A Double-Blind Randomized Controlled Trial of High Cutoff Versus Standard Hemofiltration in Critically Ill Patients With Acute Kidney Injury.

OBJECTIVES: In critically ill patients with acute kidney injury receiving vasopressors, high cytokine levels may sustain the shock state. High cutoff hemofiltration achieves greater cytokine removal in ex vivo and in animal models and may reduce the duration of shock but may also increase albumin losses. DESIGN: This was a single-center double-blind randomized controlled trial comparing continuous venovenous hemofiltration-high cutoff to continuous venovenous hemofiltration-standard. SETTING: Tertiary care hospital in Australia. PATIENTS: Vasopressor-dependent patients in acute kidney injury who were admitted to the ICU. INTERVENTIONS: Norepinephrine-free time were calculated in critically ill vasopressor-dependent patients in acute kidney injury, randomized to either continuous venovenous hemofiltration-high cutoff or continuous venovenous hemofiltration-standard. MEASUREMENT AND MAIN RESULTS: A total of 76 patients were randomized with the following characteristics (continuous venovenous hemofiltration-high cutoff vs continuous venovenous hemofiltration-standard); median age of 65 versus 70 year, percentage of males 47% versus 68%, and median Acute Physiology and Chronic Health Evaluation scores of 25 versus 23.5. The median hours of norepinephrine-free time at day 7 were 32 (0-110.8) for continuous venovenous hemofiltration-high cutoff and 56 hours (0-109.3 hr) (p = 0.520) for continuous venovenous hemofiltration-standard. Inhospital mortality was 55.6% with continuous venovenous hemofiltration-high cutoff versus 34.2% with continuous venovenous hemofiltration-standard (adjusted odds ratio, 2.49; 95% CI, 0.81-7.66; p = 0.191). There was no significant difference in time to cessation of norepinephrine (p = 0.358), time to cessation of hemofiltration (p = 0.563), and filter life (p = 0.21). Serum albumin levels (p = 0.192) were similar and the median dose of IV albumin given was 90 grams (20-212 g) for continuous venovenous hemofiltration-high cutoff and 80 grams (15-132 g) for continuous venovenous hemofiltration-standard (p = 0.252). CONCLUSIONS: In critically ill patients with acute kidney injury, continuous venovenous hemofiltration-high cutoff did not reduce the duration of vasopressor support or mortality or change albumin levels compared with continuous venovenous hemofiltration-standard.

High cut-off hemofiltration versus standard hemofiltration: effect on plasma cytokines.

PURPOSE: To study the effects of continuous veno-venous hemofiltration (CVVH) with high cut-off filters (CVVH-HCO) on plasma cytokine levels, sieving coefficient and clearance compared to CVVH using standard filters (CVVH-Std) in a nested cohort within a double-blind randomized controlled trial in severe acute kidney injury (AKI) patients. METHODS: We measured plasma and post-filter levels of IL-6, TNF-alpha, IL-8, IL-1 beta, RANTES, IL-10, IFN-gamma and IFN-alpha in both study groups. We also measured cytokine levels in the ultrafiltrate and calculated sieving coefficients and clearances. RESULTS: By 72 hours of treatment, IL-6 had decreased during both treatments (p = 0.009 and 0.005 respectively). In contrast, IL-10 had decreased with CVVH-Std (p = 0.03) but not CVVH-HCO (p = 0.135). None of the other cytokines showed changes over time. There were also no significant between group differences in plasma levels for each cytokine over the 72-hour treatment period. For all cytokines combined, however, the median sieving coefficient was higher for CVVH-HCO (0.31 vs. 0.16; p = 0.042) as was the mass removal rate by ultrafiltration (p = 0.027). While overall combined cytokine levels had fallen to 62.2% of baseline at 72 hours for CVVH-HCO (p<0.0001) and to 75.9% of baseline with CVVH-Std (p = 0.008) there were no between group differences. CONCLUSIONS: CVVH-HCO achieved greater combined sieving coefficient and mass removal rate by ultrafiltration for a group of key cytokines than CVVH-Std. However, this effect did not differentially lower their plasma level over the first 72 hours. Our study does not support the use of CVVH-HCO to lower cytokines in critically ill patients with AKI.

Nucleosome levels and toll-like receptor expression during high cut-off haemofiltration: a pilot assessment.

OBJECTIVES: To measure plasma nucleosome levels and expression of toll-like receptors (TLRs) in a pilot cohort of patients with severe acute kidney injury (AKI) within a randomised controlled trial of continuous venovenous haemofiltration with high cut-off filters (CVVH-HCO) v standard filters (CVVH-std). METHODS: We measured plasma nucleosome levels using the Cell Death Detection ELISA PLUS (10X) assay kit. We analysed plasma levels for correlation with disease severity and compared the effects of CVVH-HCO and CVVH-std on plasma nucleosome levels over the first 72 hours. We studied cell surface TLR expression on CD14-positive monocytes in a subcohort of CVVH-HCO patients. RESULTS: We did not detect nucleosomes in normal human plasma, but found elevated nucleosome levels in patients with severe AKI. Nucleosome levels at randomisation correlated weakly with Acute Physiology and Chronic Health Evaluation III scores (Pearson ρ=0.475, P=0.016). Treatment with CVVH-HCO or CVVH-std had no effect on nucleosome levels over 72 hours. The mean fluorescence intensity (MFI) ratios of TLR2 and TLR4 expression were elevated throughout the 72-hour period (range for TLR2, 0.97-3.98; range for TLR4, 0.91-10.18) and did not appear to decrease as a result of treatment with CVVH-HCO. CONCLUSIONS: Nucleosome concentration was elevated in the plasma of patients with severe AKI and mildly correlated with disease severity, but was not affected by treatment with CVVH-HCO or CVVH-std. Similarly, levels of TLR2 and TLR4 expression did not decrease over time during CVVHCrit HCO treatment.

High cut-off hemofiltration versus standard hemofiltration: a pilot assessment of effects on indices of apoptosis.

OBJECTIVES: To measure plasma pro-apoptotic and pro-necrotic activity in severe acute kidney injury (AKI) patients within a randomized controlled trial of continuous veno-venous hemofiltration with high cut-off filters (CVVH-HCO) versus standard filters (CVVH-Std). METHODS: We measured pro-apoptotic and pro-necrotic plasma activity by trypan blue exclusion cell viability assay, detection of DNA fragmentation, and by determination of caspase-3 activity and annexin V-based apoptosis and necrosis detection assay. RESULTS: Compared to no apoptosis or necrosis after incubation with healthy plasma, 14-18% of cells showed apoptosis and 4-8% showed necrosis after incubation with plasma from AKI patients. When comparing different measures of pro-apoptotic or pro-necrotic activity, CVVH-HCO and CVVH-Std showed no differential effects on such activity, which remained high over the first 3 days of treatment. However, using annexin V-FITC, there was a significant drop in pro-apoptotic activity across the filter for the CVVH-HCO group (p = 0.043) but not for the CVVH-Std group (p = 0.327) and a significant difference between the two groups (CVVH-HCO vs. CVVH-Std p = 0.006). CONCLUSIONS: Patients with severe AKI have increased pro-apoptotic and pro-necrotic activity. Although on single-pass effect assessment, CVVH-HCO was superior to CVVH-Std in decreasing annexin V-FITC-assessed pro-apoptotic activity, there was no overall attenuation of such activity during the first 3 days of treatment.

A pilot, randomized, double-blind, cross-over study of high cut-off versus high-flux dialysis membranes.

BACKGROUND: High cut-off (HCO) membranes may increase beta(2)-microglobulin (beta2M) removal compared to standard high-flux membranes. METHODS: Eight stable haemodialysis patients were enrolled in a prospective, randomized, double-blind, cross-over study and treated with HCO and high-flux membranes for 2 weeks each, between a 1-week washout period. Primary end point was serum beta2M removal. Secondary end points included serum albumin concentrations, albumin and small solute clearances. RESULTS: HCO membranes achieved significantly lower median post-dialysis beta2M concentration (10.8 vs. 14.2 mg/l; p = 0.003) and greater beta2M reduction ratio (62.3 vs. 51.0%; p < 0.002). Serum albumin decreased with HCO membranes (from 36 to 29.5 g/l; p = 0.018) but increased to 33.5 g/l after the washout period. Albumin clearance was significantly greater with HCO membranes (2.2 vs. 0.06 ml/min; p = 0.004). Urea reduction ratio was significantly lower with HCO membranes (64.8 vs. 71.5%; p < 0.001). CONCLUSION: beta2M removal was superior with HCO membranes. Reduction in serum albumin and lower small solute clearance require further investigations.

Serum free-light chain removal by high cutoff hemodialysis: optimizing removal and supportive care.

In multiple myeloma the predominant cause of irreversible renal failure is cast nephropathy, secondary to excess kappa or lambda serum free light chains (FLCs). These molecules are efficiently cleared by hemodialysis (HD) using the Gambro HCO 1100 dialyzer. To optimize the removal of FLCs by this dialyzer we have studied the effect of dialyzers in series, dialyzer change, and hemodiafiltration in 14 patients with multiple myeloma and renal failure. The clearance rates of both kappa FLCs and lambda FLCs were significantly increased on two dialyzers from 19 (7.3-34)-15.3 (9-28) mL/min to 47 (17-79)-35.5 (20-57) mL/min, respectively. Clearance rates of both FLCs decreased over the course of the dialysis sessions (both P < 0.001). Changing the dialyzer during a HD session increased lambda FLC clearance rates (22.5 [6-41] to 37.6 [9-52] mL/min; P < 0.001) and decreased kappa FLC clearance rates (39.6 [9-72] to 19 [8-59] mL/min; P < 0.003). Ultrafiltration during HD increased the clearance rates of kappa FLCs (R 0.52, P < 0.01) but not lambda FLCs (R -0.25; P < 0.076). Hemodiafiltration increased the clearance rates of both kappa (19 [SD 6.8] to 32 [SD 9.8] mL/min) and lambda FLCs (15 [SD 7.8] to 20 [SD 7.7] mL/min). Albumin replacement requirements for 8 h of HD increased from 12 g for a single dialyzer to 45 g for two dialyzers in series (P < 0.001). Different protocols are required to optimize the removal of kappa and lambda FLCs in patients with myeloma and renal failure.

Hemodialysis membrane with a high-molecular-weight cutoff and cytokine levels in sepsis complicated by acute renal failure: a phase 1 randomized trial.

BACKGROUND: Sepsis is the leading cause of acute renal failure. Intermittent hemodialysis (IHD) is a common treatment for patients with acute renal failure. However, standard hemodialysis membranes achieve only little diffusive removal of circulating cytokines. Modified membranes may enable both successful IHD treatment and simultaneous diffusive cytokine removal. STUDY DESIGN: Double-blind, crossover, randomized, controlled, phase 1 trial. SETTING & PARTICIPANTS: Tertiary intensive care unit. 10 septic patients with acute renal failure according to RIFLE class F. INTERVENTION: Each patient was treated with 4 hours of high-cutoff (HCO)-IHD and 4 hours of high-flux (HF)-IHD. OUTCOMES & MEASUREMENTS: We chose relative change in plasma interleukin 6 (IL-6) concentrations from baseline to 4 hours as the primary outcome for effective cytokine removal. We measured plasma and effluent concentrations of cytokines (IL-6, IL-8, IL-10, and IL-18) and albumin. RESULTS: Median age was 53 years (25(th) to 75(th) percentiles, 43 to 71 years). Both treatments achieved equal control of uremia. Four hours of HCO-IHD accomplished a greater decrease in plasma IL-6 levels (-30.3%) than 4 hours of HF-IHD (1.1%; P = 0.05). HCO-IHD, but not HF-IHD, achieved substantial diffusive clearance of several cytokines (IL-6, 14.1 mL/min; IL-8, 75.2 mL/min; and IL-10, 25.5 mL/min). Such clearance also was associated with greater relative decreases in plasma IL-8 and IL-10 levels in favor of HCO-IHD (P = 0.02, P = 0.04). We found significantly greater relative changes from prefilter to postfilter plasma IL-6, IL-8, and IL-10 values in favor of HCO-IHD (P = 0.02, P = 0.01, P < 0.01). During HCO-IHD, cumulative albumin loss into the effluent was 7.7 g (25(th) to 75(th) percentiles, 4.8 to 19.6) versus less than 1.0 g for HF-IHD (P < 0.01). LIMITATIONS: Small phase 1 trial. CONCLUSION: In septic patients with acute renal failure, HCO-IHD achieved simultaneous uremic control and diffusive cytokine clearances and a greater relative decrease in plasma cytokine concentrations than standard HF-IHD.

Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies.

Of patients with newly diagnosed multiple myeloma, approximately 10% have dialysis-dependent acute renal failure, with cast nephropathy, caused by monoclonal free light chains (FLC). Of these, 80 to 90% require long-term renal replacement therapy. Early treatment by plasma exchange reduces serum FLC concentrations, but randomized, controlled trials have shown no evidence of renal recovery. This outcome can be explained by the low efficiency of the procedure. A model of FLC production, distribution, and metabolism in patients with myeloma indicated that plasma exchange might remove only 25% of the total amount during a 3-wk period. For increasing FLC removal, extended hemodialysis with a protein-leaking dialyzer was used. In vitro studies indicated that the Gambro HCO 1100 dialyzer was the most efficient of seven tested. Model calculations suggested that it might remove 90% of FLC during 3 wk. This dialyzer then was evaluated in eight patients with myeloma and renal failure. Serum FLC reduced by 35 to 70% within 2 hr, but reduction rates slowed as extravascular re-equilibration occurred. FLC concentrations rebounded on successive days unless chemotherapy was effective. Five additional patients with acute renal failure that was caused by cast nephropathy then were treated aggressively, and three became dialysis independent. A total of 1.7 kg of FLC was removed from one patient during 6 wk. Extended hemodialysis with the Gambro HCO 1100 dialyzer allowed continuous, safe removal of FLC in large amounts. Proof of clinical value now will require larger studies.

Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: a case report.

OBJECTIVE: To test the ability of a novel super high-flux (SHF) membrane with a larger pore size to clear myoglobin from serum. SETTING: The intensive care unit of a university teaching hospital. SUBJECT: A patient with serotonin syndrome complicated by severe rhabodomyolysis and oliguric acute renal failure. METHOD: Initially continuous veno-venous hemofiltration was performed at 2 l/hour ultrafiltration (UF) with a standard polysulphone 1.4 m2 membrane (cutoff point, 20 kDa), followed by continuous veno-venous hemofiltration with a SHF membrane (cutoff point, 100 kDa) at 2 l/hour UF, then at 3 l/hour UF and then at 4 l/hour UF, in an attempt to clear myoglobin. RESULTS: The myoglobin concentration in the ultrafiltrate at 2 l/hour exchange was at least five times greater with the SHF membrane than with the conventional membrane (>100,000 microg/l versus 23,003 microg/l). The sieving coefficients with the SHF membrane at 3 l/hour UF and 4 l/hour UF were 72.2% and 68.8%, respectively. The amount of myoglobin removed with the conventional membrane was 1.1 g/day compared with 4.4-5.1 g/day for the SHF membrane. The SHF membrane achieved a clearance of up to 56.4 l/day, and achieved a reduction in serum myoglobin concentration from >100,000 microg/l to 16,542 microg/l in 48 hours. CONCLUSIONS: SHF hemofiltration achieved a much greater clearance of myoglobin than conventional hemofiltration, and it may provide a potential modality for the treatment of myoglobinuric acute renal failure.

Cytokine dialysis: an ex vivo study.

To test the hypothesis that dialysis using a new large pore membrane would achieve effective cytokine removal, blood from six volunteers was incubated with endotoxin (1 mg) and then circulated through a closed circuit with a polyamide membrane (nominal cut-off: 100 kDa). Hemodialysis was conducted at 1 or 9 L/hr of dialysate flow at the start of circulation and after 2 and 4 hours. The peak dialysate/plasma concentration ratios were 0.92 for interleukin (IL)-1beta, 0.67 for IL-6, 0.94 for IL-8, 0.33 for tumor necrosis factor (TNF)-a, and 0.11 for albumin. The dialysate/plasma ratios for all cytokines and albumin were decreased with increased dialysate flow from 1 to 9 L/hr (p < 0.05). Clearances for IL-1beta, IL-6, and IL-8, however, were significantly improved with increased dialysate flow (p < 0.01). There was no increase in TNF-a clearance (not significant) and a decrease in albumin clearance (p < 0.01). The peak clearance at 9 L/hr was 33 ml/min for IL-1beta, 19 for IL-6, 51 for IL-8, 11 for TNF-alpha, and 1.2 for albumin. No adsorption of cytokines was observed. We conclude that cytokine dialysis is achievable through a membrane with a high cut-off point with negligible albumin loss. These findings support the technical feasibility of this new approach to blood purification in sepsis.