Narrative Review Integrating Guidelines, CKD, Multimorbidity, and Older Adults Paul E. Stevens, FRCP,1 Edmund J. Lamb, PhD,2 and Adeera Levin, MD3 Clinical practice guidelines provide guidance in decision making relating to diagnosis, management, and treatment in specific areas of health care. They play an essential role in the evaluation and synthesis of an ever-expanding evidence base and are of increasing importance in aging societies with a high prevalence of overlapping disease comorbid conditions. Integration of chronic disease guidance is essential, particularly in older people, in order to understand critical disease interactions and the potential adverse effects that individual guideline statements may engender in different disease areas. This requires a need for flexibility that not only recognizes the differences in patients’ characteristics, but also their preferences for medical interventions and health outcomes. The question is how this can be achieved. In this article, we look at the standardization of clinical practice guidelines from the chronic kidney disease standpoint and consider how tools for integrating guidelines, such as the ADAPTE process and the knowledge-to-action cycle, can be used to guide appropriate decision making and take account of patient choice in older adults with multimorbidity. Am J Kidney Dis. 65(3):494-501. Crown Copyright ª 2015 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. INDEX WORDS: Integrating clinical practice guidelines; chronic kidney disease; multimorbidity (co-morbidity); knowledge-to-action cycle; care for older adults (elderly care).
Paul Stevens, FRCP, was an International Distinguished Medal recipient at the 2014 National Kidney Foundation Spring Clinical Meetings. The International Distinguished Medals are awarded to honor the achievement of individuals who have made significant contributions to the field of kidney disease and extended the goals of the National Kidney Foundation.
We’ve put more effort into helping folks reach old age than into helping them enjoy it. Frank A. Clark (1911-1991) There is no pleasure worth forgoing just for an extra three years in the geriatric ward.
F
Sir John Mortimer (1923-2009)
ive hundred years ago, the Spanish conquistador Juan Ponce de León set out in search of the legendary Fountain of Youth, reputed to be in Florida. He never found it, but since then, medical science and public health have demonstrated that a mythical youth-restoring fountain is not required to increase life From 1Kent Kidney Care Centre and 2Clinical Biochemistry, East Kent Hospitals University NHS Foundation Trust, Canterbury, United Kingdom; and 3University of British Columbia, Vancouver, Canada. Received May 27, 2014. Accepted in revised form September 11, 2014. Originally published online December 5, 2014. Address correspondence to Paul E. Stevens, FRCP, Kent Kidney Care Centre, East Kent Hospitals University NHS Foundation Trust, Ethelbert Road, Canterbury, Kent, CT1 3NG, United Kingdom. E-mail: [email protected] Crown Copyright 2015 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2014.09.024 494
expectancy. We now have an “epidemic” of aging, and by 2050, it is expected that the proportion of the world’s population older than 60 years will double from w11% currently to 22%.1 We also live in a time of epidemics of chronic diseases, including diabetes,2 obesity,3 cardiovascular disease,4 and chronic kidney disease (CKD),5 occurring worldwide. The consequences of these 2 trends are rapidly increasing health costs and a requirement to reassess our use of health care resources. At the same time, there is a need to improve overall standards of care, reduce variation in practice, reduce inequalities in care, and reduce waste. These driving factors, combined with the plethora of literature and sources of data available to both physicians and patients, have led to a need for clinical practice guidelines to help health professionals in their work. The expectation is that well-implemented high-quality guidelines should improve both the process of care and health- and patient-related outcomes. However, guideline duplication is common, quality is variable, and there are many potential interactions between guidelines aimed at different disease groups or conditions. We already have highlighted that confusion is the unintended consequence of guideline proliferation.6 In the 12 years since publication of the first internationally accepted definition and classification of CKD,7 there have been 2,638 peer-reviewed guidelines published relating to cardiovascular disease; 728, to older people (age $ 65 years); 529, to diabetes; and 523, to kidney disease (Fig 1). In this article, we concentrate on CKD, but the same principles apply to other chronic diseases. This article first highlights the importance of standardization of guidelines and the process by which this can be achieved, before considering the older adult with CKD, why there is a need to integrate disease Am J Kidney Dis. 2015;65(3):494-501
Integrating Guidelines for CKD 60000 50000 40000 30000 20000 10000
9
58
445
78
0 1982 - 1992 1992 - 2002 2002 - 2012 2012 - 2014 Figure 1. PubMed articles in human kidney disease, 1982 to 2014. Dark gray indicates randomized controlled trial/metaanalysis/systematic review publications (1.8% in 1982-1992, 3.5% in 1992-2002, 4.8% in 2002-2012, and 7% in 20122014). The numbers refer to published guidelines in kidney disease during each period.
guidelines, and the caveats to be considered in integrating guidance from the available evidence.
STANDARDIZATION OF GUIDELINES: THE AGREE (APPRAISAL OF GUIDELINES FOR RESEARCH AND EVALUATION) CRITERIA The utility of guidelines has been debated for centuries. Many countries have engaged in clinical practice guideline development, as well as appraisal and implementation of these guidelines at professional, institutional, regional, and national levels. Because these guidelines are seen as essential tools for promoting quality and effectiveness in health care, frameworks have been created to assess their quality and serve as a means for standardization. An internationally accepted framework has been provided by the AGREE (Appraisal of Guidelines for Research and Evaluation) collaboration that developed the AGREE instrument.8 This instrument assesses the predicted validity of a guideline and consists of 23 criteria organized in 6 domains (Table 1). Each domain is intended to capture a separate dimension of guideline quality. Guiding the management of multiple complex conditions that coexist in the same patient is a challenge and requires not simply a review of the evidence, but also the systematic evaluation of goals of care from the patient perspective. Recently published guidelines in CKD from KDIGO (Kidney Disease: Improving Global Outcomes)9 and the England and Wales NICE (National Institute for Health and Care Excellence)10 have attempted to achieve this, and we use these 2 guidelines as examples to illustrate how well CKD guidance complies with AGREE criteria (Table 1). Engagement of End Users and Patients One key deficiency common to both guidelines (and many others) is a failure to pilot guidance among Am J Kidney Dis. 2015;65(3):494-501
end users prior to publication of the recommendations. NICE pilots its subsequent quality standards (which are derived from the relevant NICE guidance and other high-quality guidance from sources accredited by NICE), but does not pilot the guidelines themselves. KDIGO included both primary care and diabetes physicians in the guideline development group, but not relevant health professionals such as nurses, pharmacists, and dieticians. Patients’ views and preferences were not sought, something that NICE does. KDIGO, as a global guideline, goes some way toward thinking about organizational barriers that may hinder international applicability, whereas national guidelines such as NICE necessarily are tailored toward a specific health care system. However, applying recommendations also may necessitate changes to organization of care within a service or a clinic, which may make it more difficult to implement them in daily practice. This was highlighted by the NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) US Commentary on the KDIGO guideline, which noted the practical issues related to implementation of recommendations concerning measurement of cystatin C.11 The NKF-KDOQI commentary also raised the question of the cost for these tests; one of the key strengths of NICE is that it undertakes cost-benefit analyses; something that KDIGO is not structured to do, given its international breadth. Question Formatting and Assessment of Evidence Both NICE and KDIGO, together with many other guideline development organizations, use the PICO (population, intervention, comparator, and outcome) question format when searching the evidence. Both organizations use the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system12 to assess the quality of the evidence and determine the strength of recommendations made from the evidence (Table 2). The quality of the evidence ranges from high quality, in which the guideline authors are confident that the estimate of the effect is close to the truth, to very low quality, in which the guideline authors have very little confidence. Although the amount of published evidence in human kidney disease is ever increasing (Fig 1), Samuels and Molony13 detail how far this field continues to lag behind other specialties in the quality of that evidence. Furthermore, they also note a number of key issues in the study of CKD populations: the systematic exclusion of high-risk patients from randomized controlled trials (RCTs) in kidney disease, overreliance in RCTs on surrogate outcomes (decline in glomerular filtration rate [GFR], doubling of serum creatinine concentration, and change in proteinuria),14 reliance on small studies, failure to recruit and follow 495
Stevens, Lamb, and Levin Table 1. AGREE Criteria: NICE and KDIGO CKD Guideline Compliance NICE
KDIGO
1. The overall objective(s) of the guideline is (are) specifically described
U
U
2. The clinical question(s) covered by the guideline is(are) specifically described
U
U
3. The patients to whom the guideline is meant to apply are specifically described
U
U
NICE
KDIGO
22. The guideline is editorially independent from the funding body
U
U
23. Conflicts of interest of guideline development members have been recorded
U
U
Editorial Independence
Scope and Purpose
Stakeholder Involvement 4. The guideline development group includes individuals from all the relevant professional groups
U
✗
5. The patients’ views and preferences have been sought
U
✗
6. The target users of the guideline are clearly defined 7. The guideline has been piloted among target users
U
U
✗
✗
8. Systematic methods were used to search for evidence
U
U
9. The criteria for selecting the evidence are clearly described
U
U
10. The methods used for formulating the recommendations are clearly described
U
U
11. The health benefits, side effects, and risks have been considered in formulating the recommendations
U
U
12. There is an explicit link between the recommendations and the supporting evidence
U
U
13. The guideline has been externally reviewed by experts prior to its publication
U
U
14. A procedure for updating the guideline is provided
U
U
15. The recommendations are specific and unambiguous
U
U
16. The different options for management of the condition are clearly presented
U
U
17. Key recommendations are easily identifiable
U
U
18. The guideline is supported with tools for application Applicability
U
U
19. The potential organizational barriers in applying the recommendations have been discussed
✗
U/✗
20. The potential cost implications of applying the recommendations have been considered
U
✗
21. The guideline presents key review criteria for monitoring and/or audit purposes
✗
✗
Rigor of Development
Clarity and Presentation
496
Table 1 (Cont’d). AGREE Criteria: NICE and KDIGO CKD Guideline Compliance
Note: U indicates compliance with the criterion, ✗ indicates noncompliance. Abbreviations: AGREE, Appraisal of Guidelines for Research and Evaluation; CKD, chronic kidney disease; KDIGO, Kidney Disease: Improving Global Outcomes; NICE, National Institute for Health and Care Excellence.
up nephrology patients for long enough to evaluate the long-term impact of interventions, failure to compare the new therapy under investigation with current best practice, and underappreciation of harms because of a failure to report. Importantly, the majority of RCTs fail to include older people with CKD despite their prevalence in all populations. All these shortcomings cast doubt on even the field’s highquality evidence, although it should be noted that all strong recommendations do not necessarily have to be underpinned by high-quality evidence. There are no RCTs involving the use of a parachute when jumping out of an aircraft.15 Nevertheless, all of us would still have confidence in a strong recommendation to use a parachute in such a circumstance, despite the weak evidence base underlying its use. Adherence to Key Recommendations Measuring adherence to a guideline through audit and quality improvement initiatives can enhance guideline use. However, in order to measure adherence, clearly defined review criteria derived from the guideline’s key recommendations are needed. Although this is partially met by the NICE Quality Standards, neither group addresses this fully. Finally, both groups conform to the necessary editorial independence; in particular, NICE’s conflict of interest policy is detailed and rigorous. Overall, KDIGO made 110 guideline recommendations as of November 2012, of which 22 had a low- or very low-quality evidence base and only 11 had a highquality evidence base. There were a few parachute-type recommendation statements, for example, temporary suspension of renin-angiotensin system (RAS) antagonists during intercurrent illness, for which, despite poorquality evidence, it was still possible to make a strong recommendation. There also were 41 ungraded statements. These of course are largely opinion and were made in areas in which the guideline development group Am J Kidney Dis. 2015;65(3):494-501
Integrating Guidelines for CKD Table 2. The KDIGO Clinical Practice Guideline Grading of Quality and Strength of Evidence Based on the GRADE System 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
C
Low
The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. 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. Implications
Gradea
Patients
Clinicians
Policy
Level 1 Most people in your situation “We recommend” would want the recommended course of action and only a small proportion would not.
Most patients should receive the recommended course of action.
Level 2 “We suggest”
Different choices will be appropriate for The recommendation is likely to different patients. Each patient needs require substantial debate and help to arrive at a management decision involvement of stakeholders consistent with her or his values and before policy can be determined. preferences.
The majority of people in your situation would want the recommended course of action, but many would not.
The recommendation can be evaluated as a candidate for developing a policy or a performance measure.
a 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. Reprinted from KDIGO Chronic Kidney Disease Work Group9 with permission of Macmillan Publishers Ltd.
thought it important to give some guidance. However, others commenting on the ungraded statements, for example, the NKF-KDOQI commentary work group, have largely endorsed these ungraded statements.
THE OLDER ADULT WITH CKD: THE NEED TO INTEGRATE DISEASE GUIDELINES It is imperative to consider characteristics of the older adult with CKD because that will determine which other disease area guidelines need to be considered when integrating kidney disease guidance. As previously stated, the world population is aging; the overall average life expectancy in the countries represented in the KDIGO guideline development group ranged from 74.3 to 82.7 years (Table 3).16 Healthy life expectancy in Table 3. Life Expectancy and Health Life Expectancy Life Expectancy (y)
Health Life Expectancy (y)
Japan
82.7
76
6.7
Spain
82.1
74
8.1
Canada
81.5
73
8.5
Netherlands
81.2
73
8.2
Country
Health Economy Burden (y)
Germany
80.7
73
7.7
United Kingdom
80.5
72
8.5
United States China
78.6 75.6
70 66
8.6 9.6
Brazil
74.3
64
10.3
Data from www.worldlifeexpectancy.com.16 Am J Kidney Dis. 2015;65(3):494-501
those same countries ranges from 64 to 76 years, a gap of 6.7 to 10.3 years that represents a significant burden for each individual health economy. Whether integration of disease guidelines can improve this situation and provide more cost-effective health care has yet to be tested. Regardless of what one believes about age, GFR thresholds, and CKD or whether one accepts cystatin C– estimated GFR as a better risk marker,17 the prevalence of reduced GFR increases exponentially with age, and the lifetime risks of CKD or lower levels of kidney function are staggering. Grams et al18 estimate that the lifetime risk of reaching a GFR , 60 mL/min/1.73 m2 from birth is 59%, greater than the estimated lifetime risks of developing diabetes (33%-39%), ischemic heart disease (32%-49%), and invasive cancer (38%-45%). Current clinical practice guidelines focus on specific diseases and often fail to overtly take into consideration the presence of comorbid conditions. However, the majority of chronic conditions are associated with one another. Older adults with CKD (or reduced GFRs) may have no comorbid conditions or may have several. More than 50% of older adults have 3 or more chronic diseases and .20% have 5 or more. In the United States, the mean number of chronic conditions per individual increased from 1.88 in the 65- to 69-year age group to 2.71 in the 80- to 84-year age group and thereafter reached a plateau.19 Seventy-four percent of people with kidney disease had 4 or more chronic diseases. Very similar findings have been reported in a number of different countries,20 and the coexistence of kidney disease frequently is a multiplier of adverse outcome.21 497
Stevens, Lamb, and Levin Box 1. Evidence-Based Indications for Renin-Angiotensin System Blockade From Clinical Practice Guidelines
CKD and proteinuria (.1 g/d) irrespective of blood pressure Hypertension and proteinuria (ACR . 300 mg/g or 30 mg/ mmol) Diabetes and proteinuria (ACR . 30 mg/g or 3 mg/mmol) Resistant hypertension at any age Chronic heart failure Post acute myocardial infarction
Abbreviations: ACR, albumin-creatinine ratio; CKD, chronic kidney disease.
Despite the similar underlying pathology driving kidney disease in CKD patients with and without comorbid conditions, the treatments suggested for CKD patients with comorbid conditions may interact with and alter the natural history of the disease. For example, consider diabetes, CKD, and acute kidney injury (AKI). Girman et al22 extracted data from a UK primary care database over 5 years in a population of nearly 2 million people. After multiple adjustment for confounders, the independent predictors of AKI were CKD (hazard ratio [HR], 3.18; 95% confidence interval [CI], 2.84-3.55), diabetes (HR, 2.26; 95% CI, 2.24-2.69), heart failure (HR, 1.95; 95% CI, 1.682.27), hypertension (HR, 1.74; 95% CI, 1.61-1.88), and obesity (HR, 1.6; 95% CI, 1.46-1.76). The incidence of AKI in those with diabetes was 7 times higher than in those without diabetes, and as with other series, the hazard for AKI increased markedly with age.22 We also know from a number of studies that AKI is associated with progression of existing CKD and with new-onset CKD,23 as well as with people who have diabetes. Thakar et al24 followed up 4,082 people with diabetes accessing either
Figure 2. Overview of relationships between the older population and different disease areas. Abbreviations: AKI, acute kidney injury; AKD, acute kidney diseases and disorders (any condition that acutely affects kidney structure and function); CKD, chronic kidney disease; CVD, cardiovascular disease. 498
• Define Health Question • Search and Screen Guidelines
• Assess Guidelines • Decide and Select
• Draft Integrated Guideline • External Review and Pilot Figure 3. The ADAPTE process. (modified from ADAPTE32).
ambulatory or inpatient services over a 5-year period from 1999 to 2004 and then followed them up for an additional 4 years. The primary outcome was reaching stage 4 CKD, and AKI was defined according to AKIN (Acute Kidney Injury Network) criteria. After multiple adjustment for confounders, the independent predictors of stage 4 CKD were baseline serum creatinine level (HR, 8.59; 95% CI, 6.07-12.15), proteinuria (HR, 3.54; 95% CI, 2.47-5.08), hypertension (HR, 1.82; 95% CI, 1.41-2.37), AKI (HR, 3.56; 95% CI, 2.76-4.61), and multiple episodes of AKI (HR, 2.02; 95% CI, 1.78-2.30). Diabetes, hypertension, and proteinuria are all predictors of progression of CKD, and guidelines strongly recommend treatment with RAS blockade to prevent or ameliorate progression of CKD. However, the evidence-based recommendations for RAS blockade encompass more than just kidney disease (Box 1), and other disease areas also strongly recommend use of RAS blockade for improvement of clinical outcomes. AKI and multiple episodes of AKI also predict progression of CKD. In the Girman et al22 study, increasing age, diabetes, hypertension, proteinuria, and heart failure all predicted AKI. Importantly, 48% of type 2 diabetic patients were being treated with RAS blockade at the time of their AKI. We know that RAS blockade associates strongly with AKI25 and that can be extended when we consider other drug interactions and combinations that markedly increase the risk. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) have long been associated with increased risk of AKI. Guidelines for people with CKD, diabetes, and cardiovascular disease do not recommend NSAID therapy, but those for osteoarthritis and low back pain do,26-29 and these are common conditions in older adults. A large case-control study (500,000 patients followed up for a mean of w6 years) examined the risk of AKI in people receiving either double therapy consisting of Am J Kidney Dis. 2015;65(3):494-501
Integrating Guidelines for CKD
an NSAID combined with a diuretic or an NSAID with RAS blockade or triple therapy with a diuretic, an NSAID, and RAS blockade.30 After controlling for confounders including other chronic diseases and drug use, triple therapy was associated with a 31% increased risk of AKI. There is complexity in the overlap between different forms of kidney disease and other coexistent chronic diseases, and this is particularly relevant to the older population (Fig 2). Thus, it is important to be careful when considering the evidence on which guideline recommendations are being made. Does the evidence cover all areas of the PICO question (population, intervention, comparator, and outcome), specifically regarding the older adult populations? Given the design of clinical trials, much of the evidence excludes older people and also those with comorbid conditions,13 and some of the outcomes that are of importance in the elderly, such as falls, quality of life, and increase in level of care, are not even considered by the evidence. For example, to prevent the progression of CKD, kidney disease guidelines recommend treatment with RAS blockade based on whether the individual has kidney disease (chiefly albuminuria/proteinuria) and by the presence or absence of hypertension and diabetes. In considering the applicability of the evidence for prevention of CKD progression in older people, one must evaluate any potential specific concerns about the applicability of the evidence for a given recommendation. If these concerns exist, the applicability of the evidence is lessened and ones’ confidence in applying the recommendation is weakened. This becomes even more relevant when factoring in other considerations, such as level of blood pressure control, risk of falls, and risk of AKI. What is the extent of the interaction between the interventions recommended and older populations with different comorbid
conditions? Can one assume that the outcomes of interest are the same in the older population, and that the outcomes selected are of the same relevance to older populations? Is the direction and strength of the relationship between the intervention and outcome the same in older populations? Caveats in Integrating Guidance From the Evidence In order to integrate guidance for the older person with kidney disease, there are some very real conflicts to resolve. Three separate but related questions have to be addressed. (1) What is the applicability of an evidence base that has largely been developed in younger age groups? (2) What is the impact of and interaction between different kidney disease phenotypes? (3) What is the influence of multiple comorbid conditions? There are a number of tools available to help integrate differing disease guideline recommendations and resolve these conflicts and problems. Two of these, the ADAPTE process and the knowledge-toaction cycle, are worth considering further. The ADAPTE process was created by an international collaboration of researchers, guideline developers, and guideline implementers with the aim of promoting clinical practice guideline development and use, through adapting existing guidelines.31 The ADAPTE manual and toolkit follow a very logical stepwise process (Fig 3) after defining the health question under consideration.32 In the context of the older patient with CKD, this would require revisiting the condition of the older population and deciding on key questions or outcomes of importance. If the health question is “When should we consider treatment with RAS antagonists in older people with kidney disease?”, the first question to ask is “What does the older population with kidney disease look like?” Subsequent
Figure 4. The knowledge-to-action cycle. (redrawn from Harrison et al33). Am J Kidney Dis. 2015;65(3):494-501
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questions would include: What is the relative importance of comorbid conditions? What implications does that have for treatment and are there any downsides to the treatments suggested? How do the different disease areas change this, in particular comparing older adults with CKD and no comorbid conditions with those with CKD and multiple comorbid conditions? In order to resolve these issues, a more sophisticated tool, such as the knowledge-to-action cycle, probably is a better choice (Fig 4).33 The knowledge-to-action cycle is the ideal method or process by which knowledge is implemented into practice within a thoughtful framework. The cycle begins by identifying the practice problem to be addressed, for example, prevention of CKD progression in the older population. The knowledge product or products that provide solutions to progression of CKD then are identified. These solutions then must be considered in the context of the local practice, health care system, and population. The barriers and facilitators for applying the solutions must be addressed. For the solutions to be effective, they must consider the entire health care system and identify and address any barriers to change and the interventions needed to enact the solutions chosen (in our example, RAS blockade). After selecting the interventions, the next step is to monitor whether they are used, the impact of their use (both desired outcomes and unintended adverse consequences such as AKI), and whether any adaptation is required. The new knowledge acquired is funneled back into the cycle, thus sustaining knowledge use, to ensure that the knowledge-to-action gap continues to be reduced or closed. The knowledge-to-action cycle has been used in a case study considering the assessment of proteinuria as a key guideline recommendation for implementation.34 To help select, tailor, and implement the interventions, the authors also used the processes described by ADAPTE. Albeit this was essentially a pilot study, it serves to demonstrate how application of these processes may successfully aid the implementation of evidence-based practice guidelines. A similar process is underway to identify practice variation and key barriers in another contentious area of kidney disease, the optimal timing for dialysis therapy initiation in patients approaching end-stage kidney failure.35 However, none of these processes adequately accounts for individual patient preference, hugely important in the elderly. After considering all the evidence, using the available tools to integrate guidelines, and arriving at recommendations commensurate with all the different disease areas, those recommendations may not necessarily fit with the older person’s preferences and priorities. Clinical practice guidelines do not routinely search for or include evidence related to patient values and preferences. So in beginning the process of guideline integration for older adults, it is important to keep in mind the guiding principles for the care of older adults with multiple comorbid conditions36: 500
1. Elicit and incorporate patient preferences. 2. Recognize the limitations of the evidence base. Have outcomes relevant to the elderly, such as physical functioning and independent living, been adequately covered by the evidence considered? 3. Consider risks and benefits, burdens, and prognosis before making any clinical management decisions. Clinicians and researchers traditionally focus prognosis on remaining life expectancy, but it is important not to lose sight of functional disability and quality of life when thinking about management decisions. 4. Evaluate treatment complexity and feasibility. Polypharmacy and its relationship to nonadherence are well known, but complex regimens also carry additional risks. 5. Maximize benefit, reduce harm, and improve quality of life. Guidelines for chronic diseases, especially those affecting the aging population, should consider the importance of multiple comorbid conditions in diagnosis, prognosis, and management; acknowledge where the gaps in the evidence are; give pointers for where guideline recommendations should be modified; address the elderly; and consider inequalities. Central to this is an informed discussion with the patient and/or caregiver about what the clinician is trying to achieve, how it might be achieved, how long it may take to achieve it, and what (if any) are the associated down sides. Integration of the KDIGO CKD guideline and the updated NICE CKD guidance together with thoughtful commentaries provided by the NKF KDOQI work group and others, combined with measures of quality of care that address the factors that serve to create the gap between life expectancy and health life expectancy, may bring us closer to achieving our stated goal.6,9,10,11 Perhaps the final step to be considered prior to implementation of such an integrated evidence-based intervention is the use of a tool to guide individual prognosis, such as the estimating prognosis for elders tool.37
ACKNOWLEDGEMENTS Drs Stevens and Levin were co-chairs and Dr Lamb was a member of the KDIGO CKD 2012 guideline development group. Dr Stevens was chair and Dr Lamb was a member of the NICE CKD 2014 guideline development group. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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Integrating Guidelines for CKD 5. Eckardt K-U, Coresh J, Devuyst O, et al. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet. 2013;382(9887):158-169. 6. Levin A, Stevens PE. Kidney disease guideline profusion and confusion: unintended consequences of different perspectives and definitions. Am J Kidney Dis. 2014;63(5):749-752. 7. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2)(suppl 1):S1-S266. 8. The AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care. 2003;12(1):18-23. 9. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150. 10. National Clinical Guideline Centre. Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care (update). National Institute for Health and Care Excellence, 2014. http:// www.nice.org.uk/guidance/cg182/resources/cg182-chronic-kidneydisease-update-full-guideline3. Accessed September 1, 2014. 11. Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63(5):713-735. 12. Guyatt GH, Oxman AD, Vist GE, et al; for the GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926. 13. Samuels JA, Molony DA. Randomized controlled trials in nephrology: state of the evidence and critiquing the evidence. Adv Chronic Kidney Dis. 2012;19(1):40-46. 14. Stevens LA, Greene T, Levey AS. Surrogate end points for clinical trials of kidney disease progression. Clin J Am Soc Nephrol. 2006;(4):874-884. 15. Smith GCS, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ. 2003;327(7429):1459-1461. 16. LeDuc Media. World life expectancy and health life expectancy. http://www.worldlifeexpectancy.com/life-expectancyresearch. Accessed September 1, 2014. 17. Shlipak MG, Matsushita K, Arnlov J, et al; CKD Prognosis Consortium. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013;369(10):932-943. 18. Grams ME, Chow EKH, Segev DL, Coresh J. Lifetime Incidence of CKD stages 3-5 in the United States. Am J Kidney Dis. 2013;62(2):245-252. 19. Wolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med. 2002;162(20):2269-2276. 20. Garcıa-Olmos L, Salvado CH, Alberquilla A, et al. Comorbidity patterns in patients with chronic diseases in general practice. PLoS One. 2012;7(2):e32141. 21. Tonelli M, Riella M. Chronic kidney disease and the ageing population. Lancet. 2014;383(9925):1278-1279. 22. Girman CJ, Kou TD, Brodovicz K, et al. Risk of acute renal failure in patients with type 2 diabetes mellitus. Diabet Med. 2012;29(5):614-621.
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23. Bedford M, Farmer C, Levin A, Ali T, Stevens P. Acute kidney injury and CKD: chicken or egg? Am J Kidney Dis. 2012;59(4):485-491. 24. Thakar CV, Christianson A, Himmelfarb J, Leonard AC. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol. 2011;6(11):2567-2572. 25. Tomlinson LA, Abel GA, Chaudhry AN, et al. ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: a longitudinal ecological study. PLoS One. 2013;8(11):e78465. 26. National Clinical Guideline Centre. Osteoarthritis: care and management in adults. National Institute for Health and Care Excellence, 2014. http://www.nice.org.uk/guidance/cg177/resources/ cg177-osteoarthritis-full-guideline3. Accessed September 1, 2014. 27. Hochberg MC, Altman RD, Toupin AK, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465-474. 28. National Collaborating Centre for Primary Care. Low back pain: early management of persistent non-specific low back pain. National Institute for Health and Care Excellence, 2014. http:// www.nice.org.uk/guidance/CG88. Accessed September 1, 2014. 29. Chou R, Qaseem A, Snow V, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147(7):478-491. 30. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013;346:e8525. 31. Fervers B, Burgers JS, Haugh MC, et al. Adaptation of clinical guidelines: literature review and proposition for a framework and procedure. Int J Qual Health Care. 2006;18(3):167-176. 32. ADAPTE Collaboration. ADAPTE Manual for Guideline Adaptation, version 1.0. http://www.g-i-n.net/document-store/workinggroups-documents/adaptation/adapte-manual-for-guideline.pdf. Accessed September 1, 2014. 33. Harrison MB, Graham ID, van den Hoek J, Dogherty EJ, Carley ME, Angus V. Guideline adaptation and implementation planning: a prospective observational study. Implement Sci. 2013;8:49. 34. Hemmelgarn BR, Manns BJ, Straus S, et al; Interdisciplinary Chronic Disease Collaboration ICDC. Knowledge translation for nephrologists: strategies for improving the identification of patients with proteinuria. J Nephrol. 2012;25(6):933-943. 35. Sood MM, Manns B, Nesrallah G; Canadian Kidney Knowledge Translation, Generation Network. Using the knowledge-to-action framework to guide the timing of dialysis initiation. Curr Opin Nephrol Hypertens. 2014;23(3):321-327. 36. American Geriatrics Society Expert Panel on the Care of Older Adults with Multimorbidity. Guiding principles for the care of older adults with multimorbidity: an approach for clinicians. J Am Geriatr Soc. 2012;60(10):E1-E25. 37. Mitchell SL, Miller SC, Teno JM, Kiely DK, Davis RB, Shaffer ML. Prediction of 6-month survival of nursing home residents with advanced dementia using ADEPT vs hospice eligibility guidelines. JAMA. 2010;304(17):1929-1935.
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Paul Stevens, FRCP, was an International Distinguished Medal recipient at the 2014 National Kidney Foundation Spring Clinical Meetings. The International Distinguished Medals are awarded to honor the achievement of individuals who have made significant contributions to the field of kidney disease and extended the goals of the National Kidney Foundation.
We’ve put more effort into helping folks reach old age than into helping them enjoy it. Frank A. Clark (1911-1991) There is no pleasure worth forgoing just for an extra three years in the geriatric ward.
F
Sir John Mortimer (1923-2009)
ive hundred years ago, the Spanish conquistador Juan Ponce de León set out in search of the legendary Fountain of Youth, reputed to be in Florida. He never found it, but since then, medical science and public health have demonstrated that a mythical youth-restoring fountain is not required to increase life From 1Kent Kidney Care Centre and 2Clinical Biochemistry, East Kent Hospitals University NHS Foundation Trust, Canterbury, United Kingdom; and 3University of British Columbia, Vancouver, Canada. Received May 27, 2014. Accepted in revised form September 11, 2014. Originally published online December 5, 2014. Address correspondence to Paul E. Stevens, FRCP, Kent Kidney Care Centre, East Kent Hospitals University NHS Foundation Trust, Ethelbert Road, Canterbury, Kent, CT1 3NG, United Kingdom. E-mail: [email protected] Crown Copyright 2015 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2014.09.024 494
expectancy. We now have an “epidemic” of aging, and by 2050, it is expected that the proportion of the world’s population older than 60 years will double from w11% currently to 22%.1 We also live in a time of epidemics of chronic diseases, including diabetes,2 obesity,3 cardiovascular disease,4 and chronic kidney disease (CKD),5 occurring worldwide. The consequences of these 2 trends are rapidly increasing health costs and a requirement to reassess our use of health care resources. At the same time, there is a need to improve overall standards of care, reduce variation in practice, reduce inequalities in care, and reduce waste. These driving factors, combined with the plethora of literature and sources of data available to both physicians and patients, have led to a need for clinical practice guidelines to help health professionals in their work. The expectation is that well-implemented high-quality guidelines should improve both the process of care and health- and patient-related outcomes. However, guideline duplication is common, quality is variable, and there are many potential interactions between guidelines aimed at different disease groups or conditions. We already have highlighted that confusion is the unintended consequence of guideline proliferation.6 In the 12 years since publication of the first internationally accepted definition and classification of CKD,7 there have been 2,638 peer-reviewed guidelines published relating to cardiovascular disease; 728, to older people (age $ 65 years); 529, to diabetes; and 523, to kidney disease (Fig 1). In this article, we concentrate on CKD, but the same principles apply to other chronic diseases. This article first highlights the importance of standardization of guidelines and the process by which this can be achieved, before considering the older adult with CKD, why there is a need to integrate disease Am J Kidney Dis. 2015;65(3):494-501
Integrating Guidelines for CKD 60000 50000 40000 30000 20000 10000
9
58
445
78
0 1982 - 1992 1992 - 2002 2002 - 2012 2012 - 2014 Figure 1. PubMed articles in human kidney disease, 1982 to 2014. Dark gray indicates randomized controlled trial/metaanalysis/systematic review publications (1.8% in 1982-1992, 3.5% in 1992-2002, 4.8% in 2002-2012, and 7% in 20122014). The numbers refer to published guidelines in kidney disease during each period.
guidelines, and the caveats to be considered in integrating guidance from the available evidence.
STANDARDIZATION OF GUIDELINES: THE AGREE (APPRAISAL OF GUIDELINES FOR RESEARCH AND EVALUATION) CRITERIA The utility of guidelines has been debated for centuries. Many countries have engaged in clinical practice guideline development, as well as appraisal and implementation of these guidelines at professional, institutional, regional, and national levels. Because these guidelines are seen as essential tools for promoting quality and effectiveness in health care, frameworks have been created to assess their quality and serve as a means for standardization. An internationally accepted framework has been provided by the AGREE (Appraisal of Guidelines for Research and Evaluation) collaboration that developed the AGREE instrument.8 This instrument assesses the predicted validity of a guideline and consists of 23 criteria organized in 6 domains (Table 1). Each domain is intended to capture a separate dimension of guideline quality. Guiding the management of multiple complex conditions that coexist in the same patient is a challenge and requires not simply a review of the evidence, but also the systematic evaluation of goals of care from the patient perspective. Recently published guidelines in CKD from KDIGO (Kidney Disease: Improving Global Outcomes)9 and the England and Wales NICE (National Institute for Health and Care Excellence)10 have attempted to achieve this, and we use these 2 guidelines as examples to illustrate how well CKD guidance complies with AGREE criteria (Table 1). Engagement of End Users and Patients One key deficiency common to both guidelines (and many others) is a failure to pilot guidance among Am J Kidney Dis. 2015;65(3):494-501
end users prior to publication of the recommendations. NICE pilots its subsequent quality standards (which are derived from the relevant NICE guidance and other high-quality guidance from sources accredited by NICE), but does not pilot the guidelines themselves. KDIGO included both primary care and diabetes physicians in the guideline development group, but not relevant health professionals such as nurses, pharmacists, and dieticians. Patients’ views and preferences were not sought, something that NICE does. KDIGO, as a global guideline, goes some way toward thinking about organizational barriers that may hinder international applicability, whereas national guidelines such as NICE necessarily are tailored toward a specific health care system. However, applying recommendations also may necessitate changes to organization of care within a service or a clinic, which may make it more difficult to implement them in daily practice. This was highlighted by the NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) US Commentary on the KDIGO guideline, which noted the practical issues related to implementation of recommendations concerning measurement of cystatin C.11 The NKF-KDOQI commentary also raised the question of the cost for these tests; one of the key strengths of NICE is that it undertakes cost-benefit analyses; something that KDIGO is not structured to do, given its international breadth. Question Formatting and Assessment of Evidence Both NICE and KDIGO, together with many other guideline development organizations, use the PICO (population, intervention, comparator, and outcome) question format when searching the evidence. Both organizations use the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system12 to assess the quality of the evidence and determine the strength of recommendations made from the evidence (Table 2). The quality of the evidence ranges from high quality, in which the guideline authors are confident that the estimate of the effect is close to the truth, to very low quality, in which the guideline authors have very little confidence. Although the amount of published evidence in human kidney disease is ever increasing (Fig 1), Samuels and Molony13 detail how far this field continues to lag behind other specialties in the quality of that evidence. Furthermore, they also note a number of key issues in the study of CKD populations: the systematic exclusion of high-risk patients from randomized controlled trials (RCTs) in kidney disease, overreliance in RCTs on surrogate outcomes (decline in glomerular filtration rate [GFR], doubling of serum creatinine concentration, and change in proteinuria),14 reliance on small studies, failure to recruit and follow 495
Stevens, Lamb, and Levin Table 1. AGREE Criteria: NICE and KDIGO CKD Guideline Compliance NICE
KDIGO
1. The overall objective(s) of the guideline is (are) specifically described
U
U
2. The clinical question(s) covered by the guideline is(are) specifically described
U
U
3. The patients to whom the guideline is meant to apply are specifically described
U
U
NICE
KDIGO
22. The guideline is editorially independent from the funding body
U
U
23. Conflicts of interest of guideline development members have been recorded
U
U
Editorial Independence
Scope and Purpose
Stakeholder Involvement 4. The guideline development group includes individuals from all the relevant professional groups
U
✗
5. The patients’ views and preferences have been sought
U
✗
6. The target users of the guideline are clearly defined 7. The guideline has been piloted among target users
U
U
✗
✗
8. Systematic methods were used to search for evidence
U
U
9. The criteria for selecting the evidence are clearly described
U
U
10. The methods used for formulating the recommendations are clearly described
U
U
11. The health benefits, side effects, and risks have been considered in formulating the recommendations
U
U
12. There is an explicit link between the recommendations and the supporting evidence
U
U
13. The guideline has been externally reviewed by experts prior to its publication
U
U
14. A procedure for updating the guideline is provided
U
U
15. The recommendations are specific and unambiguous
U
U
16. The different options for management of the condition are clearly presented
U
U
17. Key recommendations are easily identifiable
U
U
18. The guideline is supported with tools for application Applicability
U
U
19. The potential organizational barriers in applying the recommendations have been discussed
✗
U/✗
20. The potential cost implications of applying the recommendations have been considered
U
✗
21. The guideline presents key review criteria for monitoring and/or audit purposes
✗
✗
Rigor of Development
Clarity and Presentation
496
Table 1 (Cont’d). AGREE Criteria: NICE and KDIGO CKD Guideline Compliance
Note: U indicates compliance with the criterion, ✗ indicates noncompliance. Abbreviations: AGREE, Appraisal of Guidelines for Research and Evaluation; CKD, chronic kidney disease; KDIGO, Kidney Disease: Improving Global Outcomes; NICE, National Institute for Health and Care Excellence.
up nephrology patients for long enough to evaluate the long-term impact of interventions, failure to compare the new therapy under investigation with current best practice, and underappreciation of harms because of a failure to report. Importantly, the majority of RCTs fail to include older people with CKD despite their prevalence in all populations. All these shortcomings cast doubt on even the field’s highquality evidence, although it should be noted that all strong recommendations do not necessarily have to be underpinned by high-quality evidence. There are no RCTs involving the use of a parachute when jumping out of an aircraft.15 Nevertheless, all of us would still have confidence in a strong recommendation to use a parachute in such a circumstance, despite the weak evidence base underlying its use. Adherence to Key Recommendations Measuring adherence to a guideline through audit and quality improvement initiatives can enhance guideline use. However, in order to measure adherence, clearly defined review criteria derived from the guideline’s key recommendations are needed. Although this is partially met by the NICE Quality Standards, neither group addresses this fully. Finally, both groups conform to the necessary editorial independence; in particular, NICE’s conflict of interest policy is detailed and rigorous. Overall, KDIGO made 110 guideline recommendations as of November 2012, of which 22 had a low- or very low-quality evidence base and only 11 had a highquality evidence base. There were a few parachute-type recommendation statements, for example, temporary suspension of renin-angiotensin system (RAS) antagonists during intercurrent illness, for which, despite poorquality evidence, it was still possible to make a strong recommendation. There also were 41 ungraded statements. These of course are largely opinion and were made in areas in which the guideline development group Am J Kidney Dis. 2015;65(3):494-501
Integrating Guidelines for CKD Table 2. The KDIGO Clinical Practice Guideline Grading of Quality and Strength of Evidence Based on the GRADE System 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
C
Low
The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. 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. Implications
Gradea
Patients
Clinicians
Policy
Level 1 Most people in your situation “We recommend” would want the recommended course of action and only a small proportion would not.
Most patients should receive the recommended course of action.
Level 2 “We suggest”
Different choices will be appropriate for The recommendation is likely to different patients. Each patient needs require substantial debate and help to arrive at a management decision involvement of stakeholders consistent with her or his values and before policy can be determined. preferences.
The majority of people in your situation would want the recommended course of action, but many would not.
The recommendation can be evaluated as a candidate for developing a policy or a performance measure.
a 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. Reprinted from KDIGO Chronic Kidney Disease Work Group9 with permission of Macmillan Publishers Ltd.
thought it important to give some guidance. However, others commenting on the ungraded statements, for example, the NKF-KDOQI commentary work group, have largely endorsed these ungraded statements.
THE OLDER ADULT WITH CKD: THE NEED TO INTEGRATE DISEASE GUIDELINES It is imperative to consider characteristics of the older adult with CKD because that will determine which other disease area guidelines need to be considered when integrating kidney disease guidance. As previously stated, the world population is aging; the overall average life expectancy in the countries represented in the KDIGO guideline development group ranged from 74.3 to 82.7 years (Table 3).16 Healthy life expectancy in Table 3. Life Expectancy and Health Life Expectancy Life Expectancy (y)
Health Life Expectancy (y)
Japan
82.7
76
6.7
Spain
82.1
74
8.1
Canada
81.5
73
8.5
Netherlands
81.2
73
8.2
Country
Health Economy Burden (y)
Germany
80.7
73
7.7
United Kingdom
80.5
72
8.5
United States China
78.6 75.6
70 66
8.6 9.6
Brazil
74.3
64
10.3
Data from www.worldlifeexpectancy.com.16 Am J Kidney Dis. 2015;65(3):494-501
those same countries ranges from 64 to 76 years, a gap of 6.7 to 10.3 years that represents a significant burden for each individual health economy. Whether integration of disease guidelines can improve this situation and provide more cost-effective health care has yet to be tested. Regardless of what one believes about age, GFR thresholds, and CKD or whether one accepts cystatin C– estimated GFR as a better risk marker,17 the prevalence of reduced GFR increases exponentially with age, and the lifetime risks of CKD or lower levels of kidney function are staggering. Grams et al18 estimate that the lifetime risk of reaching a GFR , 60 mL/min/1.73 m2 from birth is 59%, greater than the estimated lifetime risks of developing diabetes (33%-39%), ischemic heart disease (32%-49%), and invasive cancer (38%-45%). Current clinical practice guidelines focus on specific diseases and often fail to overtly take into consideration the presence of comorbid conditions. However, the majority of chronic conditions are associated with one another. Older adults with CKD (or reduced GFRs) may have no comorbid conditions or may have several. More than 50% of older adults have 3 or more chronic diseases and .20% have 5 or more. In the United States, the mean number of chronic conditions per individual increased from 1.88 in the 65- to 69-year age group to 2.71 in the 80- to 84-year age group and thereafter reached a plateau.19 Seventy-four percent of people with kidney disease had 4 or more chronic diseases. Very similar findings have been reported in a number of different countries,20 and the coexistence of kidney disease frequently is a multiplier of adverse outcome.21 497
Stevens, Lamb, and Levin Box 1. Evidence-Based Indications for Renin-Angiotensin System Blockade From Clinical Practice Guidelines
CKD and proteinuria (.1 g/d) irrespective of blood pressure Hypertension and proteinuria (ACR . 300 mg/g or 30 mg/ mmol) Diabetes and proteinuria (ACR . 30 mg/g or 3 mg/mmol) Resistant hypertension at any age Chronic heart failure Post acute myocardial infarction
Abbreviations: ACR, albumin-creatinine ratio; CKD, chronic kidney disease.
Despite the similar underlying pathology driving kidney disease in CKD patients with and without comorbid conditions, the treatments suggested for CKD patients with comorbid conditions may interact with and alter the natural history of the disease. For example, consider diabetes, CKD, and acute kidney injury (AKI). Girman et al22 extracted data from a UK primary care database over 5 years in a population of nearly 2 million people. After multiple adjustment for confounders, the independent predictors of AKI were CKD (hazard ratio [HR], 3.18; 95% confidence interval [CI], 2.84-3.55), diabetes (HR, 2.26; 95% CI, 2.24-2.69), heart failure (HR, 1.95; 95% CI, 1.682.27), hypertension (HR, 1.74; 95% CI, 1.61-1.88), and obesity (HR, 1.6; 95% CI, 1.46-1.76). The incidence of AKI in those with diabetes was 7 times higher than in those without diabetes, and as with other series, the hazard for AKI increased markedly with age.22 We also know from a number of studies that AKI is associated with progression of existing CKD and with new-onset CKD,23 as well as with people who have diabetes. Thakar et al24 followed up 4,082 people with diabetes accessing either
Figure 2. Overview of relationships between the older population and different disease areas. Abbreviations: AKI, acute kidney injury; AKD, acute kidney diseases and disorders (any condition that acutely affects kidney structure and function); CKD, chronic kidney disease; CVD, cardiovascular disease. 498
• Define Health Question • Search and Screen Guidelines
• Assess Guidelines • Decide and Select
• Draft Integrated Guideline • External Review and Pilot Figure 3. The ADAPTE process. (modified from ADAPTE32).
ambulatory or inpatient services over a 5-year period from 1999 to 2004 and then followed them up for an additional 4 years. The primary outcome was reaching stage 4 CKD, and AKI was defined according to AKIN (Acute Kidney Injury Network) criteria. After multiple adjustment for confounders, the independent predictors of stage 4 CKD were baseline serum creatinine level (HR, 8.59; 95% CI, 6.07-12.15), proteinuria (HR, 3.54; 95% CI, 2.47-5.08), hypertension (HR, 1.82; 95% CI, 1.41-2.37), AKI (HR, 3.56; 95% CI, 2.76-4.61), and multiple episodes of AKI (HR, 2.02; 95% CI, 1.78-2.30). Diabetes, hypertension, and proteinuria are all predictors of progression of CKD, and guidelines strongly recommend treatment with RAS blockade to prevent or ameliorate progression of CKD. However, the evidence-based recommendations for RAS blockade encompass more than just kidney disease (Box 1), and other disease areas also strongly recommend use of RAS blockade for improvement of clinical outcomes. AKI and multiple episodes of AKI also predict progression of CKD. In the Girman et al22 study, increasing age, diabetes, hypertension, proteinuria, and heart failure all predicted AKI. Importantly, 48% of type 2 diabetic patients were being treated with RAS blockade at the time of their AKI. We know that RAS blockade associates strongly with AKI25 and that can be extended when we consider other drug interactions and combinations that markedly increase the risk. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) have long been associated with increased risk of AKI. Guidelines for people with CKD, diabetes, and cardiovascular disease do not recommend NSAID therapy, but those for osteoarthritis and low back pain do,26-29 and these are common conditions in older adults. A large case-control study (500,000 patients followed up for a mean of w6 years) examined the risk of AKI in people receiving either double therapy consisting of Am J Kidney Dis. 2015;65(3):494-501
Integrating Guidelines for CKD
an NSAID combined with a diuretic or an NSAID with RAS blockade or triple therapy with a diuretic, an NSAID, and RAS blockade.30 After controlling for confounders including other chronic diseases and drug use, triple therapy was associated with a 31% increased risk of AKI. There is complexity in the overlap between different forms of kidney disease and other coexistent chronic diseases, and this is particularly relevant to the older population (Fig 2). Thus, it is important to be careful when considering the evidence on which guideline recommendations are being made. Does the evidence cover all areas of the PICO question (population, intervention, comparator, and outcome), specifically regarding the older adult populations? Given the design of clinical trials, much of the evidence excludes older people and also those with comorbid conditions,13 and some of the outcomes that are of importance in the elderly, such as falls, quality of life, and increase in level of care, are not even considered by the evidence. For example, to prevent the progression of CKD, kidney disease guidelines recommend treatment with RAS blockade based on whether the individual has kidney disease (chiefly albuminuria/proteinuria) and by the presence or absence of hypertension and diabetes. In considering the applicability of the evidence for prevention of CKD progression in older people, one must evaluate any potential specific concerns about the applicability of the evidence for a given recommendation. If these concerns exist, the applicability of the evidence is lessened and ones’ confidence in applying the recommendation is weakened. This becomes even more relevant when factoring in other considerations, such as level of blood pressure control, risk of falls, and risk of AKI. What is the extent of the interaction between the interventions recommended and older populations with different comorbid
conditions? Can one assume that the outcomes of interest are the same in the older population, and that the outcomes selected are of the same relevance to older populations? Is the direction and strength of the relationship between the intervention and outcome the same in older populations? Caveats in Integrating Guidance From the Evidence In order to integrate guidance for the older person with kidney disease, there are some very real conflicts to resolve. Three separate but related questions have to be addressed. (1) What is the applicability of an evidence base that has largely been developed in younger age groups? (2) What is the impact of and interaction between different kidney disease phenotypes? (3) What is the influence of multiple comorbid conditions? There are a number of tools available to help integrate differing disease guideline recommendations and resolve these conflicts and problems. Two of these, the ADAPTE process and the knowledge-toaction cycle, are worth considering further. The ADAPTE process was created by an international collaboration of researchers, guideline developers, and guideline implementers with the aim of promoting clinical practice guideline development and use, through adapting existing guidelines.31 The ADAPTE manual and toolkit follow a very logical stepwise process (Fig 3) after defining the health question under consideration.32 In the context of the older patient with CKD, this would require revisiting the condition of the older population and deciding on key questions or outcomes of importance. If the health question is “When should we consider treatment with RAS antagonists in older people with kidney disease?”, the first question to ask is “What does the older population with kidney disease look like?” Subsequent
Figure 4. The knowledge-to-action cycle. (redrawn from Harrison et al33). Am J Kidney Dis. 2015;65(3):494-501
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questions would include: What is the relative importance of comorbid conditions? What implications does that have for treatment and are there any downsides to the treatments suggested? How do the different disease areas change this, in particular comparing older adults with CKD and no comorbid conditions with those with CKD and multiple comorbid conditions? In order to resolve these issues, a more sophisticated tool, such as the knowledge-to-action cycle, probably is a better choice (Fig 4).33 The knowledge-to-action cycle is the ideal method or process by which knowledge is implemented into practice within a thoughtful framework. The cycle begins by identifying the practice problem to be addressed, for example, prevention of CKD progression in the older population. The knowledge product or products that provide solutions to progression of CKD then are identified. These solutions then must be considered in the context of the local practice, health care system, and population. The barriers and facilitators for applying the solutions must be addressed. For the solutions to be effective, they must consider the entire health care system and identify and address any barriers to change and the interventions needed to enact the solutions chosen (in our example, RAS blockade). After selecting the interventions, the next step is to monitor whether they are used, the impact of their use (both desired outcomes and unintended adverse consequences such as AKI), and whether any adaptation is required. The new knowledge acquired is funneled back into the cycle, thus sustaining knowledge use, to ensure that the knowledge-to-action gap continues to be reduced or closed. The knowledge-to-action cycle has been used in a case study considering the assessment of proteinuria as a key guideline recommendation for implementation.34 To help select, tailor, and implement the interventions, the authors also used the processes described by ADAPTE. Albeit this was essentially a pilot study, it serves to demonstrate how application of these processes may successfully aid the implementation of evidence-based practice guidelines. A similar process is underway to identify practice variation and key barriers in another contentious area of kidney disease, the optimal timing for dialysis therapy initiation in patients approaching end-stage kidney failure.35 However, none of these processes adequately accounts for individual patient preference, hugely important in the elderly. After considering all the evidence, using the available tools to integrate guidelines, and arriving at recommendations commensurate with all the different disease areas, those recommendations may not necessarily fit with the older person’s preferences and priorities. Clinical practice guidelines do not routinely search for or include evidence related to patient values and preferences. So in beginning the process of guideline integration for older adults, it is important to keep in mind the guiding principles for the care of older adults with multiple comorbid conditions36: 500
1. Elicit and incorporate patient preferences. 2. Recognize the limitations of the evidence base. Have outcomes relevant to the elderly, such as physical functioning and independent living, been adequately covered by the evidence considered? 3. Consider risks and benefits, burdens, and prognosis before making any clinical management decisions. Clinicians and researchers traditionally focus prognosis on remaining life expectancy, but it is important not to lose sight of functional disability and quality of life when thinking about management decisions. 4. Evaluate treatment complexity and feasibility. Polypharmacy and its relationship to nonadherence are well known, but complex regimens also carry additional risks. 5. Maximize benefit, reduce harm, and improve quality of life. Guidelines for chronic diseases, especially those affecting the aging population, should consider the importance of multiple comorbid conditions in diagnosis, prognosis, and management; acknowledge where the gaps in the evidence are; give pointers for where guideline recommendations should be modified; address the elderly; and consider inequalities. Central to this is an informed discussion with the patient and/or caregiver about what the clinician is trying to achieve, how it might be achieved, how long it may take to achieve it, and what (if any) are the associated down sides. Integration of the KDIGO CKD guideline and the updated NICE CKD guidance together with thoughtful commentaries provided by the NKF KDOQI work group and others, combined with measures of quality of care that address the factors that serve to create the gap between life expectancy and health life expectancy, may bring us closer to achieving our stated goal.6,9,10,11 Perhaps the final step to be considered prior to implementation of such an integrated evidence-based intervention is the use of a tool to guide individual prognosis, such as the estimating prognosis for elders tool.37
ACKNOWLEDGEMENTS Drs Stevens and Levin were co-chairs and Dr Lamb was a member of the KDIGO CKD 2012 guideline development group. Dr Stevens was chair and Dr Lamb was a member of the NICE CKD 2014 guideline development group. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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