Clinical review: Use of renal replacement therapies in special groups of ICU patients

Acute kidney injury (AKI) in ICU patients is typically associated with other severe conditions that require special attention when renal replacement therapy (RRT) is performed. RRT includes a wide range of techniques, each with specific characteristics and implications for use in ICU patients. In the present review we discuss a wide range of conditions that can occur in ICU patients who have AKI, and the implications this has for RRT. Patients at increased risk for bleeding should be treated without anticoagulation or with regional citrate anticoagulation. In patients who are haemodynamically unstable, continuous therapies are most often employed. These therapies allow slow removal of volume and guarantee a stable blood pH. In patients with cerebral oedema, continuous therapy is recommended in order to prevent decreased cerebral blood flow, which will lead to cerebral ischemia. Continuous therapy will also prevent sudden change in serum osmolality with aggravation of cerebral oedema. Patients with hyponatraemia, as in liver failure or decompensated heart failure, require extra attention because a rapid increase of serum sodium concentration can lead to irreversible brain damage through osmotic myelinolysis. Finally, in patients with severe lactic acidosis, RRT can be used as a bridging therapy, awaiting correction of the underlying cause. Especially in ICU patients who have severe AKI, treatment with RRT requires balancing the pros and cons of different options and modalities. Exact and specific guidelines for RRT in these patients are not available for most clinical situations. In the present article we provide an update on the existing evidence

Prognostic robustness of serum creatinine based AKI definitions in patients with sepsis: a prospective cohort study

Background: It is unclear how modifications in the way to calculate serum creatinine (sCr) increase and in the cut-off value applied, influences the prognostic value of Acute Kidney Injury (AKI). We wanted to evaluate whether these modifications alter the prognostic value of AKI for prediction of mortality at 3 months, 1 and 2 years. Methods: We prospectively included 195 septic patients and evaluated the prognostic value of AKI by using three different algorithms to calculate sCr increase: either as the difference between the highest value in the first 24 h after ICU admission and a pre-admission historical (Delta HIS) or an estimated (Delta EST) baseline value, or by subtracting the ICU admission value from the sCr value 24 h after ICU admission (Delta ADM). Different cut-off levels of sCr increase (0.1, 0.2, 0.3, 0.4 and 0.5 mg/dl) were evaluated. Results: Mortality at 3 months, 1 and 2 years in AKI defined as Delta ADM > 0.3 mg/dl was 48.1 %, 63.0 % and 63.0 % vs 27.7 %, 39.8 % and 47.6 % in no AKI respectively (OR(95%CI): 2.42(1.06-5.54), 2.58(1.11-5.97) and 1.87(0.81-4.33); 0.3 mg/dl was the lowest cut-off value that was discriminatory. When AKI was defined as Delta HIS > 0.3 mg/dl or Delta EST > 0.3 mg/dl, there was no significant difference in mortality between AKI and no AKI. Conclusions: The prognostic value of a 0.3 mg/dl increase in sCr, on mortality in sepsis, depends on how this sCr increase is calculated. Only if the evolution of serum creatinine over the first 24 h after ICU admission is taken into account, an association with mortality is found

Where and when to inject low molecular weight heparin in hemodiafiltration? : a cross over randomised trial

Background and Objective : Low molecular weight heparins (LMWHs) are small enough to pass large pore dialysis membranes. Removal of LMWH if injected before the start of the session is possible during high-flux dialysis and hemodiafiltration. The aim of this study was to determine the optimal mode (place and time) of tinzaparin administration during postdilution hemodiafiltration. Study Design, Setting, Patients : In 13 chronic hemodiafiltration patients, 3 approaches of injection were compared in a randomised cross over trial: i) before the start of the session at the inlet blood line filled with rinsing solution (IN0), ii) 5 min after the start at the inlet line filled with blood (IN5) and iii) before the start of the session at the outlet blood line (OUT0). Anti-Xa activity, thrombin generation, visual clotting score and reduction ratios of urea and beta2microglobulin were measured. Results : Anti-Xa activity was lower with IN0 compared with IN5 and OUT0, and also more thrombin generation was observed with IN0. No differences were observed in visual clotting scores and no clinically relevant differences were observed in solute reduction ratio. An anti-Xa of 0.3 IU/mL was discriminative for thrombin generation. Anti-Xa levels below 0.3 IU/mL at the end of the session were associated with worse clotting scores and lower reduction ratio of urea and beta2microglobulin. Conclusions : Injection of tinzaparin at the inlet line before the start of postdilution hemodiafiltration is associated with loss of anticoagulant activity and can therefore not be recommended. Additionally, we found that an anti-Xa above 0.3 IU/mL at the end of the session is associated with less clotting and higher dialysis adequacy

Dinucleoside polyphosphates : newly detected uraemic compounds with an impact on leucocyte oxidative burst

Background. Dinucleoside polyphosphates (NpnN) have pathophysiologic roles in cardiovascular disease and are newly detected uraemic retention solutes. They were retrieved in human plasma, tissues and cells. Although their impact on several cell systems involved in vascular damage (endothelium, smooth muscle cells and thrombocytes) has been evaluated, their effect on different types of leucocytes has never been studied. Methods. This study evaluates, for the first time, the impact of NpnN on monocyte, granulocyte and lymphocyte oxidative burst activity at baseline and after stimulation with N-formyl-methionine-leucine-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA) in whole blood. Diadenosine triphosphate (Ap(3)A) to diadenosine hexaphosphate (Ap(6)A) were tested to investigate the effect of the number of phosphate groups on reactive oxygen species (ROS) production. The effect of the type of nucleoside was evaluated by comparing adenosine guanosine tetraphosphate, diguanosine tetraphosphate, uridine adenosine tetraphosphate (Up(4)A) and diadenosine tetraphosphate (Ap(4)A). Results. This study demonstrated that lymphocytes are especially susceptible to intracellular diadenosine polyphosphates. Depending on the phosphate chain length, different effects were observed. At baseline and with fMLP Ap(4)A, Ap(5)A and Ap(6)A enhanced lymphocyted-free radical production. In addition, Ap(3)A, Ap(4)A and Ap5A increased PMA-stimulated ROS production in lymphocytes. Monocytes and granulocytes parallel the lymphocyte response albeit with an inhibition of Ap(6)A on granulocytes. Considering NpnN with four phosphate groups, Up(4)A showed the most important stimulatory effects on monocytes and Ap(4)A on lymphocytes. Conclusions. NpnN mainly have a leucocyte-activating impact, most significant for Ap(4)A, considering phosphate chain length, and for Up(4)A, considering the type of nucleosides. These results suggest that the pro-inflammatory effects of NpnN can contribute to the development of atherosclerosis, probably in the early stages of chronic kidney disease, but their chemical composition affects their activity

A rapid and simple assay to determine pegylated erythropoietin in human serum

Stimulation of erythropoiesis by the third-generation erythropoietin drug, continuous erythropoietin receptor activator (CERA), a pegylated derivative of epoetin-beta, has provided valuable therapeutic benefits to patients suffering from renal anemia, but has also rapidly found application as an illicit performance-enhancing strategy in endurance sports. We present here a novel method for selective determination of CERA in serum, based on polyethylene glycol precipitation, followed by a commercial homogeneous immunoassay. The developed method was highly discriminating between serum samples from CERA-treated patients and control subjects, as the covalently linked polyethylene glycol chain in CERA strongly enhanced the solubility of the protein in a polyethylene glycol-containing medium. Intravenous administration of CERA could be detected for several weeks in the majority of subjects tested. This assay outperforms the currently available CERA detection methods in terms of simplicity, convenience, cost, and throughput, making it ideal as a screening tool for doping control

Micro-computed tomography for the quantification of blocked fibers in hemodialyzers

A novel technique based on micro-CT scanning is developed to quantify coagulation in fibers of hemodialyzers. This objectivation is needed to allow accurate assessment of thrombogenicity of dialyzers used during hemodialysis, for example when comparing different strategies to avoid coagulation and/or fiber blocking. The protocol allowed imaging at a resolution of 25 mu m, making it possible to count the open, non-coagulated fibers in a non-invasive way. In 3 fresh, non-used FX600 hemodialyzers, patent fiber counts were extremely consistent (10748 +/- 2). To illustrate the potential of this technique, different dialysis parameters currently used as surrogates for fiber blocking were evaluated during 20 hemodialysis sessions. After dialysis, the FX600 dialyzers were visually scored for clotting, dried and subsequently weighed and scanned. The number of patent fibers (10003 [ 8763,10330], range 534-10692) did not correlate with any of the recorded surrogate parameters. Micro-CT scanning is a feasible, objective, non-invasive, accurate and reproducible tool for quantification of the degree of fiber blocking in a hemodialyzer after use, making it a potential gold standard for use in studies on fiber blocking during renal replacement therapies

The removal of uremic toxins

The removal of uremic toxins. Three major groups of uremic solutes can be characterized: the small water-soluble compounds, the middle molecules, and the protein-bound compounds. Whereas small water-soluble compounds are quite easily removed by conventional hemodialysis, this is not the case for many other molecules with different physicochemical characteristics. Continuous ambulatory peritoneal dialysis (CAPD) is often characterized by better removal of those compounds. Urea and creatinine are small water-soluble compounds and the most current markers of retention and removal, but they do not exert much toxicity. This is also the case for many other small water-soluble compounds. Removal pattern by dialysis of urea and creatinine is markedly different from that of many other uremic solutes with proven toxicity. Whereas middle molecules are removed better by dialyzers containing membranes with a larger pore size, it is not clear whether this removal is sufficient to prevent the related complications. Larger pore size has virtually no effect on the removal of protein-bound toxins. Therefore, at present, the current dialytic methods do not offer many possibilities to remove protein-bound compounds. Nutritional and environmental factors as well as the residual renal function may influence the concentration of uremic toxins in the body fluids

Spontaneous variability of pre-dialysis concentrations of uremic toxins over time in stable hemodialysis patients

Background and aim : Numerous outcome studies and interventional trials in hemodialysis (HD) patients are based on uremic toxin concentrations determined at one single or a limited number of time points. The reliability of these studies however entirely depends on how representative these cross-sectional concentrations are. We therefore investigated the variability of predialysis concentrations of uremic toxins over time. Methods : Prospectively collected predialysis serum samples of the midweek session of week 0, 1, 2, 3, 4, 8, 12, and 16 were analyzed for a panel of uremic toxins in stable chronic HD patients (N = 18) while maintaining dialyzer type and dialysis mode during the study period. Results : Concentrations of the analyzed uremic toxins varied substantially between individuals, but also within stable HD patients (intra-patient variability). For urea, creatinine, beta-2-micro-globulin, and some protein-bound uremic toxins, Intra-class Correlation Coefficient (ICC) was higher than 0.7. However, for phosphorus, uric acid, symmetric and asymmetric dimethylarginine, and the protein-bound toxins hippuric acid and indoxyl sulfate, ICC values were below 0.7, implying a concentration variability within the individual patient even exceeding 65% of the observed inter-patient variability. Conclusion : Intra-patient variability may affect the interpretation of the association between a single concentration of certain uremic toxins and outcomes. When performing future outcome and interventional studies with uremic toxins other than described here, one should quantify their intra-patient variability and take into account that for solutes with a large intra-patient variability associations could be missed