Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.

Use of warfarin, clopidogrel, or aspirin associates with mortality among patients with ESRD, but the risk-benefit ratio may depend on underlying comorbidities. Here, we investigated the association between these medications and new stroke, mortality, and hospitalization in a retrospective cohort analysis of 1671 incident hemodialysis patients with preexisting atrial fibrillation. We followed patient outcomes from the time of initiation of dialysis for an average of 1.6 yr. Compared with nonuse, warfarin use associated with a significantly increased risk for new stroke (hazard ratio 1.93; 95% confidence interval 1.29 to 2.90); clopidogrel or aspirin use did not associate with increased risk for new stroke. Analysis using international normalized ratio (INR) suggested a dose-response relationship between the degree of anticoagulation and new stroke in patients on warfarin (P ϭ 0.02 for trend). Warfarin users who received no INR monitoring in the first 90 d of dialysis had the highest risk for stroke compared with nonusers (hazard ratio 2.79; 95% confidence interval 1.65 to 4.70). Warfarin use did not associate with statistically significant increases in all-cause mortality or hospitalization. In conclusion, warfarin use among patients with both ESRD and atrial fibrillation associates with an increased risk for stroke. The risk is greatest in warfarin users who do not receive in-facility INR monitoring.

The relationship between the delivered dose of hemodialysis and patient mortality remains somewhat controversial. Several observational studies have shown improved patient survival with higher levels of delivered dialysis dose. However, several other unmeasured variables, changes in patient mix or medical management may have impacted on this reported difference in mortality. The current study of a U.S. national sample of 2,311 patients from 347 dialysis units estimates the relationship of delivered hemodialysis dose to mortality, with a statistical adjustment for an extensive list of comorbidity/risk factors. Additionally this study investigated the existence of a dose beyond which more dialysis does not appear to lower mortality. We estimated patient survival using proportional hazards regression techniques, adjusting for 21 patient comorbidity/risk factors with stratification for nine Census regions. The patient sample was 2,311 Medicare hemodialysis patients treated with bicarbonate dialysate as of 12/31/90 who had end-stage renal disease for at least one year. Patient follow-up ranged between 1.5 and 2.4 years. The measurement of delivered therapy was based on two alternative measures of intradialytic urea reduction, the urea reduction ratio (URR) and Kt/V (with adjustment for urea generation and ultrafiltration). Hemodialysis patient mortality showed a strong and robust inverse correlation with delivered hemodialysis dose whether measured by Kt/V or by URR. Mortality risk was lower by 7% (P = 0.001) with each 0.1 higher level of delivered Kt/V. (Expressed in terms of URR, mortality was lower by 11% with each 5 percentage point higher URR; P = 0.001). Above a URR of 70% or a Kt/V of 1.3 these data did not provide statistical evidence of further reductions in mortality. In conclusion, the delivered dose of hemodialysis therapy is an important predictor of patient mortality. In a population of dialysis patients with a very high mortality rate, it appears that increasing the level of delivered therapy offers a practical and efficient means of lowering the mortality rate. The level of hemodialysis dose measured by URR or Kt/V beyond which the mortality rate does not continue to decrease, though not well defined with this study, appears to be above current levels of typical treatment of hemodialysis patients in the U.S.

Mortality rates for maintenance hemodialysis patients are much higher than the general population and are even greater soon after starting dialysis. Here we analyzed mortality patterns in 86,886 patients in 11 countries focusing on the early dialysis period using data from the Dialysis Outcomes and Practice Patterns Study; a prospective cohort study of in-center hemodialysis. The primary outcome was all-cause mortality, using time-dependent Cox regression, stratified by study phase adjusted for age, sex, race, and diabetes. The main predictor was time since dialysis start as divided into early (up to 120 days), intermediate (121–365 days), and late (over 365 days) periods. Mortality rates (deaths/100 patient-years) were 26.7 (95% confidence intervals 25.6, 27.9), 16.9 (16.2, 17.6), and 13.7 (13.5, 14.0) in the early, intermediate, and late periods, respectively. In each country, mortality was higher in the early compared to the intermediate period with an adjusted range from 3.10 (2.22, 4.32) in Japan to 1.15 (0.87, 1.53) in the United Kingdom. Adjusted mortality rates were similar for intermediate and late periods. The ratio of elevated mortality rates in the early to the intermediate period increased with age. Within each period, mortality was higher in the United States than in most other countries. Thus, internationally, the early hemodialysis period is a high-risk time for all countries studied, with substantial differences in mortality between countries. Efforts to improve outcomes should focus on the transition period and first few months of dialysis.

Limited health literacy is common in the United States and associates with poor clinical outcomes. Little is known about the effect of health literacy in patients with advanced kidney disease. In this prospective cohort study we describe the prevalence of limited health literacy and examine its association with the risk for mortality in hemodialysis patients. We enrolled 480 incident chronic hemodialysis patients from 77 dialysis clinics between 2005 and 2007 and followed them until April 2008. Measured using the Rapid Estimate of Adult Literacy in Medicine, 32% of patients had limited (Ͻ9th grade reading level) and 68% had adequate health literacy (Ն9th grade reading level). Limited health literacy was more likely in patients who were male and non-white and who had fewer years of education. Compared with adequate literacy, limited health literacy associated with a higher risk for death (HR 1.54; 95% CI 1.01 to 2.36) even after adjustment for age, sex, race, and diabetes. In summary, limited health literacy is common and associates with higher mortality in chronic hemodialysis patients. Addressing health literacy may improve survival for these patients.