Interventions for treating urinary stones in children

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

This review aims to assess the benefits and harms of different interventions for the treatment of urinary stones in children.

Background

Description of the condition

Urolithiasis or stone disease is a condition where crystalline mineral deposits are formed in the urinary tract. Metabolic and anatomical factors, iatrogenic and idiopathic causes all contribute to stone formation. In children infection is an important contributor to stone development.

Formation of the urinary stones is positively influenced by increased concentrations of uric acid, calcium, oxalate and cystine molecules. Crystallisation inhibitors such as citrate, magnesium, glycosaminoglycans and pyrophosphate play an important role as inhibitors in the formation of the urinary stones and their depletion may be the main cause of the stone formation.

The composition of the stones, their location in the urinary tract and prevalence of the disease varies around the world. The prevalence rate in low- to middle-income countries such as Pakistan and Turkey is 5% to 15% (Shah 1991) compared with 1% to 5% in high-income countries (Elsobky 2000; Yoshida 1990). Boys are affected more than girls with a male-to-female ratio of 3:1 (Rizvi 2002).

Urinary stones can be located in any part of the urinary tract. Many stones found in children born in low- to middle-income countries are located within the urinary bladder (Rizvi 2002; Rizvi 2003). There is some evidence to suggest that the predominant location of urinary stones has shifted from the bladder to the upper urinary tract over a 13-year period from 1987 to 2000 (Rizvi 2002). Of these, 75% to 80% have upper urinary tract stones and 5% are caused by infection (Ozokutan 2000).

The manifestation and clinical presentation of urinary stones in children differs from the adult population and can vary with age. Fifty per cent of children will present with abdominal pain, 33% with haematuria and 11% with infection. Children under the age of five years most commonly present with haematuria, while pain is a more common finding in older children. In children the localisation of pain is not as typical as in adults and flank pain radiating to the groin is rare (Santos-Victoriano 1998). Pain in children with stones can have a distribution such as appendicitis or gastroenteritis. In infants, the only presenting sign of stone disease might be urinary tract infection.

Diagnosis is confirmed by radiological evaluation which is also used to assess the size of the stone, its location, and the degree of possible urinary obstruction.

Description of the intervention

The most suitable management strategy depends on a number of factors, principally the size, location and composition of the stone. Other factors influencing management include the availability of different treatment options and local expertise, as well as anatomical variations in children with congenital abnormalities of the urinary tract. 

Extracorporeal shock wave lithotripsy (ESWL) is a commonly used therapy for children with smaller upper urinary tract stones. This technique is typically used for small to moderate stones between 4 mm to 10 mm but depends on there being adequate drainage of the urinary system below the level of the stone. ESWL can be also used for treatment of ureteric stones. Success rates and complications are significantly affected by location of the stone and can depend on the type of machine used.

In children with larger and more complex stone disease percutaneous nephrolithotomy (PCNL) is widely used. This technique is considered in children with large upper tract stones (1.5 cm or larger). Until recently this technique was limited by the availability of appropriately sized instruments; however paediatric size instruments are now available (Desai 2005).

Children with stones within the ureter or collecting system may be treated by ureterorenoscopy, although in smaller children the size of the ureteric orifice may be insufficient to accommodate an ureterorenoscope. Different lithotripsy techniques such as laser, ultrasound, and pneumatic lithotripsy can be utilised with ureterorenoscopy. This technique is being used in children with stone size from 4 mm where visualization during ESWL failed or cannot be done.

The last surgical technique used for stone removal is open stone surgery. This technique is most commonly employed in very young children with large stones or in children with a large stone which would require multiple endoscopic procedures. It is also indicated in children with a stone in the presence of congenital anomalies of the urinary system or orthopaedic anomalies where operative positioning is impossible. Open surgery is rarely indicated as first-line treatment in children. It has the advantage of very high primary stone clearance rates but this radical approach has obvious disadvantages.

A conservative method of stone removal is medical expulsion therapy. The concept of medical expulsion therapy is administration of medications to accelerate and facilitate the spontaneous passage of ureteric stones. Corticosteroids, hormones, nonsteroidal anti-inflammatory agents, calcium-channel blockers and alpha-adrenergic blockers are used in conservative management of stone disease.

The success of the intervention is measured by the stone-free rate. There is currently no stone-free rate consensus regarding the size of the stone. A child's capacity to pass a stone has been shown to be greater than in adults. This is likely due to higher tissue compliance. Kidney stones less than 3 mm are likely to pass spontaneously and the chance of passing a ureteric stone less than 5 mm is approximately 70%. The passage rate in stones greater than 5 mm does not depend on age in children older than one year (Pietrow 2002).

How the intervention might work

ESWL is deemed to be safe and effective. This technique is not thought to adversely affect kidney function or linear growth of the kidneys. There is also no risk of scarring and hypertension (Jayanthi 1999). The reported stone-free rates following treatment depend on the location and size of the stone. There is a strong positive correlation between the increasing size of the stone and ineffective stone clearance. The disadvantages of ESWL include the need for potential fluoroscopic localization of some stones and the inability to adequately focus the energy in smaller children, as the machines in use are designed for older patients. The equipment is bulky and cumbersome and difficult to move; in children the technique is typically performed under general anaesthesia, and many patients with kidney stones have significant comorbidities making this a significant consideration when multiple attempts at stone clearance may be required. Complications following ESWL are relatively commonplace and include urosepsis, haematuria, flank pain and ‘steinstrasse’. All of these complications are less common with second generation lithotripters (Kroovand 1987). The stone-free range for ESWL reported by most centres for moderate size stones is between 70% and 80% (Picramenos 1996; Van Horn 1995). ESWL is the least invasive procedure for the management of most types of stones in children.

PCNL in the children was performed first time by Woodside 1985 almost 30 years ago. Initial results were excellent with a reported stone-free rate of 100% with no complications. Subsequent publications have demonstrated a number of potential complications of PCNL include renal scarring (Wilson 1993) bleeding, postoperative infection and persistent urinary leakage.

Use of ureteroscopic techniques is similar to those in adults. Complete stone clearance rates of up to 90% have been reported with the use of a semi-rigid ureteroscope (Dogan 2011). The incidence of vesicoureteric reflux disease after ureteroscopy is very low (Thomas 1993).

Alpha-1 adrenergic receptors are located throughout the human ureter. The physiologic response to antagonism of these receptors is decreased contraction, decreased peristaltic frequency, and increased fluid bolus volume transported down the ureter. Alpha-blockers (specifically alpha-1 antagonists) increase the expulsion rate of distal ureteric stones, hence reducing the time to stone passage. The rate of spontaneous passage with no medical intervention for a stone of less than 5 mm located in the proximal ureter is 29% to 98% and 71% to 98% in the distal ureter (Segura 1997).

Why it is important to do this review

There is a lot of evidence providing information on management of stone disease in adults, but significantly less for children. Urinary stones are less prevalent in children than in adults, but are associated with significant morbidity. There is also evidence that the incidence is increasing (Clayton 2011). Once the diagnosis of stone disease in a child has been made and the child treated, the reoccurrence rate is high.

Objectives

This review aims to assess the benefits and harms of different interventions for the treatment of urinary stones in children.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at ESWL, PCNL, ureterorenoscopy, open surgery and medical expulsion therapy.

Types of participants

Inclusion criteria

All children (0 to 18 years) with urinary stones confirmed by radiological imaging who require surgical or medical intervention will be included.

Exclusion criteria

Studies must accurately detail the age of person receiving treatment to allow accurate comparison of outcomes. RCTs and quasi-RCTs including mixed populations of adults and children will be excluded unless data on children can be extracted. Studies which are including management of urinary bladder stones will be excluded as management of this is completely different to the management of the stone disease in upper urinary tract.

Types of interventions

The following interventions will be examined and compared.

  • ESWL

  • PCNL

  • Ureterorenoscopy

  • Open stone surgery

  • Medical expulsive therapy

Studies comparing surgical and medical management will be included.

Types of outcome measures

Primary outcomes
  1. Stone-free rate: complete stone clearance or clinically insignificant residual fragments ≤ 3 mm

  2. Adverse events and complications after treatment

  3. Number of second procedures for residual fragments ≥ 4 mm

Secondary outcomes
  1. Rate of second procedures for clinically insignificant residual fragments ≤ 3 mm

  2. Operative time

  3. Mean hospital stay

  4. Pain (time frame, pain scale, pain medication)

Search methods for identification of studies

Electronic searches

We will search the Cochrane Renal Group's Specialised Register through contact with the Trials Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials CENTRAL

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals & the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal-journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal & ClinicalTrials.gov

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies as well as a list of handsearched journals, conference proceedings and current awareness alerts are available in the 'Specialised Register' section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of clinical practice guidelines, review articles and relevant studies.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment, the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.

Unit of analysis issues

Multiple intervention groups are expected in this review. Careful analysis of these types of data will be taken to avoid unit of analysis errors.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing or writing to corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates (e.g. drop-outs, losses to follow-up and withdrawals) will be investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward will be critically appraised (Higgins 2011).

Assessment of heterogeneity

Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity. Subgroup analysis will be conducted for the size of the kidney stone (≥ 4 mm and < 5 mm; 5 mm to 10 mm; > 10 mm), location of the stone (renal pelvis, ureter, bladder) and for the comparison of different interventions (ESWL, PCNL, ureterorenoscopy and medical expulsion therapy). Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various treatments used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another treatment.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size.

  • Repeating the analysis excluding unpublished studies.

  • Repeating the analysis taking into account the risk of bias, as specified above.

  • Repeating the analysis excluding any very long or large studies to establish how much they dominate the results.

  • Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.

Acknowledgements

We wish to thank the referees for the comments and feedback during the preparation of this protocol.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Urolithiasis explode all trees

  2. (urolithiasis):ti,ab,kw in Trials

  3. (nephrolithiasis):ti,ab,kw in Trials

  4. (renal NEXT stone*):ti,ab,kw or (renal NEXT calcul*):ti,ab,kw or "renal colic":ti,ab,kw in Trials

  5. (kidney NEXT stone*):ti,ab,kw or (kidney NEXT calcul*):ti,ab,kw or "kidney colic":ti,ab,kw in Trials

  6. "ureteral NEXT stone*":ti,ab,kw or (ureteral NEXT calcul*):ti,ab,kw or "ureteral colic" or "ureteric colic":ti,ab,kw or (ureteric NEXT stone*):ti,ab,kw or (ureteric NEXT calcul*):ti,ab,kw in Trials

  7. (urinary NEXT stone*):ti,ab,kw or (urinary NEXT calcul*):ti,ab,kw in Trials

  8. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)

  9. MeSH descriptor Child explode all trees

  10. MeSH descriptor Infant explode all trees

  11. MeSH descriptor Adolescent, this term only

  12. (#9 OR #10 OR #11)

  13. (#8 AND#12)

MEDLINE
  1. exp Urolithiasis/

  2. (renal stone$ or renal calcul$ or renal colic).tw.

  3. (kidney stone$ or kidney calcul$ or kidney colic).tw.

  4. (ureter$ stone$ or ureter$ calcul$ or ureter$ colic).tw.

  5. (urinary stone$ or urinary calcul$).tw.

  6. urolithiasis.tw.

  7. nephrolithiasis.tw.

  8. or/1-7

  9. exp child/ or exp infant/ or Adolescent/

  10. and/8-9

EMBASE
  1. exp urolithiasis/

  2. (renal stone$ or renal calcul$ or renal colic).tw.

  3. (kidney stone$ or kidney calcul$ or kidney colic).tw.

  4. (ureter$ stone$ or ureter$ calcul$ or ureter$ colic).tw.

  5. (urinary stone$ or urinary calcul$).tw.

  6. urolithiasis.tw.

  7. nephrolithiasis.tw.

  8. or/1-7

  9. newborn/

  10. child/

  11. adolescent/

  12. or/9-11

  13. and/8,12

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

  1. Draft the protocol: LB, DC

  2. Study selection: LB, AA

  3. Extract data from studies: LB, AA

  4. Enter data into RevMan: LB, AA

  5. Carry out the analysis: LB, DC

  6. Interpret the analysis: LB, DC

  7. Draft the final review: LB, DC, MK

  8. Disagreement resolution: MK

  9. Update the review: LB

Declarations of interest

None known.

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