The Impact of Bilateral Stone Disease on Patients' Disease Progression and Health-Related Quality of Life

Abstract

Purpose:

Patients with recurring kidney stone events can expect significant morbidity and functional impairment. Few studies have evaluated the effect of bilateral kidney stones on disease progression and quality of life. We wanted to determine the association of bilateral stone disease on age of onset, and the impact on number of stone events and individual kidney stone disease-specific health-related quality of life (HRQOL) by analyzing the validated and prospectively collected Wisconsin Stone Quality of Life (WISQOL) database.

Materials and Methods:

We studied 2906 stone patients from 16 centers in North America after having completed the WISQOL questionnaire from 2014 to 2019. Kidney stone formers were assessed if kidney stones were bilateral or unilateral on imaging. Analysis with a chi-square test compared categorical variables. Bilateral kidney stone disease and its impact on HRQOL were evaluated through a multivariable linear regression model.

Results:

Of 2906 kidney stone formers, 1340 had unilateral kidney stones and 1566 had bilateral kidney stones. We observed more frequently that patients with bilateral stones had an increased number of depression/anxiety symptoms, renal tubular acidosis, and rheumatoid arthritis (all p < 0.05). Patients with bilateral stones had a younger mean (standard deviation [SD]) age of kidney stone disease onset (37.2 ± 15.8 vs 46.4 ± 15.9 years of age, p < 0.001). Bilateral kidney stone formers had a higher mean (SD) number of stone events (11.3 ± 21.8) than unilateral kidney stone formers (3.0 ± 5.1) (p < 0.001). Within our multivariable analysis, we found that HRQOL was negatively affected by the presence of bilateral stones for kidney stone patients (β = −11.2 [confidence interval: −19.5 to −3.0] points, p < 0.05).

Conclusions:

Bilateral kidney stone formers had a younger age of kidney stone disease onset and a higher number of stone events compared with unilateral kidney stone disease formers. The presence of bilateral kidney stone disease negatively impacted HRQOL.

Introduction

Simultaneous bilateral ureteral stone disease is an uncommon clinical presentation. Only about 1% to 3% of patients with urolithiasis present with bilateral ureteral stones.^1
–3 Bilateral renal stones, however, introduce the possibility of bilateral ureteral obstruction, which could lead to significant morbidity including infection, renal insufficiency, and at the very least pain. Despite the risk of recurrence and complication in this subpopulation of stone formers, little data exist concerning health-related quality of life (HRQOL) in bilateral stone disease patients.

Kidney stone disease formers report lower quality of life when compared with healthy patients.⁴ The Wisconsin Stone Quality of Life (WISQOL) disease-specific questionnaire was developed and validated for use in kidney stone formers for detecting HRQOL.^5,6 Independent predictors of HRQOL in patients with stone disease were identified, including demographic and socioeconomic factors, ethnicity, and patient expectations.^6
–8 In the present study, we utilized the WISQOL questionnaire to specifically explore the impact of bilateral stone disease on patient's HRQOL.

The objectives of this study were to compare the age of kidney stone disease onset of unilateral and bilateral stone formers, to assess the number of lifetime stone event recurrences in bilateral stone patients, and to determine the impact of bilateral nephrolithiasis on HRQOL.

Patients and Methods

We performed a retrospective cross-sectional analysis of a large multi-institutional database of kidney stone formers. Patients were recruited from 16 tertiary care outpatient centers in the United States and Canada from June 2014 to May 2019 before the COVID-19 outbreak. Institutional review board was obtained at each site before patient recruitment. Patients were eligible for study enrollment if they spoke English or French, had a history of kidney stones, and if they were older than 18 years.

Patient data were obtained at enrollment. Each patient filled out the previously validated WISQOL questionnaire.⁶ In addition, a previously validated French version of the WISQOL was available for patients recruited in Canada.⁹ The 28-question survey consists of 1- to 5-point scale for each question (total score range 28–140), with higher scores indicating better HRQOL than lower scores. The questionnaire is divided into four domains: D1 social functioning, D2 emotional functioning, D3 stone-related impact, and D4 vitality. In addition to kidney stone former-specific HRQOL, clinically relevant variables including patient comorbidities, number of previous stone events, age of onset of kidney stone disease, radiological presence of bilateral or unilateral kidney stone disease at enrollment and known family history of kidney stone disease were obtained directly from each patient. Demographic patient information such as age at enrollment, gender, ethnicity, and body mass index (BMI) was obtained from each patient. BMI was defined according to thresholds provided by the Center for Disease Control and Prevention (CDC).

An additional threshold with a BMI >40 kg/m² was defined as severe obesity. Patient use of potassium citrate or thiazide for medical therapy of kidney stones was also included. Patients were given a list of 23 occupations from the United States Bureau of Labor Statistics (BLS) with the additional options of unemployed/retired and homemaker/caregiver. To simplify data analysis, the 23 occupations were further categorized into 4 groups according to BLS guidelines. Also, kidney stone formers who chose unemployed/retired were categorized as unemployed if they were younger than 62 years and as retired if they were aged 62 years or older according to the age at which Social Security benefits first become available. Stone events were grouped as single (0–1 events), recurrent (2–5 events), and severe (≥6 events). Bilateral stone disease was defined as having at least one stone in each kidney at patient enrollment. Kidney, ureter, and bladder radiograph, ultrasound, and CT scan were used to identify kidney stone burden. Kidney stones were not excluded based on size. Patients with ureteral stones were excluded. All patient data were de-identified and anonymized before data analysis.

Statistical analyses

Baseline characteristics were analyzed using the Wilcoxon rank-sum test for age and the chi-square test for categorical variables. Univariable and multivariable linear regression analyses were performed to assess the impact of bilateral kidney stone disease on kidney stone former HRQOL. A linear relationship between our variables was assured. We assumed a normal distribution according to previous literature utilizing the WISQOL database. We used a variation inflation factor ≤10 to assure the absence of multicollinearity. Also, the Goldfeld–Quandt test was used to assure the absence of heteroscedasticity. Statistical significance was considered at α = 0.05. All statistical analyses were performed with R software environment for statistical computing and graphics (version 4.1.0 for PC; www.r-project.org)

Results

Of 2906 kidney stone formers, 1566 (53.9%) presented with simultaneous bilateral stones. Baseline demographics are listed in Table 1. Bilateral and unilateral kidney stone formers had a similar median (interquartile range [IQR]) age at enrollment (55 IQR: 43–64 vs 55 IQR: 43–65 years, p > 0.05). The mean (standard deviation [SD]) BMI was also similar between both groups (30.3 ± 7.8 vs 29.8 ± 7.2, p > 0.05).

Table 1.

Baseline Demographics and Clinical Variables of Kidney Stone Formers from the Wisconsin Stone Quality of Life Database from 2014 to 2019 According to Side of Kidney Stone

	Overall (N = 2438)	Bilateral (n = 1225)	Unilateral (n = 1050)	p
Age (years), median (IQR)	55 (43–65)	55 (43–64)	55 (43–65)	>0.05
Gender, n (%)				>0.05
Male	1265 (51.9)	632 (51.6)	549 (52.3)
Female	1173 (48.1)	593 (48.4)	501 (47.7)
Age of onset (years), median (IQR)	40 (28–54)	35 (24–49)	45 (33–59)	<0.05
Duration of disease (years), median (IQR)	8 (1–20)	13 (5–25)	3 (0–11)	<0.05
Time from event (surgery or stone passage) (years), median (IQR)	0 (0–1)	0 (0–1)	1 (0–2)	<0.05
WISQOL score (points), median (IQR)	117 (89–132)	114 (85–131)	119 (94–133)	<0.05
Occupation, n (%)				<0.05
Homemaker/stay-at-home caregiver	163 (6.7)	84 (6.9)	66 (6.3)
Management	1055 (43.3)	536 (43.8)	460 (43.8)
Manual labor	162 (6.6)	69 (5.6)	85 (8.1)
Sales	356 (14.6)	195 (15.9)	134 (12.8)
Unemployed	196 (8.0)	109 (8.9)	72 (6.9)
Retired	506 (20.8)	232 (18.9)	233 (22.2)
BMI, n (%)				>0.05
Underweight	22 (0.9)	12 (1.0)	8 (0.8)
Normal	591 (24.2)	299 (24.4)	254 (24.2)
Overweight	786 (32.2)	376 (30.7)	350 (33.3)
Obese	774 (31.7)	384 (31.3)	348 (33.1)
Super-obese	228 (9.4)	135 (11.0)	81 (7.7)
Number of events, n (%)				<0.05
Single (0–1)	841 (34.5)	213 (17.4)	548 (52.2)
Recurrent (2–5)	1003 (41.1)	541 (44.2)	400 (38.1)
Severe recurrent (≥6)	594 (24.4)	471 (38.4)	102 (9.7)
Family history, n (%)				<0.05
Yes	853 (35.0)	466 (38.0)	331 (31.5)
No	527 (21.6)	227 (18.5)	263 (25.0)

Nonstandardized WISQOL score was used (minimum–maximum is 28–140).

BMI = body mass index; IQR, interquartile range; WISQOL = Wisconsin Stone Quality of Life.

Bilateral stone disease patients had more baseline comorbidities at enrollment than unilateral stone disease patients (p = 0.023). Specifically, a higher rate of depression and anxiety was noted in the bilateral group (22.4% vs 18.4%, p = 0.010). There was a higher prevalence of renal tubular acidosis (RTA) (1.7% vs 0.8%, p = 0.029) and rheumatoid arthritis (RA) (3.4% vs 1.6%, p = 0.005) in bilateral stone patients. Supplementary Table S1 demonstrates the comorbidities present in both the groups.

Patients with bilateral stones took more medications than unilateral stone patients (1.9 ± 1.8 vs 1.6 ± 1.6, p < 0.001). Potassium citrate (21.6% vs 11.9%, p < 0.001) and xanthine oxidase inhibitors (5.8% vs 3.5%, p = 0.005) were more commonly found in bilateral stone patients. The usage of thiazide diuretics favored bilateral stone patients (15.6% vs 12.3%, p = 0.051) (Supplementary Table S2).

The mean (SD) age of onset of patients with bilateral nephrolithiasis was significantly younger than the age of onset of unilateral stone disease formers (37.2 ± 15.8 vs 46.4 ± 15.9 years, p < 0.001). Bilateral stone disease formers also had more stone episode recurrences (p < 0.001). More than 37% of bilateral stone disease patients had six episodes or more at the time of enrollment, compared with 9% of unilateral stone disease patients. There was no difference in type of stone composition between unilateral and bilateral stone disease patients.

Wisconsin Stone Quality of Life

We performed a multivariable linear regression analysis after adjusting for demographics and clinical variables (Table 2). Both the presence of bilateral and unilateral stones were independent predictors of worse WISQOL scores (β = −11.8 [confidence interval {CI}: −20.0 to −3.6] points and β = −10.6 [CI: −18.8 to −2.4] points, p < 0.05; respectively). Bilateral stone disease had a slightly greater impact than unilateral stone disease that was not statistically significant. A multivariable linear regression analysis for each subdomain was also completed. The presence of bilateral stones was an independent predictor of worse WISQOL for D1 social functioning, D2 emotional functioning, D3 stone-related impact, and D4 vitality (all p < 0.05). The presence of bilateral stones had the strongest impact on D2 emotional functioning (β = −13.7 [CI: −22.4 to −5.0] points) and the weakest impact on D3 stone-related impact (β = −9.6 [CI: −17.7 to −1.5] points). The presence of unilateral stones was an independent predictor of worse WISQOL for D1 social functioning, D2 emotional functioning, and D3 stone-related impact (p < 0.05) but not D4 vitality (p > 0.05) (Table 3).

Table 2.

Multivariable Linear Regression of Clinical Variable Effects on Kidney Stone Former Health-Related Quality of Life

	Multivariable
	β	CI	p
Presence of bilateral stones (points)	−11.2	−19.5 to −3.0	<0.05
Presence of unilateral stones (points)	−10.3	−18.5 to −2.1	<0.05

Adjusted according to ethnicity, BMI, LUTS or OAB, urinary tract infections (more than one within the past 12 months), renal tubular acidosis, depression and anxiety symptoms, occupation category, inflammatory bowel disease or irritable bowel syndrome (Crohn's, celiac, chronic diarrhea, idiopathic), short bowel or gastric bypass, diabetes mellitus type 2, gender, number of previous kidney stone events, medullary sponge kidney, and osteopenia/osteoporosis.

Nonstandardized WISQOL score was used (minimum–maximum is 28–140).

CI = confidence interval; LUTS = lower urinary tract symptoms; OAB = overactive bladder.

Table 3.

Domain-Specific Multivariable Linear Regression of Bilateral and Unilateral Stone Presence on Kidney Stone Former Health-Related Quality of Life

	Multivariable
	β	CI	p
Presence of bilateral stones (points)	—	—	—
Social functioning (D1)	−10.4	−18.7 to −2.2	<0.05
Emotional functioning (D2)	−13.7	−22.4 to −5.0	<0.05
Stone related impact (D3)	−9.6	−17.7 to −1.5	<0.05
Vitality (D4)	−9.8	−19.4 to −0.2	<0.05
Presence of unilateral stones (points)	—	—	—
Social functioning (D1)	−9.9	−18.2 to −1.6	<0.05
Emotional functioning (D2)	−12.1	−20.8 to −3.4	<0.05
Stone related impact (D3)	−8.6	−16.7 to −0.5	<0.05
Vitality (D4)	−8.6	−18.2 to 1.0	>0.05

Nonstandardized WISQOL score was used (minimum–maximum is 28–140).

GERD = gastro-esophageal reflux disease.

Discussion

Simultaneous bilateral stone disease represents a risk factor for recurrence and surgical intervention.¹⁰ Patients are also at increased risk of reduced renal function, and in rare but emergency cases acute renal injury.^11,12 Our study addresses the gaps in the literature surrounding bilateral stone disease using a comprehensive stone-specific HRQOL questionnaire as part of the WISQOL database. Bilateral stone disease patients had an earlier age of onset, increased number of lifetime stone events, and lower HRQOL compared with unilateral stone disease patients.

Bilateral stone patients developed stones at a mean age of 37 years, which was almost 10 years younger compared with their unilateral stone counterparts. One hypothesis explaining the stark difference of age of onset could be a more rapid development of symptoms in patients with bilateral stones, whereas unilateral stone formers may experience a longer asymptomatic phase. This may also represent a different pathophysiological process that not only has an earlier age of onset but also more severity in affecting both kidneys. The present study showed increased rates of RTA and RA in patients with bilateral stone disease; however, they only comprised 1.7% and 3.4% of bilateral stone patients, respectively. An increased rate of bilateral stone formers with RA could potentially be explained by more systemic inflammation.

However, we did not obtain differences in anti-TNF alpha usage (2.4% vs 2.6%, p > 0.05). Other metabolic conditions associated with stones such as hyperparathyroidism, cystinuria, gout, diabetes mellitus, or hypertension were not associated with bilateral stone formation. However, 24-hour urine measures could not be assessed, which could lead to a hypothesis that the results obtained in our study could explain the differences. Some studies suggest that family history of stone disease plays a role in age of onset.^13,14 Our study demonstrated that all kidney stone formers with a family history of a first- or second-degree relative with a history of kidney stones had an earlier age of onset compared with kidney stone formers without a history of kidney stones (p < 0.05). A study by Guerra et al. showed that family history was significantly associated with bilateral stones in young adults.¹⁵

The present study demonstrated high risk of recurrence for bilateral stone formers: more than 80% had experienced at least two episodes of recurrence, and almost 40% had more than six episodes. In unilateral stone formers, only 9% had more than six stone-event episodes. Iremashvili et al. showed that bilateral stones had higher incidences of recurrence in both univariable and multivariable analyses (hazard ratio 1.30, p = 0.016, CI: 1.05–1.62).¹⁰

The presence of nephrolithiasis is associated with decreased HRQOL, and that, even in asymptomatic stone patients.^16,17 Our study demonstrated that bilateral stone disease is an independent negative predictor of stone-specific quality of life, as bilateral stone formers had a lower score overall as well as in all subdomains scored worse on the WISQOL questionnaire (p < 0.05). The risk and unpredictability of stone events and the fear of recurrence may have a long-term impact on a patient's quality of life. Furthermore, the present study found that bilateral stone formers had significantly higher rates of depression and anxiety (22.4% vs 18.4%, p = 0.010).

We theorize that the incertitude and pain associated with stones, especially multiple stones, may exacerbate pre-existing mental health disturbances or may contribute to their development. However, another study by Lundeen et al. from our research consortium revealed no overall correlation between general stress and HRQOL using the WISQOL questionnaire.¹⁸ A study by Arzoz-Fabregas et al. also demonstrated the lack of a relationship between stone-related stress and stone recurrence. The same study showed no association with recent anxiety or depression preceding assessment.¹⁹ Bilateral location of stones may thus be an independent predictor of HRQOL, or the existence of other factors may be impacting patient's quality of life.

Bilateral stone disease patients are considered higher risk patients than unilateral stone disease formers, and in multiple aspects, this was confirmed by the present study. Some national guidelines consider bilateral kidney stones as a strong indication for metabolic stone workup. They experience earlier onset of symptoms and thus carry the burden of stone disease for a longer duration. During the course of their disease, they also have more recurrences and reduced quality of life. These findings can help urologists better understand disease progression of their patients and better predict recurrences. In terms of treatment, numerous studies have reported on the best surgical practice for bilateral stones since indications for bilateral surgery are not clearly defined.²⁰ In cases of bilateral symptomatic stones, same-session stone surgery has been shown to be safe and effective.²¹

A recent systematic review analyzed four studies comparing bilateral and unilateral ureteroscopy and showed no differences in operation time, stone-free rate, hospital stay, or complications.²² The same study demonstrated slightly higher rates of low-grade complications in same-session bilateral percutaneous nephrolithotomy (PCNL), but a recent large population study using PCNL-specific categorization found that complication rates were comparable.²³ Recent evidence confirms that a planned bilateral endoscopic surgical approach leads to a longer time to kidney stone relapse and lower risk of kidney stone relapse when compared with only a unilateral endoscopic surgical approach for bilateral kidney stone patients.²⁴ Therefore, urologists could consider treating bilateral stone formers indifferent of symptoms to positively impact HRQOL as well reducing kidney stone recurrence rates.

The present study is not without limitations. Patients were recruited at follow-up appointments with urologists at specialized tertiary care centers. Therefore, a selection bias exists resulting in overrepresentation of bilateral stone patients in our study population. However, while the proportion of bilateral stone patients may not be representative of the general population, the large study population allowed us to accurately detect trends within the bilateral stone group. In addition, we could not assess individual-patient stone burden, which may have impacted our findings. As results are based on survey data at time of enrollment, recall biases may be present such as accuracy of the number of lifetime stone events.

Also, we could not differentiate between synchronous or metachronous bilateral stone events due to the cross-sectional nature of our study. Metabolic assessment with 24-hour urine studies could not be analyzed in our study, which represents a significant limitation. The WISQOL questionnaire was only available in English and French when the data were acquired, which may have introduced a selection bias in patient recruitment. Finally, the cross-sectional nature of the study does not allow us to appreciate HRQOL trends over time. A longitudinal study observing HRQOL changes could provide an additional insight on bilateral stone patient evolution in future research. Nonetheless, to the best of our knowledge, the present study is among the first to provide insight on bilateral stone disease by leveraging the largest bilateral stone patient population.

Conclusions

Bilateral kidney stone formers had a younger age of kidney stone disease onset and a higher number of stone events compared with unilateral kidney stone formers. The presence of bilateral kidney stones negatively impacted stone-specific HRQOL. Therefore, clinicians should closely monitor disease progression in patients with bilateral kidney stone disease as well as their potential for lower HRQOL.

Footnotes

Authors' Contributions

B.L.R.: Protocol/project development, data analysis, and article writing/editing. C.D., M.-L.L., and N.B.: Protocol/project development and article writing/editing. M.B.: Data analysis. S.K.B., R.L.S., S.Y.N., J.A.A., N.M.S., S.S., D.P.V., T.D.A., J.L., T.C., V.M.P., B.H.C., V.G.B., S.A., N.E.C., J.D.H., and K.L.P.: article writing/editing.

Author Disclosure Statement

T.D.A. is a consultant for Boston Scientific and Auris Medical. N.B. is a consultant and investigator for Boston Scientific and Olympus. B.H.C. is an investigator and consultant for Boston Scientific, Cook, Storz, Olympus, Sonomotion, ADVA-Tec, Becton Dickinson, Johnson & Johnson, and The Ureteral Stent Company.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Abbreviations Used

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Supplementary Material

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