Giorgio Triolo

Circulating plasma factors induce tubular and glomerular alterations in septic burns patients

BackgroundSevere burn is a systemic illness often complicated by sepsis. Kidney is one of the organs invariably affected, and proteinuria is a constant clinical finding. We studied the relationships between proteinuria and patient outcome, severity of renal dysfunction and systemic inflammatory state in burns patients who developed sepsis-associated acute renal failure (ARF). We then tested the hypothesis that plasma in these patients induces apoptosis and functional alterations that could account for proteinuria and severity of renal dysfunction in tubular cells and podocytes.MethodsWe studied the correlation between proteinuria and indexes of systemic inflammation or renal function prospectively in 19 severe burns patients with septic shock and ARF, and we evaluated the effect of plasma on apoptosis, polarity and functional alterations in cultured human tubular cells and podocytes. As controls, we collected plasma from 10 burns patients with septic shock but without ARF, 10 burns patients with septic shock and ARF, 10 non-burns patients with septic shock without ARF, 10 chronic uremic patients and 10 healthy volunteers.ResultsSeptic burns patients with ARF presented a severe proteinuria that correlated to outcome, glomerular (creatinine/urea clearance) and tubular (fractional excretion of sodium and potassium) functional impairment and systemic inflammation (white blood cell (WBC) and platelet counts). Plasma from these patients induced a pro-apoptotic effect in tubular cells and podocytes that correlated with the extent of proteinuria. Plasma-induced apoptosis was significantly higher in septic severe burns patients with ARF with respect to those without ARF or with septic shock without burns. Moreover, plasma from septic burns patients induced an alteration of polarity in tubular cells, as well as reduced expression of the tight junction protein ZO-1 and of the endocytic receptor megalin. In podocytes, plasma from septic burns patients increased permeability to albumin and decreased the expression of the slit diaphragm protein nephrin.ConclusionPlasma from burns patients with sepsis-associated ARF contains factors that affect the function and survival of tubular cells and podocytes. These factors are likely to be involved in the pathogenesis of acute tubular injury and proteinuria, which is a negative prognostic factor and an index of renal involvement in the systemic inflammatory reaction.

Regional Citrate Anticoagulation in Critically Ill Patients Treated with Plasma Filtration and Adsorption

Background: In high-risk bleeding conditions conventional systemic anticoagulation with heparin is a contraindication to renal replacement therapy. We evaluate the feasibility and safety of regional citrate anticoagulation in high-risk bleeding conditions during coupled plasma filtration adsorption (CPFA). Methods: Thirteen critically ill patients (9 severely burned, 4 polytraumas) with septic shock and acute renal failure treated with CPFA-CVVHD by using bicarbonate-based solutions (heparin-CPFA group, 58 sessions) or with CPFA-CVVHF using citrate (citrate-CPFA group, 36 sessions). Results: Plasma flow and used cartridges showed no differences between the citrate-CPFA and heparin-CPFA groups, while lost clotted cartridges were significantly lower in the citrate-CPFA group. Blood ionized calcium (iCa2+), Ca2+ infusion, pH and bicarbonates remained constant during citrate-CPFA, with no difference between pre- and post-cartridge plasma citrate. A significant positive correlation between iCa2+ in blood and ultrafiltrate was present. Conclusions: These results demonstrate the feasibility and safety of regional citrate anticoagulation in severely burned and polytrauma septic patients treated by CPFA.

Platelet-activating factor synthesis by neutrophils, monocytes, and endothelial cells is modulated by nitric oxide production.

Nitric oxide (NO) and platelet-activating factor (PAF) can modulate the interaction between endothelial lining and circulating leukocytes. Several studies implicated the production of PAF and NO in the pathogenesis of microcirculatory alterations occurring in septic shock. However, the reciprocal interaction between PAF and NO has not been fully elucidated. In the present study, we evaluated whether the basal synthesis of NO could modulate the production of PAF by neutrophils (PMN), monocytes (MO), and endothelial cells (EC) unstimulated or stimulated with lipopolysaccharides (LPS) or tumor necrosis factor (TNF). PMN, MO, and EC, when incubated with Nω-nitro-l-arginine methyl ester (l-NAME) spontaneously synthesized PAF, with an early peak at 30 min. The effective inhibition of NO production was visualized on MO cells as generation of fluorescence reactivity by cell-permeable NO reactive dye DAF-2 DA. Also, monomethyl- l-arginine (l-NMMA) induced PAF synthesis by PMN, whereas the biologically inactive d-enantiomers of NAME (d-NAME) and of NMMA (d-NMMA) did not. Stimulation of PMN with l-NAME in presence of the exogenous NO donor nitroprusside, of the NO secondary mediator cGMP, or of the NO synthase substrate l-arginine reduced PAF synthesis, suggesting the involvement of an NO-dependent pathway on the modulation of PAF synthesis. The synthesis of PAF was enhanced by combined treatment with l-NAME and TNF or LPS. These results indicate an inhibitor effect of NO on the spontaneous and TNF or LPS-induced synthesis of PAF by human PMN, MO, and EC.

Citrate Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Patients: Success and Limits

Citrate anticoagulation has risen in interest so it is now a real alternative to heparin in the ICUs practice. Citrate provides a regional anticoagulation virtually restricted to extracorporeal circuit, where it acts by chelating ionized calcium. This issue is particularly true in patients ongoing CRRT, when the “continuous” systemic anticoagulation treatment is per se a relevant risk of bleeding. When compared with heparin most of studies with citrate reported a longer circuit survival, a lower rate of bleeding complications, and transfused packed red cell requirements. As anticoagulant for CRRT, the infusion of citrate is prolonged and it could potentially have some adverse effects. When citrate is metabolized to bicarbonate, metabolic alkalosis may occur, or for impaired metabolism citrate accumulation leads to acidosis. However, large studies with dedicated machines have indeed demonstrated that citrate anticoagulation is well tolerated, safe, and an easy to handle even in septic shock critically ill patients.

Is there a real alternative anticoagulant to heparin in continuous treatments

‘In view of past and new emerging data, regional citrate anticoagulation undoubtedly draws great interest in critical care nephrology.’ Filippo Mariano†, Ciro Tetta, Claudio Ronco and Giorgio Triolo Author for correspondence CTO Hospital, Nephrology and Dialysis Unit, Department of Medicine Area, 10126 Turin, Italy Tel.: +39 011 693 3671 Fax: +39 011 693 3672 filippo.mariano@cto.to.it Expert Rev. Med. Devices 3(1), 5–8 (2006)

When should commence dialysis: focusing on the predialysis condition.

The prevalence of chronic kidney disease (CKD), as defined by the NFK-KDOQI (the national kidney foundation kidney disease outcomes quality initiative) guidelines, is a glomerular filtration rate less than 60 mL/min/1.73 m2 or the presence of microalbuminuria. CKD is increasing worldwide, leading to an increased risk of cardiovascular disease. There is general agreement on the importance of an early referral to a nephrologist and predialysis educational programs. Establishing the protocol for an early approach may assist in preventing the progression, and the most common complications of renal disease. Predialysis education helps patients in order to choose a renal replacement therapy (hemodialysis, peritoneal dialysis, transplantation) and improve their quality of life. Furthermore, adequate predialysis care allows the nephrologist to promptly prepare for vascular or peritoneal treatment. Regrettably, patients are often referred to the nephrologist when renal failure is already fall in the advanced stage. This is caused primarily by non-nephrologists failing to identify patients at risk for imminent renal failure. Furthermore, they may be defining the patient’s degree of renal failure according to the KDOQI classification. To further complicate matters, the serum creatinine alone does not provide an adequate estimate of renal function; however, both the MDRD (the modification of diet in renal disease) equation and the Cockcroft-Gault formula permit the more reliable and accurate estimation of the all-important glomerular filtration rate (GFR). Using the MDRD equation, the KDOQI guidelines recommend referral when GFR is less than 30 mL/min/1.73 m2. Late nephrology referral is an independent risk factor for early death while on dialysis; it is also associated with a more frequent use of temporary catheters, particularly in the elderly individuals. This subject underlines the importance of a multidisciplinary predialysis approach that may bring additional benefits – beyond referral to a nephrologist – including a reduced hospitalization period and a lower mortality rate. The KDOQI guidelines recommend evaluating the benefits and risks of starting renal replacement therapy when patients reach stage 5 (estimated GFR less than 15 mL/min/1.73 m2), although the ideal period for initiation of the replacement therapy remained a source of debate.

Burns and Acute Kidney Failure

Renal alterations such as proteinuria, hematuria, and electrolyte disturbances are common in patients with severe burns. Two distinct pictures with an early and a late form of acute kidney failure (ARF) have been described: The early form occurs in the immediate postburns period and can in most cases be effectively prevented by early aggressive fluid resuscitation. The late form develops after 2–3 weeks from initial injury and is usually due to sepsis and multiorgan dysfunction syndrome. In the last 20 years, onset and outcome of acute kidney failure in these patients has been improved by early aggressive burn wound excision, new powerful antibiotics, and early enteral nutrition for maintaining gastrointestinal trophism. In patients with established ARF, early intensive extracorporeal treatment is effective in reaching a mean survival rate of 20–50% of treated patients.

The Evolution of Biocompatibility: From Microinflammation to Microvesiscles

Haemodialysis (HD) is a life-saving treatment for patients with chronic kidney disease (CKD) stage 5. CKD persists as a chronic worldwide epidemic and HD is the more frequently (70%) adopted treatment modality. Exponential growth trend continues on a global scale. The HD population becomes every year increasingly older (average age: 75 yrs) and sicker due to the associated co-morbidities such as cardiovascular disease (heart failure, coronary heart disease, and peripheral vascular disease), diabetes, hypertension, and peripheral vascular disease. Most of the complications associated with HD involve the cardiovascular system (Go et al., 2004; Culleton et al., 1999, Goodkin et al., 2003, Foley 2004; Barret, 2002). The evolution in the history of HD technology has greatly helped to make the HD procedure a safe and more biocompatible extracorporeal therapy. However, it must be admitted that despite significant improvements in HD technology and in the management of patients due to a better understanding of uremia toxicity, improvements in dialysis technology, better correction of anaemia and metabolic abnormalities, implementation of best practice guidelines, no significant improvement has been achieved in patient survival over the last decade (Rayner et al., 2004). The extracorporeal circuit offers a large surface of contact of the blood with foreign materials, namely the dialysis membrane, the tubings and the large volumes of the dialysate. The concept of biocompatibility has greatly evolved in the last two decades. Initially, numerous studies focused on the blood-dialyzer membrane interaction, leading to the activation of plasma systems (complement, coagulation, fibrinolysis). These studies helped in the understanding of some unknown effects occurring in the early stages of the HD session leading to pulmonary sequestration of leukocytes (mainly neutrophils) that explained the profound neutropenia associated with the cuproammonium membranes. The availability of reliable testing of complement-activated