Neutrophils are first responders to any kind of threat the body faces: infection, severe
trauma, cancer, surgery... They produce the cytokines, induct oxidative stress and
de-granulate toxic proteins to kill pathogens. However the new mechanism related to the
neutrophil extracellular traps release has been recognized as a new way of cell necrosis
and has been called a NETosis.
NETosis is a hugely important new mechanism of human immune responses also described in
various forms of acute kidney injury (ischemic, toxic, autoimmune). In certain kidney
diseases, neutrophils release NETs and induce cell necrosis. Whether neutrophils die
along with NET release, and if they do die, remains under study and is most likely
context dependent. Extracellular traps (ETs) can be released also by macrophages. The ETs
formation as well as macrophages extracellular traps (MET's) especially in kidney disease
are cytotoxic and elicit inflammation, contributing to necro-inflammation of the
early-injury phase of acute tubular necrosis in anti-neutrophil cytoplasmic
antibody-related renal vasculitis, anti-glomerular basement membrane disease, lupus
nephritis. Finally, acute kidney injury-related releases of dying renal cells or ETs
promote organ injuries - for example, acute respiratory distress syndrome. According to
the recent review the term 'NET formation' has been proposed as a better term to use
instead of 'NETosis'. The formation of neutrophil extracellular traps (NETs) has been
recently recognized as a unique modality of pathogen fixation (sticky extracellular
chromatin) and pathogen killing (cytotoxic histones and proteases) during host immune
responses, as well as collateral tissue damage.
Histones are potent mediators of injury in various cells. Indeed, extracellular histone
induce microvascular endothelial cells and renal epithelial cells death in vitro, forms
the pores that disrupt cell integrity and induce the cytolysis by their capacity of
binding with membrane phospholipids and activation of inflammasome in the kidney leading
to auto-entrainment of inflammation.
The activation of inflammation has been demonstrated in the experimental model of
crystalline nephropathy related to the uncontrolled oxalate urinary excretion. Inhibition
of inflammasome activation has been related with the preservation of kidney function. In
patients with kidney stone disease the presence of crystals in the urine has been
demonstrated to induce tubular epithelial cells injury that can theoretically trigger the
NET's or MET's release and tissue inflammation.
NETs are now increasingly described as new targets for therapies, however largely
under-estimated.
The role of release of ETs from neutrophils and macrophages during the kidney stone
disease has never been studied in urine but the neutrophil extracellular trap (NET)
formation-NETosis - was found significantly increased in the papillae of patients with
brushite stones compared with CaOx stones.
The key objectives of this study are:
to assess NET/MET's excretion in the urine as a non-invasive method of NET/MET'osis
measurement in patients with kidney diseases as a new biomarker of early stage of
cells damages reflecting kidney injury occurring in patients with uncontrolled
stones and other renal diseases;
to compare the NET/MET's concentrations in the urine with those in plasma
