences in pain perception remain a concern, the VAS has been widely used in clinical studies and consistently proven to be a reliable tool for pain severity.

There are some limitations to this study such as its retrospective design. However, results have raised the following question: To what extent do we, as physicians, count on the patients, as the main players, for the decision of the optional surgical treatment of URS. On the other hand, our aim was to shed light on whether any standard parameters of clinicians would be helpful in the decision tree of this painful illness. Therefore, it seems to be wise to conduct a retrospective search and examine our standard approach. Second, this study was carried out in a single center and, therefore, the results cannot be generalized to other settings. Hence, further studies in the other settings are needed to confirm these findings.

CONCLUSIONS

This study’s results indicate that pain may play a key role as a major clinical factor for treatment decisions during the course of uncomplicated upper urinary tract stone disease. First admission to the ED due to renal colic, along with multiple readmissions after diagnosis, presence of high levels of microscopic hematuria, and elevated WBC count, are also the factors associated with more severe pain. These findings may assist clinicians in identifying patients at higher risk of requiring surgery and in counseling them regarding the likely course of their disease and the potential need for surgical intervention. Furthermore, this study may serve as a foundation for future research that prioritizes patient-reported symptoms and facilitates shared decision-making between clinicians and patients regarding treatment strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.