Annamaria T. Kausz

National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification

Chronic kidney disease is a worldwide public health problem. In the United States, the incidence and prevalence of kidney failure are rising, the outcomes are poor, and the costs are high. The number of persons with kidney failure who are treated with dialysis and 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 cause, include progression to kidney failure, complications of decreased kidney function, and cardiovascular disease (CVD). Increasing evidence indicates that some of these adverse outcomes can be prevented or delayed by early detection and treatment (2). Unfortunately, chronic kidney disease is underdiagnosed and undertreated, resulting in lost opportunities for prevention (3-5), in part because of a lack of agreement on a definition and classification of stages in the progression of chronic kidney disease (6) and a lack of uniform application of simple tests for detection and evaluation. In February 2002, the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) published 15 clinical practice guidelines on chronic kidney disease [7]. The goals of the guidelines are to 1) define chronic kidney disease and classify its stages, regardless of underlying cause; 2) evaluate laboratory measurements for the clinical assessment of kidney disease; 3) associate the level of kidney function with complications of chronic kidney disease; and 4) stratify the risk for loss of kidney function and development of CVD. Our goal is to disseminate the simple definition and five-stage classification system of chronic kidney disease, to summarize the major recommendations on early detection of chronic kidney disease in adults (Table 1), and to consider some of the issues associated with these recommendations. Because of the high prevalence of early stages of chronic kidney disease in the general population, this information is particularly important for general internists and specialists. Table 1. Guidelines, Recommendations, Ratings, and Key References Methods The guidelines of the K/DOQI are based on a systematic review of the literature. The approach used for the review was outlined by the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research) (46), with modifications appropriate to the available evidence and the goals of the K/DOQI Work Group. The Work Group considered diverse topics, which would have been too large for a comprehensive review of the literature. Instead, a selective review of published evidence was used to focus on specific questions: a summary of reviews for established concepts and a review of original articles and data for new concepts. The strength of recommendations is graded according to a new classification (Table 2) recently adopted by the K/DOQI Advisory Board (see Appendix 1). Table 2. National Kidney Foundation Kidney Disease Outcomes Quality Initiative Rating of the Strength of Recommendations Framework The Work Group defined two principal outcomes of chronic kidney disease: the progressive loss of kidney function over time (Figure 1) and the development and progression of CVD. Figure 1, which defines stages of chronic kidney disease, as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes, is a model of the course of chronic kidney disease. This diagram provides a framework that has previously been lacking for the development of a public health approach to chronic kidney disease. Figure 1. Evidence model for stages in the initiation and progression of chronic kidney disease ( CKD ) and therapeutic interventions. black dark gray light gray white GFR Table 3. Risk Factors for Chronic Kidney Disease and Its Outcomes Risk factors for chronic kidney disease are defined as attributes associated with increased risk for adverse outcomes of chronic kidney disease (Table 3). The guidelines focus primarily on identifying susceptibility factors and initiation factors (to define persons at increased risk for developing chronic kidney disease) and progression factors (to define persons at high risk for worsening kidney damage and subsequent loss of kidney function). Because kidney disease usually begins late in life and progresses slowly, most persons in the stage of decreased glomerular filtration rate (GFR) die of CVD before they develop kidney failure. However, decreased GFR is associated with a wide range of complications, such as hypertension, anemia, malnutrition, bone disease, neuropathy, and decreased quality of life, which can be prevented or ameliorated by treatment at earlier stages. Treatment can also slow the progression to kidney failure. Thus, measures to prevent, detect, and treat chronic kidney disease in its earlier stages could reduce the adverse outcomes of chronic kidney disease. Cardiovascular disease deserves special consideration as a complication of chronic kidney disease because 1) CVD events are more common than kidney failure in patients with chronic kidney disease, 2) chronic kidney disease seems to be a risk factor for CVD, and 3) CVD in patients with chronic kidney disease is treatable and potentially preventable (48-50). The 1998 Report of the NKF Task Force on Cardiovascular Disease in Chronic Renal Disease recommended that patients with chronic kidney disease be considered in the highest risk group for subsequent CVD events and that most interventions that are effective in the general population should also be applied to patients with chronic kidney disease (49). Definition and Classification of Stages of Chronic Kidney Disease Guideline 1. Definition and Stages of Chronic Kidney Disease Adverse outcomes can often be prevented or delayed through early detection and treatment of chronic kidney disease. Earlier stages of chronic kidney disease can be detected through routine laboratory measurements. Chronic kidney disease is defined as either kidney damage or decreased kidney function (decreased GFR) for 3 or more months (level A recommendation). Kidney disease can be diagnosed without knowledge of its cause. Kidney damage is usually ascertained by markers rather than by kidney biopsy. According to the Work Group, persistent proteinuria is the principal marker of kidney damage (8, 9). An albumincreatinine ratio greater than 30 mg/g in untimed (spot) urine samples is usually considered abnormal; proposed sex-specific cut points are greater than 17 mg/g in men and greater than 25 mg/g in women (10, 11). Other markers of damage include abnormalities in urine sediment, abnormalities in blood and urine chemistry measurements, and abnormal findings on imaging studies. Persons with normal GFR but with markers of kidney damage are at increased risk for adverse outcomes of chronic kidney disease. Glomerular filtration rate is the best measure of overall kidney function in health and disease (12). The normal level of GFR varies according to age, sex, and body size. Normal GFR in young adults is approximately 120 to 130 mL/min per 1.73 m2 and declines with age (12-15). A GFR level less than 60 mL/min per 1.73 m2 represents loss of half or more of the adult level of normal kidney function. Below this level, the prevalence of complications of chronic kidney disease increases. Although the age-related decline in GFR has been considered part of normal aging, decreased GFR in the elderly is an independent predictor of adverse outcomes, such as death and CVD (51-53). In addition, decreased GFR in the elderly requires adjustment in drug dosages, as in other patients with chronic kidney disease (54). Therefore, the definition of chronic kidney disease is the same, regardless of age. Because GFR declines with age, the prevalence of chronic kidney disease increases with age; approximately 17% of persons older than 60 years of age have an estimated GFR less than 60 mL/min per 1.73 m2 (16). The guidelines define kidney failure as either 1) GFR less than 15 mL/min per 1.73 m2, which is accompanied in most cases by signs and symptoms of uremia, or 2) a need to start kidney replacement therapy (dialysis or transplantation). Approximately 98% of patients with kidney failure in the United States begin dialysis when their GFR is less than 15 mL/min per 1.73 m2 (17). Kidney failure is not synonymous with end-stage renal disease (ESRD). End-stage renal disease is an administrative term in the United States. It indicates that a patient is treated with dialysis or transplantation, which is the condition for payment for health care by the Medicare ESRD Program. The classification of ESRD does not include patients with kidney failure who are not treated with dialysis and transplantation. Thus, although the term ESRD provides a simple operational classification of patients according to treatment, it does not precisely define a specific level of kidney function. The level of kidney function, regardless of diagnosis, determines the stage of chronic kidney disease according to the K/DOQI chronic kidney disease classification (level A recommendation). Data from the Third National Health and Nutrition Examination Survey (NHANES III) show the increasing prevalence of complications of chronic kidney disease at lower levels of GFR (7). These data and other studies provide a strong basis for using GFR to classify the stage of severity of chronic kidney disease. Table 4 shows the classification of stages of chronic kidney disease and the prevalence of each stage, estimated by using data from NHANES III (16). Approximately 11% of the U.S. adult population (20 million persons from 1988 to 1994) have chronic kidney disease. The prevalence of early stages of disease (stages 1 to 4; 10.8%) is more than 100 times greater than the prevalence of kidney failure (stage 5; 0.1%). The burden of illness associated with earlier stages of chronic kidney disease has not been systematically studied (55,

Ferumoxytol for Treating Iron Deficiency Anemia in CKD

Iron deficiency is an important cause of anemia in patients with chronic kidney disease (CKD), but intravenous iron is infrequently used among patients who are not on dialysis. Ferumoxytol is a novel intravenous iron product that can be administered as a rapid injection. This Phase III trial randomly assigned 304 patients with CKD in a 3:1 ratio to two 510-mg doses of intravenous ferumoxytol within 5 +/- 3 d or 200 mg of elemental oral iron daily for 21 d. The increase in hemoglobin at day 35, the primary efficacy end point, was 0.82 +/- 1.24 g/dl with ferumoxytol and 0.16 +/- 1.02 g/dl with oral iron (P < 0.0001). Among patients who were not receiving erythropoiesis-stimulating agents, hemoglobin increased 0.62 +/- 1.02 g/dl with ferumoxytol and 0.13 +/- 0.93 g/dl with oral iron. Among patients who were receiving erythropoiesis-stimulating agents, hemoglobin increased 1.16 +/- 1.49 g/dl with ferumoxytol and 0.19 +/- 1.14 g/dl with oral iron. Treatment-related adverse events occurred in 10.6% of patients who were treated with ferumoxytol and 24.0% of those who were treated with oral iron; none was serious. In summary, a regimen of two doses of 510 mg of intravenous ferumoxytol administered rapidly within 5 +/- 3 d was well tolerated and had the intended therapeutic effect. This regimen may offer a new, efficient option to treat iron deficiency anemia in patients with CKD.

Anemia: A Continuing Problem Following Kidney Transplantation

Cardiovascular disease is a leading cause of death among kidney transplant recipients. Anemia, a risk factor for cardiovascular complications among patients with chronic kidney disease, has not been well characterized in kidney transplant recipients. We performed a retrospective cohort study of the prevalence of and factors associated with anemia among 240 patients who underwent kidney transplantation at our institution. The mean hematocrit (Hct) rose from 33% at 1 month after transplantation to 40% at 12 months after transplantation. The proportion of patients with Hct < 36% was 76% at transplantation and 21% and 36%, 1 year and 4 years after transplantation, respectively. Six months after transplantation, women had higher likelihood (OR = 3.61) of Hct < 36%, while higher Hct at 3 months (OR = 0.67 for 1% higher Hct) and diabetes (OR = 0.14) were associated with a lower likelihood of Hct < 36%. Similar associations were seen 12 months after transplantation. Even among patients with Hct < 30%, only 36% had iron studies, 46% received iron supplementation and 40% received recombinant human erythropoietin. Awareness of factors associated with a lower Hct may prompt better anemia screening and management, potentially improving cardiovascular outcomes among kidney transplant recipients.

Safety of Ferumoxytol in Patients With Anemia and CKD

BACKGROUND Iron deficiency anemia is a common complication in patients with chronic kidney disease (CKD). Currently available intravenous (IV) iron replacement therapies have either inconvenient regimens of administration or adverse event profiles that limit their utility in the outpatient setting. Ferumoxytol is a novel, semisynthetic, carbohydrate-coated, superparamagnetic iron oxide nanoparticle that is administered IV as an injection. The main objective of this study was to assess the safety of ferumoxytol for the treatment of patients with CKD stages 1 to 5 and 5D. STUDY DESIGN Phase 3, randomized, double-blind, placebo-controlled, crossover, multicenter study of a single 510-mg dose of ferumoxytol versus saline as placebo. SETTING & PARTICIPANTS 750 patients with CKD stages 1 to 5 and 5D. INTERVENTION An IV injection of either 17 mL of ferumoxytol or saline placebo over 17 seconds on day 0 and the alternate agent on day 7. OUTCOMES & MEASUREMENTS Descriptive comparison of adverse events, laboratory tests, and vital signs. RESULTS Of 750 randomly assigned patients with CKD, 60% were not on dialysis therapy. 713 patients received ferumoxytol, and 711 received placebo. There were 420 adverse events reported; 242 in 152 patients (21.3%) with ferumoxytol and 178 in 119 patients (16.7%) with placebo. The incidence of related adverse events was 5.2% with ferumoxytol and 4.5% with placebo. The most common related adverse events after each treatment included symptoms related to the injection/infusion site, dizziness, pruritus, headache, fatigue, and nausea. Serious adverse events occurred in 21 patients (2.9%) after ferumoxytol and 13 patients (1.8%) after placebo. Serious related adverse events were observed in 1 patient (0.1%) after each treatment. There was no meaningful decrease in blood pressure after administration of ferumoxytol or placebo. LIMITATIONS Follow-up was 7 days after each study treatment. CONCLUSIONS Ferumoxytol is well tolerated and has a safety profile similar to placebo in anemic patients with CKD stages 1 to 5 and 5D.

Physicochemical properties of ferumoxytol, a new intravenous iron preparation

Background  Intravenous iron is a critical component of anaemia management. However, currently available preparations have been associated with the release of free iron, a promoter of bacterial growth and oxidative stress.

Screening plasma aluminum levels in relation to aluminum bone disease among asymptomatic dialysis patients.

Aluminum accumulation in plasma and tissues is a well-described complication among persons undergoing peritoneal dialysis or hemodialysis. Excess bone aluminum is associated with low bone formation rates and increased risk for fractures. Current recommendations for care of patients with end-stage renal disease include screening for aluminum toxicity with plasma aluminum levels; patients with levels below 40 microg/L are considered to be at low risk for aluminum bone disease (ABD). We examined data from the Toronto Renal Osteodystrophy Study to evaluate the performance of plasma aluminum levels in screening for ABD. Two hundred fifty-eight unselected patients undergoing peritoneal dialysis (n = 143) or hemodialysis (n = 115) underwent diagnostic bone biopsy and measurement of plasma aluminum level. Sixty-nine patients (26.7%) were identified as having ABD, defined as low or normal bone formation rates with 25% or more bone surface aluminum staining. Plasma aluminum level was strongly associated with the presence of ABD; the odds ratio was 1.4 for each increase of 10 microg/L (95%CI, 1.2, 1.6). However, only 50.1% of patients with a plasma aluminum level of 40 microg/L or greater had ABD, whereas 14.2% of patients with a level below this threshold also had ABD. Using this cutoff level of 40 microg/L, the sensitivity and specificity were 65.2% and 76.7%, respectively. We conclude that although there is a correlation between high aluminum levels and ABD, a patients plasma aluminum level does not predict well the presence of ABD in spite of a relatively high prevalence of disease.

The value of vaccination in chronic kidney disease.

There has been much attention directed toward the high mortality of patients with end‐stage renal disease (ESRD), with much of the focus on cardiovascular disease. However, infectious disease is the second most common cause of death in late‐stage chronic kidney disease (CKD) patients. Although CKD patients are immunocompromised, some vaccines such as influenza, retain their efficacy and reduce infection rates with a standard immunization schedule. Other vaccines, such as hepatitis B and pneumococcal vaccines, require more frequent and/or higher doses to produce and maintain protective antibody levels. Attention has recently been given to the efficacy of influenza vaccination in ESRD patients in reducing morbidity and mortality. Centers with vaccination protocols have demonstrated reduced infection rates and resultant decreased morbidity and mortality. It could be extrapolated from this that widespread vaccination would reduce the total cost of ESRD patient care, and potentially improve patient well‐being. However, vaccination appears to be underutilized in CKD patients, and it is a readily available intervention to improve outcomes.

General Medical Care among Patients with Chronic Kidney Disease: Opportunities for Improving Outcomes

Suboptimal health care during advancing chronic kidney disease (CKD) may result in greater morbidity and cost once dialysis is started and may preclude future transplantation. Medicare data were examined for the prevalence of selected general health, diabetes, and CKD interventions in a national cohort of patients in the 2 yr before dialysis initiation and compared with a contemporaneous non-CKD cohort. A total of 24,778 individuals who were aged > or =67 yr composed the CKD cohort, and 1,046,136 individuals who were aged > or =67 yr did not have CKD. Among patients with diabetes and CKD, fewer than two thirds had claims for eye examinations, 75% for HbA(1C) testing, and 68% for lipid testing, with similar proportions in the non-CKD cohort. Among those without diabetes, 47 and 54% of the CKD and non-CKD cohorts, respectively, had claims for lipid testing. Fewer than 50 and 15% had claims for influenza and pneumococcal vaccination, respectively, with slightly lower proportions among patients with CKD. Claims for cancer tests were found for 14 to 41% and 29 to 52% of individuals with and without CKD, respectively, depending on the type of cancer. A greater proportion of patients with diabetes tended to have claims for tests in both cohorts. In the CKD cohort, claims for anemia testing and parathyroid hormone levels were available in fewer than 50 and 15%, respectively, and claims for permanent vascular access were found for only 30% of hemodialysis patients. This study provides further evidence that patients with CKD may not be receiving general health and CKD care according to current recommendations.

The Study of Treatment for Renal Insufficiency: Data and Evaluation (STRIDE), a National Registry of Chronic Kidney Disease

Optimization of care in patients with chronic kidney disease (CKD) could be the key to improved clinical and economic outcomes, both during the phase of CKD as well as in patients with end‐stage renal disease (ESRD). CKD is a major public health problem that has been insufficiently studied. There is little published information on outcomes among CKD patients, specifically, data on mortality, morbidity, and quality of life. Indeed, recent efforts by the National Kidney Foundation (NKF) have served to define the classification, evaluation, and approach to management of CKD in practice. The Study of Treatment for Renal Insufficiency: Data and Evaluation (STRIDE) registry is an initiative to study CKD patients in nephrology practices across the country. It is a prospective observational study whose objective is to profile demographic and clinical variables, practice patterns, comorbid conditions, quality of life, and outcomes in a nationally based sample of CKD patients. This article details the design, methodology, and process of enrollment into the registry.

Prevalence and Management of Anemia Among Patients with Chronic Kidney Disease in a Health Maintenance Organization

AbstractBackground: Anemia often develops among patients with chronic kidney disease (CKD) and is an important cause of cardiovascular disease among patients with end-stage renal disease (ESRD). Objective: To evaluate the epidemiology and treatment of anemia among patients with CKD by undertaking an analysis of data from one Health Maintenance Organization. Methods: The CKD cohort was comprised of 1658 patients followed between 1 January 1994 and 1 December 1997 who had serum creatinine (SCr) levels above gender-specific norms. The prevalence of anemia and epoetin-α (recombinant human erythropoietin) use was determined, and the association with anemia and kidney function was assessed with multinomial logistic regression analysis. Results: 36% of patients with CKD had anemia, with at least two hematocrit (HCT) values (separated by ≥30 days) lower than the gender-specific norm (<42% for males, <36% for females). Eleven per cent of patients had a lowest HCT value less than the gender-specific norm but ≥33%, 6% had a lowest HCT value 30 to 32.9%, and 19% had a lowest HCT value <30%. The prevalence of anemia was positively correlated with the severity of kidney dysfunction.In the multivariate analysis, the independent relative risk of an HCT value <30% versus no anemia was 84.5, 9.8 and 2.0 for patients with SCr level ≥4.0, 3.0 to 3.9 and 2.0 to 2.9 mg/dl, respectively, compared with patients with SCr level <2.0 mg/dl. Epoetin-α was prescribed for only 7.4% of patients and, more significantly, for only 23% of patients with an HCT value <30%. Even among patients with an HCT value <30% who had received care from a nephrologist, only 66% received epoetin-α. Conclusions: This study demonstrates that the prevalence of anemia among patients with CKD is high and the management of anemia is suboptimal. Suboptimal treatment of anemia during CKD may lead to increased cardiovascular morbidity and cost of care among patients with CKD and ESRD.