On-line hemodiafiltration did not induce an overproduction of oxidative stress and inflammatory cytokines in intensive care unit-acute kidney injury

In intensive care units (ICUs), around 5% of patients suffering from acute kidney injury (AKI) require renal replacement therapy (RRT) [1]. Intermittent conventional hemodialysis (IHD) and continuous venovenous hemo(dia)filtration are the 2 principal modalities used for RRT. However, the ideal renal replacement method for intensive care patients remains under scrutiny [2, 3]. It should combine the advantages of continuous RRT (CRRT) with those of IHD, be simple to implement and induce minimal work with limited cost. On-line dialysis fluids preparation may fit these conditions since it offers favorable technical possibilities and highly flexible procedures to apply various forms of cost-effective high efficiency hemodiafiltration (HDF) modalities in intermittent or sustained mode [4‐7].

On-line HDF (OL-HDF) is a RRT based on cold sterilization of dialysis fluid to prepare the infusate which is readily administered into the extracorporeal bloodstream. It necessitates a fully microbiological integrity of on-line produced dialysis fluids. In chronic dialysis facilities, this technique became a routine and safe modality of RRT and now represents the most effective dialysis therapy [8‐10]. A few reports exist about its use in ICUs and its routine application is mainly restricted to ICU facilities working with a trained nephrological team [4‐7, 11‐17]. The limited use of this technique by intensivists is largely related to the technical complexity with water treatment and HDF machines and to the potential infectious risk of on-line produced fluids infusion especially in septic patients who represent the majority of admissions in ICUs. We have previously reported our experience of OL-HDF use in ICU [11]. A regular bacteriological control of dialysis fluids showed that this technique is safe and well tolerated [11]. Whether OL-HDF modulates plasma cytokine concentration and oxidative stress production is still not investigated. The combined use of synthetic biocompatible membrane and ultrapure dialysis fluid may limit the additional inflammatory risk induced by OL-HDF. However, this potential acute inflammatory risk induced by OL intermittent HDF (OL-IHDF) which remains possible in ICU-AKI has never been evaluated. We designed therefore a study to determine whether OL-IHDF would induce an overproduction of oxidative stress, cytokines and growth factors in critically ill patients.

This observational prospective study was carried out at the Medical ICU of Lapeyronie University Hospital at Montpellier and was approved by the Ethics Research Committee of our hospital; PHRC régional: N° 2006-A00510–51.

The present study demonstrated that OL-IHDF achieved an adequate dialysis dose with a fair hemodynamic tolerance in critically ill patients, and was not associated with an increased inflammatory risk. It did not induce an overproduction of oxidative stress and of pro- and anti-inflammatory cytokines but a significant decrease of TNF_α and AOPP plasmatic levels.

On-line substitution fluid preparation is a standard feature of modern dialysis devices for chronic treatments [32]. In ICU settings, on-line RRT modalities are however rarely used and their routine application is mainly restricted to ICU facilities working with a trained nephrological team [4‐7, 9, 11‐17]. The carefulness of intensivist to use OL-IHDF is related to the potential infectious risk and deleterious effects of on-line produced fluid infusion especially in septic patients who represent the majority of those admitted to ICUs. On-line preparation is not accompanied by on-line control of the microbiological quality and inadequate infusate would be administered directly without prior product check and release. In a previous work, we have evaluated, over a 7 year-period, the purity of on-line produced ultrapure water and dialysis fluids by a weekly bacterial control monitoring in ICU settings: more than 90% of samples showed negative bacterial growth and undetectable levels of endotoxin indicating an overall compliance rate of 99% [11]. However, water and dialysis fluids may still contained cytokines-inducing substances other than endotoxins like breakdown products of microorganisms, peptidoglycans and β-glycans [33]. They have the potential capability of penetrating ultrafiltration and dialysis membranes with subsequent blood exposure and intradialytic cytokine and oxidative stress induction [34]. We aimed therefore to assess the inflammatory risk for critically ill patients receiving OL-HDF by the quantification of cytokines, oxidative stress and growth factors potentially produced during OL-IHDF.

Critically ill patients with AKI have higher circulating plasma concentration of inflammatory biomarkers implicated in RRT dependence and mortality than those without AKI [35, 36]. This inflammatory process is partly due to the generation of oxidative stress which is mainly of multifactorial origin including sepsis, and accumulation of uremic toxins in case of AKI but may be also related to RRT modalities. Indeed, online therapy itself can exacerbate oxidative stress production through leukocytes activation induced by dialysis and substitution fluids. Herein, we found that OL-IHDF did not alter superoxide anion production by leukocytes either basal or after stimulation by PMA. Our AKI patients treated by RRT have an increased levels of AOPPs [37‐39], varying from 35 to 120 μmol/L as previously reported by Du et al. [39] but lower than those observed by Lentini et al. [38]. We observed that OL-IHDF provided a slight but still significant decrease in AOPP plasma concentrations. Of note, it has been suggested earlier that AOPPs contribute to the progression of renal failure and that higher AOPP levels are associated with poor renal recovery [40]. Cytokine induction has been also considered as the trigger of the inflammatory response and a critical parameter of dialysis biocompatibility during RRT [41]. Moreover, high levels of pro-inflammatory cytokines have been associated with increased mortality in AKI [35, 42]. We found that both pro- and anti-inflammatory cytokines plasma levels did not increase after OL-IHDF suggesting that it might not alter the balance of cytokines production. Other studies reported, like us, the lack of cytokines reduction by hemodiafiltration [43]. Substance clearance is dependent on its molecular size but also on ultrafiltration rate and on whether the substitution fluid is administered before and after the filter. In our study, we used a predilution modality of HDF diluting the blood before filter passage and convection volumes were less than 30 l per session explaining, at least for a part, the observed non significative reduction of plasmatic cytokines.

Last, OL-IHDF sessions were not associated with an increased production of VGEF, EGF and MCP-1 in our patients. Enhanced production of growth factors after endothelial activation has been reported in critical conditions especially sepsis-related AKI leading to increased capillary permeability, systemic vasodilatation and multi-organ failure [44, 45]. Chancharoenthana W [46] reported however that OL-HDF provided a significant removal of VEGF and was associated with better renal outcome as compared to high-flux hemodialysis.

Furthermore, on-line IHDF was best tolerated and achieved an adequate urea reduction rate. We did not observe any pyrogenic reactions whereas data on chronic on-line HDF reported an incidence at 0.04% [47]. A low incidence of intradialytic hypotensive events was also repertoried (13.3%) lower than recently reported (18.7%) (47). However, we may not state that OL-IHDF lead to a better hemodynamic tolerance than other modalities especially continuous therapies since this study was only observational.

We must acknowledge some limitations to the study. First, our work shares the limitations of single-center studies. Our unit is indeed familiar with online therapies which are not the general rule in ICU settings. Second, the number of patients included may be considered small but a high number of OL-HDF sessions were analyzed and secure our observations. Third, our RRT patients exhibited a cellular reactivity as reflected by inflammatory and oxidative stress parameters with a medium intensity thanks to the biocompatibility membranes. An evaluation of more sensitive biomarkers like isoprostanes may evaluate more thoroughly oxidative stress. Nevertheless, most of the tested parameters were not modified during the on-line sessions performed, a result that represents our primary hypothesis in this work. Last, outcome was not studied in this study since our concern was focused on feasibility and potential risk of this technique in critically ill patients.

In conclusion, our study shows that OL-IHDF does not induce additional inflammatory risks in critically ill patients with AKI and may be used securely in these settings. On-line production of ultrapure water seems to be very useful for ICU acute renal failure as it gives possibilities for a large scale of dialysate and infusate rate prescription. Further studies should however investigate its effect on all-cause mortality in comparison to other RRT modalities.