Methods for guideline development

AIM

The overall aim of the project was to develop an evidence-based clinical practice guideline for management of anemia and chronic kidney disease (CKD). The guideline consists of recommendations, rationale statements and a summary of systematically generated evidence on relevant predefined clinical topics.

OVERVIEW PROCESS

Guideline development process included the following sequential and concurrent steps:

• Appointing Work Group members and Evidence Review Team (ERT).

• Discussing process, methods, and results.

• Developing and refining topics.

• Identifying populations, interventions or predictors, and outcomes of interest.

• Selecting topics for systematic evidence review.

• Standardizing quality assessment methodology.

• Developing and implementing literature search strategies.

• Screening abstracts and retrieving full text articles based on predefined eligibility criteria.

• Creating data extraction forms.

• Data extracting and performing critical appraisal of the literature.

• Grading the methodology and outcomes in individual studies.

• Tabulating data from individual studies into summary tables.

• Grading quality of evidence for each outcome across studies, and assessing the overall quality of evidence across outcomes with the aid of evidence profiles.

• Grading the strength of recommendations based on the quality of evidence and other considerations.

• Finalizing guideline recommendations and supporting rationale statements.

• Sending the guideline draft for peer review to the KDIGO Board of Directors in June 2011, and for public review in September 2011.

• Publishing the final version of the guideline.

The Work Group, KDIGO Co-Chairs, ERT, and KDIGO support staff met for two 2-day meetings for training in the guideline development process, topic discussion, and consensus development.

Commissioning of work group and evidence review team

KDIGO Co-Chairs appointed the Work Group Co-chairs. Work Group Co-Chairs then assembled the Work Group consisting of domain experts, including individuals with expertise in internal medicine, adult and pediatric nephrology, cardiology, hematology, oncology, hypertension, pathology, pharmacology, epidemiology and endocrinology. Tufts Center for Kidney Disease Guideline Development and Implementation at Tufts Medical Center in Boston, Massachusetts, USA was contracted to conduct systematic evidence review and provide expertise in guideline development methodology. The ERT consisted of physician-methodologists with expertise in nephrology, a project coordinator and manager, and a research assistant. The ERT instructed and advised Work Group members in all steps of literature review, critical literature appraisal, and guideline development. The Work Group and the ERT collaborated closely throughout the project.

Defining scope and topics

Work Group Co-Chairs first defined the overall scope and goals of the guideline. Work Group Co-Chairs then drafted a preliminary list of topics and key clinical questions. In light of new evidence, it was decided that an update of the topics presented in the 2006 and 2007 KDOQI guidelines would be the best approach. The Work Group and ERT further developed and refined each topic, specified screening criteria, literature search strategies, and data extraction forms (Table 8).

Table 8. Systematic review topics and screening criteria.

Identifying why, when and which patients to treat for anemia and iron deficiency
Population	All CKD stages for longitudinal, cross-sectional or RCTs. Any population for systematic reviews
Intervention	RBC transfusion, Iron (all forms, routes of administration, dosages), ESA (all forms, dosages, targets, protocols, schedules, etc), pharmacological and non-pharmacological adjuvants to ESA, Hb or iron status
Comparator	Other interventions, “no” interventions, different forms, routes of administration, dosages, targets, protocols, schedules, etc.
Outcomes	All-cause mortality, Cardiovascular events, ESRD, Quality of life, Progression of kidney disease, Transfusions, Major symptoms
Study design	RCTs, Large longitudinal (prospective or retrospective) observational studies or cross sectional studies with multivariate analyses
	N≥50 per arm
Evaluating anemia treatment, including treatment resistance
Population	Adults and children with CKD, any stage and any comorbidity (including cancer, CVD, etc.)
Intervention	RBC transfusions; Iron (all forms, routes of administration, dosages), ESA (all forms, dosages, targets, protocols, etc), pharmacological and non-pharmacological adjuvants to ESA including L-carnitine, vitamin C, androgens, pentoxifylline; other interventions used to treat or enhance the treatment of anemia or anemia-related symptoms
Comparator	Other interventions, “no” interventions, different forms, routes of administration, dosages, targets, protocols, schedules, etc.
Outcomes	Death, Cardiac events, Stroke, CKD progression, Quality of life, Thromboembolic events, Pulmonary embolism, Symptomatic deep vein thrombosis, Loss of vascular access, Transfusion requirements, Cognitive function, Sexual function, Other similar quality of life measures, Objective physical function tests, Infections, Loss of transplant eligibility due to antibody sensitization, Antibody sensitization, New cancer or progression of existing cancer, Seizure, Other clinically important adverse events, ESA dose: for comparisons of different ESA regimens and for iron and adjuvant interventions, Achieved Hb/Hb variability for comparisons of different ESA regimens and for iron and adjuvant interventions
Study Design	RCTs
	N≥50 per arm
	Minimum follow-up duration: 6 months

CKD, chronic kidney disease; CVD, cardiovascular disease; ESA, erythropoiesis-stimulating agent; ESRD, end-stage renal disease; Hb, hemoglobin; RBC, red blood cell; RCT, randomized controlled trial.

Establishing the process for guideline development

The ERT performed literature searches, organized abstract and article screening. The ERT also coordinated the methodological and analytic process of the report, defined and standardized the methodology of performing literature searches, data extraction, and summarizing the evidence. Throughout the project, the ERT offered suggestions for guideline development, led discussions on systematic review, literature searches, data extraction, assessment of quality and applicability of articles, evidence synthesis, grading of evidence and guideline recommendations, and consensus development. The Work Group took the primary role of writing the guidelines and rationale statements and retained final responsibility for the content of the guideline statements and the accompanying narrative.

The Work Group Co-Chairs prepared the first draft of the scope of work document as a series of topics to be considered by Work Group members. The scope of work document was based primarily on the existing KDOQI guidelines on anemia. At their first two-day meeting, Work Group members revised the initial working document to include all topics of interest to the Work Group. The inclusive, combined set of questions formed the basis for the deliberation and discussion that followed. The Work Group strove to ensure that all topics deemed clinically relevant and worthy of review were identified and addressed.

Formulating questions of interest

Questions of interest were formulated according to the PICODD (Population, Intervention, Comparator, Outcome, study Design and Duration of follow up) criteria. Details of the PICODD criteria are presented in Table 8.

Ranking of outcomes

The Work Group ranked outcomes of interest based on their importance for informing clinical decision making (Table 9). Mortality, cardiovascular mortality, cardiovascular events and ESRD outcomes were graded as ‘critical,' transfusion and QoL outcomes were graded as ‘high,' and all other outcomes were graded as ‘moderate.'

Table 9. Hierarchy of importance of outcomes.

Hierarchya	Outcomesb
Critical importance	Mortality, Cardiovascular mortality, Cardiovascular events, ESRD
High importance	Transfusion, Quality of life
Moderate importance	Hb (categorical and continuous), ESA dose (categorical and continuous), adverse events

ESA, erythropoiesis-stimulating agent; ESRD, end-stage renal disease; Hb, hemoglobin.

^aOutcomes of lesser importance are excluded from review.

^bThis categorization was the consensus of the Work Group for the purposes of this guideline only. The lists are not meant to reflect outcome ranking for other areas of kidney disease management. The Work Group acknowledges that not all clinicians, patients or families, or societies would rank all outcomes the same.

Literature searches and article selection

The Work Group sought to build on the evidence base and topics addressed in the previous Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in 2006 as well as the KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease 2007 update of hemoglobin target. Modules were created for randomized controlled trials (RCTs), kidney disease, anemia, and erythropoietin, transfusion, iron deficiency, and adjuvant search terms. The search terms were then limited to years 2006–2010 for studies related to anemia interventions. For transfusion the literature search was conducted from 1989–2010. A separate search was run for observational studies on iron overload and hemoglobin status as predictors for clinical outcomes (See Appendix 1 online).

The searches were run in MEDLINE, Cochrane Central Register of Controlled Clinical Trials and Cochrane Database of Systematic Reviews. The initial search for RCTs was conducted in April 2010 and subsequently updated in October of 2010. The search for observational studies was later conducted in September 2010. The search yield was also supplemented by articles provided by Work Group members through March 2012. MEDLINE search results were screened by members of the ERT for relevance using pre-defined eligibility criteria.

The total yield from the search was 4,334 abstracts for RCTs and 3,717 abstracts for observational studies. Fifty-six abstracts and 53 full texts from RCTs were accepted and 97 abstracts and 21 full texts from observational studies were accepted. Journal articles reporting original data, meta-analyses or systematic reviews were selected for evidence review. Editorials, letters, abstracts, unpublished reports and articles published in non-peer reviewed journals were not included. The Work Group also decided to exclude publications from journal supplements because of potential differences in the process of how they get solicited, selected, reviewed and edited compared to peer-reviewed publications. The overall search yield along with the number of abstracts identified and articles reviewed is presented in Table 10.

Table 10. Literature search yield of primary articles for systematic review topics.

Total abstracts from updated search	Abstracts accepted	Full text accepted	Full text extracted	Articles in summary tables
4,334 RCT	56	53	53	31
3,717 Observational	97	21	21	21

RCT, randomized controlled trial.

Data extraction

Fifty-three full text articles from RCTs were extracted by the ERT. The ERT, in consultation with the Work Group, designed forms to capture data on design, methodology, sample characteristics, interventions, comparators, outcomes, results and limitations of individual studies. Methodology and outcomes were also systematically graded (see the section on grading below) and recorded during the data extraction process.

Summary tables

Summary tables were developed for each comparison of interest. Studies included in the evidence base for the KDOQI clinical practice guidelines on Anemia in CKD and update of hemoglobin target were also incorporated if they fulfilled the inclusion criteria for the current guideline.

Summary tables contain outcomes of interest, relevant population characteristics, description of intervention and comparator, results, and quality grading for each outcome. Categorical and continuous outcomes were summarized separately. Work Group members proofed all summary table data and quality assessments. Summary tables will be available at www.kdigo.org/clinical_practice_guidelines/anemia.php.

Evidence profiles

Evidence profiles were constructed to assess and record quality grading and description of effect for each outcome across studies, and quality of overall evidence and description of net benefits or harms of intervention or comparator across all outcomes. These profiles aim to make the evidence synthesis process transparent. Decisions in the evidence profiles were based on data from the primary studies listed in corresponding summary tables, and on judgments of the ERT and the Work Group. When the body of evidence for a particular comparison of interest consisted of only one study, the summary table provided the final level of synthesis and evidence profile was not generated. Each evidence profile was initially constructed by the ERT and then reviewed, edited and approved by the Work Group.

Grading of quality of evidence for outcomes of individual studies

Methodological quality

Methodological quality (internal validity) refers to the design, conduct, and reporting of outcomes of a clinical study. Previously devised three-level classification system for quality assessment was used to grade the overall study quality and quality for all relevant outcomes in the study (Table 11). Variations of this system have been used in most KDOQI and all KDIGO guidelines and have been recommended for the US Agency for Healthcare Research and Quality Evidence-based Practice Center program (http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf).

Table 11. Classification of study quality.

Good quality	Low risk of bias and no obvious reporting errors, complete reporting of data. Must be prospective. If study of intervention, must be randomized controlled study (RCT).
Fair quality	Moderate risk of bias, but problems with study/paper are unlikely to cause major bias. If study of intervention, must be prospective.
Poor quality	High risk of bias or cannot exclude possible significant biases. Poor methods, incomplete data, reporting errors. Prospective or retrospective.

Each study was given an overall quality grade based on its design, methodology (randomization, allocation, blinding, definition of outcomes, appropriate use of statistical methods etc), conduct (drop-out percentage, outcome assessment methodologies, etc) and reporting (internal consistency, clarity, thoroughness/precision, etc). Each reported outcome was then evaluated and given an individual grade depending on the quality of reporting and methodological issues specific to that outcome. However, the quality grade of an individual outcome could not exceed the quality grade for the overall study.

Rating the quality of evidence and the strength of guideline recommendations

A structured approach, based on GRADE^{241, 242, 243} and facilitated by the use of evidence profiles was used in order to grade the quality of the overall evidence and the strength of recommendations. For each topic, the discussion on grading of the quality of the evidence was led by the ERT, and the discussion regarding the strength of the recommendations was led by the Work Group Chairs. The ‘strength of a recommendation' indicates the extent to which one can be confident that adherence to the recommendation will do more good than harm. The ‘quality of a body of evidence' refers to the extent to which our confidence in an estimate of effect is sufficient to support a particular recommendation.²⁴²

Grading the quality of evidence for each outcome

Following GRADE, the quality of a body of evidence pertaining to a particular outcome of interest was initially categorized based on study design. For questions of interventions, the initial quality grade was ‘High' when the body of evidence consisted of randomized controlled trials; ‘Low', if it consisted of observational studies; or ‘Very Low', if it consisted of studies of other study designs. For questions of interventions, the Work Group decided to use only randomized controlled trials. The grade for the quality of evidence for each intervention/outcome pair was then lowered if there were serious limitations to the methodological quality of the aggregate of studies, if there were important inconsistencies in the results across studies, if there was uncertainty about the directness of evidence including limited applicability of the findings to the population of interest, if the data were imprecise (a low event rate [0 or 1 event] in either arm or confidence interval spanning a range <0.5 to >2.0) or sparse (only 1 study or total N<100), or if there was thought to be a high likelihood of bias. The final grade for the quality of the evidence for an intervention/outcome pair could be one of the following four grades: ‘High', ‘Moderate', ‘Low' or ‘Very Low' (Table 12).

Table 12. GRADE system for grading quality of evidence.

Step 1: Starting grade for quality of evidence based on study design	Step 2: Reduce grade	Step 3: Raise grade	Final grade for quality of evidence and definition
Randomized trials = High Observational study = Low Any other evidence = Very low	Study quality −1 level if serious limitations −2 levels if very serious limitations Consistency −1 level if important inconsistency Directness −1 level if some uncertainty −2 levels if major uncertainty Other −1 level if sparse or imprecise datac −1 level if high probability of reporting bias	Strength of association +1 level is stronga, no plausible confounders +2 levels if very strongb, no major threats to validity Other +1 level if evidence of a dose-response gradient +1 level if all residual plausible confounders would have reduced the observed effect	High = Further research is unlikely to change confidence in the estimate of the effect Moderate = Further research is likely to have an important impact on confidence in the estimate of effect, and may change the estimate Low = Further research is very likely to have an important impact on confidence in the estimate, and may change the estimate Very low = Any estimate of effect is very uncertain

GRADE, Grading of Recommendations Assessment, Development, and Evaluation.

^aStrong evidence of association is defined as ‘significant relative risk of >2 (<0.5)' based on consistent evidence from two or more observational studies, with no plausible confounders.

^bVery strong evidence of association is defined as ‘significant relative risk of >5 (<0.2)' based on direct evidence with no major threats to validity.

^cSparse if there is only one study or if total N <100. Imprecise if there is a low event rate (0 or 1 event) in either arm or confidence interval spanning a range <0.5 to >2.0.

Adapted by permission from Macmillan Publishers Ltd: Kidney International. Uhlig K, Macleod A, Craig J et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 70: 2058–2065;²⁴³ accessed http://www.nature.com/ki/journal/v70/n12/pdf/5001875a.pdf

Grading the overall quality of evidence

The quality of the overall body of evidence was then determined based on the quality grades for all outcomes of interest, taking into account explicit judgments about the relative importance of each outcome. The resulting four final categories for the quality of overall evidence were: ‘A', ‘B', ‘C' or ‘D' (Table 13).

Table 13. Final grade for overall quality of evidence.

Grade	Quality of evidence	Meaning
A	High	We are confident that the true effect lies close to that of the estimate of the effect.
B	Moderate	The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
C	Low	The true effect may be substantially different from the estimate of the effect.
D	Very low	The estimate of effect is very uncertain, and often will be far from the truth.

Assessment of the net health benefit across all important clinical outcomes

The net health benefit was determined based on the anticipated balance of benefits and harms across all clinically important outcomes (Table 14). The assessment of net benefit was affected by the judgment of the Work Group and the ERT.

Table 14. Balance of benefits and harm.

When there was evidence to determine the balance of medical benefits and harm of an intervention to a patient, conclusions were categorized as follows:

• For statistically significant benefit/harm report as ‘Benefit/Harm of Drug X'.

• For non-statistically significant benefit/harm, report as ‘Possible benefit/harm of Drug X'.

• In instances where studies are inconsistent, report as ‘Possible benefit/harm of Drug X'.

• ‘No difference' can only be reported if a study is not imprecise.

• ‘Insufficient evidence' if imprecision is a factor.

Grading the strength of the recommendations

The strength of a recommendation is graded as Level 1 or Level 2. Table 15 shows the KDIGO nomenclature for grading the strength of a recommendation and the implications of each level for patients, clinicians and policy makers. Recommendations can be for or against doing something. Table 16 shows that the strength of a recommendation is determined not just by the quality of the evidence, but also by other, often complex judgments regarding the size of the net medical benefit, values and preferences, and costs. Formal decision analyses including cost analysis were not conducted.

Table 15. KDIGO nomenclature and description for grading recommendations.

Grade*	Implications
	Patients	Clinicians	Policy
Level 1 ‘We recommend'	Most people in your situation would want the recommended course of action and only a small proportion would not.	Most patients should receive the recommended course of action.	The recommendation can be evaluated as a candidate for developing a policy or a performance measure.
Level 2 ‘We suggest'	The majority of people in your situation would want the recommended course of action, but many would not.	Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences.	The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.

^*The additional category ‘Not Graded' was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Table 16. Determinants of strength of recommendation.

Factor	Comment
Balance between desirable and undesirable effects	The larger the difference between the desirable and undesirable effects, the more likely a strong recommendation is warranted. The narrower the gradient, the more likely a weak recommendation is warranted.
Quality of the evidence	The higher the quality of evidence, the more likely a strong recommendation is warranted.
Values and preferences	The more variability in values and preferences, or more uncertainty in values and preferences, the more likely a weak recommendation is warranted.
Costs (resource allocation)	The higher the costs of an intervention—that is, the more resources consumed—the less likely a strong recommendation is warranted.

Ungraded statements

This category was designed to allow the Work Group to issue general advice. Typically an ungraded statement meets the following criteria: it provides guidance based on common sense; it provides reminders of the obvious; it is not sufficiently specific to allow application of evidence to the issue and therefore it is not based on systematic evidence review. Common examples include recommendations about frequency of testing, referral to specialists, and routine medical care. We strove to minimize the use of ungraded recommendations.

This grading scheme with two levels for the strength of a recommendation together with four levels of grading the quality of the evidence, and the option of an ungraded statement for general guidance was adopted by the KDIGO Board in December 2008. The Work Group took the primary role of writing the recommendations and rationale statements and retained final responsibility for the content of the guideline statements and the accompanying narrative. The ERT reviewed draft recommendations and grades for consistency with the conclusions of the evidence review.

Format for guideline recommendations

Each chapter contains one or more specific recommendations. Within each recommendation, the strength of recommendation is indicated as level 1 or level 2 and the quality of the supporting evidence is shown as A, B, C or D. These are followed by a brief background with relevant definitions of terms and the rationale summarizing the key points of the evidence base and narrative supporting the recommendation. Where appropriate, research recommendations are suggested for future research to resolve current uncertainties.

Limitations of approach

While the literature searches were intended to be comprehensive, they were not exhaustive. MEDLINE was the only database searched. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. However, important studies known to domain experts that were missed by the electronic literature searches were added to retrieved articles and reviewed by the Work Group.

Summary of the methodological review process

Several tools and checklists have been developed to assess the quality of the methodological process for systematic review and guideline development. These include the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria,²⁴⁴ the Conference on Guideline Standardization (COGS) checklist,²⁴⁵ and the Institute of Medicine's recent Standards for Systematic Reviews²⁴⁶ and Clinical Practice Guidelines We Can Trust.²⁴⁷ Table 17 and Appendix 2 online show, respectively, the COGS criteria which correspond to the AGREE checklist and the Institute of Medicine standards, and how each one of them is addressed in this guideline.

Table 17. The Conference on Guideline Standardization (COGS) checklist²⁴⁵ for reporting clinical practice guidelines.

Topic	Description	Discussed in KDIGO Anemia Guideline
1. Overview material	Provide a structured abstract that includes the guideline's release date, status (original, revised, updated), and print and electronic sources.	Abstract and Methods for Guideline Development.
2. Focus	Describe the primary disease/condition and intervention/service/technology that the guideline addresses. Indicate any alternative preventative, diagnostic or therapeutic interventions that were considered during development.	Management of adults and children with CKD and kidney transplant recipients at risk for or with anemia.
3. Goal	Describe the goal that following the guideline is expected to achieve, including the rationale for development of a guideline on this topic.	This clinical practice guideline is intended to assist the practitioner caring for patients with CKD and anemia and to prevent deaths, cardiovascular disease events and progression to kidney failure while optimizing patients' quality of life.
4. User/setting	Describe the intended users of the guideline (e.g. provider types, patients) and the settings in which the guideline is intended to be used.	Providers: Nephrologists (adult and pediatric), Dialysis providers (including nurses), Internists, and Pediatricians. Patients: Adult and children with CKD at risk for or with anemia. Policy Makers: Those in related health fields.
5. Target population	Describe the patient population eligible for guideline recommendations and list any exclusion criteria.	CKD individuals at risk for or with anemia, adult and children.
6. Developer	Identify the organization(s) responsible for guideline development and the names/credentials/potential conflicts of interest of individuals involved in the guideline's development.	Organization: KDIGO.
7. Funding source/sponsor	Identify the funding source/sponsor and describe its role in developing and/or reporting the guideline. Disclose potential conflict of interest.	KDIGO is supported by the following consortium of sponsors: Abbott, Amgen, Bayer Schering Pharma, Belo Foundation, Bristol-Myers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole Food Company, Fresenius Medical Care, Genzyme, Hoffmann-LaRoche, JC Penney, Kyowa Hakko Kirin, NATCO—The Organization for Transplant Professionals, NKF-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical, Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma, and Wyeth. No funding is accepted for the development or reporting of specific guidelines. All stakeholders could participate in open review. Refer to Work Group Financial Disclosures.
8. Evidence collection	Describe the methods used to search the scientific literature, including the range of dates and databases searched, and criteria applied to filter the retrieved evidence.	Modules were created for randomized controlled trials (RCTs), kidney disease, anemia, and erythropoietin, transfusion, iron deficiency, and adjuvant search terms. The search terms were then limited to years 2006–2010 for studies related to anemia interventions. For transfusion the literature search was conducted from 1989–2010. A separate search was run for observational studies on iron overload and hemoglobin status as predictors for clinical outcomes. See Table 8 for screening criteria. Searches were run in MEDLINE, Cochrane Central Register of Controlled Clinical Trials and Cochrane Database of Systematic Reviews. The initial search for RCTs was conducted in April 2010 and subsequently updated in October of 2010. The search for observational studies was later conducted in September 2010. The search yield was also supplemented by articles provided by Work Group members through March 2012.
9. Recommendation grading criteria	Describe the criteria used to rate the quality of evidence that supports the recommendations and the system for describing the strength of the recommendations. Recommendation strength communicates the importance of adherence to a recommendation and is based on both the quality of the evidence and the magnitude of anticipated benefits and harms.	Quality of individual studies was graded in a three-tiered grading system (see Table 11). Quality of evidence (Table 12) was graded following the GRADE approach. Strength of the recommendation was graded in a two-level grading system which was adapted from GRADE for KDIGO with the quality of overall evidence graded on a four-tiered system (Tables 13 and 15). The Work Group could provide general guidance in ungraded statements.
10. Method for synthesizing evidence	Describe how evidence was used to create recommendations, e.g., evidence tables, meta-analysis, decision analysis.	For systematic review topics, summary tables and evidence profiles were generated. For recommendations on treatment interventions, the steps outlined by GRADE were followed.
11. Prerelease review	Describe how the guideline developer reviewed and/or tested the guidelines prior to release.	The guideline has undergone internal review by the KDIGO Board of Directors in June 2011 and external review in September 2011. Public review comments were compiled and fed back to the Work Group, which considered comments in its revision of the guideline.
12. Update plan	State whether or not there is a plan to update the guideline and, if applicable, expiration date for this version of the guideline.	There is no date set for updating. The need for updating of the guideline will depend on the publication of new evidence that would change the quality of the evidence or the estimates for the benefits and harms. Results from registered ongoing studies and other publications will be reviewed periodically to evaluate their potential to impact on the recommendations in this guideline.
13. Definitions	Define unfamiliar terms and those critical to correct application of the guideline that might be subject to misinterpretation.	Abbreviations and Acronyms.
14. Recommendations and rationale	State the recommended action precisely and the specific circumstances under which to perform it. Justify each recommendation by describing the linkage between the recommendation and its supporting evidence. Indicate the quality of evidence and the recommendation strength, based on the criteria described in Topic 9.	Each guideline chapter contains recommendations for management of CKD patients at risk for or with anemia. Each recommendation builds on a supporting rationale with evidence tables if available. The strength of the recommendation and the quality of evidence are provided in parenthesis within each recommendation.
15. Potential benefits and harm	Describe anticipated benefits and potential risks associated with implementation of guideline recommendations.	The benefits and harm for each comparison of interventions are provided in summary tables and summarized in evidence profiles. The estimated balance between potential benefits and harm was considered when formulating the recommendations.
16. Patient preferences	Describe the role of patient preferences when a recommendation involves a substantial element of personal choice or values.	Many recommendations are Level 2 or “discretionary” which indicates a greater need to help each patient arrive at a management decision consistent with her or his values and preferences.
17. Algorithm	Provide (when appropriate) a graphical description of the stages and decisions in clinical care described by the guideline.	See Chapter 4.
18. Implementation considerations	Describe anticipated barriers to application of the recommendations. Provide reference to any auxiliary documents for providers or patients that are intended to facilitate implementation. Suggest review criteria for measuring changes in care when the guideline is implemented.	These recommendations are global. Review criteria were not suggested because implementation with prioritization and development of review criteria have to proceed locally. Furthermore, most recommendations are discretionary, requiring substantial discussion among stakeholders before they can be adopted as review criteria. Suggestions were provided for future research.

CKD, chronic kidney disease; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; KDIGO, Kidney Disease: Improving Global Outcomes; RCT, randomized controlled trial.