Endoscopically Determined Stone Clearance Predicts Disease Recurrence Within 5 Years After Retrograde Intrarenal Surgery

Abstract

Objective:

To assess stone-related events (SREs) requiring retreatment in a series of 100 consecutive patients treated by retrograde intrarenal surgery (RIRS) for renal stones and to evaluate potential risk factors thereof.

Patients and Methods:

The primary outcome was incidence of SRE (medical or surgical treatment). Secondary outcomes included side of SRE, time to SRE, and late complications. Analysis of potential risk factors included high-risk stone formers (HRSFs), obesity, high stone burden, and lower pole stones. In addition, we evaluated endoscopically determined small residual fragments (SRF) of <1 mm (i.e., fragments too small for retrieval) as an independent risk factor.

Results:

Eighty-five of the 99 patients were followed up for a mean of 59 months (31–69), among whom 26 (30.1%) had SRE. Thirty-four of the 85 (40%) patients were HRSFs, 22 of whom experienced SRE (both sides) during follow-up (64.7%, p < 0.001). Eight of the 17 patients (47.1%) with SRF experienced ipsilateral side SRE compared with 13 (19.1%) of the 68 without SRF (p = 0.022, hazard ratio 2.823, 95% confidence interval [95% CI] 1.16, 6.85). Risk for ipsilateral SRE was unaffected by the presence of SRF among HRSFs (p = 0.561). Of low-risk patients with SRF, 33.3% experienced ipsilateral SRE, while those without SRF experienced no ipsilateral SRE (p < 0.001).

Conclusion:

Endoscopically determined stone clearance predicts disease recurrence within 5 years after RIRS. Even SRF are an important risk factor for future stone-related (ipsilateral) events; therefore, patients with residual fragments of any size should not be labeled “stone free” and endoscopic stone treatment should aim at complete stone clearance.

Introduction

In 2012, we published a case series of 100 consecutive patients who were treated by retrograde intrarenal surgery (RIRS) for renal stones of any size and location (Table 1).¹ In this monocentric study, patients were treated using a completely standardized technique by two experienced surgeons (M.S. and A.M.). We reported an endoscopically determined stone-free rate (SFR) of 97% after one procedure and a primary SFR of 99% after 3 months (including two patients with spontaneous clearance of residual fragments as proven by low-dose CT). Patients rated “stone free” included those with small residual fragments (SRF) of <1 mm that were too small for retrieval.

Table 1.

Characteristics of 100 Patients and Their Stones Before Initial Treatment

Characteristics	%
Sex
Male	80
Female	20
Age, years (range)	49.8 (17–80)
Stone location
Single stone	56
Multiple stones	44
Single, lower pole	39
Single, other than lower pole	17
Multiple, including lower pole	38
Multiple, other than lower pole	6
Mean cumulative stone size, mm (range)	9.8 (4–40)
CSB
4 to 10 mm	65
11 to 15 mm	25
16 to 20 mm	5
>20 mm	5
Stone composition (predominant component)
Calcium oxalate	73
Calcium phosphate	12
Brushite	1
Cystine	1
Uric acid	2
Struvite	1
No analysis available	10
Preoperative ureteral stenting
Pre-existing	6
Elective	94

CSB = cumulative stone burden.

Source: Schoenthaler et al.¹

Published SFRs after RIRS are generally high^2,3; however, little is known about the future course of those patients. In this follow-up study, we assessed stone-related events (SREs) requiring retreatment in the patients of the original case series published in 2012. Incidences of SRE were evaluated with respect to potential risk factors.

Materials and Methods

The study was approved by the local ethics committees (431/15) and performed in accordance with the ethics standards laid down in the 1964 Declaration of Helsinki and its later amendments.

All patients rated “stone free” after RIRS were eligible (complete stone clearance or SRF <1 mm as determined endoscopically at the end of the procedure).¹ Patients were routinely evaluated at our outpatient clinic and follow-up data were extracted from patient records. Primary endpoint was the incidence of SRE requiring treatment (yes/no). Secondary endpoints included the mode of treatment (medical, Double-J stent, shock wave lithotripsy [SWL], RIRS, percutaneous nephrolithotomy), side of SRE (ipsilateral, contralateral), time to first SRE, and late complications (hydronephrosis, ureteral strictures, and significant loss of renal function [>1.5× baseline creatinine]). The analysis of potential risk factors included the following: (1) patient-associated factors, such as high-risk stone formers (HRSFs, according to European Association of Urology [EAU]/American Urological Association [AUA] guidelines, Table 2)^4
–6 and obesity (body mass index [BMI] ≥30 kg/m² at the time of initial treatment); (2) stone-associated risk factors, such as high cumulative stone burden (hCSB; ≥10 mm on CT before initial treatment) and lower pole stones (LPS); and (3) treatment-associated risk factors, such as SRF (<1 mm) as described in the original surgical reports. We computed bilateral SRE for patient-associated risk factors and ipsilateral SRE for stone-associated and treatment-associated risk factors.

Table 2.

High-Risk Stone Formers

Recurrent stones (≥3 within 3 years)

Stone-associated genetic disorders (e.g., cystinuria, primary hyperoxaluria, RTA)

Stone-associated intestinal disease

Hyperparathyroidism

Nephrocalcinosis

Bilateral high stone mass

Uric acid, urate, brushite, struvite, and carbonate apatite phosphate stones

Obstructive uropathy

Solitary kidney

Family history of stones

Children and adolescents

Residual stones after treatment^e

Not applicable in the present study.

RTA = renal tubular acidosis.

Source: Preminger et al.,⁴ Turk et al.,⁵ and ⁶

Fisher's exact test^a and the Wilcoxon rank sum test^b were used to compare binary and continuous variables, respectively. Time-to-event data were analyzed using the Kaplan–Meier estimator, the log-rank test,^c and Cox regression analysis.^d The test used in each case is indicated by superscript letters. Patients were censored at the end of the follow-up period or in the case of death. p-Values of <0.05 were considered statistically significant. All statistical computations were performed using IBM SPSS Statistics (IBM SPSS Statistics for Windows, Version 23.0; IBM Corp., Armonk, NY).

Results

A total of 99 patients met the inclusion criterion “stone free” after initial RIRS. Follow-up data were obtained in 85/99 patients (86%) for a mean of 59 months (31–69). We excluded 14 patients that had not been seen at our outpatient clinic. The baseline characteristics of patients who did and did not undergo follow-up were comparable (Table 3). Death unrelated to urolithiasis was recorded in one patient and follow-up was included (no SRE until time of death).

Table 3.

Baseline Characteristics of Followed Patients and Those Without Routine Follow-Up

Characteristics	Followed-up patients (n = 85)	No routine follow-up (n = 14)	p
General
Sex, male/female	68/17	11/3	1.00^a
Age (years), mean (range)	48.9 (17–80)	43.4 (20–70)	0.22^b
BMI (kg/m²), mean (range)	28.1 (18.2–47.3)	25.4 (18.7–35.3)	0.083^b
CSB (mm), mean (range)	10.1 (4.0–40.0)	8.4 (4.0–21.0)	0.19^b
Potential risk factors
High-risk stone formers	34/85	2/14	0.064^a
Obesity (BMI ≥30 kg/m²)	27/85	3/14	0.542^a
hCSB (≥10 mm)	37/85	2/14	0.043^a
Lower pole stone(s)	66/85	10/14	0.733^a
Small residual fragments (<1 mm)	17/85	2/14	1.00^a

Fisher's exact test; ^bWilcoxon rank sum test.

BMI = body mass index; hCSB = high cumulative stone burden (≥10 mm).

Among the 85 patients, SREs occurred in 26 individuals (30.1%), SRE occurred ipsilaterally, that is, at the side of initial treatment, in 21 patients (24.7%). Imaging studies at the time of SRE were available in 22 patients (low-dose non-contrast CT in all). Herein, we found multiple recurrent calculi (2–19 calculi, 1–11 mm) in 18 patients and a single recurrent stone in 4 (6, 7, 7, and 9 mm, respectively). Modes of treatment in SRE included medical treatment in five patients, SWL in six, RIRS in nine, and multiple in six patients. Double-J stent alone or any other surgical treatment (e.g., open or laparoscopic surgery) was not performed. No late complications were recorded.

Patient-associated risk factors included a high-risk profile (HRSF, Table 2) in 34/85 patients (40%) and obesity (BMI ≥30) in 27/85 (31.8%). Stone-associated risk factors, hCSB (≥10 mm) and LPS, were found in 37/85 (43.5%) and 66/85 patients (77.6%), respectively. The treatment-associated risk factor of SRF was described in the surgical reports of 17/85 patients (20.0%). SRF were preeminently prevalent in patients with hCSB (11/37 = 29.7% vs 6/48 = 12.5%, p = 0.06^a), but not in those with LPS (12/66 = 18.2% vs 5/19 = 26.3%, p = 0.517^a).

Patients who were obese or HRSF experienced significantly more SRE than did patients who were non-obese or had a low-risk profile (44.4% vs 24.1%, p = 0.038,^d hazard ratio [HR] 2.275 [1.05–4.94] and 64.7% vs 7.8%, p < 0.001,^d HR 17.095 [5.07–57.64], respectively). A higher stone burden (hCSB ≥10 mm) was associated with more ipsilateral SRE (35.1% vs 16.7%, p = 0.057), whereas LPS were not predictive for ipsilateral SRE (24.2% vs 26.3%, p = 0.778). Eight of 17 patients with SRF experienced SRE on the ipsilateral side (47.1%) compared with 13/68 (19.1%) without (p = 0.022,^d HR 2.823, 95% confidence interval [95% CI] 1.16, 6.85; Table 4).

Table 4.

Cox Regression Model for Potential Risk Factors and Stone-Related Events

	SREs during follow-up
Risk factors	Yes	No	HR (95% CI)	p
Patient-associated risk factors	SRE (overall)
High-risk stone formers	22/34	4/51	17.095 (5.07, 57.64)	<0.001^d
Obesity (BMI ≥30 kg/m²)	12/27	14/58	2.275 (1.05, 4.94)	0.038^d
Stone-associated risk factors	SRE (ipsilateral)
hCSB (≥10 mm)	13/37	8/48	2.353 (0.98, 5.68)	0.057^d
Lower pole stones	16/66	5/19	0.865 (0.32, 2.36)	0.778^d
Small residual fragments (<1 mm)	8/17	13/68	2.823 (1.16, 6.85)	0.022^d

Cox regression model.

95% CI = 95% confidence interval; HR = hazard ratio; RIRS = retrograde intrarenal surgery; SREs = stone-related events.

Available imaging studies of patients with SRE (performed at the time of SRE) and SRF after RIRS showed multiple ipsilateral recurrent calculi in six and a single recurrent stone in one; none of these patients had contralateral recurrence. In patients with SRE and endoscopically determined complete stone clearance at the time of surgery, available imaging studies showed multiple recurrent calculi in 11 cases (9 both sides, 2 contralateral side) and a single recurrent stone in 4 (3 ipsilateral, 1 contralateral).

Kaplan–Meier estimates

In high-risk patients, SRE occurred continuously over time (Fig. 1A). In patients with SRF, Kaplan–Meier analysis showed a marked increase of ipsilateral events 1 to 3 years after initial treatment (Fig. 1B).

FIG. 1.

Kaplan–Meier analyses of stone-related events by (A) high-risk vs low-risk stone formers, (B) patients ± SRF <1 mm, (C) high-risk stone formers ± SRF, and (D) low-risk stone formers ± SRF. SRF = small residual fragments. Color images available online at www.liebertpub.com/end

High-risk vs low-risk stone formers

HRSF with or without additional risk factors (obesity, hCSB, LPS, or SRF) experienced SRE at comparable rates (Table 5 and Fig. 1C). Patients without a high-risk profile (“low-risk stone formers”) carried a higher risk for SRE if a risk factor was present (Table 5 and Fig. 1D).

Table 5.

High Risk vs Non-High Risk Stone Formers in a Cox Regression Model for Additional Risk Factors and Stone-Related Events

	SREs during follow-up
Additional risk factors	Yes	No	HR (95% CI)	p
High-risk stone formers
Obesity (BMI ≥30 kg/m²)	10/13^o	12/21^o	1.597 (0.68, 3.78)	0.287^d
hCSB (≥10 mm)	11/17ⁱ	7/17ⁱ	1.621 (0.62, 4.27)	0.382^d
Lower pole stones	13/25ⁱ	5/9ⁱ	0.753 (0.26, 2.15)	0.753^d
Small residual fragments (<1 mm)	5/8ⁱ	13/26ⁱ	1.363 (0.48, 3.87)	0.561^d
Non-high risk patients
Obesity (BMI ≥30 kg/m²)	2/14^o	2/37^o	3.046^e	0.267^d,f
hCSB (≥10 mm)	2/20ⁱ	1/31ⁱ	3.119^e	0.353^d,f
Lower pole stones	3/41ⁱ	0/10ⁱ	^e	<0.001^d,f
Small residual fragments (<1 mm)	3/9ⁱ	0/42ⁱ	^e	<0.001^d,f

SRE overall.

Cox regression model.

SRE ipsilateral to initial RIRS.

CIs not calculated due to small sample size/number of SRE.

Please consider: small sample size/number of SRE.

Stone composition of extracted calculi (initial RIRS) was available for 24/26 patients with SRE. Risk stratification based on stone composition was not possible because of low numbers (1 cystine, 1 brushite, 1 struvite, 2 carbonate apatite phosphate, 1 uric acid, and 18 calcium oxalate).

Discussion

Clinical outcome parameters relevant to the patient include mortality rate, morbidity, and health-related quality of life.⁷ SFRs are widely accepted as the single most important outcome parameter in the treatment of urolithiasis³; however, they constitute a clinical surrogate parameter and it remains unclear if and to what extent stone clearance (complete vs residual fragments) is associated with long-term morbidity or impaired quality of life after treatment.⁸ In addition, the determination of stone clearance (endoscopy, sonography, fluoroscopy, and CT) and the significance of residual fragments (number and size) remain controversial.^3,8 We defined complete stone clearance (“stone free”) following a definition that was used in the URS Global Study of the Clinical Research Office of the Endourologic Society (CROES).^1,2 Patients rated as “stone free” included those with endoscopically determined SRF <1 mm too small for active retrieval. We assessed SRE as a clinical outcome parameter relevant to the patient (as opposed to surrogate parameters like image-proven persistence or regrowth of urinary calculi). During a follow-up period of nearly 5 years, almost one-third (30.1%) of all patients described as “stone free” at the time of initial treatment experienced SRE, the vast majority of retreatments being performed on the same side.

To our knowledge, this is the first study to assess SREs in this setting (comprehensive follow-up of a series of RIRS patients, including those with complete stone clearance and patients with residual fragments). We identified “high-risk stone formers” and “obesity” as patient-associated risk factors for SRE, as expected. In addition, a high stone burden (≥10 mm) was associated with a markedly higher rate of ipsilateral SRE, but not significantly so. In the original surgical reports, we found descriptions of “small residual fragments” (SRF = fragments <1 mm”) in a considerable number of patients (17/85 followed-up patients = 20.0%). This treatment-associated risk factor was highly predictive for SRE on the ipsilateral side during follow-up (p = 0.022,^d HR 2.823). Imaging studies at the time of event revealed ipsilateral multiple recurrent calculi in most of these patients. In contrast, the imaging studies of patients without SRF after RIRS showed bilateral or contralateral stone recurrence in the majority of cases.

A few earlier studies found SRE in 21.4% to 58.6% during long-term follow-up of patients with residual fragments after minimally invasive treatment for renal stones^9

–13; however, these studies investigated residual fragments (RF) of 3 to 5 mm and follow-up was limited to patients with RF. Two studies on RF ≤4 mm after RIRS found CT-proven stone regrowth or SRE in 34% of cases¹⁴ and both SRE and spontaneous passage of fragments in 20%, respectively.¹⁵ In a single comparable study (in regard to the size of RF), Portis and colleagues found no increased risk of SRE in patients with residual fragments <2 mm after RIRS.¹⁶ This study was limited by the absence of information on follow-up rate, dropouts, medical treatment for colicky pain, and stone characteristics. None of the publications provides details regarding overall risk profiles of patients.

Indeed, the present study is the first to provide detailed data on patients with a high-risk vs low-risk profile for reoccurrence. In high-risk patients, additional risk factors (obesity, hCSB, LPS, and SRF) would not increase SRE significantly (adverse effects of additional risk factors “masked” by an overall high incidence of SRE). Conversely, in low-risk patients, SRF was associated with an increased risk for ipsilateral SRE (33% vs 0%, p < 0.001,^d Table 5). This, in fact, emphasizes the impact of SRF as the only surgical influenced factor.

Of note, all patients with a high-risk stone composition at the time of treatment experienced SRE (one cystine, one brushite, and one struvite).

The data presented in this study by and large confirm findings of earlier studies. Residual fragments are significant to the future course of patients. We hereby describe the first long-term follow-up series to illustrate the clinical significance of even miniscule residuals <1 mm. Differences between patients with or without SRF are seen most notably 1 to 3 years after treatment (possibly due to a delayed Nidus effect).

Limitations of the present study include the endoscopic assessment of stone clearance and residual fragments (initial treatment). Residual fragments may in fact have been larger than 1 mm; however, this does not alter the findings of the current study. Results may be affected by residual fragments missed by endoscopic assessment. Due to a stringent follow-up policy, we were able to obtain primary data in a high percentage of patients. However, more than 10% of patients were not included (no follow-up visits). In this study (as in daily practice), we focused on patient reported outcomes (any discomfort/pain? Any events since the last visit?) and clinical outcomes (retreatment). We performed no routine imaging studies in asymptomatic patients. Efforts on metaphylaxis and compliance appear rather ineffective considering the overall high rate of SRE in high-risk patients in this series.

Conclusions

Endoscopically determined stone clearance predicts disease recurrence within 5 years after RIRS. The current data provide clear evidence that even miniscule residual fragments after RIRS for renal calculi are of major importance to the future course of patients. Patients who have residual fragments are at a significantly higher risk for (ipsilateral) SREs. In patients with a low-risk profile for stone reoccurrence, residual fragments are the single most important predictor for ipsilateral SRE. Patients with residual fragments of any size should not be labeled “stone free.” Present-day endoscopic treatment for urinary stones should aim at complete stone clearance. Future research should focus on new technologies to facilitate the achievement of this objective.

Footnotes

Acknowledgment

Institutional funding: University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Author Disclosure Statement

M.S. has a consultant contract with Schoelly GmbH (Denzlingen, Germany). A.M. has a consultant contract with Schoelly GmbH. The other authors have no conflicts of interest or financial ties to disclose.

Abbreviations Used

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