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We reviewed a number of prospective randomized and multiple retrospective cohort studies of different dialysis prescriptions: longer dialysis time, at a frequency of at least three times a week, or a frequency of daily hemodialysis with a shorter dialysis time. Interestingly, the retrospective analyses have generally found significant survival benefits in the intensive dialysis groups, whereas more modest effects were observed in the prospective randomized controlled trials. The reason for this discrepancy may be related to the retrospective nature of the studies and possible selection bias; for example, the patients who were prescribed more frequent dialysis may have had more difficulties with volume control or high blood pressure. In contrast, the randomized controlled trials of increased dialysis frequency, which have shown indirect and modest benefits in complex coprimary end points, have small sample sizes and are plagued with difficulties in recruitment and compliance with the randomly allocated more frequent dialysis. This review, which attempts to balance the potential benefits of more frequent dialysis with the burden on the patient's lifestyle, an increased risk of access malfunction, as well as societal costs of such intensive dialysis prescriptions, concludes in favor of the conventional three times per week dialysis (at a minimum) but at longer dialysis times than is currently prescribed based on the Kt/Vurea metric alone.

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 a range of adjusted mortality ratios 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 the first few months of dialysis.

To compare the relative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing cardiovascular mortality in chronic hemodialysis patients, we conducted an observational analysis of all patients initiated on ACEI or ARB therapy undergoing chronic hemodialysis at a large dialysis provider. Survival curves with mortality hazard ratios (HRs) were generated using the Kaplan-Meier method and Cox regression. Outcomes were compared using inverse probability of treatment weighting and propensity score matching. Over 6 years, 22,800 patients were newly initiated on an ACEI and 5828 on an ARB after at least 60 days of chronic hemodialysis. After adjustment for baseline cardiovascular risk factors, there was no significant difference in the risk of cardiovascular, all-cause, or cerebrovascular mortality in patients initiated on an ARB compared with an ACEI (HR of 0.96). A third of 28,628 patients, newly started on an ACEI or ARB, went on to another antihypertensive medication in succession. After adjustment for risk factors, 701 patients initiated on combined ACEI and ARB therapy (HR of 1.45) or 6866 patients on ACEI and non-ARB antihypertensive agent (HR of 1.27) were at increased risk of cardiovascular death compared with 1758 patients initiated on an ARB and non-ACEI antihypertensive therapy. Thus, an ARB, in combination with another antihypertensive medication (but not an ACEI), may have a beneficial effect on cardiovascular mortality. As observational studies may be confounded by indication, even when adjusted, randomized clinical trials are needed to confirm these findings.

Eighty-two percent (82%) of patients initiating hemodialysis in the United States in 2006 did so with a catheter as the functioning access. Even in patients who have been followed by nephrologists for 6 months or more, 74% of patients initiated dialysis with a catheter. This is a multifactoral problem that requires attention and solutions from all stakeholders, including the nephrologist, the vascular surgeon, the hospital, and the insurance industry, as well as the patient and family. We propose a series of specific proposals that include a process for the timely referral and timely placement of a permanent access based on the patient's estimated or measured glomerular filtration rate (GFR), and a 'pay-for-performance' measure for vascular surgeons and nephrologists who admit patients with functional permanent accesses; such pay for performance would place a higher value for patients who are admitted with a functional arteriovenous (AV) fistula than for patients who are admitted with an AV graft. We also propose that hospitals develop a less permissive process for placement of PICC (peripherally inserted central catheters) lines in patients with GFR <60 ml/min and to consider surgery for access placement as 'urgent'. Finally, a more proactive educational process for patients and their families, including an 'informed non-consent' for patients who defer placement of a permanent access needs to be considered. The morbidity, mortality, and health-care costs associated with prolonged catheter use mandate urgent attention to this problem.

Dialysis patients have a greater number of hospitalization events compared to patients without renal failure. Here we studied the relationship between different post-discharge interventions and repeat hospitalization in over 126,000 prevalent hemodialysis patients to explore outpatient strategies that minimize the risk of repeat hospitalization. The primary outcome was repeat hospitalization within 30 days of discharge. Compared to pre-hospitalization values, the levels of hemoglobin, albumin, phosphorus, calcium, and parathyroid hormone and weight were significantly decreased after hospitalization. Using covariate-adjusted models, those patients whose hemoglobin was monitored within the first 7 days after discharge, followed by modification of their erythropoietin dose had a significantly reduced risk for repeat-hospitalization when compared to the patients whose hemoglobin was not checked, nor was the dose of erythropoietin changed. Similarly, administration of vitamin D within the 7 days following discharge was significantly associated with reduced repeat hospitalization when compared to patients on no vitamin D. Therefore, it appears that immediate re-evaluation of anemia management orders and resumption of vitamin D soon after discharge may be an effective way to reduce repeat hospitalization.

Background: Several studies have pointed out the influence of nutritional parameters and/or indices of inflammation on morbidity and mortality. Often, these conditions coexist, and the relative importance of poor nutritional status and chronic inflammation in terms of predicting clinical outcomes in chronic hemodialysis (CHD) patients has not been clarified., Methods: We undertook a prospective cohort study analyzing time-dependent changes in several established nutritional and inflammatory markers, and their influence on mortality in 194 CHD patients (53% male, 36% white, 30% with diabetes mellitus, mean age 55.7 +/- 15.4 years) throughout a 57-month period. Serial measurements of serum concentrations of albumin, prealbumin, creatinine, transferrin, cholesterol, and C-reactive protein (CRP), as well as normalized protein catabolic rate, postdialysis weight, and phase angle and reactance by bioelectrical impedance analysis were performed every 3 months. Clinical outcomes were simultaneously assessed using indicators of mortality., Results: Serum albumin, serum prealbumin, serum creatinine, and phase angle were significant predictors of all-cause mortality, even after adjustment for serum CRP concentrations. Serum CRP concentrations were not significantly associated with mortality. Serum albumin concentrations and phase angle were also independent predictors of cardiovascular deaths in the multivariate model., Conclusion: The nutritional status of CHD patients predicts mortality independent of concomitant presence or absence of inflammatory response. Prevention of, and timely intervention to treat uremic malnutrition by suitable means are necessary independent of the presence and/or therapy of inflammation in terms of improving clinical outcomes in CHD patients.

Background: Knowledge of urea volume of distribution (Vurea) in patients with acute renal failure (ARF) is critical in order to prescribe and monitor appropriate dialytic treatment. We have recently shown that in ARF patients, Vurea estimation by urea kinetic modeling is significantly higher than total body water (TBW) by anthropometric estimation. However, these estimates of Vurea and TBW have not been validated by isotopic methods, considered as reference measurement standards., Methods: In this study, we measured Vurea by [13C]urea and TBW by deuterium oxide (D2O) in 21 patients with ARF (14 males, 7 females, age 62.0 +/- 10.6 years old, 83% Caucasian, 17% African American) at three different centers. These measurements were compared to TBW estimates from anthropometric and bioelectrical impedance (BIA) measurements., Results: Our results show that Vurea by [13C]urea (51.0 +/- 11.7 L) is significantly higher than TBW estimated by all other methods (TBW by D2O: 38.3 +/- 9.8 L, P < 0.001; TBW by BIA: 45.7 +/- 15.7 L, P= 0.08; TBW by Watson formula: 38.3 +/- 7.3 L, P < 0.001; TBW by Chertow formula: 39.3 +/- 7.8 L, P= 0.002, all versus Vurea). Despite significant overestimation of the absolute value and considerable variation, Vurea significantly correlated with TBW by BIA (r= 0.66, P < 0.01) and TBW by D2O (r= 0.5, P= 0.04). There was also significant correlation between D2O and BIA determined TBW (r= 0.8, P < 0.001)., Conclusion: In terms of useful guidelines to prescribe a specific dose of dialysis in patients with ARF, conventional estimates of TBW as surrogates for Vurea should be used with caution. We propose that these conventional estimates of TBW should be increased by approximately 20% (a factor of 1.2) to avoid significant underdialysis.

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.

Background: Inflammation is highly prevalent in chronic hemodialysis patients. Because hemodialysis involves the contact of blood with "foreign" surfaces, and the documented activation of several humoral and cellular pathways during the procedure, the hemodialysis procedure has been suggested as a potential source of inflammation in this patient population. Earlier studies did not provide clear-cut evidence of the potential contribution of the hemodialysis procedure to inflammation, as assessed by markers of inflammation such as cytokine levels and acute-phase protein production., Methods: Nine patients were studied using primed-constant infusion of l-(l-13C) leucine 2 hours before, during, and 2 hours after a single hemodialysis session. We evaluated the effects of hemodialysis on induction of interleukin-6 (IL-6) production as well as the fractional synthetic rates (FSR) of albumin and fibrinogen, two well-known acute-phase proteins., Results: During hemodialysis, albumin FSR and fibrinogen FSR increased significantly compared to the measurements obtained during baseline period. During this period, albumin and fibrinogen FSR increased 64% and 34%, respectively, compared to baseline (P < 0.05). While the increase in IL-6 concentration was modest during hemodialysis (14%), the levels further increased at the end of the 2-hour post-hemodialysis period (68% higher compared to baseline, P < 0.05). Fibrinogen FSR also demonstrated a further increase during the post-dialysis period (17% higher compared to the intradialytic period and 58% higher compared to baseline), while albumin FSR stabilized during this period., Conclusions: The results provide clear evidence of hemodialysis-induced inflammatory response. The process is most notable during the 2-hour post-hemodialysis period.

Background: Protein-calorie malnutrition is common in chronic hemodialysis (CHD) patients and correlates with morbidity and mortality in these patients. There are limited trials evaluating the efficacy of oral nutritional supplementation in malnourished CHD patients., Methods: Eighty-five CHD patients with evidence of malnutrition were included in this prospective study. Patients were followed for a 3-month baseline period during which they received conventional nutrition counseling. This was followed by an intervention period, during which an oral nutritional supplement specifically formulated for CHD patients was given over a period of 6 months. An important element of this study was that the nutritional supplement was provided during dialysis to ensure compliance. Serial measurements of nutritional parameters including concentrations of serum albumin, prealbumin, transferrin as well as body mass index (BMI) and subjective global assessment (SGA) were obtained during the 9-month period., Results: The nutritional parameters did not change during the 3-month baseline period. Following administration of oral supplementation during hemodialysis, there were significant increases in concentrations of serum albumin (from 3.33 +/- 0.32 g/dL at baseline, to 3.65 +/- 0.26 g/dL at month 6, P < 0.0001) and serum prealbumin (from 26.1 +/- 8.6 mg/dL at baseline, to 30.7 +/- 7.4 mg/dL at month 6, P = 0.002). Mean SGA score increased 14% by the end of the study (P = 0.023). Although BMI and estimated dry weight increased also, these changes were not statistically significant. Serum transferrin did not change during the study period., Conclusion: Oral nutritional supplementation given during hemodialysis improves nutritional markers in malnourished CHD patients.

Background: An accurate estimate of volume of distribution of urea (Vurea) is critically important to guide the prescription of therapy and the quantification of delivered dialysis dose in patients with chronic and acute renal failure (ARF). While Vurea has been shown to be substantially the same as total body water (TBW) in other patient populations, this relationship has not been adequately studied in detail in ARF patients., Methods: To evaluate this question, we undertook a systematic study of these parameters in a cohort of 28 patients with ARF to analyze methods of estimating Vurea and TBW using blood-based kinetic data, anthropometric data and bioelectrical impedance analysis (BIA)., Results: The results show that Vurea estimated by double-pool Kt/V (67.9 +/- 19.2 L) and by equilibrated Kt/V (61.2 +/- 13.6 L) were statistically significantly higher than Vurea determined by single-pool Kt/V (55.3 +/- 12.9 L; difference of 16% and 11%, respectively). Determination of TBW by anthropometric measurements (Watson, 42.5 +/- 7.0 L; Hume-Weyer, 43.6 +/- 7.1 L; Chertow, 46.8 +/- 8.1 L) yielded significantly lower measures compared to TBW determined by physiological formulae and by BIA (51.1 +/- 11.6 L and 51.1 +/- 13.3 L, respectively). Most importantly, all measures of Vurea by blood-based kinetics exceeded TBW measurements by any method (7% to 50% difference)., Conclusion: Our results suggest that in terms of useful guidelines to prescribe a specific dose of dialysis in patients with acute renal failure, estimates of TBW cannot be used as a surrogate for Vurea in determining dialysis adequacy.