Sean M. Bagshaw

This article reports the conclusions of a consensus expert conference on the basic principles and nomenclature of renal replacement therapy (RRT) currently utilized to manage acute kidney injury (AKI). This multidisciplinary consensus conference discusses common definitions, components, techniques, and operations of the machines and platforms used to deliver extracorporeal therapies, utilizing a “machine-centric” rather than a “patient-centric” approach. We provide a detailed description of the performance characteristics of membranes, filters, transmembrane transport of solutes and fluid, flows, and methods of measurement of delivered treatment, focusing on continuous renal replacement therapies (CRRT) which are utilized in the management of critically ill patients with AKI. This is a consensus report on nomenclature harmonization for principles of extracorporeal renal replacement therapies. Devices and operations are classified and defined in detail to serve as guidelines for future use of terminology in papers and research.

Introduction: Intensive Care Units (ICUs) provide life-supporting treatment; however, resources are limited, so demand may exceed supply in the event of pandemics, environmental disasters, or in the context of an aging population. We hypothesized that comprehensive national data on ICU resources would permit a better understanding of regional differences in system capacity. Methods: After the 2009–2010 Influenza A (H1N1) pandemic, the Canadian Critical Care Trials Group surveyed all acute care hospitals in Canada to assess ICU capacity. Using a structured survey tool administered to physicians, respiratory therapists and nurses, we determined the number of ICU beds, ventilators, and the ability to provide specialized support for respiratory failure. Results: We identified 286 hospitals with 3170 ICU beds and 4982 mechanical ventilators for critically ill patients. Twenty-two hospitals had an ICU that routinely cared for children; 15 had dedicated pediatric ICUs. Per 100,000 population, there was substantial variability in provincial capacity, with a mean of 0.9 hospitals with ICUs (provincial range 0.4-2.8), 10 ICU beds capable of providing mechanical ventilation (provincial range 6–19), and 15 invasive mechanical ventilators (provincial range 10–24). There was only moderate correlation between ventilation capacity and population size (coefficient of determination (R²) = 0.771). Conclusion: ICU resources vary widely across Canadian provinces, and during times of increased demand, may result in geographic differences in the ability to care for critically ill patients. These results highlight the need to evolve inter-jurisdictional resource sharing during periods of substantial increase in demand, and provide background data for the development of appropriate critical care capacity benchmarks.

Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G₁ cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.

Introduction: Among critically ill patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT), the effect of convective (via continuous venovenous hemofiltration [CVVH]) versus diffusive (via continuous venovenous hemodialysis [CVVHD]) solute clearance on clinical outcomes is unclear. Our objective was to evaluate the feasibility of comparing these two modes in a randomized trial. Methods: This was a multicenter open-label parallel-group pilot randomized trial of CVVH versus CVVHD. Using concealed allocation, we randomized critically ill adults with AKI and hemodynamic instability to CVVH or CVVHD, with a prescribed small solute clearance of 35 mL/kg/hour in both arms. The primary outcome was trial feasibility, defined by randomization of >25% of eligible patients, delivery of >75% of the prescribed CRRT dose, and follow-up of >95% of patients to 60 days. A secondary analysis using a mixed-effects model examined the impact of therapy on illness severity, defined by sequential organ failure assessment (SOFA) score, over the first week. Results: We randomized 78 patients (mean age 61.5 years; 39% women; 23% with chronic kidney disease; 82% with sepsis). Baseline SOFA scores (mean 15.9, SD 3.2) were similar between groups. We recruited 55% of eligible patients, delivered >80% of the prescribed dose in each arm, and achieved 100% follow-up. SOFA tended to decline more over the first week in CVVH recipients (-0.8, 95% CI -2.1, +0.5) driven by a reduction in vasopressor requirements. Mortality (54% CVVH; 55% CVVHD) and dialysis dependence in survivors (24% CVVH; 19% CVVHD) at 60 days were similar. Conclusions: Our results suggest that a large trial comparing CVVH to CVVHD would be feasible. There is a trend toward improved vasopressor requirements among CVVH-treated patients over the first week of treatment. Trial Registration: ClinicalTrials.gov: NCT00675818

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.