Pneumonia in incident dialysis patients the United States Renal Data System

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1 NDT Advance Access published November 19, 2007 Nephrol Dial Transplant (2007) 1 of 7 doi: /ndt/gfm474 Original Article Pneumonia in incident dialysis patients the United States Renal Data System Haifeng Guo 1, Jiannong Liu 1, Allan J. Collins 1,2 and Robert N. Foley 1,2 1 United States Renal Data System Coordinating Center and 2 University of Minnesota, Minneapolis, MN, USA Abstract Background. Although clinical experience suggests that pneumonia may occur frequently in dialysis patients, its clinical epidemiology in that group remains poorly defined. Methods. Medicare claims were used to identify pneumonia episodes in patients initiating dialysis in the United States between 1996 and 2001 and followed until 31 December Results. Mean patient age was 63.8 years; 48.0% had diabetes and 9.6% used peritoneal dialysis as initial therapy. The overall incidence rate was 27.9/100 patient-years (29.0 in haemodialysis patients vs 18.2 in peritoneal dialysis patients, P < ) and remained relatively constant from year to year. On multivariate analysis, the primary associations of pneumonia [adjusted hazards ratio (AHR) >1.25 or <0.80, P < ] were chronic obstructive pulmonary disease (AHR 1.47), inability to transfer or ambulate (AHR 1.44), haemodialysis as initial therapy (AHR 1.41 vs peritoneal dialysis), age 75 (AHR 1.40 vs years), body mass index 30 kg/m 2 (AHR 0.77 vs kg/m 2 ) and age 0 19 years (AHR 0.61 vs years). Survival probabilities after pneumonia were 0.51 at 1 year. Using interval Poisson regression analysis, AHRs were 4.99 (95% confidence interval ) for death and 3.02 ( ) for cardiovascular disease in the initial 6-month interval after pneumonia, declining to 2.12 ( ) for death and 1.45 ( ) for cardiovascular disease at 5 years. Conclusions. Common in dialysis patients, pneumonia is an antecedent association of cardiovascular disease and death. Correspondence to: Robert N. Foley, MB, United States Renal Data System, 914 South 8th Street, Suite S-253, Minneapolis, MN 55404, USA. rfoley@usrds.org Keywords: end-stage renal disease; epidemiology; haemodialysis; mortality; pneumonia Introduction Although clinical experience suggests that pneumonia may occur frequently in dialysis patients, the underlying clinical epidemiology remains poorly defined. National renal registry studies rank infection as the second most frequent cause of death, with approximately onequarter of these attributed to pulmonary causes [1], and death certificate studies show that death rates from pulmonary infections are about 15 times higher in dialysis patients than in the general population [2]. However, many typical epidemiological questions, such as disease burden, risk factors and prognostic associations, have not been systematically addressed in dialysis populations. This is surprising, given the degree of comorbidity typically present in dialysis patients and their susceptibility to infection [3]. In addition, the finding that ongoing respiratory infections are associated with increased rates of myocardial infarction in a community setting [4] suggests that this issue should be explored in dialysis patients, given that dialysis patients are at enormous cardiovascular risk and pneumonia may be partly preventable. We recently reported findings from the retrospective Waves 1, 3 and 4 Dialysis Morbidity and Mortality Study showing that pneumonia was common in hemodialysis patients and was associated with poor survival [5]. It is unknown whether the findings from that study apply to current dialysis populations for several reasons, including exclusion of patients using peritoneal dialysis, a cross-sectional sampling design and a study population of patients receiving dialysis in Hence, the current national study was designed to assess the following: (i) cumulative pneumonia-free survival over time, with an emphasis on year-to-year trends in incidence rates, (ii) microbiological attribution of index events, (iii) antecedent associations, (iv) associations with cardiovascular events and (v) associations with mortality. ß The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 2of7 Subjects and methods Patients We used the Renal Beneficiary Utilization System identification and death notification files and the Centers for Medicare & Medicaid Services (CMS) Institutional Inpatient Standard Analytic Files to identify patients initiating maintenance dialysis therapy between calendar years 1996 and 2001, with Medicare as sole primary payer, and with no pneumonia episodes or hospitalizations for cardiovascular disease at the beginning of follow-up (90 days after the first dialysis treatment). The CMS Medical Evidence Report (CMS-2728) was used to define patient characteristics at dialysis inception. Definitions Maintenance dialysis was defined as use of dialysis therapy for 90 days. Medicare Part A institutional claims (inpatient hospitalization or skilled nursing facility, or out-patient home health agency) and Part B physician/supplier claims were used to define pneumonia, while Medicare hospital claims were used to define cardiovascular events, based on discharge diagnoses. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes used to define pneumonia and cardiovascular events are as follows: 1. Pneumonia: 480.xx-486.xx and Viral pneumonia (480.x, 484.1, 487.0), pneumococcal pneumonia (481), other bacterial pneumonia (482.xx, 483.x), fungal pneumonia (484.6, 484.7), and pneumonia caused by other or unspecified organisms (482.89, 482.9, 483.8, 484.3, 484.5, 484.8, 485, 486) are defined by these codes. 2. Cardiovascular events: first occurrence of myocardial infarction (410.x0, 410.x1), congestive heart failure (398.91, 402.x1, 425.x, 428.xx, 518.4), stroke (430, 431, 432.x, 433.xx, 434.xx), or peripheral vascular disease [440.xx to 444.xx (except 443.0), , 447.7]. Estimated glomerular filtration rate (GFR) was calculated from serum creatinine values immediately before the first dialysis session using the Modification in Diet and Renal Disease Study formula [6]: GFR ¼ 186 (serum creatinine in mg/dl) age (1.210 if black race) (if female). Outcome analysis For the outcome pneumonia, follow-up started after 90 days on dialysis therapy and ended at the earliest occurrence of one of the following: 1 year of follow-up, change in dialysis modality, transplantation, loss to follow-up, change in payer status or death. To evaluate the association between pneumonia and cardiovascular hospitalizations and death, follow-up for patients with pneumonia during the first year of dialysis (cases) began at the incident pneumonia date, and for patients without pneumonia (controls), at 1 year of dialysis therapy. For first cardiovascular hospitalization, follow-up ended at the earliest occurrence of the following: transplantation, loss to follow-up, change in payer status, death or 31 December 2003, for cases and controls, and at the occurrence of pneumonia for controls. For death, follow-up ended at the earliest occurrence of one of the following: transplantation, death or 31 December 2003, for cases and controls, and at the occurrence of pneumonia for controls. For outcomes of first cardiovascular hospitalization and death, the following patients were excluded: those with modality change, transplantation or change in payer status before the occurrence of the first pneumonia during the first year; those lost to follow-up; those who died or received a transplant but had no pneumonia during the first year; and those who died or received a transplant and had pneumonia on the same date. Patients with myocardial infarction, congestive heart failure, stroke or peripheral vascular disease listed as a comorbid condition on their Medical Evidence Reports were excluded from the cardiovascular outcome analysis, as were those who had cardiovascular hospitalizations before pneumonia during the first year and those who had cardiovascular hospitalizations but no pneumonia during the first year. A Cox proportional hazards model was used to identify baseline associations of first pneumonia event during the follow-up period. Kaplan Meier analysis was used to calculate cumulative survival probabilities following the first occurrence of pneumonia, with the incident pneumonia date chosen as the first day of follow-up. An interval Poisson model was used to obtain the adjusted relative risks, cardiovascular hospitalization rate and mortality rate because of non-constant temporal evolution of relative risks. The model was adjusted for incident dialysis year, modality, age, sex, race, Hispanic ethnicity, comorbid conditions, GFR, haemoglobin, serum albumin and body mass index. Results H. Guo et al. The mean patient age of the study population was 63.8 years; 48.0% had diabetes mellitus as a comorbid condition, and 9.6% used peritoneal dialysis as initial therapy (Table 1). Within a year of initiating dialysis therapy, 21.0% of the study population ( patients) developed pneumonia, an overall event rate of 27.9/100 patientyears. The corresponding rate for hospitalizations with pneumonia as primary diagnosis was 6.1/100 patientyears, for hospitalization with pneumonia as secondary diagnosis 5.7, and for out-patient-only diagnosis of pneumonia Pneumonia rates were 59% higher in haemodialysis patients than in peritoneal dialysis patients (29.0 vs 18.2/100 patient-years, respectively, P < ). From the associated microbiological spectrum, no organism was specified in 84.37% of cases; 4.73% of cases were attributed to gram-positive bacteria, and 4.01% to gram-negative bacteria (Table 2). Antecedent associations of pneumonia were calculated from Cox regression models in which first occurrence of pneumonia was the outcome variable (Tables 1 and 3). While adjusted hazards ratios for pneumonia remained similar, hazards ratios for inpatient pneumonia increased and hazards ratios

3 Pneumonia in dialysis patients 3 of 7 Table 1. Baseline characteristics and associations with pneumonia and adjusted hazards ratios (AHR) (95% CI) for all pneumonia and inpatient primary diagnosis pneumonia Characteristics All pneumonia Inpatient primary diagnosis pneumonia Percent Rate AHR P Rate AHR P All patients Incident year (reference) (reference) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.03 Initial mode of dialysis Haemodialysis ( ) < ( ) < Peritoneal dialysis (reference) (reference) Age (years) ( ) < ( ) (reference) (reference) ( ) < ( ) ( ) < ( ) < ( ) < ( ) < Female sex ( ) < ( ) 0.3 Hispanic ethnicity ( ) ( ) 0.2 Race White (reference) (reference) Black ( ) < ( ) < Asian ( ) < ( ) < Other ( ) ( ) < Diabetes mellitus ( ) ( ) 0.8 Congestive heart failure ( ) < ( ) < Atherosclerotic heart disease ( ) ( ) 0.8 Cardiac arrest or dysrhythmia ( ) ( ) 0.3 Stroke or transient ischaemic attack ( ) < ( ) 0.2 Peripheral vascular disease ( ) ( ) 1.0 Cancer ( ) < ( ) < Chronic obstructive pulmonary disease ( ) < ( ) < Smoking ( ) < ( ) < Addiction to alcohol or drugs ( ) < ( ) 0.3 Inability to ambulate or transfer ( ) < ( ) < Estimated GFR (ml/min/1.86 m 2 ) < ( ) < ( ) < (reference) 5.8 > ( ) < ( ) < Missing ( ) < ( ) 0.8 Haemoglobin (g/dl) < ( ) < ( ) (reference) 6.0 > ( ) ( ) 0.8 Missing ( ) ( ) 0.2 Serum albumin (g/dl) ( ) < ( ) < (reference) > ( ) < ( ) < Missing ( ) < ( ) 0.2 Body mass index (kg/m 2 ) < ( ) < ( ) < (reference) ( ) < ( ) < ( ) < ( ) < Missing ( ) < ( ) GFR, glomerular filtration rate. for out-patient pneumonia decreased in more recent calendar years. The main associations of pneumonia [arbitrarily defined as adjusted hazards ratios (AHR) >1.25 or <0.80, P < ] were chronic obstructive pulmonary disease (AHR 1.47), inability to transfer or ambulate (AHR 1.44), haemodialysis as initial therapy (AHR 1.41 vs peritoneal dialysis), age 75 (AHR 1.40 vs years), body mass index >30 kg/m 2 (AHR 0.77 vs kg/m 2 ) and age 0 19 years (AHR 0.61 vs years). Other baseline characteristics associated

4 4of7 Table 2. Microbiological spectrum among index pneumonia hospitalizations Organism Pneumonia diagnosis All (n ¼ ) IP primary (n ¼ ) IP secondary (n ¼ ) Outpatient only (n ¼ ) No organism identified Gram-positive bacteria Streptococcus pneumoniae Other Streptococcus species Staphylococcus species Gram-negative bacteria Pseudomonas aeruginosa Hemophilus influenzae Klebsiella pneumoniae Escherichia coli Other gram-negative Anaerobic bacteria Atypical bacteria Mycoplasma pneumoniae Legionella pneumophila Viral Fungal Other specified organism with pneumonia included female sex, non-hispanic ethnicity, white and other race, congestive heart failure, stroke or transient ischaemic attack, peripheral vascular disease, cancer, smoking, addiction to drugs or alcohol, higher estimated GFR at dialysis initiation and lower levels of haemoglobin, serum albumin and body mass index. Association patterns were generally similar when hospitalization with pneumonia as primary diagnosis, hospitalization with pneumonia as secondary diagnosis and out-patient-only diagnosis of pneumonia were used as outcomes. Cumulative survival probabilities were 0.51 at 1 year after the first occurrence of pneumonia (Figure 1). Figures 2 and 3 show adjusted mortality rates, cardiovascular hospitalization rates and associated relative risks for patients with and without pneumonia. The adjusted mortality rate was 73.2/100 patient-years and the cardiovascular hospitalization rate was 65.1/100 patient-years in the initial 6-month interval after pneumonia, declining to 31.1 for mortality and 27.8 for cardiovascular disease between 54 and 60 months later. The corresponding relative risks rates were 4.99 times at 6 months and 2.12 times at 5 years for mortality, and 3.02 and 1.45 times for cardiovascular events. H. Guo et al. All analyses were repeated after patients with chronic obstructive primary disease were excluded. The findings were virtually identical and are not presented here. Similarly, we repeated the analyses for pneumonia diagnoses in which a specific organism was identified. The antecedent associations and prognostic implications were similar to those presented here, with the exception that rates of pneumonia in which a specific organism was identified declined in successive years, such that adjusted hazards ratios were 0.65 (P < ) in 2001, compared with Discussion We found that one in five patients was diagnosed with pneumonia in the 1-year period following inception of dialysis therapy. Of pneumonia occurrences, 42% involved hospitalization, with pneumonia being the primary diagnosis in approximately half of these. Older age, inability to transfer or ambulate, chronic obstructive pulmonary disease and mode of dialysis therapy, with higher rates in haemodialysis compared with peritoneal dialysis patients, were the most obvious associations. In addition to being common, pneumonia was a harbinger of cardiovascular events and death. While the overall risk of pneumonia remained similar over time, treatment practices may have changed, as hazards ratios for inpatient pneumonia increased and hazards ratios for out-patient pneumonia decreased in more recent calendar years. The clinical epidemiology of pneumonia in dialysis patients has received comparatively little attention to date. The United States Renal Data System shows that pulmonary infections account for about 115 hospital admissions per 1000 patient-years at risk in dialysis patients [1]. Other observational studies suggest that nosocomial infections, including pneumonia, are much more common in hospitalized dialysis patients than in their non-dialyzed counterparts [7]. Death rates from pulmonary infections are estimated to be 14- to 16-fold higher in dialysis patients than in the general population [2]. In contrast to the apparent frequency with which pneumonia occurs in dialysis patients, research into risk factors and potential associations with cardiovascular events and death in this population is sparse. This is surprising when one considers that dialysis patients may be chronically immunosuppressed, by virtue of the uremic internal milieu and the very frequent coexistence of serious comorbid medical conditions [3,8]. We found pneumonia rates substantially higher than expected from general population rates. In addition, hospitalized pneumonia rates, at approximately 14/100 patient-years, appeared to be substantially higher than the 9/100 patient-years that we previously reported for haemodialysis patients from 1993 [5]. By comparison, a study of Medicare patients in the United States in 1997 reported an incidence rate for hospitalized, community-acquired pneumonia of 18.3/1000 patientyears, approximately one-fifteenth of that observed in

5 Pneumonia in dialysis patients 5of7 Table 3. Adjusted hazards ratios (AHR) (95% CI) for inpatient secondary diagnosis pneumonia and outpatient-only diagnosed pneumonia Characteristics Inpatient secondary diagnosis pneumonia Outpatient-only diagnosed pneumonia Rate AHR P Rate AHR P All patients Incident year (reference) (reference) ( ) ( ) ( ) ( ) ( ) ( ) ( ) < ( ) < ( ) < ( ) < Initial mode of dialysis Haemodialysis ( ) < ( ) < Peritoneal dialysis (reference) (reference) Age (years) ( ) < ( ) < (reference) (reference) ( ) < ( ) < ( ) < ( ) < ( ) < ( ) < Female sex ( ) ( ) < Hispanic ethnicity ( ) ( ) 0.05 Race White (reference) (reference) Black ( ) ( ) < Asian ( ) ( ) Other ( ) ( ) 0.06 Diabetes mellitus ( ) ( ) 0.5 Congestive heart failure ( ) < ( ) < Atherosclerotic heart disease ( ) ( ) 0.9 Cardiac arrest or dysrhythmia ( ) ( ) 0.4 Stroke or transient ischaemic attack ( ) < ( ) < Peripheral vascular disease ( ) ( ) Cancer ( ) < ( ) Chronic obstructive pulmonary disease ( ) < ( ) < Smoking ( ) ( ) 0.3 Addiction to alcohol or drugs ( ) < ( ) < Inability to ambulate or transfer ( ) < ( ) < Estimated GFR (ml/min/1.86 m 2 ) < ( ) ( ) < (reference) > ( ) < ( ) < Missing ( ) ( ) Haemoglobin (g/dl) < ( ) ( ) (reference) > ( ) ( ) 0.6 Missing ( ) ( ) 0.5 Serum albumin (g/dl) ( ) < ( ) < (reference) > ( ) < ( ) < Missing ( ) < ( ) 0.01 Body mass index (kg/m 2 ) < ( ) < ( ) < (reference) ( ) < ( ) < ( ) < ( ) < Missing ( ) ( ) < GFR, glomerular filtration rate. the dialysis patients we studied [9]. An identified microorganism was found in only one out of every six cases of pneumonia in our study. Similarly low yields have also been reported in general population studies. For example, one study prospectively followed four hospitals and one health maintenance organization in the United States and Canada; an attempt at microbiological confirmation was made in 29.7% of out-patients, and 5.7% had an assigned microbiological cause; microbiological tests were performed for 95.7% of patients hospitalized with pneumonia and 29.6% had an assigned microbiological cause [10].

6 6of7 0.1 Fig. 1. Cumulative survival probabilities following pneumonia. Fig. 2. Interval Poisson analysis, showing mortality rates (upper panel) and relative risks (lower panel), in patients with and without pneumonia. The error bars represent 95% confidence intervals. Associations between pneumonia and older age, immobility and chronic obstructive pulmonary disease were not unexpected. Even when adjustment was made for differences in measured comorbidity, pneumonia rates were noticeably higher in haemodialysis patients than in peritoneal dialysis patients. Possibly, higher burdens of unmeasured comorbidity may explain some of this disparity. One is tempted, nevertheless, to speculate that therapy-related factors may be H. Guo et al. partly responsible. For example, haemodialysis is predominantly practiced in institutional sessions, so that exposure levels to other haemodialysis patients and health care personnel are likely to be higher. We also found that higher body mass index was associated with a lower risk of developing pneumonia, even when extensive comorbidity and age adjustments were made. These findings mirror observations made in dialysis populations when mortality was the primary study outcome. This relatively consistent finding is surprising, because obesity is a cardinal mortality risk factor in the general population. Although the cause of this consistent but unexpected observation is unknown, it has been speculated that unrecognized inflammation may be responsible [11 22]. We found that mortality rates were considerably higher than expected after episodes of pneumonia. A similar pattern was observed for fatal and nonfatal cardiovascular event rates. End-stage renal disease is widely understood to be a state of inflammatory, endothelial and redox dysfunction [23 25]. Micro-inflammation is a pivotal contributor to the pathogenesis of atherosclerosis [26] and sepsis has profound effects on the cardiovascular system [27]. Pneumonia typically leads to macro -inflammation. Standard indices of inflammatory activity were not available in this study. Thus, our hypothesis, that pneumonia and subsequent cardiovascular events reflect sudden increases in inflammatory activity, remains speculative. The limitations of this study should be pointed out. The study was retrospective and clinical events, including pneumonia, were identified from administrative claims. Unlike classic prospective designs, a single a priori definition of pneumonia was not applied to all potential episodes and biological specimens were not collected. Several pneumonia cases occurred after admission to hospital with another serious illness, so that some of the adverse prognostic connotations may be artifactual. Pertinent medication data were not available, and some data elements, such as the baseline comorbidity assessments, are known to be incomplete in the data set we used [28]. Our study, nevertheless, may have clinical relevance. The burden of disease and the associated mortality associations might encourage dialysis health care professionals to use routinely recommended preventive measures such as vaccination for influenza and pneumococcal disease. Heightened diagnostic awareness might facilitate timely diagnosis and treatment. This study suggests that pneumonia in dialysis patients should be a focus for observational and therapeutic research. Acknowledgements. The data reported here have been supplied by the United States Renal Data System. This study was performed as a deliverable under Contract No. N01-DK (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland). We thank United States Renal Data System colleagues Nan Booth, MSW, MPH, for manuscript editing, and Beth Forrest for manuscript preparation.

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