K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease

INTRODUCTION: CHRONIC 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. 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. There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by preventive measures, early detection, and treatment. 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. 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 under development 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) and the 2003 report of the American Diabetes Association (ADA) on the Treatment of Hypertension in Adults with Diabetes. 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. BACKGROUND: Chronic Kidney Disease: Figure 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. 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). 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. 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 CKD: JNC 7 defines hypertension as systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg, respectively (Table 3). Although 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% to 75% of individuals with GFR <60 mL/min/1.73 m² (CKD Stages 3-5) have hypertension (Fig 3). Among individuals with GFR ≥60 mL/min/1.73 m ², 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. Cardiovascular Disease in CKD: CKD is a risk factor for cardiovascular disease (CVD). 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) and decreased GFR (Fig 6) 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 antihyper tensive therapy with therapy for other CVD risk factors. Recommendations 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 CKD: Most 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. 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. As 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 GUIDELINES: The 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. 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. Two 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, 8-11).