DOQI高血压治疗 EXECUTIVE SUMMARY

NKF K/DOQI GUIDELINESExecutive Summaries | Anemia | Hemodialysis | Peritoneal Dialysis |Vascular Access | Nutrition | CKD 2002 | Dyslipidemias | Bone Metabolism |Hypertension and Antihypertensive Agents | History of K/DOQIK/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney DiseaseEXECUTIVE SUMMARYINTRODUCTIONCHRONIC KIDNEY disease (CKD) is a worldwide public health issue. In the United States, there is a rising incidence and prevalence of kidney failure (Fig 1), with poor outcomes and high cost.2 The prevalence of earlier stages of CKD is approximately 100 times greater than the prevalence of kidney failure, affecting almost 11% of adults in the United States.1 There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by preventive measures, early detection, and treatment.Fig 1. Kidney failure in the United States. Incidence and prevalence of kidney failure treated by dialysis and transplantation (end-stage renal disease) in the United States. Incident patients refers to new cases during the year. Point prevalent patients refers to patient alive on December 31st of the year. Solid vertical lines represent complete data for 1998 and expected data for 2000. Projections for future years are based on extrapolation of regression equations. R2 for regression equations is given. From USRDS 2000 Annual Data Report.2 Hypertension is a cause and complication of CKD. Hypertension in CKD increases the risk of important adverse outcomes, including loss of kidney function and kidney failure, early development and accelerated progression of cardiovascular disease (CVD), and premature death.3,4 In the ongoing effort to improve outcomes of CKD, the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) appointed a Work Group and an Evidence Review Team in 2001 to develop clinical practice guidelines on hypertension and use of antihypertensive agents in CKD. During this same time, clinical practice guidelines on this topic relevant to CKD were also underdevelopment by other organizations, including the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)5,5a and the 2003 report of the American Diabetes Association (ADA) on the Treatment of Hypertension in Adults with Diabetes.6 The Work Group maintained contact with these organizations during development of these guidelines.The purpose of the Executive Summary is to provide a "stand-alone" summary of the background, scope, methods, and key recommendations, as well as the complete text of the guideline statements. Most tables and figures in the Executive Summary are taken from other sections of the document.BACKGROUNDChronic Kidney DiseaseFigure 2 is a conceptual model of CKD, which defines stages of CKD, as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes.Fig 2. Conceptual model for stages in the initiation and progression of CKD and therapeutic interventions. Shaded ellipses represent stages of CKD; unshaded ellipses represent potential antecedents or consequences of CKD. Thick arrows between ellipses represent "risk factors" associated with initiation and progression of disease that can be affected or detected by interventions: susceptibility factors (black); initiation factors (dark gray); progression factors (light gray); and end-stage factors (white). Interventions for each stage are given beneath the stage. Individuals who appear normal should be screened for CKD risk factors. Individuals known to be at increased risk for CKD should be screened for CKD. Complications refer to all complications of CKD and its treatment, including complications of decreased GFR (hypertension, anemia, malnutrition, bone disease, neuropathy, and decreased quality of life) and cardiovascular disease. Reprinted with permission.1 Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.CKD is defined as kidney damage, as confirmed by kidney biopsy or markers of damage, or glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 for ≥ 3 months (Table 1).1 Markers of kidney damage include proteinuria, abnormalities on the urine dipstick or sediment examination, or abnormalities on imaging studies of the kidneys. GFR can be estimated from prediction equations based on serum creatinine and other variables, including age, sex, race, and body size.Among individuals with CKD, the stage of disease is based on the level of GFR (Table 2), irrespective of the cause of kidney disease.1 The high prevalence of earlier stages of CKD emphasizes the importance for all health-care providers, not just kidney disease specialists, to detect, evaluate, and treat CKD.Hypertension in CKDJNC 7 defines hypertension as systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg, respectively (Table 3).5Although common in CKD, hypertension is not part of the definition of CKD. Table 4 illustrates the classification of individuals based on presence or absence of kidney damage and hypertension, and level of GFR. Approximately 50% to75% of individuals with GFR <60 mL/min/1.73 m2 (CKD Stages 3-5) have hypertension (Fig 3).1 Among individuals with GFR ≥60 mL/min/1.73 m2, distinguishing CKD Stages 1 and 2 (Table 4, shaded areas) from "hypertension" and "hypertension with decreased GFR" (Table 4, unshaded areas) requires assessment for markers of kidney damage. This is especially important in the elderly, in whom both hypertension and decreased GFR are common.Fig 3. Prevalence of high blood pressure by level of GFR, adjusted to age 60 years (NHANES III). GFR was estimated using the abbreviated MDRD Study equation. Hypertension was defined as JNC ≥ Stage 1 (SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg, or taking medications for hypertension) or JNC ≥ Stage 2 (SBP ≥ 160 or DBP ≥ 100 mm Hg). Values are adjusted to age 60 years using a polynomial regression. 95% confidence intervals are shown at selected levels of estimated GFR. Reproduced with permission.1Cardiovascular Disease in CKDCKD is a risk factor for cardiovascular disease (CVD).3,4,7 Dialysis patients have a 50 to 500 times increased risk of CVD mortality compared to age-matched individuals from the general population (Fig 4). Earlier stages of CKD are also associated with an increased risk of CVD. CKD is associated with an increased prevalence and severity of both "traditional" and "nontraditional" risk factors for CVD. Traditional risk factors include those initially described in the Framingham Study. Among traditional risk factors, hypertension is closely linked to CKD and has often been implicated as the main cause of CVD in CKD. Other traditional risk factors for CVD that are common in CKD include older age, diabetes and hyperlipidemia. Nontraditional risk factors for CVD such as inflammation, malnutrition, mineral disorders(calcium and phosphorus), and anemia are also common in CKD. In addition, albuminuria (Fig 5)8 and decreased GFR (Fig 6)9 are associated with an increased risk of CVD, even after controlling for many of these risk factors. Early detection and treatment of CKD, including detection and treatment of hypertension and other CVD risk factors, may reduce the risk of CVD in CKD. Achieving these goals in CKD will require coordinating antihypertensive therapy with therapy for other CVD risk factors.Fig 4. CVD mortality in dialysis patients (USRDS) compared to the general population (NCHS). CVD mortality defined by death due to arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction atherosclerotic heart disease, and pulmonary edema in the general population (GP), data from National Center for Health Statistics (NCHS) multiple cause of mortality data files (ICD 9 codes 402, 404, 410-414, and 425-429, 1993) compared to dialysis patients (data from USRDS special data request). HCFA form 2746, #s 23, 26-29, and 31, 1994-1996. Data are stratified by age, sex, and race. Reproduced with permission.24Fig 5. Albuminuria as a risk factor for CVD. The adjusted effect of urinary albumin concentration (UAC) on hazard function in the Prevention of Renal and Vascular End Stage Disease (PREVEND) Study. The solid line shows the estimated relationship when logarithmic hazard is modeled as a linear function of log[UAC]. The dotted lines are 95% confidence limits for a more general functional relationship, as estimated by P-splines. The hatched area represents UAC of 20 to 200 mg/L, respectively, corresponding approximately to the definition of microalbuminuria. The graphs show that as UAC increases, the hazard ratios for both cardiovascular and noncardiovascular death increases. This increase begins in individuals with UAC in the microalbuminuria range. Reproduced with permission.8Fig 6. Decreased GFR as a risk factor for CVD. Five-year probability of CVD events according to baseline estimated GFR, as observed in 45- to 64-year-old individuals enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. Hatch marks on the horizontal axis indicate number of individuals with events at corresponding level of GFR. The large increase in risk for individuals with baseline GFR <60 mL/min/1.73 m2 is apparent. The increased risk is attenuated after adjustment for other known risk factors, but remains statistically significant.Reproduced with permission.9Recommendations for antihypertensive therapy in the general population are based on observational studies and controlled trials relating blood pressure level and antihypertensive therapy to CVD risk. Few patients with CKD were included in these studies. Thus, recommendations to reduce CVD risk in CKD are based largely on extrapolation from the general population.Progression of CKDMost kidney diseases worsen progressively over time. Antihypertensive therapy affects several modifiable key factors related to the progression of kidney disease, including hypertension, proteinuria, and other mechanisms, such as increased activity of the renin-angiotensin system (RAS) (Fig 7). Several large, controlled trials have examined the effect of antihypertensive therapy on the progression of kidney disease in patients with and without hypertension. While these trials have provided important answers about therapy, the relationships among these "progression factors" are complex, and many questions remain unanswered, especially regarding the mechanisms underlying the therapeutic benefit of the interventions.Fig 7. Risk factors for kidney disease progression related to hypertension. Shaded ellipses represent stages of kidney disease (see Fig 2). Thick arrows between ellipses represent "risk factors" associated with progression of disease that can be affected by antihypertensive therapy. Thin arrows represent relationships between risk factors. Dashed lines indicate hypothesized causal relationships.Based on these considerations, the Work Group defined the following goals for antihypertensive therapy in CKD (Table 5) and strategies and therapeutic targets to achieve them (Table 6). This formulation is consistent with the JNC 7 report, which recommends lifestyle modifications and pharmacological therapy to lower blood pressure and reduce CVD risk, with modifications for "compelling indications," including CKD.5As indicated in Table 6, the Work Group recommended that clinicians consider reducing proteinuria as a goal for antihypertensive therapy in CKD. Proteinuria is important in CKD for a number of reasons (Table 7). There is strong evidence that proteinuria is a marker of kidney damage, and its presence identifies individuals with CKD. Large amounts of proteinuria are a clue to the type (diagnosis) of CKD. Higher levels of proteinuria are a risk factor for faster progression of CKD and development of CVD. Higher levels of proteinuria also identify individuals who benefit more from antihypertensive therapy. However, the Work Group decided that the evidence is not strong enough to conclude that proteinuria is a surrogate outcome for kidney disease progression. However, it was the opinion of the Work Group that proteinuria should be monitored during the course of CKD, and that under some circumstances, it would be appropriate to consider modifications to the antihypertensive regimen in patients with large amounts of proteinuria, such as a lower blood pressure goal or measures to reduce proteinuria. In general, these modifications should be undertaken in consultation with a nephrologist. The Work Group strongly recommended further research on this topic.SCOPE OF THE GUIDELINESThe Work Group was convened by the NKF Kidney Disease Outcomes Quality Initiative (K/DOQI) in response to recommendations of the NKF Task Force on CVD (Fig 8). The overall aim of the Work Group was to develop evidence-based recommendations for the evaluation and management of hypertension and use of antihypertensive agents in CKD. Topics considered are listed in Table 8. Based on the results of clinical and epidemiological studies, the Work Group defined the target population for these guidelines as patients with CKD Stages 1-4. Patients with CKD Stage 5 (kidney failure) were excluded since kidney disease progression may not be as important in patients who have already reached the stage of kidney failure, because the relationship between CVD risk and level of blood pressure is complex in kidney failure, and because of intermittent fluid shifts that affect blood pressure in hemodialysis patients. Thus, the Work Group concluded that the evidence base was not sufficient to develop strong recommendations for patients with kidney failure, and that extrapolation from the general population or from populations with earlier stages of CKD to those with kidney failure may not be appropriate. The Work Group acknowledges the importance of this topic, which will be addressed in a forthcoming K/DOQI Clinical Practice Guideline.Fig 8. Evolution of National Kidney Foundation Guidelines on Hypertension and Antihypertensive Agents in CKD. Abbreviations: Cr, serum creatinine concentration; NKF, National Kidney Foundation; CVD, cardiovascular disease; GFR, glomerular filtration rate; CKD, chronic kidney disease; K/DOQI, Kidney Disease Outcomes Quality Initiative. To convert serum creatinine from mg/dL to mmol/L, multiply by 88.4.The Work Group has included recommendations for both adults and children. Guideline 13 for children was written with careful consideration of past recommendations for the treatment of hypertension in children by JNC reports and by the National High Blood Pressure Education Program Work Group for Children and Adolescents.10Two topics are highlighted in the Guidelines in which evidence is rapidly accumulating, but the evidence base is not yet sufficient for strong or moderately strong recommendations: use of ambulatory blood pressure monitoring (Guideline 3 and Appendix 3) and additional interventions for patients with large amounts of proteinuria (Background, Guidelines 1, 8, 9, 10, 11). For these topics, recommendations were based on weak evidence and opinion.The Work Group developed the following operational definitions for these guidelines:Antihypertensive therapy includes lifestyle modifications and pharmacological therapy that reduce blood pressure, in patients with or without hypertension.Lifestyle modifications include changes in diet, exercise, and habits that may slow the progression of CKD or lower the risk of CVD. These guidelines focus specifically on lifestyle modifications that lower blood pressure, and are discussed in more detail in Guideline 6.Pharmacological therapy includes selection of antihypertensive agents and blood pressure goals. General principles of pharmacological therapy and target blood pressure for CVD risk reduction are discussed in Guideline 7. Antihypertensive agents are defined as agents that are usually prescribed to lower blood pressure. Many antihypertensive agents have effects in addition to lowering systemic blood pressure and are used for indications other than hypertension. Other agents may also lower blood pressure as a side-effect."Preferred agents" are classes of antihypertensive agents that have beneficial effects on progression of CKD or reducing CVD risk in addition to their antihypertensive effects, such as reducing proteinuria, slowing GFR decline, and inhibiting other pathogenetic mechanisms of kidney disease progression and CVD. In certain types of CKD, specific classes of antihypertensive agents, notably those that inhibit the renin-angiotensin system (RAS), are preferred agents for slowing progression of CKD. Thus, the Work Group recommended use of specific classes of antihypertensive agents in certain types of CKD, even if hypertension is not present. Preferred agents for specific types of CVD are discussed in Guideline 7. Preferred agents for CKD are discussed in Guidelines 8 , 9, 10. ACE inhibitors and angiotensin receptor blockers are discussed in Guideline 11, and diuretics are discussed in Guideline 12.These guidelines are intended for use by physicians, nurse practitioners, registered nurses, registered dietitians, masters prepared social workers, pharmacists, physician assistants, and other professionals who provide health care for patients with CKD. The information contained in these guidelines can and should be conveyed to patients and their families in an understandable manner by their physician and/or other health-care professionals. The development of educational support materials designed specifically for patients and their families should be part of the implementation of these guidelines.All guidelines should be updated whenever new, pertinent information becomes available. To anticipate when these guidelines may need to be updated, the Work Group reviewed ongoing controlled trials in the general population and in patients with CKD (Appendix 1), as those results may be pertinent to some recommendations. Given the potential for these and other studies to provide information pertinent to the assessment and treatment of hypertension in patients with CKD, it was concluded that these guidelines should be updated in about 3 to 4 years from the time of publication, and sooner if new, pertinent information becomes available before then. The K/DOQI Work Group and the Advisory Board will monitor the progress of these trials and other developments in this area and recommend updating these guidelines as indicated.METHODS FOR EVIDENCE REVIEW AND SYNTHESISK/DOQI Principles and ProcessThe development of these guidelines followed four basic principles set forth by K/DOQI (Table 9). The guidelines were developed using an evidence-based approach similar to that endorsed by the Agency for Health-Care Research and Quality.11 The Work Group reviewed all pertinent, published evidence in CKD, and critically appraised the quality of studies and the overall strength of evidence supporting each recommendation (Table 10). Additional details are given inAppendix 1 (Methods).A systematic review of pharmacological blood pressure trials with CVD outcomes in the general population was felt to be beyond the scope of the Work Group. Since JNC 7 was not yet available at the time these guidelines were being developed, it was decided to review JNC 6 and guidelines issued since then for recommendations on blood pressure targets and specific antihypertensive agents. These guidelines are reviewed in Guideline 7.This document contains 13 guidelines. The format for each guideline is outlined in Table 11. Each guideline contains one or more specific, numbered "recommendations" or "guideline statements." Each guideline contains background information, which is generally sufficient to interpret the guideline. The rationale for each guideline contains definitions, if appropriate, and a section on the strength of evidence. The strength of evidence includes a series of specific "rationale statements," each supported by evidence, and "summary tables" (if appropriate) compiling and evaluating original reports of studies. The guideline concludes with a discussion of limitations of the evidence review and a brief discussion of clinical applications, implementation issues and research recommendations regarding the topic.Review of EvidenceDetails of the search strategies and study selection are provided in Appendix A1. Table 12 lists the details of the literature search and review for each topic. Overall, 11,688 abstracts were screened by the Evidence Review Team, 899 articles were retrieved and reviewed, and data were extracted from 177 articles. Forty-seven articles were added by the Work Group. Finally, results from 76 articles were systematically listed in the summary tables in these guidelines.The Work Group evaluated the quality of each study, the strength of evidence derived from the compilation of the studies, and the strength of each guideline recommendation based on the strength of evidence and other factors. Summary tables succinctly describe the characteristics for each study according to five dimensions: study size, applicability (generalizability, based on the type of study subjects), baseline information, results based on the primary outcome (either progression of CKD or development of CVD), and methodological quality (Table 13). Only the primary outcome is represented, because studies were generally not powered to determine efficacy of interventions on secondary outcomes. Progression of kidney disease was defined by variables related to decline in GFR, such as doubling of serum creatinine or development of kidney failure (generally referred to as "end-stage renal disease" or ESRD), but often included mortality as part of a composite outcome. Development of CVD was defined by clinical events, cause-specific mortality, or total mortality. Surrogate outcomes for CKD and CVD included variables related to proteinuria or leftventricular hypertrophy, respectively. Within each of the summary tables, studies are ordered first by methodological quality (highest to lowest), then by applicability (most to least), and then by study size (largest to smallest).The number of patients (N, sample size) is used as a measure of the weight of the evidence. In general, large studies provide more precise estimates of effects or associations. In addition, results from large studies are more likely generalizable; however, large size alone does not guarantee a high degree of applicability. A study that enrolls a large number of selected patients may be less generalizable than several smaller studies that include a broad spectrum of patient populations.Applicability (also known as generalizability or external validity) addresses the issue of whether the study sample is sufficiently broad so that the results can be applied to the population of interest at large. The study sample is defined by the inclusion and exclusion criteria. A designation for applicability was assigned to each article, according to a three-level scale. In making this assessment, causes of CKD (diabetic kidney disease, nondiabetic kidney disease, and kidney disease in the kidney transplant) and sociodemographic characteristics were the primary determinants of applicability. Ifthe study is not considered broadly generalizable, reasons for the limited applicability are reported. Table 14 describes the approach to assessing applicability.In addition, baseline level of GFR (or serum creatinine), proteinuria, and blood pressure are reported to aid in the interpretation of applicability and results. For consistency, baseline data from the control group are reported.The type of results available in each study is determined by the study design, the purpose, and the question(s) being asked. Therefore, the format of the results varies across summary tables. For comparisons of blood pressure targets or antihypertensive agents as shown in Table 15, only the pre-specified primary outcomes are reported, as the sample size may not have been sufficient to evaluate secondary outcomes. For studies reporting adverse effects of ACE inhibitors or ARBs, the percentages of adverse effects are reported.Methodological quality (or internal validity) refers to the design, conduct, and reporting of the clinical study. Because studies with a variety of types of design were evaluated, a generic three-level classification of study quality was devised (Table 16).In addition to original articles, we included review articles and selected original articles for topics that were determined, a priori, not to require a systematic review of the literature. Work Group members had wide latitude in summarizing these articles. The use of published or derived tables and figures was encouraged to simplify the presentation.Extrapolation of Evidence From Studies in the General Population to Patients With CKDSome guideline statements in this document are based on evidence derived from studies on surrogate outcomes(proteinuria or left ventricular hypertrophy) in the target population, as well as evidence derived from studies on clinical outcomes (kidney disease progression or clinical CVD outcomes) in the general population and extrapolated to the target population. Some would argue that no guideline statements should be made in the absence of evidence on clinical outcomes in the target population. However, the limited number of studies on antihypertensive therapy for CVD in CKD, compared to the large number of studies in the general population, required development of criteria for extrapolating evidence from the general population to the target population. The Work Group adopted the criteria developed by the NKF Task Force on Cardiovascular Disease in Chronic Renal Disease for extrapolating evidence for CVD outcomes or mortality from the general population to the target population3,4 (Table 17).To extrapolate evidence from studies on treatment of hypertension with CVD outcomes, the following assumptions had to be met:1. The mechanisms and expression of CVD in CKD should be similar to those observed in the general population. Specifically, the features of CVD, the relationship of the risk factor (hypertension) to CVD outcomes, the mechanism of risk factor alterations (blood pressure lowering), and the responsiveness of risk factors to therapies (lifestyle modifications and pharmacological therapy) should be similar in the general populations and in patients with CKD.2. Therapies in patients with CKD should be as safe, or nearly so, as in the general population. In particular, there should not be additional adverse effects of a specific therapy that limits its usefulness in patients with CKD, either because of altered pharmacokinetics, drug interactions, or increased risk of toxicity to the kidney.3. The duration of therapy required to improve CVD outcomes in the general population should not exceed the life expectancy of patients with CKD. In other words, it should not already be too late to intervene in this generally elderly, sick, and frail population. Determining whether patients with CKD can survive for long enough to gain the benefit of therapy for CVD is a difficult question. Numerous studies show a dramatically shortened life expectancy for patients with CKD, especially patients with kidney failure. For example, the USRDS has estimated that the average life expectancy of 60- to 64-year-old patients treated by dialysis ranges from 3.6 to 5.1 years, depending on gender and race. On the other hand, the most common cause of death in kidney failure is CVD, and numerous studies of CVD in the general population have shown a benefit of interventions within 2 to 5 years, with greater and earlier benefits in patients。