International criteria for acute kidney injury: advantages and remaining challenges

• Acute Kidney Injury (AKI) is defined using widely accepted international criteria that are based on changes in serum creatinine concentration and degree of oliguria. • AKI, when defined in this way, has a strong association with poor patient outcomes, including high mortality rates and longer hospital admissions with increased resource utilisation and subsequent chronic kidney disease. • The detection of AKI using current criteria can assist with AKI diagnosis and stratification of individual patient risk. • The diagnosis of AKI requires clinical judgement to integrate the definition of AKI with the clinical situation, to determine underlying cause of AKI, and to take account of factors that may affect performance of current definitions

Classifying the unclassifiable – A Delphi study to reach consensus on the fibrotic nature of diseases

Background Traditionally, clinical research has focused on individual fibrotic diseases or fibrosis in a particular organ. However, it is possible for people to have multiple fibrotic diseases. While multi-organ fibrosis may suggest shared pathogenic mechanisms, yet there is no consensus on what constitutes a fibrotic disease and therefore fibrotic multimorbidity. Aim A Delphi study was performed to reach consensus on which diseases may be described as fibrotic. Methods Participants were asked to rate a list of diseases, sub-grouped according to eight body regions, as ‘fibrotic manifestation always present’, ‘can develop fibrotic manifestations’, ‘associated with fibrotic manifestations’ or ‘not fibrotic nor associated’. Classifications of ‘fibrotic manifestation always present’ and ‘can develop fibrotic manifestations’ were merged and termed ‘fibrotic’. Clinical consensus was defined according to the interquartile range, having met a minimum number of responses. Clinical agreement was used for classification where diseases did not meet the minimum number of responses (required for consensus measure), were only classified if there was 100% consensus on disease classification. Results After consulting experts, searching the literature and coding dictionaries, a total of 323 non-overlapping diseases which might be considered fibrotic were identified; 92 clinical specialists responded to the first round of the survey. Over three survey rounds, 240 diseases were categorized as fibrotic via clinical consensus and 25 additional diseases through clinical agreement. Conclusion Using a robust methodology, an extensive list of diseases was classified. The findings lay the foundations for studies estimating the burden of fibrotic multimorbidity, as well as investigating shared mechanisms and therapies

Contrast‐enhanced ultrasound assessed renal microvascular perfusion may predict postoperative renal complications following colorectal surgery

Colorectal surgery is associated with an above‐average mortality rate of ~15%. During surgery, maintenance of vital organ perfusion is essential in order to reduce postoperative mortality and morbidity, with renal perfusion of particular importance. Oesophageal Doppler monitors (ODM) are commonly used to try and provide accurate measures of fluid depletion during surgery, however it is unclear to what extent they reflect organ perfusion. In addition, it is not known whether macro‐ and/ or microvascular perfusion indices are associated with renal complications following colorectal surgery. Thirty‐two participants scheduled for colorectal surgery had three measures of macro‐ and microvascular renal blood flow via contrast enhanced ultrasound (CEUS), and simultaneous measures of cardiac output indicies via ODM: i) pre‐operatively; ii) intra‐operatively at the mid‐point of operation, and iii) after the conclusion of surgery. The Postoperative Morbidity Survey (POMS) was used to assess postoperative complications. Intra‐operatively, there was a significant correlation between renal microvascular flow (RT) and renal macrovascular flow (TTI) (rho=0.52; p=0.003). Intra‐operative TTI, but not RT, was associated with cardiac index (rho= ‐0.50; p=0.0003). Intra‐operative RT predicted increases in renal complications (OR 1.46; 95% CI 1.03 to 2.09) with good discrimination (C‐statistic, 0.85). Complications were not predicted by TTI or ODM‐derived indices. There was no relationship between RT and TTI before or after surgery. ODM measures of haemodynamic status do not correlate with renal microvascular blood flow, and as such are likely not suitable to determine vital organ perfusion. Only CEUS‐derived measures of microvascular perfusion were predictive of postoperative renal complications

Utility of electronic AKI alerts in intensive care: A national multicentre cohort study

Background: Electronic AKI alerts highlight changes in serum creatinine compared to the patient's own baseline. Our aim was to identify all AKI alerts and describe the relationship between electronic AKI alerts and outcome for AKI treated in the Intensive Care Unit (ICU) in a national multicentre cohort. Methods: A prospective cohort study was undertaken between November 2013 and April 2016, collecting data on electronic AKI alerts issued. Results: 10% of 47,090 incident AKI alerts were associated with ICU admission. 90-day mortality was 38.2%. Within the ICU cohort 48.8% alerted in ICU. 51.2% were transferred to ICU within 7 days of the alert, of which 37.8% alerted in a hospital setting (HA-AKI) and 62.2% in a community setting (CA-AKI). Mortality was higher in patients transferred to ICU following the alert compared to those who had an incident alert on the ICU (p < 0.001), and was higher in HA-AKI (45.3%) compared to CA-AKI (39.5%) (35.0%, p = 0.01). In the surviving patients, the proportion of patient recovering renal function following, was significantly higher in HA-AKI alerting (84.2%, p = 0.004) and CA-AKI alerting patients (87.6%, p < 0.001) compared to patients alerting on the ICU (78.3%). Conclusion: The study provides a nationwide characterisation of AKI in ICU highlighting the high incidence and its impact on patient outcome. The data also suggests that within the cohort of AKI patients treated in the ICU there are significant differences in the presentation and outcome between those patients that require transfer to the ICU after AKI is identified and those who develop AKI following ICU admission. Moreover, the study demonstrates that using AKI e-alerts provides a centralised resource which does not rely on clinical diagnosis of AKI or coding, resulting in a robust data set which can be used to define the incidence and outcome of AKI in the ICU setting

Distinct Properties of Hexameric but Functionally Conserved Mycobacterium tuberculosis Transcription-Repair Coupling Factor

Transcription coupled nucleotide excision repair (TC-NER) is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd) is a transcription repair coupling factor, involved in repair of template strand during transcription. Mfd from M. tuberculosis (MtbMfd) is 1234 amino-acids long harboring characteristic modules for different activities. Mtbmfd complemented Escherichia coli mfd (Ecomfd) deficient strain, enhanced survival of UV irradiated cells and increased the road-block repression in vivo. The protein exhibited ATPase activity, which was stimulated ∼1.5-fold in the presence of DNA. While the C-terminal domain (CTD) comprising amino acids 630 to 1234 showed ∼2-fold elevated ATPase activity than MtbMfd, the N-terminal domain (NTD) containing the first 433 amino acid residues was able to bind ATP but deficient in hydrolysis. Overexpression of NTD of MtbMfd led to growth defect and hypersensitivity to UV light. Deletion of 184 amino acids from the C-terminal end of MtbMfd (MfdΔC) increased the ATPase activity by ∼10-fold and correspondingly exhibited efficient translocation along DNA as compared to the MtbMfd and CTD. Surprisingly, MtbMfd was found to be distributed in monomer and hexamer forms both in vivo and in vitro and the monomer showed increased susceptibility to proteases compared to the hexamer. MfdΔC, on the other hand, was predominantly monomeric in solution implicating the extreme C-terminal region in oligomerization of the protein. Thus, although the MtbMfd resembles EcoMfd in many of its reaction characteristics, some of its hitherto unknown distinct properties hint at its species specific role in mycobacteria during transcription-coupled repair

'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Reconstruction of bacterial transcription-coupled repair at single-molecule resolution

International audienc

Barriers and enablers to the implementation of a complex quality improvement intervention for acute kidney injury: A qualitative evaluation of stakeholder perceptions of the Tackling AKI study

Background Acute kidney injury in hospital patients is common and associated with reduced survival and higher healthcare costs. The Tackling Acute Kidney Injury (TAKI) quality improvement project aimed to reduce mortality rates in patients with acute kidney injury by implementing a multicomponent intervention comprising of an electronic alert, care bundle and education in five UK hospitals across a variety of wards. A parallel developmental evaluation using a case study approach was conducted to provide the implementation teams with insights into factors that might impact intervention implementation and fidelity. The qualitative element of the evaluation will be reported. Methods 29 semi-structured interviews with implementation teams across the five hospitals were carried out to identify perceived barriers and enablers to implementation. Interviews were taped and transcribed verbatim and Framework analysis was conducted. Results Interviews generated four ‘barriers and enablers’ to implementation themes: i) practical/contextual factors, ii) skills and make-up of the TAKI implementation team, iii) design, development and implementation approach, iv) staff knowledge, attitudes, behaviours and support. Enablers included availability of specialist teams (e.g. educational teams), multi-disciplinary implementation teams with strong leadership, team-based package completion and proactive staff. Barriers were frequently the converse of facilitators. Conclusions Despite diversity of sites, a range of common local factors–contextual, intervention-based and individual–were identified as potential barriers and enablers to fidelity, including intervention structure/design and process of/approach to implementation. Future efforts should focus on early identification and management of barriers and tailored optimisation of known enablers such as leadership and multidisciplinary teams to encourage buy-in. Improved measures of real-time intervention and implementation fidelity would further assist local teams to target their support during such quality improvement initiatives

Exploring haemodynamics of haemodialysis using extrema points analysis model

Background: Haemodialysis is a form of renal replacement therapy used to treat patients with end stage renal failure. It is becoming more appreciated that haemodialysis patients exhibit higher rates of multiple end organ damage compared to the general population. There is also a strong emerging evidence that haemodialysis itself causes circulatory stress. We aimed at examining haemodynamic patterns during haemodialysis using a new model and test that model against a normal control. Methods: We hypothesised that blood pressures generated by each heart beat constantly vary between local peaks and troughs (local extrema), the frequency and amplitude of which is regulated to maintain optimal organ perfusion. We also hypothesised that such model could reveal multiple haemodynamic aberrations during HD. Using a non-invasive cardiac output monitoring device (Finometer®) we compared various haemodynamic parameters using the above model between a haemodialysis patient during a dialysis session and an exercised normal control after comparison at rest. Results: Measurements yielded 29,751 data points for each haemodynamic parameter. Extrema points frequency of mean arterial blood pressure was higher in the HD subject compared to the normal control (0.761Hz IQR 0.5-0.818 vs 0.468Hz IQR 0.223-0.872, P < 0.0001). Similarly, extrema points frequency of systolic blood pressure was significantly higher in haemodialysis compared to normal. In contrary, the frequency of extrema points for TPR was higher in the normal control compared to HD (0.947 IQR 0.520-1.512 vs 0.845 IQR 0.730-1.569, P < 0.0001) with significantly higher amplitudes. Conclusion: Haemodialysis patients potentially exhibit an aberrant haemodynamic behaviour characterised by higher extrema frequencies of mean arterial blood pressure and lower extrema frequencies of total peripheral resistance. This, in theory, could lead to higher variation in organ perfusion and may be detrimental to vulnerable vascular beds

Haemodynamic consequences of changing potassium concentrations in haemodialysis fluids

<p>Abstract</p> <p>Background</p> <p>A rapid decrease of serum potassium concentrations during haemodialysis produces a significant increase in blood pressure parameters at the end of the session, even if effects on intra-dialysis pressure are not seen. Paradoxically, in animal models potassium is a vasodilator and decreases myocardial contractility. The purpose of this trial is to study the precise haemodynamic consequences induced by acute changes in potassium concentration during haemodialysis.</p> <p>Methods</p> <p>In 24 patients, 288 dialysis sessions, using a randomised single blind crossover design, we compared six dialysate sequences with different potassium profiles. The dialysis sessions were divided into 3 tertiles, casually modulating potassium concentration in the dialysate between the value normally used K and the two cut-off points K+1 and K-1 mmol/l. Haemodynamics were evaluated in a non-invasive manner using a finger beat-to-beat monitor.</p> <p>Results</p> <p>Comparing K-1 and K+1, differences were found within the tertiles regarding systolic (+5.3, +6.6, +2.3 mmHg, p < 0.05, < 0.05, ns) and mean blood pressure (+4.3, +6.4, -0.5 mmHg, p < 0.01, < 0.01, ns), as well as peripheral resistance (+212, +253, -4 dyne.sec.cm^-5, p < 0.05, < 0.05, ns). The stroke volume showed a non-statistically-significant inverse trend (-3.1, -5.2, -0.2 ml). 18 hypotension episodes were recorded during the course of the study. 72% with K-1, 11% with K and 17% with K+1 (p < 0.01 for comparison K-1 vs. K and K-1 vs. K+1).</p> <p>Conclusions</p> <p>A rapid decrease in the concentration of serum potassium during the initial stage of the dialysis-obtained by reducing the concentration of potassium in the dialysate-translated into a decrease of systolic and mean blood pressure mediated by a decrease in peripheral resistance. The risk of intra-dialysis hypotension inversely correlates to the potassium concentration in the dialysate.</p> <p>Trial Registration Number</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01224314">NCT01224314</a></p