Justin Westhuyzen

Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit

IntroductionTo evaluate the utility of urinary cystatin C (uCysC) as a diagnostic marker of acute kidney injury (AKI) and sepsis, and predictor of mortality in critically ill patients.MethodsThis was a two-center, prospective AKI observational study and post hoc sepsis subgroup analysis of 444 general intensive care unit (ICU) patients. uCysC and plasma creatinine were measured at entry to the ICU. AKI was defined as a 50% or 0.3-mg/dL increase in plasma creatinine above baseline. Sepsis was defined clinically. Mortality data were collected up to 30 days. The diagnostic and predictive performances of uCysC were assessed from the area under the receiver operator characteristic curve (AUC) and the odds ratio (OR). Multivariate logistic regression was used to adjust for covariates.ResultsEighty-one (18%) patients had sepsis, 198 (45%) had AKI, and 64 (14%) died within 30 days. AUCs for diagnosis by using uCysC were as follows: sepsis, 0.80, (95% confidence interval (CI), 0.74 to 0.87); AKI, 0.70 (CI, 0.64 to 0.75); and death within 30 days, 0.64 (CI, 0.56 to 0.72). After adjustment for covariates, uCysC remained independently associated with sepsis, AKI, and mortality with odds ratios (CI) of 3.43 (2.46 to 4.78), 1.49 (1.14 to 1.95), and 1.60 (1.16 to 2.21), respectively. Concentrations of uCysC were significantly higher in the presence of sepsis (P < 0.0001) or AKI (P < 0.0001). No interaction was found between sepsis and AKI on the uCysC concentrations (P = 0.53).ConclusionsUrinary cystatin C was independently associated with AKI, sepsis, and death within 30 days.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN012606000032550.

Early detection of acute kidney injury: Emerging new biomarkers (Review Article)

SUMMARY:  Acute kidney injury (AKI) has recently become the preferred term to describe the syndrome of acute renal failure (ARF) with ‘failure’ or ‘ARF’ restricted to patients who have AKI and need renal replacement therapy. 1 This allows capture of the broader clinical spectrum of modest reductions in creatinine, which are themselves known to be associated with major increases in both short‐ and long‐term mortality risk. 2–5 It is hoped that this change in nomenclature will facilitate an expansion of our understanding of the underlying pathophysiology and also facilitate definitions of AKI, which allow comparisons among clinical trials of patients with similar duration and severity of illness. This review will cover the need for early detection of AKI and the role of urinary and plasma biomarkers, including enzymuria. The primary message is that use of existing criteria to diagnose AKI, namely elevation of the serum creatinine with or without oliguria, results in identification that is too late to allow successful intervention. New biomarkers are essential to change the dire prognosis of this common condition.

Effect of preoperative supplementation with α-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations

Augmentation of antioxidant defenses may help protect tissues against ischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation.

Oxidation of low density lipoprotein in hemodialysis patients: effect of dialysis and comparison with matched controls

End stage renal failure is associated with lipoprotein abnormalities and a high prevalence of premature atherosclerosis. Oxidative modification of low density lipoprotein (LDL) may be promoted by hemodialysis increasing its atherogenicity. The oxidative status of LDL was therefore examined in female subjects before and after routine hemodialysis (HD; n = 10) and compared with women of similar age without significant renal disease (n = 19). There were no significant differences between the groups in the LDL fatty acid composition, or in the content of reactive amino acid groups (lysine) before or after exposure to Cu2+. The kinetics of LDL oxidation by Cu2+ showed no significant differences between the groups with respect to the lag time, the level of conjugated dienes before and after oxidation, or the maximal rate of oxidation during the propagation phase. No acute effects of HD were demonstrated. The present study provides no evidence that circulating LDL isolated from HD patients is more extensively modified or more susceptible to oxidation in vitro than gender-matched controls without renal failure.

Evidence for Oxidative Stress during in vitro Dialysis

The evidence for oxidative stress during haemodialysis is controversial. We therefore examined markers of oxidative stress and lipid peroxidation using an in vitro dialysis circuit. A unit of fresh blood (500 ml) therapeutically removed from each of 7 haemochromatosis patients was oxygenated and circulated for 4 h at 37 degrees C through a cuprophane dialyser (Clirans C08) against saline dialysate (1,000 ml recirculating; +FIL group). In a second series of experiments (n = 7), the dialyser was omitted from the circuit (-FIL group). Concentrations of anti-oxidants and malondialdehyde (MDA) were measured at 7 time points during the study. Blood thiol concentrations decreased by 25.6% in the +FIL group (p < 0.05) but were unchanged in the -FIL group (p > 0.05; group comparison, p = 0.006). There were no significant differences between the groups, for the lipid-soluble anti-oxidants alpha-tocopherol, retinol and beta-carotene. Plasma MDA concentrations increased in both circuits (p < 0.001, respectively, no difference between groups). However, the susceptibility of red blood cells to lipid peroxidation (as determined by MDA production following a challenge with hydrogen peroxide) was unchanged by 120 min of dialysis. These in vitro experiments provide supporting evidence that haemodialysis is accompanied by measurable oxidative stress and plasma lipid peroxidation.

Effect of Dialyzer Reprocessing with Renalin on Serum Beta-2-Microglobulin and Complement Activation in Hemodialysis Patients

The peracetic acid-based sterilant Renalin is increasingly being used for reprocessing hemodialyzers. In order to evaluate the effects of reprocessing on beta 2-microglobulin (beta 2M) kinetics and complement activation in chronic hemodialysis patients, we compared 4 dialyzer membranes on 1st, 2nd and 4th use of the membrane. Dialysis with new cuprammonium rayon dialyzers (0.8 m2) for 4 h resulted in a nonsignificant increase in serum beta 2M concentrations of 10.7% (corrected for changes in extracellular volume) and significant generation of the complement component C3a des Arg. On reuse, minimal changes in serum beta 2M levels were noted and complement activation was absent. Dialysis with new cellulose acetate (CA, 1.5 m2), polyacrylonitrile (AN69 HF, 1.6 m2) or polymethylmethacrylate (PMMA, 1.6 m2) membranes resulted in significant decreases in serum beta 2M levels (19.5, 31.7 and 50.8%, respectively). Reprocessing had negligible effects on the removal of beta 2M by CA and AN69, but by the 4th use halved the effectiveness of PMMA. Reprocessing reduced the significant generation of C3a des Arg observed with new CA and PMMA membranes. We conclude that, except for PMMA, Renalin reprocessing has minor effects on the ability of the membranes to remove beta 2M and improves the biocompatibility of all membranes studied.

Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass

Markers of renal tubular injury were examined in 21 patients (16 male, 5 female, mean age 57.4 years) undergoing cardiac surgery utilising cardiopulmonary bypass. Postoperative urine outputs were very high (200-250 ml/h at 1-2 h), decreasing to 100 ml/h by 6 h. Although creatinine clearances did not vary significantly in the postoperative period (P = 0.16), significant changes were noted in the urinary concentrations of three tubular markers relative to creatinine concentration (P < 0.001). Urinary beta 2-microglobulin increased from negligible levels (median 0.01 mg/mmol creatinine) to peak at 4 h (median 4.55 mg/mmol), in part due to interference with its reabsorption by the plasma volume expander Haemaccel. Concentrations of the brush border antigen adenosine deaminase binding protein increased 6-fold, from a median of 5.03 arbitrary units (AU)/mumol to 31.2 AU/mumol at 48 h. The lysosomal enzyme N-acetyl-beta-D-glucosaminidase increased nearly 4-fold, from 0.68 units/mmol to 2.64 units/mmol at 48 h. Our results suggest that cardiac surgery utilising cardiopulmonary bypass is associated with acute tubular injury which can occur in the absence of overt changes in creatinine clearance.

Monitoring of extracellular and total body water during haemodialysis using multifrequency bio-electrical impedance analysis.

Multifrequency bio-electrical impedance analysis (MFBIA) was evaluated as a technique for monitoring changes in extracellular and total body water (ECW and TBW, respectively) of 15 subjects during dialysis. Dilution analysis, using deuterium oxide and sodium bromide, was also performed on each subject before dialysis so that prediction equations for ECW and TBW based on the MFBIA measures could be developed. These prediction equations were then used to estimate water compartment volume changes during dialysis and compared with volumetric measures of the dialysate removed. The results show that MFBIA does not accurately measure ECW and TBW changes during dialysis. The MFBIA measures tend to overestimate the changes and are not sufficiently precise to be clinically useful.

Evaluation of a novel vitamin E coated cellulosic membrane hollow fiber dialyzer.

Adverse physiologic effects accompany hemodialysis. Biocompatible dialyzer membranes may both limit oxidative stress and decrease &bgr;2-microglobulin production, thereby reducing patient morbidity. We compared standard solute clearance, lipid, and antioxidant effects of a novel cellulosic membrane dialyzer modified with covalently bonded vitamin E (Excebrane Clirans E15, Terumo Australia) with standard cellulosic and polysulphone membrane dialyzers. Stable adult hemodialysis patients taking no lipid lowering or antioxidant therapy (n = 17; 9 male, 8 female) were recruited into a 10 week, prospective, unblinded study. Measurements were made at baseline on their usual dialyzer and after 2, 4, and 10 weeks of Excebrane use. Excebrane demonstrated good in vivo clearance of standard solutes relative to surface area. Predialysis &bgr;2-microglobulin levels were unchanged with time and were significantly lower postdialysis than with cellulose acetate (p < 0.05). Oxidized low density lipoprotein levels as measured by nitrotyrosine residues were high predialysis, but tended to decrease with both membranes (p > 0.05). Total antioxidant status fell during dialysis (p < 0.0005), but plasma vitamin A and E concentrations increased (p = 0.007 and p = 0.02, respectively). Baseline vitamin A levels were high in all patients and, along with vitamin E, total antioxidant status and lipid profiles did not change over time with Excebrane use. Excebrane is an efficient, biocompatible membrane with no deleterious effects on &bgr;2-microglobulin or lipids. More long-term study is merited.