[Show abstract][Hide abstract] ABSTRACT: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients.
Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort.
Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality.
Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.
PLoS ONE 01/2014; 9(5):e97251. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Factors explaining the association between impaired kidney function and venous thrombosis have not been identified so far. The aim of our study was to determine whether the association between impaired kidney function and venous thrombosis can be explained by the concurrent presence of genetic or acquired venous thrombosis risk factors.
The glomerular filtration rate was estimated (eGFR) in 2473 venous thrombosis patients and 2936 controls from a population-based case-control study. Kidney function was grouped into 6 categories based on percentiles of the eGFR in the controls (>50th percentile [reference], 10th-50th percentile, 5th-10th percentile, 2.5th-5th percentile, 1st-2.5th percentile, and <1st percentile). Several hemostatic factors showed a procoagulant shift with decreasing kidney function in controls, most notably factor VIII and von Willebrand factor (VWF). As compared with eGFR> 50th percentile, factor VIII levels (adjusted mean difference of 60 IU/dl for the <1st eGFR percentile category) and VWF levels (adjusted mean difference of 60 IU/dl for the <1st eGFR percentile category) increased with each percentile category. The ORs for venous thrombosis similarly increased across the categories from 1.1 (95%CI,0.9-1.3) for the 10th-50th percentile to 3.7 (95%CI,2.4-5.7) for the <1st percentile category. Adjustment for factor VIII or von Willebrand factor attenuated these ORs indicating an effect of eGFR on thrombosis through these factors. Adjustments for other risk factors for venous thrombosis did not affect the ORs.
Impaired kidney function affects venous thrombosis risk via concurrently raised factor VIII and von Willebrand factor levels.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: There are only a few risk factors known for primary patency loss in patients with an arteriovenous graft or fistula. Furthermore, a limited number of studies have investigated the association between arteriovenous access modality and primary patency loss and mortality. The aim of this study was to investigate risk factors for patency loss and to investigate the association between graft versus fistula use and outcomes (patency loss and mortality). METHODS: We prospectively followed 919 incident hemodialysis patients and calculated hazard ratios (HRs) for putative risk factors of primary patency loss using Cox regression. Furthermore, HRs were calculated to study the association between graft versus fistula use and two-year primary patency loss and two-year mortality. RESULTS: Cardiovascular disease, prior catheter use, lowest tertile of albumin, highest tertile of hsCRP, and lowest tertile of fetuin-A were associated with primary patency loss in both patients with grafts and fistulas. Increased age, female sex, and diabetes mellitus were only associated with primary patency loss in patients with a fistula. We did not observe an association between primary patency loss and BMI, residual GFR, levels of calcium, phosphorus, and total cholesterol. Furthermore, graft use as compared with fistula use was associated with an 1.4-fold(95%CI 1.0-1.9) increased risk of primary patency loss and with an 1.5-fold(95%CI 1.0-2.2) increased mortality risk. CONCLUSION: Cardiovascular disease, prior catheter use, albumin, hsCRP, and fetuin-A are risk factors for patency loss. Graft use as compared with fistula use was associated with an increased risk of patency loss and mortality.
[Show abstract][Hide abstract] ABSTRACT: Functional variants in the IL6 gene, in particular the -174G/C polymorphism (rs1800795), affect the mortality risk in dialysis patients. Peritoneal dialysis (PD) patients harbouring the C allele of the -174G/C polymorphism of IL6 showed faster peritoneal transport. The aim of this study was to investigate this IL6 variant as risk factor for mortality and technique failure in a large cohort of Caucasian PD patients.
A Dutch multicentre cohort of 398 incident PD patients (NECOSAD) was analysed. Survival analysis was performed for death and technique failure with a maximum follow-up of 5 years. A combined PD cohort from Amsterdam (Academic Medical Center, N = 71) and Brussels (Université catholique de Louvain Medical School, N = 102) was used for independent replication.
In NECOSAD, 105 patients died on dialysis [incidence rate 10.3/100 person-years (py)], and 138 patients experienced technique failure (16.2/100 py), with peritonitis as important cause. Patients with the C/C genotype had a 71% increased mortality risk compared to patients with the G/G genotype (95% confidence interval 0.98-2.98); this effect was mainly a long-term effect: a 2.7-fold increased mortality risk was found in patients having survived 2 years since the start on dialysis, and a 1.7-fold increased risk for the combined end point (mortality or technique failure). In the combined replication cohort, no increased risks were found in patients with the C/C genotype.
The C/C genotype of the -174G/C polymorphism was associated with an increased mortality risk in 398 Dutch incident PD patients. The existence of substantial differences between the two academic replication cohorts and the discovery cohort from NECOSAD and the limited power of these cohorts prevented an independent replication of the NECOSAD findings.
[Show abstract][Hide abstract] ABSTRACT: Background and OBJECTIVES: In automated peritoneal dialysis (APD), a patient's peritoneal membrane is more intensively exposed to fresh dialysate than it is in continuous ambulatory peritoneal dialysis (CAPD). Our aim was to study, in incident peritoneal dialysis (PD) patients, the influence of APD-compared with that of CAPD-on peritoneal transport over 4 years.Design, Setting, Participants, and Measurements: Patients were included if at least 2 annual standard permeability analyses (SPAs) performed with 3.86% glucose were available while the patient was using the same modality with which they had started PD (APD or CAPD). Patients were followed until their first modality switch. Differences in the pattern of SPA outcomes over time were tested using repeated-measures models adjusted for age, sex, comorbidity, primary kidney disease, and year of PD start. RESULTS: The 59 CAPD patients enrolled were older than the 47 APD patients enrolled (mean age: 58 ± 14 years vs 49 ± 14 years; p < 0.01), and they had started PD earlier (mean start year: 2000 vs 2002). Over time, no differences in solute (p > 0.19) or fluid transport (p > 0.13) were observed. Similarly, free water transport (p = 0.43) and small-pore transport (p = 0.31) were not different between the modalities. Over time, patients on APD showed a faster decline in effective lymphatic absorption rate (ELAR: p = 0.02) and in transcapillary ultrafiltration (TCUF: p = 0.07, adjusted p = 0.05). Further adjustment did not change the results. CONCLUSIONS: Compared with patients starting on CAPD, those starting on APD experienced a faster decline in ELAR and TCUF. Other transport parameters were not different over time between the groups.
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 04/2012;
[Show abstract][Hide abstract] ABSTRACT: In this paper we discuss estimation of transition probabilities for semi-Markov multi-state models. Non-parametric and semi-parametric estimators of the transition probabilities for a large class of models (forward going models) are proposed. Large sample theory is derived using the functional delta method and the use of resampling is proposed to derive confidence bands for the transition probabilities. The last part of the paper concerns the presentation of the main ideas of the R implementation of the proposed estimators, and data from a renal replacement study are used to illustrate the behavior of the estimators proposed.
The International Journal of Biostatistics 01/2012; 8(1):23. · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whether the risk of both venous and arterial thrombosis is increased in dialysis patients as compared to the general population is unknown. In addition, it is unknown which subgroups are at highest risk. Furthermore, it is unknown whether having a history of venous thrombosis or arterial thrombosis prior to dialysis treatment increases mortality risk. A total of 455 dialysis patients were followed for objectively verified symptomatic thrombotic events between January 1997 and June 2009. The incidence rates in dialysis patients as compared to the general population was 5.6-fold (95% CI 3.1-8.9) increased for venous thrombosis, 11.9-fold (95% CI 9.3-14.9) increased for myocardial infarction, and 8.4-fold (95% CI 5.7-11.5) increased for ischaemic stroke. The combination of haemodialysis, lowest tertile of albumin, history of venous thrombosis, and malignancy was associated with subsequent venous thrombosis. Increased age, renal vascular disease, diabetes, high cholesterol levels, history of venous thrombosis, and history of arterial thrombosis were associated with subsequent arterial thrombosis. The all-cause mortality risk was 1.9-fold (95% CI 1.1-3.3) increased for patients with a history of venous thrombosis and 1.9-fold (95% CI 1.4-2.6) increased for patients with a history of arterial thrombosis. A potential limitation of this study was that in some risk categories associations with venous thrombosis did not reach statistical significance due to small numbers. In conclusion, dialysis patients have clearly elevated risks of venous thrombosis and arterial thrombosis and occurrence of venous thrombosis or arterial thrombosis prior to the start of dialysis is associated with an increased mortality risk.
Thrombosis and Haemostasis 12/2011; 106(6):1046-52. · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ethnic minority patients on dialysis are reported to have better survival rates relative to Caucasians. The reasons for this finding are not fully understood and European studies are scarce. This study examined whether ethnic differences in survival could be explained by patient characteristics, including psychosocial factors.
We analysed data of the Netherlands Cooperative Study on the Adequacy of Dialysis study, an observational prospective cohort study of patients who started dialysis between 1997 and 2007 in the Netherlands. Ethnicity was classified as Caucasian, Black or Asian, assessed by local nurses. Data collected at the start of dialysis treatment included demographic, clinical and psychosocial characteristics. Psychosocial characteristics included data on health-related quality of life (HRQoL), mental health status and general health perception. Cox proportional hazards analysis was used to explore ethnic survival differences.
One thousand seven hundred and ninety-one patients were Caucasian, 45 Black and 108 Asian. The ethnic groups differed significantly in age, residual glomerular filtration rate, diabetes mellitus, erythropoietin use, plasma calcium, parathormone and creatinine, marital status and general health perception. No ethnic differences were found in HRQoL and mental health status. Crude hazard ratios (HRs) for mortality for Caucasians compared to Blacks and Asians were 3.1 [95% confidence interval (CI) 1.6-5.9] and 1.1 (95% CI 0.9-1.5), respectively. After adjustment for a range of potential explanatory variables, including psychosocial factors, the HRs were 2.5 (95% CI 1.2-4.9) compared with Blacks and 1.2 (95% CI 0.9-1.6) compared with Asians.
Although patient numbers were rather small, this study demonstrates, with 95% confidence, better survival for Black compared to Caucasian dialysis patients and equal survival for Asian compared to Caucasian dialysis patients in the Netherlands. This could not be explained by patient characteristics, including psychosocial factors.
[Show abstract][Hide abstract] ABSTRACT: Genetic association studies are a means to investigate the causal role of genes in diseases in order to unravel pathways involved in the etiology of disease. There are two types of genetic association studies: hypothesis-driven studies, i.e. candidate gene studies, targeting genes with a known or presumed role in pathways or diseases of interest, and non-hypothesis-driven studies, i.e. genome-wide association studies, aiming for the discovery of new genetic associations. This educational article is an introduction to genetic association studies for nephrologists and researchers in the domain of kidney disease.
Nephron Clinical Practice 08/2011; 119(3):c236-9. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although women have a survival advantage in the general population, women on dialysis have similar mortality to men. We hypothesized that this paired mortality risk during dialysis may be explained by a relative excess of cardiovascular-related mortality in women.
We compared 5-year age-stratified cardiovascular and noncardiovascular mortality rates, relative risks, and hazard ratios in a European cohort of incident adult dialysis patients (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry) with the European general population (Eurostat). Cause of death was recorded by ERA-EDTA codes in dialysis patients and by International Statistical Classification of Diseases codes in the general population.
Overall, sex did not have a predictive effect on outcome in dialysis. Stratification into age categories and causes of death showed greater noncardiovascular mortality in young women (<45 years). In other age categories (45 to 55 and >55 years), women presented lower cardiovascular mortality. This cardiovascular benefit was, however, smaller than in the general population. Stratification by diabetic nephropathy showed that diabetic women in all age categories remained at increased mortality risk compared with men, an effect mainly attributed to the noncardiovascular component.
Mortality rates and causes of death in men and women on dialysis vary with age. Increased noncardiovascular mortality may explain the loss of the survival advantage of women on dialysis. Both young and diabetic women starting dialysis are at a higher mortality risk than equal men.
Clinical Journal of the American Society of Nephrology 07/2011; 6(7):1722-30. · 5.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective.
A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed.
The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money.
Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting.
Pharmacogenetics and Genomics 07/2011; 21(7):417-25. · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serum alkaline phosphatase (AP) is associated with vascular calcification and mortality in hemodialysis patients, but AP derives from various tissues of origin. The aim of this study was to assess the effect of bone-specific AP (BAP) on morbidity and mortality in dialysis patients.
From a prospective cohort study of incident dialysis patients in The Netherlands, all patients with measured BAP at 12 months after the start of dialysis (baseline) were included in the analysis (n = 800; mean age, 59 ± 15 years; mean BAP = 18 ± 13 U/L). By Cox regression analyses, we assessed the impact of BAP levels on short-term mortality (6 months) and longer-term mortality (4-year follow-up).
High levels of BAP strongly affected short-term mortality. After adjustment for confounders, patients in the highest BAP tertile had a 5.7-fold increased risk of death within 6 months compared with patients in the lowest tertile. The effect applied to both cardiovascular and noncardiovascular mortality. Furthermore, high levels of BAP were associated with increased cardiovascular mortality in the longer term. In comparison with total AP, the effect sizes related to clinical outcomes were much higher for BAP.
High levels of BAP were strongly associated with short-term mortality in dialysis patients, pointing out the important impact of bone turnover. Longitudinal assessments of BAP may be useful for the treatment monitoring in clinical practice in dialysis patients.
Clinical Journal of the American Society of Nephrology 05/2011; 6(7):1752-9. · 5.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We compared the decline of RRF in patients starting dialysis on APD with those starting on CAPD, because a faster decline on APD has been suggested.
NECOSAD patients starting dialysis on APD or CAPD with RRF at baseline were included and followed for 3 years. Residual GFR (rGFR) was the mean of urea and creatinine clearances. Differences in yearly decline of rGFR were estimated in analyses with linear repeated measures models, whereas the risk of complete loss of RRF was estimated by calculating hazard ratios (HRs) for APD compared with CAPD. As-treated (AT) and intention-to-treat (ITT) designs were used. All of the analyses were adjusted for age, gender, comorbidity, and primary kidney disease and stratified according to follow-up and mean baseline GFR.
The 505 CAPD and 78 APD patients had no major baseline differences. No differences were found in the analyses on yearly decline of rGFR. APD patients did have a higher risk of losing RRF in the first year (ITT crude HR 2.43 [confidence interval 95%, 1.48 to 4.00], adjusted 2.66 [1.60 to 4.44]; AT crude 1.89 [1.04 to 3.45], adjusted 2.15 [1.16 to 3.98]). The higher risk of losing all RRF was most pronounced in patients with the highest rGFR at baseline (ITT; crude 3.91 [1.54 to 9.94], adjusted 1.85 to 14.17).
The risk of losing RRF is higher for patients starting dialysis on APD compared with those starting on CAPD, especially in the first year.
Clinical Journal of the American Society of Nephrology 03/2011; 6(3):537-42. · 5.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association between cholesterol and mortality is reversed in end-stage renal disease (ESRD). This phenomenon has many potential explanations, one of them being 'time discrepancy of competing risks'. It states that hypercholesterolaemia is beneficial only in the short term, while it worsens survival over a long-term interval. It is also proposed that the reversed relationship between cholesterol and outcome is due to confounding protein-energy wasting. The aim of the study was to verify the hypothesis of time discrepancy of competing risks in 1191 incident dialysis patients (Netherlands Cooperative Study on the Adequacy of Dialysis).
Conditional Cox proportional hazards analysis was applied, where associations between cholesterol level and short-term versus long-term mortality were being compared. Furthermore, to evaluate associations between cholesterol and outcome free from confounding, Mendelian randomization was introduced, using apolipoprotein E (apoE) genotype.
Hypercholesterolaemia (>240 mg/dL) was associated with improved 5-year survival when compared to the low cholesterol group (<200 mg/dL), hazard ratio (HR) = 0.62 (0.47-0.82), P < 0.001. However, conditional Cox proportional hazards analysis revealed that the reverse association between high cholesterol and all-cause mortality was evident only during the first year of follow-up, HR = 0.43 (0.23-0.80), P < 0.01, and then, gradually, declined. The apoE genotype significantly affected cholesterol concentration. The ε2 carriers, associated with low cholesterol, had significantly increased risk of non-cardiovascular mortality.
Reverse association between cholesterol concentration and mortality in dialysis patients is short-termed, consistent with the hypothesis of time discrepancy of competing risks. Low cholesterol appeared to affect non-cardiovascular mortality in ESRD patients free from confounders.
[Show abstract][Hide abstract] ABSTRACT: Despite a lack of strong evidence, automated peritoneal dialysis (APD) is often prescribed on account of an expected better quality of life (QoL) than that expected with continuous ambulatory peritoneal dialysis (CAPD). Our aim was to analyze differences in QoL in patients starting dialysis on APD or on CAPD with a follow-up of 3 years.
Adult patients in the prospective NECOSAD cohort who started dialysis on APD or CAPD were included 3 months after the start of dialysis. The Medical Outcomes Survey Short Form 36 [SF-36 (Medical Outcomes Trust and QualityMetric, Lincoln, RI, USA)] and Kidney Disease and Quality of Life Short Form [KDQOL-SF (KDQOL Working Group, Santa Monica, CA, USA)] questionnaires were used to measure QoL. Differences in QoL over time were calculated using linear mixed models. Patients were followed until transplantation, death, or a first switch to any other dialysis modality.
The clinical and social characteristics of the 64 APD and 486 CAPD patients were slightly different at baseline. In the crude analysis, the pattern of the mental summary score differed between the modalities (p = 0.03, adjusted p = 0.06), because of a different pattern for role function emotional (p = 0.03, adjusted p = 0.05). The pattern of the physical summary score was not different between the groups. Scores on dialysis staff encouragement had a different pattern over time (p = 0.01), because of an inequality in scores 3 months after the start of dialysis, which disappeared after 18 months on dialysis. Over time, patients on APD scored higher on sexual function. After adjustment for age, sex, glomerular filtration rate, comorbidity, and primary kidney disease, that difference disappeared. This study showed no major differences in QoL on the KDQOL-SF and the SF-36 between the two modalities.
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 02/2011; 31(2):138-47.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND OBJECTIVE: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective. METHODS: A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rate