Renée de Mutsert

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.

Association between Body Mass Index and Mortality Is Similar in the Hemodialysis Population and the General Population at High Age and Equal Duration of Follow-Up

The association of body mass index (BMI) with mortality in hemodialysis patients has been found to be reversed in comparison with the general population. This study examined the association of BMI with mortality in the hemodialysis population and the general population when age and time of follow-up were made strictly comparable. Hemodialysis patients who were aged 50 to 75 yr at the start of follow-up were selected from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 (NECOSAD), a prospective cohort study in incident dialysis patients in the Netherlands (n = 722; age 66 +/- 7 yr; BMI 25.3 +/- 4.5 kg/m(2)), and compared with adults who were aged 50 to 75 yr and included in the Hoorn Study, a population-based prospective cohort study in the same country (n = 2436; age 62 +/- 7 yr; BMI 26.5 +/- 3.6 kg/m(2)). In both populations, 2- and 7-yr standardized mortality rates were calculated for categories of BMI. Adjusted hazard ratios (HR) of BMI categories were calculated with a BMI of 22.5 to 25 kg/m(2) as the reference category within each population. In 7 yr of follow-up, standardized mortality rates were approximately 10 times higher in the hemodialysis population than those in the general population. Compared with the reference category, the HR of BMI <18.5 kg/m(2) was 2.0 (95% confidence interval [CI]1.2 to 3.4) in the hemodialysis population and 2.3 (95% CI 0.7 to 7.5) in the general population. Obesity (BMI >or=30 kg/m(2)) was associated with a HR of 1.2 (95% CI 0.8 to 1.7) in the hemodialysis population and 1.3 (95% CI 0.9 to 2.0) in the general population. In conclusion, a hemodialysis population and a general population with comparable age and equal duration of follow-up showed similar mortality risk patterns associated with BMI. This suggests that there is no reverse epidemiology of BMI and mortality in hemodialysis patients. The clinical implication of this study is that to improve survival in the hemodialysis population, more attention should be paid to patients who are underweight instead of overweight.

Survival analysis: time-dependent effects and time-varying risk factors

In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only.

Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose–response meta-regression

AIMS Heart rate variability (HRV) is associated with cardiovascular disease (CVD) in individuals with known CVD. It is less clear whether HRV is associated with a first cardiovascular event. Therefore, we performed a meta-analysis to study the association between HRV and incident cardiovascular events in populations without known CVD. METHODS AND RESULTS We performed a meta-analysis and dose-response meta-regression of studies assessing the association between HRV and CVD. We searched Pubmed, Embase, Web of Science, Cochrane library, ScienceDirect, and CINAHL up to December 2011 for eligible studies. We selected studies that used the standard deviation of the normalized N-N interval (SDNN), low-frequency (LF) or high-frequency (HF) spectral component as a measure of HRV. Primary outcomes were (non)fatal cardiovascular events. Eight studies with a total number of 21 988 participants were included. The pooled relative risk (RR) comparing the lowest level to the highest level of SDNN was 1.35 (95% CI 1.10, 1.67). The pooled RRs for LF and HF were 1.45 (95% CI 1.12, 1.87) and 1.32 (95% CI 0.96, 1.81), respectively. In a meta-regression, the predicted RR of incident CVD of the 10th and 90th HRV (SDNN) percentiles compared with the 50th percentile were 1.50 (95% CI 1.22, 1.83) and 0.67 (95% CI 0.41, 1.09). CONCLUSION In conclusion, low HRV is associated with a 32-45% increased risk of a first cardiovascular event in populations without known CVD. An increase in SDNN of 1% results in an ∼1% lower risk of fatal or non-fatal CVD.

Subjective global assessment of nutritional status is strongly associated with mortality in chronic dialysis patients

BACKGROUND The subjective global assessment of nutritional status (SGA) is used to assess the nutritional status of chronic dialysis patients, but longitudinal data in relation to mortality risk are lacking. OBJECTIVE Our objective was to study the long-term and time-dependent associations of the SGA with mortality risk in chronic dialysis patients. DESIGN In a prospective, longitudinal, observational, multicenter study of incident dialysis patients, the 7-point SGA [7 = normal nutritional status; 1 = severe protein-energy wasting (PEW)] was assessed 3 and 6 mo after the start of dialysis and subsequently every 6 mo during 7 y of follow-up. With Cox regression analysis, we calculated hazard ratios (HRs) of the baseline and time-dependent SGA measurements, adjusted for age, sex, treatment modality, primary kidney diseases, and comorbidity. RESULTS In total, 1601 patients were included [mean (+/-SD) age: 59 +/- 15 y; 61% men; 23% with moderate PEW (SGA(4-5)), and 5% with severe PEW (SGA(1-3))]. There was a dose-dependent trend of the 7-point SGA with mortality. Compared with a normal nutritional status at baseline, SGA(4-5) (HR: 1.6; 95% CI: 1.3, 1.9) and SGA(1-3) (HR: 2.1; 95% CI: 1.5, 2.8) were associated with an increase in 7-y mortality. Time-dependently, these associations were stronger: SGA(4-5) (HR: 2.1; 95% CI: 1.7, 2.5) and SGA(1-3) (HR: 5.0; 95% CI: 3.8, 6.5). CONCLUSIONS In dialysis patients, PEW at baseline assessed with SGA was associated with a 2-fold increased mortality risk in 7 y of follow-up. Time-dependently, this association was even stronger, which indicated that PEW was associated with a remarkably high risk of short-term mortality. These data imply that the 7-point SGA may validly distinguish different degrees of PEW associated with increasing risks of mortality.

The effect of joint exposures: examining the presence of interaction

Clinical epidemiological studies investigate whether an exposure, or risk factor, is causally related to the development or progression of a disease or mortality. It might be of interest to study whether this relation is different in different types of patients. To address such research questions, the presence of interaction among risk factors can be examined. Causal interaction between two risk factors is considered most clinically relevant in epidemiology. Causal interaction occurs when two risk factors act together in causing disease and is explicitly defined as a deviation from additivity on a risk difference scale. Statistical interaction can be evaluated on both an additive (absolute risk) and multiplicative (relative risk) scale, depending on the model that is used. When using logistic regression models, which are multiplicative models, several measures of additive interaction are presented to evaluate whether the magnitude of an association differs across subgroups: the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), or the synergy index (S). For a transparent presentation of interaction effects the recent Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement advises reporting the separate effect of each exposure as well as the joint effect compared with the unexposed group as a joint reference category to permit evaluation of both additive and multiplicative interaction.

Overweight in Early Adulthood, Adult Weight Change, and Risk of Type 2 Diabetes, Cardiovascular Diseases, and Certain Cancers in Men: a Cohort Study

The relative importance of overweight after childhood and excess weight gain during adulthood remains unclear. In 39,909 male participants of the Health Professionals Follow-Up Study who were 40-75 years of age in 1986 and were followed until 2008, we documented 8,755 incident cases of obesity-related chronic diseases (type 2 diabetes mellitus, cardiovascular diseases, and colorectal, renal, pancreatic, and esophageal cancers). We calculated composite and cause-specific hazard ratios using a model that included body mass index (BMI; weight (kg)/height (m)(2)) at 21 years of age, weight change since age 21 years, smoking, alcohol consumption, and family histories of myocardial infarction, colon cancer, and diabetes. Compared with a BMI at 21 years of 18.5-22.9, the composite hazard ratio for a BMI of 23-24.9 was 1.22 (95% confidence interval (CI): 1.16, 1.29), that for a BMI of 25.0-27.4 was 1.57 (95% CI: 1.48, 1.67), that for a BMI of 27.5-29.9 was 2.40 (95% CI: 2.17, 2.65), and that for a BMI ≥30.0 was 3.15 (95% CI: 2.76, 3.60). The composite hazard ratios for adult weight gain compared with a stable weight were 1.12 (95% CI: 1.03, 1.22) for a gain of 2.5-4.9 kg, 1.41 (95% CI: 1.31, 1.52) for a gain of 5-9.9 kg, 1.72 (95% CI: 1.59, 1.86) for a gain of 10-14.9 kg, and 2.45 (95% CI: 2.27, 2.63) for a gain ≥15 kg. Adiposity in early adulthood and adult weight gain were both associated with marked increases in the risk of major chronic diseases in middle-aged and older men, and these associations were already apparent at modest levels of overweight and weight gain.

Use of a renal-specific oral supplement by haemodialysis patients with low protein intake does not increase the need for phosphate binders and may prevent a decline in nutritional status and quality of life

BACKGROUND Protein-energy wasting is a frequent and debilitating condition in maintenance dialysis. We randomly tested if an energy-dense, phosphate-restricted, renal-specific oral supplement could maintain adequate nutritional intake and prevent malnutrition in maintenance haemodialysis patients with insufficient intake. METHODS Eighty-six patients were assigned to a standard care (CTRL) group or were prescribed two 125-ml packs of Renilon 7.5(R) daily for 3 months (SUPP). Dietary intake, serum (S) albumin, prealbumin, protein nitrogen appearance (nPNA), C-reactive protein, subjective global assessment (SGA) and quality of life (QOL) were recorded at baseline and after 3 months. RESULTS While intention to treat analysis (ITT) did not reveal strong statistically significant changes in dietary intake between groups, per protocol (PP) analysis showed that the SUPP group increased protein (P < 0.01) and energy (P < 0.01) intakes. In contrast, protein and energy intakes further deteriorated in the CTRL group (PP). Although there was no difference in serum albumin and prealbumin changes between groups, in the total population serum albumin and prealbumin changes were positively associated with the increment in protein intake (r = 0.29, P = 0.01 and r = 0.27, P = 0.02, respectively). The SUPP group did not increase phosphate intake, phosphataemia remained unaffected, and the use of phosphate binders remained stable or decreased. The SUPP group exhibited improved SGA and QOL (P < 0.05). CONCLUSION This study shows that providing maintenance haemodialysis patients with insufficient intake with a renal-specific oral supplement may prevent deterioration in nutritional indices and QOL without increasing the need for phosphate binders.

Obesity and mortality risk among younger dialysis patients

BACKGROUND AND OBJECTIVES Many studies show that obesity in dialysis patients is not strongly associated with mortality but not whether this modest association is constant over age. This study investigated the extent to which the relation of body mass index (BMI) and mortality differs between younger and older dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Adult dialysis patients were prospectively followed from their first dialysis treatment for 7 years or until death or transplantation. Patients were stratified by age (<65 or ≥65 years) and baseline BMI (<20, 20-24 [reference], 25-29, and ≥30 kg/m(2)). RESULTS The study sample included 984 patients younger than 65 years and 765 patients 65 years or older; cumulative survival proportions at end of follow-up were 50% and 16%. Age-standardized mortality rate was 1.7 times higher in obese younger patients than those with normal BMI, corresponding to an excess rate of 5.2 deaths/100 patient-years. Mortality rates were almost equal between obese older patients and those with normal BMI. Excess rates of younger and older patients with low compared with normal BMI were 8.7 and 1.1 deaths/100 patient-years. After adjustment for age, sex, smoking, comorbidity, and treatment modality, hazard ratios by increasing BMI were 2.00, 1, 0.95, and 1.57 for younger patients and 1.07, 1, 0.88, and 0.91 for older patients, implying that obesity is a 1.7-fold (95% confidence interval, 1.1- to 2.9-fold) stronger risk factor in younger than older patients. CONCLUSIONS In contrast to older dialysis patients, younger patients with low or very high BMI had a substantially elevated risk for death.