Biomarkers of inflammation during continuous renal replacement therapy: sensors, players, or targets? A reply to the letter by Villa et al.

In recent years, after all the attention has been focused on the dose for continuous renal replacement therapy (CRRT) in sepsis and systemic inflammation response syndrome (SIRS), the relatively negative results of all those studies did urge our expectations on new approaches regarding CRRT in sepsis and SIRS. So far, after the failure of the major randomized studies on dose, attention is now drawn to new membranes that could better eliminate massive amounts of unbound mediators in wider spectrum and also in greater magnitude Nevertheless, for septic acute kidney injury, the recommended dose will remain 35 ml/kg/h until the IVOIRE (hIgh VOlume in Intensive Care) study will be published. In this new armamentarium, we have distinguished the first tools that can still be called membranes ranging from AN69 Surface Treated (ST), SEPTEX, polymethylmetacrylate, to Oxiris that can still run with a CRRT device. Polymyxin B is still a kind of membrane although it has a larger surface, but it can run in a hemoperfusion system and is also much more selective. Adsorptive columns and sorbents are not anymore membranes but are seen as cartridges as the surface is extremely huge when compared with that of membranes (more than 500 m). They can still run in a hemoperfusion device. At the very end, we do have apheresis or selective plasma exchange (also very close to sorbents and columns) but we have very few data up to now regarding sepsis. Regarding spectrum, CytoSorb seems to be very promising although it is not able to capture endotoxin and IL-10. Oxiris is also promising as it can capture endotoxin and cytokines. AN69 ST is very powerful to capture numerous cytokines and especially high-mobility group box 1 protein (a very upstream cytokine). Polymethylmetacrylate has also the power to capture endotoxin and numerous other cytokines probably with a larger magnitude than Oxiris although this is not proven. Lastly, high-porosity membranes (Septex) may play a role especially when used in continuous venovenous hemodialysis mode. At the end, if we look for a more enlarged spectrum and a higher magnitude, CytoSorb might be seen as the most promising although not having the ability to fix endotoxin. Future studies will tell us which membrane or sorbent will be most useful in the adjunctive treatment for sepsis.

Atrial natriuretic peptide (ANP) is a peptide hormone released from the cardiac atria during hypervolemia. Though named for its well-known renal effect, ANP has been demonstrated to acutely increase vascular permeability in vivo. Experimentally, this phenomenon was associated with a marked shedding of the endothelial glycocalyx, at least for supraphysiological intravascular concentrations. This study investigates the impact and mechanism of action of physiological doses of ANP and related peptides on the vascular barrier. In isolated guinea pig hearts, prepared and perfused in a modified Langendorff mode with and without the intravascular presence of the colloid hydroxyethyl starch (HES), we measured functional changes in vascular permeability and glycocalyx shedding related to intracoronary infusion of physiological concentrations of A-, B- and C-type natriuretic peptide (ANP, BNP and CNP). Significant coronary venous washout of glycocalyx constituents (syndecan-1 and heparan sulfate) was observed. As tested for ANP, this effect was positively related to the intracoronary concentration. Intravascular shedding of the glycocalyx was morphologically confirmed by electron microscopy. Also, functional vascular barrier competence decreased, as indicated by significant increases in transudate formation and HES extravasation. Ortho-phenanthroline, a non-specific inhibitor of matrix metalloproteases, was able to reduce ANP-induced glycocalyx shedding. These findings suggest participation of natriuretic peptides in pathophysiological processes like heart failure, inflammation or sepsis. Inhibition of metalloproteases might serve as a basis for future therapeutical options.