Search

Objectives: To derive a pooled estimate of the incidence and outcomes of sepsis-associated acute kidney injury (SA-AKI) in ICU patients and to explore the impact of differing definitions of SA-AKI on these estimates., Data Sources: Medline, Medline Epub, EMBASE, and Cochrane CENTRAL between 1990 and 2023., Study Selection: Randomized clinical trials and prospective cohort studies of adults admitted to the ICU with either sepsis and/or SA-AKI., Data Extraction: Data were extracted in duplicate. Risk of bias was assessed using adapted standard tools. Data were pooled using a random-effects model. Heterogeneity was assessed by using a single covariate logistic regression model. The primary outcome was the proportion of participants in ICU with sepsis who developed AKI., Data Synthesis: A total of 189 studies met inclusion criteria. One hundred fifty-four reported an incidence of SA-AKI, including 150,978 participants. The pooled proportion of patients who developed SA-AKI across all definitions was 0.40 (95% CI, 0.37-0.42) and 0.52 (95% CI, 0.48-0.56) when only the Risk Injury Failure Loss End-Stage, Acute Kidney Injury Network, and Improving Global Outcomes definitions were used to define SA-AKI. There was significant variation in the incidence of SA-AKI depending on the definition of AKI used and whether AKI defined by urine output criteria was included; the incidence was lowest when receipt of renal replacement therapy was used to define AKI (0.26; 95% CI, 0.24-0.28), and highest when the Acute Kidney Injury Network score was used (0.57; 95% CI, 0.45-0.69; p < 0.01). Sixty-seven studies including 29,455 participants reported at least one SA-AKI outcome. At final follow-up, the proportion of patients with SA-AKI who had died was 0.48 (95% CI, 0.43-0.53), and the proportion of surviving patients who remained on dialysis was 0.10 (95% CI, 0.04-0.17)., Conclusions: SA-AKI is common in ICU patients with sepsis and carries a high risk of death and persisting kidney impairment. The incidence and outcomes of SA-AKI vary significantly depending on the definition of AKI used., Competing Interests: Dr. Bagshaw is supported by a Canada Research Chair in Critical Care Outcomes and Systems Evaluation. Drs. Bagshaw and Hammond received funding from Baxter. Dr. Bagshaw received funding from Novartis, Bioporto, and Sea Star Medical. Dr. Hammond received funding from CSL Behring, Grifols, and Revimmune. Dr. Venkatesh’s institution received funding from Baxter and the National Health and Medical Research Council. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: The optimal time to initiate renal replacement therapy in critically ill patients with acute kidney injury is controversial. We investigated the effect of such earlier versus later initiation of renal replacement therapy on the primary outcome of 28-day mortality and other patient-centered secondary outcomes., Design: We searched MEDLINE (via PubMed), EMBASE, and Cochrane databases to July 17, 2020, and included randomized controlled trials comparing earlier versus later renal replacement therapy., Setting: Multiple centers involved in eight trials., Patients: Total of 4,588 trial participants., Intervention: Two independents investigators screened and extracted data using a predefined form. We selected randomized controlled trials in critically ill adult patients with acute kidney injury and compared of earlier versus later initiation of renal replacement therapy regardless of modality., Measurements and Main Results: Overall, 28-day mortality was similar between earlier and later renal replacement therapy initiation (38.43% vs 38.06%, respectively; risk ratio, 1.01; [95% CI, 0.94-1.09]; I2 = 0%). Earlier renal replacement therapy, however, shortened hospital length of stay (mean difference, -2.14 d; [95% CI, -4.13 to -0.14]) and ICU length of stay (mean difference, -1.18 d; [95% CI, -1.95 to -0.42]). In contrast, later renal replacement therapy decreased the use of renal replacement therapy (relative risk, 0.69; [95% CI, 0.58-0.82]) and lowered the risk of catheter-related blood stream infection (risk ratio, 0.50, [95% CI, 0.29-0.86). Among survivors, renal replacement therapy dependence at day 28 was similar between earlier and later renal replacement therapy initiation (risk ratio, 0.98; [95% CI, 0.66-1.40])., Conclusions: Earlier or later initiation of renal replacement therapy did not affect mortality. However, earlier renal replacement therapy was associated with significantly shorter ICU and hospital length of stay, whereas later renal replacement therapy was associated with decreased use of renal replacement therapy and decreased risk of catheter-related blood stream infection. These findings can be used to guide the management of critically ill patients with acute kidney injury., Competing Interests: Dr. Neto reported receiving lecture fee from Drager outside the submitted work. Dr. Yanase reported receiving scholarship for PhD course in Monash University from Japan Student Services Organization and Endeavour Scholarship. Dr. Wald reports receiving speaker fees and unrestricted research funding from Baxter. Dr. Bagshaw reported receiving fees for scientific advisory and grants from Baxter; he reported receiving fees for scientific advisory from Diagnostics and Spectral Medical, Canada, all outside the submitted work; he is supported by a Canada Research Chair in Critical Care Nephrology. Dr. Bellomo reported receiving grants from Baxter International outside the submitted work. The remaining authors have disclosed that they have no potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown., Design: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use., Setting: Twenty-nine university-affiliated teaching hospitals in seven countries., Patients: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline., Interventions: None., Measurements and Main Results: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death., Conclusions: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury., Competing Interests: Dr. Skrifvars reports having received a research grant from GE Healthcare, travel reimbursements, and lecture fees from BARD Medical (Ireland), and he received personal research funding from Medicinska Understodsforeningen Liv och Halsa, Finska Läkaresallskapet, Sigrid Juselius Stiftelse, and Svenska Kulturfonden. Dr. Presneill’s institution received funding from the Australian National Health and Medical Research Council (NHMRC) (project grant ID 545902); he received support from the Victorian Transport Accident Commission (project grant ID D162); and he disclosed off-label product use of erythropoietin trial in traumatic brain injury. Dr. Nichol has received support from the Health Research Board of Ireland. Dr. Little received support for article research from the NHMRC, and she also disclosed off-label product use of Epoetin alfa. Drs. McArthur’s and Cooper’s institutions received funding from the NHMRC. Dr. Cooper’s institution received funding from the Transport Accident Commission and Pressura Neuro. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Objectives: To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury., Design: Interventional Study., Setting: Research Institute., Subjects: Adult Merino ewes., Interventions: Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis., Measurements and Main Results: Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%)., Conclusions: In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

Objectives: To assess the attitudes of practitioners with respect to net ultrafiltration prescription and practice among critically ill patients with acute kidney injury treated with renal replacement therapy., Design: Multinational internet-assisted survey., Setting: Critical care practitioners involved with 14 societies in 80 countries., Subjects: Intervention: MEASUREMENT AND MAIN RESULTS:: Of 2,567 practitioners who initiated the survey, 1,569 (61.1%) completed the survey. Most practitioners were intensivists (72.7%) with a median duration of 13.2 years of practice (interquartile range, 7.2-22.0 yr). Two third of practitioners (71.0%; regional range, 55.0-95.5%) reported using continuous renal replacement therapy with a net ultrafiltration rate prescription of median 80.0 mL/hr (interquartile range, 49.0-111.0 mL/hr) for hemodynamically unstable and a maximal rate of 299.0 mL/hr (interquartile range, 200.0-365.0 mL/hr) for hemodynamically stable patients, with regional variation. Only a third of practitioners (31.5%; range, 13.7-47.8%) assessed hourly net fluid balance during continuous renal replacement therapy. Hemodynamic instability was reported in 20% (range, 20-38%) of patients and practitioners decreased the rate of fluid removal (70.3%); started or increased the dose of a vasopressor (51.5%); completely stopped fluid removal (35.8%); and administered a fluid bolus (31.6%), with significant regional variation. Compared with physicians, nurses were most likely to report patient intolerance to net ultrafiltration (73.4% vs 81.3%; p = 0.002), frequent interruptions (40.4% vs 54.5%; p < 0.001), and unavailability of trained staff (11.9% vs 15.6%; p = 0.04), whereas physicians reported unavailability of dialysis machines (14.3% vs 6.1%; p < 0.001) and costs associated with treatment as barriers (12.1% vs 3.0%; p < 0.001) with significant regional variation., Conclusions: Our study provides new knowledge about the presence and extent of international practice variation in net ultrafiltration. We also identified barriers and specific targets for quality improvement initiatives. Our data reflect the need for evidence-based practice guidelines for net ultrafiltration.

Objectives: To study hemodynamic changes within continuous renal replacement therapy circuits and evaluate their relationship with continuous renal replacement therapy longevity., Design: Analysis of downloaded variables recorded by continuous renal replacement therapy machines during multiple episodes of clinical care., Setting: Tertiary ICU in Melbourne, Australia., Patients: Cohort of 149 ICU patients: 428 episodes of continuous renal replacement therapy., Interventions: None., Measurements and Main Results: Indices of continuous renal replacement therapy function representing 554,991 minutes were assessed including blood flow, access pressure, effluent pressure, prefilter pressure, and return pressure. We defined three patterns of artificial kidney failure: early (≤ 12 hr), intermediate (> 12-24 hr), and late (> 24 hr) in 35%, 31%, and 34% of circuits, respectively. Mean access pressure in late artificial kidney failure was 7.5 mm Hg (7.1-7.9 mm Hg) less negative than early failing circuits and pressures demonstrated lower variability in such late failing circuits. Access dysfunction, defined as access pressure less than or equal to -200 mm Hg occurred in the first 4 hours in 118 circuits (27%) which had a shorter (median [interquartile range]) life at 12.9 hr [5.5-21.3 hr]) hours than access dysfunction-free circuits (18.8 hr [10.1-33.4 hr]; p < 0.0001). Multivariate analysis found the first occurrence of access dysfunction (as a time-varying covariate) was independently associated with increased hazard of subsequent failure (hazard ratio, 1.75; 1.36-2.26). Classification and regression tree analysis of summary pressure indices in the first 2 hours confirmed minimum access pressure to be a significant predictor, as well as indices of transmembrane pressure and return pressure. A pressure-based predictor correctly identified early and late failing circuits (86.2% and 93.6% specificity, respectively)., Conclusions: Access dysfunction is a predictor of continuous renal replacement therapy circuit failure. Future monitoring of continuous renal replacement therapy hemodynamics may facilitate remedial actions to improve circuit function.

Objectives: To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury., Design: Interventional study., Setting: Research institute., Subjects: Adult Merino ewes., Interventions: Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann's solution over 15 min) was administered., Measurements and Main Results: In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (-48% ± 5%), medullary PO2 (-56% ± 4%), and urinary PO2 (-54% ± 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary PO2 (+280% ± 90%), urinary PO2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2., Conclusions: In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention.

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.

Objectives: Angiotensin II is an emerging therapy for septic acute kidney injury, but it is unknown if its vasoconstrictor action induces renal hypoxia. We therefore examined the effects of angiotensin II on intrarenal PO2 in ovine sepsis. We also assessed the validity of urinary PO2 as a surrogate measure of medullary PO2., Design: Interventional study., Setting: Research Institute., Subjects: Sixteen adult Merino ewes (n = 8/group)., Interventions: Sheep were instrumented with fiber-optic probes in the renal cortex, medulla, and within a bladder catheter to measure PO2. Conscious sheep were infused with Escherichia coli for 32 hours. At 24-30 hours, angiotensin II (0.5-33.0 ng/kg/min) or saline vehicle was infused., Measurements and Main Results: Septic acute kidney injury was characterized by hypotension and a 60% ± 6% decrease in creatinine clearance. During sepsis, medullary PO2 decreased from 36 ± 1 to 30 ± 3 mm Hg after 1 hour and to 20 ± 2 mm Hg after 24 hours; at these times, urinary PO2 was 42 ± 2, 34 ± 2, and 23 ± 2 mm Hg. Increases in urinary neutrophil gelatinase-associated lipocalin (12% ± 3%) and serum creatinine (60% ± 23%) were only detected at 8 and 24 hours, respectively. IV infusion of angiotensin II, at 24 hours of sepsis, restored arterial pressure and improved creatinine clearance, while not exacerbating medullary or urinary hypoxia., Conclusions: In septic acute kidney injury, renal medullary and urinary hypoxia developed several hours before increases in currently used biomarkers. Angiotensin II transiently improved renal function without worsening medullary hypoxia. In septic acute kidney injury, angiotensin II appears to be a safe, effective therapy, and urinary PO2 may be used to detect medullary hypoxia.

Objective: The histopathologic changes associated with septic acute kidney injury are poorly understood, in part, because of the lack of biopsy data in humans. Animal models of septic acute kidney injury may help define such changes. Therefore, we performed a systematic review of the histopathologic changes found in modern experimental septic acute kidney injury models., Data Sources: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, and PubMed (from January 2007 to February 2015)., Study Selection: We reviewed experimental studies reporting findings on the histopathology of contemporary experimental septic acute kidney injury., Data Extraction: We focused on the presence or the absence of acute tubular necrosis, tubular cell apoptosis, and other nonspecific findings., Data Synthesis: We identified 102 studies in 1,059 animals. Among the 1,059 animals, 53 (5.0%) did not have any renal histopathologic changes, but acute tubular necrosis was found in 184 (17.4%). The prevalence of acute tubular necrosis was not related to animal size or model of sepsis and was only found in models with low cardiac output and decreased renal blood flow (p < 0.0001). Only 21 studies (170 animals) assessed the prevalence of tubular cell apoptosis, which was reported in 158 animals (92.9%). The prevalence of tubular cell apoptosis was significantly higher in studies using small animals (p < 0.0001) and in peritonitis models (p < 0.0001). Simultaneous acute tubular necrosis and tubular cell apoptosis was rare (55 animals [32.4%]) and only seen with decreased cardiac output and renal blood flow. Nonspecific changes (vacuolization of tubular cells, loss of brush border, and tubular cell swelling) were each observed in 423 (39.9%), 250 (23.6%) and 243 (22.9%) animals, respectively., Conclusions: In models of experimental septic acute kidney injury in contemporary articles, acute tubular necrosis was relatively uncommon and, when present, reflected the presence of an associated low cardiac output or low renal blood flow syndrome. Tubular cell apoptosis seemed frequent in the few studies in which it was investigated. Nonspecific morphologic changes, however, were the most common histopathologic findings.

Objective: To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy., Design: Post hoc analysis of data from a multicenter, randomized, controlled trial., Setting: Thirty-five ICUs in Australia and New Zealand., Patients: Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study., Interventions: Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes., Measurements and Main Results: Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111 g/L; p < 0.001). Mean daily hemoglobin was 88 ± 7 and 99 ± 12 g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316 ± 261 mL of RBC, whereas nonsurvivors received 302 ± 362 mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital., Conclusions: In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials.

Objectives: To determine whether there is a decrease in renal cortical or medullary perfusion and oxygenation in a conscious large animal model of hyperdynamic septic shock with acute kidney injury., Design: Interventional animal study., Setting: University-affiliated research institute., Subjects: Eight merino ewes., Interventions: Sheep were surgically instrumented with pulmonary and renal artery flow probes in the renal cortex and medulla, combination fiber-optic probes comprising a fluorescence optode to measure tissue PO2, and a laser-Doppler probe to assess tissue perfusion. Sepsis was induced by infusion of live Escherichia coli for 24 hours followed by 24-hour recovery., Measurements and Main Results: In unanesthetized normal sheep, resting levels of cortical and medullary tissue PO2 were 29.5 ± 4.4 and 29.1 ± 4.3 mm Hg, respectively. During infusion of E. coli, hyperdynamic sepsis developed with hypotension, tachycardia, increased cardiac output, increased renal blood flow, oliguria, decreased creatinine clearance, and increased serum creatinine. Renal oxygen delivery increased while renal oxygen consumption was unchanged. During sepsis, cortical tissue PO2 increased from 29.4 ± 4.3 to 36.3 ± 3.5 mm Hg (p < 0.001), whereas medullary oxygenation decreased from 29.6 ± 4.7 to 13.1 ± 2.7 mm Hg (p < 0.001). Cortical perfusion was not significantly changed, but medullary perfusion decreased (671 BPU [500-900 BPU] to 480 BPU [349-661 BPU]; geometric mean [95% CI]; p < 0.001)., Conclusions: In a large animal model of hyperdynamic sepsis, renal hyperemia was associated with preserved cortical oxygenation and perfusion, but decreased medullary oxygenation and perfusion. Medullary hypoxia due to intrarenal blood flow redistribution may be one of the factors causing acute kidney injury in sepsis.

Objectives: To explore the relationship between timing of continuous renal replacement therapy commencement and clinical outcomes in critically ill patients with acute kidney injury. The primary outcomes were all-cause mortality at 28 and 90 days., Design: Nested observational cohort study using data from the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study., Setting: Twenty-three ICUs in Australia and New Zealand., Patients: Four hundred thirty-nine critically ill patients with acute kidney injury Risk, Injury, Failure, Loss, End-stage kidney disease-injury (RIFLE-I) criteria., Interventions: None., Measurements and Main Results: The time between RIFLE-I acute kidney injury and randomization in the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study (proxy for continuous renal replacement therapy commencement) was the variable of interest. All baseline variables in the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study were assessed. Multivariable Cox, logistic, and linear regression models were used to assess the independent relationship of time of onset of RIFLE-I acute kidney injury and randomization and patient outcomes. The median time between RIFLE-I acute kidney injury and continuous renal replacement therapy commencement was 17.6 hours (interquartile range, 7.1-46 hr). Based on four groups of continuous renal replacement therapy commencement ([group 1; reference]: < 7.1, [group 2]: ≥ 7.1 to < 17.6, [group 3]: ≥ 17.6 to < 46.0, [group 4]: ≥ 46.0 hr), earlier commencement of continuous renal replacement therapy was not associated with a significantly lower risk of death at 28 days (hazard ratio for group 2: 1.06, 95% CI: 0.62-1.81; p = 0.83; hazard ratio for group 3: 1.23, 95% CI: 0.71-2.12; p = 0.46; hazard ratio for group 4: 1.33, 95% CI: 0.77-2.31; p = 0.31). Similar findings were observed for death at 90 days., Conclusions: In a subgroup of participants of the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study, earlier commencement of continuous renal replacement therapy relative to RIFLE-I acute kidney injury was not significantly associated with improved survival. Additional studies with larger sample sizes and broader commencement times are warranted.

Objective: To determine the influence of the renal sympathetic nerves on the pathogenesis of septic acute kidney injury., Design: Interventional control study to determine the effects of renal denervation in ovine hyperdynamic sepsis., Setting: Research Institute., Subjects: Twenty-four adult Merino ewes., Interventions: The effects of infusion of angiotensin II and norepinephrine and induction of hyperdynamic sepsis by administration of live Escherichia coli were examined in control sheep and in sheep at 2 weeks after bilateral renal denervation (n = 10/group)., Measurements and Main Results: Systemic hemodynamics and renal function were measured in conscious sheep instrumented with flow probes on the pulmonary and renal arteries. Angiotensin II, but not norepinephrine, had a greater pressor effect in denervated animals. Sepsis increased cardiac output by 60%, renal blood flow by 35%, and arterial lactate by approximately four-fold. The denervated compared with the control group had a greater degree of hypotension during sepsis (68 vs 81 mm Hg; p = 0.003) and a reduction in the early polyuric response (from 496 to 160 mL at 2-8 hr of sepsis; p < 0.001). Creatinine clearance decreased similarly in both groups., Conclusions: In experimental hyperdynamic sepsis, renal denervation was associated with greater hypotension and a loss of the initial diuresis, but no significant change in creatinine clearance. In sepsis, the renal nerves help support arterial pressure and determine the initial diuretic response, but septic acute kidney injury developed similarly in the innervated and denervated groups.

Objective: Acute kidney injury in the critically ill is an independent risk factor for adverse outcome. The magnitude of the impact of acute kidney injury on outcome, however, is still unclear. This study aimed to estimate the excess mortality attributable to acute kidney injury., Design: We performed a sequentially matched analysis according to the day of acute kidney injury diagnosis after ICU admission. Patients with acute kidney injury and those without acute kidney injury were matched according to age, sex, ICU admission diagnosis, Simplified Acute Physiology Score II without renal and age components, and the propensity to develop acute kidney injury at each of the four matching time points., Setting: Cohort of 16 participating ICUs from the prospective Finnish Acute Kidney Injury study., Patients: Cohort of 2,719 consecutive patients with either emergency admission or elective postsurgical patients with an expected ICU stay greater than 24 hours., Interventions: None., Measurements and Main Results: Of the 2,719 patients included in the study, acute kidney injury developed in 1,081 patients (39.8%) according to the Kidney Disease: Improving Global Outcomes-definition during ICU treatment on days 1-5. Of these, 477 patients were successfully matched to 477 patients who did not develop acute kidney injury. The 90-day mortality of the matched patients with acute kidney injury was 125 of 477 (26.2%) compared with 84 of 477 (17.6%) for their matched controls without acute kidney injury. Thus, the absolute excess 90-day mortality attributable to acute kidney injury was estimated at 8.6 percentage points (95% CI, 2.6-17.6 percentage points). The population attributable risk (95% CI) of 90-day mortality associated with acute kidney injury was 19.6% (10.3-34.1%)., Conclusions: In general ICU patients, the absolute excess 90-day mortality statistically attributable to acute kidney injury is substantial (8.6%), and the population attributable risk was nearly 20%. Our findings are useful in planning suitably powered future clinical trials to prevent and treat acute kidney injury in critically ill patients.

Objectives: Our understanding of septic acute kidney injury is limited. We therefore assessed renal histopathological changes induced by septic acute kidney injury and their evolution during recovery., Design: Prospective experimental study., Setting: Physiology Research Institute., Subjects: Twenty-two Merino sheep., Intervention: We induced septic acute kidney injury by continuous i.v. infusion of Escherichia coli. We studied histology, immunohistochemistry, markers of apoptosis, and expression of nitric oxide synthase isoforms and hypoxia-inducible factor-1α. Analysis was performed on kidneys from normal sheep, sheep with septic acute kidney injury, and sheep after recovery from septic acute kidney injury., Measurements and Main Results: In normal, septic, and recovery sheep, respectively, serum creatinine was (median) 82 (interquartile range, 70-85), 289 (171-477), and 70 (51-91) μmol/L and renal blood flow was 270 ± 42, 653 ± 210, and 250 ± 49 mL/min. There were no histological differences between baseline, acute kidney injury, and recovery sheep. There was no evidence of macrophage or myofibroblast infiltration, no evidence of caspase-3 cleavage to suggest activation of apoptotic pathways, and no increase in neutrophil gelatinase-associated lipocalin to suggest tubular injury. Similarly, quantification of apoptosis revealed no differences between the normal and septic groups (normal: median, 3; interquartile range, 0-5 cells per visual field and septic acute kidney injury: median, 3.5; interquartile range, 0-8 cells per visual field; p = 0.618), but in the recovery group, there was increased apoptosis (median, 14; interquartile range, 4-34 cells per visual field; p = 0.002). Expression of all nitric oxide synthase subtypes increased significantly in the renal cortex during septic acute kidney injury but tended to decrease in the medulla. Medullary hypoxia-inducible factor gene expression decreased from 1.00 (95% CI, 0.74-1.36) to 0.26 (95% CI, 0.09-0.76) in recovery (p = 0.0106). Both inducible nitric oxide synthase and neuronal nitric oxide synthase expressions correlated with renal blood flow., Conclusion: The lack of any tubular injury or increased apoptosis, the increased expression of all cortical nitric oxide synthase isoforms, and the link between inducible nitric oxide synthase and neuronal nitric oxide synthase with renal blood flow suggest in this experimental model that severe sepsis acute kidney injury can develop in the absence of histological or immunohistological changes and may be functional in nature.

Objectives: Cardiac surgery-associated acute kidney injury occurs in up to 50% of patients and is associated with increased mortality and morbidity. This study aimed to discover if perioperative urinary alkalinization with sodium bicarbonate infusion reduces the prevalence of cardiac surgery-associated acute kidney injury., Design: This study was a phase IIb multicenter double-blind randomized controlled trial., Setting: This study was conducted in three tertiary hospitals in New Zealand and Australia., Patients: A total of 427 patients scheduled to undergo elective cardiac surgery, who were at increased risk of development of cardiac surgery-associated acute kidney injury using recognized risk factors., Measurements and Main Results: Patients were randomly allocated to receive either sodium bicarbonate (n = 215) or sodium chloride (n = 212) infusion, commencing at the start of anesthesia, in a dose of 0.5 mEq/kg/hr for the first hour and then 0.2 mmol/kg/hr for 23 hours. The primary outcome measure was the number of patients with development of cardiac surgery-associated acute kidney injury, defined as an increase in creatinine greater than 25% or 0.5 mg/dL (44 µmol/L) from baseline to peak value within the first five postoperative days. Significant differences among the groups in both plasma and urinary biochemistry were achieved 6 hours after commencement of the infusion, and these changes persisted for more than 24 hours. A total of 100 out of 215 patients (47% [95% CI, 40%-53%]) in the sodium bicarbonate group and 93 of 212 patients (44% [95% CI, 37%-51%]) in the sodium chloride group with development of acute kidney injury within the first five postoperative days (p = 0.58). There were also no significant differences in ventilation hours, ICU or hospital length of stay, or mortality., Conclusions: Perioperative alkalinization of blood and urine using an infusion of sodium bicarbonate did not result in a decrease in the prevalence of acute kidney injury in patients following cardiac surgery.

Objective: To examine associations between mean daily fluid balance during intensive care unit study enrollment and clinical outcomes in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level (RENAL) replacement therapy study., Design: Statistical analysis of data from multicenter, randomized, controlled trials., Setting: Thirty-five intensive care units in Australia and New Zealand., Patients: Cohort of 1453 patients enrolled in the RENAL study., Interventions: We analyzed the association between daily fluid balance on clinical outcomes using multivariable logistic regression, Cox proportional hazards, time-dependent analysis, and repeated measure analysis models., Measurements and Main Results: During intensive care unit stay, mean daily fluid balance among survivors was -234 mL/day compared with +560 mL/day among nonsurvivors (p < .0001). Mean cumulative fluid balance over the same period was -1941 vs. +1755 mL (p = .0003). A negative mean daily fluid balance during study treatment was independently associated with a decreased risk of death at 90 days (odds ratio 0.318; 95% confidence interval 0.24-0.43; p < .000.1) and with increased survival time (p < .0001). In addition, a negative mean daily fluid balance was associated with significantly increased renal replacement-free days (p = .0017), intensive care unit-free days (p < .0001), and hospital-free days (p = .01). These findings were unaltered after the application of different statistical models., Conclusions: In the RENAL study, a negative mean daily fluid balance was consistently associated with improved clinical outcomes. Fluid balance may be a target for specific manipulation in future interventional trials of critically ill patients receiving renal replacement therapy.

Objective: In septic patients, decreased renal perfusion is considered to play a major role in the pathogenesis of acute kidney injury. However, the accurate measurement of renal blood flow in such patients is problematic and invasive. We sought to overcome such obstacles by measuring renal blood flow in septic patients with acute kidney injury using cine phase-contrast magnetic resonance imaging., Design: Pilot observational study., Setting: University-affiliated general adult intensive care unit., Patients: Ten adult patients with established septic acute kidney injury and 11 normal volunteers., Interventions: Cine phase-contrast magnetic resonance imaging measurement of renal blood flow and cardiac output., Measurements and Main Results: The median age of the study patients was 62.5 yrs and eight were male. At the time of magnetic resonance imaging, eight patients were mechanically ventilated, nine were on continuous hemofiltration, and five required vasopressors. Cine phase-contrast magnetic resonance imaging examinations were carried out without complication. Median renal blood flow was 482 mL/min (range 335-1137) in septic acute kidney injury and 1260 mL/min (range 791-1750) in healthy controls (p = .003). Renal blood flow indexed to body surface area was 244 mL/min/m2 (range 165-662) in septic acute kidney injury and 525 mL/min/m2 (range 438-869) in controls (p = .004). In patients with septic acute kidney injury, median cardiac index was 3.5 L/min/m2 (range 1.6-8.7), and median renal fraction of cardiac output was only 7.1% (range 4.4-10.8). There was no rank correlation between renal blood flow index and creatinine clearance in patients with septic acute kidney injury (r = .26, p = .45)., Conclusions: Cine phase-contrast magnetic resonance imaging can be used to noninvasively and safely assess renal perfusion during critical illness in man. Near-simultaneous accurate measurement of cardiac output enables organ blood flow to be assessed in the context of the global circulation. Renal blood flow seems consistently reduced as a fraction of cardiac output in established septic acute kidney injury. Cine phase-contrast magnetic resonance imaging may be a valuable tool to further investigate renal blood flow and the effects of therapies on renal blood flow in critical illness.

Objectives: To describe current practice for the discontinuation of continuous renal replacement therapy in a multinational setting and to identify variables associated with successful discontinuation. The approach to discontinue continuous renal replacement therapy may affect patient outcomes. However, there is lack of information on how and under what conditions continuous renal replacement therapy is discontinued., Design: Post hoc analysis of a prospective observational study., Setting: Fifty-four intensive care units in 23 countries., Patients: Five hundred twenty-nine patients (52.6%) who survived initial therapy among 1006 patients treated with continuous renal replacement therapy., Interventions: None., Measurements and Main Results: Three hundred thirteen patients were removed successfully from continuous renal replacement therapy and did not require any renal replacement therapy for at least 7 days and were classified as the "success" group and the rest (216 patients) were classified as the "repeat-RRT" (renal replacement therapy) group. Patients in the "success" group had lower hospital mortality (28.5% vs. 42.7%, p < .0001) compared with patients in the "repeat-RRT" group. They also had lower creatinine and urea concentrations and a higher urine output at the time of stopping continuous renal replacement therapy. Multivariate logistic regression analysis for successful discontinuation of continuous renal replacement therapy identified urine output (during the 24 hrs before stopping continuous renal replacement therapy: odds ratio, 1.078 per 100 mL/day increase) and creatinine (odds ratio, 0.996 per [micro]mol/L increase) as significant predictors of successful cessation. The area under the receiver operating characteristic curve to predict successful discontinuation of continuous renal replacement therapy was 0.808 for urine output and 0.635 for creatinine. The predictive ability of urine output was negatively affected by the use of diuretics (area under the receiver operating characteristic curve, 0.671 with diuretics and 0.845 without diuretics)., Conclusions: We report on the current practice of discontinuing continuous renal replacement therapy in a multinational setting. Urine output at the time of initial cessation of continuous renal replacement therapy was the most important predictor of successful discontinuation, especially if occurring without the administration of diuretics.

Septic acute kidney injury accounts for close to 50% of all cases of acute kidney injury in the intensive care unit and, in its various forms, affects between 15% and 20% of intensive care unit patients. However, there is little we really know about its pathophysiology. Although hemodynamic factors might play a role in the loss of glomerular filtration rate, they may not act through the induction of renal ischemia. Septic acute renal failure may, at least in patients with a hyperdynamic circulation, represent a unique form of acute renal failure: hyperemic acute renal failure. Measurements of renal blood flow in septic humans are now needed to resolve this pivotal pathophysiological question. Whatever may happen to renal blood flow during septic acute kidney injury in humans, the evidence available suggests that urinalysis fails to provide useful diagnostic or prognostic information in this setting. In addition, nonhemodynamic mechanisms of cell injury are likely to be at work. These mechanisms are likely due to a combination of immunologic, toxic, and inflammatory factors that may affect the microvasculature and the tubular cells. Among these mechanisms, apoptosis may turn out to be important. It is possible that, as evidence accumulates, the paradigms currently used to explain acute renal failure in sepsis will shift from ischemia and vasoconstriction to hyperemia and vasodilation and from acute tubular necrosis to acute tubular apoptosis or simply tubular cell dysfunction or exfoliation. If this were to happen, our therapeutic approaches would also be profoundly altered.

The use of norepinephrine, and probably vasopressor therapy in general, in intensive care patients with hypotensive vasodilatation despite fluid resuscitation and evidence of acute kidney injury remains the subject of much debate and controversy. Although there is concern about the use of these drugs, these concerns are unfounded. At this time, the experimental and human data strongly suggest that, in these patients, vasopressor therapy is safe and probably beneficial from a renal, and probably general, point of view. On the basis of currently available evidence, in hypotensive vasodilated patients with acute kidney injury, restoration of blood pressure within autoregulatory values should occur promptly with noradrenaline and be sustained until such vasodilatation dissipates. The additional role of other vasopressors in these situations remains unclear. The addition of vasopressin may be helpful in individual patients, but widespread use is not supported by evidence. Alpha-dose dopamine has no advantages over noradrenaline and is not as reliably effective in restoring blood pressure and urine output. Its widespread use cannot be supported in patients with vasodilatation and acute kidney injury. Other vasopressor drugs such as epinephrine and phenylephrine may be similar in efficacy to noradrenaline. However, experience and available data with their use is vastly less than with noradrenaline. Adrenaline, in addition, is associated with hyperglycemia, hyperlactatemia, acidosis, and hypokalemia. Terlipressin appears useful in patients with acute kidney injury secondary to hepatorenal syndrome. Whether it is superior to noradrenaline in this setting remains uncertain, and more studies are needed before recommendations can be made.

Acute kidney injury (AKI) is commonly and increasingly encountered in patients with critical illness. In the past, epidemiologic studies have consistently found that oliguria further increases the risk of death from AKI. Compared with patients outside the intensive care unit (ICU), critically ill patients are more likely to have volume overload as a result of impaired solute and water excretion. Recently, broad changes have occurred in ICU practice, such as early goal-directed therapy in sepsis, which may further compound volume overload in the ICU patient with oliguric AKI. Evidence has also emerged to suggest that a positive fluid accumulation in ICU patients can unfavorably affect outcome. Thus, the ICU patient with oliguric AKI presents a dilemma with limited therapeutic options. These would include optimization of systemic hemodynamics, added fluid therapy, administration of loop diuretics, or finally, the initiation of renal replacement therapy. Interestingly, recent survey data and observational studies indicate that a majority of intensivists use loop diuretics, specifically furosemide, at some point during the course of illness in patients with AKI. Paradoxically, loop diuretics have been found in several clinical studies of patients with AKI to be potentially detrimental or, at the least, lack effectiveness for improving clinical outcomes. This contradiction between clinical practice and available evidence would suggest there is equipoise and need for higher-quality evidence to better characterize the role of loop diuretics in ICU patients with AKI.

Extracorporeal therapy has expanded significantly over the past few decades from solely artificial renal replacement therapy. In patients with multiple organ dysfunction syndrome, it becomes necessary to provide multiple organ support therapy. Technological advances have opened the door to a multifaceted intervention directed at supporting the function of multiple organs through the treatment of blood. Indications for "old" therapies such as hemofiltration and adsorption have been expanded, and using these therapies in combination further enhances blood detoxification capabilities. Furthermore, new devices are constantly in development. Nanotechnology allows us to refine membrane characteristics and design innovative monitoring/biofeedback devices. Miniaturization is leading down the path of wearable/implantable devices. With the incorporation of viable cells within medical devices, these instruments become capable not only of detoxification but synthetic functions as well, bringing us closer to the holy grail of complete replacement of organ function. This article provides a brief overview of current and future direction in extracorporeal support in the critical care setting.

Objective: To appraise the literature on the effect of initial renal replacement therapy (RRT) modality on clinical outcomes., Design: Systematic review and meta-analysis., Setting: Academic medical center., Patients and Participants: Adult critically ill patients with acute kidney injury., Interventions: Continuous vs. intermittent RRT., Measurements and Results: MEDLINE, EMBASE, Cochrane Controlled Clinical Trials Register, and other sources were searched. We identified nine unique randomized trials (n = 1,403). No trial satisfied all quality indicators and several had limitations related to selection bias, randomization, imbalances in patient characteristics, and high treatment crossover. No trial standardized the timing, criteria, for initiation or dose of RRT. There was no statistical evidence that initial modality influenced mortality (odds ratio, 0.99; 95% confidence interval, 0.78-1.26, p = .93; I2 = 11%; nine trials, n = 1,403) or recovery to RRT independence (odds ratio, 0.76; 95% confidence interval, 0.28-2.07, p = .59; I2 = 0%; four trials, n = 306). There was suggestion that continuous RRT had fewer episodes of hemodynamic instability and better control of fluid balance., Conclusions: We identified numerous issues related to study design, conduct, and quality that dispute the validity and question any inferences that can be drawn from these trials. In the context of these limitations, the initial RRT modality did not seem to affect mortality or recovery to RRT independence. There is urgent need for additional high-quality and suitably powered trials to adequately address this issue.

Objective: In experimental septic acute renal failure, urinary analysis is used to help diagnose and classify renal injury. However, the scientific basis for such use has not been systematically evaluated. Thus, we appraised the value of common urinary findings for the diagnosis and classification of experimental septic acute renal failure., Design: Systematic review., Setting: Academic medical center and university-based research laboratory., Subjects: Experimental studies describing urinary biochemistry, derived indexes, and microscopy in septic acute renal failure., Interventions: None., Measurements and Main Results: Twenty-seven articles fulfilled all inclusion criteria. Due to heterogeneity, no formal quantitative analysis was possible. The methods for induction of sepsis and models were variable. The urinary sodium, fractional excretion of sodium, and urine osmolality were reported in only four (15%), 21 (78%), and seven (26%) studies, respectively. The fractional excretion of sodium exhibited a decrease, no change, or an increase from baseline in 11 (52%), five (24%), and five (24%) studies, respectively. The urine osmolality decreased from baseline in all endotoxin-induced models but showed an early transient increase in six (22%) studies of cecal-ligation perforation. Proteinuria or urinary enzymuria was reported in only seven (26%) studies. Urinary microscopy was described in one study. Only ten studies (37%) simultaneously reported on histopathology. In all these studies, histology either was normal or showed minor ultrastructural changes on electron microscopy., Conclusions: No conclusions are possible on how several urinary tests perform in diagnosing or classifying acute renal failure or in predicting the presence of acute tubular necrosis in experimental sepsis. Additional research is necessary to define the diagnostic and prognostic value of urinalysis in experimental sepsis.

Objective: To assess the effect of high-dose N-acetylcysteine on renal function in cardiac surgery patients at higher risk of postoperative renal failure., Design: Multiblind, placebo-controlled, randomized, phase II clinical trial., Setting: Operating rooms and intensive care units of two tertiary referral hospitals., Patients: A total of 60 cardiac surgery patients at higher risk of postoperative renal failure., Interventions: Patients were allocated to either 24 hrs of high-dose N-acetylcysteine infusion (300 mg/kg body weight in 5% glucose, 1.7 L) or placebo (5% glucose, 1.7 L)., Measurements and Main Results: The primary outcome measure was the absolute change in serum creatinine from baseline to peak value within the first five postoperative days. Secondary outcomes included the relative change in serum creatinine, peak serum creatinine level, serum cystatin C, and in urinary output. Further outcomes were needed for renal replacement therapy, length of ventilation, and length of stay in the intensive care unit and hospital. Randomization was successful and patients were well balanced for preoperative and intraoperative characteristics. There was no significant attenuation in the increase in serum creatinine from baseline to peak when comparing N-acetylcysteine with placebo (64.5 +/- 91.2 and 38.0 +/- 42.4 mumol/L, respectively; p = .15). Also, there was no attenuation in the increase in serum cystatin C from baseline to peak for N-acetylcysteine compared with placebo (0.45 +/- 0.43 and 0.30 +/- 0.33 mg/L, respectively; p = .40). Likewise, there was no evidence for differences in any other clinical outcome., Conclusions: In this phase II, randomized, controlled trial, high-dose N-acetylcysteine was no more effective than placebo in attenuating cardiopulmonary bypass-related acute renal failure in high-risk cardiac surgery patients.

Objective: High cutoff hemofilters are characterized by an increased effective pore size designed to facilitate the elimination of inflammatory mediators in sepsis. Clinical data on this new renal replacement modality are lacking., Design: Prospective, randomized clinical trial., Setting: University hospital, intensive care units., Patients: : Thirty patients with sepsis-induced acute renal failure., Intervention: Patients were allocated to high cutoff (n = 20) or conventional (n = 10) hemofiltration in a 2:1 ratio. Median renal replacement dose was 31 mL/kg/hr. For high cutoff hemofiltration, a high-flux hemofilter with an in vivo cutoff point of approximately 60 kilodaltons was used. Conventional hemofiltration was performed with a standard high-flux hemofilter (PF11S). The impacts of high cutoff hemofiltration on the need for norepinephrine and on plasma levels and clearance rates for interleukin (IL)-6 and IL-1 receptor antagonist (IL-1ra) were analyzed. Absolute values, but also adjusted values (expressed as proportion of baseline), were analyzed. The observation period was restricted to 48 hrs., Main Results: Apart from higher antithrombin III levels at entry into the study, main clinical and laboratory parameters were comparable between both groups. The median norepinephrine dose at entry into the study was 0.30 microg/kg/min in the high cutoff group and 0.21 microg/kg/min in the conventional hemofiltration group (p = .448). Only the high cutoff group showed a significant decline (p = .0002) in "adjusted" norepinephrine dose over time. Clearance rates for IL-6 and IL-1ra were significantly higher in the high cutoff hemofiltration group (p < .0001), which translated into a significant decline of the corresponding plasma levels (p = .0465 for IL-6; p = .0293 for IL-1ra)., Conclusion: In this pilot study, high cutoff hemofiltration has been shown to exert a beneficial effect on the need for norepinephrine in septic patients with acute renal failure. In addition, we demonstrate that high cutoff hemofiltration is superior to conventional hemofiltration in the elimination of IL-6 and IL-1ra from the circulating blood of septic patients.

Objective: The Acute Dialysis Quality Initiative (ADQI) Group published a consensus definition (the RIFLE criteria) for acute renal failure. We sought to assess the ability of the RIFLE criteria to predict mortality in hospital patients., Design: Retrospective single-center study., Setting: University-affiliated hospital., Patients: All patients admitted to the study hospital between January 2000 and December 2002. Patients were excluded if they were younger than 15 yrs old, were on chronic dialysis, or had kidney transplant or if their length of hospital stay was <24 hrs., Interventions: None., Measurements and Main Results: We included 20,126 patients. Mean age was 64 yrs, 14.7% of patients required intensive care unit admission, and hospital mortality was 8.0%. According to the RIFLE criteria, 9.1% of all patients were in the Risk category for acute renal failure, 5.2% were in the Injury category, and 3.7% were in the Failure category. There was an almost linear increase in hospital mortality from Normal to Failure (Normal, 4.4%; Risk, 15.1%; Injury, 29.2%; and Failure, 41.1%). Multivariate logistic regression analysis showed that all RIFLE criteria were significantly predictive factors for hospital mortality, with an almost linear increase in odds ratios from Risk to Failure (odds ratios, Risk 2.5, Injury 5.4, Failure 10.1)., Conclusions: The RIFLE criteria for acute renal failure classified close to 20% of our study patients as having some degrees of acute impairment in renal function and were useful in predicting their hospital mortality.

Objective: Acute renal failure is common in septic patients. Fenoldopam, a dopamine-1 receptor agonist, increases renal blood flow and may, therefore, reduce the risk of acute renal failure in such patients. Accordingly, we sought to determine the safety and efficacy of fenoldopam for the prevention of acute renal failure in septic patients., Design: Prospective, double-blind, placebo-controlled trial., Setting: Three multidisciplinary intensive care units at a university hospital., Patients: Three hundred septic patients with baseline serum creatinine concentrations <150 micromol/L., Interventions: We randomized patients to a continuous infusion of either fenoldopam (n = 150) at 0.09 microg x kg x min or placebo (n = 150) while in the intensive care unit. The primary outcome measure was the incidence of acute renal failure, defined as a serum creatinine concentration increase to >150 micromol/L, during study drug infusion., Measurements and Main Results: The incidence of acute renal failure was significantly lower in the fenoldopam group compared with the control group (29 vs. 51 patients; p = .006). The odds ratio of developing acute renal failure for patients treated with fenoldopam was estimated to be 0.47 (p = .005). The difference in the incidence of severe acute renal failure (creatinine >300 mumol/L), however, failed to achieve statistical significance (10 vs. 21; p = .056). The length of intensive care unit stay in surviving patients was significantly lower in the fenoldopam group compared with the control group (10.64 +/- 9.3 vs. 13.4 +/- 14.0; p < .001). There were no complications of fenoldopam infusion. A direct effect of treatment on the probability of death, beyond its effect on acute renal failure, was not significant (odds ratio = 0.68, p = .1)., Conclusions: Compared with placebo, low-dose fenoldopam resulted in a smaller increase in serum creatinine in septic patients. The clinical significance of this finding is uncertain. A large multiple-center trial is now needed to confirm these findings.

Objective: Several different severity scoring systems specific to acute renal failure have been proposed. However, most validation studies of these scoring systems were conducted in a single center or in a small number of centers, often the same ones used for their development. Therefore, it is not known whether such severity scoring systems may be widely applied., Design: Prospective clinical investigation., Setting: Intensive care units., Patients: One thousand seven hundred and forty-two intensive care unit patients with acute renal failure who were either treated with renal replacement therapy or fulfilled predefined criteria., Interventions: Demographic and clinical information and outcomes were measured., Measurements and Main Results: Scores for four acute renal failure-specific scoring systems and two general scoring systems (Simplified Acute Physiology Score II and Sequential Organ Failure Assessment) were calculated, and their discrimination and calibration were tested with receiver operating characteristic curves and Hosmer-Lemeshow goodness-of fit-tests. For the receiver operating characteristic curves, blood lactate levels were also used as a reference. All scores had an area under the receiver operating characteristic curve <0.7 (Mehta 0.670, Liano 0.698, Chertow 0.610, Paganini 0.643, Simplified Acute Physiology Score II 0.645, Sequential Organ Failure Assessment 0.675, lactate 0.639). For scores that can calculate predicted mortality, the Hosmer-Lemeshow goodness-of-fit test showed poor calibration., Conclusions: None of the scoring systems tested had a high level of discrimination or calibration to predict mortality for patients with acute renal failure when tested in a broad cohort of patients from multiple countries. A large, multiple-center database might be needed to improve the discrimination and calibration of acute renal failure scoring system.

Modern CRRT machines can deliver therapy that resembles IHD, and IHD treatments can be slowed to deliver therapy over 10-12 hours, which resembles CRRT. Bellomo R, Cass A, Cole L, et al; RENAL Replacement Therapy Study Investigators: Intensity of continuous renalreplacement therapy in critically ill patients. RRT was performed in 96.8% of accelerated-strategy patients and 61.8% of patients in the standard therapy patients, where RRT was discouraged unless conventional indications developed or AKI persisted for greater than 72 hours. Initially, dialysis nurses were consulted for ICU patients, but due to their high workload, they were often unable to respond in a timely manner to the increasing needs associated with a therapy that was delivered 24 hr/d in sicker and sicker patients. [Extracted from the article]

Objectives: To explore the relationship between timing of continuous renal replacement therapy commencement and clinical outcomes in critically ill patients with acute kidney injury. The primary outcomes were all-cause mortality at 28 and 90 days. Design: Nested observational cohort study using data from the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study. Setting: Twenty-three ICUs in Australia and New Zealand. Patients: Four hundred thirty-nine critically ill patients with acute kidney injury Risk, Injury, Failure, Loss, End-stage kidney disease-injury (RIFLE-I) criteria. Interventions: None. Measurements and Main Results: The time between RIFLE-I acute kidney injury and randomization in the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study (proxy for continuous renal replacement therapy commencement) was the variable of interest. All baseline variables in the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study were assessed. Multivariable Cox, logistic, and linear regression models were used to assess the independent relationship of time of onset of RIFLE-I acute kidney injury and randomization and patient outcomes. The median time between RIFLE-I acute kidney injury and continuous renal replacement therapy commencement was 17.6 hours (interquartile range, 7.1-46 hr). Based on four groups of continuous renal replacement therapy commencement ([group 1; reference]: <7.1, [group 2]: ⩾ 7.1 to < 17.6, [group 3]: ⩾ 17.6 to < 46.0, [group 4]: ⩾ 46.0hr), earlier commencement of continuous renal replacement therapy was not associated with a significantly lower risk of death at 28 days (hazard ratio for group 2: 1.06, 95% Cl: 0.62-1.81; p = 0.83; hazard ratio for group 3: 1.23, 95% Cl: 0.71-2.12; p = 0.46; hazard ratio for group 4: 1.33, 95% Cl: 0.77- 2.31 ;p = 0.31). Similar findings were observed for death at 90 days. Conclusions: In a subgroup of participants of the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study, earlier commencement of continuous renal replacement therapy relative to RIFLE-I acute kidney injury was not significantly associated with improved survival. Additional studies with larger sample sizes and broader commencement times are warranted. [ABSTRACT FROM AUTHOR]

The article reports on a study of the value of novel and conventional serum biomarkers in predicting acute kidney injury (AKI) among adult cardiac surgical patients. It examined concentrations of plasma neutrophil gelatinase-associated lipocalin (NGAL) serum cystatin C, creatinine, and urea of 100 cardiac surgical patients. It showed that plasma NGAL and serum cystatin C were conventional biomarkers which are good in identifying patients who developed AKI after cardiac surgery.

Objectives: Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis.Design: Interventional study.Setting: Research Institute.Subjects: Adult Merino ewes.Interventions: Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg).Measurements and Main Results: Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours.Conclusions: IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients. [ABSTRACT FROM AUTHOR]

Objective: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy.Design: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial.Setting: ICUs.Patients: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively).Interventions: IV angiotensin II or placebo.Measurements and Main Results: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively.Conclusions: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II. [ABSTRACT FROM AUTHOR]

The article reviews what is known about the pathophysiology of septic acute kidney injury. This disease represent a unique form of acute renal disease: hyperemic acute renal failure, at least in patients with a hyperdynamic circulation. Evidence suggests that urinalysis is not effective in diagnosis and prognosis of septic kidney injury. The authors also discuss the limitations and strengths of evidences on septic acute renal failure as well as areas which requires further investigation.