Intima-media thickness at the near or far wall of the common carotid artery in cardiovascular risk assessment.

Aims: Current guidelines recommend measuring carotid intima-media thickness (IMT) at the far wall of the common carotid artery (CCA). We aimed to precisely quantify associations of near vs. far wall CCA-IMT with the risk for atherosclerotic cardiovascular disease (CVD, defined as coronary heart disease or stroke) and their added predictive values. Methods and results: We analysed individual records of 41 941 participants from 16 prospective studies in the Proof-ATHERO consortium {mean age 61 years [standard deviation (SD) = 11]; 53% female; 16% prior CVD}. Mean baseline values of near and far wall CCA-IMT were 0.83 (SD = 0.28) and 0.82 (SD = 0.27) mm, differed by a mean of 0.02 mm (95% limits of agreement: -0.40 to 0.43), and were moderately correlated [r = 0.44; 95% confidence interval (CI): 0.39-0.49). Over a median follow-up of 9.3 years, we recorded 10 423 CVD events. We pooled study-specific hazard ratios for CVD using random-effects meta-analysis. Near and far wall CCA-IMT values were approximately linearly associated with CVD risk. The respective hazard ratios per SD higher value were 1.18 (95% CI: 1.14-1.22; I² = 30.7%) and 1.20 (1.18-1.23; I² = 5.3%) when adjusted for age, sex, and prior CVD and 1.09 (1.07-1.12; I² = 8.4%) and 1.14 (1.12-1.16; I²=1.3%) upon multivariable adjustment (all P < 0.001). Assessing CCA-IMT at both walls provided a greater C-index improvement than assessing CCA-IMT at one wall only [+0.0046 vs. +0.0023 for near (P < 0.001), +0.0037 for far wall (P = 0.006)]. Conclusions: The associations of near and far wall CCA-IMT with incident CVD were positive, approximately linear, and similarly strong. Improvement in risk discrimination was highest when CCA-IMT was measured at both walls.

Physical intradialytic patient-reported outcome measures in haemodialysis and haemodiafiltration: A cross-over study.

AIM: Standard haemodialysis (sHD) is associated with a poor survival and marked adverse intradialytic patient-reported outcome measures (ID-PROMs). Whereas physical ID-PROMs (PID-PROMs) are alleviated by cool dialysate (cHD), survival is prolonged by haemodiafiltration (HDF). So far, PID-PROMs are not prospectively compared between HD and HDF. METHODS: To assess whether PID-PROMs and thermal perception differ between sHD, cHD, low volume HDF (lvHDF) and high volume HDF (hvHDF), 40 patients were cross-over randomized to each modality for 2 weeks. Dialysate temperature (Td ) was 36.5°C, except in cHD (Td 35.5°C). Target convection volumes were 15 L in lvHDF and ≥ 23 L in hvHDF. PID-PROMs were evaluated with a modified Dialysis Symptom Index (mDSI) and thermal perception with the Visual Analogue Scale Thermal Perception (VAS-TP). Tb and room temperature were measured as well. RESULTS: Except for the item 'feeling cold' during cHD (p = .01), PID-PROMs did not differ between modalities, but varied markedly between patients (11/13 items, p < .05). Tb increased in sHD, lvHDF, and hvHDF (+0.30, 0.35, 0.38°C, respectively, all p < .0005), but remained stable in cHD (+0.04°C, p = .43). Thermal perception remained unaltered in sHD and both HDF modalities, but shifted towards cold in cHD (p = .007). CONCLUSION: (1) PID-PROMs did not differ between modalities, but varied markedly between patients. Hence, PID-PROMs are largely patient-dependent. (2) While Tb increased in sHD, lvHDF and hvHDF, thermal perception did not change. Yet, whereas Tb remained unaltered in cHD, cold perception emerged. Hence, as for bothersome cold sensations, cHD should be avoided in perceptive individuals.

Long-term peridialytic blood pressure changes are related to mortality.

BACKGROUND: In chronic haemodialysis (HD) patients, the relationship between long-term peridialytic blood pressure (BP) changes and mortality has not been investigated. METHODS: To evaluate whether long-term changes in peridialytic BP are related to mortality and whether treatment with HD or haemodiafiltration (HDF) differs in this respect, the combined individual participant data of three randomized controlled trials comparing HD with HDF were used. Time-varying Cox regression and joint models were applied. RESULTS: During a median follow-up of 2.94 years, 609 of 2011 patients died. As for pre-dialytic systolic BP (pre-SBP), a severe decline (≥21 mmHg) in the preceding 6 months was independently related to increased mortality [hazard ratio (HR) 1.61, P = .01] when compared with a moderate increase. Likewise, a severe decline in post-dialytic diastolic BP (DBP) was associated with increased mortality (adjusted HR 1.96, P < .0005). In contrast, joint models showed that every 5-mmHg increase in pre-SBP and post-DBP during total follow-up was related to reduced mortality (adjusted HR 0.97, P = .01 and 0.94, P = .03, respectively). No interaction was observed between BP changes and treatment modality. CONCLUSION: Severe declines in pre-SBP and post-DBP in the preceding 6 months were independently related to mortality. Therefore peridialytic BP values should be interpreted in the context of their changes and not solely as an absolute value.

High-Volume Hemodiafiltration and Cool Hemodialysis Have a Beneficial Effect on Intradialytic Hemodynamics: A Randomized Cross-Over Trial of Four Intermittent Dialysis Strategies.

Introduction: Compared to standard hemodialysis (S-HD), postdilution hemodiafiltration (HDF) has been associated with improved survival. Methods: To assess whether intradialytic hemodynamics may play a role in this respect, 40 chronic dialysis patients were cross-over randomized to S-HD (dialysate temperature [Td] 36.5 °C), cooled HD (C-HD; Td 35.5 °C), and HDF (low-volume [LV-HDF)] and high-volume [HV-HDF], both Td 36.5 °C, convection volume 15 liters, and at least 23 liters per session, respectively), each for 2 weeks. Blood pressure (BP) was measured every 15 minutes. The primary endpoint was the number of intradialytic hypotensive (IDH) episodes per session. IDH was defined as systolic BP (SBP) less than 90 mmHg for predialysis SBP less than 160 mmHg and less than 100 mmHg for predialysis SBP greater than or equal to 160 mmHg, independent of symptoms and interventions. A post hoc analysis on early-onset IDH was performed as well. Secondary endpoints included intradialytic courses of SBP, diastolic BP (DBP) and mean arterial pressure (MAP). Results: During S-HD, IDH occurred 0.68 episodes per session, which was 3.2 and 2.5 times higher than during C-HD (0.21 per session, P < 0.0005) and HV-HDF (0.27 per session, P < 0.0005), respectively. Whereas the latter 2 strategies showed similar frequencies, HV-HDF differed significantly from LV-HDF (P = 0.02). A comparable trend was observed for early-onset IDH: S-HD (0.32 per session), C-HD (0.07 per session, P < 0.0005) and HV-HDF (0.10 per session, P = 0.001). SBP, DBP, and MAP declined during S-HD (-6.8, -5.2, -5.2 mmHg per session; P = 0.004, P < 0.0005, P = 0.002 respectively), which was markedly different from C-HD (P < 0.01). Conclusion: Though C-HD and HV-HDF showed the lowest IDH frequency and the best intradialytic hemodynamic stability, all parameters were most disrupted in S-HD. Therefore, the survival benefit of HV-HDF over S-HD may be partly caused by a more beneficial intradialytic BP profile.

Why and how high volume hemodiafiltration may reduce cardiovascular mortality in stage 5 chronic kidney disease dialysis patients? A comprehensive literature review on mechanisms involved.

Online hemodiafiltration (HDF) is an established renal replacement modality for patients with end stage chronic kidney disease that is now gaining rapid clinical acceptance worldwide. Currently, there is a growing body of evidence indicating that treatment with HDF is associated with better outcomes and reduced cardiovascular mortality for dialysis patients. In this comprehensive review, we provide an update on the potential mechanisms which may improve survival in HDF treated patients. The strongest evidence is for better hemodynamic stability and reduced endothelial dysfunction associated with HDF treatments. Clinically, this is marked by a reduced incidence of intradialytic hypotensive episodes, with a better hemodynamic response to ultrafiltration, mediated by an increase in total peripheral vascular resistance and extra-vascular fluid recruitment, most likely driven by the negative thermal balance associated with online HDF therapy. In addition, endothelial function appears to be improved due to a combination of a reduction of the inflammatory and oxidative stress complex syndrome and exposure to circulating cardiovascular uremic toxins. Reports of reversed cardiovascular remodeling effects with HDF may be confounded by volume and blood pressure management, which are strongly linked to center clinical practices. Currently, treatment with HDF appears to improve the survival of dialysis patients predominantly due to a reduction in their cardiovascular burden, and this reduction is linked to the sessional convection volume exchanged.

Effect of various dialysis modalities on intradialytic hemodynamics, tissue injury and patient discomfort in chronic dialysis patients: design of a randomized cross-over study (HOLLANT).

BACKGROUND: From a recent meta-analysis it appeared that online post-dilution hemodiafiltration (HDF), especially with a high convection volume (HV-HDF), is associated with superior overall and cardiovascular survival, if compared to standard hemodialysis (HD). The mechanism(s) behind this effect, however, is (are) still unclear. In this respect, a lower incidence of intradialytic hypotension (IDH), and hence less tissue injury, may play a role. To address these items, the HOLLANT study was designed. METHODS: HOLLANT is a Dutch multicentre randomized controlled cross-over trial. In total, 40 prevalent dialysis patients will be included and, after a run-in phase, exposed to standard HD, HD with cooled dialysate, low-volume HDF and high-volume HDF (Dialog iQ® machine) in a randomized fashion. The primary endpoint is an intradialytic nadir in systolic blood pressure (SBP) of < 90 and < 100 mmHg for patients with predialysis SBP < 159 and ≥ 160 mmHg, respectively. The main secondary outcomes are 1) intradialytic left ventricle (LV) chamber quantification and deformation, 2) intradialytic hemodynamic profile of SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure (PP), 3) organ and tissue damage, such as the release of specific cellular components, and 4) patient reported symptoms and thermal perceptions during each modality. DISCUSSION: The current trial is primarily designed to test the hypothesis that a lower incidence of intradialytic hypotension contributes to the superior survival of (HV)-HDF. A secondary objective of this investigation is the question whether changes in the intradialytic blood pressure profile correlate with organ dysfunction and tissue damage, and/or patient discomfort. TRIAL REGISTRATION: Registered Report Identifier: NCT03249532 # ( ClinicalTrials.gov ). Date of registration: 2017/08/15.

Change in FGF23 concentration over time and its association with all-cause mortality in patients treated with haemodialysis or haemodiafiltration.

BACKGROUND: Previous studies in patients on haemodialysis (HD) have shown an association of fibroblast growth factor 23 (FGF23) with all-cause mortality. As of yet, the result of FGF23 lowering on mortality is unknown in this population. METHODS: FGF23 was measured in a subset of 404 patients from the Dutch CONvective TRansport STudy (CONTRAST study) [a randomized trial in prevalent dialysis patients comparing HD and haemodiafiltration (HDF) with clinical outcome] at baseline and Months 6 and 12. A substantial decline of FGF23 change over time was anticipated in patients randomized to HDF since HDF induces higher dialytic clearance of FGF23. The associations of both baseline FGF23 and 6-months change in FGF23 with all-cause mortality were analysed. In addition, the difference in FGF23 change between HD and HDF was explored. Furthermore, the role of dialysis modality in the association between FGF23 change and outcome was analysed. RESULTS: No association was observed between quartiles of baseline FGF23 and all-cause mortality. Over 6 months, FGF23 declined in patients on HDF, whereas FGF23 remained stable in patients on HD. A decrease in FGF23 was not associated with improved survival compared with a stable FGF23 concentration. However, increasing FGF23 was associated with a significantly higher mortality risk, both in crude and fully adjusted models [hazard ratio 2.01 (95% confidence interval 1.30-3.09)]. CONCLUSION: Whereas no association between a single value of FGF23 and all-cause mortality was found, increasing FGF23 concentrations did identify patients at risk for mortality. Since lowering FGF23 did not improve outcome, this study found no argument for therapeutically lowering FGF23.

The effect of natriuretic C-type peptide and its change over time on mortality in patients on haemodialysis or haemodiafiltration.

BACKGROUND: C-type natriuretic peptide (CNP) and its co-product N-terminal proCNP (NTproCNP) have been associated with beneficial effects on the cardiovascular system. In prevalent dialysis patients, however, a relation between NTproCNP and mortality has not yet been investigated. Furthermore, as a middle molecular weight substance, its concentration might be influenced by dialysis modality. METHODS: In a cohort of patients treated with haemodialysis (HD) or haemodiafiltration (HDF), levels of NTproCNP were measured at baseline and 6, 12, 24 and 36 months. The relation between serum NTproCNP and mortality and the relation between the 6-month rate of change of NTproCNP and mortality were analysed using Cox regression models. For the longitudinal analyses, linear mixed models were used. RESULTS: In total, 406 subjects were studied. The median baseline serum NTproCNP was 93 pmol/L and the median follow-up was 2.97 years. No relation between baseline NTproCNP or its rate of change over 6 months and mortality was found. NTproCNP levels remained stable in HD patients, whereas NTproCNP decreased significantly in HDF patients. The relative decline depended on the magnitude of the convection volume. CONCLUSIONS: In our study, levels of NTproCNP appear strongly elevated in prevalent dialysis patients. Second, while NTproCNP remains unaltered in HD patients, its levels decline in individuals treated with HDF, with the decline dependent on the magnitude of the convection volume. Third, NTproCNP is not related to mortality in this population. Thus NTproCNP does not seem to be a useful marker for mortality risk in dialysis patients.

The probability of receiving a kidney transplantation in end-stage kidney disease patients who are treated with haemodiafiltration or haemodialysis: a pooled individual participant data from four randomised controlled trials.

BACKGROUND: Due to a critical shortage of available kidney grafts, most patients with Stage 5 Chronic Kidney Disease (CKD5) require bridging dialysis support. It remains unclear whether treatment by different dialysis modalities changes the selection and/or preparation of a potential transplant candidate. Therefore, we assessed whether the likelihood of receiving kidney transplant (both living or deceased kidney donors) differs between haemodialysis (HD) and online haemodiafiltration (HDF) in patients with CKD5D. METHODS: Individual participant data from four randomised controlled trials comparing online HDF with HD were used. Information on kidney transplant was obtained during follow-up. The likelihood of receiving a kidney transplant was compared between HD and HDF, and evaluated across different subgroups: age, sex, diabetes, history of cardiovascular disease, albumin, dialysis vintage, fistula, and level of convection volume standardized to body surface area. Hazard ratios (HRs), with corresponding 95% confidence intervals (95% CI), comparing the effect of online HDF versus HD on the likelihood of receiving a kidney transplant, were estimated using Cox proportional hazards models with a random effect for study. RESULTS: After a median follow-up of 2.5 years (Q1 to Q3: 1.9-3.0), 331 of the 1620 (20.4%) patients with CKD5D received a kidney transplant. This concerned 22% (n = 179) of patients who were treated with online HDF compared with 19% (n = 152) of patients who were treated with HD. No differences in the likelihood of undergoing a kidney transplant were found between the two dialysis modalities in both the crude analyse (HR: 1.07, 95% CI: 0.86-1.33) and adjusted analysis for age, sex, diabetes, cardiovascular history, albumin, and creatinine (HR: 1.15, 95%-CI: 0.92-1.44). There was no evidence for a differential effect across subgroups based on patient- and disease-characteristics nor in different categories of convection volumes. CONCLUSIONS: Treatment with HD and HDF does not affect the selection and/or preparation of CKD5D patients for kidney transplant given that the likelihood of receiving a kidney transplant does not differ between the dialysis modalities. These finding persisted across a variety of subgroups differing in patient and disease characteristics and is not affected by the level of convection volume delivered during HDF treatment sessions.

Long-Term Peridialytic Blood Pressure Patterns in Patients Treated by Hemodialysis and Hemodiafiltration.

INTRODUCTION: Online postdilution hemodiafiltration (HDF) is associated with a lower all-cause and cardiovascular mortality than hemodialysis (HD). This may depend on a superior peridialytic (pre- and postdialysis, and the difference between these 2 parameters) hemodynamic profile. METHODS: In this retrospective cohort analysis of individual participant data (IPD) from 3 randomized controlled trials (RCTs) (n = 2011), the effect of HDF and HD on 2-year peridialytic blood pressure (BP) patterns was assessed. Long-term peridialytic systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP), as well as the deltas (post- minus predialytic) were assessed in the total group of patients. Thereafter, these variables were compared between patients on HD and HDF, and in the latter group between quartiles of convection volume. RESULTS: Mean pre- and postdialysis SBP, DBP, and MAP declined significantly during follow-up (predialytic: SBP -2.16 mm Hg, DBP -2.88 mm Hg, MAP -2.64 mm Hg), PP increased (predialytic 0.96 mm Hg). Peridialytic deltas remained unaltered. Differences between the 2 modalities, or between quartiles of convection volume were not observed. BP changes were independent of various baseline characteristics, including the decline in body weight over time. CONCLUSION: We speculate that the combination of a decreasing SBP and an increasing PP may be the clinical sequelae of a worsening cardiovascular system. Because especially HDF with a high convection volume has been associated with a beneficial effect on survival, our study does not support the view that superior peridialytic BP control contributes to this effect.

Role of Albumin Assay on Calcium Levels and Prescription of Phosphate Binders in Chronic Hemodialysis Patients.

BACKGROUND/AIMS: In hemodialysis (HD) patients, the bromcresol green (BCG) assay overestimates, whereas the bromcresol purple (BCP) assay underestimates albumin concentration. Since corrected calcium concentrations depend on albumin, the albumin assay may have implications for the management of bone mineral disorders. METHODS: A subset of patients from CONTRAST, a cohort of prevalent HD patients, was analyzed. Bone mineral parameters and prescription of medication were compared between patients in whom albumin was assessed by BCP versus BCG. RESULTS: Albumin was assessed by BCP in 331 patients (9 of 25 centers) and by BCG in 175 patients (16 of 25 centers). Albumin was the lowest in the BCP group (34.5 ± 4.2 vs. 40.3 ± 3.1 g/L; p < 0.0005). Measured calcium levels and the prescription of calcium-based phosphate binders were similar in both groups. Corrected calcium levels, however, were markedly higher in the BCP group (2.45 ± 0.18 vs. 2.33 ± 0.18 mmol/L; p < 0.0005). CONCLUSION: These findings suggest that calcium levels are not corrected for albumin in clinical practice when considering the prescription of calcium-free or calcium-based phosphate-binders in dialysis patients.

Long-term clinical parameters after switching to nocturnal haemodialysis: a Dutch propensity-score-matched cohort study comparing patients on nocturnal haemodialysis with patients on three-times-a-week haemodialysis/haemodiafiltration.

OBJECTIVES: Nocturnal haemodialysis (NHD), characterised by 8-hour sessions ≥3 times a week, is known to improve clinical parameters in the short term compared with conventional-schedule haemodialysis (HD), generally 3×3.5-4 hours a week. We studied long-term effects of NHD and used patients on conventional HD/haemodiafiltration (HDF) as controls. DESIGN: Four-year prospective follow-up of patients who switched to NHD; we compared patients with patients on HD/HDF using propensity score matching. SETTING: 28 Dutch dialysis centres. PARTICIPANTS: We included 159 patients starting with NHD any time since 2004, aged 56.7±12.9 years, with median dialysis vintage 2.3 (0.9-5.1) years. We propensity-score matched 100 patients on NHD to 100 on HD/HDF. PRIMARY AND SECONDARY OUTCOME MEASURES: Control of hypertension (predialysis blood pressure, number of antihypertensives), phosphate (phosphate, number of phosphate binders), nutritional status and inflammation (albumin, C reactive protein and postdialysis weight) and anaemia (erythropoiesis-stimulating agent (ESA) resistance). RESULTS: Switching to NHD was associated with a non-significant reduction of antihypertensives compared with HD/HDF (OR <2 types 2.17, 95% CI 0.86 to 5.50, P=0.11); and a prolonged lower need for phosphate binders (OR <2 types 1.83, 95% CI 1.10 to 3.03, P=0.02). NHD was not associated with significant changes in blood pressure or phosphate. NHD was associated with significantly higher albumin over time compared with HD/HDF (0.70 g/L/year, 95% CI 0.10 to 1.30, P=0.02). ESA resistance decreased significantly in NHD compared with HD/HDF, resulting in a 33% lower ESA dose in the long term. CONCLUSIONS: After switching to NHD, the lower need for antihypertensives, phosphate binders and ESA persists for at least 4 years. These sustained improvements in NHD contrast significantly with the course of these parameters during continued treatment with conventional-schedule HD and HDF. NHD provides an optimal form of dialysis, also suitable for patients expected to have a long waiting time for transplantation or those convicted to indefinite dialysis.

Left ventricular geometric patterns in end-stage kidney disease: Determinants and course over time.

INTRODUCTION: While concentric left ventricular hypertrophy (cLVH) predominates in non-dialysis-dependent chronic kidney disease (CKD), eccentric left ventricular hypertrophy (eLVH) is most prevalent in dialysis-dependent CKD stage 5 (CKD5D). In these patients, the risk of sudden death is 5× higher than in individuals with cLVH. Currently, it is unknown which factors determine left ventricular (LV) geometry and how it changes over time in CKD5D. METHODS: Data from participants of the CONvective TRAnsport Study who underwent serial transthoracic echocardiography were used. Based on left ventricular mass (LVM) and relative wall thickness (RWT), 4 types of left ventricular geometry were distinguished: normal, concentric remodeling, eLVH, and cLVH. Determinants of eLVH were assessed with logistic regression. Left ventricular geometry of patients who died and survived were compared. Long-term changes in RWT and LVM were evaluated with a linear mixed model. FINDINGS: Three hundred twenty-two patients (63.1 ± 13.3 years) were included. At baseline, LVH was present in 71% (cLVH: 27%; eLVH: 44%). Prior cardiovascular disease (CVD) was positively associated with eLVH and ß-blocker use inversely. None of the putative volume parameters showed any relationship with eLVH. Although eLVH was most prevalent in non-survivors, the distribution of left ventricular geometry did not vary over time. DISCUSSION: The finding that previous CVD was positively associated with eLVH may result from the permanent high cardiac output and the strong tendency for aortic valve calcification in this group of long-term hemodialysis patients, who suffer generally also from chronic anemia and various other metabolic derangements. No association was found between eLVH and parameters of fluid balance. The distribution of left ventricular geometry did not alter over time. The assumption that LV geometry worsens over time in susceptible individuals, who then suffer from a high risk of dying, may explain these findings.

Achieving high convection volumes in postdilution online hemodiafiltration: a prospective multicenter study.

Background. Available evidence suggests a reduced mortality risk for patients treated with high-volume postdilution hemodiafiltration (HDF) when compared with hemodialysis (HD) patients. As the magnitude of the convection volume depends on treatment-related factors rather than patient-related characteristics, we prospectively investigated whether a high convection volume (defined as ≥22 L/session) is feasible in the majority of patients (>75%). Methods. A multicenter study was performed in adult prevalent dialysis patients. Nonparticipating eligible patients formed the control group. Using a stepwise protocol, treatment time (up to 4 hours), blood flow rate (up to 400 mL/min) and filtration fraction (up to 33%) were optimized as much as possible. The convection volume was determined at the end of this optimization phase and at 4 and 8 weeks thereafter. Results. Baseline characteristics were comparable in participants (n = 86) and controls (n = 58). At the end of the optimization and 8 weeks thereafter, 71/86 (83%) and 66/83 (80%) of the patients achieved high-volume HDF (mean 25.5 ± 3.6 and 26.0 ± 3.4 L/session, respectively). While treatment time remained unaltered, mean blood flow rate increased by 27% and filtration fraction increased by 23%. Patients with <22 L/session had a higher percentage of central venous catheters (CVCs), a shorter treatment time and lower blood flow rate when compared with patients with ≥22 L/session. Conclusions. High-volume HDF is feasible in a clear majority of dialysis patients. Since none of the patients agreed to increase treatment time, these findings indicate that high-volume HDF is feasible just by increasing blood flow rate and filtration fraction.

The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials: the example of renal transplantation in hemodialysis trials.

Background: During the follow-up in a randomized controlled trial (RCT), participants may receive additional (non-randomly allocated) treatment that affects the outcome. Typically such additional treatment is not taken into account in evaluation of the results. Two pivotal trials of the effects of hemodiafiltration (HDF) versus hemodialysis (HD) on mortality in patients with end-stage renal disease reported differing results. We set out to evaluate to what extent methods to take other treatments (i.e. renal transplantation) into account may explain the difference in findings between RCTs. This is illustrated using a clinical example of two RCTs estimating the effect of HDF versus HD on mortality. Methods: Using individual patient data from the Estudio de Supervivencia de Hemodiafiltración On-Line (ESHOL; n = 902) and The Dutch CONvective TRAnsport STudy (CONTRAST; n = 714) trials, five methods for estimating the effect of HDF versus HD on all-cause mortality were compared: intention-to-treat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PP excl ; exclusion of patients who receive transplantation), PP cens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TA ext ) with additional adjustment for variables related to both the risk of receiving a transplant and the risk of an outcome (transplantation-outcome confounders). Cox proportional hazards models were applied. Results: Unadjusted ITT analysis of all-cause mortality led to differing results between CONTRAST and ESHOL: hazard ratio (HR) 0.95 (95% CI 0.75-1.20) and HR 0.76 (95% CI 0.59-0.97), respectively; difference between 5 and 24% risk reductions. Similar differences between the two trials were observed for the other unadjusted analytical methods (PP cens, PP excl , TA) The HRs of HDF versus HD treatment became more similar after adding transplantation as a time-varying covariate and including transplantation-outcome confounders: HR 0.89 (95% CI 0.69-1.13) in CONTRAST and HR 0.80 (95% CI 0.62-1.02) in ESHOL. Conclusions: The apparent differences in estimated treatment effects between two dialysis trials were to a large extent attributable to differences in applied methodology for taking renal transplantation into account in their final analyses. Our results exemplify the necessity of careful consideration of the treatment effect of interest when estimating the therapeutic effect in RCTs in which participants may receive additional treatments.

A closer look at the trajectory of physical functioning in chronic hemodialysis.

Background: in chronic hemodialysis, physical functioning (PF) is known to be poor. We set out to assess to what extent chronic dialysis patients are able to maintain a good physical condition over time and what the influence of age is on the trajectory of PF. Methods: we used data form 714 prevalent hemodialysis patients, enrolled in the CONvective TRAnsport STudy (CONTRAST). The PF subscale of the KDQOL SF-36 was assessed at baseline (n = 679) and during 2 years of follow-up (n = 298). Baseline PF score (0-100) was categorized into tertiles (good, intermediate and low). Change of PF of ≥ 5 points was considered clinically relevant. A regression model was applied to assess factors related to 'decline of PF (≥5 points)/low PF (0-33) at follow-up'. Results: during follow-up, only 15.3 % (1 out of 6) of patients succeeded in maintaining a good physical condition, the remainder deteriorated or died. Of the older patients (≥75) only 3.6% remained in a good physical condition. Factors related to decline/low PF were increasing age (odds ratio [OR] = 1.96 [95% CI: 1.03-3.72] for 65-74 years and OR = 2.38 [95%CI: 1.17-4.84] for ≥75 years compared to <65 years) and albumin (OR = 1.10 [95%CI: 1.01-1.18] per g/L decrease). Conclusion: very few hemodialysis patients maintain a good physical condition over a 2-year time span. Especially in older patients, physical performance is poor and decline is faster than in the healthy population. These findings should be taken into account when considering dialysis in older patients and more emphasis should be placed to attempts for improving physical condition.

Serum sclerostin: relation with mortality and impact of hemodiafiltration.

BACKGROUND: The glycoprotein sclerostin (Scl; 22 kDa), which is involved in bone metabolism, may play a role in vascular calcification in haemodialysis (HD) patients. In the present study, we investigated the relation between serum Scl (sScl) and mortality. The effects of dialysis modality and the magnitude of the convection volume in haemodiafiltration (HDF) on sScl were also investigated. METHODS: In a subset of patients from the CONTRAST study, a randomized controlled trial comparing HDF with HD, sScl was measured at baseline and at intervals of 6, 12, 24 and 36 months. Patients were divided into quartiles, according to their baseline sScl. The relation between time-varying sScl and mortality with a 4-year follow-up period was investigated using crude and adjusted Cox regression models. Linear mixed models were used for longitudinal measurements of sScl. RESULTS: The mean (±standard deviation) age of 396 test subjects was 63.6 (±13.9 years), 61.6% were male and the median follow-up was 2.9 years. Subjects with the highest sScl had a lower mortality risk than those with the lowest concentrations [adjusted hazard ratio 0.51 (95% confidence interval, CI, 0.31-0.86, P = 0.01)]. Stratified models showed a stable sScl in patients treated with HD (Δ +2.9 pmol/L/year, 95% CI -0.5 to +6.3, P = 0.09) and a decreasing concentration in those treated with HDF (Δ -4.5 pmol/L/year, 95% CI -8.0 to -0.9, P = 0.02). The relative change in the latter group was related to the magnitude of the convection volume. CONCLUSIONS: (i) A high sScl is associated with a lower mortality risk in patients with end-stage kidney disease; (ii) treatment with HDF causes sScl to fall; and (iii) the relative decline in patients treated with HDF is dependent on the magnitude of the convection volume.

Mortality reduction by post-dilution online-haemodiafiltration: a cause-specific analysis.

Background: From an individual participant data (IPD) meta-analysis from four randomized controlled trials comparing haemodialysis (HD) with post-dilution online-haemodiafiltration (ol-HDF), previously it appeared that HDF decreases all-cause mortality by 14% (95% confidence interval 25; 1) and fatal cardiovascular disease (CVD) by 23% (39; 3). Significant differences were not found for fatal infections and sudden death. So far, it is unclear, however, whether the reduced mortality risk of HDF is only due to a decrease in CVD events and if so, which CVD in particular is prevented, if compared with HD. Methods: The IPD base was used for the present study. Hazard ratios and 95% confidence intervals for cause-specific mortality overall and in thirds of the convection volume were calculated using the Cox proportional hazard regression models. Annualized mortality and numbers needed to treat (NNT) were calculated as well. Results: Besides 554 patients dying from CVD, fatal infections and sudden death, 215 participants died from 'other causes', such as withdrawal from treatment and malignancies. In this group, the mortality risk was comparable between HD and ol-HDF patients, both overall and in thirds of the convection volume. Subdivision of CVD mortality in fatal cardiac, non-cardiac and unclassified CVD showed that ol-HDF was only associated with a lower risk of cardiac casualties [0.64 (0.61; 0.90)]. Annual mortality rates also suggest that the reduction in CVD death is mainly due to a decrease in cardiac fatalities, including both ischaemic heart disease and congestion. Overall, 32 and 75 patients, respectively, need to be treated by high-volume HDF (HV-HDF) to prevent one all-cause and one CVD death, respectively, per year. Conclusion: The beneficial effect of ol-HDF on all-cause and CVD mortality appears to be mainly due to a reduction in fatal cardiac events, including ischaemic heart disease as well as congestion. In HV-HDF, the NNT to prevent one CVD death is 75 per year.

Comparing Tests Assessing Protein-Energy Wasting: Relation With Quality of Life.

OBJECTIVE: Protein-energy wasting (PEW), a state of decreased bodily protein and energy fuels, is highly prevalent among hemodialysis patients. The best method to determine PEW, however, remains debated. As an independent, negative association between PEW and quality of life (QOL) has been demonstrated, establishing which nutrition-related test correlates best with QOL may help to identify how PEW should preferably be assessed. DESIGN AND METHODS: Data were used from CONTRAST, a cohort of end-stage kidney disease patients. At baseline, Subjective Global Assessment (SGA), Malnutrition Inflammation Score (MIS), Geriatric Nutritional Risk Index, composite score on protein-energy nutritional status, normalized protein nitrogen appearance, body mass index, serum albumin, and serum creatinine were determined. QOL was assessed by the Kidney Disease Quality of Life Short Form 1.3. The present study reports on 2 general and 11 kidney disease-specific QOL scores. Spearman's rho (ρ) was calculated to determine correlations between nutrition-related tests and QOL domains. Twelve months after randomization, a sensitivity analysis was performed to test the robustness of the results. RESULTS: Of 714 patients, 489 representative subjects were available for analysis. All tests correlated with the Physical Component Score, except body mass index. Only SGA and MIS correlated significantly with the Mental Component Score. SGA correlated significantly with 10 of 11 kidney disease-specific QOL domains. The MIS not only correlated significantly with all (11) kidney disease-specific QOL domains but also with higher correlation coefficients. CONCLUSION: Of the 8 investigated nutrition-related tests, only MIS correlates with all QOL domains (13 of 13) with the strongest associations.