Elisabeth W. Boeschoten

Relative Contribution of Residual Renal Function and Different Measures of Adequacy to Survival in Hemodialysis Patients: An analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2

A high delivered Kt/V(urea) (dKt/V(urea)) is advocated in the U.S. National Kidney Foundation Dialysis Outcomes Quality Initiative guidelines on hemodialysis (HD) adequacy, irrespective of the presence of residual renal function. The contribution of treatment adequacy and residual renal function to patient survival was investigated. The Netherlands Cooperative Study on the Adequacy of Dialysis is a prospective multicenter study that includes incident ESRD patients older than 18 yr. The longitudinal data on residual renal function and dialysis adequacy of patients who were treated with HD 3 mo after the initiation of dialysis (n = 740) were analyzed. The mean renal Kt/V(urea) (rKt/V(urea)) at 3 mo was 0.7/wk (SD 0.6) and the dKt/V(urea) at 3 mo was 2.7/wk (SD 0.8). Both components of urea clearance were associated with a better survival (for each increase of 1/wk in rKt/V(urea), relative risk of death = 0.44 [P < 0.0001]; dKt/V(urea), relative risk of death = 0.76 [P < 0.01]). However, the effect of dKt/V(urea) on mortality was strongly dependent on the presence of rKt/V(urea), low values for dKt/V(urea) of <2.9/wk being associated with a significantly higher mortality in anuric patients only. Furthermore, an excess of ultrafiltration in relation to interdialytic weight gain was associated with an increase in mortality independent of dKt/V(urea). In conclusion, residual renal clearance seems to be an important predictor of survival in HD patients, and the dKt/V(urea) should be tuned appropriately to the presence of renal function. Further studies are required to substantiate the important role of fluid balance in HD adequacy.

The relative importance of residual renal function compared with peritoneal clearance for patient survival and quality of life: an analysis of the netherlands cooperative study on the adequacy of dialysis (Necosad)-2

BACKGROUND The guidelines from the US National Kidney Foundation Dialysis Outcomes Quality Initiative on peritoneal dialysis (PD) assume equivalence between the peritoneal and the renal solute clearance. The authors examined in a prospective cohort study of incident dialysis patients the relative contribution of residual renal function and peritoneal clearance to patient survival and quality of life (QoL). METHODS The authors analyzed the longitudinal data on residual renal function, clearance by dialysis, and QoL of those patients who were treated with PD 3 months after the start of dialysis and participated in a prospective multicenter study in the Netherlands (n = 413). RESULTS The mean age was 52 years, the mean residual glomerular filtration rate (rGFR) at 3 months was 4.1 mL/min/1.73 m2 (SD: 2.7), and the mean peritoneal creatinine clearance (pCrCl) at 3 months was 4.1 mL/min/1.73 m2 (SD: 1.1). The 2-year survival was 84%. For each mL/min/1.73 m2 increase in rGFR, a 12% reduction in mortality rate was found (relative risk of death [RR] = 0.88, P = 0.039). In contrast, no significant effect of pCrCl on patient survival was established (RR = 0.91, P = 0.47). The differential impact of rGFR and pCrCl was confirmed in an analysis on combined patient and technique survival and in an analysis on a number of generic and disease-specific dimensions of QoL. CONCLUSION The beneficial effect of renal clearance and the absence of an effect of peritoneal clearance in the range of values common in current practice on patient outcome indicate that the 2 components of total solute clearance should not be regarded as equivalent. Higher peritoneal clearance targets do not necessarily improve patient outcome.

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.

Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study

BACKGROUND The majority of dialysis patients suffer from vitamin D deficiency, which might contribute to an adverse health outcome. We aimed to elucidate whether European dialysis patients with low 25-hydroxyvitamin D (25(OH)D) levels are at increased risk of mortality and specific fatal events. METHODS This was a prospective cohort study of incident dialysis patients in the Netherlands (the NECOSAD). We selected all patients with measured 25(OH)D at 12 months after the start of dialysis, the baseline for our study. By Cox regression analyses, we assessed the impact of 25(OH)D levels on short-term (6 months of follow-up) as well as longer-term mortality (3 years of follow-up). Associations of 25(OH)D levels with cardiovascular and non-cardiovascular mortality were also determined. RESULTS The data from 762 patients (39% females, age 59 ± 15 years, 25(OH)D = 18 ± 11 ng/mL) were available. Fifty-one and 213 patients died during a follow-up of 6 months and 3 years, respectively. After adjustments for possible confounders, the hazard ratio (HR) (with 95% CI) for mortality was 2.0 (1.0-3.8) for short-term and 1.5 (1.0-2.1) for longer-term mortality when comparing patients with 25(OH)D levels ≤ 10 ng/mL with those presenting with 25(OH)D levels > 10 ng/mL. Adjusted HRs for cardiovascular mortality were 2.7 (1.1-6.5) and 1.7 (1.1-2.7) for short- and longer-term mortality, respectively. For non-cardiovascular mortality, we observed no relevant association overall. The impact of 25(OH)D levels on clinical events was modified by parathyroid hormone (PTH) status, with low 25(OH)D levels meaningfully affecting outcomes only in patients with PTH levels above the median of 123 pmol/L. CONCLUSIONS Vitamin D deficiency in dialysis patients is associated with an adverse health outcome, in particular with short-term cardiovascular mortality. Intervention studies are urgently needed to evaluate whether vitamin D supplementation improves health outcomes of dialysis patients.

Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients

BACKGROUND Previous studies have shown that simple imaging methods may be useful for detection of vascular calcifications in dialysis patients. Based on annual, plain chest X-rays during follow-up on dialysis, we studied the associations of mineral metabolism with the presence and progression of aortic calcification. In addition, we assessed the impact of aortic calcification on mortality. METHODS Three hundred and eighty-four patients who started haemodialysis or peritoneal dialysis between 1997 and 2007 were included (age 61 ± 15 years, 64% male, 61% haemodialysis). Annual chest X-rays were screened for calcification in the aortic arch, and patients were categorized as having no, moderate or severe calcification. Progression was defined as an increase in calcification category during follow-up on dialysis. RESULTS At baseline, 96 (25%) patients had severe, 205 (53%) patients had moderate and 83 (22%) patients had no aortic calcification. For 237 of the 288 patients with no or moderate calcifications at baseline, X-rays were available for follow-up. During follow-up (mean 2.3 years), aortic calcification progressed in 71 patients (30%). We found that baseline plasma calcium > 9.5 mg/dL and iPTH > 300 pg/mL were associated with progression [odds ratios of 3.1, 95% confidence interval (1.2-8.2) and 4.4 (1.4-14.1), respectively]. Progression of aortic calcification was significantly associated with increased risk of all-cause mortality (hazard ratio: 1.9; 95% CI: 1.2-3.1) and cardiovascular mortality (hazard ratio: 2.7; 95% CI: 1.3-5.6). CONCLUSIONS Aortic calcification progressed in almost a third of the patients during dialysis. Hypercalcaemia and hyperparathyroidism were associated with an increased risk of progression. Progression of aortic calcification was significantly related to an increased mortality risk.

Illness perceptions in dialysis patients and their association with quality of life

The present study explored illness perceptions of end stage renal disease (ESRD) patients on both haemodialysis (HD) and peritoneal dialysis (PD) treatment, and their associations with quality of life. Leventhals self-regulation model (SRM) was used as a theoretical framework. Illness perceptions and quality of life were assessed with the IPQ-R and the SF-36 in 91 HD and 42 PD patients participating in the NECOSAD-study. Compared to HD patients, PD patients experienced more personal control and had a better understanding of the illness. Illness perceptions explained from 17 to 51% of the variance in quality of life scores. Perception of more symptoms, more consequences and lower personal control were associated with lower well-being. The concept of illness perceptions is useful in understanding the impact of ESRD and of dialysis treatment on quality of life. Interventions aimed at providing more knowledge about ESRD and dialysis, and provision of skills to coping with the illness and its consequences may improve quality of life in dialysis patients.

Adjustment for Comorbidity in Studies on Health Status in ESRD Patients: Which Comorbidity Index to Use?

Health status can be an important outcome in studies on patients with end-stage renal disease (ESRD). In these studies, adjustment for prognostic factors, such as comorbidity, often has to be made. None of the comorbidity indices that are commonly used in research on ESRD patients has been validated for studies on health status. This study evaluated three existing indices (Khan, Davies, and Charlson) and four indices specifically developed for use in studies on health status. In a large prospective multi-center study (NECOSAD-2), new ESRD patients were included (n = 1041). Comorbidity was assessed at the start of dialysis. Health status was assessed with the physical and mental component summary score of the SF-36 (PCS and MCS), the symptoms dimension of the KDQOL-SF, and the Karnofsky Scale. Patient data were randomly allocated to a modeling or a testing set. The new indices were developed in the modeling set. The three existing indices explained about the same percentage of variance in the PCS (7 to 8%), MCS (1 to 3%), symptoms (2 to 4%), and Karnofsky (10 to 12%). The new indices performed better than the existing indices in the modeling population (13% PCS, 10% MCS, 10% symptoms, 18% Karnofsky), but not in the testing population (8% PCS, 1% MCS, 3% symptoms, 8% Karnofsky). Individual comorbidities explained more variance in PCS (10 to 15%), MCS (1 to 7%), symptoms (6 to 11%), and Karnofsky (11 to 18%) than comorbidity indices. The Khan, Davies, and the Charlson indices will adjust to the same extent for the potential confounding effect of comorbidity in studies with health status as an outcome. Separate comorbidity diagnoses will adjust best for comorbidity.

Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model

BACKGROUND Declining residual renal function, as indicated by the glomerular filtration rate (GFR), is associated with an increased mortality risk in patients with end-stage renal disease (ESRD) on dialysis. METHODS We monitored GFR and mortality in 1800 haemodialysis (HD) and peritoneal dialysis (PD) patients in 1996-2006. We used a marginal structural model to estimate the causal effects both of GFR when it was not completely lost and of the subsequent full loss of GFR on mortality, avoiding the drawbacks of standard regression models that include covariates to adjust for confounding. Instead, effect estimates were adjusted for possible baseline and time-varying confounders using inverse probability weighting. RESULTS We estimated a hazard ratio (HR) corresponding to the effect of the full loss of GFR on mortality, as compared to not having fully lost GFR, of 1.50 [95% confidence interval (CI) 1.09-2.07]. The HR corresponding to the effect of GFR when GFR is not (yet) fully lost on mortality was 0.97 (95% CI 0.92-1.02) (per mL/min/1.73 m(2)). We found no significant difference in the effect of GFR on mortality between patients starting on PD and HD. CONCLUSIONS Preventing or delaying the full loss of GFR can improve survival in dialysis patients. This supports the importance that is given to the effect of treatment options for patients with ESRD on the rate of decline of the residual renal function.