Diana C. Grootendorst

Cardiovascular and noncardiovascular mortality among patients starting dialysis

CONTEXT Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. DESIGN, SETTING, AND PATIENTS Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). MAIN OUTCOME MEASURES Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. RESULTS Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). CONCLUSION Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.

Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey

Objective To find an effective screening strategy for detecting patients with chronic kidney disease and to describe the natural course of the disease. Design Eight year follow-up of a cross sectional health survey (the HUNT II study). Setting Nord-Tr�ndelag County, Norway Participants 65�604 people (70.6 % of all adults aged ≥20 in the county). Main outcome measures Incident end stage renal disease (ESRD) and cardiovascular mortality monitored by individual linkage to central registries. Results 3069/65 604 (4.7%) people had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), so we would need to screen 20.6 people (95% confidence interval 20.0 to 21.2) to identify one case. Restriction of screening to those with hypertension, diabetes, or age >55 would identify 93.2% (92.4% to 94.0%) of patients with chronic kidney disease, with a number needed to screen of 8.7 (8.5 to 9.0). Restriction of screening according to guidelines of the United States kidney disease outcomes quality initiative (US KDOQI) gave similar results, but restriction according to the United Kingdoms chronic kidney disease guidelines detected only 60.9% (59.1% to 62.8%) of cases. Screening only people with previously known diabetes or hypertension detected 44.2% (42.7% to 45.7%) of all cases, with a number needed to screen of six. During the eight year follow-up only 38 of the 3069 people with chronic kidney disease progressed to end stage renal disease, and the risk was especially low in people without diabetes or hypertension, women, and those aged ≥70 or with a glomerular filtration rate 45-59 ml/min/1.73 m2 at screening. In contrast, there was a high cardiovascular mortality: 3.5, 7.4, and 10.1 deaths per 100 person years among people with a glomerular filtration rate 45-59, 30-44, and <30 ml/min/1.73 m2, respectively. Conclusion Screening people with hypertension, diabetes mellitus, or age >55 was the most effective strategy to detect patients with chronic kidney disease, but the risk of end stage renal disease among those detected was low.

Performance of the Cockcroft-Gault, MDRD, and New CKD-EPI Formulas in Relation to GFR, Age, and Body Size

BACKGROUND AND OBJECTIVES We compared the estimations of Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to a gold standard GFR measurement using (125)I-iothalamate, within strata of GFR, gender, age, body weight, and body mass index (BMI). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS For people who previously underwent a GFR measurement, bias, precision, and accuracies between measured and estimated kidney functions were calculated within strata of the variables. The relation between the absolute bias and the variables was tested with linear regression analysis. RESULTS Overall (n = 271, 44% male, mean measured GFR 72.6 ml/min per 1.73 m(2) [SD 30.4 ml/min per 1.73 m(2)]), mean bias was smallest for MDRD (P < 0.01). CKD-EPI had highest accuracy (P < 0.01 compared with Cockcroft-Gault), which did not differ from MDRD (P = 0.14). The absolute bias of all formulas was related to age. For MDRD and CKD-EPI, absolute bias was also related to the GFR; for Cockcroft-Gault, it was related to body weight and BMI as well. In all extreme subgroups, MDRD and CKD-EPI provided highest accuracies. CONCLUSIONS The absolute bias of all formulas is influenced by age; CKD-EPI and MDRD are also influenced by GFR. Cockcroft-Gault is additionally influenced by body weight and BMI. In general, CKD-EPI gives the best estimation of GFR, although its accuracy is close to that of the MDRD.

Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD

Background: Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD. Methods: In a crossover study, 38 patients with COPD (mean (SD) age 63.1 (7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV1) 61.0 (12.6)% predicted) received 500 μg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly. Results: Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p<0.001), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p>0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and α2-macroglobulin in sputum and the release of tumour necrosis factor α from blood cells were significantly reduced by roflumilast compared with placebo treatment (p<0.05 for all). Post-bronchodilator FEV1 improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018). Conclusion: PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV1.

Association between serum albumin and mortality in dialysis patients is partly explained by inflammation, and not by malnutrition.

OBJECTIVE We investigated the effects of inflammatory and nutritional status on the association between serum albumin and mortality in hemodialysis (HD) and peritoneal dialysis (PD) patients. DESIGN AND PATIENTS This was a prospective cohort study of incident dialysis patients starting HD or PD. Inflammation (C-reactive protein >or=5 or >or=10 mg/L), malnutrition (1 to 5 on the 7-point subjective global assessment [SGA]), and low protein intake (normalized protein equivalent of nitrogen appearance [nPNA] <0.99 g/kg/day) were measured at 3 months after the start of dialysis. SETTING The study involved 38 dialysis centers in The Netherlands. MAIN OUTCOME MEASURE We ascertained all-cause mortality during the first 2 years after the start of dialysis. RESULTS In total, 700 patients were included (mean SD age, 59 [+/-15] years; serum albumin, 3.3 (0.7) g/dL; 60% men; 454 starting HD, and 246 starting PD). The 2-year mortality was 21%. In HD patients, the mortality (hazard ratio [HR], with 95% confidence interval [95% CI]) per unit decrease in serum albumin (g/dL) was 1.47 (95% CI, 1.07 to 2.00). Adjustment for SGA did not decrease this risk, whereas adjustment for nPNA decreased the HR to 1.45 (95% CI, 1.06 to 1.97). The mortality risk decreased to 1.30 (95% CI, 0.95 to 1.78) after adjustment for inflammation, and did not further decrease after additional adjustment for SGA and nPNA. Additional adjustments for age, sex, and comorbidity decreased the HR to 1.09 (95% CI, 0.79 to 1.51). In PD patients, the effects of adjustments on the mortality risk of serum albumin (1.38; 95% CI, 0.87 to 2.20) were similar. CONCLUSION In dialysis patients, a 1-g/dL decrease in serum albumin was associated with an increased mortality risk of 47% in HD patients and 38% in PD patients. These mortality risks were in part explained by the inflammatory pathway. The mortality risks associated with serum albumin were not a consequence of malnutrition, as measured with SGA and nPNA. These findings imply that nutritional status cannot be assessed with precision by the measurement of serum albumin in dialysis patients.

Excess mortality due to interaction between protein-energy wasting, inflammation and cardiovascular disease in chronic dialysis patients

BACKGROUND Protein-energy wasting (PEW), inflammation and cardiovascular diseases (CVD) clearly contribute to the high mortality in chronic dialysis. Our aim was to examine the presence of additive interaction between these three risk factors in their association with long-term mortality in dialysis patients. METHODS Patients from a prospective multi-centre cohort study among ESRD patients starting with their first dialysis treatment [the Netherlands Co-operative Study on the Adequacy of Dialysis-2 (NECOSAD-II)] with complete data on these risk factors were included (n = 815, age: 59 +/- 15 years, 60% men, 65% HD). Hazard ratios (HR) were calculated for all-cause mortality in 7 years of follow-up. The presence of interaction between the three risk factors was examined, based on additivity of effects. RESULTS Of all patients, 10% only suffered from PEW (1-5 on the 7-point subjective global assessment), 11% from inflammation (CRP >/=10 mg/L), 14% from CVD and 22% had any combination of two components. Only 6% of the patients had all three risk factors. Patients with either PEW (HR: 1.6, 95% CI: 1.3-2.0), inflammation (1.6, 1.3-2.0) or CVD (1.7, 1.4-2.1) had an increased mortality risk. In patients with all three risk factors, the crude mortality rate of 45/100 person-years was 16 deaths/100 person-years higher than expected from the addition of the solo effects of PEW, inflammation and CVD. The relative excess risk due to interaction was 2.9 (95% CI: 0.3-5.4), implying additive interaction. After adjustment for age, sex, treatment modality, primary kidney diseases, diabetes and malignancy the HR for patients with all three risk factors was 4.8 (95% CI: 3.2-7.2). CONCLUSIONS The concurrent presence of PEW, inflammation and CVD increased the mortality risk strikingly more than expected, implying that PEW interacts with inflammation and CVD in dialysis patients.

Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis

Bronchial biopsy specimens from chronic obstructive pulmonary disease (COPD) patients demonstrate increased numbers of CD8+ T-lymphocytes, macrophages and, in some studies, neutrophils and eosinophils. Smoking cessation affects the rate of forced expiratory volume in one second (FEV1) decline in COPD, but the effect on inflammation is uncertain. Bronchial biopsy inflammatory cell counts were compared in current and ex-smokers with COPD. A pooled analysis of subepithelial inflammatory cell count data from three bronchial biopsy studies that included COPD patients who were either current or ex-smokers was performed. Cell count data from 101 subjects, 65 current smokers and 36 ex-smokers, were analysed for the following cell types: CD4+ and CD8+ T-lymphocytes, CD68+ (monocytes/macrophages), neutrophil elastase+ (neutrophils), EG2+ (eosinophils), mast cell tryptase+ and cells mRNA-positive for tumour necrosis factor-α. Current smokers and ex-smokers were similar in terms of lung function, as measured by FEV1 (% predicted), forced vital capacity (FVC) and FEV1/FVC. The results demonstrate that there were no significant differences between smokers and ex-smokers in the numbers of any of the inflammatory cell types or markers analysed. It is concluded that, in established chronic obstructive pulmonary disease, the bronchial mucosal inflammatory cell infiltrate is similar in ex-smokers and those that continue to smoke.

Benefit of kidney transplantation beyond 70 years of age

Background. Kidney transplantation generally improves long-term survival in patients with end-stage renal disease. However, in patients older than 70 years of age, only limited data are available that directly compare the potential survival benefit of transplantation versus dialysis. Methods. All patients aged above 70 years who started dialysis between 1990 and 2005 and were waitlisted for kidney transplantation were included in the study. They were categorized according to time periods of inclusion (1990–99 vs 2000–05). Survival rates of altogether 286 dialysis patients were analyzed with a Kaplan–Meier model, as well as with a time-dependent Cox model. Comparisons were made between those who received a transplant and those who did not, and further between the two time periods. Results. Median age at inclusion was 73.6 years (interquartile range 72.3–75.6). Two hundred and thirty-three patients (81%) received a kidney transplant during follow-up. Transplant recipients experienced an increased mortality in the first year after transplantation when compared to waitlisted patients. Patients starting dialysis between 1990 and 1999 had no significant long-term benefit of transplantation; HR for death 1.01 (0.58–1.75). In contrast, there was a substantial long-term benefit of transplantation among those starting dialysis after 2000; HR for death 0.40 (0.19–0.83), P = 0.014. Conclusions. Survival after kidney transplantation in patients over 70 years has improved during the last decade and offers a survival advantage over dialysis treatment. Our experience supports the use of kidney transplantation in this age group if an increased early post-operative risk is accepted. This transplant policy may be challenged for priority reasons.

The MDRD formula does not reflect GFR in ESRD patients

BACKGROUND The Modification of Diet in Renal Disease (MDRD) equation is widely used for the estimation of glomerular filtration rate (GFR) from plasma creatinine. It has been well validated in patients with various degrees of impaired kidney function, but not in patients with end-stage renal disease (ESRD). Plasma creatinine is determined by GFR and muscle mass. Importance of the latter may increase at low GFR. Our aim was to firstly compare estimated GFR (eGFR by MDRD equation) with measured GFR (mGFR, mean of creatinine and urea clearance) just before the start of dialysis. Secondly, the relationship of eGFR and mGFR with mortality and muscle mass was analysed. METHODS ESRD patients with 24-h urine collections and a plasma sample available at the start of dialysis [n = 569, 61% male, mean (standard deviation) age 58 (15) years] were selected from the Netherlands Cooperative Study on the Adequacy of Dialysis. Incident dialysis patients were followed until death, transplantation or end of study. RESULTS mGFR was 6.0 (2.6) and eGFR was 6.8 (2.4) mL/min/1.73 m(2). Although eGFR overestimated mGFR with only 0.8 mL/min/1.73 m(2), limits of agreement ranged from - 4.1 to + 5.6 mL/min/1.73 m(2). The highest eGFR values were associated with the highest mortality rates [adjusted hazard ratio 1.4 (1.0, 1.9)]. eGFR but not mGFR was associated with muscle mass (P = 0.001). CONCLUSIONS These data imply that estimation of GFR by equations using plasma creatinine in the denominator cannot be used for this purpose in patients with ESRD because the effect of GFR on plasma creatinine is overruled by that of muscle mass.

The analysis of competing events like cause-specific mortality—beware of the Kaplan–Meier method

Kaplan-Meier analysis is a popular method used for analysing time-to-event data. In case of competing event analyses such as that of cardiovascular and non-cardiovascular mortality, however, the Kaplan-Meier method profoundly overestimates the cumulative mortality probabilities for each of the separate causes of death. This article provides an introduction to the problem of competing events in Kaplan-Meier analysis. It explains cumulative incidence competing risk analysis and demonstrates on a cohort of elderly dialysis patients that, in contrast to the Kaplan-Meier method, application of this method yields unbiased estimates of the cumulative probabilities for cause-specific mortality.