Management of Chronic Kidney Disease Stages 1 – 3 Prepared for: Agency for Healthcare Research and...

Management of Chronic Kidney Disease Stages 1–3

Prepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

AHRQ comparative effectiveness review (CER) process

Overview of chronic kidney disease stages 1–3 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

Outline of Material

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

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.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development


The strength of evidence is classified into four broad ratings:

Strength of Evidence Ratings

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 2010;63:513-23. PMID: 19595577.

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 60–89 mL/min/ 1.73 m2

Stage 3a: A GFR of 45–59 mL/min/1.73 m2

Stage 3b: A GFR of 30–44 mL/min/1.73 m2

Stage 4: A GFR of 15–29 mL/min/1.73 m2

Stage 5: A GFR <15 mL/min/1.73 m2 or kidney failure treated by dialysis or transplantation

Background: Chronic Kidney Disease Stages

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 Jul;80(1):17-28. PMID: 21150873.National Kidney Foundation. Am J Kidney Dis 2001 Feb;29(2 Suppl 1):S1-S266. PMID: 11904577.

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%).

Background: Public Health Impact

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_questionnaires.htm. Coresh J, Selvin E, Stevens LA, et al. JAMA 2007 Nov 7;298(17):2038-47. PMID: 17986697.

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

Background: Risk Factors and Comorbidities

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_questionnaires.htm.Coresh J, Selvin E, Stevens LA, et al. JAMA 2007 Nov 7;298(17):2038-47. PMID: 17986697.

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

Background: Associated Adverse Outcomes


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

Factors That Impact the Potential Benefit of Screening Adults for CKD Stages 1–3


Comparative effectiveness and comparative adverse effects related to treatments for CKD stages 1–3

Treatments for CKD stages 1–3 alone or in combination included: Angiotensin-converting enzyme inhibitor Angiotensin II receptor blocker Calcium channel blocker Beta-blocker Diuretic Various diets Multicomponent interventions

Clinical Questions Addressed in the CER: Treatments for CKD Stages 1–3


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

Clinical Questions Addressed in the CER:

Clinical Outcomes of Interest From Treatments


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?

Clinical Questions Addressed in the CER: Screening and Monitoring


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

0.43–0.83; 3 trials, n = 861 patients

Strength of Evidence = Moderate

In patients with CKD stages 1–3 with only microalbuminuria or impaired eGFR, ACEIs did not reduce the risk for ESRD when compared with a placebo.*

Clinical Bottom Line: Risk for ESRD in Patients With CKD Stages 1–3 Treated With ACEIs


* These results were not given a strength of evidence rating.

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 0.67–0.90; 3 trials, n = 4,652 patients Strength of Evidence: High

Clinical Bottom Line: Risk for ESRD in Patients With CKD Stages 1–3 Treated With ARBs


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

Clinical Bottom Line: Risk for ESRD in Patients With CKD Stages 1–3 Treated With Other Interventions


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)

Clinical Bottom Line: Risk for Mortality in Patients With CKD Stages 1–3 Treated With ACEIs or ARBs (1 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 0.66–0.96; 8 trials, n = 3,440 patients). Strength of Evidence: Moderate

Clinical Bottom Line: Risk for Mortality in Patients With CKD Stages 1–3 Treated With ACEIs or ARBs (2 of 2)


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 0.68–0.95; 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 0.54–0.98; 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 0.41–0.95; 6 trials, n = 10,369 patients) versus a control.

In patients with CKD stages 1–3, high-dose versus low-dose statins had similar risks for mortality. Strength of Evidence: Low

Clinical Bottom Line: Risk for Mortality in Patients With CKD Stages 1–3 Treated With Statins


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 0.53–0.91; 2 trials, n = 2,173 patients). Strength of Evidence: Low

Clinical Bottom Line: Risk for Mortality in Patients With CKD Stages 1–3 Treated With Beta-Blockers


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

Clinical Bottom Line: Risk for Mortality in Patients With CKD Stages 1–3 Treated With Other Interventions


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

Adverse Effects of Treatment


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

Evidence was insufficient to determine if systematic screening of high-risk adults and monitoring of patients with CKD stages 1–3 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

Clinical Bottom Line: Screening and Monitoring


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 1–3 who might benefit from early initiation of treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and/or statins.

Clinical Bottom Line: Screening and Monitoring in Subpopulations


In patients with CKD stages 1–3 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 1–3 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.

Conclusions: Treatment (1 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.

Conclusions: Treatment (2 of 2)


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.

Conclusions: Screening and Monitoring


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 1–3

Gaps in Knowledge


.

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

What To Discuss With Your Patients


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.


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