KDOQI (Kidney Disease Outcomes Quality Initiative)

NKF KDOQI GUIDELINES

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KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification

PART 6.  ASSOCIATION OF LEVEL OF GFR WITH COMPLICATIONS IN ADULTS

GUIDELINE 7. ASSOCIATION OF LEVEL OF GFR WITH HYPERTENSION

High blood pressure is both a cause and a complication of chronic kidney disease. As a complication, high blood pressure may develop early during the course of chronic kidney disease and is associated with adverse outcomes—in particular, faster loss of kidney function and development of cardiovascular disease.

BACKGROUND

High blood pressure can be either a cause or a consequence of chronic kidney disease. Adverse outcomes of high blood pressure in chronic kidney disease include faster decline in kidney function and cardiovascular disease. The appropriate evaluation and management of high blood pressure remains a major component of the care of patients with chronic kidney disease.

High blood pressure is a well-recognized public health problem in the United States. Based on epidemiological data from the National High Blood Pressure Education Program and the National Health and Nutrition Examination Surveys, the rates of detection, treatment, and control of high blood pressure have improved dramatically over the past five decades. Concomitantly, the rates of stroke, myocardial infarction, and heart failure have decreased by approximately 15% to 40%.244 However, during the same time, high blood pressure as a cause of ESRD has increased at an annualized rate of 10% for the last several years, and cardiovascular disease is the leading cause of death in ESRD.4,245,246 In part this may be due to inadequate control of high blood pressure in patients with chronic kidney disease.

In 1998, the NKF published the Report of the Task Force on Cardiovascular Disease in Chronic Renal Disease.9 One of the major goals of the Task Force was to assess current knowledge about the association of high blood pressure and cardiovascular disease in chronic kidney disease. Portions of the Task Force Report are reproduced in this guideline with permission of the authors.247,248 More recently, the NKF published a Report on Management of Hypertension in Adults with Renal Diseases and Diabetes from the Executive Committees of the Councils on Hypertension and Diabetic Kidney Disease.249

In July of 2001, the NKF initiated a KDOQI Work Group specifically to conduct a detailed review of evidence and to develop clinical practice guidelines for the management of blood pressure in chronic kidney disease to prevent progression of kidney disease and development and progression of cardiovascular disease in chronic kidney disease. The goal of this guideline is to provide a selected review of the literature relating high blood pressure to adverse outcomes of chronic kidney disease and to describe the association of the level of GFR with high blood pressure, as reported in NHANES III. Guideline 13 describes the relationship of high blood pressure to progression of kidney disease.

RATIONALE

Definition

Consensus panels in the United States and other countries have defined hypertension in adults as systolic blood pressure greater than 140 mm Hg and/or diastolic blood pressure greater than 90 mm Hg. The Sixth Report of the Joint National Committee for the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-VI) classifies categories of blood pressure levels as shown in Table 71.

JNC-VI recommends a goal blood pressure of <140/90 mm Hg for individuals with high blood pressure without diabetes, cardiovascular disease, or chronic kidney disease. For individuals with high blood pressure and decreased kidney function, the recommended goal is <130/85 mm Hg.

Strength of Evidence

High blood pressure develops during the course of chronic kidney disease (R). High blood pressure is a well-described complication of chronic kidney disease. The prevalence of high blood pressure is approximately 80% in hemodialysis patients and 50% in peritoneal dialysis patients.250,251 In patients with earlier stages of kidney disease, high blood pressure is also highly prevalent, varying with patient characteristics such as the cause of kidney disease and level of kidney function.252 There are many causes of high blood pressure in chronic kidney disease. The clinically more important pathogenetic mechanisms of high blood pressure are listed in Table 72.248

High blood pressure is associated with worse outcomes in chronic kidney disease (R). In the general population, there is a strong, graded relationship between the level of blood pressure and all-cause mortality and fatal and nonfatal cardiovascular disease. Optimal levels of systolic and diastolic blood pressure are defined as less than 120 and 80 mm Hg, respectively. Among patients with chronic kidney disease, there is also substantial evidence of a relationship between elevated levels of blood pressure and cardiovascular risk. In addition, high blood pressure is associated with a greater rate of decline in kidney function and risk of development of kidney failure. However, the optimal level of blood pressure to minimize adverse outcomes for cardiovascular and kidney disease has not been established.

Progression of kidney disease. This subject is reviewed in more detail in Guideline 13. The following represent a few of the many studies that demonstrate these relationships.

Diabetic kidney disease. Numerous epidemiological studies and clinical trials have shown a relationship between the level of blood pressure and faster progression of diabetic kidney disease. Figure 17 shows the relationship in one of the earliest randomized trials.253

Figure 17

Relationship between blood pressure and progression of diabetic kidney disease. Mean arterial blood pressure, albumin excretion rate, and GFR in patients with type 1 diabetes randomly assigned to a reduction in mean arterial pressure of 10 mm Hg using metoprolol at 100 to 400 mg/d, hydralazine at 50 to 200 mg/d, and furosemide at 80 to 500 mg/d versus no antihypertensive therapy. Solid circles represent the treated group. Open circles represent the control group. Vertical lines represent standard error. Study was stopped earlier in the control group because of faster decline in GFR. Reprinted with permission.253

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Nondiabetic kidney diseases. The Modification of Diet in Renal Disease Study showed a significant relationship between the rate of decline in GFR and level of blood pressure among patients with predominantly nondiabetic kidney disease. This relationship was affected by the baseline level of urine protein (Fig 18).255

Figure 18

Relationship between mean arterial blood pressure and GFR decline. Mean GFR decline and achieved follow-up blood pressure in MDRD Study A (patients with baseline GFR 25 to 55 mL/min/1.73 m2). Regression lines relating the estimated mean GFR decline over 3 years to mean follow-up MAP for groups of patients defined according to baseline proteinuria. Within each group, a 3-slope model was used with break points at 92 and 98 mm Hg. Reprinted with permission.255

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Diseases in the kidney transplant. A relationship between level of blood pressure and progression of kidney disease has now been shown among kidney transplant recipients. The Collaborative Transplant Group documented that higher blood pressure after kidney transplantation is associated with more rapid development of graft failure256 (Fig 19).

Figure 19

Relationship between systolic blood pressure and graft survival. Association of systolic blood pressure at 1 year with subsequent graft survival in recipients of cadaveric kidney transplants. Ranges of systolic blood pressure value in mm Hg and number of patients studied in the subgroups are indicated. The association of systolic blood pressure with graft survival at seven years was statistically significant (P < 0.0001). Reproduced with permission.256

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Cardiovascular disease and mortality. The prevalence of cardiovascular disease and related outcomes in patients with decreased GFR has not been evaluated in large-scale epidemiological studies, and little is known about CVD mortality and morbidity in these patients. Several studies have shown a high prevalence of left ventricular hypertrophy (LVH) in patients with decreased GFR and patients beginning dialysis. In one study, a higher level of systolic blood pressure, lower level of kidney function, more severe anemia, and older age were independently associated with higher left ventricular mass index.257 A few studies have shown a relationship between higher systolic blood pressure and clinical cardiovascular disease events.258,259 Among dialysis patients, higher blood pressure is clearly associated with development of cardiovascular disease. Table 73 shows the relationship between mean arterial pressure and various cardiovascular disease outcomes in a prospective cohort of incident dialysis patients.260 Left ventricular hypertrophy and congestive heart failure were both strongly associated with subsequent mortality. However, lower rather than higher blood pressure was associated with a higher risk of death.

The association between level of blood pressure and mortality does not appear to be consistent, with a number of studies reporting either positive or negative associations.248 One recent study showed a bimodal distribution ("U-shaped" relationship) with excess risk in hemodialysis patients with normal or low blood pressure, as well as in patients with very high blood pressure262 (Fig 20).

Figure 20

Mortality versus systolic blood pressure in hemodialysis patients. Dialysis Clinic, Inc. prevalent cohort (1992 to 1996, n = 5433).262 Cox regression analysis including age, race, gender, and diagnosis as baseline covariates, and predialysis or postdialysis systolic blood pressure, albumin, and Kt/V as time-dependent covariates. Reprinted with permission.248

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It is likely that excess risk in patients with low blood pressure reflects confounding effects of underlying or pre-existing cardiovascular disease on mortality, while the true relationship of blood pressure to mortality is reflected in the excess risk in patients with very high blood pressure as in the general population.

Overall, these studies demonstrate that high blood pressure is associated with faster progression of chronic kidney disease, development of cardiovascular disease, and, likely, higher mortality in patients with chronic kidney disease.

Prevalence of high blood pressure is related to the level of GFR. Patients with chronic kidney disease have a high prevalence of high blood pressure, even when GFR is only mildly reduced (S).

Figure 21

Prevalence of high blood pressure by level of GFR in the MDRD Study. High blood pressure was defined as classification by study investigators based on patient history (including the use of antihypertensive drugs) and review of medical records. GFR was measured by urinary clearance of 125I-iothalamate. Patients were ranked by GFR into 10 groups, each containing 179 or 180 patients. Data are presented as mean values standard errors.

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Figure 21 shows the relationship between GFR and prevalence of hypertension among 1,795 patients in the baseline cohort of the MDRD Study.263 At GFR levels of 60 to 90 mL/min/1.73 m2, the prevalence of high blood pressure was approximately 65% to 75%. In this study, high blood pressure was defined by patient history (including the use of antihypertensive medications) and medical records, rather than the level of blood pressure. In addition to GFR level, the prevalence of high blood pressure was significantly greater among men and individuals with higher body mass index, black race, and older age.

Figure 22

Prevalence of high blood pressure by level of GFR, adjusted to age 60 years (NHANES III). Predicted prevalence of high blood pressure among adult participants age 20 years and older in NHANES III, 1988 to 1994. Values are adjusted to age 60 years using a polynomial regression. 95% confidence intervals are shown at selected levels of estimated GFR.

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Figure 22 shows the prevalence of high blood pressure by level of GFR among 15,600 patients participating in the NHANES III. Two levels of high blood pressure are depicted: JNC Stage 1 or greater (systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg, or taking medications for high blood pressure); and JNC Stage 2 or greater (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg).

In NHANES III, the approximately 40% prevalence of high blood pressure among individuals with GFR of approximately 90 mL/min/1.73 m2 was lower than in the MDRD Study, presumably because not all patients with GFR in this range in NHANES III had chronic kidney disease. Among patients with lower GFR, the prevalence of high blood pressure is similar to that observed in the MDRD Study. Notably, the prevalence of JNC Stage 2 high blood pressure is approximately 20% among individuals with GFR 15 to 30 mL/min/1.73 m2, which is approximately 2-fold greater than among patients with higher GFR.

High blood pressure is not optimally controlled in patients with chronic kidney disease (S). A recent analysis of the NHANES III database assesses the level of blood pressure control among individuals with decreased kidney function.5 Decreased kidney function was defined as elevated serum creatinine ( 1.6 mg/dL in men or 1.4 mg/dL in women).

An estimated 3% (5.6 million) of the US population had elevated serum creatinine according to this definition, and of these 70% had high blood pressure. Among individuals with decreased kidney function and high blood pressure, 75% received treatment. However, only 11% of individuals with high blood pressure and elevated serum creatinine had blood pressure <130/85 mm Hg, and 27% had blood pressure <140/90. Treated individuals had a mean blood pressure of 147/77 mm Hg, with 48% prescribed only one antihypertensive medication. Thus, it appears that additional efforts will be necessary to lower systolic blood pressure. Multi-drug therapy may be necessary in the majority of patients.

Figure 23

Prevalence of elevated serum creatinine by JNC-VI blood pressure category and self-reported treatment with anti-hypertensive medications (NHANES III). Bars indicate standard errors. Reprinted with permission.5

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Figure 24

Estimated number of individuals with elevated serum creatinine by JNC-VI blood pressure category and self-reported treatment with anti-hypertensive medications (NHANES III). Bars indicate standard errors. Reprinted with permission.5

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Figures 23 and 24 show the prevalence and number of individuals with elevated serum creatinine among patients receiving and not receiving antihypertensive therapy, according to blood pressure category. The largest number of treated and untreated individuals have JNC Stage 1 high blood pressure (140 to 159/90 to 99 mm Hg).

Treatment of high blood pressure in chronic kidney disease should include specification of target blood pressure levels, nonpharmacologic therapy, and specific antihypertensive agents for the prevention of progression of kidney disease (Guideline 13) and development of cardiovascular disease in patients with chronic kidney disease (Guideline 15) (R). Specific recommendations for evaluation and management of high blood pressure in chronic kidney disease are beyond the scope of this guideline. The investigation of antihypertensive agents to prevent or delay the progression of chronic kidney disease and development of cardiovascular disease is a rapidly evolving. A number of guidelines and recommendations have been developed. In addition, the role of non-pharmacologic therapy for the treatment of high blood pressure, and as adjuncts in the prevention and treatment of cardiovascular disease, are also under investigation. Recommendations by other groups and recent studies are reviewed in Guidelines 13 and 15.

LIMITATIONS

Unlike other guidelines in Part 6, this guideline is not based on a systematic review of the literature. Another limitation is the lack of large-scale cohort studies and clinical trials correlating blood pressure levels to subsequent loss of GFR and cardiovascular disease events. Since both chronic kidney disease and cardiovascular disease are chronic illnesses, observational studies are subject to confounding by "survival bias," whereby patients with more severe risk factors may not have survived to be entered into the study, thereby minimizing the apparent association between risk factors and outcomes. Thus, clinical trials may be required to determine the optimal level of blood pressure to prevent or slow progression of chronic kidney and development of cardiovascular disease.

A major limitation of cross-sectional studies has been the absence of a clear definition of chronic kidney disease. Since many patients with chronic kidney disease are not detected until late in the course, studies that rely on clinical diagnosis are subject to misclassification. The strong relationship between prevalence of high blood pressure and GFR level observed in NHANES III, irrespective of diagnosis of chronic kidney disease, is especially important in confirming the link between decreased GFR and high blood pressure. However, cross-sectional studies do not permit determination of the causal relationship between these variables. Thus, they cannot determine whether high blood pressure is a cause or a complication of chronic kidney disease, or whether both high blood pressure and decreased GFR are caused by a third factor, such as aging. Nonetheless, the data from both the MDRD Study and NHANES III show a high prevalence of high blood pressure among persons with decreased GFR, justifying the emphasis on monitoring and treatment of high blood pressure in patients with chronic kidney disease.

CLINICAL APPLICATIONS

Detection, evaluation and management of high blood pressure should be the goal for all health care providers for patients with chronic kidney disease. Providers must be aware of lower recommended target levels for blood pressure for patients with chronic kidney disease, specific recommendations for classes of antihypertensive agents, and the role of nonpharmacologic therapy.

IMPLEMENTATION ISSUES

Measuring blood pressure at routine health encounters is widely recommended and practiced. The large number of individuals with blood pressure above the target goal suggests a number of possible obstacles to implementation, such as:

The high prevalence of earlier stages of chronic kidney disease requires a coordinated national effort by governmental agencies and nongovernmental organizations to address these issues.

RESEARCH RECOMMENDATIONS

A broad set of recommendations for research on high blood pressure in chronic kidney disease was developed by the NKF Task Force on Cardiovascular Disease in Chronic Renal Disease.248 Recommendations for observational studies are reproduced in Table 74 and for clinical trials in Table 75.



2002 National Kidney Foundation, Inc