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      Cardiovascular Burden Associated with Uremic Toxins in Patients with Chronic Kidney Disease

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          Background: Retention of uremic toxins in patients with chronic kidney disease (CKD) negatively affects multiple organ systems, including the cardiovascular system, resulting in significant morbidity and mortality. Alleviation of the adverse effects of uremic toxins is an important priority in the management of CKD. Scope: This review focuses on the evidence for the influence of uremic toxins on cardiovascular morbidity and mortality among patients with CKD and slowly developing uremia. The cardiovascular effects of acute kidney injury and rapidly developing azotemia are beyond the scope of this review and will not be discussed. Data on potential treatment options aimed at ameliorating the toxic effects of uremic toxins are summarized. Findings: Uremic toxins are associated with significant cardiovascular morbidity and mortality in patients with CKD. While a number of preclinical studies have detailed these effects, clinical studies directly evaluating cardiovascular outcomes consequent to the presence of uremic toxins have only recently become available. Conclusion: Uremic toxins play an important role in the progression of cardiovascular disease in patients with CKD. Further studies are needed to better characterize the impact of these compounds on cardiovascular outcomes. Beneficial treatments are currently available that, in preliminary studies, appear to neutralize some of the adverse effects of uremic toxins. Large randomized clinical trials are needed to further determine the utility of these varied therapeutic agents.

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          Most cited references 66

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          Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.
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            End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1.1 to 1.2), 1.8 with an estimated GFR of 30 to 44 ml per minute per 1.73 m2 (95 percent confidence interval, 1.7 to 1.9), 3.2 with an estimated GFR of 15 to 29 ml per minute per 1.73 m2 (95 percent confidence interval, 3.1 to 3.4), and 5.9 with an estimated GFR of less than 15 ml per minute per 1.73 m2 (95 percent confidence interval, 5.4 to 6.5). The adjusted hazard ratio for cardiovascular events also increased inversely with the estimated GFR: 1.4 (95 percent confidence interval, 1.4 to 1.5), 2.0 (95 percent confidence interval, 1.9 to 2.1), 2.8 (95 percent confidence interval, 2.6 to 2.9), and 3.4 (95 percent confidence interval, 3.1 to 3.8), respectively. The adjusted risk of hospitalization with a reduced estimated GFR followed a similar pattern. An independent, graded association was observed between a reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization in a large, community-based population. These findings highlight the clinical and public health importance of chronic renal insufficiency. Copyright 2004 Massachusetts Medical Society
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              Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.

              Chronic kidney disease is the primary cause of end-stage renal disease in the United States. The purpose of this study was to understand the natural history of chronic kidney disease with regard to progression to renal replacement therapy (transplant or dialysis) and death in a representative patient population. In 1996 we identified 27 998 patients in our health plan who had estimated glomerular filtration rates of less than 90 mL/min per 1.73 m(2) on 2 separate measurements at least 90 days apart. We followed up patients from the index date of the first glomerular filtration rates of less than 90 mL/min per 1.73 m(2) until renal replacement therapy, death, disenrollment from the health plan, or June 30, 2001. We extracted from the computerized medical records the prevalence of the following comorbidities at the index date and end point: hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, hyperlipidemia, and renal anemia. Our data showed that the rate of renal replacement therapy over the 5-year observation period was 1.1%, 1.3%, and 19.9%, respectively, for the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) stages 2, 3, and 4, but that the mortality rate was 19.5%, 24.3%, and 45.7%. Thus, death was far more common than dialysis at all stages. In addition, congestive heart failure, coronary artery disease, diabetes, and anemia were more prevalent in the patients who died but hypertension prevalence was similar across all stages. Our data suggest that efforts to reduce mortality in this population should be focused on treatment and prevention of coronary artery disease, congestive heart failure, diabetes mellitus, and anemia.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                August 2013
                06 August 2013
                : 38
                : 2
                : 136-148
                aUniversity of California Irvine School of Medicine, Orange, Calif., and bVirginia Commonwealth University Health System, Richmond, Va., USA
                Author notes
                *Domenic A. Sica, MD, Virginia Commonwealth University Health System, Richmond, VA 23298-0160 (USA), E-Mail
                351758 Am J Nephrol 2013;38:136-148
                © 2013 S. Karger AG, Basel

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