Joseph A. Vassalotti

Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients

BACKGROUND Levels of advanced glycation end products (AGEs), well-known proinflammatory compounds, are markedly elevated in patients with renal failure, raising the speculation that they have a role as cardiovascular risk factors in this population. Although elevated AGE levels in patients with renal failure have been attributed to impaired renal clearance and increased endogenous AGE formation, recent data suggest an important role for diet as a source of AGEs. METHODS To determine the relationship between dietary AGE content and serum AGE levels, a cross-sectional study was performed in our long-term dialysis patients. Dietary AGE intake was estimated by means of dietary records and questionnaires, and sera were obtained for measurement of 2 well-characterized AGEs, carboxymethyl-lysine (CML) and methylglyoxal (MG) derivatives. RESULTS The study population included 189 patients; 139 hemodialysis and 50 peritoneal dialysis patients. Serum CML level correlated significantly with dietary AGE intake, based on either 3-day food records (r = 0.5; P = 0.003) or dietary questionnaires (r = 0.22; P = 0.03). Although no correlation was observed with nutrient intake (protein, fat, saturated fat, or carbohydrate), both serum CML and MG levels correlated with blood urea nitrogen (r = 0.2; P = 0.03 and r = 0.2; P = 0.02, respectively) and serum albumin levels (r = 0.16; P = 0.04 and r = 0.18; P = 0.02, respectively). CONCLUSION Data indicate that dietary AGE content, independently of other diet constituents, is an important contributor to excess serum AGE levels in patients with renal failure. Moreover, the lack of correlation between serum AGE levels and dietary protein, fat, and carbohydrate intake indicates that a reduction in dietary AGE content can be obtained safely without compromising the content of obligatory nutrients.

CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004

BACKGROUND The prevalence of chronic kidney disease (CKD) is increasing in the United States, caused in part by older age and increasing prevalences of hypertension and type 2 diabetes. CKD is silent and undetected until advanced stages. The study of populations with earlier stages of kidney disease may improve outcomes of CKD. METHODS The Kidney Early Evaluation Program (KEEP), a National Kidney Foundation program, is a targeted community-based health-screening program enrolling individuals 18 years and older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. Participants who had received transplants or were on regular dialysis treatment were excluded from this analysis. The National Health and Nutrition Examination Survey (NHANES) 1999-2004 was a nationally representative cross-sectional survey; participants were interviewed in their homes and/or received standardized medical examinations in mobile examination centers. RESULTS Of the 61,675 KEEP participants, 16,689 (27.1%) were found to have CKD. In the NHANES sample of 14,632 participants, 2,734 (15.3%) had CKD. Older age, smoking, obesity, diabetes, hypertension, and cardiovascular disease were associated significantly with CKD in both KEEP and NHANES (P < 0.05 for all). Of note, the likelihood for CKD in African Americans differed between KEEP (odds ratio, 0.81; P < 0.001) and NHANES (odds ratio, 1.10; P = 0.2). CONCLUSION A greater prevalence of CKD was detected in the KEEP screening than in the NHANES data. KEEP has the limitations common to population-screening studies and conclusions for population-attributable risk may be limited. The targeted nature of the KEEP screening program and the large sample size with clinical characteristics comparable to NHANES validates KEEP as a valuable cohort to explore health associations for the CKD and at-risk-for-CKD populations in the United States.

CKD and cardiovascular disease in screened high-risk volunteer and general populations: the Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND Chronic kidney disease (CKD) is recognized as an independent cardiovascular disease risk state. The relationship between CKD and cardiovascular disease in volunteer and general populations has not been explored. METHODS The National Kidney Foundation Kidney Early Evaluation Program (KEEP) is a community-based health-screening program to raise kidney disease awareness and detect CKD for early disease intervention in individuals 18 years or older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. KEEP volunteers completed surveys and underwent blood pressure and laboratory testing. Estimated glomerular filtration rate (eGFR) was computed, and urine albumin-creatinine ratio (ACR) was measured. In KEEP, CKD was defined as eGFR less than 60 mL/min/1.73 m(2) or ACR of 30 mg/g or greater. Cardiovascular disease was defined as self-reported myocardial infarction or stroke. Data were compared with National Health and Nutrition Examination Survey (NHANES) 1999-2004 data for prevalence of cardiovascular disease risk factors and cardiovascular outcomes. RESULTS Of 69,244 KEEP participants, mean age was 53.4 +/- 15.7 years, 68.3% were women, 33.0% were African American, and 27.6% had diabetes. Of 17,061 NHANES participants, mean age was 45.1 +/- 0.27 years, 52% were women, 11.2% were African American, and 6.7% had diabetes. In KEEP, 26.8% had CKD, and in NHANES, 15.3%. ACR was the dominant positive screening test for younger age groups, and eGFR, for older age groups, for both populations. Prevalences of myocardial infarction or stroke were 16.5% in KEEP and 15.1% in NHANES (P < 0.001) and 7.8% in KEEP and 3.7% in NHANES (P < 0.001) for individuals with and without CKD, respectively. In adjusted analysis of both KEEP and NHANES data, CKD was associated with a significantly increased risk of prevalent myocardial infarction or stroke (odds ratio, 1.34; 95% confidence interval, 1.25 to 1.43; odds ratio, 1.37; 95% confidence interval, 1.10 to 1.70, respectively). In KEEP, short-term mortality was greater in individuals with CKD (1.52 versus 0.33 events/1,000 patient-years). CONCLUSIONS CKD is independently associated with myocardial infarction or stroke in participants in a voluntary screening program and a randomly selected survey population. Heightened concerns regarding risks in volunteers yielded greater cardiovascular disease prevalence in KEEP, which was associated with increased short-term mortality.

Comparison of the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study Equations: Risk Factors for and Complications of CKD and Mortality in the Kidney Early Evaluation Program (KEEP)

BACKGROUND The National Kidney Foundation has recommended that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation replace the Modification of Diet in Renal Disease (MDRD) Study equation. Before implementing this change in the Kidney Early Evaluation Program (KEEP), we compared characteristics of reclassified individuals and mortality risk predictions using the new equation. METHODS Of 123,704 eligible KEEP participants, 116,321 with data available for this analysis were included. Glomerular filtration rate (GFR) was estimated using the MDRD Study (eGFR(MDRD)) and CKD-EPI (eGFR(CKD-EPI)) equations with creatinine level calibrated to standardized methods. Participants were characterized by eGFR category: >120, 90-119, 60-89, 45-59, 30-44, and <30 mL/min/1.73 m(2). Clinical characteristics ascertained included age, race, sex, diabetes, hypertension, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and anemia. Mortality was determined over a median of 3.7 years of follow-up. RESULTS The prevalence of eGFR(CKD-EPI) <60 mL/min/1.73 m(2) was 14.3% compared with 16.8% using eGFR(MDRD). Using eGFR(CKD-EPI), 20,355 participants (17.5%) were reclassified to higher eGFR categories, and 3,107 (2.7%), to lower categories. Participants reclassified upward were younger and less likely to have chronic conditions, with a lower risk of mortality. A total of 3,601 deaths (3.1%) were reported. Compared with participants classified to eGFR of 45-59 mL/min/1.73 m(2) using both equations, those with eGFR(CKD-EPI) of 60-89 mL/min/1.73 m(2) had a lower mortality incidence rate (6.4 [95% CI, 5.1-7.7] vs 18.5 [95% CI, 17.1-19.9]). Results were similar for all eGFR categories. Net reclassification improvement was 0.159 (P < 0.001). CONCLUSIONS The CKD-EPI equation reclassifies people at lower risk of CKD and death into higher eGFR categories, suggesting more accurate categorization. The CKD-EPI equation will be used to report eGFR in KEEP.

Fistula First Breakthrough Initiative: Targeting Catheter Last in Fistula First

An arteriovenous fistula (AVF) is the optimal vascular access for hemodialysis (HD), because it is associated with prolonged survival, fewer infections, lower hospitalization rates, and reduced costs. The AVF First breakthrough initiative (FFBI) has made dramatic progress, effectively promoting the increase in the national AVF prevalence since the program’s inception from 32% in May 2003 to nearly 60% in 2011. Central venous catheter (CVC) use has stabilized and recently decreased slightly for prevalent patients (treated more than 90 days), while CVC usage in the first 90 days remains unacceptably high at nearly 80%. This high prevalence of CVC utilization suggests important specific improvement goals for FFBI. In addition to the current 66% AVF goal, the initiative should include specific CVC usage target(s), based on the KDOQI goal of less than 10% in patients undergoing HD for more than 90 days, and a substantially improved initial target from the current CVC proportion. These specific CVC targets would be disseminated through the ESRD networks to individual dialysis facilities, further emphasizing CVC avoidance in the transition from advanced CKD to chronic kidney failure, while continuing to decrease CVC by prompt conversion of CVC‐based hemodialysis patients to permanent vascular access, utilizing an AVF whenever feasible.

Prevalence and associations of anemia of CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND Early identification of anemia of chronic kidney disease may be important for the development of preventive strategies. We compared anemia prevalence and characteristics in the National Kidney Foundation Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004 populations. METHODS Clinical, demographic, and laboratory data were collected from August 2000 to December 31, 2006, from participants in KEEP, a community-based health-screening program targeting individuals 18 years and older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. Anemia was defined as hemoglobin level less than 13.5 g/dL for men and less than 12.0 g/dL for women (Kidney Disease Outcomes Quality Initiative [KDOQI] 2006) or less than 13.0 g/dL for men and less than 12.0 g/dL for women (World Health Organization [WHO]). RESULTS In KEEP (n = 70,069), 68.3% of participants, and in NHANES (n = 17,061), 52% of participants, were women. African Americans represented 33.9% of the KEEP and 11.2% of the NHANES cohorts, and Hispanics comprised 12.4% of KEEP and 13.2% of NHANES. Using the KDOQI classification, anemia was present in 13.9% and 6.3% of KEEP and NHANES participants, whereas using the WHO classification, anemia was present in 11.8% and 5.3%, respectively. In adjusted analysis of KEEP data, KDOQI-defined anemia was significantly more likely in men (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.23 to 1.37); this pattern was reversed when using WHO-defined anemia (OR, 0.68; 95% CI, 0.64 to 0.72). Adjusted odds of anemia were greater for African American than white KEEP participants (OR, 2.98; 95% CI, 2.80 to 3.16; OR, 3.00; 95% CI, 2.81 to 3.20 for KDOQI- and WHO-defined anemia, respectively). CONCLUSION Anemia was twice as common in the targeted KEEP chronic kidney disease screening program cohort than in the NHANES sample population. African Americans had a 3-fold increased likelihood of anemia compared with whites. Targeted screening can identify anemia in a high-risk population.

Screening populations at increased risk of CKD: the Kidney Early Evaluation Program (KEEP) and the public health problem.

The epidemiological characteristics of the US end-stage renal disease population growth and increased costs in the late 1980s framed the public health agenda for the development of a community-based chronic kidney disease (CKD) screening program. Development of the National Kidney Foundation Kidney Early Evaluation Program (KEEP) included 2 preliminary screening programs, the Computerized Assessment of Risk and Education and the KEEP pilot, which was organized around the African American Study of Kidney Diseases clinical centers. The current KEEP program, launched in August 2000, targets individuals with diabetes, hypertension, or a family history of diabetes or hypertension or CKD. The screening includes informed consent, health screening questionnaire, diagnostic panel, and physician consultation. Participants are followed up by telephone and mail. Of 100,000 KEEP participants screened, 28.7% have CKD and 6.7% self-reported CKD stages 1 to 5. Conversely, National Health and Nutrition Examination Survey 1999-2002 results show 13.1% CKD prevalence; 2.9% of women and 17.9% of men with an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) self-report CKD. CKD prevalences in KEEP by stage are 3.1% for stage 1; 4.8%, stage 2; 19.7%, stage 3; and 1.1%, stages 4 and 5, confirming the ability of this targeted screening program to detect CKD early. In addition to identifying individuals at increased risk of kidney disease, KEEPs structured data collection provides an opportunity to advance knowledge about kidney disease and advance the CKD public health agenda.

Who Should Be Targeted for CKD Screening? Impact of Diabetes, Hypertension, and Cardiovascular Disease

To address the highly complex interrelated nature of chronic kidney disease (CKD) and diabetes, hypertension, and cardiovascular disease, we examined CKD prevalence by the predictive effect of demographic factors, comorbid conditions, and CKD risk factors by using National Health and Nutrition Examination Survey (NHANES) 1999-2004 data. NHANES is a nationally representative cross-sectional series of surveys with a complex stratified multistage sampling design. NHANES 1999-2004 participants (n = 15,332; age > or = 20 years) were interviewed in their homes and asked to participate in standardized medical examinations in mobile centers and provide samples for laboratory tests. Weighted logistic regression modeling was used to assess the importance of individual CKD risk factors. Multiple logistic regressions were performed on patient cohorts, with increasing levels of CKD severity defined by means of estimated glomerular filtration rate. A branching diagram was constructed to address the distribution of CKD grouped by diabetes, hypertension, and cardiovascular disease status. CKD prevalence increases with age (39.2% for age > or = 60 years). For ages 20 to 59 years, CKD prevalence was greater for participants with diabetes (33.8%) than for those without diabetes (8.2%) and for participants with both diabetes and hypertension (43%) than for diabetic participants without hypertension (25.5%) or nondiabetic participants with hypertension (15.2%). The prevalence was 6.8% for nondiabetic participants without hypertension. Effects of cardiovascular disease are less dramatic when hypertension and diabetes are considered. A CKD screening approach targeting individuals 60 years and older or those with diabetes or hypertension likely would be useful from a public health standpoint.

National Kidney Foundation consensus conference on cardiovascular and kidney diseases and diabetes risk: an integrated therapeutic approach to reduce events

Cardiovascular disease (CVD) is the most common cause of death in industrialized nations. Type 2 diabetes is a CVD risk factor that confers risk similar to a previous myocardial infarction in an individual who does not have diabetes. In addition, the most common cause of chronic kidney disease (CKD) is diabetes. Together, diabetes and hypertension account for more than two-thirds of CVD risk, and other risk factors such as dyslipidemia contribute to the remainder of CVD risk. CKD, particularly with presence of significant albuminuria, should be considered an additional cardiovascular risk factor. There is no consensus on how to assess and stratify risk for patients with kidney disease across subspecialties that commonly treat such patients. This paper summarizes the results of a consensus conference utilizing a patient case to discuss the integrated management of hypertension, kidney disease, dyslipidemia, diabetes, and heart failure across disciplines.

Trends in Mineral Metabolism: Kidney Early Evaluation Program (KEEP) and the National Health and Nutrition Examination Survey (NHANES) 1999-2004

BACKGROUND Chronic kidney disease (CKD) is associated with mineral metabolism dysregulation, cardiovascular disease, and premature mortality. No study specifically examined mineral metabolism trends in a generalizable sample of patients at increased CKD risk. METHODS This cross-sectional analysis from November 1, 2005, to December 31, 2006, of calcium, phosphorus, and parathyroid hormone (PTH) includes 2,646 individuals with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m(2) in the National Kidney Foundation Kidney Early Evaluation Program (KEEP), a community-based health-screening program targeting individuals 18 years and older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. A parallel analysis of National Health and Nutrition Examination Survey (NHANES) 1999-2004 data was performed. RESULTS In KEEP, as eGFR decreased from 55 to less than 60 mL/min/1.73 m(2) to less than 30 mL/min/1.73 m(2), calcium level decreased (9.55 +/- 0.47 to 9.34 +/- 0.62 mg/dL; P < 0.001), phosphorus level increased (3.70 +/- 0.59 to 4.15 +/- 0.80 mg/dL; P < 0.001), and PTH level increased (66.3 +/- 36.3 to 164 +/- 109 pg/mL; mean, 80.8 +/- 57.0 pg/mL; P < 0.001). NHANES 1999-2004 showed similar trends, with PTH values not as high. Individuals within opinion-based Kidney Disease Outcomes Quality Initiatives targets from the highest to the lowest eGFR group were as follows: calcium, 93.0% to 92.3% (KEEP) and 97.4% to 89.6% (NHANES); phosphorus, 90.4% to 90.3% (KEEP) and 91.6% to 87.1% (NHANES); and PTH, 46.1% to 31.2% (KEEP) and 56.4% to 36.1% (NHANES). CONCLUSIONS In a community-based CKD screening population, increased PTH level occurs early in patients with stage 3, typically with normal calcium and phosphorus levels. These findings support the importance of including PTH with calcium and phosphorus monitoring for individuals with eGFR less than 60 mL/min/1.73 m(2).