Michael W. Steffes

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,

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes

Members of the International Expert Committee have recommended that diabetes should be diagnosed if A1C is ≤6.5%, without need to measure the plasma glucose concentration (1). We are concerned that practical limitations will lead to false positives and negatives with this approach. A given A1C instrument may identify some but not other abnormal hemoglobins (http://www.ngsp.org/prog/index2.html). How, therefore, can we be sure whether a hemoglobinopathy is causing (or preventing) diagnosis? Before diagnosis, should we not also exclude iron deficiency anemia, which may increase A1C by 1–1.5%, as well as hemolytic anemia and renal failure or chronic infections, which also lower …

Structural-functional relationships in diabetic nephropathy.

Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.

REVERSAL OF LESIONS OF DIABETIC NEPHROPATHY AFTER PANCREAS TRANSPLANTATION

Background In patients with type 1 diabetes mellitus who do not have uremia and have not received a kidney transplant, pancreas transplantation does not ameliorate established lesions of diabetic nephropathy within five years after transplantation, but the effects of longer periods of normoglycemia are unknown. Methods We studied kidney function and performed renal biopsies before pancreas transplantation and 5 and 10 years thereafter in eight patients with type 1 diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. The biopsy samples were analyzed morphometrically. Results All patients had persistently normal glycosylated hemoglobin values after transplantation. The median urinary albumin excretion rate was 103 mg per day before transplantation, 30 mg per day 5 years after transplantation, and 20 mg per day 10 years after transplantation (P=0.07 for the comparison of values at base line and at 5 years; P=0.11 for the comparison between base ...

Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults

BACKGROUND Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose. METHODS We compared the prognostic value of glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990-1992 period) of the Atherosclerosis Risk in Communities (ARIC) study. RESULTS The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose. CONCLUSIONS In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.

Continuous glucose monitoring and intensive treatment of type 1 diabetes

BACKGROUND The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

Prevention of Diabetic Renal Disease with Special Reference to Microalbuminuria

In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1–6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacement therapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRD is not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacement therapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-diependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal disease followed by intervention.

A Strong Dose-Response Relation Between Serum Concentrations of Persistent Organic Pollutants and Diabetes Results from the National Health and Examination Survey 1999–2002

OBJECTIVE—Low-level exposure to some persistent organic pollutants (POPs) has recently become a focus because of their possible link with the risk of diabetes. RESEARCH DESIGN AND METHODS—Cross-sectional associations of the serum concentrations of POPs with diabetes prevalence were investigated in 2,016 adult participants in the National Health and Nutrition Examination Survey 1999–2002. Six POPs (2,2′,4,4′,5,5′-hexachlorobiphenyl, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin, oxychlordane, p,p′-dichlorodiphenyltrichloroethane, and trans-nonachlor) were selected, because they were detectable in ≥80% of participants. RESULTS—Compared with subjects with serum concentrations below the limit of detection, after adjustment for age, sex, race and ethnicity, poverty income ratio, BMI, and waist circumference, diabetes prevalence was strongly positively associated with lipid-adjusted serum concentrations of all six POPs. When the participants were classified according to the sum of category numbers of the six POPs, adjusted odds ratios were 1.0, 14.0, 14.7, 38.3, and 37.7 (P for trend < 0.001). The association was consistent in stratified analyses and stronger in younger participants, Mexican Americans, and obese individuals. CONCLUSIONS—There were striking dose-response relations between serum concentrations of six selected POPs and the prevalence of diabetes. The strong graded association could offer a compelling challenge to future epidemiologic and toxicological research.

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

BACKGROUND Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain. METHODS We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy). RESULTS Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95% CI, -4.4 to -0.2; P=0.03). CONCLUSIONS Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.).

γ-Glutamyltransferase Is a Predictor of Incident Diabetes and Hypertension: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Background: γ-Glutamyltransferase (GGT), which maintains cellular concentrations of glutathione, may be a marker of oxidative stress, and GGT itself may produce oxidative stress. We performed a prospective study to examine whether serum GGT predicts diabetes and hypertension. Methods: Study participants were 4844 black and white men and women 18–30 years of age in 1985–1986; they were reexamined 2, 5, 7, 10, and 15 years later. Year 0 GGT cutpoints were 12, 17, 25, and 36 U/L (overall 25th, 50th, 75th, and 90th percentiles; the laboratory cutpoints for abnormal are 40 U/L in women and 50 U/L in men). We deleted 32 participants with prevalent diabetes and 140 participants with prevalent hypertension from the respective incidence analyses. Results: After adjustment for study center, race, sex, and age in proportional hazards regression, the hazard ratios across year 0 GGT categories were 1.0, 1.6, 1.7, 4.0 (95% confidence interval, 2.0–8.1), and 5.5 (2.7–11.1) for 15-year incident diabetes and 1.0, 1.2, 1.7 (1.2–2.2), 2.3 (1.7–3.2), and 2.3 (1.7–3.2) for hypertension. Additional adjustment for year 0 alcohol consumption, body mass index, cigarette smoking, and physical activity attenuated this relationship, but GGT remained a significant predictor. Conclusions: Serum GGT within a range regarded as physiologically normal is associated with incident diabetes and hypertension. Considering known functionality of GGT, these associations are consistent with a role for oxidative stress in risk for diabetes and hypertension.