Jonathan Himmelfarb

Acute Kidney Injury Increases Risk of ESRD among Elderly

Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged > or = 67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for > or = 2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease.

Incidence and Mortality of Acute Renal Failure in Medicare Beneficiaries, 1992 to 2001

This studys objective was to determine the incidence and mortality of acute renal failure (ARF) in Medicare beneficiaries. Data were from hospitalized Medicare beneficiaries (5,403,015 discharges) between 1992 and 2001 from the 5% sample of Medicare claims. For 1992 to 2001, the overall incidence rate of ARF was 23.8 cases per 1000 discharges, with rates increasing by approximately 11% per year. Older age, male gender, and black race were strongly associated (P < 0.0001) with ARF. The overall in-hospital death rate was 4.6% in discharges without ARF, 15.2% in discharges with ARF coded as the principal diagnosis, and 32.6% in discharges with ARF as a secondary diagnosis. In-hospital death rates were 32.9% in discharges with ARF that required renal dialysis and 27.5% in those with ARF that did not require dialysis. Death within 90 d after hospital admission was 13.1% in discharges without ARF, 34.5% in discharges with ARF coded as the principal diagnosis, and 48.6% in discharges with ARF as a secondary diagnosis. Discharges with ARF were more (P < 0.0001) likely to have intensive care and other acute organ dysfunction than those without ARF. For discharges both with and without ARF, rates for death within 90 d after hospital admission showed a declining trend. In conclusion, the incidence rate of ARF in Medicare beneficiaries has been increasing. Those of older age, male gender, and black race are more likely to have ARF. These data show ARF to be a major contributor to morbidity and mortality in hospitalized patients.

Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.

CONTEXT The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. OBJECTIVE To determine whether clopidogrel reduces early failure of hemodialysis fistulas. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. INTERVENTION Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. MAIN OUTCOME MEASURES The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. RESULTS Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). CONCLUSION Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

Timing of Initiation of Dialysis in Critically Ill Patients with Acute Kidney Injury

Among critically ill patients, acute kidney injury (AKI) is a relatively common complication that is associated with an increased risk for death and other complications. To date, no treatment has been developed to prevent or attenuate established AKI. Dialysis often is required, but the optimal timing of initiation of dialysis is unknown. Data from the Program to Improve Care in Acute Renal Disease (PICARD), a multicenter observational study of AKI, were analyzed. Among 243 patients who did not have chronic kidney disease and who required dialysis for severe AKI, we examined the risk for death within 60 d from the diagnosis of AKI by the blood urea nitrogen (BUN) concentration at the start of dialysis (BUN < or = 76 mg/dl in the low degree of azotemia group [n = 122] versus BUN > 76 mg/dl in the high degree of azotemia group [n = 121]). Standard Kaplan-Meier product limit estimates, proportional hazards (Cox) regression methods, and a propensity score approach were used to account for selection effects. Crude survival rates were slightly lower for patients who started dialysis at higher BUN concentrations, despite a lesser burden of organ system failure. Adjusted for age, hepatic failure, sepsis, thrombocytopenia, and serum creatinine and stratified by site and initial dialysis modality, the relative risk for death that was associated with initiation of dialysis at a higher BUN was 1.85 (95% confidence interval 1.16 to 2.96). Further adjustment for the propensity score did not materially alter the association (relative risk 1.97; 95% confidence interval 1.21 to 3.20). Among critically ill patients with AKI, initiation of dialysis at higher BUN concentrations was associated with an increased risk for death. Although the results could reflect residual confounding by severity of illness, they provide a rationale for prospective testing of alternative dialysis initiation strategies in critically ill patients with severe AKI.

Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Oxidative stress in uremia.

Purpose of reviewOxidative stress has been described as ‘a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. In uremic patients, an increase in oxidative stress may occur because of the loss of residual renal function, and may be exacerbated by dialysis. This review will focus on the emerging biochemical evidence of an increase in oxidative stress in uremic patients, the relationship with renal replacement therapy, and the potential linkages to acute-phase inflammation, malnutrition, and adverse cardiovascular outcomes in uremic patients. Recent findingsMany studies from multiple research laboratories around the world have recently utilized in-vivo biomarkers to describe increased oxidative stress in uremic patients. An emerging literature suggests that there are links between an increase in oxidative stress, endothelial dysfunction, an increase in acute-phase inflammation, and an accelerated risk of cardiovascular complications in dialysis patients. Additional uremia-associated metabolic abnormalities, including hyperhomocysteinemia, intravenous iron exposure, and biocompatibility changes related to dialysis, may contribute to an increase in oxidative stress. Finally, two well-conducted pilot clinical randomized trials have suggested that antioxidant therapy may have efficacy in reducing cardiovascular events in uremic patients. SummaryThe implications of the findings of a generalized increase in oxidative stress associated with uremia have led to the suggestion that antioxidative therapy may be efficacious in reducing cardiovascular complications. Pilot studies have suggested potential efficacy for this approach. However, further large-scale randomized clinical trials will be required to establish a compelling, evidence-based approach to the use of antioxidants in patients with uremia.

Oxidative Stress Is Increased in Critically Ill Patients with Acute Renal Failure

Patients with acute renal failure (ARF) experience a high mortality rate. Dysregulated inflammation and altered metabolism may increase oxidative stress in ARF patients. Thirty-eight patients who met the Program to Improve Care in Acute Renal Disease (PICARD) Study inclusion criteria underwent plasma protein oxidation and plasma cytokine measurements. For comparison, similar measurements were also performed in 21 critically ill patients without ARF, 28 patients with ESRD, and 49 healthy subjects. Plasma protein thiol oxidation was measured by spectrophotometry. Plasma protein carbonyl content and cytokine concentrations were measured by ELISA. Plasma protein thiol oxidation and carbonyl content were markedly different in ARF patients compared with healthy subjects, ESRD patients, and critically ill patients (P < 0.001 in all cases). There were significant but less marked differences in plasma protein oxidation between ESRD patients and critically ill patients compared with healthy subjects. Plasma protein thiol oxidation in ARF patients improved with dialysis (P < 0.001); however, there was significant plasma oxidant reaccumulation during the interdialytic period (P < 0.001) not due to rebound equilibration of compartmentalized solutes. Plasma proinflammatory cytokine levels were significantly higher (P < 0.05) in ARF patients and critically ill patients than in healthy subjects. Plasma protein oxidation is markedly increased in ARF patients compared with healthy subjects, ESRD patients, and critically ill patients. Increased oxidative stress may be an important target for nutritional and pharmacologic therapy in ARF patients.

Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysis therapy

BACKGROUND Hypoalbuminemia is a powerful predictor of cardiovascular mortality in maintenance hemodialysis patients. Increased biomarkers of acute-phase inflammation and oxidative stress are highly prevalent and also correlate with cardiovascular morbidity and mortality. The extent to which hypoalbuminemia, biomarkers of inflammation, and biomarkers of oxidative stress are linked in this patient population is unknown. We hypothesized that a high proportion of hypoalbuminemic hemodialysis patients also would manifest increased levels of biomarkers of inflammation and oxidative stress. METHODS We surveyed 600 maintenance hemodialysis patients and identified 18 severely hypoalbuminemic patients (serum albumin level < 3.2 g/dL [32 g/L]) without recent infection or hospitalization. We then identified 18 age-, race-, sex-, and diabetes-matched normoalbuminemic hemodialysis patients, as well as 18 age-, race-, sex-, and diabetes-matched healthy subjects, for cohort comparison. Measurements of plasma interleukin-6 (IL-6) levels, plasma protein reduced thiol content, plasma protein carbonyl content, and plasma free F2-isoprostane levels, as well as serum concentrations of C-reactive protein (CRP) and prealbumin, were performed for study purposes. RESULTS Levels of serum CRP, IL-6, plasma protein thiol oxidation, and protein carbonyl formation were significantly elevated in both hypoalbuminemic and normoalbuminemic hemodialysis patients compared with healthy subjects and also were significantly different in hypoalbuminemic maintenance dialysis patients compared with normoalbuminemic hemodialysis patients. Prealbumin levels were significantly lower in hypoalbuminemic hemodialysis patients than in other groups. CONCLUSION There is a high prevalence of inflammation and oxidative stress in the maintenance hemodialysis population. Levels of inflammatory and oxidative stress biomarkers are increased further in hypoalbuminemic compared with normoalbuminemic dialysis patients. Hypoalbuminemia, acute-phase inflammation, and oxidative stress may act synergistically to increase cardiovascular morbidity and mortality risk in maintenance hemodialysis patients.

Oxidative Stress and Inflammation Are Associated with Adiposity in Moderate to Severe CKD

Adiposity contributes to inflammation and oxidative stress in the general population, but this association has not been examined in the chronic kidney disease (CKD) population. We investigated the relationship between body mass index, body fat percentage, and markers of inflammation (C-reactive protein) and oxidative stress (F(2)-isoprostanes and protein thiols) in 184 patients with stages III to IV CKD and 43 healthy controls. We found that, on average, patients with CKD had 62% higher F(2)-isoprostanes, 7% lower protein thiols (a measure of endogenous anti-oxidant capacity, inversely related to protein oxidation), and 150% higher C-reactive protein levels than healthy controls (all unadjusted P < 0.001). In separate multivariable linear regression models, body mass index and body fat percentage each positively correlated with levels of F(2)-isoprostanes and C-reactive protein and negatively correlated with levels of protein thiols among patients with CKD after adjusting for age, sex, race, hypertension, diabetes mellitus, smoking history, estimated glomerular filtration rate, total cholesterol, serum albumin, and study site. We conclude that increased adiposity may amplify the oxidative stress and inflammation that accompany moderate to severe CKD. Interventions focused on weight loss may decrease the inflammatory and oxidative burden in CKD, which may ultimately attenuate cardiovascular risk in this population.

Intradialytic Blood Volume Monitoring in Ambulatory Hemodialysis Patients: A Randomized Trial

Complications related to inadequate volume management are common during hemodialysis. This trial tested the hypothesis that availability of an intradialytic blood volume monitoring (IBVM) device improves fluid removal, reducing morbidity. A six-center, randomized trial with 6 mo of intervention comparing IBVM using Crit-Line versus conventional clinical monitoring was conducted. The average rate of non-access-related hospitalizations was compared across treatment groups using Poisson regression. Mortality analysis used the Kaplan Meier method. A total of 227 patients were randomized to Crit-Line, and 216 were randomized to conventional monitoring. Both groups had similar baseline characteristics. During the study, no differences in weight, BP, or number of dialysis-related complications were observed. There were 120 and 81 non-access-related hospitalizations in the Crit-Line and conventional monitoring groups. The adjusted risk ratio for non-access-related and access-related hospitalization was 1.61 (95% confidence interval 1.15 to 2.25; P = 0.01) and 1.52 (95% confidence interval 1.02 to 2.28; P = 0.04) for the Crit-Line monitoring group. Mortality was 8.7% in the Crit-Line monitoring group and 3.3% in the conventional group (P = 0.021). Standardized mortality ratios comparing the Crit-Line and conventional monitoring groups to the prevalent hemodialysis population were 0.77 (NS) and 0.26 (P < 0.001). Hospitalization rates were 1.51 and 1.03 events/yr in the Crit-Line and standard monitoring groups, compared with 2.01 for the prevalent hemodialysis population. IBVM was associated with higher nonvascular and vascular access-related hospitalizations and mortality compared with conventional monitoring. The atypically low hospitalization and mortality rates for the conventional monitoring group suggest that these findings should be generalized to the US hemodialysis population with caution.