Marijke Dekker

Impact of fluid status and inflammation and their interaction on survival: a study in an international hemodialysis patient cohort

In hemodialysis patients extracellular fluid overload is a predictor of all-cause and cardiovascular mortality, and a relation with inflammation has been reported in previous studies. The magnitude and nature of this interaction and the effects of moderate fluid overload and extracellular fluid depletion on survival are still unclear. We present the results of an international cohort study in 8883 hemodialysis patients from the European MONDO initiative database where, during a three-month baseline period, fluid status was assessed using bioimpedance and inflammation by C-reactive protein. All-cause mortality was recorded during 12 months of follow up. In a second analysis a three-month baseline period was added to the first baseline period, and changes in fluid and inflammation status were related to all-cause mortality during six-month follow up. Both pre-dialysis estimated fluid overload and fluid depletion were associated with an increased mortality, already apparent at moderate levels of estimated pre-dialysis fluid overload (1.1-2.5L); hazard ratio 1.64 (95% confidence interval 1.35-1.98). In contrast, post-dialysis estimated fluid depletion was associated with a survival benefit (0.74 [0.62-0.90]). The concurrent presence of fluid overload and inflammation was associated with the highest risk of death. Thus, while pre-dialysis fluid overload was associated with inflammation, even in the absence of inflammation, fluid overload remained a significant risk factor for short-term mortality, even following improvement of fluid status.

High-Flux Hemodialysis and High-Volume Hemodiafiltration Improve Serum Calcification Propensity

Background Calciprotein particles (CPPs) may play an important role in the calcification process. The calcification propensity of serum (T50) is highly predictive of all-cause mortality in chronic kidney disease patients. Whether T50 is therapeutically improvable, by high-flux hemodialysis (HD) or hemodiafiltration (HDF), has not been studied yet. Methods We designed a cross-sectional single center study, and included stable prevalent in-center dialysis patients on HD or HDF. Patients were divided into two groups based on dialysis modality, were on a thrice-weekly schedule, had a dialysis vintage of > 3 months and vascular access providing a blood flow rate > 300 ml/min. Calcification propensity of serum was measured by the time of transformation from primary to secondary CPP (T50 test), by time-resolved nephelometry. Results We included 64 patients, mean convective volume was 21.7L (SD 3.3L). In the pooled analysis, T50 levels increased in both the HD and HDF group with pre- and post-dialysis (mean (SD)) of 244(64) - 301(57) and 253(55) - 304(61) min respectively (P = 0.43(HD vs. HDF)). The mean increase in T50 was 26.29% for HD and 21.97% for HDF patients (P = 0.61 (HD vs. HDF)). The delta values (Δ) of calcium, phosphate and serum albumin were equal in both groups. Baseline T50 was negatively correlated with phosphate, and positively correlated with serum magnesium and fetuin-A. The ΔT50 was mostly influenced by Δ phosphate (r = -0.342; P = 0.002 HD and r = -0.396; P<0.001 HDF) in both groups. Conclusions HD and HDF patients present with same baseline T50 calcification propensity values pre-dialysis. Calcification propensity is significantly improved during both HD and HDF sessions without significant differences between both modalities.

Diagnosis of acute myocardial infarction in hemodialysis patients may be feasible by comparing variation of cardiac troponins during acute presentation to baseline variation.

Acute myocardial infarction (AMI) is defined as a dynamic change in cardiac troponin (cTn) with at least one cTn value exceeding the 99 th percentile of a reference population in combination with typical clinical symptoms. In hemodialysis (HD) patients, a broad range of cTn concentrations is found, partially due to patient-specific comorbidities. Therefore, the 99 th percentile cannot be used in HD patients and decision algorithms to diagnose AMI should be based on temporal variations of troponin. In this study, relative and absolute variations of cTn in a large population of asymptomatic hemodialysis patients were established during a period of 15 months. Patients were stratified according to their history of coronary artery disease (CAD). An intra-individual long term variation of 23% for cTroponin I (cTnI) and 12% for cTroponin T (cTnT) was found for patients without a history of CAD. The corresponding reference change values (RCVs) were 69% and 39% respectively. For patients with a history of CAD this variation was 29% for cTnI and 10% for cTnT, with RCVs of 86% and 35% respectively. During follow up, 27 HD patients developed an acute myocardial infarction (AMI). During these events, irrespective of CAD history, cTnI increased>172% and cTnT increased>97% above baseline cTn as measured during clinically stable periods three months separate to the event. Therefore, if a HD patient has symptoms of an acute event and a cTn increase that exceeds the RCVs described here, AMI may be suspected. If the troponin increase exceeds 172% for cTnI or 97% for cTnT, AMI is likely.

Fluid Overload and Inflammation Axis

Extracellular fluid overload (FO), which is assessed using bioimpedance technologies, is an important predictor of outcome in dialysis patients and in patients with early stages of chronic kidney disease. While traditional cardiovascular abnormalities are assumed to mediate this risk, recently also, the importance of noncardiovascular factors, such as systemic inflammation and malnutrition has been shown. While both FO and inflammation are independent risk factors for mortality, recent studies have shown that their combined presence can lead to a cumulative risk profile. From a pathophysiologic viewpoint, FO and inflammation can also be mutually reinforcing. Inflammation could contribute to FO by hypoalbuminemia, capillary leakage, and a (unnoticed) decline in lean and/or fat tissue mass resulting in incorrect estimation of dry weight. Reciprocally, FO could lead to inflammation by the translocation of endotoxins through a congested bowel wall or by a proinflammatory effect of tissue sodium. The relative importance of these putative factors is, however, not clear yet and epidemiological studies have shown no clear temporal direction regarding the relationship between FO and inflammation. FO and inflammation appear to be part of (dynamic) clusters of risk factors, including malnutrition and hyponatremia. Technology-guided fluid management of the often vulnerable dialysis patient with FO and inflammation cannot yet be based on evidence from randomized controlled trials, in which these specific patients were in general not included. In the absence of those trials, treatment should be based on identifying actionable causes of inflammation and on the judicious removal of excess volume based on frequent clinical reassessment.

Novel Insights into the Pathogenesis and Prevention of Intradialytic Hypotension

Background: Intradialytic hypotension (IDH) is a common complication of haemodialysis (HD) and associated with adverse outcomes, especially when a nadir definition (systolic blood pressure <90 mm Hg) is used. The pathogenesis of IDH is directly linked to the discontinuous nature of the HD treatment, in combination with patient-related factors such as age, diabetes mellitus and cardiac failure. Summary: Although the decline in blood volume due to removal of fluid by ultrafiltration is the prime mover, thermally induced reflex vasodilation compromises the haemodynamic response to hypovolemia. Recent studies have stressed the relevance of changes in tissue perfusion during HD, which may translate in long-term organ damage. Monitoring changes in tissue perfusion, for which emerging evidence becomes available, appears to have great promise in the fine-tuning of the dialysis procedure. Key Messages: While it is unlikely that IDH can be completely prevented, reduction in inter-dialytic weight gain, prevention of an increase in core temperature by adjusting the dialysate temperature and more frequent or prolonged dialysis treatment remain cornerstones in providing a more comfortable and safe treatment.

Practical value of anti-xa activity in the evaluation of extracorporeal circuit anticoagulation during haemodialysis : Results of a cross-sectional single-centre study

Background/Aims: Anticoagulation of the extracorporeal circuit is essential for adequate haemodialysis (HD). Low molecular weight heparins (LMWHs) are safe and sufficient towards achieving this goal. In the Netherlands, dosage is based on bodyweight and adjusted based on clinical events. LMWH levels during dialysis can be quantified through measurement of the anti-Xa activity and a target range of 0.5-1.0 IU/mL has been proposed. We aimed to evaluate the practical value of the anti-Xa activity to guide LMWH dosage in HD patients. Additionally, the value of the activated partial thromboplastin time (APTT) was investigated. Methods: All prevalent adult HD patients of our dialysis clinic were included. APTT and anti-Xa activity were measured before, during and after 2 dialysis sessions. Clinical and dialysis characteristics, including LMWH dosage, were derived from digital patient charts. Results: Our final study cohort consisted of 83 patients. LMWH dosage during dialysis was appropriate for bodyweight in 61% of cases, of which 50% reached an anti-Xa activity within the putative target range of 0.5-1.0 IU/mL. Forty-six percent of patients had an anti-Xa activity >1.0 IU/mL. Anti-Xa levels during and after dialysis were significantly correlated (r = 0.803, p < 0.01). No thrombotic or haemorrhagic complications were observed in this study. Correlation of APTT with anti-Xa activity was poor. Conclusion: Anti-Xa activity measurements during dialysis can identify patients in whom LMWH dosage should be lowered in a subsequent dialysis session. Whether such an intervention leads to a decrease in haemorrhagic complications needs to be evaluated in prospective studies.