Chronic kidney disease is a major public health problem throughout the world. In the United States, kidney failure is becoming increasingly common and is associated with poor health outcomes and high medical expenditures. In this country, the number of patients treated with dialysis or transplantation is projected to increase from 340,000 in 1999 to 651,000 in 2010.¹

The major outcomes of chronic kidney disease, regardless of the specific diagnosis (i.e., type of kidney disease), include progression to kidney failure, complications from decreased kidney function, and development of cardiovascular disease. Increasing evidence shows that early detection and treatment often can prevent or delay some of these adverse outcomes.² However, opportunities for prevention may be lost because chronic kidney disease is not diagnosed or is treated insufficiently.^3–6 One reason is lack of agreement about the definition of chronic kidney disease, as well as the classification of its stages. Another reason is lack of uniform application of simple tests for the detection and evaluation of the disease.

In February 2002, the Kidney Disease Outcome Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF)^7,8 published clinical practice guidelines on chronic kidney disease. The goals of the Work Group that developed the guidelines were as follows: to define chronic kidney disease and classify its stages, regardless of the underlying cause; to evaluate laboratory measurements for clinical assessment of kidney disease; to associate the level of kidney function with the complications of chronic kidney disease; and to stratify risk for the loss of kidney function and the development of cardiovascular disease.

The leaders of the NKF recognized the role of family physicians in providing medical care for patients with chronic kidney disease (particularly during the early stages when interventions might slow disease progression) and therefore wanted the guidelines to be practical and accessible to primary care physicians. To these ends, a family physician was invited to be an active participant in the guidelines Work Group and a member of the K/DOQI Advisory Board, which oversees all guidelines developed under its auspices. At present, there are only about 5,000 nephrologists in the United States. With the projected increase in the number of patients diagnosed with chronic kidney disease (especially as defined by the NKF guidelines^7,8), a strong partnership with family physicians and general internists will be necessary.

The first purpose of this article is to disseminate the simple definition and the five-stage classification system of chronic kidney disease that were developed through an evidence-based process and justified with existing literature. The second purpose is to describe the six guidelines with the most immediate relevance to family physicians. Guidelines on evaluation, treatment, and risk factors are reviewed in part I of this two-part article. Part II⁹ reviews guidelines on estimation of glomerular filtration rate, assessment of proteinuria, and use of markers of chronic kidney disease other than proteinuria.

Background

The NKF Work Group defined two principal outcomes of chronic kidney disease: progressive loss of kidney function and development of complications, particularly cardiovascular disease.

Progressive loss of kidney function over time in most patients with chronic kidney disease is a well-known outcome. Because of the older age at onset for many forms of kidney disease and the slow rate of decline in kidney function, decreased kidney function is far more common than kidney failure, for which replacement therapy (dialysis or transplantation) becomes necessary.

Decreased kidney function is associated with complications in virtually all organ systems. Therapeutic interventions in the earlier stages may prevent or ameliorate some of these complications, as well as slow progression to kidney failure. Cardiovascular disease is considered an outcome of chronic kidney disease for several reasons. First, cardiovascular events are more common than kidney failure in patients with chronic kidney disease. In addition, chronic kidney disease appears to be a risk factor for cardiovascular disease.

Cardiovascular disease in patients with chronic kidney disease is treatable, as well as potentially preventable. A 1998 report from the NKF Task Force on Cardiovascular Disease¹⁰ recommended that patients with chronic kidney disease be considered in the “highest risk” group for subsequent cardiovascular events, and that most interventions that are effective in the general population should be applied to patients with chronic kidney disease.^11,12

The NKF guidelines^7,8 are based on a systematic literature review using an approach adapted from the one used by the Agency for Healthcare Research and Quality. A uniform format for summarizing strength of evidence was developed based on an evaluation of study size, applicability, results, and methodologic quality. Guideline statements were prepared from the analysis of this review. Each rationale statement was graded according to the supporting level of evidence (Table 1).⁷ Note that the evidence grading system differs from the system used in American Family Physician: only AFP’s evidence level C (consensus/expert opinion) compares with the NKF grade O (opinion).

In preparing the guidelines, 18,153 abstracts were screened, 1,045 articles were reviewed, and results were extracted from 367 articles. Many rationale statements are based on a structured review of evidence specifically for the guidelines (NKF grade S or C)⁷; however, most guidelines are based in part on unstructured review or opinion.

Guideline 1: Definition and Stages of Chronic Kidney Disease

Early detection and treatment often can prevent or delay adverse outcomes in patients with chronic kidney disease. Routine laboratory tests can detect the disease in its earlier stages (NKF grades R and O).⁷

A definition of chronic kidney disease is provided in Table 2.⁷ The presence of the disease should be established based on the occurrence of kidney damage and the level of kidney function (i.e., glomerular filtration rate [GFR]), regardless of the specific diagnosis. Disease stage should be assigned based on the level of kidney function, also regardless of the specific diagnosis.⁷

Kidney damage usually is ascertained by the presence or absence of certain markers, rather than by kidney biopsy. The NKF guidelines^7,8 emphasize persistent proteinuria as a marker of kidney damage, because proteinuria has been studied most thoroughly¹³ and is identified readily using a simple office procedure. A ratio of greater than 30 mg of albumin to 1 g of creatinine in an untimed (spot) urine sample usually is considered abnormal. Other markers of kidney damage include abnormalities in urine sediment, blood, and urine chemistries, and abnormal findings on imaging studies. Patients who have normal kidney function but have markers of kidney damage are at increased risk for adverse outcomes of chronic kidney disease.

The GFR is considered the best measure of overall kidney function.¹⁴ Normal GFR varies according to patient age, sex, and body size. In young adults, the normal GFR is approximately 120 to 130 mL per minute per 1.73 m² and declines with age.^14–17 A GFR level below 60 mL per minute per 1.73 m² represents loss of one half or more of the adult level of normal kidney function. Traditionally, an age-related decline in GFR has been considered “normal.” However, a decreased GFR in an elderly patient requires adjustment of drug dosages¹⁸ and appears to be an independent predictor of adverse outcomes such as mortality and cardiovascular disease.^19–21

The definition of chronic kidney disease is not modified based on patient age. The situation is analogous to the situation with blood pressure levels and the definition and prevalence of hypertension. Blood pressure rises with age, but hypertension in elderly persons is associated with adverse outcomes; however, the definition of hypertension is not age dependent, and the majority of elderly persons are classified as having hypertension.²² Similarly, because of the age-related decline in GFR, the prevalence of chronic kidney disease increases with age; approximately 17 percent of persons older than 60 years have an estimated GFR of less than 60 mL per minute per 1.73 m^2.6

Kidney failure is defined as a GFR below 15 mL per minute per 1.73 m², usually accompanied by signs and symptoms of uremia, or as the need for initiation of kidney replacement therapy for management of the complications of a decreased GFR. In the United States, approximately 98 percent of patients begin dialysis when their GFR falls below 15 mL per minute per 1.73 m^2.23

Kidney failure is not synonymous with end-stage renal disease (ESRD). In the United States, “end-stage renal disease” is an administrative term based on the conditions for health care payment by the Medicare ESRD Program for patients treated with dialysis or transplantation. However, the term does not include patients with kidney failure who are not treated with dialysis or transplantation. Thus, although the term “end-stage renal disease” is in widespread use and provides a simple operational classification of patients according to treatment, it does not precisely define a stage of severity in kidney disease.

As demonstrated in Table 3,^6,7,24–26 more than 20 million adults in the United States have chronic kidney disease, and millions more are at risk of developing the disease. Patients who have diabetes mellitus and hypertension are at highest risk. As the number of patients with diabetes and hypertension continues to increase, the number of patients with chronic kidney disease also will increase. Consequently, clear definition and classification of the stages of disease severity are needed to assess patients for the development and progression of chronic kidney disease.

The NKF classification of the stages of chronic kidney disease supports communication between physicians. The classification system helps clear up the ambiguities caused by vague terms such as “chronic renal insufficiency” and “chronic renal failure.” Using the NKF system, family physicians can ask nephrologist consultants more precise questions and can expect more precise answers. For example, at what stage does the nephrologist want to see a potential kidney transplant recipient? What interventions should be used at each stage to give a patient the best chance of preserving kidney function?

Staging of chronic kidney disease also allows physicians to talk more clearly with patients. For example, use of the word “kidney” rather than “renal” facilitates communication. In addition, patients are becoming accustomed to dealing with numbers (cholesterol levels, blood pressure measurements, blood sugar levels). Knowing their GFR and the type of personal interventions that may slow the decline in GFR allows patients to take greater control of their disease.

Guideline 2: Evaluation and Treatment of Chronic Kidney Disease

Patients with chronic kidney disease should be evaluated to determine the following: specific diagnosis (type of kidney disease), comorbid conditions, disease severity (assessed by the level of kidney function), complications (related to the level of kidney function), risk for loss of kidney function, and risk for development of cardiovascular disease (NKF grades R and O).⁷

Treatment of patients with chronic kidney disease includes the following: therapy based on the specific diagnosis, evaluation, and management of comorbid conditions; measures to slow loss of kidney function; measures to prevent and treat cardiovascular disease; measures to prevent and treat complications of decreased kidney function; preparation for kidney failure and kidney replacement therapy; and replacement of kidney function by dialysis or transplantation if signs and symptoms of uremia are present.

Medications should be reviewed at all visits. Dosage adjustments should be based on the level of kidney function. It is important to detect drug interactions, as well as potentially adverse effects of medications on kidney function or complications of chronic kidney disease. If possible, therapeutic drug monitoring should be performed.

A clinical action plan should be developed for each patient, with the plan based on the disease stage (Table 3).^6,7,24–26 Self-management behaviors should be incorporated into the treatment plan at all stages of the disease.

Patients with chronic kidney disease should be referred to a nephrologist for consultation and co-management if a clinical action plan cannot be prepared, the appropriate evaluation cannot be performed, or the recommended treatment cannot be implemented. In most cases, patients with a GFR below 30 mL per minute per 1.73 m² should be referred to a nephrologist (NKF grade O).⁷

Diagnosis of chronic kidney disease traditionally is based on pathology and etiology. A simplified classification emphasizes diseases in the native kidneys (broadly divided into those that are diabetic or nondiabetic in origin) and kidney disease in the transplant patient. In the United States, diabetic kidney disease is the most common cause of kidney failure; its earliest manifestation is microalbuminuria with a normal or elevated GFR. Of note, the NKF guidelines⁷ classify patients who have diabetes and microalbuminuria with a normal GFR as having stage 1 chronic kidney disease. Nondiabetic kidney disease includes glomerular, vascular, tubulointerstitial, and cystic kidney diseases.

Specific treatment depends on the diagnosis, and a thorough search for “reversible causes” of kidney disease should be conducted. The remainder of the action plan is based on the stage of chronic kidney disease, irrespective of the diagnosis (Table 3).^6,7,24–26

Guideline 3: Risk Factors for Chronic Kidney Disease

The risk of developing chronic kidney disease is increased in some patients without kidney damage and with a normal or elevated GFR (NKF grade R).⁷ During the routine health care visit, all patients should be assessed for increased risk based on clinical and sociodemographic factors (Table 4).⁷

Patients determined to be at increased risk for kidney disease should undergo testing for markers of kidney damage and an estimation of their GFR. Patients found to have chronic kidney disease should be evaluated and treated as specified in NKF guideline 2. Patients at increased risk who are found not to have chronic kidney disease should be advised to follow a program of risk factor reduction (if appropriate) and should be reevaluated periodically.

During the routine health care visit, patients should be asked specifically about clinical and sociodemographic factors that have been implicated as susceptibility or initiation factors for chronic kidney disease. If any of these factors are present, patients should be assessed for albuminuria, and GFR should be estimated. The prevalence of persons at increased risk for chronic kidney disease has not been determined. However, the number of these persons is likely to far exceed the number of patients with the disease. Particular emphasis should be given to patients with diabetes mellitus, hypertension, family history of chronic kidney disease, age older than 60 years, and U.S. racial or ethnic minority status.

Guideline 3 is problematic for family physicians who have the task of identifying patients at risk for kidney disease. In preparing the NKF guideline, the Work Group evaluated evidence for the definition, classification, and prevalence of risk factors (NKF grade R).⁷ However, the issue of universal testing for kidney disease or testing of patients at increased risk for kidney disease has not been studied systematically. In the United States, testing currently is not recommended, except in patients with hypertension, diabetes, or known kidney disease.²⁷

Based on personal opinion and experience, the Work Group members recommend testing of patients who are at increased risk for kidney disease. In fact, a focus of the public awareness campaign stemming from the NKF guidelines is to encourage patients who think they may be at increased risk to tell their physician, and for the physician to test at-risk patients for albuminuria and GFR. Nonetheless, more research is needed to clearly identify the risks and benefits (both clinical and economic) of testing large segments of the U.S. population.