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Proposed Research Title for the Topic:
Comparative Effectiveness Screening, Monitoring and Treatment of Early Chronic Kidney Disease in Adults
Open for comment until Mar. 26, 2010.



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Comment Key Questions - AHRQ Effective Health Care Program





■KQ1: In asymptomatic adults at increased (or average) risk for chronic kidney disease (CKD)/CKD complications, what direct evidence is there that systematic CKD screening improves clinical outcomes?
■KQ2: What harms result from systematic CKD screening in asymptomatic adults at increased (or average) risk for CKD/CKD complications?
■KQ3: Among adults with early (screen-detected or clinically-detected) CKD, what direct evidence is there that monitoring for worsening kidney function and/or kidney damage improves clinical outcomes?
■KQ4: Among adults with early (screen-detected or clinically-detected) CKD, what harms result from monitoring for worsening kidney function/kidney damage?
■KQ5: Among adults with early (screen-detected or clinically-detected) CKD, what direct evidence is there that treatment (“renal specific” and/or of vascular disease/vascular risk factors) improves clinical outcomes?
■KQ6: Among adults with early (screen-detected or clinically-detected) CKD, what harms result from treatment (“renal specific” and/or of vascular disease/vascular risk factors)?

Background
Definition of Early Chronic Kidney Disease (CKD)
Much debate has centered on how best to define early manifestations of kidney disease. Currently, the National Kidney Foundation, as part of its Kidney Disease Outcomes Quality Initiative (K/DOQI),1 has defined chronic kidney disease (CKD) as “kidney damage for ≥ 3 months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate, manifest by either: pathological abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests.” However, the vast majority of the published literature focuses on the presence of a reduced estimated glomerular filtration rate (eGFR 30 to <60 mL/min/1.73 m2) or some evidence of kidney damage, typically the presence of microalbuminuria (defined as a urinary albumin: creatinine ratio of 30–300 mg/g). This initial K/DOQI definition was based on cross-sectional data only. However, based on a meta-analysis examining the longitudinal association of kidney damage with clinical outcomes in 1.5 million people, a recent consensus conference on Chronic Kidney Disease: Definition, Classification and Prognosis, led by the KDIGO (Kidney Disease: Improving Global Outcomes) foundation, advocated that the current K/DOQI definition of CKD be preserved.2 Therefore, for the purpose of this document, early CKD will be defined as either 1) a mild reduction in eGFR (eGFR between 30 and <60 mL/min/1.73 m2) or 2) the presence of microalbuminuria (24-hour urine albumin of 30–300 mg or a urine albumin:creatinine ratio of between 30–300 mg/g). Additional/alternative definitions, such as combining information for GFR and albuminuria, will be evaluated as appropriate.

Epidemiology of CKD
The burden of CKD has increased over time from approximately 10 percent of the United States population in 1988–1994 to 13.1 percent in 1999–2004.3 It is estimated that 26.3 million people in the U.S. have mild-to-moderate CKD (eGFR <60 mL/min/1.73 m2).3 The number of patients with end-stage kidney disease (ESKD) who require hemodialysis also is increasing. In 2006, 101,306 patients began hemodialysis and 327,754 were receiving hemodialysis, representing respective increases of 71.4 percent and 84.2 percent when compared with data from 1995.4 It has been estimated that more than 700,000 individuals in the U.S. will have ESKD by 2015.5

Association of CKD with Adverse Clinical Outcomes
Numerous adverse health outcomes have been associated with the presence of early kidney disease. The majority of evidence associating early CKD with adverse outcomes is derived from cohort or observational studies. The vast majority of studies have suggested that an eGFR between 30–60 ml/min is associated with an increased risk of mortality,6 cardiovascular disease,7 fractures,8 bone density loss,9 infections,10 cognitive impairment,11 and frailty. Similarly, there appears to exist a graded relationship between the severity of proteinuria and adverse health outcomes, including mortality,12 ESKD,13 and cardiovascular disease.14 Finally, there appears to be a multiplicative interaction between reduced eGFR and increased albuminuria and outcomes.13

How Does Early CKD Influence Adverse Outcomes?
There are a number of possible explanations for the observed association of early CKD with adverse health outcomes. First, early CKD may be associated with a number of nontraditional risk factors for mortality and CVD, such as increased inflammation or mineral bone disorders. Second, early CKD may be a marker for undiagnosed or advanced vascular disease. Early CKD has many of the same risk factors as vascular disease, so that early CKD may simply be a marker for undiagnosed vascular disease or for a worse prognosis among individuals with known vascular disease. Third, early CKD may be a marker for individuals less likely to receive proven medical therapies. For example, among individuals with a myocardial infarction, those with CKD are less likely to receive proven therapies such as coronary artery bypass, angiotensin-converting enzyme inhibitors, β-blockers, or statin medications.15 Systematic undertreatment may then underlie the association between early CKD and adverse health outcomes. Finally, these associations may be related to a combination of the above mechanisms.

Screening for early CKD
Causes of early CKD can be broken down into primary kidney diseases (primarily glomerulonephritis) versus those diseases in which the kidney damage is secondary to other medical conditions such as diabetes and hypertension. Most early CKD is related to age-related decline in kidney function and secondary causes of kidney damage. NHANES data on CKD prevalence in U.S. adults aged 20 and older illustrates the importance of age, diabetes, hypertension, and obesity as predictors of CKD (Figure 2) and indicates that screening targeted to these groups should identify a higher percentage of individuals with previously undiagnosed early CKD. A high screening yield in itself, however, is not evidence to support the benefit of screening; rather, screening for early CKD may be beneficial only if by enabling earlier CKD diagnosis it facilitates intervention(s) that improve clinical outcomes more than if CKD is not diagnosed or is diagnosed at a later time or stage.



Figure 2. Prevalence of CKD in U.S. adults age 20 and older as a function of age, diabetes, hypertension, and obesity (USRDS Annual Data Report, 2009).

Monitoring Early CKD
Unlike many clinical conditions, early CKD is asymptomatic. Therefore, monitoring these CKD patients for progressive kidney dysfunction and/or damage is only possible with laboratory testing. Yet, there is little available research pertaining to the benefits, harms, and optimal frequency of monitoring kidney function and/or damage (i.e., either of eGFR or albuminuria) in these individuals. Conceptually, monitoring of early CKD may be beneficial only if it prompts intervention that improves clinical outcomes more than less frequent or no monitoring. A possible limitation of systematic kidney function/damage monitoring is that the vast majority of individuals with early CKD are more likely to die than to develop ESKD.16 We are currently unaware of any recommendations for how frequently eGFR should be measured in those with early CKD. The UK NICE guidelines suggest “more frequent monitoring” in CKD patients with worsening kidney function and a “relaxed frequency” of eGFR measurement in those patients with stable kidney function (http://www.renal.org/CKDguide/full/SupportingEvidence1.htm). The American Diabetes Association currently recommends annual measurement of creatinine and of urine albumin excretion for all patients with type 2 diabetes (after ≥ 5 years in patients with type 1 diabetes).17

Treatment of early CKD
Treatment of the vast majority of nonprimary kidney disease has typically been directed at the associated underlying condition(s), such as blood pressure or blood sugar control,17 with general targets of therapy for these conditions sometimes being modified for individual CKD patients.18 Among individuals with proteinuria there has been a suggestion that, in select populations, the severity of proteinuria is a reliable surrogate marker for progression of kidney disease.19 As such, certain therapies have been directed at proteinuria reduction, though the benefits of these therapies have recently been called into question.20 Other therapies for CKD involve the treatment of complications associated with CKD, though these complications are likely to occur later in the course of CKD.

Population(s)
KQ 1-2
■Asymptomatic adults (≥18 years) not known to have CKD:
■Unknown eGFR or last known eGFR ≥60 ml/min (based on creatinine or creatinine-based formulas or cystatin C or cystatin C-based formulas).
■Unknown urine albumin or last known urine albumin/creatinine ratio <30 mg/g or last known 24-hr urine albumin <30 mg.
■Adults at increased risk will be defined as those at increased risk for CKD or CKD complications. Patient factors that may define increased risk include existing vascular disease (e.g., coronary artery disease [CAD], peripheral artery disease [PAD], cerebrovascular disease [CVD]), vascular risk factors (e.g., hypertension, diabetes, obesity, hyperlipidemia, smoking, male gender, older age, family history of early CAD), race, and family history of CKD.
■Adults at average risk will be those without factors that may increase the risk of CKD and/or CKD-related complications.
KQ 3-6
■Adults (≥18 years) with early CKD (i.e., an eGFR of 30 to <60 ml/min and/or a urinary albumin/creatinine ratio of 30–300 mg/gm or a 24-hr urine albumin of 30–300 mg).

Interventions
KQ 1-2

■Systematic screening (universal, targeted, or opportunistic, but not haphazard) by using eGFR (creatinine or creatinine-based formulas, cystatin C or cystatin C-based formulas), albuminuria, or proteinuria. Comparisons of screening versus no screening, different screening intervals (e.g., frequent vs. infrequent), or different screening parameters will be eligible. The focus will be on screening methods that are feasible within a primary care setting.

KQ 3-4
■Monitoring with measures of eGFR (creatinine or creatinine-based formulas, cystatin C or cystatin C-based formulas), albuminuria, and/or proteinuria. Comparisons of monitoring versus no monitoring, different monitoring intervals (e.g., frequent vs. infrequent), or different monitoring parameters will be eligible. The focus will be on monitoring methods that are feasible within a primary care setting.

KQ 5-6
■Renal-specific treatments to be considered:
■Angiotensin converting enzyme inhibitors (ACEIs).
■Angiotensin receptor blockers (ARBs).
■ACEI/ARB combinations.
■Aldosterone antagonists.
■Low-protein diets.
■Nephrology specialist referral.
■Avoidance of gadolinium.
■Avoidance of nonsteroidal antiinflammatory drugs (NSAIDS).
■Avoidance of imaging contrast agents.
■Treatments targeted at vascular disease or vascular risk factors to be considered:
■Angiotensin converting enzyme inhibitors (ACEIs).
■Angiotensin receptor blockers (ARBs).
■ACEI/ARB combinations.
■Aldosterone antagonists.
■Blood pressure control.
■Glycemic control in patients with diabetes.
■Obesity treatment.
■Lipid control.
■Smoking cessation.
■Comparison of individual active treatments (whether high-dose or low-dose) versus placebo, versus each other, and versus different combinations will be eligible.

Outcomes
Benefits: KQ1, 3 & 5
■Clinical outcomes:
■Reduced mortality.
■Reduced/delayed incidence of ESKD (i.e., hemodialysis or transplantation).
■Cardiovascular morbidity (e.g., myocardial infarction and other coronary artery disease events, congestive heart failure symptoms, arrhythmia events, stroke).
■Physical functioning/well-being/activities of daily living (ADL).
■Measures of quality of life (QOL).
■Will consider studies in which these outcomes were primary or secondary, acknowledging this difference.
■Improvement in intermediate outcomes may be evaluated, but these outcomes will not be considered sufficient evidence of clinically important benefit from CKD screening:
■Delayed progression of CKD (e.g., eGFR decline, worsened albuminuria or proteinuria, worse CKD stage).
■Prevention of CKD intermediate-outcome complications (e.g., hypertension, anemia, hyperparathyroidism, hyperphosphatemia).
Harms: KQ 2, 4, 6
■Misclassification/false-positive diagnosis, unnecessary tests, unnecessary treatment.
■Worsened eGFR, hyperkalemia, hypotension, hospitalization, other.

Timing
KQ 1, 3, 5
■Clinical outcomes: ≥1 year.

KQ 2, 4, 6
■Harms: no minimum duration.

Settings
KQ1-6
■Population-based cohort or community-dwelling primary-care outpatients.
■Study designs to be randomized controlled trials (RCT) or controlled clinical trials (CCT); if appropriate RCTs or CCTs are not available, will consider observational studies.

Definition of Terms
Abbreviations:
KQ = key question, CKD = chronic kidney disease, CAD = coronary artery disease, PAD = peripheral arterial disease, CVD = cerebrovascular disease, eGFR = estimated glomerular filtration rate, ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, ESKD = end-stage kidney disease, QOL = quality of life.

Definitions:
CKD complications/CKD clinical outcomes: mortality, impaired quality of life, ESKD, cardiovascular morbidity (e.g., myocardial infarction, stroke).

Early CKD: eGFR 30 to <60 ml/min based on creatinine or creatinine-based formulas or cystatin C or cystatin C-based formulas (with substages of 30 to <45 mL/min and 45 to <60 mL/min), and/or 24-hour urine albumin of 30–300 mg or a urine albumin/creatinine ratio of 30–300 mg/g identified by systematic screening or clinically (e.g., if within 1 year of clinical diagnosis).

Patient factors (that may increase risk for CKD and CKD-related complications) include: existing vascular disease (e.g., coronary artery disease [CAD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]), vascular risk factors (e.g., hypertension, diabetes, obesity, hyperlipidemia, smoking, male gender, older age, family history of early CAD), CKD severity factors (eGFR, proteinuria), race, and family history of CKD.

Systematic CKD screening: Systematic indicates that the CKD screening may be universal, targeted, or opportunistic, but that it is not haphazard.

Treatment, renal-specific: ACEIs, ARBs, ACE/ARB combinations, aldosterone antagonists, low-protein diet, avoidance of imaging contrast agents/NSAIDs/gadolinium, and nephrology referral.

Treatment of vascular disease or vascular risk factors: ACEIs, ARBs, ACE/ARB combinations, aldosterone antagonists, other blood pressure control, glycemic control, lipid control, obesity treatment, smoking cessation.


References
1.National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(Suppl 1):S1-266.
2.Hogan M. KDIGO conference proposes changes to CKD classification, but not to the definition. Nephrology Times 2009;2(12):9-10.
3.Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038-47.
4.United States Renal Data System Web site. Annual Data Report: Vol Three: Reference Tables on End-Stage Renal Disease, p. 78-82. Available at: www.usrds.org/adr_2008.htm. Accessed January 2010.
5.Gilbertson DT, Liu J, Xue JL, et al. Projecting the number of patients with end-stage renal disease in the United States to the year 2015. J Am Soc Nephrol 2005;16:3736-41.
6.Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.
7.Weiner DE, Tabatabai S, Tighiouart H, et al. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis 2006;48:392-401.
8.Ensrud KE, Lui LY, Taylor BC, et al, for the Osteoporotic Fractures Research Group. Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med 2007;167:133-9.
9.Ishani A, Paudel M, Taylor BC, et al, for the Osteoporotic Fractures in Men (MrOS) Study Group. Renal function and rate of hip bone loss in older men: the Osteoporotic Fractures in Men Study. Osteoporos Int 2008;19:1549-56.
10.James MT, Quan H, Tonelli M, et al, for the Alberta Kidney Disease Network. CKD and risk of hospitalization and death with pneumonia. Am J Kidney Dis 2009;54:24-32.
11.Khatri M, Nickolas T, Moon YP, et al. CKD associates with cognitive decline. J Am Soc Nephrol 2009;20:2427-32.
12.Rifkin DE, Katz R, Chonchol M, et al. Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. Nephrol Dial Transplant Dec 15. Epub 15 Dec 2009.
13.Ishani A, Grandits GA, Grimm RH, et al. Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the multiple risk factor intervention trial. J Am Soc Nephrol 2006;17:1444-52.
14.Ninomiya T, Perkovic V, de Galan BE, for the ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009;20:1813-21.
15.Snyder JJ, Collins AJ. KDOQI hypertension, dyslipidemia, and diabetes care guidelines and current care patterns in the United States CKD population: National Health and Nutrition Examination Survey 1999-2004. Am J Nephrol 2009;30:44-54.
16.Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004;164:659-63.
17.American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care 2009;32(Suppl 1):S13-S61.
18.Chobanian AV, Bakris GL, Black HR, et al, for the National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-72.
19.Levey AS, Cattran D, Friedman A, et al. Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 2009;54:205-26.
20.Nelson RG, Tuttle KR. Prevention of diabetic kidney disease: negative clinical trials with renin-angiotensin system inhibitors. Am J Kidney Dis Epub 11 Dec 2009.