Publications by authors named "John R Prowle"

79 Publications

Acute kidney injury in the critically ill: an updated review on pathophysiology and management.

Intensive Care Med 2021 Aug 2;47(8):835-850. Epub 2021 Jul 2.

Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven University, Herestraat 49, B3000, Leuven, Belgium.

Acute kidney injury (AKI) is now recognized as a heterogeneous syndrome that not only affects acute morbidity and mortality, but also a patient's long-term prognosis. In this narrative review, an update on various aspects of AKI in critically ill patients will be provided. Focus will be on prediction and early detection of AKI (e.g., the role of biomarkers to identify high-risk patients and the use of machine learning to predict AKI), aspects of pathophysiology and progress in the recognition of different phenotypes of AKI, as well as an update on nephrotoxicity and organ cross-talk. In addition, prevention of AKI (focusing on fluid management, kidney perfusion pressure, and the choice of vasopressor) and supportive treatment of AKI is discussed. Finally, post-AKI risk of long-term sequelae including incident or progression of chronic kidney disease, cardiovascular events and mortality, will be addressed.
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http://dx.doi.org/10.1007/s00134-021-06454-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249842PMC
August 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 May 11. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
May 2021

Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom.

Intensive Care Med 2021 05 11;47(5):549-565. Epub 2021 May 11.

Brain & Behaviour Lab, Dept. Of Computing, Imperial College London, London, UK.

Purpose: The trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions.

Methods: We included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget ( https://www.CovidUK.ICU ).

Results: Data for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO/FiO on the day of death was 12.3(8.9-18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO/FiO in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06-1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17-2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04-1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99-1.79]; P = 0.057) immediately prior to application of prone positioning were associated with lack of oxygenation response. Prone positioning was not applied to 76% of patients with moderate hypoxemia and 45% of those with severe hypoxemia and patients who died without receiving proning interventions had more missed opportunities for prone intervention [7 (3-15.5) versus 2 (0-6); P < 0.001]. Despite the severity of gas exchange deficit, most patients received lung-protective ventilation with tidal volumes less than 8 mL/kg and plateau pressures less than 30cmHO. This was despite systematic errors in measurement of height and derived ideal body weight.

Conclusions: Refractory hypoxaemia remains a major association with mortality, yet evidence based ARDS interventions, in particular prone positioning, were not implemented and had delayed application with an associated reduced responsiveness. Real-time service evaluation techniques offer opportunities to assess the delivery of care and improve protocolised implementation of evidence-based ARDS interventions, which might be associated with improvements in survival.
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http://dx.doi.org/10.1007/s00134-021-06389-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111053PMC
May 2021

Fluid balance-adjusted creatinine in diagnosing acute kidney injury in the critically ill.

Acta Anaesthesiol Scand 2021 May 7. Epub 2021 May 7.

Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Acute kidney injury (AKI) is often diagnosed based on plasma creatinine (Cr) only. Adjustment of Cr for cumulative fluid balance due to potential dilution of Cr and subsequently missed Cr-based diagnosis of AKI has been suggested, albeit the physiological rationale for these adjustments is questionable. Furthermore, whether these adjustments lead to a different incidence of AKI when used in conjunction with urine output (UO) criteria is unknown.

Methods: This was a post hoc analysis of the Finnish Acute Kidney Injury study. Hourly UO and daily plasma Cr were measured during the first 5 days of intensive care unit admission. Cr values were adjusted following the previously used formula and combined with the UO criteria. Resulting incidences and mortality rates were compared with the results based on unadjusted values.

Results: In total, 2044 critically ill patients were analyzed. The mean difference between the adjusted and unadjusted Cr of all 7279 observations was 5 (±15) µmol/L. Using adjusted Cr in combination with UO and renal replacement therapy criteria resulted in the diagnosis of 19 (1%) additional AKI patients. The absolute difference in the incidence was 0.9% (95% confidence interval [CI]: 0.3%-1.6%). Mortality rates were not significantly different between the reclassified AKI patients using the full set of Kidney Disease: Improving Global Outcomes criteria.

Conclusion: Fluid balance-adjusted Cr resulted in little change in AKI incidence, and only minor differences in mortality between patients who changed category after adjustment and those who did not. Using adjusted Cr values to diagnose AKI does not seem worthwhile in critically ill patients.
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http://dx.doi.org/10.1111/aas.13841DOI Listing
May 2021

Emergency hospital admissions associated with non-communicable diseases 1998-2018 in England, Wales and Scotland: an ecological study.

Clin Med (Lond) 2021 03;21(2):e179-e185

The Royal London Hospital, London, UK and William Harvey Research Institute, London, UK.

Background: Non-communicable diseases (NCDs) are increasingly prevalent and were responsible for 40.5 million deaths (71%) globally in 2016. We examined the number of NCD-related emergency hospital admissions during the years 1998 to 2018 in the UK.

Methods: Demographic features for those admitted as an emergency with NCDs as their primary diagnosis were collated for all admissions in England, Wales and Scotland. NCDs recorded as secondary diagnoses for all admissions in England from 2012 to 2018 were additionally recorded.

Results: We identified 120,662,155 emergency episodes of care. From 1998 to 2018 there was an increase from 1,416,233 to 1,892,501 in annual emergency admissions due to NCDs. This, however, represented a fall in the proportion of NCD among all emergency admissions, from 33.4% to 26.9%. Mean age of all patients admitted increased from 46.3 to 53.8 years.

Conclusion: Despite a fall in proportion of NCD admissions, the population acutely admitted to hospital was increasingly elderly and increasingly comorbid.
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http://dx.doi.org/10.7861/clinmed.2020-0830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002810PMC
March 2021

Ethnicity and outcomes in patients hospitalised with COVID-19 infection in East London: an observational cohort study.

BMJ Open 2021 01 17;11(1):e042140. Epub 2021 Jan 17.

William Harvey Research Institute, Queen Mary University of London, London, UK, EC1M 6BQ.

Objective: To describe outcomes within different ethnic groups of a cohort of hospitalised patients with confirmed COVID-19 infection. To quantify and describe the impact of a number of prognostic factors, including frailty and inflammatory markers.

Setting: Five acute National Health Service Hospitals in east London.

Design: Prospectively defined observational study using registry data.

Participants: 1737 patients aged 16 years or over admitted to hospital with confirmed COVID-19 infection between 1 January and 13 May 2020.

Main Outcome Measures: The primary outcome was 30-day mortality from time of first hospital admission with COVID-19 diagnosis during or prior to admission. Secondary outcomes were 90-day mortality, intensive care unit (ICU) admission, ICU and hospital length of stay and type and duration of organ support. Multivariable survival analyses were adjusted for potential confounders.

Results: 1737 were included in our analysis of whom 511 had died by day 30 (29%). 538 (31%) were from Asian, 340 (20%) black and 707 (40%) white backgrounds. Compared with white patients, those from minority ethnic backgrounds were younger, with differing comorbidity profiles and less frailty. Asian and black patients were more likely to be admitted to ICU and to receive invasive ventilation (OR 1.54, (95% CI 1.06 to 2.23); p=0.023 and OR 1.80 (95% CI 1.20 to 2.71); p=0.005, respectively). After adjustment for age and sex, patients from Asian (HR 1.49 (95% CI 1.19 to 1.86); p<0.001) and black (HR 1.30 (95% CI 1.02 to 1.65); p=0.036) backgrounds were more likely to die. These findings persisted across a range of risk factor-adjusted analyses accounting for major comorbidities, obesity, smoking, frailty and ABO blood group.

Conclusions: Patients from Asian and black backgrounds had higher mortality from COVID-19 infection despite controlling for all previously identified confounders and frailty. Higher rates of invasive ventilation indicate greater acute disease severity. Our analyses suggest that patients of Asian and black backgrounds suffered disproportionate rates of premature death from COVID-19.
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http://dx.doi.org/10.1136/bmjopen-2020-042140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813387PMC
January 2021

Long-term outcomes following vehicle trauma related acute kidney injury requiring renal replacement therapy: a nationwide population study.

Sci Rep 2020 11 25;10(1):20572. Epub 2020 Nov 25.

Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Zhong-Zheng District, Taipei, 100, Taiwan.

Acute kidney injury (AKI) is a frequent complication of traumatic injury; however, long-term outcomes such as mortality and end-stage kidney disease (ESKD) have been rarely reported in this important patient population. We compared the long-term outcome of vehicle-traumatic and non-traumatic AKI requiring renal replacement therapy (AKI-RRT). This nationwide cohort study used data from the Taiwan National Health Insurance Research Database. Vehicle-trauma patients who were suffered from vehicle accidents developing AKI-RRT during hospitalization were identified, and matching non-traumatic AKI-RRT patients were identified between 2000 and 2010. The incidences of ESKD, 30-day, and long-term mortality were evaluated, and clinical and demographic associations with these outcomes were identified using Cox proportional hazards regression models. 546 vehicle-traumatic AKI-RRT patients, median age 47.6 years (interquartile range: 29.0-64.3) and 76.4% male, were identified. Compared to non-traumatic AKI-RRT, vehicle-traumatic AKI-RRT patients had longer length of stay in hospital [median (IQR):15 (5-34) days vs. 6 (3-11) days; p < 0.001). After propensity matching with non-traumatic AKI-RRT cases with similar demographic and clinical characteristics. Vehicle-traumatic AKI-RRT patients had lower rates of long-term mortality (adjusted hazard ratio (HR), 0.473; 95% CI, 0.392-0.571; p < 0.001), but similar rates of ESKD (HR, 1.166; 95% CI, 0.829-1.638; p = 0.377) and short-term risk of death (HR, 1.134; 95% CI, 0.894-1.438; p = 0.301) as non-traumatic AKI-RRT patients. In competing risk models that focused on ESKD, vehicle-traumatic AKI-RRT patients were associated with lower ESKD rates (HR, 0.552; 95% CI, 0.325-0.937; p = 0.028) than non-traumatic AKI-RRT patients. Despite severe injuries, vehicle-traumatic AKI-RRT patients had better long-term survival than non-traumatic AKI-RRT patients, but a similar risk of ESKD. Our results provide a better understanding of long-term outcomes after vehicle-traumatic AKI-RRT.
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http://dx.doi.org/10.1038/s41598-020-77556-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689526PMC
November 2020

Socioeconomic deprivation and long-term outcomes after elective surgery: analysis of prospective data from two observational studies.

Br J Anaesth 2021 Mar 18;126(3):642-651. Epub 2020 Nov 18.

Centre for Perioperative Medicine, Department of Targeted Intervention, UK; Surgical Outcomes Research Centre, University College London, London, UK; Health Services Research Centre, National Institute of Academic Anaesthesia, London, UK.

Background: Socioeconomic deprivation is associated with health inequalities. We explored relationships between socioeconomic group and outcomes after elective surgery in the UK National Health Service (NHS).

Methods: We combined data from two observational studies in 115 NHS hospitals and determined socioeconomic group using the Index of Multiple Deprivation (IMD) quintiles based on place of residence. Postoperative complications and 3-yr survival were assessed using logistic and Cox regression. Univariate analyses were adjusted for age differences between IMD quintiles. Multivariable analyses were used to account for other baseline risk factors including sex and comorbid disease. Results are reported as n (%), hazard ratios (HR) or odds ratios (OR) with 95% confidence intervals.

Results: Postoperative complications developed in 971/9051 patients (10.7%) and 1597/9043 patients (17.7%) died within 3 yr. Complication rates increased with deprivation (reference group least-deprived IMD5): IMD1 (OR=1.44 [1.17-1.78]; P<0.001), IMD2 (OR=1.38 [1.12-1.70]; P<0.01), IMD3 (OR=1.09 [0.88-1.35]: P=0.44), IMD4 (OR=0.89 [0.71-1.11]; P=0.30). More patients from the most deprived quintile died (IMD1) (n=349, 18.8%) compared with the least deprived (IMD5) (n=297, 15.9%) with a trend across the socioeconomic spectrum (P=0.01). After age adjustment, patients in the most deprived areas experienced reduced 3-yr survival: IMD1 (HR=1.43 [1.23-1.67]; P<0.0001), IMD2 (HR=1.35 [1.15-1.57]; P<0.001), IMD3 (HR=1.04 [0.89-1.23]; P=0.60), and IMD4 (HR=1.11 [0.95-1.30]; P=0.19). This finding persisted in risk-adjusted analyses. Increased complication rates only partially explained this reduced survival.

Conclusions: Socioeconomic deprivation is associated with worse long-term outcomes after elective surgery. This risk factor should be considered when planning perioperative care for patients from deprived areas.
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http://dx.doi.org/10.1016/j.bja.2020.10.019DOI Listing
March 2021

Prognostic association of routinely measured biomarkers in patients admitted to critical care: a systematic review.

Biomarkers 2021 Feb 5;26(1):1-12. Epub 2020 Nov 5.

Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS Trust, London, UK.

Purpose: To examine reported prognostic associations of routine blood measurements in the intensive care unit.

Materials And Methods: We searched PubMed, EMBASE through 28 May 2020 to identify all studies in adult critical care investigating associations between parameters measured routinely in whole blood, plasma or serum, and length of stay or mortality. Registration: PROSPERO; CRD42019122058.

Results: A total of 128 studies, reporting 28 different putative prognostic biomarkers, met eligibility criteria. Those most frequently examined were red cell distribution width, neutrophil-to-lymphocyte ratio, C-reactive protein, and platelet count. A higher red cell distribution width, a lower platelet count, and a higher neutrophil-to-lymphocyte ratio were consistently associated with both increased mortality and length of stay. A lower level of albumin was consistently associated with greater mortality. C-reactive protein was inconsistent. Most studies (n = 110) used regression modelling with wide variation in variable selection and covariate-adjustment; none externally validated the proposed predictive models.

Conclusions: Simple regression models have so far proved inadequate for the complexity of data available from routine blood sampling in critical care. Adoption of a direct causal framework may help better assess mechanistic processes, aid design of future studies, and guide clinical decision making using routine data.
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http://dx.doi.org/10.1080/1354750X.2020.1842498DOI Listing
February 2021

Variability in Serum Sodium Concentration and Prognostic Significance in Severe Traumatic Brain Injury: A Multicenter Observational Study.

Neurocrit Care 2021 06 2;34(3):899-907. Epub 2020 Oct 2.

Intensive Care Unit, Royal Melbourne Hospital, Level 5, B Block, Parkville, VIC, 3050, Australia.

Background/objective: Dysnatremia is common in severe traumatic brain injury (TBI) patients and may contribute to mortality. However, serum sodium variability has not been studied in TBI patients. We hypothesized that such variability would be independently associated with mortality.

Methods: We collected 6-hourly serum sodium levels for the first 7 days of ICU admission from 240 severe TBI patients in 14 neurotrauma ICUs in Europe and Australia. We evaluated the association between daily serum sodium standard deviation (dNa), an index of variability, and 28-day mortality.

Results: Patients were 46 ± 19 years of age with a median initial GCS of 6 [4-8]. Overall hospital mortality was 28%. Hypernatremia and hyponatremia occurred in 64% and 24% of patients, respectively. Over the first 7 days in ICU, serum sodium standard deviation was 2.8 [2.0-3.9] mmol/L. Maximum daily serum sodium standard deviation (dNa) occurred at a median of 2 [1-4] days after admission. There was a significant progressive decrease in dNa over the first 7 days (coefficient - 0.15 95% CI [- 0.18 to - 0.12], p < 0.001). After adjusting for baseline TBI severity, diabetes insipidus, the use of osmotherapy, the occurrence of hypernatremia, and hyponatremia and center, dNa was significantly independently associated with 28-day mortality (HR 1.27 95% CI (1.01-1.61), p = 0.048).

Conclusions: Our study demonstrates that daily serum sodium variability is an independent predictor of 28-day mortality in severe TBI patients. Further prospective investigations are necessary to confirm the significance of sodium variability in larger cohorts of TBI patients and test whether attenuating such variability confers outcome benefits to such patients.
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http://dx.doi.org/10.1007/s12028-020-01118-8DOI Listing
June 2021

Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.

Kidney Int 2020 08 26;98(2):294-309. Epub 2020 Apr 26.

Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address:

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address.
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http://dx.doi.org/10.1016/j.kint.2020.04.020DOI Listing
August 2020

Acute kidney injury and adverse outcomes of critical illness: correlation or causation?

Clin Kidney J 2020 Apr 18;13(2):133-141. Epub 2019 Nov 18.

Critical Care and Perioperative Medicine Research Group, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK.

Critically ill patients who develop acute kidney injury (AKI) are more than twice as likely to die in hospital. However, it is not clear to what extent AKI is the cause of excess mortality, or merely a correlate of illness severity. The Bradford Hill criteria for causality (plausibility, temporality, magnitude, specificity, analogy, experiment & coherence, biological gradient and consistency) were applied to assess the extent to which AKI may be causative in adverse short-term outcomes of critical illness. Plausible mechanisms exist to explain increased risk of death after AKI, both from direct pathophysiological effects of renal dysfunction and mechanisms of organ cross-talk in multiple-organ failure. The temporal relationship between increased mortality following AKI is consistent with its pathophysiology. AKI is associated with substantially increased mortality, an association that persists after accounting for known confounders. A biological gradient exists between increasing severity of AKI and increasing short-term mortality. This graded association shares similar features to the increased mortality observed in ARDS; an analogous condition with a multifactorial aetiology. Evidence for the outcomes of AKI from retrospective cohort studies and experimental animal models is coherent however both of these forms of evidence have intrinsic biases and shortcomings. The relationship between AKI and risk of death is maintained across a range of patient ages, comorbidities and underlying diagnoses. In conclusion many features of the relationship between AKI and short-term mortality suggest causality. Prevention and mitigation of AKI and its complications are valid targets for studies seeking to improve short-term survival in critical care.
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http://dx.doi.org/10.1093/ckj/sfz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147312PMC
April 2020

Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study.

Intensive Care Med 2020 05 6;46(5):943-953. Epub 2020 Feb 6.

Department of Medicine, Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA, 92161, USA.

Purpose: The aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI).

Methods: The RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724).

Results: 364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C-C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78-0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75.

Conclusion: Elevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.
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http://dx.doi.org/10.1007/s00134-019-05919-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210248PMC
May 2020

The role of goal-directed therapy in the prevention of acute kidney injury after major gastrointestinal surgery: Substudy of the OPTIMISE trial.

Eur J Anaesthesiol 2019 12;36(12):924-932

From the Department of Peri-operative Medicine and Pain, Royal London Hospital, London, UK (NM), UCD School of Medicine (PTM, PD), Clinical Research Centre, UCD School of Medicine, University College Dublin, Dublin, Ireland (RI) and William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK (RMP, JRP).

Background: Acute kidney injury (AKI) is an important adverse outcome after major surgery. Peri-operative goal-directed haemodynamic therapy (GDT) may improve outcomes by reducing complications such as AKI.

Objective: To determine if GDT was associated with a reduced incidence of postoperative AKI according to specific renal biomarkers.

Design: Prospective substudy of the OPTIMISE trial, a multicentre randomised controlled trial comparing peri-operative GDT to usual patient care.

Setting: Four UK National Health Service hospitals.

Patients: A total of 287 high-risk patients aged at least 50 years undergoing major gastrointestinal surgery.

Outcome Measures: The primary outcome measure was AKI defined as urinary neutrophil gelatinase-associated lipase (NGAL) at least 150 ng ml 24 and 72 h after surgery. Secondary outcomes were between-group differences in NGAL measurements and NGAL : creatinine ratios 24 and 72 h after surgery and AKI stage 2 or greater according to Kidney Disease Improving Global Outcomes (KDIGO) criteria within 30 days of surgery.

Results: In total, 20 of 287 patients (7%) experienced postoperative AKI of KDIGO grade 2 or 3 within 30 days. The proportion of patients with urinary NGAL at least 150 ng ml 24 or 72 h after surgery was similar in the two groups [GDT 31/144 (21.5%) patients vs. usual patient care 28/143 (19.6%) patients; P = 0.88]. Absolute values of urinary NGAL were also similar at 24 h (GDT 53.5 vs. usual patient care 44.1 ng ml; P = 0.38) and 72 h (GDT 45.1 vs. usual patient care 41.1 ng ml; P = 0.50) as were urinary NGAL : creatinine ratios at 24 h (GDT 45 vs. usual patient care 43 ng mg; P = 0.63) and 72 h (GDT 66 vs. usual patient care 63 ng mg; P = 0.62). The incidence of KDIGO-defined AKI was also similar between the groups [GDT 9/144 (6%) patients vs. usual patient care 11/143 (8%) patients; P = 0.80].

Conclusion: In this trial, GDT did not reduce the incidence of AKI amongst high-risk patients undergoing major gastrointestinal surgery. This may reflect improving standards in usual patient care.

Trial Registration: OPTIMISE Trial Registration ISRCTN04386758.
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http://dx.doi.org/10.1097/EJA.0000000000001104DOI Listing
December 2019

Elevated urea-to-creatinine ratio provides a biochemical signature of muscle catabolism and persistent critical illness after major trauma.

Intensive Care Med 2019 12 17;45(12):1718-1731. Epub 2019 Sep 17.

Critical Care and Perioperative Medicine Research Group, Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS Trust, Whitechapel Road, London, E1 1BB, UK.

Purpose: Muscle wasting is common amongst patients with persistent critical illness and associated with increased urea production, but reduced creatinine production. We hypothesised that elevated urea:creatinine ratio would provide a biochemical signature of muscle catabolism and characterise prolonged intensive care (ICU) admissions after major trauma.

Methods: Using pre-specified hypotheses, we analysed two existing data sets of adults surviving ≥ 10 days following admission to ICU after major trauma. We analysed trauma-ICU admissions to the major trauma centre serving the North East London and Essex Trauma Network, with a verification cohort of trauma-ICU cases from the MIMIC-III database. We compared serum urea, creatinine, and urea:creatinine ratio (ratio of concentrations in mmol/L) between patients with persistent critical illness (defined as ICU stay of ≥ 10 days) and those discharged from ICU before day 10. In a sub-group undergoing sequential abdominal computerised tomography (CT), we measured change in cross-sectional muscle area (psoas muscle at L4 vertebral level and total muscle at L3 level) and assessed for relationships with urea:creatinine ratio and ICU stay. Results are provided as median [interquartile range].

Results: We included 1173 patients between February 1st, 2012 and May 1st, 2016. In patients with ICU stay ≥ 10 days, day 10 urea:creatinine ratio had increased by 133% [72-215], from 62 [46-78] to 141 [114-178], p < 0.001; this rise was larger (p < 0.001) than in patients discharged from ICU before day 10, 59% [11-122%], 61 [45-75] to 97 [67-128], p < 0.001. A similar separation in trajectory of urea:creatinine ratio was observed in 2876 trauma-ICU admissions from MIMIC-III. In 107 patients undergoing serial CTs, decrease in L4 psoas and L3 muscle cross-sectional areas between CTs significantly correlated with time elapsed (R = 0.64 and R = 0.59, respectively). Rate of muscle decrease was significantly greater (p < 0.001 for interaction terms) in 53/107 patients with the second CT during evolving, current or recent persistent critical illness. In this group, at the second CT urea:creatinine ratio negatively correlated with L4 psoas and L3 muscle cross-sectional areas (R 0.39, p < 0.001 and 0.44, p < 0.001).

Conclusion: Elevated urea:creatinine ratio accompanies skeletal muscle wasting representing a biochemical signature of persistent critical illness after major trauma. If prospectively confirmed, urea:creatinine ratio is a potential surrogate of catabolism to examine in epidemiological and interventional studies.
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http://dx.doi.org/10.1007/s00134-019-05760-5DOI Listing
December 2019

Managing Chloride and Bicarbonate in the Prevention and Treatment of Acute Kidney Injury.

Semin Nephrol 2019 09;39(5):473-483

Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; Department of Renal Medicine and Transplantation, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom. Electronic address:

Intravenous crystalloid therapy is one of the most ubiquitous aspects of hospital and critical care medicine. In recent years, there has been increasing focus on the electrolyte composition, and particularly chloride content, of crystalloid solutions. This has led to increasing clinical adoption of balanced solutions, containing substrates for bicarbonate generation and consequently a lower chloride content, in place of 0.9% saline. In this article we review the physiochemical rationale for avoidance of 0.9% saline and the effects of hyperchloremic acidosis on renal physiology. Finally, we review the current evidence and rationale for use of balanced solutions greater than 0.9% saline in acutely ill patients in a variety of clinical settings, as well as considering the role for sodium bicarbonate in preventing or correcting metabolic acidosis. In conclusion, there is a strong physiological rationale for avoidance of iatrogenic hyperchloremic acidosis from 0.9% saline administration in acutely unwell patients and an association with adverse renal outcomes in several studies. However, evidence from large definitive multicenter randomized trials is not yet available to establish the dose-relationship between 0.9% saline administration and potential harm and inform us if some 0.9% saline use is acceptable or if any exposure confers harm.
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http://dx.doi.org/10.1016/j.semnephrol.2019.06.007DOI Listing
September 2019

Introduction: Acute Kidney Injury Management in 2019: Somethings Old Somethings New.

Authors:
John R Prowle

Semin Nephrol 2019 09;39(5):419-420

Adult Critical Care Unit Department of Renal Medicine and Transplantation The Royal London Hospital, Barts Health NHS Trust London, UK; William Harvey Research Institute Queen Mary University of London London, UK.

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http://dx.doi.org/10.1016/j.semnephrol.2019.06.001DOI Listing
September 2019

Trauma-associated acute kidney injury.

Curr Opin Crit Care 2019 12;25(6):565-572

Adult Critical Care Unit, Royal London Hospital, Barts Health NHS Trust.

Purpose Of Review: A summary of recent research into the epidemiology, cause, management and outcomes of trauma-associated acute kidney injury (AKI). There is an increasing focus on subtypes of AKI to better target clinical management and future research.

Recent Findings: AKI associated with trauma occurs in 20-24% of patients admitted to ICU. On the basis of creatinine and/or urine output, AKI occurs in the first few days of traumatic illness. Although various associations have been identified, shock and high-volume blood transfusion are the most consistent risks for development of trauma-associated AKI. Short-term outcomes appear worse for patients with AKI, but extent of longer term kidney function recovery remains unknown. Recent research in the general critical care population is beginning to better inform AKI management; however, currently, preventive and supportive strategies remain the mainstay of AKI management after trauma.

Summary: Well-designed, prospective research is required to better understand the phenotype, pathophysiology and recovery trajectory of trauma-associated AKI. Only then can potentially unique therapeutic targets be developed for this common subtype of AKI.
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http://dx.doi.org/10.1097/MCC.0000000000000655DOI Listing
December 2019

Early Osmotherapy in Severe Traumatic Brain Injury: An International Multicenter Study.

J Neurotrauma 2020 01 10;37(1):178-184. Epub 2019 Sep 10.

Intensive Care Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.

The optimal osmotic agent to treat intracranial hypertension in patients with severe traumatic brain injury (TBI) remains uncertain. We aimed to test whether the choice of mannitol or hypertonic saline (HTS) as early (first 96 h) osmotherapy in these patients might be associated with a difference in mortality. We retrospectively analyzed data from 2015 from 14 tertiary intensive care units (ICUs) in Australia, UK, and Europe treating severe TBI patients with intracranial pressure (ICP) monitoring and compared mortality in those who received mannitol only versus HTS only. We performed multi-variable analysis adjusting for site and illness severity (Injury Severity Score, extended IMPACT score, and mean ICP over the first 96 h) using Cox proportional hazards regression. We collected data on 262 patients and compared patients who received early osmotherapy with mannitol alone ( = 46) with those who received HTS alone ( = 46). Mannitol patients were older (median age, 49.2 (19.2) vs. 40.5 (16.8) years;  = 0.02), with higher Injury Severity Scores (42 (15.9) vs. 32.1 [11.3];  = 0.001), and IMPACT-TBI predicted 6-month mortality (34.5% [23-46] vs. 25% [13-38];  = 0.02), but had similar APACHE-II scores, and mean and maximum ICPs over the first 96 h. The unadjusted hazard ratio for in-hospital mortality in patients receiving only mannitol was 3.35 (95% confidence interval [CI], 1.60-7.03;  = 0.001). After adjustment for key mortality predictors, the hazard ratio for in-hospital mortality in patients receiving only mannitol was 2.64 (95% CI, 0.96-7.30;  = 0.06). The choice of early osmotherapy in severe TBI patients may affect survival, or simply reflect clinician beliefs about their different roles, and warrants controlled investigation.
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http://dx.doi.org/10.1089/neu.2019.6399DOI Listing
January 2020

Deserved attention for acute kidney injury after major trauma.

Intensive Care Med 2019 06 23;45(6):907-908. Epub 2019 Apr 23.

Renal Research Group Ullevål, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

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http://dx.doi.org/10.1007/s00134-019-05609-xDOI Listing
June 2019

Acute Kidney Injury and Risk of Death After Elective Surgery: Prospective Analysis of Data From an International Cohort Study.

Anesth Analg 2019 05;128(5):1022-1029

From the William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.

Background: Postoperative acute kidney injury (AKI) is associated with a high mortality rate. However, the relationship among AKI, its associations, and mortality is not well understood.

Methods: Planned analysis of data was collected during an international 7-day cohort study of adults undergoing elective in-patient surgery. AKI was defined using Kidney Disease Improving Global Outcomes criteria. Patients missing preoperative creatinine data were excluded. We used multivariable logistic regression to examine the relationships among preoperative creatinine-based estimated glomerular filtration rate (eGFR), postoperative AKI, and hospital mortality, accounting for the effects of age, major comorbid diseases, and nature and severity of surgical intervention on outcomes. We similarly modeled preoperative associations of AKI. Data are presented as n (%) or odds ratios (ORs) with 95% confidence intervals.

Results: A total of 36,357 patients were included, 743 (2.0%) of whom developed AKI with 73 (9.8%) deaths in hospital. AKI affected 73 of 196 (37.2%) of all patients who died. Mortality was strongly associated with the severity of AKI (stage 1: OR, 2.57 [1.3-5.0]; stage 2: OR, 8.6 [5.0-15.1]; stage 3: OR, 30.1 [18.5-49.0]). Low preoperative eGFR was strongly associated with AKI. However, in our model, lower eGFR was not associated with increasing mortality in patients who did not develop AKI. Conversely, in older patients, high preoperative eGFR (>90 mL·minute·1.73 m) was associated with an increasing risk of death, potentially reflecting poor muscle mass.

Conclusions: The occurrence and severity of AKI are strongly associated with risk of death after surgery. However, the relationship between preoperative renal function as assessed by serum creatinine-based eGFR and risk of death dependent on patient age and whether AKI develops postoperatively.
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http://dx.doi.org/10.1213/ANE.0000000000003923DOI Listing
May 2019

The incidence and associations of acute kidney injury in trauma patients admitted to critical care: A systematic review and meta-analysis.

J Trauma Acute Care Surg 2019 01;86(1):141-147

From the Adult Critical Care Unit (R.Y.H., A.J.F., C.J.K., J.R.P.), The Royal London Hospital, Barts Health NHS Trust; William Harvey Research Institute (R.W.H., A.J.F., C.J.K., J.R.P.), Queen Mary University of London; and Department of Renal Medicine and Transplantation (C.J.K., J.R.P.), The Royal London Hospital, Barts Health, NHS Trust, London, United Kingdom.

Background: As more patients are surviving the initial effects of traumatic injury clinicians are faced with managing the systemic complications of severe tissue injury. Of these, acute kidney injury (AKI) may be a sentinel complication contributing to adverse outcomes.

Objective: To establish the incidence of AKI in patients admitted to critical care after major trauma, to explore any risk factors and to evaluate the association of AKI with outcomes.

Data Sources: Systematic search of MEDLINE, Excerpta Medica database and Cochrane library from January 2004 to April 2018.

Study Selection: Studies of adult major trauma patients admitted to critical care that applied consensus AKI criteria (risk injury failure loss end stage [RIFLE], AKI network, or kidney disease improving global outcomes) and reported clinical outcomes were assessed (PROSPERO Registration: CRD42017056781). Of the 35 full-text articles selected from the screening, 17 (48.6%) studies were included.

Data Extraction And Synthesis: We followed the PRISMA guidelines and study quality was assessed using the Newcastle-Ottawa score. The pooled incidence of AKI and relative risk of death were estimated using random-effects models.

Main Outcomes And Measures: Incidence of AKI was the primary outcome. The secondary outcome was study-defined mortality.

Results: We included 17 articles describing AKI outcomes in 24,267 trauma patients. The pooled incidence of AKI was 20.4% (95% confidence interval [CI], 16.5-24.9). Twelve studies reported the breakdown of stages of AKI with 55.7% of patients classified as RIFLE-R or stage 1, 30.3% as RIFLE-I or stage 2, and 14.0% as RIFLE-F or stage 3. The pooled relative risk of death with AKI compared was 3.6 (95% CI, 2.4-5.3). In addition, there was a concordant increase in odds of death among six studies that adjusted for multiple variables (adjusted odds ratio, 2.7; 95% CI, 1.9-3.8; p = <0.01).

Conclusion: Acute kidney injury is common after major trauma and associated with increased mortality. Future research is warranted to reduce the potential for harm associated with this subtype of AKI.

Level Of Evidence: Systematic review and meta-analysis, level III.
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http://dx.doi.org/10.1097/TA.0000000000002085DOI Listing
January 2019

Continuous renal replacement therapy: individualization of the prescription.

Curr Opin Crit Care 2018 12;24(6):443-449

Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS Trust.

Purpose Of Review: Continuous renal replacement therapy (CRRT) is now the mainstay of renal organ support in the critically ill. As our understanding of CRRT delivery and its impact on patient outcomes improves there is a focus on researching the potential benefits of tailored, patient-specific treatments to meet dynamic needs.

Recent Findings: The most up-to-date studies investigating aspects of CRRT prescription that can be individualized: CRRT dose, timing, fluid management, membrane selection, anticoagulation and vascular access are reviewed. The use of different doses of CRRT lack conventional high-quality evidence and importantly studies reveal variation in assessment of dose delivery. Research reveals conflicting evidence for clinicians in distinguishing which patients will benefit from 'watchful waiting' vs. early initiation of CRRT. Both dynamic CRRT dosing and precision fluid management using CRRT are difficult to investigate and currently only observational data supports individualization of prescriptions. Similarly, individualization of membrane choice is largely experimental.

Summary: Clinicians have limited evidence to individualize the prescription of CRRT. To develop this, we need to understand the requirements for renal support for individual patients, such as electrolyte imbalance, fluid overload or clearance of systemic inflammatory mediators to allow us to target these abnormalities in appropriately designed randomized trials.
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http://dx.doi.org/10.1097/MCC.0000000000000546DOI Listing
December 2018

Natriuretic Peptides: A Role in Early Septic Acute Kidney Injury?

Anesthesiology 2018 08;129(2):235-237

From the Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (N.A.) the Critical Care and Perioperative Medicine Research Group, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom (J.R.P.) the Adult Critical Care Unit and Department of Renal Medicine and Transplantation, The Royal London Hospital, Barts Health National Health Service Trust, London, United Kingdom (J.R.P.).

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http://dx.doi.org/10.1097/ALN.0000000000002307DOI Listing
August 2018

MicroRNAs in Acute Kidney Injury.

Nephron 2018 5;140(2):124-128. Epub 2018 Jun 5.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

Background: It is increasingly recognised that improved diagnosis, prognosis and treatment of acute kidney injury (AKI) requires an understanding of distinct underling cellular and molecular mechanisms (endotypes) that may distinguish overtly similar clinical AKI presentations. One important avenue of research is the post-transcriptional regulation of gene expression in response to kidney injury mediated by microRNAs.

Summary: This mini-review summarises the use of microRNAs as diagnostic and prognostic biomarkers in AKI. The contribution of microRNAs to the pathophysiology of AKI will be highlighted along with the potential for therapeutic applications. Key Messages: While there is great potential for a better understanding of AKI, microRNAs form a complex regulatory network. Understanding the role and significance of microRNAs in the context of AKI and critical illness is a major endeavour in translational medicine, requiring the integration of clinical and experimental data.
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http://dx.doi.org/10.1159/000490204DOI Listing
September 2019

Renal Blood Flow Measurement in Early Clinical Sepsis-Can You Catch a Shadow?

Authors:
John R Prowle

Crit Care Med 2018 06;46(6):1028-1030

Adult Critical Care Unit, The Royal London Hospital; Department of Renal Medicine and Transplantation, The Royal London Hospital, Barts Health NHS Trust; and William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.

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http://dx.doi.org/10.1097/CCM.0000000000003108DOI Listing
June 2018

Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II.

Crit Care Med 2018 06;46(6):949-957

The University of Melbourne, Melbourne, VIC, Australia Austin Hospital, Heidelberg, VIC, Australia Department of Intensive Care, Royal Melbourne Hospital, Melbourne, VIC, Australia.

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.
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http://dx.doi.org/10.1097/CCM.0000000000003092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959265PMC
June 2018

Acute Kidney Injury in Trauma Patients Admitted to Critical Care: Development and Validation of a Diagnostic Prediction Model.

Sci Rep 2018 02 26;8(1):3665. Epub 2018 Feb 26.

Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS Trust, Whitechapel Road, London, E1 1BB, UK.

Acute Kidney Injury (AKI) complicating major trauma is associated with increased mortality and morbidity. Traumatic AKI has specific risk factors and predictable time-course facilitating diagnostic modelling. In a single centre, retrospective observational study we developed risk prediction models for AKI after trauma based on data around intensive care admission. Models predicting AKI were developed using data from 830 patients, using data reduction followed by logistic regression, and were independently validated in a further 564 patients. AKI occurred in 163/830 (19.6%) with 42 (5.1%) receiving renal replacement therapy (RRT). First serum creatinine and phosphate, units of blood transfused in first 24 h, age and Charlson score discriminated need for RRT and AKI early after trauma. For RRT c-statistics were good to excellent: development: 0.92 (0.88-0.96), validation: 0.91 (0.86-0.97). Modelling AKI stage 2-3, c-statistics were also good, development: 0.81 (0.75-0.88) and validation: 0.83 (0.74-0.92). The model predicting AKI stage 1-3 performed moderately, development: c-statistic 0.77 (0.72-0.81), validation: 0.70 (0.64-0.77). Despite good discrimination of need for RRT, positive predictive values (PPV) at the optimal cut-off were only 23.0% (13.7-42.7) in development. However, PPV for the alternative endpoint of RRT and/or death improved to 41.2% (34.8-48.1) highlighting death as a clinically relevant endpoint to RRT.
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http://dx.doi.org/10.1038/s41598-018-21929-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827665PMC
February 2018
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