Mark Devonald

The definition of acute kidney injury and its use in practice.

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.

A real-time electronic alert to improve detection of acute kidney injury in a large teaching hospital

BACKGROUND Acute kidney injury (AKI) is a common and serious problem in hospitalized patients. Early detection is critical for optimal management but in practice is currently inadequate. To improve outcomes in AKI, development of early detection tools is essential. METHODS We developed an automated real-time electronic alert system employing algorithms which combined internationally recognized criteria for AKI [Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN)]. All adult patients admitted to Nottingham University Hospitals were included. Where a patients serum creatinine increased sufficiently to define AKI, an electronic alert was issued, with referral to an intranet-based AKI guideline. Incidence of AKI Stages 1-3, in-hospital mortality, length of stay and distribution between specialties is reported. RESULTS Between May 2011 and April 2013, 59,921 alerts resulted from 22,754 admission episodes, associated with 15,550 different patients. Overall incidence of AKI for inpatients was 10.7%. Highest AKI stage reached was: Stage 1 in 7.2%, Stage 2 in 2.2% and Stage 3 in 1.3%. In-hospital mortality for all AKI stages was 18.5% and increased with AKI stage (12.5, 28.4, 35.7% for Stages 1, 2 and 3 AKI, respectively). Median length of stay was 9 days for all AKI. CONCLUSIONS This is the first fully automated real time AKI e-alert system, using AKIN and RIFLE criteria, to be introduced to a large National Health Service hospital. It has provided one of the biggest single-centre AKI datasets in the UK revealing mortality rates which increase with AKI stage. It is likely to have improved detection and management of AKI. The methodology is transferable to other acute hospitals.

How acute kidney injury is investigated and managed in UK intensive care units—a survey of current practice

BACKGROUND Optimal management of acute kidney injury (AKI) remains controversial, particularly with respect to acutely unwell patients in the intensive care unit (ICU). This is likely to be attributable to the currently poor evidence base. Attempts to introduce guidance and consistency have been made over recent years, such as the AKI Network (AKIN) staging system and, in the UK, recommendations from the 2009 National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report into AKI. We wished to ascertain how AKI is investigated and managed in intensive care units in the UK, and whether these recent initiatives have made any difference to clinical practice. METHODS This is an online survey of all general adult UK ICUs between December 2009 and May 2010. RESULTS One hundred and eighty-eight out of two hundred and thirty-three units (80%) started the survey; 167 (72%) completed it. Only 19.2% of respondents routinely use AKIN or Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria for diagnosis and staging of AKI. A nephrologist is never or rarely consulted about patients with AKI in over 40% of the units. Only 46.4% have 24-h access to a renal ultrasound service. Continuous venovenous haemofiltration (CVVH) is the most commonly used form of renal replacement therapy (RRT) but intermittent haemodialysis (IHD) is used infrequently. Continuous RRTs (CRRTs) are managed almost exclusively by intensivists, whereas IHD is managed predominantly by nephrologists. The most frequently used criteria for initiating RRT are hyperkalaemia, fluid overload and pH. Most units have a standard RRT protocol and 35 mL/kg/h is the most frequently prescribed dose of CVVH. Only 51% of the units assess the delivered dose of RRT. CONCLUSIONS Considerable variation exists in the investigation and management of AKI in UK ICUs. Despite increasing recognition of the importance of AKI, few ICUs are aware of RIFLE and AKIN criteria.

Remote conditioning or erythropoietin before surgery primes kidneys to clear ischemia-reperfusion-damaged cells: a renoprotective mechanism?

Acute kidney injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury (AKI). Clinical trials suggest that preoperative erythropoietin (EPO) or remote ischemic preconditioning may have a renoprotective effect. Using a porcine model of warm ischemia-reperfusion-induced AKI (40-min bilateral cross-clamping of renal arteries, 48-h reperfusion), we examined the renoprotective efficacy of EPO (1,000 iu/kg iv.) or remote ischemic preconditioning (3 cycles, 5-min inflation/deflation to 200 mmHg of a hindlimb sphygmomanometer cuff). Ischemia-reperfusion induced significant kidney injury at 24 and 48 h (χ(2), 1 degree of freedom, >10 for 6/7 histopathological features). At 2 h, a panel of biomarkers including plasma creatinine, neutrophil gelatinase-associated lipocalin, and IL-1β, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pretreated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48-h reperfusion, plasma IL-1β and the number of subcapsular cells in G2-M arrest were reduced after preoperative EPO, but not after remote ischemic preconditioning. These data suggest an intrarenal mechanism acting within cortical cells that may underpin a renoprotective function for preoperative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified.

Micronutrient and amino acid losses in acute renal replacement therapy

Purpose of reviewA wide range of renal replacement therapies is now available to support patients with acute kidney injury. These treatments utilize diffusion, convection or a combination of these mechanisms to remove metabolic waste products from the bloodstream. It is inevitable that physiologically important substances including micronutrients will also be removed. Here we review current knowledge of the extent of micronutrient loss, how it varies between treatment modalities and its clinical significance. Recent findingsVery few studies have specifically investigated micronutrient loss in renal replacement therapy for acute kidney injury. Recent data suggest that trace elements and amino acids are lost during intermittent dialysis, hybrid therapies such as sustained low-efficiency diafiltration and continuous therapies. Extent of micronutrient loss appears to vary with treatment type, with continuous convection-based treatments probably causing greatest losses. SummaryPatients with acute kidney injury are at high risk of disease-related malnutrition. The use of renal replacement therapy, although often essential for life support, results in loss of micronutrients into the filtrate or dialysate. Losses are probably greater with continuous convective treatments, but it is not yet known whether these losses are clinically significant or whether their replacement would improve patient outcomes.

Remote effects of acute kidney injury in a porcine model

Acute kidney injury (AKI) is a common and serious condition with no specific treatment. An episode of AKI may affect organs distant from the kidney, further increasing the morbidity associated with AKI. The mechanism of organ cross talk after AKI is unclear. The renal and immune systems of pigs and humans are alike. Using a preclinical animal (porcine) model, we tested the hypothesis that early effects of AKI on distant organs is by immune cell infiltration, leading to inflammatory cytokine production, extravasation, and edema. In 29 pigs exposed to either sham surgery or renal ischemia-reperfusion (control, n = 12; AKI, n = 17), we assessed remote organ (liver, lung, brain) effects in the short (from 2- to 48-h reperfusion) and longer term (5 wk later) using immunofluorescence (for leukocyte infiltration, apoptosis), a cytokine array, tissue elemental analysis (e.g., electrolytes), blood hematology and chemistry (e.g., liver enzymes), and PCR (for inflammatory markers). AKI elicited significant, short-term (∼24 h) increments in enzymes indicative of acute liver damage (e.g. , AST: ALT ratio; P = 0.02) and influenced tissue biochemistry in some remote organs (e.g., lung tissue [Ca(2+)] increased; P = 0.04). These effects largely resolved after 48 h, and no further histopathology, edema, apoptosis, or immune cell infiltration was noted in the liver, lung, or hippocampus in the short and longer term. AKI has subtle biochemical effects on remote organs in the short term, including a transient increment in markers of acute liver damage. These effects resolved by 48 h, and no further remote organ histopathology, apoptosis, edema, or immune cell infiltration was noted.

Renal function monitoring in heart failure – what is the optimal frequency? A narrative review

The second most common cause of hospitalization due to adverse drug reactions in the UK is renal dysfunction due to diuretics, particularly in patients with heart failure, where diuretic therapy is a mainstay of treatment regimens. Therefore, the optimal frequency for monitoring renal function in these patients is an important consideration for preventing renal failure and hospitalization. This review looks at the current evidence for optimal monitoring practices of renal function in patients with heart failure according to national and international guidelines on the management of heart failure (AHA/NICE/ESC/SIGN). Current guidance of renal function monitoring is in large part based on expert opinion, with a lack of clinical studies that have specifically evaluated the optimal frequency of renal function monitoring in patients with heart failure. Furthermore, there is variability between guidelines, and recommendations are typically nonspecific. Safer prescribing of diuretics in combination with other antiheart failure treatments requires better evidence for frequency of renal function monitoring. We suggest developing more personalized monitoring rather than from the current medication‐based guidance. Such flexible clinical guidelines could be implemented using intelligent clinical decision support systems. Personalized renal function monitoring would be more effective in preventing renal decline, rather than reacting to it.

Nanotechnology tracks to the renal ward

The phospholipid bilayer is a highly dynamic structure. Approximately 2% is recycled every 5–10 min, so the whole membrane is recycled every 1–2 h. The process involves constant formation of endosomes that bud off by endocytosis from the plasma membrane and become internalised into the cytoplasm. These endosomes, together with their associated intra-membranous proteins, represent a snapshot of that cells plasma membrane composition. Further rounds of endocytosis within the endosomes themselves generate intracellular multivesicular bodies. Upon fusing with the plasma membrane, these endosomes release their contents into the circulation (they were first identified in the maturing mammalian reticulocyte) or, in the case of renal tubular epithelial cells, into the urine. The resultant urinary ‘exosomes’ may be characterised by their size (generally 20–100 nm) and density (1.10-1.19 mg ml−1). They are representative of the plasma membrane from which they originated and therefore offer a potential window into the pathophysiology of the kidney, providing information about changes in membrane or cytosolic composition from specific segments of the nephron. Chronic kidney disease (CKD) is highly prevalent and is expected to increase further in the next 5–10 years because of the rising prevalence of obesity and diabetes. Acute kidney injury (AKI), the loss of kidney function over hours to days, is also very common, being seen in up to 20% of acute hospital admissions. There are often delays in detection of both AKI and CKD, which can lead to worse clinical outcomes. The use of urinary biomarkers is key to the early detection of kidney disease (and also to some systemic conditions that might lead to changes in renal epithelial composition). Urine is an excellent fluid for biomarker discovery and development, having sufficient quantities of measureable peptides and/or proteins and being relatively easy to obtain non-invasively in reasonable quantities (assuming the patient is not oliguric). Hence, some urinary biomarkers such as albumin/creatinine ratio (ACR) are already used in routine clinical practice. Detection of increased ACR might, for example, be the first sign of diabetic nephropathy. AKI is currently defined by an increase in serum creatinine or a fall in urine output, but these changes can occur relatively late with respect to the renal injury, potentially leading to delays in treatment. Urinary biomarkers such as neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) have shown promise as novel early biomarkers of AKI. Biomarker discovery and development is an active field of basic and clinical research. More detailed examination of the urinary proteome, including analysis of exosomes, creates further opportunity for discovery of clinically useful early biomarkers of disease. Putative exosomal biomarkers of AKI have been reported, such as the Na+/H+ exchanger isoform 3 (NHE3) (du Cheyron et al. 2003) and Fetuin-A (Zhou et al. 2006) but with improved technology for exosome analysis, more sensitive and specific biomarkers might be discovered. To date, the difficulty with determining and quantifying urinary exosomes has been their lability, small size and particular density. Accurate and reproducible identification has been labour intensive and expensive, and has required specific laboratory equipment and skills (e.g. Western blotting). A new study published in the current issue of the Journal of Physiology (Oosthuyzen et al. 2013) suggests a novel approach that may change this situation. Using nanoparticle tracking analysis (NTA) Oosthuyzen et al. successfully identified a range of particle sizes in urine, including those classified typically as exosomes. They validated the technique by fluorescently tagging known exosomal proteins such as CD24 (a cell surface marker) and aquaporin 2 (AQP2) and co-localising their fluorescent read-out in the range of particle sizes typically defining exosomes (20–100 nm). They prospectively identified an increase in the output of urinary exosomes tagged with AQP2 under known stimulatory conditions (treatment with the arginine vasopressin analogue, desmopressin). The authors conducted their studies in a cell line, then in an animal model, and finally in five healthy volunteers and a patient with central diabetes insipidus treated with desmopressin. The authors also established optimal conditions for urine storage for potential use in biomarker discovery studies using NTA. So what exactly is NTA? NTA was invented in the UK by Dr Bob Carr who subsequently founded Nanosight Ltd (http://www.nanosight.com/) in 2003. NTA is used to observe (in conjunction with a high-powered microscope) and analyse (using specialised software) particle movement within a solution. The rate of movement of these particles (Brownian motion) is determined by a number of factors including particle size, viscosity and temperature of the liquid but is not affected by particle density or refractive index. Thus, using NTA, a size distribution profile of small (10–1000 nm) particles in solution (e.g. urine) can be produced with minimal sample preparation and hence time associated with the procedure. With further development, refinements and validation then it may be possible for the analysis to be done in real time with little to no preparation. However, given the complexity of the equipment required, a simple point of care (‘bedside’) test would appear to be some time off. Nevertheless, by describing optimal handling of samples for NTA of urinary exosomes, the authors have contributed to bringing this exciting technique a step closer to routine clinical use. No doubt researchers in acute and chronic kidney disease, interested in identification of disease biomarkers, will take note.