I. EXECUTIVE SUMMARY
`I. EXECUTIVE SUMMARY
`
`MPI EXHIBIT 1146 PAGE 1
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`MPI EXHIBIT 1146 PAGE 1
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`

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`EXECUTIVE SUMMARY
`
`INTRODUCTION
`Chronic kidney disease (CKD) is a worldwide
`public health problem affecting more than 50
`million people, and more than 1 million of them
`are receiving kidney replacement therapy.1,2 The
`National Kidney Foundation-Kidney Disease
`Outcomes Quality Initiative™ (NKF-KDOQI™)
`Clinical Practice Guidelines (CPGs) and Clinical
`Practice Recommendations (CPRs) on CKD esti-
`mates that CKD affects 11% of the US popula-
`tion,3 and those affected are at increased risk of
`cardiovascular disease (CVD) and kidney fail-
`ure. Kidney failure represents about 1% of the
`prevalent cases of CKD in the United States,3
`and the prevalence of kidney failure treated by
`dialysis or transplantation is projected to in-
`crease from 453,000 in 2003 to 651,000 in
`2010.3,4
`Management of CKD is costly. The Medicare
`CKD stage 5 population nearly doubled in the
`last 10 years, and the CKD population expanded,
`as well. Together, they account for 16.5% of
`Medicare expenditures, nearly double that of 10
`years ago, and the total costs for kidney disease
`now approach 24% of Medicare expenditures.4
`A growing body of evidence suggests that some
`of the adverse outcomes of CKD can be pre-
`vented or delayed by preventive measures, early
`detection, and treatment.
`NKF-KDOQI™ CPGs presently offer strate-
`gies to manage hypertension,5 dyslipidemia,6
`bone disease,7 anemia,8 nutrition,9 and CVD10 in
`patients with CKD. The present Guidelines ex-
`tend the scope of the NKF-KDOQI™ CPGs and
`CPRs by offering strategies to diagnose and
`manage patients with diabetes and CKD.
`
`BACKGROUND
`
`Epidemic of Diabetes
`Nearly 21 million people in the United States,
`or 7% of the population, have diabetes, and about
`a third of those with diabetes are unaware they
`have the disease. About 5% to 10% of diabetes in
`the United States is type 1, which develops as a
`consequence of the body’s failure to produce
`insulin. In some racial and ethnic groups, the
`proportion of cases attributable to type 1 diabetes
`is even less.11 Most cases of diabetes in the
`United States and elsewhere are type 2, which
`
`develops because of the body’s failure to pro-
`duce sufficient insulin and properly use the insu-
`lin it produces. Worldwide, 171 million people
`have diabetes.
`Diabetes prevalence is increasing most rapidly
`in the developed countries and in developing
`countries undergoing transition from traditional
`to modern lifestyles.12,13 In the general US popu-
`lation, estimates from national surveys14 show
`an 8-fold increase in the prevalence of diagnosed
`diabetes between 1958 and 2000. The San Anto-
`nio Heart Study15 suggests an increasing inci-
`dence rate of type 2 diabetes is responsible, in
`part, for the increasing prevalence among Mexi-
`can Americans and for a borderline significant
`trend in non-Hispanic whites. The investigators
`attribute the greater prevalence of diabetes in this
`population more to the increasing incidence than
`to the decrease in cardiovascular mortality re-
`ported among people with diabetes nationally.16
`Other factors responsible for the increasing preva-
`lence of diabetes include changes in diagnostic
`criteria, increased public awareness, decreasing
`overall mortality, growth in minority popula-
`tions, a dramatic increase in the magnitude and
`frequency of obesity, and the widespread adop-
`tion of a sedentary lifestyle.14 Most of the in-
`crease in diabetes prevalence is attributable to
`type 2 diabetes, and although much of this in-
`crease is occurring in adults, children and adoles-
`cents increasingly are affected. However, a world-
`wide increase in the incidence of type 1 diabetes
`also has been noted, particularly among children
`younger than 5 years.17
`Projections of the future burden of diabetes in
`the US population suggest that the prevalence of
`diabetes will increase 165% between 2000 and
`2050, with the greatest increases in the popula-
`tion older than 75 years and among African
`Americans.18 The global burden of diabetes is
`expected to double between 2000 and 2030, with
`the greatest increases in prevalence occurring in
`the Middle East, sub-Saharan Africa, and In-
`dia.19 Moreover, the development of type 2 dia-
`betes during the childbearing years also will
`
`© 2007 by the National Kidney Foundation, Inc.
`0272-6386/07/4902-0102$32.00/0
`doi:10.1053/j.ajkd.2006.12.005
`
`American Journal of Kidney Diseases, Vol 49, No 2, Suppl 2 (February), 2007: pp S13-S19
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`S14
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`Executive Summary
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`increase, primarily in the developing countries
`(CPR 3, Fig 27).19 Projections regarding the
`future burden of diabetes are based on increasing
`life expectancy, population growth, and progres-
`sive urbanization.20 Of growing concern is the
`belief that these estimates may be too low be-
`cause they do not account for the increasing
`frequency and magnitude of obesity and other
`major risk factors for diabetes.
`As the population of patients with diabetes of
`long duration grows, reports of a dramatically
`increasing burden of diabetic kidney disease
`(DKD) are appearing from developed coun-
`tries,21 as well as from Africa,22,23 India,24 the
`Pacific Islands,25 and Asia,26,27 where infectious
`disease previously posed the greatest threat28
`(see CPR 3). Increased risk and more rapid
`progression of DKD29,30 also have been reported
`in immigrants from developing to developed
`countries.31,32
`
`PROBLEM OF DIABETES AND CKD
`Diabetes is the leading cause of CKD in devel-
`oped countries and rapidly is becoming the lead-
`ing cause in developing countries as a conse-
`quence of the global increase in type 2 diabetes
`and obesity.33 In the United States, microalbumin-
`uria is found in 43%, and macroalbuminuria, in
`8% of those with a history of diabetes.3 More-
`over, diabetes accounts for 45% of prevalent
`kidney failure, up from 18% in 1980.4
`Substantial underdiagnosis of both diabetes
`and CKD leads to lost opportunities for preven-
`tion, and inadequate or inappropriate care of
`patients with diabetes and CKD may contribute
`to disease progression. Nevertheless, diabetes
`care has improved as the benefits of meticulous
`management have become widely accepted and
`the use of angiotensin-converting enzyme (ACE)
`inhibitors, angiotensin receptor blockers (ARBs),
`and statins has increased in patients with diabe-
`tes.4 Even so, fewer than 1 in 4 patients with
`diabetes receives at
`least 1 hemoglobin A1c
`(HbA1c) test, at least 1 lipid test, and at least 1
`glucose testing strip each year, reflecting the
`need for better assessment of these high-risk
`patients.4
`DKD refers to kidney disease that is specific to
`diabetes. Although kidney biopsy is required to
`diagnose diabetic glomerulopathy definitively, in
`most cases, careful screening of diabetic patients
`
`can identify people with DKD without the need
`for kidney biopsy. DKD is based in part on the
`finding of elevated urinary albumin excretion,
`which is divided arbitrarily into: (1) microalbu-
`minuria, a modest elevation of albumin thought
`to be associated with stable kidney function, but
`a greater risk of macroalbuminuria and kidney
`failure; and (2) macroalbuminuria, a higher eleva-
`tion of albumin associated with progressive de-
`cline in glomerular filtration rate (GFR), an in-
`crease in systemic blood pressure, and a high risk
`of kidney failure.
`Most professional societies concerned with
`diabetes and kidney disease now advocate screen-
`ing for microalbuminuria in patients with diabe-
`tes, and the suggested screening plan, adapted
`from the American Diabetes Association (ADA)
`guideline, is shown in Guideline 1, Fig 6.34,35
`Screening should begin 5 years after diagnosis of
`type 1 diabetes and at the time of diagnosis of
`type 2 diabetes because of the inability to estab-
`lish the onset of type 2 diabetes with certainty.
`Because urinary albumin excretion has an intra-
`individual coefficient of variation (CV) of ap-
`proximately 40%,36 multiple positive test results
`are required for classification. Definitions of DKD
`by albuminuria and stage are shown in Guideline
`1, Table 6.
`Evidence for the usefulness of estimated GFR
`(eGFR) alone as a screening test for CKD in
`diabetes is less secure. Many patients with diabe-
`tes and CKD may have elevated or high-normal
`GFRs, particularly in the early years after diagno-
`sis. Therefore, markers of kidney damage are
`required to detect early stages of CKD; eGFR
`alone can only detect CKD stage 3 or worse
`(Guideline 1, Table 6).
`Because diabetes is a common condition, coinci-
`dence with other nondiabetic CKD is relatively
`frequent. Accordingly, evaluation of a person with
`atypical features should, in selected cases, include
`additional diagnostic testing, depending on the clini-
`cal presentation. Care should be used in determin-
`ing the appropriate diagnostic tests because admin-
`istration of radiographic contrast, with or without
`angiography, may pose greater risks in people with
`diabetes and CKD than in others.
`
`Diabetes, CKD, and CVD
`Diabetes is one of the most important risk
`factors for CVD. The risk imparted by diabetes
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`Executive Summary
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`S15
`
`has been described as a CVD risk equivalent
`because the likelihood of future events may
`approach that of people without diabetes who
`have already had a myocardial infarction.37 Such
`observations have led to recommendations from
`both the ADA and the American Heart Associa-
`tion (AHA) for intensive cardiovascular risk fac-
`tor management in people with diabetes (Table
`1).34,38 CKD also imparts an extremely high risk
`of CVD. The NKF and the AHA recently issued
`guidelines and scientific statements recommend-
`ing that people with CKD be considered in the
`highest risk category for CVD.3,39 For those with
`both diabetes and CKD, the outlook is far worse
`than for either condition alone because this com-
`bination is a powerful predictor of major adverse
`cardiovascular events and death. The relation-
`ship between CKD severity and risk is continu-
`ous. People with diabetes and microalbuminuria
`have twice the CVD risk of those with normoalbu-
`minuria,40 and as albuminuria increases and GFR
`decreases, CVD risk increases progressively.41-43
`In an analysis of patients with type 2 diabetes
`from the UK Prospective Diabetes Study
`(UKPDS), rates of death and progression to
`macroalbuminuria were equal at the microalbu-
`minuric stage.41 However, at the macroalbumin-
`uric stage, the death rate outpaced the rate of
`kidney disease progression (Fig 2). More people
`who reach CKD stage 3 will die, primarily of
`CVD, than progress to kidney failure, especially
`if they also have diabetes.3,44
`In the Background, a focused review of rela-
`tionships among diabetes, CKD, and CVD rel-
`evant
`to people with CKD stages 1 to 4 is
`presented. The review includes a discussion of
`intensive risk factor management for the preven-
`tion of CVD, the evaluation of coronary heart
`disease in patients with diabetes, and medical
`management and coronary revascularization in
`these patients. Specific recommendations for
`CKD stage 5 are provided in the NKF-KDOQI™
`Guidelines for CVD in Dialysis Patients.10
`People with diabetes and CKD are at high risk
`to both lose kidney function and experience
`major adverse cardiovascular events (Back-
`ground, Fig 4). Treatment of risk factors reduces
`the likelihood of these outcomes. Fortunately,
`treatment strategies are largely shared for reduc-
`ing kidney and cardiovascular risks. The present
`CPGs and CPRs for diabetes and CKD are con-
`
`sistent with those already established for the
`treatment of diabetes and CVD by the ADA and
`AHA.34,38 Goals of the management approaches
`recommended here are intended to mitigate the
`devastating consequences of the spectrum of
`vascular complications, including kidney, heart,
`and others.
`
`GOALS OF CPG AND CPR PROCESS
`These CPGs seek to improve outcomes in
`patients with diabetes and CKD by providing
`strategies for the diagnosis (Guideline 1) and
`management (Guidelines 3 to 5 and CPRs 1 to 4)
`of CKD in the setting of diabetes and for the
`management of diabetes in the setting of CKD
`(Guideline 2). The general treatment of diabetes
`is beyond the scope of this guideline and is
`addressed comprehensively in the ADA guide-
`lines.34
`As part of an evolution in the development of
`CPGs, the Work Group divided its recommenda-
`tions, which are based on a systematic review of
`the literature, into a series of Guidelines and
`CPRs. The Guidelines were based on a consen-
`sus within the Work Group that the strength of
`the evidence was sufficient to make definitive
`statements about appropriate clinical practice.
`When the strength of the evidence was not suffi-
`cient to make such statements, the Work Group
`offered CPRs based on the best available evi-
`dence and expert opinion. As new data become
`available, the strength of the evidence for many
`of the CPRs may become sufficient for the CPRs
`to become CPGs, illustrating the need for recur-
`ring reviews and updates of this document. Many
`of the research recommendations proposed by
`the Work Group were developed with the goal of
`strengthening the evidence for the CPRs to deter-
`mine whether they should become Guidelines in
`the future.
`The term “definitive” must be used with cau-
`tion, particularly in the context of CPGs. Uncer-
`tainty is an immutable element of all scientific
`research, and the establishment of a Guideline
`should neither preclude nor render unethical fur-
`ther inquiry. Rather, the establishment of guide-
`lines represents an evolving process that seeks to
`ensure that each patient receives the best pos-
`sible care within the context of presently avail-
`able medical knowledge.
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`Executive Summary
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`Figure 1. Percentage of patients in each group of the Steno Study who reached the intensive-treatment goals at a mean
`of 7.8 years.
`Abbreviation: BP, blood pressure. Reprinted with permission.45
`
`Scope
`The target population of these CPGs is pa-
`tients with CKD stages 1 to 5, including dialysis
`and transplant patients. However, the emphasis
`is on stages 1 to 4 because the evidence in stage 5
`is either lacking or addressed in other NKF-
`KDOQI™ Guidelines. Consideration is given to
`the diagnosis, impact, and management of diabe-
`tes and CKD in children, adults, the elderly,
`pregnant women, and different racial and ethnic
`groups.
`The intended readers are practitioners who
`manage patients with diabetes and CKD, includ-
`ing, but not limited to, primary care providers,
`nephrologists, cardiologists, endocrinologists/
`diabetologists, physician’s assistants, nurse prac-
`titioners, nurses, dietitians, pharmacists, social
`workers, and diabetes educators. By reviewing
`scientific evidence from throughout the world,
`coordinating our efforts with guideline develop-
`ment processes elsewhere, and including in the
`Work Group experts from Latin America and
`Europe, as well as from North America, we
`believe this document has relevance beyond prac-
`titioners in North America.
`
`The Value of Multifaceted Intervention
`Although these and other guidelines present
`recommendations for the management of risk
`factors separately, in reality, multiple risk factors
`are managed concurrently in patients with diabe-
`tes and CKD. In the Steno Study, a multifaceted
`
`approach aimed at optimal management for a
`group of risk factors was evaluated in patients
`with type 2 diabetes and microalbuminuria.45,46
`The intervention had multiple targets, including
`behavioral modification and pharmacological
`therapies for hyperglycemia, hypertension (em-
`phasizing renin-angiotensin system [RAS] inhibi-
`tors), dyslipidemia, CVD prevention with aspi-
`rin, and a vitamin/mineral supplement (CPR 2,
`Table 48). This intensive intervention was com-
`pared with usual care. A mean decrease in albu-
`minuria (albumin decreased 20 mg/24 h) was
`observed in the intensive-intervention group,
`whereas a mean increase occurred in patients in
`the usual-care group (albumin increased 30 mg/24
`h). Albuminuria progression and the composite
`outcome of CVD events or death were decreased
`in the group treated intensively (CPR 2, Fig 26).
`However, which facets of the intervention are
`associated with reduced risk is uncertain. Further-
`more, because the intensive intervention in-
`creased the use of RAS inhibitors, the contribu-
`tion of other treatments is unclear. Despite these
`limitations, the Work Group recognizes the impor-
`tance of addressing multiple risk factors in an
`integrated fashion. The incremental effects of a
`multifaceted approach appear to add up to sub-
`stantial clinical benefits, even when each of the
`therapeutic goals is not met (Fig 1). A long-term,
`targeted, intensive intervention involving mul-
`tiple risk factors and using currently available
`therapeutic agents reduces the risk of cardiovas-
`
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`Executive Summary
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`cular and microvascular events by about 50%
`among patients with type 2 diabetes and mi-
`croalbuminuria.45
`
`SUMMARY
`Multiple important, but unanswerable, ques-
`tions arose during the development of each Guide-
`line and CPR. These questions led to research
`recommendations that should be high priorities
`to improve the care of patients with diabetes and
`CKD. The Work Group recognizes the impor-
`tance of bringing new treatments into clinical
`research for DKD, especially for patients who
`have progressive kidney disease despite the cur-
`rent standard of care. Promising treatments, in-
`cluding novel agents and potential new uses of
`existing agents, are currently in phase 2/3 trials
`for DKD. These recommendations and the new
`treatments in clinical trials are described in the
`Research Recommendations section.
`
`CPG AND CPR STATEMENTS
`Guideline 1: Screening and Diagnosis of
`DKD
`CKD in patients with diabetes may or may
`not represent DKD. In the absence of an
`established diagnosis, the evaluation of pa-
`tients with diabetes and kidney disease should
`include investigation into the underlying
`cause(s).
`1.1 Patients with diabetes should be screened
`annually for DKD. Initial screening should
`commence:
`● 5 years after the diagnosis of type 1
`diabetes; (A) or
`● From diagnosis of type 2 diabetes. (B)
`1.1.1 Screening should include:
`● Measurements of urinary albu-
`min-creatinine ratio (ACR) in
`a spot urine sample; (B)
`● Measurement of serum creati-
`nine and estimation of GFR.
`(B)
`1.2 An elevated ACR should be confirmed in
`the absence of urinary tract infection
`with 2 additional first-void specimens
`collected over the next 3 to 6 months. (B)
`● Microalbuminuria is defined as an
`ACR between 30-300 mg/g.
`
`● Macroalbuminuria is defined as an
`ACR > 300 mg/g.
`● 2 of 3 samples should fall within the
`microalbuminuric or macroalbumin-
`uric range to confirm classification.
`1.3 In most patients with diabetes, CKD
`should be attributable to diabetes if:
`● Macroalbuminuria is present; (B) or
`● Microalbuminuria is present
`䡩 in the presence of diabetic retinopa-
`thy, (B)
`䡩 in type 1 diabetes of at least 10
`years’ duration. (A)
`1.4 Other cause(s) of CKD should be consid-
`ered in the presence of any of the follow-
`ing circumstances: (B)
`● Absence of diabetic retinopathy;
`● Low or rapidly decreasing GFR;
`● Rapidly increasing proteinuria or ne-
`phrotic syndrome;
`● Refractory hypertension;
`● Presence of active urinary sediment;
`● Signs or symptoms of other systemic
`disease; or
`● >30% reduction in GFR within 2-3
`months after initiation of an ACE
`inhibitor or ARB.
`
`Guideline 2: Management of
`Hyperglycemia and General Diabetes Care
`in CKD
`Hyperglycemia, the defining feature of dia-
`betes, is a fundamental cause of vascular tar-
`get-organ complications, including kidney dis-
`ease. Intensive treatment of hyperglycemia
`prevents DKD and may slow progression of
`established kidney disease.
`2.1 Target HbA1c for people with diabetes
`should be < 7.0%,
`irrespective of the
`presence or absence of CKD. (A)
`
`Guideline 3: Management of
`Hypertension in Diabetes and CKD
`Most people with diabetes and CKD have
`hypertension. Treatment of hypertension slows
`the progression of CKD.
`3.1 Hypertensive people with diabetes and
`CKD stages 1-4 should be treated with an
`ACE inhibitor or an ARB, usually in
`combination with a diuretic. (A)
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`Executive Summary
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`3.2 Target blood pressure in diabetes and
`CKD stages 1-4 should be < 130/80 mm
`Hg. (B)
`
`Guideline 4: Management of Dyslipidemia
`in Diabetes and CKD
`Dyslipidemia is common in people with dia-
`betes and CKD. The risk of CVD is greatly
`increased in this population. People with dia-
`betes and CKD should be treated according to
`current guidelines for high-risk groups.
`4.1 Target low-density lipoprotein cholesterol
`(LDL-C) in people with diabetes and
`CKD stages 1-4 should be < 100 mg/dL;
`<70 mg/dL is a therapeutic option. (B)
`4.2 People with diabetes, CKD stages 1-4, and
`LDL-C > 100 mg/dL should be treated
`with a statin. (B)
`4.3 Treatment with a statin should not be
`initiated in patients with type 2 diabetes
`on maintenance hemodialysis therapy who
`do not have a specific cardiovascular
`indication for treatment. (A)
`
`Guideline 5: Nutritional Management in
`Diabetes and CKD
`Management of diabetes and CKD should
`include nutritional intervention. Dietary modi-
`fications may reduce the progression of CKD.
`5.1 Target dietary protein intake for people
`with diabetes and CKD stages 1-4 should
`be the recommended daily allowance
`(RDA) of 0.8 g/kg body weight per day.
`(B)
`
`CPR 1: Management of Albuminuria in
`Normotensive Patients With Diabetes and
`Albuminuria as a Surrogate Marker
`Treatments that decrease urinary albumin
`excretion may slow the progression of DKD
`and improve clinical outcomes, even in the
`absence of hypertension. However, most people
`with diabetes and albuminuria have hyperten-
`sion; management of hypertension in these
`patients is reviewed in Guideline 3.
`1.1 Normotensive people with diabetes and
`macroalbuminuria should be treated with
`an ACE inhibitor or an ARB. (C)
`1.2 Treatment with an ACE inhibitor or an
`ARB may be considered in normotensive
`
`people with diabetes and microalbumin-
`uria. (C)
`1.3 Albuminuria reduction may be consid-
`ered a treatment target in DKD. (C)
`
`CPR 2: Multifaceted Approach to
`Intervention in Diabetes and CKD
`Multiple risk factors are managed concur-
`rently in patients with diabetes and CKD, and
`the incremental effects of treating each of
`these risk factors appear to add up to substan-
`tial clinical benefits.
`2.1 The care of people with diabetes and
`CKD should incorporate a multifaceted
`approach to intervention that includes
`instruction in healthy behaviors and treat-
`ments to reduce risk factors. (C)
`2.2 Target body mass index (BMI) for people
`with diabetes and CKD should be within
`the normal range (18.5-24.9 kg/m2). (C)
`
`CPR 3: Diabetes and CKD in Special
`Populations
`The increasing incidence of diabetes in chil-
`dren, young adults, the elderly, and members
`of disadvantaged and transitional populations
`is responsible for an increasing incidence of
`DKD in these groups. Racial/ethnic differ-
`ences in susceptibility to DKD also may play a
`role. In pregnant women, the presence of dia-
`betes and CKD may adversely affect the health
`of both the mother and her offspring.
`3.1 Screening and interventions for diabetes
`and CKD should focus on populations at
`greatest risk. (C)
`3.2 Although management of diabetes and
`CKD in special populations should follow
`the same principles as management in the
`majority population, there are special
`considerations in the treatment of chil-
`dren, adolescents, and the elderly. (C)
`3.3 Population-based interventions may be
`the most cost-effective means for address-
`ing the burden of CKD in special popula-
`tions. Implementation and evaluation of
`population-based interventions should
`take into account the heterogeneity of the
`populations at risk. (C)
`3.4 Specialists in high-risk pregnancy and
`kidney disease should co-manage preg-
`
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`Executive Summary
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`nancy in women with diabetes and CKD.
`(C)
`3.5 Treatment of DKD with RAS inhibitors
`before pregnancy may improve fetal and
`maternal outcomes, but these medicines
`should be discontinued as soon as a men-
`strual period is missed or after a positive
`pregnancy test. (C)
`3.6 Insulin should be used to control hypergly-
`cemia if pharmacological therapy is neces-
`sary in pregnant women with diabetes
`and CKD. (C)
`CPR 4: Behavioral Self-Management in
`Diabetes and CKD
`Behavioral self-management in patients with
`diabetes and CKD is particularly challenging
`
`because of the intensive nature of the diabetes
`regimen. Education alone is not sufficient to
`promote and sustain healthy behavior change,
`particularly with such a complex regimen.
`
`4.1 Self-management strategies should be key
`components of a multifaceted treatment
`plan with attention to multiple behaviors:
`(C)
`● Monitoring and treatment of glycemia,
`● Blood pressure,
`● Nutrition,
`● Smoking cessation,
`● Exercise, and
`● Adherence to medicines.
`
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`II. CLINICAL PRACTICE GUIDELINES
`ll. CLINICAL PRACTICE GUIDELINES
`
`MPI EXHIBIT 1146 PAGE 9
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`BACKGROUND
`
`INTRODUCTION
`Chronic kidney disease (CKD) is a worldwide
`public health problem affecting more than 50
`million people, and more than 1 million of them
`are receiving kidney replacement therapy.1,2 The
`National Kidney Foundation-Kidney Disease
`Outcomes Quality Initiative™ (NKF-KDOQI™)
`Clinical Practice Guidelines (CPGs) on CKD
`estimate that CKD affects 11% of the US popula-
`tion,3 and those affected are at increased risk of
`cardiovascular disease (CVD) and kidney fail-
`ure. Kidney failure represents about 1% of the
`prevalent cases of CKD in the United States,3
`and the prevalence of kidney failure treated by
`dialysis or transplantation is projected to in-
`crease from 453,000 in 2003 to 651,000 in
`2010.3,4
`Management of CKD is costly. The Medicare
`CKD stage 5 population nearly doubled in the
`last 10 years, and the CKD population expanded,
`as well. Together, they account for 16.5% of
`Medicare expenditures, nearly double that of 10
`years ago, and the total costs for kidney disease
`now approach 24% of Medicare expenditures.4
`A growing body of evidence suggests that some
`of the adverse outcomes of CKD can be pre-
`vented or delayed by preventive measures, early
`detection, and treatment.
`NKF-KDOQI™ CPGs presently offer strate-
`gies to manage hypertension,5 dyslipidemia,6
`bone disease,7 anemia,8 nutrition,9 and CVD10 in
`patients with CKD. The present Guideline ex-
`tends the scope of the NKF-KDOQI™ CPGs by
`offering strategies to diagnose and manage the
`treatment of patients with diabetes and CKD.
`
`PROBLEM OF DIABETES AND CKD
`Diabetes is the leading cause of CKD in devel-
`oped countries and is rapidly becoming the lead-
`ing cause in developing countries as a conse-
`quence of the global increase in type 2 diabetes
`and obesity.33 In the United States, microalbumin-
`uria is found in 43%, and macroalbuminuria, in
`8% of those with a history of diabetes.3 More-
`over, diabetes accounts for 45% of prevalent
`kidney failure, up from 18% in 1980.4
`Substantial underdiagnosis of both diabetes
`and CKD leads to lost opportunities for preven-
`tion, and inadequate or inappropriate care of
`
`patients with diabetes and CKD may contribute
`to disease progression. Nevertheless, diabetes
`care has improved because the benefits of meticu-
`lous management have become widely accepted
`and the use of angiotensin-converting enzyme
`(ACE) inhibitors, angiotensin receptor blockers
`(ARBs), and statins has increased in patients
`with diabetes.4 Even so, fewer than 1 in 4 pa-
`tients with diabetes receives at least 1 hemoglo-
`bin A1c (HbA1c) test, at least 1 lipid test, and at
`least 1 glucose testing strip each year, reflecting
`the need for better assessment of these high-risk
`patients.4
`
`GOALS OF CPG AND CPR PROCESS
`This CPG seeks to improve outcomes in pa-
`tients with diabetes and CKD by providing strat-
`egies for the diagnosis (Guideline 1) and manage-
`ment (Guidelines 3 to 5 and CPRs 1 to 4) of CKD
`in the setting of diabetes and for the management
`of diabetes in the setting of CKD (Guideline 2).
`The general treatment of diabetes is beyond the
`scope of this guideline, and it is comprehensively
`addressed in the American Diabetes Association
`(ADA) guidelines.34
`As part of an evolution in the development of
`CPGs, the Work Group divided its recommenda-
`tions, which are based on a systematic review of
`the literature, into a series of Guidelines and
`Clinical practice recommendations (CPRs). The
`Guidelines were based on a consensus within the
`Work Group that the strength of the evidence
`was sufficient to make definitive statements about
`appropriate clinical practice. When the strength
`of the evidence was not sufficient to make such
`statements, the Work Group offered CPRs based
`on the best available evidence and on expert
`opinion. As new data become available,
`the
`strength of the evidence for many of the CPRs
`may become sufficient for the CPRs to become
`CPGs, illustrating the need for recurring reviews
`and updates of this document. Many of the
`research recommendations proposed by the Work
`Group were developed with the goal of strength-
`ening the evidence for the CPRs to determine
`whether they should become Guidelines in the
`future.
`The term “definitive” must be used with cau-
`tion, particularly in the context of CPGs. Uncer-
`tainty is an immutable element of all scientific
`
`American Journal of Kidney Diseases, Vol 49, No 2, Suppl 2 (February), 2007: pp S21-S41
`
`S21
`
`MPI EXHIBIT 1146 PAGE 10
`
`

`

`S22
`
`Background
`
`research, and the establishment of a Guideline
`should neither preclude nor render unethical fur-
`ther inquiry. Rather, the establishment of guide-
`lines represents an evolving process that seeks to
`ensure that each patient receives the best pos-
`sible care within the context of presently avail-
`able medical knowledge.
`
`Scope
`The target population of this CPG is patients
`with CKD stages 1 to 5, including dialysis and
`transplant patients. However, the emphasis is on
`stages 1 to 4 because the evidence in stage 5 is
`either lacking or addressed in other NKF-
`KDOQI™ Guidelines. Consideration is given to
`the diagnosis, impact, and management of diabe-
`tes and CKD in children, adults, the elderly,
`pregnant women, and different racial and ethnic
`groups.
`The intended readers are practitioners who
`manage patients with diabetes and CKD, includ-
`ing, but not limited to, primary care providers,
`nephrologists, cardiologists, endocrinologists/
`diabetologists, physician’s assistants, nurse prac-
`titioners, nurses, dietitians, pharmacists, social
`workers, and diabetes educators. By reviewing
`scientific evidence from throughout the world,
`coordinating our efforts with guideline develop-
`ment processes elsewhere, and including in the
`Work Group experts from Latin America and
`Europe, as well as from North America, we
`believe this document has relevance beyond prac-
`titioners in North America.
`
`DIABETES AS A PUBLIC HEALTH MANDATE
`
`An Epidemic
`Nearly 21 million people in the United States,
`or 7% of the population, have diabetes, and about
`a third of those with diabetes are unaware they
`have the disease. About 5% to 10% of diabetes in
`the United States is type 1, which develops as a
`consequence of the body’s failure to produce
`insulin. In some racial and ethnic groups, the
`proportion of cases attributable to type 1 diabetes
`is even less.11 Most cases of diabetes in the
`United States and elsewhere are type 2, which
`develops because of the body’s failure to pro-
`duce sufficient insulin and properly use the insu-
`lin it produces. Worldwide, 171 million people
`have diabetes.
`
`Diabetes prevalence is increasing most rapidly
`in the developed countries and in developing
`countries undergoing transition from traditional
`to modern lifestyles.12,13 In the general US popu-
`lation, estimates from national surveys14 show
`an 8-fold increase in the prevalence of diagnosed
`diabetes between 1958 and 2000. The San Anto-
`nio Heart Study15 suggests an increasing inci-
`dence rate of type 2 diabetes is responsible, in
`part, for the increasing prevalence among Mexi-
`can Americans and for a borderline significant
`trend in non-Hispanic whites. The investigators
`attribute the greater prevalence of diabetes in this
`population more to the increasing incidence than
`to the decrease in cardiovascular mortality re-
`ported among people with diabetes nationally.16
`Other factors responsible for the increasing preva-
`lence of diabetes include changes in diagnostic
`criteria, increased public awareness, decreasing
`overall mortality, growth in minority popula-
`tions, a dramatic increase in the magnitude and
`frequency of obesity, and the widespread adop-
`tion of a sedentary lifestyle.14 Most of the in-
`crease in diabetes prevalence is attributable to
`type 2 diabetes, and although much of this in-
`crease is o