National Kidney Disease Education Program Research Articles

Weighing the Evidence: The Challenge of Developing Evidence-Based Renal Dosing Strategies

Evaluating drug dosing to account for patient renal function is one of the primary review functions of a hospital pharmacist. Available estimates of renal function have known limitations, but laboratory and medical advances have improved the detection and classification of kidney disease. How do new, more accurate methods of classifying renal disease apply to the interpretation of drug dose recommendations derived by other, less accurate methods? The application of these new strategies to medication dose evaluation lacks clarity. The Cockcroft-Gault estimation of creatinine clearance (CrCl) was introduced in 1976 and has been a standard consideration for drug dose evaluation in adult patients with renal impairment. Although it has been routinely used, this method has recognized limitations. For example, the standard modification to account for female gender in the Cockcroft-Gault equation is theoretical; the original study population did not include female patients. The Modification of Diet in Renal Disease (MDRD) estimation of glomerular filtration rate (GFR) was introduced in 1999 and generally provides a more accurate assessment of renal function than traditional estimates in adult patients. Because the MDRD equation was not available or generally accepted as a method for classifying kidney function during the development of most marketed drugs, clinicians may be unsure about how to apply estimated GFR to drug dose evaluation. Both Cockcroft-Gault and MDRD estimates are based on studies in patients with stable renal function. In contrast, hospitalized patients often demonstrate dynamic renal function due to changing clinical status and comorbidities. National Kidney Disease Education Program (NKDEP) guidance on drug dosing recognizes this limitation and acknowledges that available estimates do not account for all factors that affect serum creatinine concentrations. Available estimates lack accuracy for patients with body size or muscle mass extremes. Some clinicians using the Cockcroft-Gault equation round the low serum creatinine values in elderly patients to another value, such as 1 mg/dL, or utilize ideal body weight to overcome these limitations. However, these approaches are not evidence-based, and researchers have demonstrated that these modifications are less accurate. 2-5 A standardized technique to calibrate serum creatinine assays introduced several years ago is now expected to be fully implemented nationally. Standardization minimizes variation of serum creatinine assay results between clinical laboratories and should lead to more consistent dosing for drugs eliminated renally. Changes to serum creatinine reference ranges would have been expected at most facilities upon implementation. Standardization has generally resulted in higher CrCl values as estimated by the CockcroftGault equation. According to the NKDEP, because the original study samples are no longer available and the creatinine assay method used to derive the CockcroftGault equation is no longer utilized, the equation cannot be re-expressed to the new standardized creatinine values. In contrast, standardized calibration of serum creatinine assays increases the accuracy of estimating GFR by the MDRD method. Current US Food and Drug Administration (FDA) guidance for the industry on pharmacokinetics published in 1998 acknowledges measured serum creatinine concentrations or estimated CrCl as recognized methods to classify kidney function for drug dosing. Draft guidance posted for review in 2010 reflects the significant changes in the body of knowledge in classifying renal disease and incorporates MDRD as well as Cockcroft-Gault estimates of kidney function. According to the NKDEP, clinicians should use either the MDRD equation or the Cockcroft-Gault equation to estimate kidney function for drug dosing.

Chronic Kidney Disease Epidemiology Collaboration Versus Modification of Diet in Renal Disease Equations for Renal Function Evaluation in Patients Undergoing Partial Nephrectomy

A novel equation, the Chronic Kidney Disease Epidemiology Collaboration, has been proposed to replace the Modification of Diet in Renal Disease for estimated glomerular filtration rate due to higher accuracy, particularly in the setting of normal renal function. We compared these equations in patients with 2 functioning kidneys undergoing partial nephrectomy. We assembled a cohort of 1,158 patients from 5 institutions who underwent partial nephrectomy between 1991 and 2009. Only subjects with 2 functioning kidneys were included in the study. The end points were baseline estimated glomerular filtration rate, last followup estimated glomerular filtration rate (3 to 18 months), absolute and percent change estimated glomerular filtration rate ([absolute change/baseline] × 100%), and proportion of newly developed chronic kidney disease stage III. The agreement between the equations was evaluated using Bland-Altman plots and the McNemar test for paired observations. Mean baseline estimated glomerular filtration rate derived from the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations were 73 and 77 ml/minute/1.73 m(2), respectively, and following surgery were 63 and 67 ml/minute/1.73 m(2), respectively. Mean percent change estimated glomerular filtration rate was -12% for both equations (p = 0.2). The proportion of patients with newly developed chronic kidney disease stage III following surgery was 32% and 25%, according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations, respectively (p = 0.001). For patients with 2 functioning kidneys undergoing partial nephrectomy the Chronic Kidney Disease Epidemiology Collaboration equation provides slightly higher glomerular filtration rate estimates compared to the Modification of Diet in Renal Disease equation, with 7% fewer patients categorized as having chronic kidney disease stage III or worse.

Kidney Friendly: What the National Kidney Disease Education Program Strategic Plan Means for Dietetic Practice

Kidney Friendly: What the National Kidney Disease Education Program Strategic Plan Means for Dietetic Practice

Données actuelles sur le dosage de l'excrétion urinaire de l'albumine

Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the erro-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences has been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no referance materials for either analyte in urine. The recommanded reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethicity) nor the continuous increase in risk related to albumin excretion. Clinical needs have been identified for standardization of (a) urine collection methodes, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Optimal Preparation for ESRD

Clinical guidelines for the care of patients with progressive chronic kidney disease (CKD) have been developed by a broad range of organizations within the kidney community. Despite consensus among these guidelines and significant effort on the part of federal agencies, voluntary health organizations, and professional groups, existing data suggest that much work remains to achieve acceptable levels of recommended care. Several small studies have described CKD interventions to improve outcomes, but there are few examples of large-scale attempts to improve CKD care in a systematic way. Southern California Kaiser Permanente has developed a population management approach to CKD in a health maintenance organization setting that has improved outcomes. The Indian Health Service, an agency of the Public Health Service that provides direct care to American Indians and Alaska Natives, has enhanced its diabetes care delivery system to address the renal complications of diabetes. This effort may explain a significant decrease in the incidence rate of ESRD among American Indians with diabetes. Because much of the burden of CKD falls on ethnic and racial groups with decreased access to care, enhancing CKD care in the primary setting may offer the best opportunity to improve outcomes. The National Kidney Disease Education Program in collaboration with community heath centers has developed a model to improve outcomes through application of the chronic care model to CKD management in primary settings that serve high-risk populations.

Consider correction factor for selected drugs

Pharmacists may want to correct the laboratory-reported serum creatinine value when selecting the dosage of carboplatin, dofetilide, ganciclovir, gentamicin, and tobramycin. Those drugs, said Leigh Ann Milburn, a member of the National Kidney Disease Education Program Laboratory Working Group, have a narrow therapeutic range and their clearance depends heavily on kidney function. The five drugs named by Milburn were approved for the U.S. market before 2000. In late 2005, the Laboratory Working Group issued recommendations for improving serum creatinine measurement. The group recommended that the manufacturers of in vitro diagnostic devices recalibrate their serum creatinine assay methods to be traceable to isotope-dilution mass spectrometry (IDMS). At least one maker of in vitro diagnostic devices has provided an equation for converting IDMS-traceable serum creatinine values to non- IDMS-traceable values. The purpose is to help clinicians adjust drug dosages in accordance with drug manufacturers’ instructions, which oftentimes are based on the Cockcroft-Gault equation.

The National Kidney Disease Education Program: Improving Understanding, Detection, and Management of CKD

The National Kidney Disease Education Program (NKDEP), an initiative of the National Institute of Diabetes and Digestive and Kidney Diseases, works to reduce the morbidity and mortality caused by chronic kidney disease (CKD) and its complications. Established in 2000, the NKDEP initially focused on increasing awareness in at-risk populations and helping the laboratory community recalibrate serum creatinine measurement methods and begin using a revised equation to estimate glomerular filtration rate. Expanding its focus in recent years, the NKDEP now works to improve provider practices by collaborating with health systems, community health centers, and professional associations to encourage testing and treatment of patients. Among its top priorities is to develop such resources as clinical encounter tools, patient education aids, and training programs that help primary care professionals better identify and care for patients with CKD. Other priorities include improving the coordination of federal responses to CKD and addressing the standardization of measurement and reporting of urine albumin. Improving CKD detection and management is an important challenge. To succeed, the NKDEP must work in close partnership with the renal community, public health agencies, professional associations, and voluntary organizations that serve at-risk and patient communities.

Individuals With a Family History of ESRD Are a High-Risk Population for CKD: Implications for Targeted Surveillance and Intervention Activities

Activities intended to improve the detection, treatment, and control of chronic kidney disease (CKD) should be incorporated into existing health care systems and targeted to high-risk populations to avoid redundancy and waste of resources. One high-risk population consists of first- or second-degree family members of patients with end-stage renal disease (ESRD), who are 2 to 3 times as likely to have incident ESRD, have high rates of impaired kidney function and undetected and uncontrolled high blood pressure, and are more likely to be obese. These individuals usually are unaware of their underlying CKD and may discount their own risk of ESRD. The ESRD Network 6 Family History Project shows that the ESRD Networks, which constitute a national CKD surveillance system for patients with stage 5 CKD, may be an existing resource that can be used to identify relatives of incident patients with ESRD and provide these families with information about CKD. Nationally available resources have been developed by the National Kidney Disease Education Program for use with these at-risk families. Individuals interested in population-based CKD control activities should be aware of and use these resources.

Current Issues in Measurement and Reporting of Urinary Albumin Excretion

Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion. Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Status of chronic kidney disease prevention programs: International Federation of Kidney Foundation Members 2005/2007

The International Federation of Kidney Foundations surveyed its members on chronic kidney disease 'prevention' programs in their regions and countries in 2005 and 2007. A profile was developed, representing 28 countries (56% response). Some form of screening activity was reported in 24 of the 28 countries (85.7%). Two countries (7%) had, or anticipated development of, legislated national screening. Programs were conducted by kidney foundations or research groups, and were variously population based, focused on high risk groups or opportunistic. Tests in 63% of responding programs included weight, height, blood pressure, blood glucose, dipstick urinalysis and serum creatinine. Several programs used the USA's Kidney Early Evaluation Program's and International Society of Nephrology's templates. World Kidney Day activities contributed significantly. Stated needs were for more government recognition, firm policies and approaches, and critically, resources. Repeat responders reported progress in 2007, particularly in government interest and education delivery. Despite difficulties, programs are developing in many regions. Most need more resources and some members need substantial and sustained assistance.

Laboratory issues in measuring and reporting urine albumin

Urine albumin is an important biomarker for kidney damage, and its measurement is recommended by clinical practice guidelines in many countries for identifying and managing patients with kidney disease. A recent publication reviewed current practices in measurement and reporting of urine albumin concentrations and made recommendations for improvement [1]. The paper reflected the work of the Laboratory Working Group of the National Kidney Disease Education Program (NKDEP, USA) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Joint Committee for Standardization of Albumin in Urine. Historically, the concentration of albumin excreted in 24 h was used to evaluate kidney function. The difficulty of collecting 24 h urine samples has lead to the common recommendation to use an untimed urine collection and to report the ratio of the albumin concentration to the creatinine concentration. This albumin:creatinine ratio (ACR) is widely viewed as an acceptable surrogate for the albumin excretion rate. The recommendations from various professional organizations, however, vary regarding the type of urine samples to collect for measurement of ACR (e.g. firstmorning void, random), the reporting units to use and the criteria for interpretation of the results. Most recommendations use a single decision threshold to identify patients with clinically significant albuminuria, despite the variation of both the albumin and creatinine excretion rates with time of day, exercise, gender, race and other factors. Further complicating the use of a single decision threshold is the increasing evidence that albumin excretion functions as a continuous variable in predicting a progressive increase in risk for complications related to decreased kidney function [2,3]. A number of urine collection issues need careful investigation before improved recommendations for practice can be developed. A wide range of estimates have been reported for the biologic variability of albumin and creatinine in urine samples collected at different times of the day. The evidence supports the conclusion that the ACR is less vari

Attitudes and Behaviors of African Americans Regarding Early Detection of Kidney Disease

Chronic kidney disease (CKD) is an African American public health crisis. To inform interventions, the National Kidney Disease Education Program surveyed African Americans about their attitudes and behaviors regarding early detection of kidney disease and screening. Cross-sectional study. 2,017 African Americans from 7 states (Georgia, Maryland, Ohio, Mississippi, Louisiana, Missouri, and Tennessee) selected by using a random-digit dialing telephone survey (response rate, 42.4%). Demographic, risk, knowledge, and behavior variables. Perception of CKD as a top health concern, perceived risk of getting kidney disease, and accurate knowledge about CKD and its prevention. Only 23.5% of African Americans were screened for kidney disease in the last year. Although almost half (43.7%) of African Americans had a CKD risk factor, only 2.8% reported that CKD was a top health concern. Almost half knew the correct definition of kidney disease (48.6%), but few knew a test to diagnose CKD (23.7%) or that African Americans were at greater risk of developing CKD (18.1%). African Americans who had diabetes (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.17 to 4.76), hypertension (OR, 1.78; 95% CI, 1.28 to 2.44), at least a bachelor's degree (OR, 1.77; 95% CI, 1.17 to 2.66), who had spoken with a medical professional (OR, 1.85; 95% CI, 1.19 to 2.85) or their family (OR, 1.61; 95% CI, 1.11 to 2.38) about kidney disease, who knew that a family history of kidney disease is a risk factor (OR, 2.32; 95% CI, 1.08 to 5.0), and who had been tested for CKD in the last year (OR, 1.45; 95% CI, 1.03 to 2.0) were more likely to correctly perceive themselves at increased risk. Respondents were primarily African American women from urban areas. Most African Americans have poor knowledge about CKD, do not perceive it as an important health problem, and are not getting screened. To increase early detection of kidney disease through screenings, educational efforts linking kidney disease prevention to other diseases that are health priorities for African Americans are necessary.

The National Kidney Disease Education Program and other related efforts in the United States

The National Kidney Disease Education Program (NKDEP) works to reduce the morbidity and mortality caused by chronic kidney disease (CKD) and its complications through educational efforts targeted towards at‐risk communities, patients and health‐care professionals. NKDEP aims to improve early detection of CKD, facilitate identification of patients at greatest risk for progression to kidney failure and promote evidence‐based interventions. Barriers to achieving these goals include confusion and misunderstanding of the laboratory tests used to identify and monitor patients with CKD. Through the Laboratory Working Group, NKDEP has collaborated with the clinical chemistry community to standardize creatinine measurements, promote the routine reporting of eGFR and standardize the measurement and reporting of urine albumin. It is hoped that these efforts will improve screening, clinical care and research in CKD and facilitate the implementation of evidence‐based care recommended by the National Kidney Foundation and others.

The Internet as a Tool for the Renal Community

The Internet has impacted health care. With the introduction of the personal health record (PHR), patients have an opportunity to track their physician visits, medications, and laboratory values online in a pleasant and informative learning environment. The PHR is a secure, online, Internet-accessible method of storing and easily retrieving health information about one's medical history, physician visits, laboratory values, and medications. The American Association of Kidney Patients (AAKP) has taken the leadership role in developing a PHR for patients of the kidney community. There are several barriers that patients experience when using the Web for health resources. These include inaccurate or self-serving information and marketing statements that can be misleading and dangerous. Poorly written or inappropriate information for patients can be problematic, as can an abundance of extraneous information. For the most part, the public often has no way to judge what is and is not credible based on the context of the article alone. This article gives the reader a review of several Web resources that are available for patients and also for renal professionals. They are largely from large nonprofit organizations like the AAKP, National Kidney Foundation, Medical Education Institute, American Society of Nephrology, or The Nephron Information Center (nephron.com). This article also reviews sites from The National Kidney Disease Education Program, Hypertension-Dialysis and Clinical Nephrology, National Institute of Diabetes and Digestive and Kidney Diseases, and DaVita.

Acute kidney injury: time to shift from creatinine to the estimated glomerular filtration rate?

Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Although several groups are working on developing and validating biomarkers of kidney injury and the glomerular filtration rate (GFR), the proposed diagnostic criteria from the Acute Kidney Injury Network are based on an absolute increase in serum creatinine ≥0.3 mg/dl (≥26.4 μmol/l), a percentage increase in serum creatinine ≥50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria <0.5 ml/kg per hour for more than 6 hours) [1]. A recent report from the Laboratory Working Group of the National Kidney Disease Education Program, however, recommends that serum creatinine alone should not be used to assess the GFR or to detect the presence of kidney disease because it is affected by the GFR and by factors independent of the GFR, including age, sex, race, body size, diet, certain drugs, and laboratory analytical methods [2]. Rather, the Working Group suggests implementing the estimated GFR using the Modification of Diet in Renal Disease (MDRD) study [2]. In analogy with chronic kidney disease, implementation of the MDRD equation would probably grant more clinically useful information to assess AKI.

Urine albumin: Recommendations for standardization

A joint working group of the National Kidney Disease Education Program (NKDEP, USA) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has the objective of improv...

Screening Is Part of Kidney Disease Education

The National Kidney Disease Education Program (NKDEP), an initiative of the National Institutes of Health, works to reduce the morbidity and mortality caused by chronic kidney disease (CKD) and its complications through educational efforts targeted toward at-risk communities, patients, and health care professionals. Specifically, NKDEP aims to improve early detection of CKD, facilitate identification of patients who are at greatest risk for progression to kidney failure, and promote evidence-based interventions to slow progression of kidney disease. Guided by the Healthy People 2010 (1) objectives for CKD, NKDEP, based in the National Institute of Diabetes and Digestive and Kidney Diseases, works collaboratively with partners throughout the National Institutes of Health, other federal agencies, and voluntary organizations to develop educational messages and deliver them to communities at risk, patients, and health care providers. Effective communication to the public, patients, and health care professionals is critical to achieving the public health mission of NKDEP. NKDEP emphasizes that screening to identify people with CKD as early as possible in the course of their disease is important because effective interventions that can arrest or retard progression exist; however, several factors mitigate against early screening. Most individuals are asymptomatic until late in the course of their disease. A disproportionate burden of CKD is borne by people with decreased access to and decreased trust in the health care system. Use of the screening tests—creatinine-based calculation of estimated GFR (eGFR) and urine albumin/creatinine ratio (UACR), which provide estimates of GFR and daily albumin excretion, respectively—has been hampered by lack of standardization in measurement and reporting (2,3). Health care providers may lack understanding of CKD, screening methods, and the benefits of early intervention. Clinicians may not understand the tests, may not feel confident in explaining results to patients, and may not know which diagnostic (4) and therapeutic …

The authors of the article cited above respond:

Krouwer (1) makes a valid point that total error for a measurement procedure must include analytical nonspecificity influences (referred to as “random patient interferences” by Krouwer) as well as mean calibration bias and imprecision components. Fig. 3 in the report from the Laboratory Working Group (LWG) of the National Kidney Disease Education Program showed boundaries for combinations of bias and imprecision that would contribute no more than a 10% change in root mean square error for estimates of glomerular filtration rate …

Certification of Creatinine in a Human Serum Reference Material by GC-MS and LC-MS

To meet recommendations given by the Laboratory Working Group of the National Kidney Disease Education Program for improving serum creatinine measurements, NIST developed standard reference material (SRM) 967 Creatinine in Frozen Human Serum. SRM 967 is intended for use by laboratories and in vitro diagnostic equipment manufacturers for the calibration and evaluation of routine clinical methods. The SRM was produced from 2 serum pools with different creatinine concentrations. The concentrations were certified using a higher-order isotope-dilution GC-MS method and an isotope-dilution LC-MS method. The LC-MS method is a potential higher-order reference measurement procedure. The GC-MS mean (CV) concentrations were 67.0 (0.9%) mumol/L for serum pool 1 and 346.1 (0.45%) mumol/L for serum pool 2. The LC-MS results were 66.1 (0.2%) mumol/L and 346.3 (0.2%) mumol/L, respectively. For serum pool 1, there was a 1.4% difference between the mean GC-MS and LC-MS measurements, and a 0.10% difference for serum pool 2. The results from the 2 methods were combined to give the certified concentrations and expanded uncertainties. The certified concentration (expanded uncertainty) of SRM 967 was 66.5 (1.8) mumol/L for serum pool 1 (a value close to the diagnostically important concentration of 88.4 mumol/L) and 346.2 (7.4) mumol/L for serum pool 2 (a concentration corresponding to that expected in a patient with chronic kidney disease).

New creatinine sensor for point-of-care testing of creatinine meets the National Kidney Disease Education Program guidelines

Addition of the measurement of creatinine concentration in whole blood on the ABL837 FLEX blood gas analyzer (Radiometer Medical ApS, Copenhagen, Denmark) allows fast and reliable reporting of creatinine in point-of-care testing (POCT). The new creatinine sensor follows the international recommendations of the National Kidney Disease Education Program Laboratory Working Group as of January 2006 with respect to acceptable performance, reference method and traceability. Validation tests show that the creatinine sensor has excellent performance and thus has the potential to change the poor track record of creatinine testing in plasma and whole blood in both the clinical laboratory and POCT. This article describes the clinical needs and the methods currently available for creatinine measurement and presents performance tests carried out by the manufacturer.