Heparin versus prostacyclin in continuous hemodiafiltration for acute renal failure: effects on platelet function in the systemic circulation and across the filter.

Continuous venovenous hemodiafiltration (CVVHDF) is the treatment of choice for critically-ill patients suffering from acute renal failure (ARF). One major problem of extracorporeal circuits is their thrombogenicity, which requires pharmacological blockade of primary (platelet-dependent) or secondary (plasmatic) haemostasis, increasing the patient's bleeding risk. Our study assessed platelet function during CVVHDF, comparing anticoagulant versus antiplatelet pharmacological strategies, commonly used to avoid circuit clotting. Twenty-three critically-ill patients with ARF, requiring CVVHDF were randomized to a prostacyclin analogue (PGI) or to unfractionated heparin (UFH). Ex vivo platelet function, assessed by optical aggregometry (OPA) induced by collagen or ADP, was studied in peripheral blood at baseline, 4 and 24 hrs after starting CVVHDF, and at 4 hrs within the circuit, before and after the filter (n=9). Coagulation was also monitored. PGI significantly inhibited ADP-induced OPA of peripheral platelets: maximal aggregation (Tmax) was reduced at 4 and 24 hrs by 20%, while collagen-induced Tmax was significantly reduced at 4 hrs only. In the UFH group, collagen-induced OPA in peripheral platelets was significantly inhibited: slopes of OPA tracings were decreased by 25%, lag time was prolonged by 22%, Tmax decreased by 10% already at 4 hrs. ADP-induced OPA showed a similar, but non-significant trend. UFH expectedly prolonged aPTT. In the UFH group, platelet responsiveness to collagen was significantly increased by 30% in post-filter versus pre-filter samples. This effect was blunted in the PGI group. UFH does not protect platelets from filter-induced activation and is associated with a reduced function of systemic platelets. Platelet-inhibiting agents might better prevent the activatory effect of the filter.

Oxidative stress and 'monocyte reprogramming' in septic patients with acute kidney injury requiring CRRT.

Oxidative stress (OS) and monocyte HLA-DR expression are known to be predictive of mortality in sepsis; nevertheless, limited information exists regarding sepsis with acute kidney injury (AKI). The aim of the study was to correlate these markers with outcome in septic patients with AKI requiring continuous renal replacement therapy (CRRT). Advanced oxidation protein products (AOPP) were measured in 32 patients on days 1, 3, 7, 14, 21, and 28. In 14 we assessed the percentage of monocytes expressing HLA-DR (%DR+) and the HLA-DR mean fluorescence intensity (MFI). 20 healthy volunteers, 17 septic patients without AKI and 20 septic AKI patients not treated by CRRT were used for comparison. The mortality rate was 59%. Septic CRRT patients had higher AOPP and lower %DR+ (p < 0.001, both) than healthy controls. They also had higher AOPP than septic patients who did not develop AKI (p < 0.001). No difference was found in AOPP, %DR+ and MFI between survivors and non-survivors (day 1 and subsequent measurements). No correlation was seen between severity scores and OS/HLA-DR. OS and HLA-DR expression are altered in septic patients with AKI undergoing CRRT. However, this study was not able to confirm the usefulness of these markers in predicting survival in this subset of patients.

Pulse high-volume hemofiltration in critically ill patients: a new approach for patients with septic shock.

Mortality rates in septic shock remain unacceptably high despite advances in our understanding of the syndrome and its treatment. Humoral factors are increasingly recognized to participate in the pathogenesis of septic shock, giving a biological rationale to therapies that might remove varied and potentially dangerous humoral mediators. While plasma water exchange in the form of hemofiltration can remove circulating cytokines in septic patients, the procedure, as routinely performed, does not have a substantial impact on their plasma levels. More intensive plasma water exchange, as high-volume hemofiltration (HVHF)can reduce levels of these mediators and potentially improve clinical outcomes. However, there are concerns about the feasibility and costs of HVHF as a continuous modality--very high volumes are difficult to maintain over 24 hours and solute kinetics are not optimized by this regimen. We propose pulse HVHF (PHVHF)-HVHF of 85 ml/kg/hr for 6-8 hours followed by continuous venovenous hemofiltration (CVVH) of 35 ml/kg/hr for 16-18 hours-as a new method to combine the advantages of HVHFimprove solute kinetics, and minimize logistic problems. We treated 15 critically ill patients with severe sepsis and septic shock using daily PHVHF in order to evaluate the feasibility of the technique, its effects on hemodynamics, and the impact of the treatment on pathologic apoptosis in sepsis. Hemodynamic improvements were obtained after 6 hours of PHVHF and were maintained subsequently by standard CVVHas demonstrated by the reduction in norepinephrine dose. PHVHFbut not CVVHsignificantly reduces apoptotic plasma activity within 1 hour and the pattern was maintained in the following hours. PHVHF appears to be a feasible modality that may provide the same or greater benefits as HVHFwhile reducing the workload and cost.

Oxidant and carbonyl stress-related apoptosis in end-stage kidney disease: impact of membrane flux.

Apoptosis is a highly regulated process which mostly affects cell-mediated immunity. In this open-label, randomized, prospective clinical study, we determined the impact in 10 hemodialysis patients treated with high-, medium-, and low-flux membranes on spontaneous or plasma-induced apoptosis, on monocytes, as well as on oxidant and carbonyl stress. High- and medium-flux membranes significantly reduced patients' plasma-dependent proapoptotic activity on U937 monocytic cell lines. Patients who had the highest levels of plasma-induced proapoptotic activity exhibited the highest plasma levels of advanced oxidation protein products (AOPPs) and carbonyls. Plasma carbonyl residues but not AOPPs were significantly lowered. Finally, a significant correlation could be drawn between the extent of plasma-induced proapoptotic activity and both plasma carbonyl and AOPP levels.

Practice patterns in the management of acute renal failure in the critically ill patient: an international survey.

BACKGROUND: Several controversies have developed over acute renal failure (ARF) definition and treatment: which approach to patient care is most desirable and which form of renal replacement therapy (RRT) should be applied is an everyday matter of debate. There is also disagreement on clinical practice for RRT including the best timing to start, vascular access, anti-coagulation, membranes, equipment and finally, if continuous or intermittent techniques should be preferred. In this lack of harmony, the epidemiology of ARF has recently displayed an outbreak of cases in the intensive care units and nephrologists and intensivists are now called to work together in the case of such a syndrome. SUBJECTS AND METHODS: We report on the responses of 560 contributors, mostly coming from Europe, to a questionnaire submitted during the third International Course on Critical Care Nephrology held in Vicenza, Italy in June 2004. The questionnaire was divided into several sections concerning demographic and medical information, definition of ARF, practice of RRT, current opinions about clinical advantages and problems related to different RRTs and modalities, and beliefs on alternative indications to extracorporeal treatments. RESULTS: More then 200 different definitions of ARF and about 90 RRT start criteria were reported. Oliguria and RIFLE (an acronym classifying ARF in different levels of severity: Risk of renal dysfunction; Injury to the kidney; Failure of kidney function; Loss of kidney function; End-stage kidney disease.) were the most frequent criteria used to define ARF. In 10% of centres all forms of renal replacement techniques are available, and in 70% of cases two or more different techniques are available: absolute analysis of different techniques showed that continuous renal replacement therapies are utilized by 511 specialists (91%), intermittent haemodialysis by 387 (69%) and sustained low efficiency dialysis by 136 (24%). Treatment prescription showed significant differences among specialists, 60% of intensivists being uncertain on RRT dose prescription compared to 40% of nephrologists (P = 0.002). The most frequently selected dosage was '35 ml/kg/h' for urea (25%) and creatinine targets (26%), and '2-3 l/h' for the septic dose (25%). Of the participants, 90% said that they used RRT for non-renal indications, 60% although responders admitted the lack of scientific evidence as a limiting factor to its use. CONCLUSIONS: New classifications such as RIFLE criteria might improve well-known uncertainty about ARF definition. Different RRT techniques are available in most centres, but a general lack of treatment dose standardization is noted by our survey. Non-renal indications to RRT still need to find a definitive role in routine practice.

A new machine for continuous renal replacement therapy: from development to clinical testing.

A new continuous renal replacement therapy machine has been designed to fulfill the expectations of nephrologists and intensivists operating in the common ground of critical care nephrology. The new equipment is called Prismaflex and it is the natural evolution of the PRISMA machine that has been utilized worldwide for continuous renal replacement therapy in the last 10 years. The authors performed a preliminary alpha-trial to establish the usability, flexibility and reliability of the new device. Accuracy was also tested by recording various operational parameters during different intermittent and continuous renal replacement modalities during 62 treatments. This article will describe our first experience with this new device and touch upon the historic and technologic background leading to its development.

Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival.

INTRODUCTION: Severe sepsis is the leading cause of mortality in critically ill patients. Abnormal concentrations of inflammatory mediators appear to be involved in the pathogenesis of sepsis. Based on the humoral theory of sepsis, a potential therapeutic approach involves high-volume haemofiltration (HVHF), which has exhibited beneficial effects in severe sepsis, improving haemodynamics and unselectively removing proinflammatory and anti-inflammatory mediators. However, concerns have been expressed about the feasibility and costs of continuous HVHF. Here we evaluate a new modality, namely pulse HVHF (PHVHF; 24-hour schedule: HVHF 85 ml/kg per hour for 6-8 hours followed by continuous venovenous haemofiltration 35 ml/kg per hour for 16-18 hours). METHOD: Fifteen critically ill patients (seven male; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score 31.2, mean Simplified Acute Physiology Score [SAPS] II 62, and mean Sequential Organ Failure Assessment 14.2) with severe sepsis underwent daily PHVHF. We measured changes in haemodynamic variables and evaluated the dose of noradrenaline required to maintain mean arterial pressure above 70 mmHg during and after pulse therapy at 6 and 12 hours. PHVHF was performed with 250 ml/min blood flow rate. The bicarbonate-based replacement fluid was used at a 1:1 ratio in simultaneous pre-dilution and post-dilution. RESULTS: No treatment was prematurely discontinued. Haemodynamics were improved by PHVHF, allowing a significant reduction in noradrenaline dose during and at the end of the PHVHF session; this reduction was maintained at 6 and 12 hours after pulse treatment (P = 0.001). There was also an improvement in systolic blood pressure (P = 0.04). There were no changes in temperature, cardiac index, oxygenation, arterial pH or urine output during the period of observation. The mean daily Kt/V was 1.92. Predicted mortality rates were 72% (based on APACHE II score) and 68% (based on SAPS II score), and the observed 28-day mortality was 47%. CONCLUSION: PHVHF is a feasible modality and improves haemodynamics both during and after therapy. It may be a beneficial adjuvant treatment for severe sepsis/septic shock in terms of patient survival, and it represents a compromise between continuous renal replacement therapy and HVHF.

In vivo validation of the adequacy calculator for continuous renal replacement therapies.

INTRODUCTION: The study was conducted to validate in vivo the Adequacy Calculator, a Microsoft Excel-based program, designed to assess the prescription and delivery of renal replacement therapy in the critical care setting. METHODS: The design was a prospective cohort study, set in two intensive care units of teaching hospitals. The participants were 30 consecutive critically ill patients with acute renal failure treated with 106 continuous renal replacement therapies (CRRT). Urea clearance computation was performed with the Adequacy Calculator (KCALC). Simultaneous blood and effluent urea samples were collected to measure the effectively delivered urea clearance (KDEL) at the beginning of each treatment and, during 73 treatments, between the 18th and 24th treatment hour. The correlation between 179 computed and 179 measured clearances was assessed. Fractional clearances for urea were calculated as spKt/V (where sp represents single pool, K is clearance, t is time, and V is urea volume of distribution) obtained from software prescription and compared with the delivered spKt/V obtained from empirical data. RESULTS: We found that the value of clearance predicted by the calculator was strongly correlated with the value obtained from computation on blood and dialysate determination (r = 0.97) during the first 24 treatment hours, regardless of the renal replacement modality used. The delivered spKt/V (1.25) was less than prescribed (1.4) from the Adequacy Calculator by 10.7%, owing to therapy downtime. CONCLUSION: The Adequacy Calculator is a simple tool for prescribing CRRT and for predicting the delivered dose. The calculator might be a helpful tool for standardizing therapy and for comparing disparate treatments, making it possible to perform large multi-centre studies on CRRT.

Uremic toxins: a new focus on an old subject.

The uremic syndrome is characterized by an accumulation of uremic toxins due to inadequate kidney function. The European Uremic Toxin (EUTox) Work Group has listed 90 compounds considered to be uremic toxins. Sixty-eight have a molecular weight less than 500 Da, 12 exceed 12,000 Da, and 10 have a molecular weight between 500 and 12,000 Da. Twenty-five solutes (28%) are protein bound. The kinetics of urea removal is not representative of other molecules such as protein-bound solutes or the middle molecules, making Kt/V misleading. Clearances of urea, even in well-dialyzed patients, amount to only one-sixth of physiological clearance. In contrast to native kidney function, the removal of uremic toxins in dialysis is achieved by a one-step membrane-based process and is intermittent. The resulting sawtooth plasma concentrations of uremic toxins contrast with the continuous function of native kidneys, which provides constant solute clearances and mass removal rates. Our increasing knowledge of uremic toxins will help guide future treatment strategies to remove them.

Phosphate kinetics during different dialysis modalities.

BACKGROUND: An abnormal serum phosphate concentration is common in acute renal failure patients, with a reported incidence of 65-80%. Phosphate removal and kinetics during intermittent hemodialysis (IHD) have been investigated, but there is no information on its kinetics during slow low-efficiency dialysis (SLED) and continuous renal replacement therapy (CRRT). METHODS: Eight IHD, 8 SLED, and 10 continuous venovenous hemofiltration (CVVH) patients with a residual renal clearance of <4.0 ml/min were studied during a single treatment to evaluate phosphate removal and kinetics. CVVH was studied the first 24 h after initiation. Dialysis/replacement fluid contained no phosphate. Kt/V, clearance of urea (Ku), inorganic phosphate (Kp) and solute removal was determined by direct dialysate quantification (DDQ). RESULTS: Kp recorded with the three techniques were: IHD, 126.9 +/- 18.4 ml/min; SLED, 58.0 +/- 15.8 ml/min, and CVVH, 31.5 +/- 6.0 ml/min. However, in shorter dialysis treatment the total removal of phosphate was significantly lower than in longer dialysis (IHD, 29.9 +/- 7.7 mmol; SLED, 37.6 +/- 9.6 mmol; CVVH, 66.7 +/- 18.9 mmol, p = 0.001). The duration of treatment is the only factor determining phosphate removal (r = 0.7, p < 0.0001 by linear correlation model). Like IHD, phosphate kinetics during SLED could not be explained by the two-pool kinetic model, and the rebound of phosphate extended beyond 1 h after dialysis. Rebound, however, is less marked than in short dialysis. CONCLUSION: These results are reliable evidence about amount of phosphate removal and behavior of intradialytic phosphate kinetics in renal failure patients undergoing different dialysis modalities. These data will help clinicians plan phosphate supplementation and treatment intensity.

Protective effect of urate oxidase on uric acid induced-monocyte apoptosis.

Uremic patients have a higher risk of infection and malignancy than normal subjects. Previous studies have deomonstrated that monocytes isolated from uremic patients display an increased apoptosis rate compared to normal subjects; furthermore uremic plasma can increase apoptosis rates on U937, a human monocytic cell line. In several pathological conditions, precipitation of uric acid crystals can lead to renal insufficiency or acute renal failure by different mechanisms. In recent studies uric acid has been shown to induce inflammatory response from monocytes and it has been suggested to be involved in cell dysfunction. Rasburicase is a new recombinant urate oxidase developed to prevent and treat hyperuricaemia in patients with cancer or renal failure; it degrades uric acid to allantoin, a less toxic and more soluble product. In the present study, we aimed at determining whether uric acid may be a factor affecting U937 apoptosis, and whether urate oxidase may reduces or even prevent uric acid induced cell apoptosis. Hoechst staining and internucleosome ledder fragmentation of DNA showed that uric acid increased the percentage of apoptotic cells comparing to the control and that when the U937 cells were incubated with uric acid and urate oxidase the percentage of apoptosis significantly decreased (from 43+/-7% to 19+/- 3%, p<0.05). Also, the activity of caspase-8 and caspase-3 showed the same trend (caspase 3: from 2.7+/-0.53 to 1.6+/-0.42; caspase-8: from 2.2+/-0.43 to 1.3+/-0.57). A reduction of intracellular reduced glutathione (GSH) concentration was found in uric acid treated cells while the addition of urate oxidase in the uric acid incubated cells decreased the GSH extrusion. The concentration of TNF-alpha was increased in the sample incubated with uric acid comparing to the control. Uric acid is an inducer of apoptosis on U937 cell line, and therefore it may be a component of the mosaic of uremic toxins both in acute and chronic renal disease. We can hypothesize that uric acid might be directly involved in the apoptotic process trough the activation of both death receptor and mitochondrial-mediated pathways. We have, also, demonstrated that urate oxidase is able to prevent at least in part, the effect of uric acid on U937 apoptosis. This effect might be a result of different mechanisms of action.