Management of Chronic Kidney Disease Stages 1

1
Management of Chronic Kidney Disease Stages 13

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Outline of Material

• AHRQ comparative effectiveness review (CER)
  process
• Overview of chronic kidney disease stages 13
• Treatment options
• Questions addressed by the CER
• Evidence-based conclusions about the
  effectiveness and adverse effects of treatment,
  screening, and monitoring
• Summary of conclusions
• Gaps in knowledge
• What to discuss with your patients

Fink HA, Ishani A, Taylor BC, et al. Comparative
Effectiveness Review No. 37. Available at
www.effectivehealthcare.ahrq.gov/ckd.cfm.
3
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, the public, and
  others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Research
  Summaries and the full report are available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

4
Strength of Evidence Ratings

• The strength of evidence is classified into four
  broad ratings

High High confidence that further research is very unlikely to change the confidence in the estimate of effect, meaning that the evidence reflects the true effect.
Moderate Moderate confidence that further research may change our confidence in the estimate of effect and may change the estimate.
Low Low confidence that further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate, meaning there is low confidence that the evidence reflects the true effect.
Insufficient Evidence either is unavailable or does not permit a conclusion.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.AHRQ
  Methods Guide for Effectiveness and Comparative
  Effectiveness Reviews. Available at
  www.effectivehealthcare.ahrq.gov/methodsguide.cfm.
  Owens DK, Lohr KN, Atkins D, et al. J Clin
  Epidemiol 201063513-23. PMID 19595577.

5
Background Chronic Kidney Disease Stages

• Chronic kidney disease (CKD) is usually
  asymptomatic, except in the most advanced stages.
• Current definitions of chronic kidney disease
  stages are
• Stage 1 Kidney damage with a glomerular
  filtration rate (GFR) 90 mL/min/1.73 m2
• Stage 2 Kidney damage with a GFR of 6089
  mL/min/ 1.73 m2
• Stage 3a A GFR of 4559 mL/min/1.73 m2
• Stage 3b A GFR of 3044 mL/min/1.73 m2
• Stage 4 A GFR of 1529 mL/min/1.73 m2
• Stage 5 A GFR lt15 mL/min/1.73 m2 or kidney
  failure treated by dialysis or transplantation

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.
• Levy AS, et al. Kidney Int 2010 Jul80(1)17-28.
  PMID 21150873.
• National Kidney Foundation. Am J Kidney Dis 2001
  Feb29(2 Suppl 1)S1-S266. PMID 11904577.

6
Background Public Health Impact

• An estimated 22.4 million adults in the United
  States 20 years of age or older have chronic
  kidney disease (CKD) stage 1, 2, or 3.
• The prevalence of CKD is rising for every CKD
  stage, with a particular increase in the
  prevalence of stage 3.
• Estimates indicate that more than 700,000
  Americans will have end-stage renal disease by
  2015.
• CKD prevalence increases with age and is somewhat
  higher in women (12.6) than in men (9.7).

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.
• CDC. National Health and Nutrition Examination
  Survey. Available at www.cdc.gov/nchs/nhanes/nhane
  s_questionnaires.htm. Coresh J, Selvin E,
  Stevens LA, et al. JAMA 2007 Nov
  7298(17)2038-47. PMID 17986697.

7
Background Risk Factors and Comorbidities

• In most patients with chronic kidney disease,
  kidney damage is associated with other medical
  conditions, such as diabetes and hypertension.
• Other risk factors and comorbidities include
• Cardiovascular disease
• Older age
• Obesity
• Family history
• African-American, Native-American, or Hispanic
  ethnicity

Fink HA, Ishani A, Taylor BC, et al. Comparative
Effectiveness Review No. 37. Available at
www.effectivehealthcare.ahrq.gov/ckd.cfm. CDC.
National Health and Nutrition Examination Survey.
Available at www.cdc.gov/nchs/nhanes/nhanes_questi
onnaires.htm. Coresh J, Selvin E, Stevens LA, et
al. JAMA 2007 Nov 7298(17)2038-47. PMID
17986697.
8
Background Associated Adverse Outcomes

• Chronic kidney disease is associated with an
  increased risk of the following adverse outcomes
• Mortality
• Cardiovascular disease
• Fractures
• Bone loss
• Infections
• Cognitive impairment
• Frailty

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

9
Factors That Impact the Potential Benefit of
Screening Adults for CKD Stages 13

• Whether undiagnosed chronic kidney disease (CKD)
  is sufficiently prevalent in the population
  overall or in certain high-risk groups
• Whether CKD is associated with significant
  adverse health consequences and/or health care
  costs
• Whether CKD is accurately diagnosable while
  asymptomatic
• Whether there are valid and reliable screening
  tests for CKD that are acceptable to patients and
  available in primary care settings
• Whether there are treatments for patients with
  CKD that improve clinically important health
  outcomes

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

10
Clinical Questions Addressed in the CER
Treatments for CKD Stages 13

• Comparative effectiveness and comparative adverse
  effects related to treatments for CKD stages 13
• Treatments for CKD stages 13 alone or in
  combination included
• Angiotensin-converting enzyme inhibitor
• Angiotensin II receptor blocker
• Calcium channel blocker
• Beta-blocker
• Diuretic
• Various diets
• Multicomponent interventions

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

11
Clinical Questions Addressed in the CER
Clinical Outcomes of Interest From Treatments

• Primary clinical outcomes
• Reduced mortality
• Incident end-stage renal disease
• Secondary clinical outcomes
• Cardiovascular complications (myocardial
  infarction, cerebrovascular accident, congestive
  heart failure)
• Improved quality of life
• Intermediate outcomes
• Reduced incident stage 4 chronic kidney disease
• Doubling of creatinine
• Halving of the estimated glomerular filtration
  rate

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

12
Clinical Questions Addressed in the CER
Screening and Monitoring

• Benefits and adverse effects of screening for
  chronic kidney disease (CKD)
• Is there direct evidence that screening for CKD
  is associated with improved clinical outcomes?
• What are the harms associated with systematic CKD
  screening?
• Benefits and adverse effects of monitoring
• Is there direct evidence that monitoring for
  worsening kidney function and/or kidney damage
  improves clinical outcomes?
• What are the harms associated with monitoring for
  worsening kidney function/kidney damage?

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

13
Clinical Bottom Line Risk for ESRD in Patients
With CKD Stages 13 Treated With ACEIs

• In patients with overt proteinuria, diabetes, and
  hypertension, ACEIs decreased the risk of ESRD by
  40 percent versus a placebo.
• ARR 8.7 12 versus 20.7 RR 0.60, 95 CI
  0.430.83 3 trials, n 861 patients
• Strength of Evidence Moderate
• In patients with CKD stages 13 with only
  microalbuminuria or impaired eGFR, ACEIs did not
  reduce the risk for ESRD when compared with a
  placebo.

These results were not given a strength of
evidence rating.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

14
Clinical Bottom Line Risk for ESRD in Patients
With CKD Stages 13 Treated With ARBs

• ARBs reduced the relative risk of ESRD by 22
  percent versus a placebo in trials consisting
  mostly of patients with overt proteinuria, most
  of whom had diabetes and hypertension.
• ARR 2.9 10 versus 12.9 RR 0.78, 95 CI
  0.670.90 3 trials, n 4,652 patients
• Strength of Evidence High

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

15
Clinical Bottom Line Risk for ESRD in Patients
With CKD Stages 13 Treated With Other
Interventions

• The risk of end-stage renal disease (ESRD) was
  not significantly different between these
  comparisons (Strength of Evidence Low)
• Beta-blocker versus placebo
• Calcium channel blocker versus placebo
• Calcium channel blocker versus beta-blocker
• Statin versus a control
• Strict versus standard blood pressure control
• Low-protein diet versus usual diet
• Carbohydrate-restricted, low-iron-available,
  polyphenol-enriched diet versus low-protein diet

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

16
Clinical Bottom Line Risk for Mortality in
Patients With CKD Stages 13 Treated With ACEIs
or ARBs (1 of 2)

• The risk for mortality was not significantly
  different for these comparisons
• ACEI versus placebo (SOE Moderate)
• ARB versus placebo (SOE High)
• ACEI versus ARB, CCB, or beta-blocker (SOE Low)
• ARB versus CCB (SOE Low)
• ACEI plus ARB versus ACEI (SOE Moderate)
• ACEI plus ARB versus ACEI or ARB (SOE Moderate)
• ACEI plus diuretic versus placebo (SOE Low)

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

17
Clinical Bottom Line Risk for Mortality in
Patients With CKD Stages 13 Treated With ACEIs
or ARBs (2 of 2)

• Subgroup Analysis
• Only in patients with microalbuminuria who had
  cardiovascular disease or diabetes with other
  cardiovascular risk factors did an ACEI reduce
  the mortality risk by 21 percent versus placebo
  (ARR 2.8 9.3 vs. 12.1 RR 0.79, 95 CI
  0.660.96 8 trials, n 3,440 patients).
• Strength of Evidence Moderate

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

18
Clinical Bottom Line Risk for Mortality in
Patients With CKD Stages 13 Treated With Statins

• In patients with hyperlipidemia and decreased
  eGFR or creatinine clearance, statins reduced the
  mortality risk by 20 percent versus a control
  (ARR 1.6 7.1 vs. 8.7 RR 0.80, 95 CI
  0.680.95 8 trials, n 13,964 patients).
• Strength of Evidence High
• The risk for myocardial infarction was reduced by
  28 percent (ARR 2.6 6.8 vs. 9.4 RR 0.72,
  95 CI 0.540.98 2 trials, n 2,015 patients)
  versus a control.
• The risk for stroke was reduced by 38 percent
  (ARR 0.9 1.4 vs. 2.3 RR 0.62, 95 CI
  0.410.95 6 trials, n 10,369 patients) versus
  a control.
• In patients with CKD stages 13, high-dose versus
  low-dose statins had similar risks for mortality.
• Strength of Evidence Low

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

19
Clinical Bottom Line Risk for Mortality in
Patients With CKD Stages 13 Treated With
Beta-Blockers

• A beta-blocker versus placebo reduced the
  mortality risk by 31 percent among patients with
  congestive heart failure and impaired eGFR (ARR
  5.7 12.4 vs. 18.1 RR 0.69, 95 CI
  0.530.91 2 trials, n 2,173 patients).
• Strength of Evidence Low

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

20
Clinical Bottom Line Risk for Mortality in
Patients With CKD Stages 13 Treated With Other
Interventions

• The risk for mortality was not significantly
  different for these comparisons (Strength of
  Evidence Low)
• Calcium channel blocker versus placebo
• Strict versus standard blood pressure-target
  treatment
• Gemfibrozil versus placebo
• Dietary interventions

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

21
Adverse Effects of Treatment

• Withdrawals and adverse effects were reported in
  only a few randomized clinical trials, and
  evidence was insufficient to permit any
  conclusions. The adverse events reported
  generally were consistent with the known
  potential adverse effects of these treatments
  (e.g., hypotension with antihypertensive
  medications, cough with ACEIs, hyperkalemia with
  ACEIs and ARBs).
• Strength of Evidence Insufficient

Clinicians should refer to the U.S. Food and
Drug Administration label for each of these
agents for full information on adverse effects.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

22
Clinical Bottom Line Screening and Monitoring

• Evidence was insufficient to determine if
  systematic screening of high-risk adults and
  monitoring of patients with CKD stages 13 have a
  direct effect on clinical outcomes or adverse
  effects.
• Indirect evidence suggests potential harms from
  CKD screening and monitoring may include
  misclassification of patients with CKD,
  unnecessary tests and their associated adverse
  effects, psychological effects of being labeled
  with CKD, adverse effects associated with
  pharmacological treatments initiated or changed
  after a CKD diagnosis, and possible financial and
  insurance ramifications of a new CKD diagnosis.
• Strength of Evidence Insufficient

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

23
Clinical Bottom Line Screening and Monitoring in
Subpopulations

• Indirect evidence from the treatment outcomes of
  the comparative effectiveness review suggests
• Screening populations at high risk for developing
  chronic kidney disease (patients with diabetes,
  hypertension, or cardiovascular disease) and
  monitoring patients who already have early signs
  of kidney disease for albuminuria and the
  estimated glomerular filtration rate may help
  identify those patients with chronic kidney
  disease stages 13 who might benefit from early
  initiation of treatment with angiotensin-convertin
  g enzyme inhibitors or angiotensin II receptor
  blockers and/or statins.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

24
Conclusions Treatment (1 of 2)

• In patients with CKD stages 13 who have overt
  proteinuria (macroalbuminuria) with concomitant
  diabetes and hypertension, an ACEI or an ARB will
  reduce the risk of ESRD.
• In patients with CKD stages 13 with only
  microalbuminuria or impaired eGFR, ACEIs did not
  reduce the risk for ESRD when compared with a
  placebo, but these trials were not powered to
  detect a difference.
• There was no increased benefit for reducing the
  risk of ESRD if an ACEI and an ARB were taken as
  combination therapy when compared with taking
  either an ACEI or an ARB alone.
• Taking an ACEI or an ARB did not reduce the risk
  of mortality, except when an ACEI was used for
  patients with microalbuminuria and cardiovascular
  disease or diabetes and other cardiovascular risk
  factors.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

25
Conclusions Treatment (2 of 2)

• Statins reduced the risk for mortality,
  myocardial infarction, and stroke in patients
  with hyperlipidemia and impaired eGFR.
• Beta-blockers may reduce mortality in patients
  with congestive heart failure and impaired eGFR.
• Many patients who experienced improved outcomes
  had a pre-existing clinical indication for the
  treatment studied regardless of CKD status.
• Adverse events were reported in only a few
  randomized clinical trials. Those reported
  generally were consistent with the known
  potential adverse effects of these treatments.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

26
Conclusions Screening and Monitoring

• Evidence is insufficient to determine if
  screening for or monitoring of early stage
  chronic kidney disease improves clinical
  outcomes.
• Indirect evidence suggests that screening and
  monitoring may benefit specific subgroups of
  patients.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

27
Gaps in Knowledge

• The systematic review identified areas where
  clear evidence is not available
• Whether clinical outcomes are improved from
  systematic screening for CKD in patients at high
  risk for developing CKD (e.g., patients with
  diabetes, hypertension, or CV disease) or
  systematic CKD monitoring for worsened kidney
  function or damage, especially in patients with
  CKD who also have hypertension, diabetes, or CV
  disease
• If one-time measures of albuminuria or eGFR have
  the specificity and sensitivity to diagnose
  persistent CKD or CKD progression
• Whether the clinical outcome benefits differ for
  a specific treatment between patients with
  recently worsened kidney function or damage (as
  detectable by monitoring) when compared with
  those with stable CKD
• The long-term impact of treatment on clinical
  outcomes
• The impact of dietary intervention or
  intensification of treatment (e.g., tight vs.
  standard blood pressure control, high vs.
  standard statin dose) on clinical outcomes for
  patients with CKD stages 13

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.
• .

28
What To Discuss With Your Patients

• The presence and stage of chronic kidney disease
  (CKD)
• The risk of CKD if they have high blood pressure,
  cardiovascular disease, diabetes, or acute kidney
  disease
• The evidence about the benefits and adverse
  effects of treatments for CKD

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.

29
Resource for Patients

• Medicines for Early Stage Kidney Disease, A
  Review of the Research for Adults With Diabetes
  or High Blood Pressure is a free patient
  resource. It can help patients talk with their
  health care professionals about the many options
  for treatment. It provides information about
• Chronic kidney disease and its causes and
  symptoms
• The role of medications in helping to protect
  kidney function
• For electronic copies of this patient resource,
  visit www.effectivehealthcare. ahrq.gov/ckd.cfm.

• Fink HA, Ishani A, Taylor BC, et al. Comparative
  Effectiveness Review No. 37. Available at
  www.effectivehealthcare.ahrq.gov/ckd.cfm.