Author's Accepted Manuscript Evaluation and Medical Management of Kidney Stones in Children Gregory E. Tasian, Lawrence Copelovitch
PII: DOI: Reference:
S0022-5347(14)03821-X 10.1016/j.juro.2014.04.108 JURO 11578
To appear in: The Journal of Urology Accepted Date: 16 April 2014 Please cite this article as: Tasian GE, Copelovitch L, Evaluation and Medical Management of Kidney Stones in Children, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.04.108. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.
ACCEPTED MANUSCRIPT
Evaluation and Medical Management of Kidney Stones in Children
1
RI PT
Gregory E. Tasian MD, MSc1, 2 and Lawrence Copelovitch MD2, 3
Department of Surgery, Division of Urology, The Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania Perelman School of Medicine at the University of Pennsylvania
3
Department of Pediatrics, Division of Nephrology, The Children’s Hospital of
Word Count: 3861
M AN U
Philadelphia, Philadelphia, Pennsylvania
SC
2
Corresponding Author:
TE D
Keywords: Nephrolithiasis, Child, Drug Therapy, Diet Therapy, Diagnostic Imaging
EP
Gregory E. Tasian MD, MSc
The Children’s Hospital of Philadelphia
AC C
34th Street and Civic Center Blvd Department of Surgery, Division of Urology, 3rd Floor- Wood Center Philadelphia, PA 19104-4399 Phone: 215.590.0317 Fax 215.590.3985 E-mail: [email protected]
ACCEPTED MANUSCRIPT
Abstract Purpose: To appraise the current literature on the diagnostic evaluation and dietary and pharmacologic management of children with nephrolithiasis.
RI PT
Materials and Methods: In this comprehensive review on the evaluation, dietary, and pharmacologic management of children with nephrolithiasis, we searched MEDLINE,
EMBASE, and the Cochrane Library from their inceptions to March 2014 for published
SC
articles in English on therapy and kidney stones in children (age 0 – 18 years). Based on review of the titles and abstracts, 110 of the 1,014 articles (11%) were potentially
M AN U
relevant to the diagnostic evaluation and medical management of nephrolithiasis in children. We summarized this literature, and drew upon studies performed in adult populations to augment areas in which no studies of sufficient quality have been performed in children and to highlight areas in need of research.
TE D
Results: Over the last 25 years, the incidence of nephrolithiasis among children has increased by approximately 6-10% annually and is now 50 per 100,000 adolescents. Kidney stones that form during childhood have a similar composition to those that form
EP
in adults. Approximately 75-80% of stones are composed of predominantly calcium oxalate, 5-10% are predominantly calcium phosphate, 10-20% struvite, and 5% are pure
AC C
uric acid. The recurrence rate of nephrolithiasis for patients in whom stones form during childhood is poorly defined. Ultrasound should be used as the initial imaging study to evaluate children with suspected nephrolithiasis, with non-contrast CT reserved for children in whom ultrasound is non-diagnostic and the suspicion of nephrolithiasis remains high. Current treatment strategies for children with kidney stone disease are based largely on extrapolation of studies performed among adult stone formers and single
ACCEPTED MANUSCRIPT
institution cohort or case series studies of children. Tamsulosin likely increases the spontaneous passage of ureteral stones in children. Increased water intake and reducing salt consumption should be recommended for all children with a history of kidney stones.
RI PT
Potassium citrate is a potentially effective medication for children with calcium oxalate stones and concomitant hypocitraturia as well as children with uric acid stones; however, long-term compliance with therapy and the effect on reducing stone recurrence among
SC
children are unknown. Based largely on efficacy in adult populations, thiazide diuretics should be considered in the treatment of children with calcium-based stones and
M AN U
persistent hypercalciuria refractory to reductions in salt intake.
Conclusions: The incidence of kidney stone disease among children is increasing, yet few randomized clinical trials or high quality observational studies have assessed whether dietary or pharmacologic interventions reduce the recurrence of kidney stones among
TE D
children. Collaborative efforts and randomized clinical trials are needed to determine the efficacy and effectiveness of alternative treatments for children with nephrolithiasis, particularly those with calcium oxalate stones and concomitant hypercalciuria and
EP
hypocitraturia. Additional areas in need of study are the optimal length of time for a trial of stone passage in children, the cost-effectiveness of medical expulsive therapy versus
AC C
analgesics alone, and the size and location of stones for which medical expulsive therapy is most effective.
ACCEPTED MANUSCRIPT
Introduction Nephrolithiasis is a major source of morbidity and health care expenditures in United States (US). Over the last 20 years, the prevalence of nephrolithiasis has increased
RI PT
70% among adults and the gender gap between men and women is narrowing.1
Furthermore, nephrolithiasis, once considered an adult disease, has become increasingly prevalent among children. Over the last 25 years, the incidence of nephrolithiasis among
SC
children has increased by approximately 6-10% annually and is now 50 per 100,000
adolescents.2 In 2000, nephrolithiasis accounted for $2.1 billion in annual US health care
M AN U
expenditures.3 This increase in the incidence of nephrolithiasis in children has implications for future health care spending, health services allocation, and will increase the prevalence of what, for many, is a chronic condition associated with substantial pain and morbidity.4 Most importantly, the emergence of kidney stones as a pediatric disease
TE D
necessitates that specialists who care for children with nephrolithiasis understand the optimal strategies to evaluate children with kidney stones and the effectiveness of nonsurgical interventions to decrease the risk of recurrence.
EP
The purpose of this review is to appraise the current literature on the diagnostic and metabolic evaluation of and dietary and pharmacologic interventions for children
AC C
with nephrolithiasis. A comprehensive review of the large number of, but rare, genetic diseases that cause kidney stones in childhood have been covered elsewhere and are beyond the scope of this review. Similarly, medical management for stones due to infectious causes, primary hyperoxaluria, and cystinuria are also not discussed. Finally, although this review focuses on the management of pediatric nephrolithiasis, it also draws upon studies performed in adult populations to augment areas in which no studies
ACCEPTED MANUSCRIPT
of sufficient quality have been performed in children and to highlight areas in need of research. Particular attention is paid to the as yet unknown effectiveness of alternative treatment strategies in reducing the recurrence of kidney stone disease in childhood.
RI PT
Methods
In consultation with a reference librarian, we searched MEDLINE, EMBASE, and the Cochrane Library from their inceptions to March 2014 for published articles on
SC
kidney stones in children. Search terms and/or keywords included “kidney stone OR urolith* OR nephrolith*”. The explosion feature of each database was employed
M AN U
and the search was limited to studies on subjects 18 years or younger, English language publications, and human studies. We excluded case reports, expert opinions, and editorials. Abstracts were reviewed to identify articles on evaluation and medical therapy of pediatric nephrolithiasis. In addition, the bibliographies of all potentially
TE D
relevant primary articles and review articles identified in the search were read to identify other relevant articles not detected in the database search. Full search terms are available upon request.
EP
Search Results
A total of 1,014 unique references were retrieved. No additional studies were
AC C
identified from review of article references. Eighteen previous systematic reviews were identified through search of the Cochrane library, although these were based on studies of adults. Based on review of the titles and abstracts, 110 of the 1,012 articles (11%) were potentially relevant to and within the scope of this review.
Acute Management
ACCEPTED MANUSCRIPT
Diagnostic Imaging Clinical practice guidelines and evidence support using ultrasound as the initial imaging study for children with suspected nephrolithiasis and reserving CT
RI PT
only for children with a non-diagnostic ultrasound in whom the clinical suspicion
for stones remains high. Although ultrasound is less sensitive and specific than CT,5, 6 ultrasound accurately identifies clinically significant kidney stones in children. In a study
SC
of 50 patients less than 18 years old with suspected nephrolithiasis, Passerotti et al.
determined the diagnostic performance of ultrasound to accurately localize kidney stones.
M AN U
Using CT as the gold standard, the sensitivity and specificity of ultrasound was 70% and 100%, respectively, when the radiologists interpreting the ultrasounds were blinded to CT results. In this population, the positive predictive value of ultrasound was 96% and the negative predictive value was 62%.6 Of the 13 stones that were not visualized on
TE D
ultrasound, only one was larger than 5mm. Three stones that were not visualized by ultrasound were in the ureter and the remainder were non-obstructive stones in the kidney. The authors therefore concluded that stones missed by ultrasound were likely of little
EP
clinical consequence. Similarly, Johnson et al. found that ultrasound correctly identified 89% of stones requiring surgical intervention.5
AC C
Non-contrast CT has nearly 100% sensitivity and specificity to identify kidney
stones. CT, however, delivers ionizing radiation, which is associated with an increased risk of cancer.7 Although the attributable risk of cancer from a single CT scan performed for kidney stones is small (0.2-0.3% above baseline), the cumulative risk is higher for those undergoing repeated studies.8 Highlighting the cumulative risk of radiation exposure, Routh et al. analyzed 7,921 children with kidney stones treated at hospitals
ACCEPTED MANUSCRIPT
within the Pediatric Hospital Inpatient Sample and observed that over 2,600 children underwent a median of 2 CT scans for a single kidney stone episode.9 Additionally, the
greater sensitivity of developing tissues to the effects of radiation.
RI PT
risk may be higher in children than in adults because of a longer life expectancy and
Given the good sensitivity of ultrasound in detecting clinically significant
stones and the radiation risk associated with CT, the American Urological Association
SC
in 2012, and the European Association of Urology in 2013 developed imaging guidelines for children with suspected nephrolithiasis.10, 11 Both groups recommend ultrasound as
M AN U
the first-line imaging modality with non-contrast CT reserved if ultrasound is nondiagnostic. Additionally, the Image Gently Alliance, founded by the Society for Pediatric Radiology, American College of Radiology, American Society for Radiologic Technologists, and the American Association of Physicists in Medicine,
TE D
began its campaign in 2007 to lower radiation exposure among children who need diagnostic imaging.12 Currently, it is not known if these guidelines will reduce unnecessary CT utilization. Future studies are necessary to identify barriers to selective
EP
use of CT in children with suspected nephrolithiasis.
AC C
Medical Expulsive Therapy
There have been few studies on patient and stone characteristics that predict
whether a ureteral stone will pass spontaneously in children. However, similar to stones in adults, it stands to reason that smaller, distal ureteral stones are more likely to pass than are larger, more proximal stones.13 For those stones in which spontaneous passage is deemed possible (usually < 10mm), medical expulsive therapy (MET), the use of alpha-
ACCEPTED MANUSCRIPT
blockers or calcium channel blockers to increase stone passage, may increase passage of ureteral stones and thus obviate the need for surgical intervention. The causal pathway underlying the potential effect of MET on stone passage is that alpha and calcium
RI PT
channel blockers dilate the ureter due to high densities of α1a, α1d, and calcium channel receptors in smooth muscle of the distal third of the ureter and ureterovesical junction. In adults, two meta-analyses of randomized controlled trials have been
SC
performed.14, 15 Both meta-analyses demonstrated that tamsulosin and nifedipine
increased passage of ureteral stones. Among adults, alpha-blockers also decrease time to
effective relative to analgesics alone.17
M AN U
stone passage,16 decrease analgesic requirements,16 and have been shown to be cost-
The evidence for the efficacy of MET in children is relatively sparse. To date, only three studies have tested whether MET increases the passage of ureteral stones
TE D
among children. Aydogdu and colleagues conducted a retrospective cohort study of 20 children who were prescribed ibuprofen and 19 who were prescribed doxazosin for ureteral stones.18 They did not observe any association between doxazosin and
EP
spontaneous passage. However, their sample size would have had only 10% power to detect a 15% difference in passage rates between the groups. Mokhless and colleagues
AC C
performed a prospective cohort study in which children with distal ureteral stones received tamsulosin or ibuprofen and placebo.19 More stones passed in the tamsulosin cohort (88%) versus the placebo group (64%; p < 0.01) and the time to passage was also shorter among those receiving tamsulosin (8 vs. 14 days; p
PII: DOI: Reference:
S0022-5347(14)03821-X 10.1016/j.juro.2014.04.108 JURO 11578
To appear in: The Journal of Urology Accepted Date: 16 April 2014 Please cite this article as: Tasian GE, Copelovitch L, Evaluation and Medical Management of Kidney Stones in Children, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.04.108. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.
ACCEPTED MANUSCRIPT
Evaluation and Medical Management of Kidney Stones in Children
1
RI PT
Gregory E. Tasian MD, MSc1, 2 and Lawrence Copelovitch MD2, 3
Department of Surgery, Division of Urology, The Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania Perelman School of Medicine at the University of Pennsylvania
3
Department of Pediatrics, Division of Nephrology, The Children’s Hospital of
Word Count: 3861
M AN U
Philadelphia, Philadelphia, Pennsylvania
SC
2
Corresponding Author:
TE D
Keywords: Nephrolithiasis, Child, Drug Therapy, Diet Therapy, Diagnostic Imaging
EP
Gregory E. Tasian MD, MSc
The Children’s Hospital of Philadelphia
AC C
34th Street and Civic Center Blvd Department of Surgery, Division of Urology, 3rd Floor- Wood Center Philadelphia, PA 19104-4399 Phone: 215.590.0317 Fax 215.590.3985 E-mail: [email protected]
ACCEPTED MANUSCRIPT
Abstract Purpose: To appraise the current literature on the diagnostic evaluation and dietary and pharmacologic management of children with nephrolithiasis.
RI PT
Materials and Methods: In this comprehensive review on the evaluation, dietary, and pharmacologic management of children with nephrolithiasis, we searched MEDLINE,
EMBASE, and the Cochrane Library from their inceptions to March 2014 for published
SC
articles in English on therapy and kidney stones in children (age 0 – 18 years). Based on review of the titles and abstracts, 110 of the 1,014 articles (11%) were potentially
M AN U
relevant to the diagnostic evaluation and medical management of nephrolithiasis in children. We summarized this literature, and drew upon studies performed in adult populations to augment areas in which no studies of sufficient quality have been performed in children and to highlight areas in need of research.
TE D
Results: Over the last 25 years, the incidence of nephrolithiasis among children has increased by approximately 6-10% annually and is now 50 per 100,000 adolescents. Kidney stones that form during childhood have a similar composition to those that form
EP
in adults. Approximately 75-80% of stones are composed of predominantly calcium oxalate, 5-10% are predominantly calcium phosphate, 10-20% struvite, and 5% are pure
AC C
uric acid. The recurrence rate of nephrolithiasis for patients in whom stones form during childhood is poorly defined. Ultrasound should be used as the initial imaging study to evaluate children with suspected nephrolithiasis, with non-contrast CT reserved for children in whom ultrasound is non-diagnostic and the suspicion of nephrolithiasis remains high. Current treatment strategies for children with kidney stone disease are based largely on extrapolation of studies performed among adult stone formers and single
ACCEPTED MANUSCRIPT
institution cohort or case series studies of children. Tamsulosin likely increases the spontaneous passage of ureteral stones in children. Increased water intake and reducing salt consumption should be recommended for all children with a history of kidney stones.
RI PT
Potassium citrate is a potentially effective medication for children with calcium oxalate stones and concomitant hypocitraturia as well as children with uric acid stones; however, long-term compliance with therapy and the effect on reducing stone recurrence among
SC
children are unknown. Based largely on efficacy in adult populations, thiazide diuretics should be considered in the treatment of children with calcium-based stones and
M AN U
persistent hypercalciuria refractory to reductions in salt intake.
Conclusions: The incidence of kidney stone disease among children is increasing, yet few randomized clinical trials or high quality observational studies have assessed whether dietary or pharmacologic interventions reduce the recurrence of kidney stones among
TE D
children. Collaborative efforts and randomized clinical trials are needed to determine the efficacy and effectiveness of alternative treatments for children with nephrolithiasis, particularly those with calcium oxalate stones and concomitant hypercalciuria and
EP
hypocitraturia. Additional areas in need of study are the optimal length of time for a trial of stone passage in children, the cost-effectiveness of medical expulsive therapy versus
AC C
analgesics alone, and the size and location of stones for which medical expulsive therapy is most effective.
ACCEPTED MANUSCRIPT
Introduction Nephrolithiasis is a major source of morbidity and health care expenditures in United States (US). Over the last 20 years, the prevalence of nephrolithiasis has increased
RI PT
70% among adults and the gender gap between men and women is narrowing.1
Furthermore, nephrolithiasis, once considered an adult disease, has become increasingly prevalent among children. Over the last 25 years, the incidence of nephrolithiasis among
SC
children has increased by approximately 6-10% annually and is now 50 per 100,000
adolescents.2 In 2000, nephrolithiasis accounted for $2.1 billion in annual US health care
M AN U
expenditures.3 This increase in the incidence of nephrolithiasis in children has implications for future health care spending, health services allocation, and will increase the prevalence of what, for many, is a chronic condition associated with substantial pain and morbidity.4 Most importantly, the emergence of kidney stones as a pediatric disease
TE D
necessitates that specialists who care for children with nephrolithiasis understand the optimal strategies to evaluate children with kidney stones and the effectiveness of nonsurgical interventions to decrease the risk of recurrence.
EP
The purpose of this review is to appraise the current literature on the diagnostic and metabolic evaluation of and dietary and pharmacologic interventions for children
AC C
with nephrolithiasis. A comprehensive review of the large number of, but rare, genetic diseases that cause kidney stones in childhood have been covered elsewhere and are beyond the scope of this review. Similarly, medical management for stones due to infectious causes, primary hyperoxaluria, and cystinuria are also not discussed. Finally, although this review focuses on the management of pediatric nephrolithiasis, it also draws upon studies performed in adult populations to augment areas in which no studies
ACCEPTED MANUSCRIPT
of sufficient quality have been performed in children and to highlight areas in need of research. Particular attention is paid to the as yet unknown effectiveness of alternative treatment strategies in reducing the recurrence of kidney stone disease in childhood.
RI PT
Methods
In consultation with a reference librarian, we searched MEDLINE, EMBASE, and the Cochrane Library from their inceptions to March 2014 for published articles on
SC
kidney stones in children. Search terms and/or keywords included “kidney stone OR urolith* OR nephrolith*”. The explosion feature of each database was employed
M AN U
and the search was limited to studies on subjects 18 years or younger, English language publications, and human studies. We excluded case reports, expert opinions, and editorials. Abstracts were reviewed to identify articles on evaluation and medical therapy of pediatric nephrolithiasis. In addition, the bibliographies of all potentially
TE D
relevant primary articles and review articles identified in the search were read to identify other relevant articles not detected in the database search. Full search terms are available upon request.
EP
Search Results
A total of 1,014 unique references were retrieved. No additional studies were
AC C
identified from review of article references. Eighteen previous systematic reviews were identified through search of the Cochrane library, although these were based on studies of adults. Based on review of the titles and abstracts, 110 of the 1,012 articles (11%) were potentially relevant to and within the scope of this review.
Acute Management
ACCEPTED MANUSCRIPT
Diagnostic Imaging Clinical practice guidelines and evidence support using ultrasound as the initial imaging study for children with suspected nephrolithiasis and reserving CT
RI PT
only for children with a non-diagnostic ultrasound in whom the clinical suspicion
for stones remains high. Although ultrasound is less sensitive and specific than CT,5, 6 ultrasound accurately identifies clinically significant kidney stones in children. In a study
SC
of 50 patients less than 18 years old with suspected nephrolithiasis, Passerotti et al.
determined the diagnostic performance of ultrasound to accurately localize kidney stones.
M AN U
Using CT as the gold standard, the sensitivity and specificity of ultrasound was 70% and 100%, respectively, when the radiologists interpreting the ultrasounds were blinded to CT results. In this population, the positive predictive value of ultrasound was 96% and the negative predictive value was 62%.6 Of the 13 stones that were not visualized on
TE D
ultrasound, only one was larger than 5mm. Three stones that were not visualized by ultrasound were in the ureter and the remainder were non-obstructive stones in the kidney. The authors therefore concluded that stones missed by ultrasound were likely of little
EP
clinical consequence. Similarly, Johnson et al. found that ultrasound correctly identified 89% of stones requiring surgical intervention.5
AC C
Non-contrast CT has nearly 100% sensitivity and specificity to identify kidney
stones. CT, however, delivers ionizing radiation, which is associated with an increased risk of cancer.7 Although the attributable risk of cancer from a single CT scan performed for kidney stones is small (0.2-0.3% above baseline), the cumulative risk is higher for those undergoing repeated studies.8 Highlighting the cumulative risk of radiation exposure, Routh et al. analyzed 7,921 children with kidney stones treated at hospitals
ACCEPTED MANUSCRIPT
within the Pediatric Hospital Inpatient Sample and observed that over 2,600 children underwent a median of 2 CT scans for a single kidney stone episode.9 Additionally, the
greater sensitivity of developing tissues to the effects of radiation.
RI PT
risk may be higher in children than in adults because of a longer life expectancy and
Given the good sensitivity of ultrasound in detecting clinically significant
stones and the radiation risk associated with CT, the American Urological Association
SC
in 2012, and the European Association of Urology in 2013 developed imaging guidelines for children with suspected nephrolithiasis.10, 11 Both groups recommend ultrasound as
M AN U
the first-line imaging modality with non-contrast CT reserved if ultrasound is nondiagnostic. Additionally, the Image Gently Alliance, founded by the Society for Pediatric Radiology, American College of Radiology, American Society for Radiologic Technologists, and the American Association of Physicists in Medicine,
TE D
began its campaign in 2007 to lower radiation exposure among children who need diagnostic imaging.12 Currently, it is not known if these guidelines will reduce unnecessary CT utilization. Future studies are necessary to identify barriers to selective
EP
use of CT in children with suspected nephrolithiasis.
AC C
Medical Expulsive Therapy
There have been few studies on patient and stone characteristics that predict
whether a ureteral stone will pass spontaneously in children. However, similar to stones in adults, it stands to reason that smaller, distal ureteral stones are more likely to pass than are larger, more proximal stones.13 For those stones in which spontaneous passage is deemed possible (usually < 10mm), medical expulsive therapy (MET), the use of alpha-
ACCEPTED MANUSCRIPT
blockers or calcium channel blockers to increase stone passage, may increase passage of ureteral stones and thus obviate the need for surgical intervention. The causal pathway underlying the potential effect of MET on stone passage is that alpha and calcium
RI PT
channel blockers dilate the ureter due to high densities of α1a, α1d, and calcium channel receptors in smooth muscle of the distal third of the ureter and ureterovesical junction. In adults, two meta-analyses of randomized controlled trials have been
SC
performed.14, 15 Both meta-analyses demonstrated that tamsulosin and nifedipine
increased passage of ureteral stones. Among adults, alpha-blockers also decrease time to
effective relative to analgesics alone.17
M AN U
stone passage,16 decrease analgesic requirements,16 and have been shown to be cost-
The evidence for the efficacy of MET in children is relatively sparse. To date, only three studies have tested whether MET increases the passage of ureteral stones
TE D
among children. Aydogdu and colleagues conducted a retrospective cohort study of 20 children who were prescribed ibuprofen and 19 who were prescribed doxazosin for ureteral stones.18 They did not observe any association between doxazosin and
EP
spontaneous passage. However, their sample size would have had only 10% power to detect a 15% difference in passage rates between the groups. Mokhless and colleagues
AC C
performed a prospective cohort study in which children with distal ureteral stones received tamsulosin or ibuprofen and placebo.19 More stones passed in the tamsulosin cohort (88%) versus the placebo group (64%; p < 0.01) and the time to passage was also shorter among those receiving tamsulosin (8 vs. 14 days; p
