John R. Prowle

Low avidity recognition of self-antigen by T cells permits escape from central tolerance.

The immunodominant epitope of myelin basic protein, Ac1-9, is encephalitogenic in H-2u mice. We have previously demonstrated that this epitope displays low affinity for I-Au and have suggested that the avidity of T cell recognition in the thymus may be compromised, enabling autoreactive T cells to escape self-tolerance. We have addressed this hypothesis directly by constructing transgenic mice expressing an encephalitogenic T cell receptor (TCR). Parenteral administration of Ac1-9 had no discernable impact on developing thymocytes. In contrast, peptide analogs displaying far higher affinity for I-Au, provoked deletion of CD4+ CD8+ cells and transient down-regulation of the TCR by mature CD4+ CD8- thymocytes. The use of analogs of intermediate affinity permitted a margin of error to be defined for the induction of tolerance and confirmed that the affinity of Ac1-9 lies well below the critical threshold.

Fluid balance and acute kidney injury

Intravenous fluids are widely administered to patients who have, or are at risk of, acute kidney injury (AKI). However, deleterious consequences of overzealous fluid therapy are increasingly being recognized. Salt and water overload can predispose to organ dysfunction, impaired wound healing and nosocomial infection, particularly in patients with AKI, in whom fluid challenges are frequent and excretion is impaired. In this Review article, we discuss how interstitial edema can further delay renal recovery and why conservative fluid strategies are now being advocated. Applying these strategies in critical illness is challenging. Although volume resuscitation is needed to restore cardiac output, it often leads to tissue edema, thereby contributing to ongoing organ dysfunction. Conservative strategies of fluid management mandate a switch towards neutral balance and then negative balance once hemodynamic stabilization is achieved. In patients with AKI, this strategy might require renal replacement therapy to be given earlier than when more-liberal fluid management is used. However, hypovolemia and renal hypoperfusion can occur in patients with AKI if excessive fluid removal is pursued with diuretics or extracorporeal therapy. Thus, accurate assessment of fluid status and careful definition of targets are needed at all stages to improve clinical outcomes. A conservative strategy of fluid management was recently tested and found to be effective in a large, randomized, controlled trial in patients with acute lung injury. Similar randomized, controlled studies in patients with AKI now seem justified.

Oliguria as predictive biomarker of acute kidney injury in critically ill patients

IntroductionDuring critical illness, oliguria is often used as a biomarker of acute kidney injury (AKI). However, its relationship with the subsequent development of AKI has not been prospectively evaluated.MethodsWe documented urine output and daily serum creatinine concentration in patients admitted for more than 24 hours in seven intensive care units (ICUs) from six countries over a period of two to four weeks. Oliguria was defined by a urine output < 0.5 ml/kg/hr. Data were collected until the occurrence of creatinine-defined AKI (AKI-Cr), designated by RIFLE-Injury class or greater using creatinine criteria (RIFLE-I[Cr]), or until ICU discharge. Episodes of oliguria were classified by longest duration of consecutive oliguria during each day were correlated with new AKI-Cr the next day, examining cut-offs for oliguria of greater than 1,2,3,4,5,6, or 12 hr duration,ResultsWe studied 239 patients during 723 days. Overall, 32 patients had AKI on ICU admission, while in 23, AKI-Cr developed in ICU. Oliguria of greater than one hour was significantly associated with AKI-Cr the next day. On receiver-operator characteristic area under the curve (ROCAUC) analysis, oliguria showed fair predictive ability for AKI-Cr (ROCAUC = 0.75; CI:0.64-0.85). The presence of 4 hrs or more oliguria provided the best discrimination (sensitivity 52% (0.31-0.73%), specificity 86% (0.84-0.89%), positive likelihood ratio 3.8 (2.2-5.6), P < 0.0001) with negative predictive value of 98% (0.97-0.99). Oliguria preceding AKI-Cr was more likely to be associated with lower blood pressure, higher heart rate and use of vasopressors or inotropes and was more likely to prompt clinical intervention. However, only 30 of 487 individual episodes of oliguria preceded the new occurrence of AKI-Cr the next day.ConclusionsOliguria was significantly associated with the occurrence of new AKI-Cr, however oliguria occurred frequently compared to the small number of patients (~10%) developing AKI-Cr in the ICU, so that most episodes of oliguria were not followed by renal injury. Consequently, the occurrence of short periods (1-6 hr) of oliguria lacked utility in discriminating patients with incipient AKI-Cr (positive likelihood ratios of 2-4, with > 10 considered indicative of a useful screening test). However, oliguria accompanied by hemodynamic compromise or increasing vasopressor dose may represent a clinically useful trigger for other early biomarkers of renal injury.

Fluid management for the prevention and attenuation of acute kidney injury

In patients with acute kidney injury (AKI), optimization of systemic haemodynamics is central to the clinical management. However, considerable debate exists regarding the efficacy, nature, extent and duration of fluid resuscitation, particularly when the patient has undergone major surgery or is in septic shock. Crucially, volume resuscitation might be required to maintain or restore cardiac output. However, resultant fluid accumulation and tissue oedema can substantially contribute to ongoing organ dysfunction and, particularly in patients developing AKI, serious clinical consequences. In this Review, we discuss the conflict between the desire to achieve adequate resuscitation of shock and the need to mitigate the harmful effects of fluid overload. In patients with AKI, limiting and resolving fluid overload might prompt earlier use of renal replacement therapy. However, rapid or early excessive fluid removal with diuretics or extracorporeal therapy might lead to hypovolaemia and recurrent renal injury. Optimal management might involve a period of guided fluid resuscitation, followed by management of an even fluid balance and, finally, an appropriate rate of fluid removal. To obtain best clinical outcomes, serial fluid status assessment and careful definition of cardiovascular and renal targets will be required during fluid resuscitation and removal.

Clinical review: Volume of fluid resuscitation and the incidence of acute kidney injury - a systematic review

Intravenous fluids are widely administered to maintain renal perfusion and prevent acute kidney injury (AKI). However, fluid overload is of concern during AKI. Using the Pubmed database (up to October 2011) we identified all randomised controlled studies of goal-directed therapy (GDT)-based fluid resuscitation (FR) reporting renal outcomes and documenting fluid given during perioperative care. In 24 perioperative studies, GDT was associated with decreased risk of postoperative AKI (odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.39 to 0.89) but additional fluid given was limited (median: 555 ml). Moreover, the decrease in AKI was greatest (OR = 0.47, 95% CI = 0.29 to 0.76) in the 10 studies where FR was the same between GDT and control groups. Inotropic drug use in GDT patients was associated with decreased AKI (OR = 0.52, 95% CI = 0.34 to 0.80, P = 0.003), whereas studies not involving inotropic drugs found no effect (OR = 0.75, 95% CI = 0.37 to 1.53, P = 0.43). The greatest protection from AKI occurred in patients with no difference in total fluid delivery and use of inotropes (OR = 0.46, 95% CI = 0.27 to 0.76, P = 0.0036). GDT-based FR may decrease AKI in surgical patients; however, this effect requires little overall FR and appears most effective when supported by inotropic drugs.

Acquired bloodstream infection in the intensive care unit: incidence and attributable mortality

IntroductionTo estimate the incidence of intensive care unit (ICU)-acquired bloodstream infection (BSI) and its independent effect on hospital mortality.MethodsWe retrospectively studied acquisition of BSI during admissions of >72 hours to adult ICUs from two university-affiliated hospitals. We obtained demographics, illness severity and co-morbidity data from ICU databases and microbiological diagnoses from departmental electronic records. We assessed survival at hospital discharge or at 90 days if still hospitalized.ResultsWe identified 6339 ICU admissions, 330 of which were complicated by BSI (5.2%). Median time to first positive culture was 7 days (IQR 5-12). Overall mortality was 23.5%, 41.2% in patients with BSI and 22.5% in those without. Patients who developed BSI had higher illness severity at ICU admission (median APACHE III score: 79 vs. 68, P < 0.001). After controlling for illness severity and baseline demographics by Cox proportional-hazard model, BSI remained independently associated with risk of death (hazard ratio from diagnosis 2.89; 95% confidence interval 2.41-3.46; P < 0.001). However, only 5% of the deaths in this model could be attributed to acquired-BSI, equivalent to an absolute decrease in survival of 1% of the total population. When analyzed by microbiological classification, Candida, Staphylococcus aureus and gram-negative bacilli infections were independently associated with increased risk of death. In a sub-group analysis intravascular catheter associated BSI remained associated with significant risk of death (hazard ratio 2.64; 95% confidence interval 1.44-4.83; P = 0.002).ConclusionsICU-acquired BSI is associated with greater in-hospital mortality, but complicates only 5% of ICU admissions and its absolute effect on population mortality is limited. These findings have implications for the design and interpretation of clinical trials.

Renal replacement therapy in acute kidney injury: controversy and consensus.

Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future.

Continuous renal replacement therapy: recent advances and future research.

Continuous renal replacement therapy (CRRT) is the preferred treatment for acute kidney injury (AKI) in intensive care units (ICUs) throughout much of the developed world. Despite its widespread use, however, no formal proof exists that patient outcomes are improved when CRRT is used in preference to intermittent hemodialysis (IHD). In addition, controversy and center-specific practice variation in the clinical application of CRRT continues, owing to a lack of randomized multicenter studies of both CRRT and IHD providing level 1 data to inform clinical practice. Now, however, the publication of results from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study and the Randomized Evaluation of Normal versus Augmented Level Renal Replacement Therapy (RENAL) trial have provided an unparalleled quantity of information to guide clinicians. These pivotal trials investigated different intensities of CRRT in the ICU and provided level 1 evidence that effluent flow rates >25 ml/kg per hour do not improve outcomes in patients in the ICU. In this Review, we discuss the background and results of the ATN and RENAL trials and the emerging consensus that CRRT is the most appropriate treatment for AKI in vasopressor-dependent patients in the ICU. Finally, we describe the remaining controversies regarding the use of CRRT and the questions that remain to be answered.

Pilot double‐blind, randomized controlled trial of short‐term atorvastatin for prevention of acute kidney injury after cardiac surgery

Aim:  To test whether short‐term perioperative administration of oral atorvastatin could reduce incidence of postoperative acute kidney injury (AKI) in cardiac surgical patients.

Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: A pilot investigation*

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.