Clinical Practice Guidelines

KDIGO Guideline for CKD Classification and Management

The Work Group developing the KDIGO Clinical Practice Guideline on Chronic Kidney Disease Classification and Management is chaired by Drs. Adeera Levin and Paul Stevens. It is anticipated that this guideline will publish in the first half of 2012.

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Guideline Workgroup Roster

NAME/AFFILIATION	CONTACT INFORMATION
Co-Chair: Adeera Levin, MD, FRCPC Professor of Medicine UBC Division of Nephrology Director Kidney Function Clinic Executive Director Provincial Renal Agency	1081 Burrard Street Providence Bldg, Room 6010A Vancouver, BC V6Z 1Y6 CANADA/td>
Co-Chair: Paul E Stevens, MB, FRCP Consultant Nephrologist & Clinical Director Vascular Surgery, Interventional Radiology, Renal & Urology Services Kent and Canterbury Hospital Ethelbert Road	Kent and Canterbury Hospital Ethelbert Road Canterbury, Kent CT1 3NG
Rudy Bilous, MD Newcastle University	South Tees Hospitals NHS Trust, Academic Centre, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UNITED KINGDOM
Josef Coresh, MD, PhD Johns Hopkins University Bloomberg School of Public Health	Johns Hopkins University Bloomberg School of Public Health 2024 E. Monument, Suite 2-600 Baltimore, MD 21287 USA
Angel de Francisco, MD Hospital Universitario Valdecilla	Hospital Universitario Valdecilla Servicio de Nefrología Avda Valdecilla s/n Santander E–39008 SPAIN
Paul de Jong, MD, PhD University Hospital Groningen	University Hospital Groningen Division of Nephrology Hanzeplaein 1, Groningen 9713 EZ NETHERLANDS
Kathryn Griffith, BM, BS, MSc, MRCP, MRCGP University Health Centre York University	University Health Centre, York University, York YO10 5DD UNITED KINGDOM
Brenda Hemmelgarn, MD, PhD Associate Professor Division of Nephrology Depts of Medicine and Community Health Sciences University of Calgary	Foothills Medical Center 1403 29th St NW Calgary, Alberta T2N 2T9 CANADA
Kunitoshi Iseki, MD University Hospital of The Ryukyus	Dialysis Unit, University Hospital of The Ryukyus 207 Uehara Nishihara, Okinawa 903-0215 JAPAN
Edmund Lamb, PhD FRCPath Consultant Clinical Scientist (Biochemistry) and Head of Department Department of Clinical Biochemistry	East Kent Hospitals NHS Trust, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG UNITED KINGDOM
Andrew S Levey, MD Dr Gerald J and Dorothy R. Friedman Professor of Medicine	William B. Schwartz Division of Nephrology Tufts Medical Center 800 Washington St., Box 391 Boston, MA 02111 USA
Miguel C Riella, MD Chief of Nephrology Evangelic University Hospital	2689 Iguassu Ave Curitiba, Parana 80240-030 BRAZIL
Michael G Shlipak, MPH, MD General Internal Medicine Section, San Francisco VA Medical Center	Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco 4150 Clement Street, 111A1, San Francisco, CA 94121 USA
HaiYan Wang, MD The First Hospital Peking University	Department of Nephrology The First Hospital Peking University No. 8 Xishiku Street Xicheng District Beijing 100034 PEOPLES REPUBLIC OF CHINA
Colin White MD, FRCPC, FAAP, FASN Clinical Assistant Professor University of British Columbia Pediatric Nephrologist, Director of Dialysis, Fellowship Program Director BC’s Children’s Hospital	BC’s Children’s Hospital 4480 Oak Street, ACB K4–151, Division of Nephrology Vancouver, BC, V6H 3V4 CANADA
Christopher Winearls, DPhil, MB Oxford Kidney Unit, The Churchill, Oxford Radcliffe Hospitals NHS Trust	Oxford Radcliffe Hospitals NHS Trust, Old Road, Headington, OXFORD OX3 7LJ UNITED KINGDOM

Guideline Scope

RATIONALE

Justification for updating guidelines for CKD Definition, Evaluation, Classification and Stratification

In 2002, the US based KDOQI group published the Guideline on definition, classification and evaluation of chronic kidney disease, which proposed simplified definitions of CKD, and a staging system. The guideline document also described issues related to measurement of kidney function that had previously not been identified by the clinical community. This publication revolutionized the concept of CKD, and has generated substantial research, controversy and communication and influenced public policy and laboratory practice since its publication in 2002.

Given the increased evidence base, implementation experiences, and the controversies since the original publication, and international interest in understanding and improving the outcomes of people living with kidney disease, there is a need for an international group of physicians and researchers to review, revise and update those original guidelines.

There has been increasing published data to support the adverse consequences and outcomes in patients with eGFR <60 mL/min, irrespective of the etiology of the reduced kidney function, or the duration of the impairment. Thus, while there are numerous discussions about the ‘labelling’ of individuals with CKD due to the sole finding of eGFR <60 mL/min, the data continue to support use of that cut off value as a threshold for increased risk for adverse outcomes in general, and as a threshold to define high risk and CKD populations.

Use of widespread laboratory eGFR reporting has led to the identification of patients with abnormal eGFR who may or may not be at increased risk of progression of CKD, and thus do not indiscriminately need referral to nephrology services. Confusion in clinical practice has developed as the “identification” of a condition has created the need for appropriate stratification of risk and modified action plans for different subgroups of individuals regarding further evaluation, referral, or treatment.

The goal of this guideline is to clarify the definition and classification system, with minor changes which facilitate risk profiling, and develop appropriate guidance as to the management and care of patients with CKD.

Chronic Kidney Disease is an important problem worldwide

Chronic kidney disease (CKD) implies some abnormality of kidney structure and/or function, may sometimes be progressive, and is often long-term and irreversible. However, the diagnosis is often delayed or missed because of lack specific symptoms until CKD is at an advanced stage. Treatment of end stage kidney disease with dialysis or kidney transplantation is very expensive and significant increased costs and poor clinical outcomes are associated with the late referral of people with end stage renal disease. Therefore, identification of people at earlier stages of CKD, appropriate management and earlier referral of those who would benefit from specialist renal services would lead to an increase in both economic and clinical effectiveness.

Although the majority of people with CKD do not progress to end stage kidney disease they are at an increased risk for clinical events from cardiovascular disease (CVD) acute kidney injury (AKI), or hospitalisation and death. If CKD is detected early the associated complications and the potential progression to kidney failure may be delayed or even prevented through appropriate interventions. Note that this remains to proven in appropriately powered randomized trials. Nonetheless, regular testing of high-risk groups (people with diabetes, hypertension, cardiovascular disease or known kidney disease, and the elderly) can give an early indication of kidney damage, thus permitting the introduction of interventions at an early stage, and aiding our ability to test these interventions. Furthermore, identification of those with reduced kidney function, who are at increased risk from adverse effects of drugs, intravascular radiocontrast administration, and surgical procedures should lead to improved patient safety. Factors associated with progression of CKD and with increased cardiovascular risk are similar and targeting of these risk factors may both reduce CVD in people with CKD and reduce progression of CKD to end stage kidney disease.

It will be important to ensure a good understanding of the utility, pitfalls and opportunities of using the classification system to improve the care of patients both known and not known to the nephrology community.

General Summary

1. Overview: The guideline (GL) will offer best practice and evidence based advice on the evaluation and approach to management of CKD.
   1. The target population for the guideline is people with CKD who may be identified either by incidental or targeted testing.
   2. The target population includes adults and children. Elderly are an important subgroup. The guideline will cover the spectrum of individuals with CKD from paediatrics to the elderly, underscoring current issues at the extremes of age with respect to the evidence base, especially implementation and management issues.
   3. The target condition is CKD of any or unknown aetiology. A list of common aetiologies and an approach to make a corresponding presumptive diagnosis will be provided. A comprehensive list of possible aetiologies is not practical and guidance on detailed work-up for specific aetiologies of CKD is beyond the scope of this document (readers will be referred to other pertinent documents) We will describe how knowledge of the common aetiology of CKD may be important in prognostication and management
   4. The target audience of the guideline is general practioners, non-nephrology specialists (cardiologists, endocrinologists etc), nephrologists, clinical chemists and other practitioners caring for adults and children with CKD. The guideline is also expected to be suitable for use in public policy and other healthcare arenas
   5. The target healthcare setting is primary and secondary care, including referral to tertiary care.
2. The guideline will provide information, advice and education to support people/carers in diagnosis and self-management of CKD.
3. The guideline aims to provide a blueprint for an approach to CKD care in an international context. While the guideline will be sensitive to ethnic issues, and geographical considerations, it is expected that subsequent regional adaptation will be required for specific healthcare settings or contexts.
4. Research recommendations will be described in sufficient detail to inform an ongoing research agenda for the international community, and include not only important study questions to be answered, but also define methodologies, definitions of populations, and outcome measurement issues.

Topics that will not be covered

1. Evaluation and management of people receiving renal replacement therapy (management of kidney failure by dialysis or kidney transplant)
2. Specific approaches to people with acute kidney injury, glomerulonephritides or rapidly progressive glomerulonephritides
3. Work up or treatment of each of the specific causes of CKD, such as glomerular and tubulointerstitial disease, or nephrotic syndrome
4. Population based screening for CKD
5. Management of pregnancy in women with CKD or of pregnant women who develop kidney disease
6. Detailed management of specific disorders ( haematological, metabolic) associated with CKD. Existing KDIGO guidance in anaemia, metabolic bone disease and hypertension will be cross-referenced.

Following pages:

1. Table : Describes proposed 2011 KDIGO GL structure
2. Text: Describes suggested 2011 KDIGO GL format

Table: Proposed 2011 KDIGO Guideline Structure

Guideline number	Suggested changes/ differences from last GL; new developments/ approach to evidence review	Key points & Contentious areas to be addressed and highlighted
Guideline 1. Definition and Stages of Chronic Kidney Disease	Stages modified and enriched to include different degrees of proteinuria, as well as splitting Stage 3 into A and B Who has kidney damage/disease? (see below)	Definition of CKD: Rationale for maintaining definition in its entirety Acknowledge possible pitfalls and offer guidance as to how these might be addressed Address the issue/consequences of Disease labelling Utility of proteinuria as a prognosticator Stress need for identification of aetiology where possible Multi-dimensional staging (ie TNM classification) : consider adding additional information above and beyond Consortium data to help with action plans
Guideline 2. Identification and Evaluation of Chronic Kidney Disease	Start with: A patient has abnormal eGFR or proteinuria or both.... How do I further identify and evaluate CKD?	This GL will address individuals found to have abnormal eGFR or UACR either discovered incidentally or in targeted high risk populations Mention high risk populations (evidence?) After abnormal eGFR or UACR found, what additional tests should be performed, in whom, when and how often? Importance of context and repetition of testing. Reinforce concepts in Guideline 1 How much emphasis on diagnosis and work up? Specific management may be impacted by specific diagnosis, thus it may be important to ensure that diagnoses are appropriately sought (guided by clinical context). Describe for common conditions. It is beyond the scope of the GL to describe extensive detailed workup.
Guideline 3. Estimation of GFR	New equations Increasing interest in ethnic differences Previously GL 4	Measuring kidney function directly is not often feasible or necessary. Thus, estimating equations exist to assess kidney function in clinical practice. Standardization of creatinine: IDMS traceable methods Address ‘within individual’ biological variability of creatinine and thus eGFR (quantitate % change and address why eGFR will vary and by how much it varies in people with no decline in true GFR) see GL5** Age & ethnicity Equations adjusted for ethnicity need to be validated against gold standard GFR measurement. Users should be aware of methods, shortcomings and issues related to estimating equations. Role of Cystatin C in discriminating Implications for laboratories and policies re: changes in assays, equations etc
Guideline 4. Estimation of Proteinuria	Issues of measurement Previously GL 5	Measurement of protein excretion is important in the evaluation. We recommend using methods readily available to the clinician recognizing that this will vary depending on region. 24 hr urine protein is the traditional gold standard for quantifying proteinuria; however estimation of protein excretion can be done using uACR or uPCR ; each giving non-precise estimates of total protein. In clinical practice, these measures have utility for prognostication and risk prediction using broad categories of absent, present, mild moderate etc. Spot urine testing of ACR vs PCR vs reagent strip (including point of care ACR strips) Variability within individuals: extrapolations to 24 hr collections (including ACR equivalence to PCR) ?Influence of age (urinary creatinine level) Remove microalbuminuria from lexicon; suggest just albuminuria mild, moderate, severe
Guideline 5. Definition of progression of Chronic Kidney Disease	New   data review ** generate new data	What constitutes a true change in GFR and how is this defined in terms of GL3 Context  of change (acute vs chronic) Duration and stability of change Frequency of testing will impact scatter ?Include increasing albuminuria here too Prediction of kidney failure
Guideline 6. Adverse events  and patient safety issues common to patients with CKD	New Sections on AKI, infection, patient safety, medicines management Narrative. No evidence review Formulate as research question as not ready for prime time: Role of AKI (including ‘silent  AKI’ in the community)	Common agents and situations in which patients with CKD are at increased risk for adverse outcomes (AKI) Drugs Infections Investigations (e.g radiocontrast media including gadolinium, bowel prep ) Procedures Infection risk (?relation to other outcomes) Drug dosing and toxicities (what is and is not known) Vaccinations as intervention against infections
Guideline 7. Pitfalls in Investigation of CVD in CKD populations Cardiovascular Disease	Data review?	Caveats of testing and interpretation : narrative (BNP, Troponin, radionuclide stress testing etc)
Guideline 8. Management of CKD complications	Replaces old GL 7-12 narrative review	Cross reference to KDIGO Anaemia, Bone mineral disease and Hypertension GLs: links to GL and key statements from other GL Frequency of checking Hb, Ca, P, PTH, bicarbonate, proteinuria Targeting proteinuria as an issue to discuss overtly re: controversy as target vs assessment  tool  Individualize recommendations based on complexity/ age/other co-morbidities for frequency, intensity of management
Guideline 9. Recommendations for Best Practice (non CKD specific)	New Brief sections on frequency of testing, Planning for RRT (Tx and Dialysis/EoL)	Recommendations largely cross-referenced from other GLs Management of etc BP Targets Other nutritional aspects, lipids Life-style (exercise, smoking, diet) QoL, physical functioning
10. Research Recommendations	Based on GLs 1-9 define remaining key questions of importance to clinicians and researchers	Emphasize the use of the classification system to describe and stratify populations for enrolment into interventional studies. ( ie emphasize need to conduct meaningful studies to inform clinical practice) Use classification system to inform study design and reporting of subgroups of interest, important outcomes and interventions (test the utility of TNM type classification for outcomes of interest). Discuss the importance/validity of surrogate outcomes  (change in eGFR/ proteinuria/ categorical vs continuous outcomes) Questions of interest: Need to understand the heterogeneity of the populations despite similar eGFR/proteinuria configurations Identify the 5 most important questions to answer in the next 3-7 years from perspective of pts, health care systems and public policy. Eg. Which patients will benefit from renin-angiotensin system blockade in prevention of progression of CKD and which patients will not? What are the blood pressure targets in management of patients with CKD? What is the role of uric acid in progression of CKD?

Suggested Guideline Format

In order to facilitate uptake, we suggest that we follow the previous (KDOQI) CKD guideline format, underscore those items that are different or altered and cite the rationale for changes. Simplification and reduced density can be accomplished given the profound increase in literature base that exists since original 2002 publication.

Part 1. Executive Summary

Overview of scope, rationale for update, and how this update differs (and why) from the original guideline.

Key statements and implications (key priorities for implementation)

Evidence review (dates/ times/change in methods and impact/considerations for changing statements)

Part 2. Background

See above overview for some of this. Suggest it be short, with lots of references, instead of encyclopaedic. Potential here to discuss some of the advances/changes since 2002 knowledge base re CKD internationally, including issues regarding ethnicity and equations, knowledge re progression to ESRD vs progression to CVD events etc. Include the controversies regarding ‘labelling’ of individuals, and population projections, and why acknowledging these is so important.

Part 3. Methodological Approach

Part 4. Chronic kidney disease as an international public health problem

Needs updating with a very international focus…using data from each region of the world if possible would be a good way to ensure international acceptance of the guideline. Also discuss here the shortcomings of international data (ascertainment bias; lack of resources; need for/implications of targeted or population screening)

Part 5. Definition and classification of stages of chronic kidney disease

Guideline 1. Definition and Stages of Chronic Kidney Disease

Clarify definition (needs to be clearly explained regarding various controversies/issues arising from the consensus conference)

Address issues/consequences of disease mis-labelling

Review rationale for revisiting staging system: updated with the split into 3A and 3B plus addition of proteinuria suffix at all stages (?subdivision of proteinuria – see below in GL 4 though).

Evidence base here will be heavily dependent on London meeting publications, and will need to acknowledge data generated from different groups/investigators over the last 10 yrs, and in different populations (ethnicity, aging etc, Japanese, North American etc)

Multi-dimensional staging: Address the issues overtly. Whether or not there is a known or presumptive aetiological diagnosis, and how it is not essential for the staging system, or definition, but does help in management and prognosis. At what stage are patient outcomes significantly affected? Does this change with age, gender, ethnicity, presence or absence of proteinuria, underlying aetiology?

Guideline 2. Identification and Evaluation of Chronic Kidney Disease

Clarify for this guideline that the finding of abnormal GFR may be the result of incidental finding or targeted testing. Whether to or how to conduct screening is beyond the scope for this guideline.

Separate defining CKD from subsequent identification and intervention thresholds. Note that some of the ‘confusion’ has arisen because of lack of ability to clearly articulate ‘definition/identification’ and ‘intervention’ thresholds, so this concept will need to be expanded upon. (eg. threshold for intervention for proteinuria might be ACR 30 mg/mmol (PCR 50 mg) if associated with haematuria and/or hypertension or ACR 70 mg/mmol (PCR 100 mg/mmol) if just isolated proteinuria and normal GFR)

Discuss here the issue of diagnostic procedures: ultrasound, biopsies etc?

Role of primary kidney diagnosis and how much to pursue? (pragmatic and economic considerations, international context)

Consider a table or new analysis(?) which describes relative “severity of CKD” by the constellation of eGFR + proteinuria, + associated abnormalities ( Hb, PO4, BP, ? age) so that isolated abnormalities of eGFR +/- uACR can be examined separately from those in whom other abnormalities are found? The concept of isolated eGFR abnormalities vs other?

Part 6. Evaluation of laboratory measurements for clinical assessment of chronic kidney disease

Guideline 3. Estimation of GFR

What is the best test to measure kidney function in routine clinical practice?

Outstanding issues:

• creatinine - standardisation still an issue - many methods 'traceable' to IDMS but this doesn’t mean they give equivalent results; specificity still an issue - enzymatic assays preferred; biological variability considerations, how many samples, when to sample, influence of meat or fish containing meals, reporting units (mg/dL or umol/L); address why eGFR will vary and by how much it varies in people with no decline in true GFR

Cystatin C – does it have a role? If so what is it?

• eGFR estimating equations. Which equation MDRD/CKD-EPI, ?others. Age and ethnicity considerations.

Evidence review here will examine diagnostic accuracy of existing equations: strict criteria for accepting different equations (comparison against gold standard measurement of eGFR; if creatinine based, need to use calibrated creatinine).

May be that a recommendation is required clarifying that which equation should be used is dependent on the location of the laboratory, confidence in equations, calibration technologies etc.

Need to be both guiding and clear that outstanding issues remain for any estimating equation, and the important issue is that of laboratory reporting transparency/ consistency and ongoing communication with physicians.

These issues below are not for evidence review but need to be considered:

Should we give advice re laboratory reporting as >60 or >90? (? Laboratories should report......): should we advise concomitant testing of UACR/UPCR?

What about drug prescribing and GFR (BSA adjustments or not); note that drug prescribing guideline should be? Done (Consider under GL9?)

Paediatrics vs people less than 18 years of age – which equation? newborns vs adolescents: Raise the issues but how do we address this? Leave for research recommendations?

Guideline 4. Assessment of Proteinuria

Measurement issues: should we have clinical guidelines and also tackle guidelines/recommendations for laboratories? ACR vs PCR, how albumin is measured (immunoassay/HPLC), which sample (random/MSU/EMU/timed), stability/storage conditions, antigen excess

Reporting issues: ie concentration or creatinine ratio, standardisation not introduced yet, no reference method, relationship of ACR to PCR, non-albumin proteinuria - how important is it? Should cut-offs be age/gender/race specific or not, should diabetic/non-diabetic cut-offs differ?

Abolition of the term microalbuminuria because there is a continuum of risk from normalbuminuria upwards?

Point of care testing or lab testing, binding to plastic containers/losses on centrifugation. Biological variability considerations – how many samples?

Clinical practice implications regarding re: timing of, collection of and interpretation of UACR or UPCR once these issues have been better understood.

Part 7. Progression of Chronic Kidney Disease

Restructured part together with a restructured Part 7 will include prognostic value of the new refined system: that is, the association of level of eGFR/or staging system for identifying those likely to progress, likely to die, likely to have events but also considers special considerations of concomitant diabetes and cardiovascular disease.

Guideline 5. Definition of Progression of Chronic Kidney Disease

What constitutes progression of CKD? Evidence review: progression scores, disease specific, age, ethnicity, obesity? Is there enough robust evidence to make a statement here, or rather recommend best research?

If progression is defined by a change in eGFR when can we be confident that the change in GFR recorded represents a true change in kidney function?

What about the role of AKI in progression of CKD? Consider “silent” AKI here (episodes of acute dysfunction in association with infection, dehydration, drugs etc in the community – see GL6).

How many tests do we have to do and how often? Over 6 m vs annual vs ?

Importance of defining progression (vs change due to acute situation)

In association with change in UACR or in association with developing Hb, Ca, PO4, bicarbonate, PTH etc abnormalities : This may be a research question, or could it be answered with some analysis of existing databases?

Part 8. Chronic Kidney Disease Complications, Risk for Adverse Events and Recommendations for Best Practice

This section also looks at the association of level of eGFR/or staging system for identifying those likely to have complications and/or adverse events (AKI, infection, drug toxicity).

Guideline 6. Adverse events and patient safety events common to patients with CKD

Infection (and prevention of infection), AKI, drug toxicities, investigations (radiocontrast media, bowel prep), patient safety/adverse events, hospitalisation, death (narrative review)

Guideline 7. Pitfalls in Investigation of CVD in CKD Populations

Caveats of specific tests for CVD in CKD as a novel aspect

• proBNP, Troponin : use in population studies vs individual
• radionuclide stress tests
• Clearance, interference with/ from other proteins/ active vs fragments

Guideline 8. Management of Chronic Kidney Disease Complications

Replaces old GL 7-12. This section cross references to other KDIGO Guidelines (Anaemia, Bone Disease, Hypertension) with statements about when to check Hb, Ca, P, PTH etc

Add: Proteinuria, who to treat and how, intervention thresholds

Guideline 9. Recommendations for Best Practice

Management and follow up issues:

What is the best way to deal with this given that there are few studies that describe the utility of different approaches to care delivery in cohorts of similarly identified CKD patients? Also the intended audience for the guideline is international.

Given that there are a number of new guidelines in progress, this may be a good place to summarize those, and give generic recommendations re; testing frequency etc?

Set of generic statements (BP control, use of ACEi, anaemia thresholds, calcium phosphate, PTH etc testing frequency and possible therapies and recommendations for best practice)

Planning for kidney failure and RRT (Tx, Dx, End of life) – the ‘golden year’

Also need to look at areas not covered such as bicarbonate, life-style, QoL, physical functioning or to delete this and just apportion manageable aspects, explain why other aspects not addressed ( no data)

Part 9. Approach to chronic kidney disease using these guidelines

Approach to CKD and implementation of guidelines, International focus, define Implementation strategies, and results of different types if data available

Research Recommendations

see Table

Part 10. Appendices

Appendix 1. Methods for Review of Articles: this is likely to be in the methods section

Appendix 2. Kidney Function and Associated Conditions: Overview of international collaborative group (KDIGO London output? )

Appendix 3. Members of the KDIGO team

1. KDIGO advisory board members

2. Work group and evidence review team membership and support group

3. Declarations of conflicts of interests

Part 11. Acknowledgements

Bibliography

Disclaimers