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Metabolic investigations
Intervention evidence review (A)
NICE Guideline, No. 118
Authors
National Guideline Centre (UK).1. Metabolic investigations
1.1. Review question: In people with renal or ureteric stones, what is the clinical and cost effectiveness of stone analysis, blood tests and urine tests compared to no test, when each is followed by the appropriate treatment for renal and ureteric stones, in order to improve patient outcomes?
1.2. Introduction
Laboratory testing can define a metabolic diagnosis in stone patients. Subsequent treatment can reduce the risk of recurrence of stones by modifying an individual’s metabolic status accordingly. Certain stone subgroups such as uric acid stones and cystine stones have established therapeutic pathways. However, the therapeutic pathway for the largest subgroup, mixed calcium stones, is unclear. Due to the size of this population, this group of stones have the biggest implications in terms of health resources.
Laboratory testing for a metabolic abnormality can range from basic testing which includes a stone analysis only, to advanced testing including blood and urine tests. Current practice is varied and it is currently unclear which metabolic laboratory tests should be done and whether testing should be done for all people with a stone, or just those at high risk of developing a recurrent stone. PICO table
For full details see the review protocol in appendix A.
1.3. Clinical evidence
1.3.1. Included studies
No relevant clinical studies were identified.
See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix H.
1.3.2. Excluded studies
See the excluded studies list in appendix I.
1.3.3. Summary of clinical studies included in the evidence review
None.
1.4. Economic evidence
1.4.1. Included studies
No relevant health economic studies were identified.
1.4.2. Excluded studies
No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.
See also the health economic study selection flow chart in appendix G.
1.4.3. Unit costs
1.5. Resource costs
The committee has made recommendations, for adults, based on this review (see section □) that stone analysis and serum calcium should be ‘considered’.
Unlike for stronger recommendations stating that interventions should be adopted, it is not possible to make a judgement about the potential resource impact to the NHS of recommendations regarding interventions that could be used, as uptake is too difficult to predict.
However, the committee noted that where this recommendation is implemented there is not expected to be a substantial impact on resources.
The recommendations made by the committee, for children, based on this review (see section Error! Reference source not found.) are not expected to have a substantial impact n resources.
1.6. Evidence statements
1.6.1. Clinical evidence statements
- No relevant published evidence was identified.
1.6.2. Health economic evidence statements
- No relevant economic evaluations were identified.
1.7. The committee’s discussion of the evidence
1.7.1. Interpreting the evidence
1.7.1.1. The outcomes that matter most
The committee agreed that stone recurrence, stone interventions, metabolic abnormalities found, quality of life, adverse events relating to the test or to the treatment and the number of people receiving treatment were the outcomes that were critical for decision making.
There was no evidence found for any of these outcomes.
1.7.1.2. The quality of the evidence
No evidence was found.
1.7.1.3. Benefits and harms
The committee considered that current practice for metabolic testing is variable and inconsistent, and can include a variety of different tests and combinations of tests. Basic metabolic testing would involve a stone analysis and serum calcium testing, and more advanced testing may include blood tests and urine tests carried out as a 24 hour urine collection, or commonly spot urine ratios in paediatric practice. In current practice, not all laboratories can do all metabolic tests, and therefore the samples may be sent externally to laboratories that can.
The committee discussed the benefits of conducting metabolic tests. They noted that stone analysis allows the composition of the stone to be identified, which can impact on the therapeutic pathway. For instance, there are known treatments for uric acid stones, cystine stones, and APRT deficiency; although the treatment pathway for calcium stones, the most common type of stone, is less well defined.
Serum calcium is also usually part of a basic metabolic workup, as this can lead to identification of treatable hypercalcaemic conditions such as primary hyperparathyroidism, which is common in people who produce stones. The committee noted that measuring calcium is inexpensive and therefore likely to be cost effective. The committee agreed that stone analysis and serum calcium should be a minimum standard of testing that can lead to identification of rare but impactful conditions that could be managed and treated. Given the lack of evidence however, and a lack of certainty on the cost effectiveness of stone analysis, a consider recommendation was made for stone analysis. The committee agreed that serum calcium should be measured in people with stones due to its low cost and potential for diagnosing conditions such as primary hyperparathroidism.
The committee also discussed that urine testing (different abnormalities can be tested for from a urine sample) can lead to the identification of conditions such as hypercalciuria and hypocitraturia, and noted that these conditions have been identified in the Prevention of Recurrence review (chapter K) as having effective treatments to prevent a future stone. However, the committee were unclear on both the clinical and cost effectiveness of these tests, and therefore agreed that a research recommendation would be beneficial in this area, to assess whether a full laboratory metabolic work up has additional benefit clinically, compared to stone analysis alone, and to assess the cost effectiveness of this. The committee agreed that this guidance could potentially reduce the amount of unnecessary testing, and increase the uptake of more specific, targeted tests. This may also lead to standardisation of metabolic testing within the UK.
The committee considered current practice regarding metabolic and laboratory testing in children and young people and noted that there is much variability around the country. They agreed that referral to a paediatric nephrologist or paediatric urologist with expertise in this area for assessment and metabolic investigations should be considered, but noted that many centres have paediatricians with an interest in nephrology who share care with a paediatric nephrologist who could undertake such investigations themselves.
1.7.2. Cost effectiveness and resource use
No economic evidence was identified for this question.
Unit costs were presented to the committee of different tests that might be undertaken as part of metabolic investigation. These were based on costs from the committee member’s hospitals. A stone analysis costs around £25. Blood tests are low cost at a few pounds. Urine tests are much more variable depending on the test themselves, with testing for citrate, oxalate, or cystine being the most expensive.
Ideally the committee wanted to know who should have metabolic testing (for example, perhaps only individuals considered high risk like recurrent stone formers), and what tests should be used. A stone analysis for example that provides information on the composition of the stone would direct the usefulness of investigation of any further abnormalities noted in blood and/or urine tests. The comparators involved are different combinations of tests, and can vary in cost depending on what tests are involved.
The trade-offs involved around metabolic testing are dependent on the prevalence of the conditions that will be identified, what management might be involved - and the effectiveness of the management at changing the probability of recurrence. Uncertainty around these factors for all the conditions that metabolic tests might predict makes it difficult to infer cost effectiveness. There are however two groups in particular where the prevalence is small but identifying the metabolic abnormality would lead to management pathways that are specific and well established – these are uric acid and cystine stones, and therefore there is a large benefit to identifying these people. The largest group, which is also more difficult to manage is the mixed calcium stones.
The committee consensus was that there should be a minimum standard on the type of metabolic work-up that should take place. Different tests provide different information. A stone analysis can identify the stone composition, then this can help identify the rare conditions that have management pathways (uric acid stones and cystine stones). Serum calcium can also identify primary hyperparathyroidism as those with high serum calcium would then have a parathyroid hormone test which would diagnose this. There was no clinical or economic evidence to support this, as the cost effectiveness, as mentioned above would depend on the prevalence of these rare conditions - and the benefit identification would lead to - traded-off against the cost of testing an initial population with stones. The prevalence of hyperparathyroidism in a renal stones population can be high because people with hypertparathyroidism are more likely to produce stones. Because a serum calcium test is low cost, and the population affected by renal stones is not very large (around 80,000 per year based on 2017 Hospital Episode Statistics data), a strong recommendation would not have a substantial resource impact, and thus an offer recommendation was made.
Anecdotally, more than half of patients do not have a stone available for analysis. Also not all hospitals have the facilities to undertake a stone analysis and the stone would have to be sent to another laboratory for analysis. As this was a consider recommendation, the resource impact of this is unclear. A stone is also more likely to be available if a patient had a URS, rather than an SWL (as the stone was fragmented and passed on its own – unless the patient brought it in), so the population this would apply to, is not likely to be the whole renal stones population. The committee also agreed that more stones being analysed is not likely to have a service impact as the stones can be analysed with the current services available.
A workup involving more tests in the majority of stone formers that do not fit into these rare disease groups (calcium stone formers) would be more costly, and this is the subject of a research recommendation to assess whether a full laboratory metabolic work up has additional benefit, compared to stone analysis alone, and to assess the cost effectiveness of this.
In children, it is generally established practice that they would have a more thorough metabolic workup than adults due to higher lifetime risk of recurrence and greater likelihood of an underlying genetic/metabolic cause than adults. Practice varies as to what tests specifically this might include. The committee opinion was that referral to a paediatric nephrologist or paediatric urologist who has expertise in laboratory tests for metabolic conditions, for appropriate investigation, should be considered. The child population with renal stones is very small.
1.7.3. Other factors the committee took into account
In the review on the prevention of recurrence, the committee made recommendations for certain interventions in subgroups of people with particular types of stones. This means that a stone analysis to be able to identify the type of stone would be a precursor to offering these interventions. As it has not been proven whether a stone analysis is cost effective in all patients, then those recommendations are ‘consider’ recommendations to reflect the strength of certainty in the balance of benefits and costs. This is because as explained above, assessing cost effectiveness of testing also requires knowledge of the effectiveness of interventions. Clinical questions often assess individual parts of a pathway, but these need to be taken together when assessing cost effectiveness because individual parts of a pathway have an impact on the rest of the pathway.
References
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- 3.
- Clifford-Mobley O, Sjogren A, Lindner E, Rumsby G. Urine oxalate biological variation in patients with primary hyperoxaluria. Urolithiasis. 2016; 44(4):333–7 [PubMed: 26857252]
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- Da Silva SFR, De Matos DC, Da Silva SL, Daher EDF, Campos HDH, Da Silva CAB. Chemical and morphological analysis of kidney stones: a double-blind comparative study. Acta Cirurgica Brasileira. 2010; 25(5):444–8 [PubMed: 20877956]
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- Gambaro G, Croppi E, Coe F, Lingeman J, Moe O, Worcester E et al. Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. Journal of Nephrology. 2016; 29(6):715–34 [PMC free article: PMC5080344] [PubMed: 27456839]
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Appendices
Appendix A. Review protocols
Question number: 5.1
Relevant section of Scope: 5 Metabolic investigations
| Field | Content |
|---|---|
| Review question | In people with renal or ureteric stones, what is the clinical and cost effectiveness of stone analysis, blood test and urine test compared to no test, when each is followed by the appropriate treatment for renal and ureteric stones, in order to improve patient outcomes? |
| Type of review question |
Diagnostic test-and-treat A review of health economic evidence related to the same review question was conducted in parallel with this review. For details see the health economic review protocol for this NICE guideline. |
| Objective of the review | To evaluate the clinical effectiveness of different metabolic tests/workups involving various tests when followed up by treatment for people with renal and ureteric stones |
| Eligibility criteria – population / disease / condition / issue / domain | All people with renal or ureteric stones. |
| Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s) | Index tests:
|
| Eligibility criteria – comparator(s) / control or reference (gold) standard |
Comparator index test: No test Comparator intervention: Diet/fluid |
| Outcomes and prioritisation |
Stone recurrence Stone interventions (surgery/admission /MET) Metabolic abnormalities found Quality of life Adverse events related to test Adverse events related to treatment Number of people receiving treatment |
| Eligibility criteria – study design | Randomised trials |
| Other inclusion exclusion criteria | - |
| Proposed sensitivity / subgroup analysis, or meta-regression |
Stratification – groups that cannot be combined: Adults (≥16 years) Children and young people (<16 years) First stone formers Recurrent stone formers Obese people People with malabsorptive gut disease Subgroups: People with diabetes |
| Selection process – duplicate screening / selection / analysis |
|
| Data management (software) |
|
| Information sources – databases and dates |
|
| Identify if an update | Not applicable |
| Author contacts |
https://www |
| Highlight if amendment to previous protocol | For details please see section 4.5 of Developing NICE guidelines: the manual. |
| Search strategy – for one database | For details please see appendix B |
| Data collection process – forms / duplicate | A standardised evidence table format will be used, and published as appendix D of the evidence report. |
| Data items – define all variables to be collected | For details please see evidence tables in Appendix D (clinical evidence tables) or H (health economic evidence tables). |
| Methods for assessing bias at outcome / study level |
Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group
http://www [Please document any deviations/alternative approach when GRADE isn’t used or if a modified GRADE approach has been used for non-intervention or non-comparative studies.] |
| Criteria for quantitative synthesis | For details please see section 6.4 of Developing NICE guidelines: the manual. |
| Methods for quantitative analysis – combining studies and exploring (in)consistency | For details please see the separate Methods report for this guideline. |
| Meta-bias assessment – publication bias, selective reporting bias | For details please see section 6.2 of Developing NICE guidelines: the manual. |
| Confidence in cumulative evidence | For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual. |
| Rationale / context – what is known | For details please see the introduction to the evidence review. |
| Describe contributions of authors and guarantor |
A multidisciplinary committee developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Andrew Dickinson in line with section 3 of Developing NICE guidelines: the manual. Staff from NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details please see Developing NICE guidelines: the manual. |
| Sources of funding / support | NGC is funded by NICE and hosted by the Royal College of Physicians. |
| Name of sponsor | NGC is funded by NICE and hosted by the Royal College of Physicians. |
| Roles of sponsor | NICE funds NGC to develop guidelines for those working in the NHS, public health and social care in England. |
| PROSPERO registration number | Not registered |
Table 3Health economic review protocol
| Review question | All questions – health economic evidence |
|---|---|
| Objectives | To identify economic studies relevant to any of the review questions. |
| Search criteria |
|
| Search strategy | An economic study search will be undertaken using population-specific terms and an economic study filter – see Appendix G [in the Full guideline]. |
| Review strategy | Studies not meeting any of the search criteria above will be excluded. Studies published before 2002, abstract-only studies and studies from non-OECD countries or the USA will also be excluded. Each remaining study will be assessed for applicability and methodological limitations using the NICE economic evaluation checklist which can be found in Appendix G of the 2014 NICE guidelines manual.13 Inclusion and exclusion criteria
Where there is discretion The health economist will make a decision based on the relative applicability and quality of the available evidence for that question, in discussion with the Committee if required. The ultimate aim is to include economic studies that are helpful for decision-making in the context of the guideline and the current NHS setting. If several studies are considered of sufficiently high applicability and methodological quality that they could all be included, then the health economist, in discussion with the Committee if required, may decide to include only the most applicable studies and to selectively exclude the remaining studies. All studies excluded on the basis of applicability or methodological limitations will be listed with explanation as excluded economic studies in Appendix M. The health economist will be guided by the following hierarchies. Setting:
|
Appendix B. Literature search strategies
The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017
For more detailed information, please see the Methodology Review. [Add cross reference]
B.1. Clinical search literature search strategy
A search was constructed using the following approach:
- Population AND Prognostic/risk factor terms AND Study filter(s)
A separate search was performed to identify studies about metabolic investigations (test-and-treat approach).
B.1.1. Metabolic investigations
Table 4Database date parameters and filters used
| Database | Dates searched | Search filter used |
|---|---|---|
| Medline (OVID) | 1946 – 7 December 2017 |
Exclusions Observational studies Diagnostic tests studies Prognostic studies |
| Embase (OVID) | 1974 – 7 December 2017 |
Exclusions Observational studies Diagnostic tests studies Prognostic studies |
| The Cochrane Library (Wiley) |
Cochrane Reviews to 2017 Issue 12 of 12 CENTRAL to 2017 Issue 11 of 12 DARE, and NHSEED to 2015 Issue 2 of 4 HTA to 2016 Issue 4 of 4 | None |
Medline (Ovid) search terms
| 1. | exp urolithiasis/ |
| 2. | (nephrolitiasis or nephrolith or nephroliths or urolithias?s or ureterolithias?s).ti,ab. |
| 3. | ((renal or kidney* or urinary or ureter* or urethra*) adj3 (stone* or calculi or calculus or calculosis or lithiasis or c?olic*)).ti,ab. |
| 4. | stone disease*.ti,ab. |
| 5. | ((calculi or calculus or calcium oxalate or cystine) adj3 (crystal* or stone* or lithiasis)).ti,ab. |
| 6. | or/1–5 |
| 7. | letter/ |
| 8. | editorial/ |
| 9. | news/ |
| 10. | exp historical article/ |
| 11. | Anecdotes as Topic/ |
| 12. | comment/ |
| 13. | case report/ |
| 14. | (letter or comment*).ti. |
| 15. | or/7–14 |
| 16. | randomized controlled trial/ or random*.ti,ab. |
| 17. | 15 not 16 |
| 18. | animals/ not humans/ |
| 19. | exp Animals, Laboratory/ |
| 20. | exp Animal Experimentation/ |
| 21. | exp Models, Animal/ |
| 22. | exp Rodentia/ |
| 23. | (rat or rats or mouse or mice).ti. |
| 24. | or/17–23 |
| 25. | 6 not 24 |
| 26. | limit 25 to English language |
| 27. | Hypercalcemia/ |
| 28. | (hypercalcemia or hypercalcaemia).ti,ab. |
| 29. | Hypercalciuria/ |
| 30. | hypercalciuria.ti,ab. |
| 31. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (calcium or Ca)).ti,ab. |
| 32. | exp Hyperoxaluria/ |
| 33. | hyperoxaluria.ti,ab. |
| 34. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (oxalate* or C2O4-2 or ethanedioate)).ti,ab. |
| 35. | hyperuricosuria.ti,ab. |
| 36. | Hyperuricemia/ |
| 37. | (hyperuricemia or hyperuricaemia).ti,ab. |
| 38. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 uric acid).ti,ab. |
| 39. | hypernatriuria.ti,ab. |
| 40. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (sodium or Na)).ti,ab. |
| 41. | Cystine/ |
| 42. | Cystinuria/ |
| 43. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 cystine).ti,ab. |
| 44. | hypocitraturia.ti,ab. |
| 45. | ((reduce* or decrease* or low* or less* or drop*) adj3 citrate*).ti,ab. |
| 46. | hypomagnesuria.ti,ab. |
| 47. | ((reduce* or decrease* or low* or less* or drop*) adj3 (magnesium or Mg)).ti,ab. |
| 48. | ((metabolic* or blood* or urine) adj2 (analys* or test* or investigat*)).ti,ab. |
| 49. | (urinalysis or full blood count or FBC).ti,ab. |
| 50. | or/27–49 |
| 51. | 26 and 50 |
| 52. | prognosis/ |
| 53. | (predict* or prognos*).ti,ab. |
| 54. | Logistic models/ |
| 55. | Disease progression/ |
| 56. | or/52–55 |
| 57. | Epidemiologic studies/ |
| 58. | Observational study/ |
| 59. | exp Cohort studies/ |
| 60. | (cohort adj (study or studies or analys* or data)).ti,ab. |
| 61. | ((follow up or observational or uncontrolled or non randomi#ed or epidemiologic*) adj (study or studies or data)).ti,ab. |
| 62. | ((longitudinal or retrospective or prospective or cross sectional) and (study or studies or review or analys* or cohort* or data)).ti,ab. |
| 63. | Controlled Before-After Studies/ |
| 64. | Historically Controlled Study/ |
| 65. | Interrupted Time Series Analysis/ |
| 66. | (before adj2 after adj2 (study or studies or data)).ti,ab. |
| 67. | or/57–66 |
| 68. | exp case control study/ |
| 69. | case control*.ti,ab. |
| 70. | or/68–69 |
| 71. | 67 or 70 |
| 72. | Cross-sectional studies/ |
| 73. | (cross sectional and (study or studies or review or analys* or cohort* or data)).ti,ab. |
| 74. | or/72–73 |
| 75. | 67 or 74 |
| 76. | 67 or 70 or 74 |
| 77. | exp “sensitivity and specificity”/ |
| 78. | (sensitivity or specificity).ti,ab. |
| 79. | ((pre test or pretest or post test) adj probability).ti,ab. |
| 80. | (predictive value* or PPV or NPV).ti,ab. |
| 81. | likelihood ratio*.ti,ab. |
| 82. | likelihood function/ |
| 83. | ((area under adj4 curve) or AUC).ti,ab. |
| 84. | (receive* operat* characteristic* or receive* operat* curve* or ROC curve*).ti,ab. |
| 85. | (diagnos* adj3 (performance* or accurac* or utilit* or value* or efficien* or effectiveness)).ti,ab. |
| 86. | gold standard.ab. |
| 87. | or/77–86 |
| 88. | 56 or 76 or 87 |
| 89. | 51 and 88 |
Embase (Ovid) search terms
| 1. | exp urolithiasis/ |
| 2. | (nephrolitiasis or nephrolith or nephroliths or urolithias?s or ureterolithias?s).ti,ab. |
| 3. | ((renal or kidney* or urinary or ureter* or urethra*) adj3 (stone* or calculi or calculus or calculosis or lithiasis or c?olic*)).ti,ab. |
| 4. | stone disease*.ti,ab. |
| 5. | ((calculi or calculus or calcium oxalate or cystine) adj3 (crystal* or stone* or lithiasis)).ti,ab. |
| 6. | or/1–5 |
| 7. | letter.pt. or letter/ |
| 8. | note.pt. |
| 9. | editorial.pt. |
| 10. | case report/ or case study/ |
| 11. | (letter or comment*).ti. |
| 12. | or/7–11 |
| 13. | randomized controlled trial/ or random*.ti,ab. |
| 14. | 12 not 13 |
| 15. | animal/ not human/ |
| 16. | nonhuman/ |
| 17. | exp Animal Experiment/ |
| 18. | exp Experimental Animal/ |
| 19. | animal model/ |
| 20. | exp Rodent/ |
| 21. | (rat or rats or mouse or mice).ti. |
| 22. | or/14–21 |
| 23. | 6 not 22 |
| 24. | limit 23 to English language |
| 25. | *hypercalcemia/ |
| 26. | (hypercalcemia or hypercalcaemia).ti,ab. |
| 27. | *hypercalciuria/ |
| 28. | hypercalciuria.ti,ab. |
| 29. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (calcium or Ca)).ti,ab. |
| 30. | exp *hyperoxaluria/ |
| 31. | hyperoxaluria.ti,ab. |
| 32. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (oxalate* or C2O4-2 or ethanedioate)).ti,ab. |
| 33. | hyperuricosuria.ti,ab. |
| 34. | *hyperuricemia/ |
| 35. | (hyperuricemia or hyperuricaemia).ti,ab. |
| 36. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 uric acid).ti,ab. |
| 37. | hypernatriuria.ti,ab. |
| 38. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (sodium or Na)).ti,ab. |
| 39. | *cystine/ |
| 40. | *cystinuria/ |
| 41. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 cystine).ti,ab. |
| 42. | hypocitraturia.ti,ab. |
| 43. | ((reduce* or decrease* or low* or less* or drop*) adj3 citrate*).ti,ab. |
| 44. | hypomagnesuria.ti,ab. |
| 45. | ((reduce* or decrease* or low* or less* or drop*) adj3 (magnesium or Mg)).ti,ab. |
| 46. | ((metabolic* or blood* or urine) adj2 (analys* or test* or investigat*)).ti,ab. |
| 47. | (urinalysis or full blood count or FBC).ti,ab. |
| 48. | or/25–47 |
| 49. | 24 and 48 |
| 50. | Clinical study/ |
| 51. | Observational study/ |
| 52. | family study/ |
| 53. | longitudinal study/ |
| 54. | retrospective study/ |
| 55. | prospective study/ |
| 56. | cohort analysis/ |
| 57. | follow-up/ |
| 58. | cohort*.ti,ab. |
| 59. | 57 and 58 |
| 60. | (cohort adj (study or studies or analys* or data)).ti,ab. |
| 61. | ((follow up or observational or uncontrolled or non randomi#ed or epidemiologic*) adj (study or studies or data)).ti,ab. |
| 62. | ((longitudinal or retrospective or prospective or cross sectional) and (study or studies or review or analys* or cohort* or data)).ti,ab. |
| 63. | (before adj2 after adj2 (study or studies or data)).ti,ab. |
| 64. | or/50–56,59–63 |
| 65. | exp case control study/ |
| 66. | case control*.ti,ab. |
| 67. | or/65–66 |
| 68. | 64 or 67 |
| 69. | cross-sectional study/ |
| 70. | (cross sectional and (study or studies or review or analys* or cohort* or data)).ti,ab. |
| 71. | or/69–70 |
| 72. | 64 or 71 |
| 73. | 64 or 67 or 71 |
| 74. | exp “sensitivity and specificity”/ |
| 75. | (sensitivity or specificity).ti,ab. |
| 76. | ((pre test or pretest or post test) adj probability).ti,ab. |
| 77. | (predictive value* or PPV or NPV).ti,ab. |
| 78. | likelihood ratio*.ti,ab. |
| 79. | ((area under adj4 curve) or AUC).ti,ab. |
| 80. | (receive* operat* characteristic* or receive* operat* curve* or ROC curve*).ti,ab. |
| 81. | (diagnos* adj3 (performance* or accurac* or utilit* or value* or efficien* or effectiveness)).ti,ab. |
| 82. | diagnostic accuracy/ |
| 83. | diagnostic test accuracy study/ |
| 84. | gold standard.ab. |
| 85. | or/74–84 |
| 86. | exp prognosis/ |
| 87. | prognostic assessment/ |
| 88. | (predict* or prognos*).ti,ab. |
| 89. | disease course/ |
| 90. | statistical model/ |
| 91. | or/86–90 |
| 92. | 73 or 85 or 91 |
| 93. | 49 and 92 |
Cochrane Library (Wiley) search terms
| #1. | MeSH descriptor: [Urolithiasis] explode all trees |
| #2. | (nephrolitiasis or nephrolith or urolithiasis):ti,ab |
| #3. | ((renal or kidney or urinary or ureteric or ureteral or ureter) near/2 (stone* or calculi or calculus or calculosis or lithiasis or colic)):ti,ab |
| #4. | (stone disease*):ti,ab |
| #5. | ((calculi or calculus or calcium oxalate or cystine) near/2 (crystal* or stone* or lithiasis)):ti,ab |
| #6. | (or #1–#5) |
| #7. | MeSH descriptor: [Hypercalcemia] explode all trees |
| #8. | (hypercalcemia or hypercalcaemia):ti,ab |
| #9. | MeSH descriptor: [Hypercalciuria] explode all trees |
| #10. | hypercalciuria:ti,ab |
| #11. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 (calcium or Ca)):ti,ab |
| #12. | MeSH descriptor: [Hyperoxaluria] explode all trees |
| #13. | hyperoxaluria:ti,ab |
| #14. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 (oxalate* or C2O4-2 or ethanedioate)):ti,ab |
| #15. | hyperuricosuria:ti,ab |
| #16. | MeSH descriptor: [Hyperuricemia] explode all trees |
| #17. | (hyperuricemia or hyperuricaemia):ti,ab |
| #18. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 uric acid):ti,ab |
| #19. | hypernatriuria:ti,ab |
| #20. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 (sodium or Na)):ti,ab |
| #21. | MeSH descriptor: [Cystine] explode all trees |
| #22. | MeSH descriptor: [Cystinuria] explode all trees |
| #23. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 cystine):ti,ab |
| #24. | hypocitraturia:ti,ab |
| #25. | ((reduce* or decrease* or low* or less* or drop*) near/3 citrate*):ti,ab |
| #26. | hypomagnesuria:ti,ab |
| #27. | ((reduce* or decrease* or low* or less* or drop*) near/3 (magnesium or Mg)):ti,ab |
| #28. | ((metabolic* or blood* or urine) near/2 (analys* or test* or investigat*)):ti,ab |
| #29. | (urinalysis or full blood count or FBC):ti,ab |
| #30. | (or #7–#29) |
| #31. | #6 and #30 |
B.1.2. Metabolic investigations – test-and-treat approach
Table 5Database date parameters and filters used
| Database | Dates searched | Search filter used |
|---|---|---|
| Medline (OVID) | 1946 – 23 January 2018 |
Exclusions Randomised controlled trials Systematic review studies |
| Embase (OVID) | 1974 – 23 January 2018 |
Exclusions Randomised controlled trials Systematic review studies |
| The Cochrane Library (Wiley) |
Cochrane Reviews to 2018 Issue 1 of 12 CENTRAL to 2018 Issue 12 of 12 DARE, and NHSEED to 2015 Issue 2 of 4 HTA to 2016 Issue 4 of 4 | None |
Medline (Ovid) search terms
| 1. | exp urolithiasis/ |
| 2. | (nephrolitiasis or nephrolith or nephroliths or urolithias?s or ureterolithias?s).ti,ab. |
| 3. | ((renal or kidney* or urinary or ureter* or urethra*) adj3 (stone* or calculi or calculus or calculosis or lithiasis or c?olic*)).ti,ab. |
| 4. | stone disease*.ti,ab. |
| 5. | ((calculi or calculus or calcium oxalate or cystine) adj3 (crystal* or stone* or lithiasis)).ti,ab. |
| 6. | or/1–5 |
| 7. | letter/ |
| 8. | editorial/ |
| 9. | news/ |
| 10. | exp historical article/ |
| 11. | Anecdotes as Topic/ |
| 12. | comment/ |
| 13. | case report/ |
| 14. | (letter or comment*).ti. |
| 15. | or/7–14 |
| 16. | randomized controlled trial/ or random*.ti,ab. |
| 17. | 15 not 16 |
| 18. | animals/ not humans/ |
| 19. | exp Animals, Laboratory/ |
| 20. | exp Animal Experimentation/ |
| 21. | exp Models, Animal/ |
| 22. | exp Rodentia/ |
| 23. | (rat or rats or mouse or mice).ti. |
| 24. | or/17–23 |
| 25. | 6 not 24 |
| 26. | limit 25 to English language |
| 27. | ((stone* or calculi or calculus or crystal*) adj3 (analys* or test* or investigat* or evaluat* or etiolog* or morpholog* or compos*)).ti,ab. |
| 28. | Chemistry Techniques, Analytical/ |
| 29. | (chemical adj (analys* or analytic* or test* or investigat* or technique*)).ti,ab. |
| 30. | Crystallography/ |
| 31. | (optical crystallography or stereomicroscopy or thermogravimetry or thermal analysis).ti,ab. |
| 32. | ((scanning electron or polari?ed or polari?ing) adj microscopy).ti,ab. |
| 33. | X-Ray Diffraction/ |
| 34. | (x ray adj2 diffraction).ti,ab. |
| 35. | Spectrum Analysis/ |
| 36. | (spectrum adj2 analy*).ti,ab. |
| 37. | X-Ray Absorption Spectroscopy/ |
| 38. | ((x ray or xray or infra red or infrared or Raman or Fourier) adj3 spectroscopy).ti,ab. |
| 39. | (dual adj (source or energy) adj (CT or computed tomograph*)).ti,ab. |
| 40. | or/27–39 |
| 41. | ((metabolic* or blood* or urine or 24h or 24 hour) adj2 (analys* or test* or investigat*)).ti,ab. |
| 42. | (urinalysis or full blood count or FBC).ti,ab. |
| 43. | Hypercalcemia/ |
| 44. | (hypercalcemia or hypercalcaemia).ti,ab. |
| 45. | Hypercalciuria/ |
| 46. | hypercalciuria.ti,ab. |
| 47. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (calcium or Ca)).ti,ab. |
| 48. | Hyperuricemia/ |
| 49. | (hyperuricemia or hyperuricaemia or hyperuricosuria or hyper uricosuria or hypo uricosuria or hypouricosuria).ti,ab. |
| 50. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten* or reduce* or decrease* or low* or less* or drop*) adj3 uric acid).ti,ab. |
| 51. | exp Hyperoxaluria/ |
| 52. | hyperoxaluria.ti,ab. |
| 53. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (oxalate* or C2O4-2 or ethanedioate)).ti,ab. |
| 54. | hypocitraturia.ti,ab. |
| 55. | ((reduce* or decrease* or low* or less* or drop*) adj3 citrate*).ti,ab. |
| 56. | hypernatriuria.ti,ab. |
| 57. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (sodium or Na)).ti,ab. |
| 58. | Cystine/ |
| 59. | Cystinuria/ |
| 60. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 cystine).ti,ab. |
| 61. | or/40–60 |
| 62. | 26 and 61 |
| 63. | randomized controlled trial.pt. |
| 64. | controlled clinical trial.pt. |
| 65. | randomi#ed.ti,ab. |
| 66. | placebo.ab. |
| 67. | randomly.ti,ab. |
| 68. | Clinical Trials as topic.sh. |
| 69. | trial.ti. |
| 70. | or/63–69 |
| 71. | Meta-Analysis/ |
| 72. | exp Meta-Analysis as Topic/ |
| 73. | (meta analy* or metanaly* or metaanaly* or meta regression).ti,ab. |
| 74. | ((systematic* or evidence*) adj3 (review* or overview*)).ti,ab. |
| 75. | (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab. |
| 76. | (search strategy or search criteria or systematic search or study selection or data extraction).ab. |
| 77. | (search* adj4 literature).ab. |
| 78. | (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab. |
| 79. | cochrane.jw. |
| 80. | ((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab. |
| 81. | or/71–80 |
| 82. | 62 and (70 or 81) |
Embase (Ovid) search terms
| 1. | exp urolithiasis/ |
| 2. | (nephrolitiasis or nephrolith or nephroliths or urolithias?s or ureterolithias?s).ti,ab. |
| 3. | ((renal or kidney* or urinary or ureter* or urethra*) adj3 (stone* or calculi or calculus or calculosis or lithiasis or c?olic*)).ti,ab. |
| 4. | stone disease*.ti,ab. |
| 5. | ((calculi or calculus or calcium oxalate or cystine) adj3 (crystal* or stone* or lithiasis)).ti,ab. |
| 6. | or/1–5 |
| 7. | letter.pt. or letter/ |
| 8. | note.pt. |
| 9. | editorial.pt. |
| 10. | case report/ or case study/ |
| 11. | (letter or comment*).ti. |
| 12. | or/7–11 |
| 13. | randomized controlled trial/ or random*.ti,ab. |
| 14. | 12 not 13 |
| 15. | animal/ not human/ |
| 16. | nonhuman/ |
| 17. | exp Animal Experiment/ |
| 18. | exp Experimental Animal/ |
| 19. | animal model/ |
| 20. | exp Rodent/ |
| 21. | (rat or rats or mouse or mice).ti. |
| 22. | or/14–21 |
| 23. | 6 not 22 |
| 24. | limit 23 to English language |
| 25. | stone analysis/ |
| 26. | ((stone* or calculi or calculus or crystal*) adj3 (analys* or test* or investigat* or evaluat* or etiolog* or morpholog* or compos*)).ti,ab. |
| 27. | *chemical analysis/ |
| 28. | (chemical adj (analys* or analytic* or test* or investigat* or technique*)).ti,ab. |
| 29. | *crystallography/ |
| 30. | (optical crystallography or stereomicroscopy or thermogravimetry or thermal analysis).ti,ab. |
| 31. | ((scanning electron or polari?ed or polari?ing) adj microscopy).ti,ab. |
| 32. | *x ray diffraction/ |
| 33. | (x ray adj2 diffraction).ti,ab. |
| 34. | *spectroscopy/ |
| 35. | *x ray absorption spectroscopy/ |
| 36. | ((x ray or xray or infra red or infrared or Raman or Fourier) adj3 spectroscopy).ti,ab. |
| 37. | (dual adj (source or energy) adj (CT or computed tomograph*)).ti,ab. |
| 38. | or/25–37 |
| 39. | *urinalysis/ |
| 40. | ((metabolic* or blood* or urine or 24h or 24 hour) adj2 (analys* or test* or investigat*)).ti,ab. |
| 41. | (urinalysis or full blood count or FBC).ti,ab. |
| 42. | *hypercalcemia/ |
| 43. | (hypercalcemia or hypercalcaemia).ti,ab. |
| 44. | *hypercalciuria/ |
| 45. | hypercalciuria.ti,ab. |
| 46. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (calcium or Ca)).ti,ab. |
| 47. | *hyperuricemia/ |
| 48. | (hyperuricemia or hyperuricaemia or hyperuricosuria or hyper uricosuria or hypo uricosuria or hypouricosuria).ti,ab. |
| 49. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten* or reduce* or decrease* or low* or less* or drop*) adj3 uric acid).ti,ab. |
| 50. | exp *hyperoxaluria/ |
| 51. | hyperoxaluria.ti,ab. |
| 52. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (oxalate* or C2O4-2 or ethanedioate)).ti,ab. |
| 53. | hypocitraturia.ti,ab. |
| 54. | ((reduce* or decrease* or low* or less* or drop*) adj3 citrate*).ti,ab. |
| 55. | hypernatriuria.ti,ab. |
| 56. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 (sodium or Na)).ti,ab. |
| 57. | *cystine/ |
| 58. | *cystinuria/ |
| 59. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) adj3 cystine).ti,ab. |
| 60. | or/38–59 |
| 61. | 24 and 60 |
| 62. | random*.ti,ab. |
| 63. | factorial*.ti,ab. |
| 64. | (crossover* or cross over*).ti,ab. |
| 65. | ((doubl* or singl*) adj blind*).ti,ab. |
| 66. | (assign* or allocat* or volunteer* or placebo*).ti,ab. |
| 67. | crossover procedure/ |
| 68. | single blind procedure/ |
| 69. | randomized controlled trial/ |
| 70. | double blind procedure/ |
| 71. | or/62–70 |
| 72. | systematic review/ |
| 73. | meta-analysis/ |
| 74. | (meta analy* or metanaly* or metaanaly* or meta regression).ti,ab. |
| 75. | ((systematic* or evidence*) adj3 (review* or overview*)).ti,ab. |
| 76. | (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab. |
| 77. | (search strategy or search criteria or systematic search or study selection or data extraction).ab. |
| 78. | (search* adj4 literature).ab. |
| 79. | (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab. |
| 80. | cochrane.jw. |
| 81. | ((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab. |
| 82. | or/72–81 |
| 83. | 61 and (71 or 82) |
Cochrane Library (Wiley) search terms
| #1. | MeSH descriptor: [Urolithiasis] explode all trees |
| #2. | (nephrolitiasis or nephrolith or urolithiasis):ti,ab |
| #3. | ((renal or kidney or urinary or ureteric or ureteral or ureter) near/2 (stone* or calculi or calculus or calculosis or lithiasis or colic)):ti,ab |
| #4. | (stone disease*):ti,ab |
| #5. | ((calculi or calculus or calcium oxalate or cystine) near/2 (crystal* or stone* or lithiasis)):ti,ab |
| #6. | (or #1–#5) |
| #7. | ((stone* or calculi or calculus or crystal*) near/3 (analys* or test* or investigat* or evaluat* or etiolog* or morpholog* or compos*)):ti,ab |
| #8. | MeSH descriptor: [Chemistry Techniques, Analytical] explode all trees |
| #9. | chemical near/1 (analys* or analytic* or test* or investigat* or technique*):ti,ab |
| #10. | MeSH descriptor: [Crystallography] explode all trees |
| #11. | (optical crystallography or stereomicroscopy or thermogravimetry or thermal analysis):ti,ab |
| #12. | ((scanning electron or polari?ed or polari?ing) near microscopy):ti,ab |
| #13. | MeSH descriptor: [X-Ray Diffraction] explode all trees |
| #14. | (x ray near/2 diffraction):ti,ab |
| #15. | MeSH descriptor: [Spectrum Analysis] explode all trees |
| #16. | (spectrum near/2 analy*):ti,ab |
| #17. | MeSH descriptor: [X-Ray Absorption Spectroscopy] explode all trees |
| #18. | ((x ray or xray or infra red or infrared or Raman or Fourier) near/3 spectroscopy):ti,ab |
| #19. | (dual near/1 (source or energy) near/1 (CT or computed tomograph*)):ti,ab |
| #20. | (or #7–#19) |
| #21. | ((metabolic* or blood* or urine or 24h or 24 hour) near/2 (analys* or test* or investigat*)):ti,ab |
| #22. | (urinalysis or full blood count or FBC):ti,ab |
| #23. | MeSH descriptor: [Hypercalcemia] explode all trees |
| #24. | (hypercalcemia or hypercalcaemia):ti,ab |
| #25. | MeSH descriptor: [Hypercalciuria] explode all trees |
| #26. | hypercalciuria:ti,ab |
| #27. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 (calcium or Ca)):ti,ab |
| #28. | MeSH descriptor: [Hyperuricemia] explode all trees |
| #29. | (hyperuricemia or hyperuricaemia or hyperuricosuria or hyper uricosuria or hypo uricosuria or hypouricosuria):ti,ab |
| #30. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten* or reduce* or decrease* or low* or less* or drop*) near/3 uric acid):ti,ab |
| #31. | MeSH descriptor: [Hyperoxaluria] explode all trees |
| #32. | hyperoxaluria:ti,ab |
| #33. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 (oxalate* or C2O4-2 or ethanedioate)):ti,ab |
| #34. | hypocitraturia:ti,ab |
| #35. | ((reduce* or decrease* or low* or less* or drop*) near/3 citrate*):ti,ab |
| #36. | hypernatriuria:ti,ab |
| #37. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 (sodium or Na)):ti,ab |
| #38. | MeSH descriptor: [Cystine] explode all trees |
| #39. | MeSH descriptor: [Cystinuria] explode all trees |
| #40. | ((high* or raise* or increase* or elevat* or excess* or lift* or uplift* or inflat* or heighten*) near/3 cystine):ti,ab |
| #41. | (or #20–#40) |
| #42. | #6 and #41 |
B.2. Health Economics literature search strategy
Health economic evidence was identified by conducting a broad search relating to renal and ureteric stones population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics studies.
Table 6Database date parameters and filters used
| Database | Dates searched | Search filter used |
|---|---|---|
| Medline | 2014 – 9 March 2018 |
Exclusions Health economics studies |
| Embase | 2014 – 9 March 2018 |
Exclusions Health economics studies |
| Centre for Research and Dissemination (CRD) |
HTA - Inception – 9 March 2018 NHSEED - Inception to March 2015 | None |
Medline (Ovid) search terms
| 1. | exp urolithiasis/ |
| 2. | (nephrolitiasis or nephrolith or nephroliths or urolithias?s or ureterolithias?s).ti,ab. |
| 3. | ((renal or kidney* or urinary or ureter* or urethra*) adj3 (stone* or calculi or calculus or calculosis or lithiasis or c?olic*)).ti,ab. |
| 4. | stone disease*.ti,ab. |
| 5. | ((calculi or calculus or calcium oxalate or cystine) adj3 (crystal* or stone* or lithiasis)).ti,ab. |
| 6. | or/1–5 |
| 7. | letter/ |
| 8. | editorial/ |
| 9. | news/ |
| 10. | exp historical article/ |
| 11. | Anecdotes as Topic/ |
| 12. | comment/ |
| 13. | case report/ |
| 14. | (letter or comment*).ti. |
| 15. | or/7–14 |
| 16. | randomized controlled trial/ or random*.ti,ab. |
| 17. | 15 not 16 |
| 18. | animals/ not humans/ |
| 19. | exp Animals, Laboratory/ |
| 20. | exp Animal Experimentation/ |
| 21. | exp Models, Animal/ |
| 22. | exp Rodentia/ |
| 23. | (rat or rats or mouse or mice).ti. |
| 24. | or/17–23 |
| 25. | 6 not 24 |
| 26. | limit 25 to English language |
| 27. | Economics/ |
| 28. | Value of life/ |
| 29. | exp “Costs and Cost Analysis”/ |
| 30. | exp Economics, Hospital/ |
| 31. | exp Economics, Medical/ |
| 32. | Economics, Nursing/ |
| 33. | Economics, Pharmaceutical/ |
| 34. | exp “Fees and Charges”/ |
| 35. | exp Budgets/ |
| 36. | budget*.ti,ab. |
| 37. | cost*.ti. |
| 38. | (economic* or pharmaco?economic*).ti. |
| 39. | (price* or pricing*).ti,ab. |
| 40. | (cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab. |
| 41. | (financ* or fee or fees).ti,ab. |
| 42. | (value adj2 (money or monetary)).ti,ab. |
| 43. | or/27–42 |
| 44. | 26 and 43 |
Embase (Ovid) search terms
| 1. | exp urolithiasis/ |
| 2. | (nephrolitiasis or nephrolith or nephroliths or urolithias?s or ureterolithias?s).ti,ab. |
| 3. | ((renal or kidney* or urinary or ureter* or urethra*) adj3 (stone* or calculi or calculus or calculosis or lithiasis or c?olic*)).ti,ab. |
| 4. | stone disease*.ti,ab. |
| 5. | ((calculi or calculus or calcium oxalate or cystine) adj3 (crystal* or stone* or lithiasis)).ti,ab. |
| 6. | or/1–5 |
| 7. | letter.pt. or letter/ |
| 8. | note.pt. |
| 9. | editorial.pt. |
| 10. | case report/ or case study/ |
| 11. | (letter or comment*).ti. |
| 12. | or/7–11 |
| 13. | randomized controlled trial/ or random*.ti,ab. |
| 14. | 12 not 13 |
| 15. | animal/ not human/ |
| 16. | nonhuman/ |
| 17. | exp Animal Experiment/ |
| 18. | exp Experimental Animal/ |
| 19. | animal model/ |
| 20. | exp Rodent/ |
| 21. | (rat or rats or mouse or mice).ti. |
| 22. | or/14–21 |
| 23. | 6 not 22 |
| 24. | limit 23 to English language |
| 25. | health economics/ |
| 26. | exp economic evaluation/ |
| 27. | exp health care cost/ |
| 28. | exp fee/ |
| 29. | budget/ |
| 30. | funding/ |
| 31. | budget*.ti,ab. |
| 32. | cost*.ti. |
| 33. | (economic* or pharmaco?economic*).ti. |
| 34. | (price* or pricing*).ti,ab. |
| 35. | (cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab. |
| 36. | (financ* or fee or fees).ti,ab. |
| 37. | (value adj2 (money or monetary)).ti,ab. |
| 38. | or/25–37 |
| 39. | 24 and 38 |
NHS EED and HTA (CRD) search terms
| #1. | MeSH DESCRIPTOR urolithiasis EXPLODE ALL TREES |
| #2. | (((nephrolitiasis or nephrolith or urolithiasis))) |
| #3. | ((((renal or kidney or urinary or ureteric or ureteral or ureter or urethra*) adj2 (stone* or calculi or calculus or calculosis or lithiasis or colic)))) |
| #4. | ((stone disease*)) |
| #5. | ((((calculi or calculus) adj2 (stone* or lithiasis)))) |
| #6. | (#1 OR #2 OR #3 OR #4 OR #5) |
Appendix C. Clinical evidence selection
Figure 1Flow chart of clinical study selection for the review of metabolic investigations
Appendix D. Clinical evidence tables
None.
Appendix E. Forest plots
None
Appendix F. GRADE tables
None.
Appendix G. Health economic evidence selection
Figure 2Flow chart of economic study selection for the guideline
Appendix H. Health economic evidence tables
None
Appendix I. Excluded studies
I.1. Excluded clinical studies
Table 7Studies excluded from the clinical review
| Study | Exclusion reason |
|---|---|
| Auge 20061 | Incorrect study design (case-control study) |
| Channa 20072 | Incorrect study design (cohort study) |
| Clifford-Mobley 20163 | Incorrect population (people with hyperoxaluria) |
| Da Silva 20104 | Incorrect study design (cross-sectional study) |
| Dhandapani 20165 | Incorrect study design (cohort study) |
| Durgawale 20106 | Incorrect study design (cohort study) |
| Ferraro 20177 | Incorrect study design (regression analysis of recurrence rate) |
| Gambaro 20168 | Incorrect study design (narrative review and consensus statements) |
| Hess 20129 | Incorrect study design (non-systematic review) |
| Krautschick 199910 | Incorrect study design (non-systematic review) |
| Naseri 201012 | Incorrect study design (cohort study) |
| Naseri 201311 | Incorrect study design (non-systematic review) |
| Orakzai 200414 | Incorrect study design (cohort study) |
| Skolarikos 201515 | Incorrect study design (narrative review and consensus statements) |
| Tiselius 201716 | Incorrect study design (non-systematic review) |
I.2. Excluded health economic studies
None
Appendix J. Research recommendations
J.1. Full metabolic assessment
Research Question: What is the clinical and cost effectiveness of full metabolic assessment compared with standard advice alone, in people with recurrent calcium oxalate stones?
Background
Prevalence of stone risk factors in a single centre study of a London medical stone clinic: low urine volume, hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia was 5.6%, 38%, 7.9%, 18% and 23% respectively (Ferraro 2015 QJM). Other large studies have found that 10–20% of stone formers have initial urine volumes < 1 litre/24h.
There is no accepted practice in terms of which, if any, of the identified biochemical risk factors are treated.
Example protocol treatments for each test result are given below. Efficacy is proven only for low urine volume. Stone analysis by infra-red spectroscopy – allows precise diagnosis of non-calcium stones.
- low urine volume <2L/24hr - increase fluid intake >2.5 L/24h aiming to pass >2L urine/24h.
- hypercalciuria >7 mmol/24hr (6.5 mmol/24h in females): salt reduction, > 10 mmol/24h: salt reduction and thiazide diuretic
- hyperoxaluria >400 micromole/24hr: avoid high oxalate foods, take/recommend calcium supplements
- hyperuricosuria > 4.0 mmol/24hr - reduce animal protein intake, potassium citrate to enable urine pH>6.5, allopurinol if gout
- hypocitraturia <2.5 mmol/24hr - potassium citrate 10 ml (28 mmol) tds
| PICO question |
Population: Adults with multiple or recurrent renal or ureteric stones (two or more confirmed stone episodes within the last 5 years) made predominantly of calcium oxalate, where there is no clinically obvious underlying cause. All have received general diet and fluid advice and basic safety blood tests. Intervention:
Outcomes: Primary: stone related events (including spontaneous stone passage, flank pain, infections, new stone growth or the need for intervention) Secondary: metabolic abnormalities found, Quality of life (EQ-5D-3L), cost- per QALY,, resource use: metabolic abnormalities corrected; metabolic interventions provided (tests done, treating abnormalities), compliance. Follow up: 36–60 months |
|---|---|
| Importance to patients or the population | Recurrent kidney stone formers often have severe disruption to their lives with frequent episodes of severe pain and multiple surgical procedures. A number of RCTs have shown the benefit of treating certain metabolic abnormalities associated with kidney stones (e.g. hypercalciuria, hypocitraturia). There are no test-treat RCTs assessing the effectiveness of full metabolic assessment to detect abnormalities which might be corrected to help reduce stone related events. The research will allow an evidenced approach to the metabolic evaluation of idiopathic calcium oxalate stone forming patients, which is the largest single group of patients with renal and ureteric stones. Currently, metabolic evaluation consists of non-standardised sequence of tests, is not applied systematically to this patient group, and the outcomes are often biochemical rather than symptom-based. |
| Relevance to NICE guidance | This research will reduce the existing uncertainty regarding which metabolic tests should be done in the largest single group of patients with renal and ureteric stones. It will assess the clinical effectiveness and cost-effectiveness of a full test and treat approach. There is currently no evidence in a UK based study on which to base recommendations. It will enable future guidelines to clearly recommend an evidence based approach to the prevention of recurrent stones in this large group of patients. |
| Relevance to the NHS | Kidney stones are very common and there has been a large increase in hospital episodes and resource use for kidney stones. It is thought that this is a public health problem related to dietary changes and increases in obesity hypertension and diabetes. Kidney stone prevention is very patchy around the country and there is much uncertainty about the value of full metabolic assessment. This research would standardise the approach to the metabolic evaluation so giving the largest single group of stone patients equal access to the correct evaluation and treatment. By correctly assessing patients and treating appropriately the incidence of recurrent stone episodes should be reduced so reducing the need to access health resources, in particular imaging and surgery. Equally, information would be obtained on the cost, necessity and benefit of metabolic tests which would then inform decisions on whether testing should be a tertiary level or more generally available NHS service. |
| National priorities | There is a strong link between diabetes, obesity and kidney stones and limiting the impact of these conditions is one of the top research priorities of the NHS. It is also a priority to test interventions and maximize effectiveness and cost-effectiveness. |
| Current evidence base | The current evidence base does not allow the Guideline Committee to make a recommendation apart from a consensus recommendations and therefore the grade and the recommendations are not an improvement on other published guidelines. There is a need for a stronger evidence based recommendation of the correct use of metabolic testing in patients with renal and ureteric stones. |
| Equality | Currently full metabolic evaluation is available to patients without defined criteria, and in only a handful of centres throughout the country. This research will allow a case to be made for more accessible testing if required, or concentration in a specialist centres on a referral basis. |
| Study design | Diagnostic test and treat |
| Feasibility | The time scale will need to be 36–60 months to ensure adequate follow-up so that differences in interventions can be seen between the groups. The cost will be acceptable as the metabolic test panel is standard in the NHS centres that provide it. |
| Other comments | This trial is important to ensure that metabolic evaluation is standardised in this large stone-forming group, and therefore the correct treatment to reduce their lifetime risk of recurrent stone episodes. Previous large scale studies have all been epidemiological or have used biochemical outcomes, rather than patient outcomes, and have not assessed costeffectiveness. |
| Importance | High: the research is essential to inform future updates of key recommendations in the guideline. |
Tables
Table 1PICO characteristics of review question
| Population | People (adults, children and young people) with symptomatic and asymptomatic renal or ureteric stones |
|---|---|
| Index test + treatment | Index tests:
|
| Comparison | Comparator index test:
|
| Outcomes |
|
| Study design | Randomised controlled trials (RCTs) |
Table 2UK costs of tests
| Test | Cost | Sources |
|---|---|---|
| Stone analysis | £25.44 | 1 GC member |
| Blood tests: | ||
| calcium levels | £1.38 – £.3.33 (a) | 3 GC members |
| uric acid levels | £0.90 – £1.36 | 3 GC members |
| Urine tests: | ||
| calcium levels | £2.34 – £2.37 | 2 GC members |
| oxalate levels | £20.50 – £30.40 | 3 GC members |
| uric acid levels | £1.23 – £2.44 | 2 GC members |
| citrate level | £10.51 – £30.40 | 3 GC members |
| sodium level | £1.30 – £2.36 | 3 GC members |
| Cystine |
for spot analysis (screening) = £8.53 more complex testing: = £38.40 – £69.61 | 3 GC members |
| Urine pH | £3.09 – £11.28 | 1 GC member |
| Volume (24h) | Dependent on tests undertaken on the urine (so including any of the above costs), and some consumable costs for the equipment loaned to the patient. | |
- (a)
£3.33 is for a bone profile
Final
Intervention evidence review (A)
This evidence review was developed by the National Guideline Centre
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.