When to assess for RRT

National Guideline Centre (UK)

When to assess for RRT

Renal replacement therapy and conservative management

Evidence review

NICE Guideline, No. 107

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2018 Oct.

ISBN-13: 978-1-4731-3107-1

1. When to assess for RRT

1.1. Review question: When should people with progression to later stages of CKD be assessed for RRT?

1.2. Introduction

The NICE guideline on Chronic Kidney Disease in adults (CG182) makes recommendations about when people should be initially referred to nephrology services in secondary care. Recommendations are needed on when the process of assessment and preparation for RRT or conservative management should commence. This review applies to people requiring referral to secondary care renal services and those already in these services but who are not yet having assessment for RRT.

1.3. PICO table

For full details see the review protocol in appendix A.

Table 1

PICO characteristics of review question.

1.4. Clinical evidence

1.4.1. Included studies

No randomised studies were identified. One non-randomised study was included in the review;⁵⁸ this is summarised in Table 2 below. Evidence from this study is summarised in the clinical evidence summary below (Table 3).

See also the study selection flow chart in appendix C, study evidence tables in appendix D, GRADE tables in appendix F and forest plots in appendix E.

1.4.2. Excluded studies

See the excluded studies list in appendix I.

1.4.3. Summary of clinical studies included in the evidence review

Table 2

Summary of studies included in the evidence review.

See appendix D for full evidence tables.

1.4.4. Quality assessment of clinical studies included in the evidence review

Table 3

Clinical evidence summary: Late referral versus early referral.

See appendix F for full GRADE tables.

1.5. Economic evidence

1.5.1. Included studies

No relevant health economic studies were included.

1.5.2. Excluded studies

No health economic studies that were relevant to this question were identified but excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in appendix G.

1.5.3. Unit costs

Relevant current UK unit costs were provided to the committee to aid consideration of cost effectiveness. Costs of nephrology outpatient appointments are summarised in Table 4. Costs of CKD-related inpatient admissions are summarised in Table 5. If a patient starts dialysis urgently requiring inpatient admission this will incur an additional inpatient stay cost (as well as the hospital dialysis costs recorded separately). Access-related costs are summarised in Table 6.

Table 4

UK NHS reference costs 2015/16 for nephrology outpatient appointments.

Table 5

UK NHS reference costs 2015/16 for CKD inpatient admissions.

Table 6

UK NHS reference costs 2015/16 for dialysis access-related inpatient and outpatient procedures.

1.6. Resource impact

The recommendations made based on this review (see section Error! Reference source not found.) are not expected to have a substantial impact on resources.

1.7. Evidence statements

1.7.1. Clinical evidence statements

There was no evidence identified for quality of life, hospitalisation, time to failure of RRT form, late referral rates, pre-emptive transplantation rates, proportion starting on modality of choice, proportion receiving RRT after assessment, symptom scores/functional measures, psychological distress and mental wellbeing, cognitive impairment, experience of care, growth, malignancy or adverse events.

There was no clinically important difference in all-cause mortality from day 90 to 1 year (1 study, very low quality evidence).

There was a clinically important harm of late referral for all-cause mortality in the first 90 days (1 study, very low quality evidence).

1.7.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.8. The committee’s discussion of the evidence

1.8.1. Interpreting the evidence

1.8.1.1. The outcomes that matter most

Critical outcomes were mortality, quality of life, hospitalisation, symptom scores and time to failure of RRT.

Other important outcomes were numbers of measures of mental wellbeing and cognitive impairment, malignancy and adverse events. Growth is considered an important outcome in children. We were also interested in outcomes representing people’s experience of care.

1.8.1.2. The quality of the evidence

The GC noted that the only study identified for this review did not specifically assess the importance of the timing of referral for RRT assessment but rather assessed the importance of the timing of a nephrology referral. A nephrology referral may be for a variety of reasons other than assessment for RRT, including investigating the aetiology of the condition and actions to treat and monitor the condition and preserve renal function. The assessment for RRT happens within renal services, but often requires transfer of patient care from an individual consultant-led review to a multidisciplinary review. This usually follows recognition that the person with kidney disease has now reached a stage where plans need to be made to manage the progressive nature of their condition, and the multidisciplinary team is needed to cover all aspects of the person’s care and future care plans. Therefore, the committee agreed that this evidence was appropriate to include but noted that it did not exactly mirror the target intervention of the review

The committee noted that the evidence identified in this review represented a comparison between very late referral versus not very late referral. The very late referral group perhaps more accurately represented people having an unplanned start to dialysis, although the population had been documented as having a diagnosis of CKD for at least one year. The committee noted the impact of the study being set in the US with a different primary care system than in the UK.

The committee noted that referral to nephrologist is only a proxy for the full multidisciplinary assessment required.

1.8.1.3. Benefits and harms

The evidence showed at 90 days there was a harm of late referral in terms of higher mortality compared to earlier referral. At 90 days to a year the difference in mortality was no longer clinically different

The committee discussed how practically the amount of time required for assessment reflects both the speed of accomplishing the various tasks involved in assessment but also the time needed for people to deliberate over decisions that have to be made in this period.

The committee noted that alongside the more obvious benefits of early referral (for example ensuring full preparation and assessment, avoiding unplanned starts and improving pre-emptive transplantation rates) there are potential harms of early referral in the form of unnecessary treatment or psychological burden for people who are referred for consideration of RRT but then never go on to require it. Therefore when considering when to refer for assessment there is a need to balance allowing sufficient time to prepare for RRT with minimising referral of those that will never receive it.

1.8.2. Cost effectiveness and resource use

No relevant health economic studies were identified.

The potential benefits of assessing people earlier described above (reducing unplanned starters and increasing pre-emptive transplant rates) may result in lower resource use and benefits to patients that may increase QALYs. The committee highlighted that reducing unplanned starters would be expected to reduce costs because they will generally require a hospital admission for a number of days and it is likely it will also require additional access procedures. Improving access to pre-emptive transplant was also considered likely to result in better outcomes for patients and may reduce costs (due to avoiding starting dialysis and reducing transplant failure).

However, conversely the potential harms described above (assessment in people who do not go on to need RRT) would increase resource use and could potentially have a negative impact on patient QALYs if quality of life was reduced. The cost of this would relate to outpatient appointments for general assessment for RRT and, in parallel, assessment and tests to assess suitability for transplant. A series of healthcare contacts with doctors and/or nurses is required to support the decision making process. If dialysis access is created, this will be associated with resource use such as an outpatient appointment with a surgeon, scans, the surgery itself and follow-up.

No studies were available that allowed quantitative assessment of this trade-off. However, the committee felt that referring people at least 1 year before it is anticipated they would need RRT was practical and would strike a reasonable balance between maximising adequate assessment and preparation without unduly increasing the number of people being assessed. The committee highlighted that this generally reflects current practice should not be a significant change in practice or have a substantial resource impact to the NHS in England.

1.8.3. Other considerations

None.

References

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Appendices

Appendix A. Review protocols

Table 7. Review protocol: When to assess for RRT

Table 8. Health economic review protocol

Appendix B. Literature search strategies

B.1. Clinical search literature search strategy

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869

For more detailed information, please see the Methodology Review.

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 9. Database date parameters and filters used

Line 81 (Medline) and line 75 (Embase) were added to the search strategy to reduce the number of items retrieved for observational studies as the overall results from the search were very large.
This was checked to ensure that relevant studies were not excluded.

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to renal replacement therapy 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.

Table 10. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review of when to assess for RRT

Appendix D. Clinical evidence tables

Download PDF (168K)

Appendix E. Forest plots

E.1. Late referral versus early referral for RRT in people diagnosed with chronic renal failure

Figure 2. Mortality (90 days)

Figure 3. Mortality (90 days-1 year)

Appendix F. GRADE tables

Table 11. Clinical evidence profile: Late referral versus early referral for RRT in people diagnosed with chronic renal failure

Appendix G. Health economic evidence selection

Figure 4. Flow 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 12. Studies excluded from the clinical review

I.2. Excluded health economic studies

Studies that meet the review protocol population and interventions and economic study design criteria but have not been included in the review based on applicability and/or methodological quality are summarised below with reasons for exclusion.

Table 13. Studies excluded from the health economic review

Final

Guideline number NG107

These evidence reviews were 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.

Bookshelf ID: NBK577491PMID: 35133751

Table 1PICO characteristics of review question

Population	Children, young people and adults with CKD stage 3 to 5 Stratified by: Age (<2, 2 to <18, 18 to <70, ≥70) BAME vs non-BAME Diabetes mellitus vs no diabetes mellitus
Intervention(s)	Assessment for RRT; Early
Comparison(s)	Assessment for RRT; Late
Outcomes	Critical Patient, family/carer health-related QoL (continuous) Mortality (dichotomous and time to event) Hospitalisation (rates or continuous) Time to failure of RRT form (time to event) Important Late referral rates (rates or dichotomous) Pre-emptive transplantation rates (rates or dichotomous) Proportion starting on modality of choice (rates or dichotomous) Proportion receiving RRT after assessment (rates or dichotomous) Symptom scores and functional measures (continuous) Psychological distress and mental wellbeing (continuous) Cognitive impairment (dichotomous) Patient, family/carer experience of care (continuous) Growth (continuous) Malignancy (dichotomous) Adverse events Infections (dichotomous) Vascular access issues (dichotomous) Dialysis access issues (dichotomous) Acute transplant rejection episodes (dichotomous)
Study design	RCTs only, if insufficient RCT evidence, NRS that adjust for key confounders (age, ethnicity, comorbidities and baseline health) will be included

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Winkelmayer 2003⁵⁸

Retrospective cohort study

N=3014

Early versus late nephrologist referral

(1): Early, n= 1975, patients who saw a nephrologist >90 days before their first chronic dialysis

(2): Late, n=1039, patients who were not seen >90 days before their first chronic dialysis

Adults who had been diagnosed with a renal disease >1 year before first dialysis – no lower or upper age limit

Prevalence of diabetes of 45%

Ethnicity 74% white

Critical:

Mortality (0-90 days, 90 days -1 year)

Setting: USA

Table 3Clinical evidence summary: Late referral versus early referral

Late compared to early referral for RRT
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with early referral	Risk difference with late (95% CI)
All-cause mortality	3014 (1 study) 90 days	VERY LOW¹ due to risk of bias	HR 1.75 (1.48 to 2.08)	235 per 1000	139 more per 1000 (from 92 more to 192 more)
All-cause mortality	2178 (1 study) 90 days-1 year	VERY LOW¹ due to risk of bias	HR 1.03 (0.84 to 1.26)	274 per 1000	7 more per 1000 (from 38 fewer to 58 more)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

Table 4UK NHS reference costs 2015/16 for nephrology outpatient appointments

Currency code	Currency description	No. of attendances	National average unit cost
Consultant led
WF01A	Non-Admitted Face to Face Attendance, Follow-Up	576,355	£153
WF01B	Non-Admitted Face to Face Attendance, First	88,492	£194
WF01C	Non-Admitted Non-Face to Face Attendance, Follow-Up	9,450	£86
WF01D	Non-Admitted Non-Face to Face Attendance, First	1,399	£72
WF02A	Multiprofessional Non-Admitted Face to Face Attendance, Follow-Up	29,964	£169
WF02B	Multiprofessional Non-Admitted Face to Face Attendance, First	2,951	£206
WF02C	Multiprofessional Non-Admitted Non Face to Face Attendance, Follow-Up	11	£139
Non-consultant led
WF01A	Non-Admitted Face to Face Attendance, Follow-Up	92,331	£108
WF01B	Non-Admitted Face to Face Attendance, First	6,947	£130
WF01C	Non-Admitted Non-Face to Face Attendance, Follow-Up	8,587	£45
WF01D	Non-Admitted Non-Face to Face Attendance, First	328	£96
WF02A	Multiprofessional Non-Admitted Face to Face Attendance, Follow-Up	452	£135
WF02B	Multiprofessional Non-Admitted Face to Face Attendance, First	24	£139

: Source: NHS reference costs 2015/16¹⁰

Table 5UK NHS reference costs 2015/16 for CKD inpatient admissions

Admission	Currency code	Currency description	Number of FCEs	National average unit cost	Weighted average
Elective inpatient	LA08G	Chronic Kidney Disease with Interventions, with CC Score 6+	155	£6,344	£2,369
Elective inpatient	LA08H	Chronic Kidney Disease with Interventions, with CC Score 3-5	327	£4,420
Elective inpatient	LA08J	Chronic Kidney Disease with Interventions, with CC Score 0-2	686	£3,475
Elective inpatient	LA08K	Chronic Kidney Disease without Interventions, with CC Score 11+	74	£2,737
Elective inpatient	LA08L	Chronic Kidney Disease without Interventions, with CC Score 8-10	151	£2,368
Elective inpatient	LA08M	Chronic Kidney Disease without Interventions, with CC Score 5-7	317	£1,782
Elective inpatient	LA08N	Chronic Kidney Disease without Interventions, with CC Score 3-4	437	£1,446
Elective inpatient	LA08P	Chronic Kidney Disease without Interventions, with CC Score 0-2	1,362	£1,281
Non-elective long stay	LA08G	Chronic Kidney Disease with Interventions, with CC Score 6+	764	£7,122	£3,398
Non-elective long stay	LA08H	Chronic Kidney Disease with Interventions, with CC Score 3-5	610	£5,083
Non-elective long stay	LA08J	Chronic Kidney Disease with Interventions, with CC Score 0-2	541	£3,826
Non-elective long stay	LA08K	Chronic Kidney Disease without Interventions, with CC Score 11+	480	£3,939
Non-elective long stay	LA08L	Chronic Kidney Disease without Interventions, with CC Score 8-10	963	£3,405
Non-elective long stay	LA08M	Chronic Kidney Disease without Interventions, with CC Score 5-7	1,655	£2,967
Non-elective long stay	LA08N	Chronic Kidney Disease without Interventions, with CC Score 3-4	1,416	£2,446
Non-elective long stay	LA08P	Chronic Kidney Disease without Interventions, with CC Score 0-2	1,761	£2,085
Non-elective short stay	LA08H	Chronic Kidney Disease with Interventions, with CC Score 3-5	13	£988	£687
Non-elective short stay	LA08J	Chronic Kidney Disease with Interventions, with CC Score 0-2	13	£793
Non-elective short stay	LA08K	Chronic Kidney Disease without Interventions, with CC Score 11+	126	£613
Non-elective short stay	LA08L	Chronic Kidney Disease without Interventions, with CC Score 8-10	378	£570
Non-elective short stay	LA08M	Chronic Kidney Disease without Interventions, with CC Score 5-7	923	£552
Non-elective short stay	LA08N	Chronic Kidney Disease without Interventions, with CC Score 3-4	1,012	£592
Non-elective short stay	LA08P	Chronic Kidney Disease without Interventions, with CC Score 0-2	2,234	£808
Day case	LA08J	Chronic Kidney Disease with Interventions, with CC Score 0-2	2	£604	£379
Day case	LA08K	Chronic Kidney Disease without Interventions, with CC Score 11+	9	£670
Day case	LA08L	Chronic Kidney Disease without Interventions, with CC Score 8-10	11	£311
Day case	LA08M	Chronic Kidney Disease without Interventions, with CC Score 5-7	137	£331
Day case	LA08N	Chronic Kidney Disease without Interventions, with CC Score 3-4	408	£340
Day case	LA08P	Chronic Kidney Disease without Interventions, with CC Score 0-2	1,940	£389
Regular Day or Night Admissions	LA08L	Chronic Kidney Disease without Interventions, with CC Score 8-10	2	£359	£365
Regular Day or Night Admissions	LA08M	Chronic Kidney Disease without Interventions, with CC Score 5-7	7	£355
Regular Day or Night Admissions	LA08N	Chronic Kidney Disease without Interventions, with CC Score 3-4	10	£337
Regular Day or Night Admissions	LA08P	Chronic Kidney Disease without Interventions, with CC Score 0-2	1,652	£365

: Source: NHS reference costs 2015/16¹⁰

: Abbreviations: FCE = finished consultant episodes

Table 6UK NHS reference costs 2015/16 for dialysis access-related inpatient and outpatient procedures

Currency description	Currency code	Admission	Number of FCEs	National average unit cost	Weighted average
HD access: tunnelled line
Adults
Insertion of Tunnelled Central Venous Catheter, 19 years and over	YR41A	Elective inpatient	544	£1,558	£1,149
		Non-elective long stay	280	£2,157
		Non-elective short stay	1,042	£2,043
		Day case	3573	£750
		Regular Day or Night Admissions	73	£1,038
		Out-patient	2	£368
Attention to Central Venous Catheter, 19 years and over	YR43A	Elective inpatient	752	£1,062	£383
		Non-elective long stay	9	£3,738
		Non-elective short stay	946	£917
		Day case	44697	£354
		Regular Day or Night Admissions	10651	£407
		Out-patient	90	£98
Removal of Central Venous Catheter, 19 years and over	YR44A	Elective inpatient	314	£1,043	£570
		Non-elective long stay	25	£4,336
		Non-elective short stay	797	£1,109
		Day case	6880	£459
		Regular Day or Night Admissions	793	£727
		Out-patient	95	£198
Children
Insertion of Tunnelled Central Venous Catheter, 18 years and under	YR41B	Elective inpatient	114	£2,886	£2,367
		Non-elective long stay	11	£5,926
		Non-elective short stay	77	£2,536
		Day case	145	£1,640
		Regular Day or Night Admissions	3	£343
Attention to Central Venous Catheter, 18 years and under	YR43B	Elective inpatient	95	£1,209	£650
		Non-elective long stay	8	£4,672
		Non-elective short stay	232	£712
		Day case	2392	£654
		Regular Day or Night Admissions	353	£342
Removal of Central Venous Catheter, 18 years and under	YR44B	Elective inpatient	172	£1,533	£1,323
		Non-elective long stay	11	£16,682
		Non-elective short stay	164	£1,243
		Day case	894	£1,163
		Regular Day or Night Admissions	80	£708
HD access: AV fistula or graft
Open Arteriovenous Fistula, Graft or Shunt Procedures	YQ42Z	Elective inpatient	2735	£2,451	£2,012
		Non-elective long stay	144	£3,661
		Non-elective short stay	306	£1,826
		Day case	5291	£1,763
		Regular Day or Night Admissions	9	£665
		Out-patient	28	£199
Attention to Arteriovenous Fistula, Graft or Shunt	YR48Z	Elective inpatient	647	£1,715	£1,433
		Non-elective long stay	140	£2,824
		Non-elective short stay	359	£2,079
		Day case	2978	£1,235
		Regular Day or Night Admissions	17	£523
		Out-patient	3	£228
PD access: PD catheter
Renal Replacement Peritoneal Dialysis Associated Procedures	LA05Z	Elective inpatient	892	£1,819	£1,148
		Non-elective long stay	32	£5,701
		Non-elective short stay	297	£1,288
		Day case	1,588	£996
		Regular Day or Night Admissions	46	£339
		Out-patient	470	£71

: Source: NHS reference costs 2015/16¹⁰

: Abbreviations: FCE = finished consultant episodes

(a): HRG YR43A/B Attention to Central Venous Catheter, includes OPCS L921 Fibrin sheath stripping of access catheter, L922 Wire brushing of access catheter, L923 Thrombolysis of access catheter, L928 Other specified unblocking of access catheter, L929 Unspecified unblocking of access catheter, L913 Attention to central venous catheter NEC

(b): HRG YQ42 includes OPCS L746 Creation of graft fistula for dialysis, L741 Insertion of arteriovenous prosthesis, L742 Creation of arteriovenous fistula NEC, L743 Attention to arteriovenous shunt, L744 Banding of arteriovenous fistula, L745 Thrombectomy of arteriovenous fistula, L748 Other specified arteriovenous shunt, L749 Unspecified arteriovenous shunt, L752 Repair of acquired arteriovenous fistula

(c): HRG YR48 includes OPCS L746 Injection of radiocontrast substance into arteriovenous fistula

(d): HRG LA05 includes OPCS X411 Insertion of ambulatory peritoneal dialysis catheter, X412 Removal of ambulatory peritoneal dialysis catheter, X418 Other specified placement of ambulatory apparatus for compensation for renal failure, X419 Unspecified placement of ambulatory apparatus for compensation for renal failure, X421 Insertion of temporary peritoneal dialysis catheter, X428 Other specified placement of other apparatus for compensation for renal failure, X429 Unspecified placement of other apparatus for compensation for renal failure.

Table 7Review protocol: When to assess for RRT

Field	Content
Review question	When should people progressing through later stages of CKD be assessed for RRT?
Type of review question	Intervention
Objective of the review	Identify evidence of clinical and cost effectiveness of different timing strategies for RRT assessment
Eligibility criteria – population / disease / condition / issue / domain	Children, young people and adults with CKD stage 3 to 5 Stratified by: Age (<2, 2 to <18, 18 to <70, ≥70) BAME vs non-BAME DM vs no DM
Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s)	Early assessment by eGFR (e.g. 15-20/20-25/25-30ml/min) Late assessment by eGFR (e.g. 10-15ml/min) Early assessment by time from start of dialysis (either actual or estimated from risk tool – e.g. Tangri score) Late assessment by time from start of dialysis (either actual or estimated from risk tool – e.g. Tangri score) Assessment to include at minimum consultation with RRT specialist healthcare professional, aimed at decision making around RRT/conservative management and/or preparation for RRT
Eligibility criteria – comparator(s) / control or reference (gold) standard	Any early strategy compared with any late strategy
Outcomes and prioritisation	Critical Patient, family/carer health-related QoL (continuous) Mortality (dichotomous and time to event) Hospitalisation (rates or continuous) Time to failure of RRT form (time to event) Important Symptom scores and functional measures (continuous) Late referral rates (rates or dichotomous) Pre-emptive transplantation rates (rates or dichotomous) Proportion starting on modality of choice (rates or dichotomous) Proportion receiving RRT after assessment (rates or dichotomous) Psychological distress and mental wellbeing (continuous) Cognitive impairment (dichotomous) Patient, family/carer experience of care (continuous) Growth (continuous) Malignancy (dichotomous) Adverse events Infections (dichotomous) Vascular access issues (dichotomous) Dialysis access issues (dichotomous) Acute transplant rejection episodes (dichotomous) When outcomes are reported at multiple timepoints, the later timepoints will be prioritised. All outcomes must be reported after at least 4 weeks of the intervention under investigation. The outcomes of mortality and hospitalisation must be reported after at least 6 months. For quality of life, symptom scores/functional measures, psychological distress/mental wellbeing and experience of care, any validated measures will be accepted. Absolute MIDs of 30 per 1000 will be used for mortality and modality failure. Absolute MIDs of 100 per 1000 will be used for all other outcomes dichotomous outcomes. Where relative MIDs are required (if absolute effects are unavailable), 0.90 to 1.11 will be used for mortality and modality failure. The default relative MIDs of 0.8 to 1.25 will be used for all other dichotomous outcomes. Default continuous MIDs of 0.5x SD will be used for all continuous outcomes, except where published, validated MIDs exist.
Eligibility criteria – study design	RCTs only, if insufficient RCT evidence, NRS that adjust for key confounders (age, ethnicity, comorbidities and baseline health) will be included
Other inclusion exclusion criteria
Proposed sensitivity / subgroup analysis, or meta-regression	Different modalities of RRT
Selection process – duplicate screening / selection / analysis	No duplicate screening was deemed necessary for this question, for more information please see the separate Methods report for this guideline.
Data management (software)	Pairwise meta-analyses were performed using Cochrane Review Manager (RevMan5). GRADEpro was used to assess the quality of evidence for each outcome. Endnote was used for bibliography, citations, sifting and reference management.
Information sources – databases and dates	Clinical search databases to be used: Medline, Embase, Cochrane Library Date: All years Health economics search databases to be used: Medline, Embase, NHSEED, HTA Date: Medline, Embase from 2014 NHSEED, HTA – all years Language: Restrict to English only Supplementary search techniques: backward citation searching Key papers: Not known
Identify if an update	Not an update
Author contacts	https://www.nice.org.uk/guidance/indevelopment/gid-ng10019
Highlight if amendment to previous protocol	Not an amendment
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 appendices 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.gradeworkinggroup.org/
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 Jan Dudley 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 8Health economic review protocol

Review question	All questions – health economic evidence
Objectives	To identify economic studies relevant to any of the review questions.
Search criteria	Populations, interventions and comparators must be as specified in the individual review protocol above. Studies must be of a relevant economic study design (cost-utility analysis, cost-effectiveness analysis, cost-benefit analysis, cost-consequences analysis, comparative cost analysis). Studies must not be a letter, editorial or commentary, or a review of economic evaluations. (Recent reviews will be ordered although not reviewed; the bibliographies will be checked for relevant studies, which will then be ordered.) Unpublished reports will not be considered unless submitted as part of a call for evidence. Studies must be in English.
Search strategy	An economic study search will be undertaken using population-specific terms and an economic study filter – see Appendix B.2 Health economics literature search strategy.
Review strategy	Studies not meeting any of the search criteria above will be excluded. Studies published before 2001, 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 2012 NICE guidelines manual.³⁹ Each included study is summarised in an economic evidence profile and an evidence table. Any excluded studies are detailed in the excluded studies table with the reason for exclusion in Appendix I. Inclusion and exclusion criteria If a study is rated as both ‘Directly applicable’ and with ‘Minor limitations’ then it will be included in the guideline. If a study is rated as either ‘Not applicable’ or with ‘Very serious limitations’ then it will usually be excluded from the guideline. If a study is rated as ‘Partially applicable’, with ‘Potentially serious limitations’ or both then there is discretion over whether it should be included. 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. For example, if a high quality study from a UK perspective is available a similar study from another country’s perspective may be excluded. The health economist will be guided by the following hierarchies. Setting: UK NHS (most applicable). OECD countries with predominantly public health insurance systems (for example, France, Germany, Sweden). OECD countries with predominantly private health insurance systems (for example, Switzerland). Studies set in non-OECD countries or in the USA will have been excluded before being assessed for applicability and methodological limitations. Economic study type: Cost-utility analysis (most applicable). Other type of full economic evaluation (cost-benefit analysis, cost-effectiveness analysis, cost-consequences analysis). Comparative cost analysis. Non-comparative cost analyses including cost-of-illness studies will have been excluded before being assessed for applicability and methodological limitations. Year of analysis: The more recent the study, the more applicable it will be. Studies published in 2001 or later but that depend on unit costs and resource data entirely or predominantly from before 2001 will be rated as ‘Not applicable’. Studies published before 2001 will have been excluded before being assessed for applicability and methodological limitations. Quality and relevance of effectiveness data used in the economic analysis: The more closely the clinical effectiveness data used in the economic analysis matches with the outcomes of the studies included in the clinical review the more useful the analysis will be for decision-making in the guideline. The following will be rated as ‘Very serious limitations’ and excluded: economic analyses undertaken as part of clinical studies that are excluded from the clinical review; economic models where relative treatment effects are based entirely on studies that are excluded from the clinical review; comparative costing analyses that only look at the cost of delivering dialysis (as current UK NHS reference costs are considered a more relevant estimate of this for the guideline); within-trial economic analyses based on non-randomised studies that do not meet the minimum adjustment criteria outlined in the main review protocol.

Table 9Database date parameters and filters used

Database

Dates searched

Search filter used

Medline (OVID)

1946 – 11 December 2017

Exclusions

Randomised controlled trials

Systematic review studies

Observational studies

Embase (OVID)

1974 – 11 December 2017

Exclusions

Randomised controlled trials

Systematic review studies

Observational studies

The Cochrane Library (Wiley)

Cochrane Reviews to 2017 Issue 12 of12

CENTRAL to 2017 Issue 11 of12

DARE, and NHSEED to 2015 Issue 2 of 4

HTA to 2016 Issue 4 of 4

None

Medline (Ovid) search terms

1.	exp Renal Replacement Therapy/
2.	((renal or kidney) adj2 replace*).ti,ab.
3.	(hemodiafilt* or haemodiafilt* or (biofilt* adj1 acetate-free)).ti,ab.
4.	(hemodialys* or haemodialys*).ti,ab.
5.	((kidney* or renal) adj3 (transplant* or graft*)).ti,ab.
6.	capd.ti,ab.
7.	dialys*.ti,ab.
8.	(artificial adj1 kidney*).ti,ab.
9.	or/1-8
10.	limit 9 to English language
11.	letter/
12.	editorial/
13.	news/
14.	exp historical article/
15.	Anecdotes as Topic/
16.	comment/
17.	case report/
18.	(letter or comment*).ti.
19.	or/11-18
20.	randomized controlled trial/ or random*.ti,ab.
21.	19 not 20
22.	animals/ not humans/
23.	Animals, Laboratory/
24.	exp animal experiment/
25.	exp animal model/
26.	exp Rodentia/
27.	(rat or rats or mouse or mice).ti.
28.	or/21-27
29.	10 not 28
30.	randomized controlled trial.pt.
31.	controlled clinical trial.pt.
32.	randomi#ed.ti,ab.
33.	placebo.ab.
34.	drug therapy.fs.
35.	randomly.ti,ab.
36.	trial.ab.
37.	groups.ab.
38.	or/30-37
39.	Clinical Trials as topic.sh.
40.	trial.ti.
41.	or/30-33,35,39-40
42.	Meta-Analysis/
43.	Meta-Analysis as Topic/
44.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
45.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
46.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
47.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
48.	(search* adj4 literature).ab.
49.	(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.
50.	cochrane.jw.
51.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
52.	or/42-51
53.	29 and (41 or 52)
54.	exp Renal Replacement Therapy/
55.	((renal or kidney) adj2 replace).ti,ab.
56.	(hemodiafilt* or haemodiafilt* or haemofilt* or hemofilt*).ti,ab.
57.	(hemodialys* or haemodialys*).ti,ab.
58.	((kidney* or renal or pre-empt* or preempt) adj3 (transplant or graft*)).ti,ab.
59.	(capd or apd or ccpd or dialys*).ti,ab.
60.	or/54-59
61.	letter/
62.	editorial/
63.	news/
64.	exp historical article/
65.	Anecdotes as Topic/
66.	comment/
67.	case report/
68.	(letter or comment*).ti.
69.	or/61-68
70.	randomized controlled trial/ or random*.ti,ab.
71.	147 not 148
72.	animals/ not humans/
73.	Animals, Laboratory/
74.	exp Animal Experimentation/
75.	exp Models, Animal/
76.	exp Rodentia/
77.	(rat or rats or mouse or mice).ti.
78.	or/72-77
79.	60 not 78
80.	limit 79 to English language
81.	(mycophenolic acid or azathioprine or sirolimus or everolimus or tacrolimus or cyclosporin* or steroid or calcineurin inhibitor or anaemi* or anemi* or vitamin d or immunosuppres*).ti.¹
82.	80 not 81
83.	Epidemiologic studies/
84.	Observational study/
85.	exp Cohort studies/
86.	(cohort adj (study or studies or analys* or data)).ti,ab.
87.	((follow up or observational or uncontrolled or non randomi#ed or epidemiologic*) adj (study or studies or data)).ti,ab.
88.	((longitudinal or retrospective or prospective or cross sectional) and (study or studies or review or analys* or cohort* or data)).ti,ab.
89.	Controlled Before-After Studies/
90.	Historically Controlled Study/
91.	Interrupted Time Series Analysis/
92.	(before adj2 after adj2 (study or studies or data)).ti,ab.
93.	or/83-92
94.	Registries/
95.	Management Audit/ or Clinical Audit/ or Nursing Audit/ or Medical Audit/
96.	(registry or registries).ti,ab.
97.	(audit or audits or auditor or auditors or auditing or auditable).ti,ab.
98.	or/94-97
99.	93 or 98
100.	82 and 99
101.	100 not 53
102.	53 or 101

Embase (Ovid) search terms

1.	exp *renal replacement therapy/
2.	((renal or kidney) adj2 replace*).ti,ab.
3.	(hemodiafilt* or haemodiafilt* or (biofilt* adj1 acetate-free)).ti,ab.
4.	(hemodialys* or haemodialys*).ti,ab.
5.	((kidney* or renal) adj3 (transplant* or graft*)).ti,ab.
6.	capd.ti,ab.
7.	dialys*.ti,ab.
8.	(artificial adj1 kidney*).ti,ab.
9.	or/1-8
10.	limit 9 to English language
11.	letter.pt. or letter/
12.	note.pt.
13.	editorial.pt.
14.	case report/ or case study/
15.	(letter or comment*).ti.
16.	or/11-15
17.	randomized controlled trial/ or random*.ti,ab.
18.	16 not 17
19.	animal/ not human/
20.	nonhuman/
21.	exp Animal Experiment/
22.	exp Experimental Animal/
23.	animal model/
24.	exp Rodent/
25.	(rat or rats or mouse or mice).ti.
26.	or/18-25
27.	10 not 26
28.	random*.ti,ab.
29.	factorial*.ti,ab.
30.	(crossover* or cross over*).ti,ab.
31.	((doubl* or singl) adj blind).ti,ab.
32.	(assign* or allocat* or volunteer* or placebo*).ti,ab.
33.	crossover procedure/
34.	single blind procedure/
35.	randomized controlled trial/
36.	double blind procedure/
37.	or/28-36
38.	systematic review/
39.	meta-analysis/
40.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
41.	((systematic or evidence) adj3 (review* or overview*)).ti,ab.
42.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
43.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
44.	(search* adj4 literature).ab.
45.	(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.
46.	cochrane.jw.
47.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
48.	or/38-47
49.	27 and (37 or 48)
50.	*renal replacement therapy/
51.	((renal or kidney) adj2 replace).ti,ab.
52.	(hemodiafilt* or haemodiafilt* or haemofilt* or hemofilt*).ti,ab.
53.	(hemodialys* or haemodialys*).ti,ab.
54.	((kidney* or renal or pre-empt* or preempt) adj3 (transplant or graft*)).ti,ab.
55.	(capd or apd or ccpd or dialys*).ti,ab.
56.	or/50-55
57.	letter.pt. or letter/
58.	note.pt.
59.	editorial.pt.
60.	case report/ or case study/
61.	(letter or comment*).ti.
62.	or/57-61
63.	randomized controlled trial/ or random*.ti,ab.
64.	62 not 63
65.	animal/ not human/
66.	nonhuman/
67.	exp Animal Experiment/
68.	exp Experimental Animal/
69.	animal model/
70.	exp Rodent/
71.	(rat or rats or mouse or mice).ti.
72.	or/64-71
73.	56 not 72
74.	limit 73 to English language
75.	(mycophenolic acid or azathioprine or sirolimus or everolimus or tacrolimus or cyclosporin* or steroid or calcineurin inhibitor or anaemi* or anemi* or vitamin d or immunosuppres*).ti.¹
76.	74 not 75
77.	Clinical study/
78.	Observational study/
79.	family study/
80.	longitudinal study/
81.	retrospective study/
82.	prospective study/
83.	cohort analysis/
84.	follow-up/
85.	cohort*.ti,ab.
86.	84 and 85
87.	(cohort adj (study or studies or analys* or data)).ti,ab.
88.	((follow up or observational or uncontrolled or non randomi#ed or epidemiologic*) adj (study or studies or data)).ti,ab.
89.	((longitudinal or retrospective or prospective or cross sectional) and (study or studies or review or analys* or cohort* or data)).ti,ab.
90.	(before adj2 after adj2 (study or studies or data)).ti,ab.
91.	or/77-83,86-90
92.	register/
93.	medical audit/
94.	(registry or registries).ti,ab.
95.	(audit or audits or auditor or auditors or auditing or auditable).ti,ab.
96.	or/92-95
97.	91 or 96
98.	76 and 97
99.	98 not 49
100.	49 or 99

Cochrane Library (Wiley) search terms

#1.	MeSH descriptor: [Renal Replacement Therapy] explode all trees
#2.	((renal or kidney) near/2 replace):ti,ab
#3.	(hemodiafilt* or haemodiafilt* or haemofilt* or hemofilt*):ti,ab
#4.	(hemodialys* or haemodialys*):ti,ab
#5.	((kidney* or renal or pre-empt* or preempt) near/3 (transplant or graft*)):ti,ab
#6.	(capd or apd or ccpd or dialys*):ti,ab
#7.	(biofilt* near/1 acetate-free):ti,ab
#8.	(artificial near/1 kidney*):ti,ab
#9.	(or #1-#8)

Table 10Database date parameters and filters used

Database

Dates searched

Search filter used

Medline & Embase

2014 – 11 December 2017

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA & NHS EED- Inception – 11 December 2017

None

Medline (Ovid) search terms

1.	exp Renal Replacement Therapy/
2.	((renal or kidney) adj2 replace*).ti,ab.
3.	(hemodiafilt* or haemodiafilt* or (biofilt* adj1 acetate-free)).ti,ab.
4.	(hemodialys* or haemodialys*).ti,ab.
5.	((kidney* or renal) adj3 (transplant* or graft*)).ti,ab.
6.	capd.ti,ab.
7.	dialys*.ti,ab.
8.	(artificial adj1 kidney*).ti,ab.
9.	or/1-8
10.	limit 9 to English language
11.	letter/
12.	editorial/
13.	news/
14.	exp historical article/
15.	Anecdotes as Topic/
16.	comment/
17.	case report/
18.	(letter or comment*).ti.
19.	or/11-18
20.	randomized controlled trial/ or random*.ti,ab.
21.	19 not 20
22.	animals/ not humans/
23.	Animals, Laboratory/
24.	exp animal experiment/
25.	exp animal model/
26.	exp Rodentia/
27.	(rat or rats or mouse or mice).ti.
28.	or/21-27
29.	10 not 28
30.	Economics/
31.	Value of life/
32.	exp “Costs and Cost Analysis”/
33.	exp Economics, Hospital/
34.	exp Economics, Medical/
35.	Economics, Nursing/
36.	Economics, Pharmaceutical/
37.	exp “Fees and Charges”/
38.	exp Budgets/
39.	budget*.ti,ab.
40.	cost*.ti.
41.	(economic* or pharmaco?economic*).ti.
42.	(price* or pricing*).ti,ab.
43.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
44.	(financ* or fee or fees).ti,ab.
45.	(value adj2 (money or monetary)).ti,ab.
46.	or/30-45
47.	29 and 46

Embase (Ovid) search terms

1.	exp renal replacement therapy/
2.	((renal or kidney) adj2 replace*).ti,ab.
3.	(hemodiafilt* or haemodiafilt* or (biofilt* adj1 acetate-free)).ti,ab.
4.	(hemodialys* or haemodialys*).ti,ab.
5.	((kidney* or renal) adj3 (transplant* or graft*)).ti,ab.
6.	capd.ti,ab.
7.	dialys*.ti,ab.
8.	(artificial adj1 kidney*).ti,ab.
9.	or/1-8
10.	limit 9 to English language
11.	letter.pt. or letter/
12.	note.pt.
13.	editorial.pt.
14.	case report/ or case study/
15.	(letter or comment*).ti.
16.	or/11-15
17.	randomized controlled trial/ or random*.ti,ab.
18.	16 not 17
19.	animal/ not human/
20.	nonhuman/
21.	exp Animal Experiment/
22.	exp Experimental Animal/
23.	animal model/
24.	exp Rodent/
25.	(rat or rats or mouse or mice).ti.
26.	or/18-25
27.	10 not 26
28.	*health economics/
29.	exp *economic evaluation/
30.	exp *health care cost/
31.	exp *fee/
32.	budget/
33.	funding/
34.	budget*.ti,ab.
35.	cost*.ti.
36.	(economic* or pharmaco?economic*).ti.
37.	(price* or pricing*).ti,ab.
38.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
39.	(financ* or fee or fees).ti,ab.
40.	(value adj2 (money or monetary)).ti,ab.
41.	or/28-40
42.	27 and 41

NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR Renal Replacement Therapy EXPLODE ALL TREES
#2.	(((renal or kidney) adj2 replace*))
#3.	((hemodiafilt* or haemodiafilt* or (biofilt* adj1 acetate-free)))
#4.	((hemodialys* or haemodialys*))
#5.	(((kidney* or renal) adj3 (transplant* or graft*)))
#6.	(capd)
#7.	(dialys*)
#8.	((artificial adj1 kidney*))
#9.	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8

Figure 1Flow chart of clinical study selection for the review of when to assess for RRT

Figure 2Mortality (90 days)

Figure 3Mortality (90 days-1 year)

Table 11Clinical evidence profile: Late referral versus early referral for RRT in people diagnosed with chronic renal failure

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Late	Early referral	Relative (95% CI)	Absolute	Quality	Importance
All-cause mortality (follow-up 90 days)
1	observational studies	serious¹	no serious inconsistency	no serious indirectness	serious²	none	363/1039 (34.9%)	465/1975 (23.5%)	HR 1.75 (1.48 to 2.08)	139 more per 1000 (from 92 more to 192 more)	⊕◯◯◯ VERY LOW	CRITICAL
All-cause mortality (follow-up 90 days-1 year)
1	observational studies	serious¹	no serious inconsistency	no serious indirectness	serious²	none	190/676 (28.1%)	411/1502 (27.4%)	HR 1.03 (0.84 to 1.26)	7 more per 1000 (from 38 fewer to 58 more)	⊕◯◯◯ VERY LOW	CRITICAL

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

Figure 4Flow chart of economic study selection for the guideline

A = starting RRT

B = modality of RRT, subgroups and CM

C = sequencing

D = planning for RRT

E = When to assess

F = what to assess

G = Indicators for switching or stopping RRT

I = diet and fluids

J = frequency of review

L = decision support interventions

M = coordinating care

Note: Reviews H and K do not have an economic component

▬

Table 12Studies excluded from the clinical review

Study	Exclusion reason
Arora 2015¹	Not review population
Avorn 2002²	Inappropriate comparison. No adjustment for confounders
Ballerini 2002³	Non-English study
Caskey 2003⁴	No adjustment for confounders
Chen 2010⁵	No adjustment for confounders
Chow 2008⁶	No adjustment for confounders
Churchill 1997⁷	Systematic review - references checked
Curtis 2002⁸	Not review population. No adjustment for confounders
De Jager 2011⁹	No adjustment for confounders
Dogan 2005¹¹	No adjustment for confounders
Ellis 1998¹²	No adjustment for confounders
Gallego 2003¹³	Non-English study
Goransson 2001¹⁴	No adjustment for confounders
Hasegawa 2009¹⁵	Inappropriate comparison
Hayashi 2016¹⁶	No adjustment for confounders
Helal 2010¹⁷	Abstract only
Herget-Rosenthal 2010¹⁸	Not review population. No adjustment for confounders
Hoffmann 2006¹⁹	Non-English study
Hommel 2012²⁰	No adjustment for confounders
Ilhan 2013²¹	No adjustment for confounders
Inaguma 2011²²	No adjustment for confounders
Jakubovic 2013²³	Inappropriate comparison
Jungers 1993²⁷	No adjustment for confounders
Jungers 1997²⁶	Non-English study
Jungers 2001²⁵	No adjustment for confounders
Jungers 2006²⁴	No adjustment for confounders
Kessler 2003²⁸	No adjustment for confounders
Kim 2013²⁹	No adjustment for confounders
Kumar 2012³⁰	No adjustment for confounders
Lameire 1997³²	No adjustment for confounders. No relevant outcomes
Lameire 1999³¹	No adjustment for confounders. No relevant outcomes
Lhotta 2003³³	No adjustment for confounders
Lin 2003³⁵	Not review population. No adjustment for confounders
Lin 2004³⁴	No adjustment for confounders
Lorenzo 2004³⁶	Not review population. No adjustment for confounders
Mezei 2010³⁷	Conference abstract only
Nakamura 2007³⁸	No adjustment for confounders
Parameswaran 2011⁴⁰	No adjustment for confounders
Pena 2006⁴¹	No adjustment for confounders
Ratcliffe 1984⁴²	No adjustment for confounders
Ravani 2003⁴³	No adjustment for confounders
Roubicek 2000⁴⁴	No adjustment for confounders
Sabath 2003⁴⁵	Non-English study
Schmidt 1998⁴⁶	No adjustment for confounders
Sesso 1996⁴⁷	Inappropriate comparison
Shiao 2008⁴⁸	No adjustment for confounders
Stack 2003⁴⁹	Not review population
Van Biesen 1998⁵¹	No adjustment for confounders
Van Biesen 1999⁵⁰	No adjustment for confounders
Wijewickrama 2010⁵²	Conference abstract only
Winkelmayer 2001⁵³	Inappropriate comparison. No adjustment for confounders
Winkelmayer 2001⁵⁴	Inappropriate comparison
Winkelmayer 2002⁵⁷	Inappropriate comparison
Winkelmayer 2007⁵⁶	No relevant outcomes
Winkelmayer 2011⁵⁵	Inappropriate comparison
Wu 2003⁵⁹	No adjustment for confounders
Yang 2017⁶⁰	Inappropriate comparison
Yokoyama 2009⁶¹	Not review population

Table 13Studies excluded from the health economic review

Reference	Reason for exclusion
None.