Objectives Hospital-acquired acute kidney injury (HA-AKI) is associated with a high risk of mortality. Prediction models or rules may identify those most at risk of HA-AKI. This study externally validated one of the few clinical prediction rules (CPRs) derived in a general medicine cohort using clinical information and data from an acute hospitals electronic system on admission: the acute kidney injury prediction score (APS). Design, setting and participants External validation in a single UK non-specialist acute hospital (2013?2015, 12?554 episodes); four cohorts: adult medical and general surgical populations, with and without a known preadmission baseline serum creatinine (SCr). Methods Performance assessed by discrimination using area under the receiver operating characteristic curves (AUCROC) and calibration. Results HA-AKI incidence within 7?days (kidney disease: improving global outcomes (KDIGO) change in SCr) was 8.1% (n=409) of medical patients with known baseline SCr, 6.6% (n=141) in those without a baseline, 4.9% (n=204) in surgical patients with baseline and 4% (n=49) in those without. Across the four cohorts AUCROC were: medical with known baseline 0.65 (95% CIs 0.62 to 0.67) and no baseline 0.71 (0.67 to 0.75), surgical with baseline 0.66 (0.62 to 0.70) and no baseline 0.68 (0.58 to 0.75). For calibration, in medicine and surgical cohorts with baseline SCr, Hosmer-Lemeshow p values were non-significant, suggesting acceptable calibration. In the medical cohort, at a cut-off of five points on the APS to predict HA-AKI, positive predictive value was 16% (13?18%) and negative predictive value 94% (93?94%). Of medical patients with HA-AKI, those with an APS e5 had a significantly increased risk of death (28% vs 18%, OR 1.8 (95% CI 1.1 to 2.9), p=0.015). Conclusions On external validation the APS on admission shows moderate discrimination and acceptable calibration to predict HA-AKI and may be useful as a severity marker when HA-AKI occurs. Harnessing linked data from primary care may be one way to achieve more accurate risk prediction.
Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D, Honore PM, Joannes-Boyau O, Joannidis M, Korhonen A-M, Lavrentieva A, Mehta RL, Palevsky P, Roessler E, Ronco C, Uchino S, Vazquez JA, Vidal Andrade E, Webb S, Kellum JA (2015) Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study,INTENSIVE CARE MEDICINE41(8)pp. 1411-1423
Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which
is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is
encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and
trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area
challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are
discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen
sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored.
Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the
blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance
against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of
novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the
development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this
common, multifactorial condition.
Perioperative interventions, targeted to increase global blood flow defined by explicit measured goals, reduce postoperative complications. Consequently, reliable non-invasive estimation of the cardiac output could have far-reaching benefit.
This study compared a non-invasive Doppler device ? the ultrasonic cardiac output monitor (USCOM) ? with the oesophageal Doppler monitor (ODM), on 25 patients during major abdominal surgery. Stroke volume was determined by USCOM (SVUSCOM) and ODM (SVODM) pre and post fluid challenges.
A e 10% change (?) SVUSCOM had a sensitivity of 94% and specificity of 88% to detect a e 10% ? SVODM; the area under the receiver operating curve was 0.94 (95% CI 0.90?0.99). Concordance was 98%, using an exclusion zone of <10% ? SVODM. 135 measurements gave median SVUSCOM 80 ml (interquartile range 65?93 ml) and SVODM 86 ml (69?100 ml); mean bias was 5.9 ml (limits of agreement ?20 to +30 ml) and percentage error 30%.
Following fluid challenges SVUSCOM showed good concordance and accurately discriminated a change e 10% in SVODM.
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2015 and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2015. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
Assessment of volume and hydration status is far from easy and therefore technology such as bioelectrical impedance vector analysis (BIVA) may complement our examination techniques. This study highlights the fact that clinical assessment of volume balance and BIVA may correlate, but whether the routine use of BIVA will avoid significant volume overload in the critically ill remains unknown. Further studies are
needed but at the moment appear a little way off.
The objective of this study was to externally
validate a clinical prediction rule (CPR)?the ?Shapiro
criteria??to predict bacteraemia in an acute medical
Prospectively collected data, retrospectively
evaluated over 11 months in an AMU in the UK. From
4810 admissions, 635 patients (13%) had blood
cultures (BCs) performed. The 100 cases of true
bacteraemia were compared with a randomly selected
sample of 100 control cases where BCs were sterile.
To predict bacteraemia (at a cut-off score of
two points), the Shapiro criteria had a sensitivity of 97%
(95% CIs 91% to 99%), specificity 37% (28% to 47%),
positive likelihood ratio 1.54 (1.3 to 1.8) and a negative
likelihood ratio of 0.08 (0.03 to 0.25). The area under
the receiver operating curve was 0.80 (0.74 to 0.86),
and the Hosmer?Lemeshow p value was 0.45.
A cut-off score of two points on the
Shapiro criteria had high sensitivity to predict
bacteraemia in a study of acute general medical
admissions. Application of the rule in patients being
considered for a BC could identify those at low risk of
bacteraemia. Though the model demonstrated good
discrimination, the lengthy number of variables (13)
and difficulty automating the CPR may limit its use.
Fluid therapy with saline is considered by some to confer a notable risk of acute kidney injury and mortality. However, data from the SPLIT trial ? the first large, randomized controlled trial to compare saline to a 'balanced' solution ? do not indicate any marked signal of harm in critically ill patients.
Postoperative increases in serum creatinine concentration, by amounts historically viewed as trivial, are associated with increased morbidity and mortality. Acute kidney injury is common, affecting one in ?ve patients admitted with acute medical disease and up to four in ?ve patients admitted to intensive care, of whom one in two have had operations. This review is focused principally on the identi?cation of patients at risk of acute kidney injury and the prevention of injury. In the main, there are no interventions that directly treat the damaged kidney. The
management of acute kidney injury is based on correction of dehy dration, hypotension, and urinary tract obstruction, stopping nephrotoxic drugs, giving antibiotics for bacterial infection, and commencing renal replacement therapy if necessary.
Acute kidney injury is a major health care problem. Improving recognition of those at risk and highlighting those who have developed AKI at an earlier stage remains a priority for research and clinical practice. Prediction models to risk-stratify patients and electronic alerts for AKI are two approaches that could address previously highlighted shortcomings in management and facilitate timely intervention. We describe and critique available prediction models and the effects of the use of AKI alerts on patient outcomes are reviewed. Finally, the potential for prediction models to enrich population subsets for other diagnostic approaches and potential research, including biomarkers of AKI, are discussed.
Sepsis-associated acute kidney injury (SA-AKI) is an independent predictor of increased mortality and morbidity. It is essential that further advances in the treatment of sepsis should prioritize targeted therapies in SA-AKI in order to improve these bleak outcomes. As yet, a unique therapy that effectively reduces the impact of acute kidney injury has not been demonstrated. However, the emergence of novel targeted therapies, perhaps in combination, has the possibility of significantly reducing the long-term sequelae of an episode of SA-AKI. In this review, we will focus on the shared etiology of these conditions and how this is managed with targeted therapy and finally the emerging novel therapies that may play an additional role to current treatment strategies.
There is increasing evidence that fluid overload and
acute kidney injury (AKI) are associated but the exact
cause-effect relationship remains unclear. Wang and
colleagues analysed patients admitted to 30 intensive
care units in China and found that fluid accumulation
was independently associated with an increased risk
of AKI and mortality. This commentary focuses on the
close pathophysiological link between AKI and fluid
overload and discusses the implications for clinical
practice. It outlines some of the challenges, including
the difficulty in diagnosing fluid overload reliably with
current methods, and stresses the importance of
personalised fluid therapy with physiological end-points
to avoid the deleterious effects of fluid overload.
The use of goal-directed therapy as part of an enhanced recovery programme is well established in terms of management of the modern high-risk surgical patient in order to reduce both morbidity and mortality. The mechanisms behind this improvement are debated, but a reduction in the development of post-operative complications including acute kidney injury may be relevant. A recent study examining this relationship has been reported and is discussed here.
Acute kidney injury (AKI) is associated with increased morbidity and mortality. Although there are many causes of AKI, it is known that patients undergoing high-risk surgery are known to be at significant risk. Although much effort has centred on the minimum arterial pressure needed to maintain renal perfusion, this tends to be based on relatively crude measures such as the mean arterial pressure (MAP), which is widely used as an index for the optimal blood pressure. The rationale behind maintaining MAP is to provide adequate organ perfusion, although this is difficult to assess other than by applying crude end-points. Recent studies have examined the progression of AKI as defined by the KDIGO criteria in terms of time-weighted average values for premorbid and within-ICU haemodynamic pressure-related parameters. Although principally performed on patients who had undergone cardiovascular surgery and who were on vasopressor support, some interesting results were obtained suggesting that crude MAP may not be an adequate target in AKI. In patients with AKI progression, greater observed deficits in mean perfusion pressure, diastolic arterial perfusion, and diastolic perfusion pressures were observed. This study may highlight potential modifiable risk factors for the prevention of progression of AKI, and hopefully translate into improved outcomes.
Oliguria is a common phenomenon that is found in hospitalized patients . Although a rapid reduction in urine excretion rate may reflect a precipitous fall in the glomerular filtration rate, in many cases it may not. Given the common physiological finding of oliguria, we explore the relationship between the functional biomarker of renal injury (oliguria) with the increasing number of markers of renal injury to see if this
combination may aid in risk stratification.
Traditionally, assessment of the cardiac output has been limited to theatre or the intensive care unit. However, non-invasive cardiac output estimation is now readily available, and its application may have wider benefit in the emergency setting. The non-invasive ultrasonic cardiac output monitor (USCOM) was investigated to determine its learning curve and inter-rater reliability. Four trainee operators each performed stroke volume measurements on 25 volunteers, compared to an experienced operator pre- and post-passive leg raise. Inter-rater reliability was then assessed on 24 acute emergency in-patients. Mean percentage difference in stroke volume decreased from 19% (95% confidence intervals 14?23) across volunteers 1?5, to 6% (4?8) for the last 5 volunteers scanned. Consequently, on acute emergency in-patients, excellent inter-rater reliability (Lin?s concordance correlation coefficient (Ác) 0.96 (0.92?0.98)) and agreement of a change e10% in stroke volume following passive leg raise on 23/24 cases were found. Following a training period of less than 5 h, USCOM stroke volume measurements demonstrated excellent inter-rater reliability.
There are numerous causes of a raised core temperature. A fever occurring in sepsis may be associated with a survival benefit. However, this is not the case for non-infective triggers. Where heat generation exceeds heat loss and the core temperature rises above that set by the hypothalamus, a combination of cellular, local, organ-specific, and systemic effects occurs and puts
the individual at risk of both short-term and long-term dysfunction which, if severe or sustained, may lead to death. This narrative review is part of a series that will outline the pathophysiology of pyrogenic and non-pyrogenic fever, concentrating primarily on the pathophysiology of non-septic causes.
The National Early Warning Score (NEWS), proposed as a standardised track and trigger system, may perform less well in acute exacerbation of COPD (AECOPD). This study externally validated NEWS and modifications (Chronic Respiratory Early Warning Score (CREWS) and Salford-NEWS) in AECOPD.
An observational cohort study (2012?2014, two UK acute medical units (AMUs)), compared AECOPD (2361 admissions, 942 individuals, International Statistical Classification of Diseases and Related Health Problems-10 J40?J44 codes) with AMU patients (37?109 admissions, 20?415 individuals).
In-hospital mortality prediction was done by admission NEWS, CREWS and Salford-NEWS assessed by discrimination (area under receiver operating characteristic curves (AUROCs)) and calibration (plots and Hosmer-Lemeshow (H-L) goodness-of-fit).
Median admission NEWS in AECOPD was 4 (IQR 2?6) versus 1 (0?3) in AMUs (pd0.001), despite mortality of 4.5% in both. AECOPD AUROCs were NEWS 0.74 (95% CI 0.66 to 0.82), CREWS 0.72 (0.63 to 0.80) and Salford-NEWS 0.62 (0.53 to 0.70). AMU NEWS AUROC was 0.77 (0.75 to 0.78). At threshold NEWS=5 for AECOPD (44% of admissions), positive predictive value (PPV) of death was 8% (5 to 11) and negative predictive value (NPV) was 98% (97 to 99) versus AMU patients PPV of 17% (16 to 19) and NPV of 97% (97 to 97). For NEWS in AECOPD H-L p value=0.202.
This first validation of the NEWS in AECOPD found modest discrimination to predict mortality. Lower specificity of NEWS in patients with AECOPD versus other AMU patients reflects acute and chronic respiratory physiological disturbance (including hypoxia), with resultant low PPV at NEWS=5. CREWS and Salford-NEWS, adjusting for chronic hypoxia, increased the specificity and PPV but there was no gain in discrimination.
Joannidis M., Druml W., Forni L.G., Groeneveld A.B.J., Honore P.M., Hoste E., Ostermann M., Oudemans?van Straaten H.M., Schetz M. (2017) Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: Expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine,Intensive Care Medicine43(6)pp. 730-749
Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and
To determine and update previous recommendations for the prevention of AKI, specifically the role of fluids, diuretics, inotropes, vasopressors/vasodilators, hormonal and nutritional interventions, sedatives, statins, remote ischaemic preconditioning and care bundles.
A systematic search of the literature was performed for studies published between 1966 and March 2017 using these potential protective strategies in adult patients at risk of AKI. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, exposure to potentially nephrotoxic drugs and radiocontrast. Clinical endpoints included incidence or grade of AKI, the need for renal replacement therapy and mortality. Studies were graded according to the international GRADE system.
We formulated 12 recommendations, 13 suggestions and seven best practice statements. The few strong recommendations with high-level evidence are mostly against the intervention in question (starches, low-dose dopamine, statins in cardiac surgery). Strong recommendations with lower-level evidence include controlled fluid resuscitation with crystalloids, avoiding fluid overload, titration of norepinephrine to a target MAP of 65?70 mmHg (unless chronic hypertension) and not using diuretics or levosimendan for kidney protection solely.
The results of recent randomised controlled trials have allowed the formulation of new recommendations and/or increase the strength of previous recommendations. On the other hand, in many domains the available evidence remains insufficient, resulting from the limited quality of the clinical trials and the poor reporting of kidney outcomes.
Chawla L.S., Bellomo R., Bihorac A., Goldstein S.L., Siew E.D., Bagshaw S.M., Bittleman D., Cruz D., Endre Z., Fitzgerald R.L., Forni L., Kane-Gill S.L., Hoste E., Koyner J., Liu K.D., MacEdo E., Mehta R., Murray P., Nadim M., Ostermann M., Palevsky P.M., Pannu N., Rosner M., Wald R., Zarbock A., Ronco C., Kellum J.A. (2017) Acute kidney disease and renal recovery: Consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup,Nature Reviews Nephrology13(4)pp. 241-257
Nature Publishing Group
Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.
Hospital-acquired acute kidney injury (HA-AKI) is associated with a high risk of mortality. Prediction models or rules may identify those most at risk of HA-AKI. This study externally validated one of the few clinical prediction rules (CPRs) derived in a general medicine cohort using clinical information and data from an acute hospitals electronic system on admission: the acute kidney injury prediction score (APS).
Design, setting and participants:
External validation in a single UK non-specialist acute hospital (2013?2015, 12 554 episodes); four cohorts: adult medical and general surgical populations, with and without a known preadmission baseline serum creatinine (SCr).
Performance assessed by discrimination using area under the receiver operating characteristic curves (AUCROC) and calibration.
HA-AKI incidence within 7 days (kidney disease: improving global outcomes (KDIGO) change in SCr) was 8.1% (n=409) of medical patients with known baseline SCr, 6.6% (n=141) in those without a baseline, 4.9% (n=204) in surgical patients with baseline and 4% (n=49) in those without. Across the four cohorts AUCROC were: medical with known baseline 0.65 (95% CIs 0.62 to 0.67) and no baseline 0.71 (0.67 to 0.75), surgical with baseline 0.66 (0.62 to 0.70) and no baseline 0.68 (0.58 to 0.75). For calibration, in medicine and surgical cohorts with
baseline SCr, Hosmer-Lemeshow p values were nonsignificant, suggesting acceptable calibration. In the medical cohort, at a cut-off of five points on the APS to predict HA-AKI, positive predictive value was 16% (13?18%) and negative predictive value 94% (93?94%). Of medical patients with HA-AKI, those with an APS e5 had a significantly increased risk of death (28% vs 18%, OR 1.8 (95% CI 1.1 to 2.9), p=0.015).
On external validation the APS on admission shows moderate discrimination and acceptable calibration to predict HA-AKI and may be useful as a severity marker when HA-AKI occurs. Harnessing linked data from primary care may be one way to achieve more accurate risk prediction.
It is now well over a decade since attempts at harmonization of acute renal failure into a definable entity termed acute kidney injury. This has led to several landmark studies outlining the epidemiology of acute kidney injury, particularly in the critically ill, as well as providing insights into the long-term effects of the syndrome. Despite the introduction of consensus definitions and improvement in recognition, this has not been translated into outcome benefits as yet. The introduction of novel biomarkers associated with renal damage was primarily aimed at aiding early recognition of acute kidney injury. We argue that, in the future, using biomarkers may not only alert to acute kidney injury but may direct therapy in a personalized fashion rather than a one-size-fits-all approach.
A growing body of evidence suggests
even small rises in serum creatinine (SCr) are of
considerable clinical relevance. Given that participants
in endurance events are exposed to potential (repeated)
renal insults, a systematic review was undertaken to
collate current evidence for acute kidney injury (AKI),
complicating such events.
A systematic review of studies and case
reports meeting inclusion criteria on Medline and
EMBASE (inception to October 2015). Included: studies
with markers of renal function before and after
endurance or ultraendurance events; case reports of
severe AKI. Two reviewers assessed risk of bias using
the Newcastle-Ottawa scale.
Eleven case report publications (n=27
individuals) of severe AKI, were retrieved, with risk
factors including systemic illness or nephrotoxic
medications usually identified. From 30 studies of
endurance and ultraendurance events, mean rise in SCr
was 29 (±12.3) mmol/L after marathon or
ultramarathon (17 studies, n=568 participants) events.
Where follow-up tests were conducted, SCr returned to
baseline within 48 hours. Rises in biomarkers suggest
potential parenchymal insult, rather than simply muscle
breakdown. However, evidence of long-term
deleterious effects is lacking.
Raised levels of SCr are reported
immediately after endurance events. It is not clear
whether this is either clinically significant, or if
repeated participation predisposes to long-term
sequelae. The aetiology of severe exercise-associated
AKI is usually multifactorial, with risk factors generally
identified in the rare cases reported. On-site
biochemistry, urine analysis and biomarkers of AKI
may help identify collapsed runners who are at
significant short-term risk and allow suitable follow-up.
Cameron L.K., Lei K., Smith S., Doyle N.L., Doyle J.F., Flynn K., Purchase N., Smith J., Chan K., Kamara F., Kidane N.G., Forni Lui G., Harrington D., Hampson G., Ostermann M. (2017) Vitamin D levels in critically ill patients with acute kidney injury: A protocol for a prospective cohort study (VID-AKI),BMJ Open7(7)016486
BMJ Publishing Group
Acute kidney injury (AKI) affects more than
50% of critically ill patients. The formation of calcitriol,
the active vitamin D metabolite, from the main inactive
circulating form, 25-hydroxyvitamin D (25(OH)D), occurs
primarily in the proximal renal tubules. This results in
a theoretical basis for reduction in levels of calcitriol
over the course of an AKI. Vitamin D deficiency is highly
prevalent in critically ill adults, and has been associated
with increased rates of sepsis, longer hospital stays and
increased mortality. The primary objective of this study is
to perform serial measurements of 25(OH)D and calcitriol
(1,25(OH)2D), as well as parathyroid hormone (PTH) and
fibroblast growth factor 23 (FGF23) levels, in critically
ill adult patients with and without AKI, and to determine
whether patients with AKI have significantly lower vitamin
D metabolite concentrations. The secondary objectives are
to describe dynamic changes in vitamin D metabolites,
PTH and FGF23 during critical illness; to compare vitamin
D metabolite concentrations in patients with AKI with and
without renal replacement therapy; and to investigate
whether there is an association between vitamin D status
Methods and analysis
230 general adult intensive care
patients will be recruited. The AKI arm will include 115
critically ill patients with AKI Kidney Disease Improving
Global Outcome stage II or stage III. The comparison group
will include 115 patients who require cardiovascular
or respiratory support, but who do not have AKI. Serial
measurements of vitamin D metabolites and associated
hormones will be taken on prespecified days. Patients will
be recruited from two large teaching Trusts in England.
Data will be analysed using standard statistical methods.
Ethics and dissemination
Ethical approval was obtained.
Upon completion, the study team will submit the study
report for publication in a peer-reviewed scientific journal
and for conference presentation.
Trial registration number NCT02869919; Pre-results.
Peng Z., Yu K., Ostermann M., Xi X., Hsu R., Vincent J.-L., Prowle J.R., Du B., Gallagher M., Wang C., Murugan R., Qiu H., RimmelÃ© T., Li J., Forni Lui G., Kashani K., Ronco C., Kellum J.A. (2018) Pragmatic studies for acute kidney injury: Consensus report of the Acute Disease Quality Initiative (ADQI) 19 Workgroup,Journal of Critical Care44pp. 337-344
W.B. Saunders/Elsevier Inc.
Acute kidney injury (AKI) has become a major medical and financial burden in China along with the rest
of the world. There have been considerable advances in the understanding of the epidemiology and pathogenesis
of AKI. However, there is no consensus regarding the optimal care for patients. The Acute Disease Quality Initiative
(ADQI) 19 meeting focused on identifying and designing relevant and achievable AKI-related studies in
Materials & methods:
he working group developed a list of preliminary questions and objectives and performed
analysis of the existing literature. Relevant studies were identified through a literature search using the MEDLINE
database and bibliographies of relevant research and review articles. We then used a two-step Delphi process to
prioritize a research agenda and proposed specific study designs to address unmet needs.
Important gaps in existing knowledge were identified and pragmatic studies were proposed in three distinct
areas: care bundles for AKI prevention, renal replacement therapy (RRT) for AKI, and fluid management. In
addition, the use of biomarkers to guide clinical trials was discussed.
Consensus was reached on a research agenda for AKI with a specific focus on pragmatic trials in
Singh Rishabh, Dodkins J., Doyle J.F., Forni L.G. (2018) Acute Kidney Injury Biomarkers: What Do They Tell Us?,In: Ding Xiaoqiang, Rosner Mitchell H., Ronco Claudio (eds.), Acute Kidney Injury - Basic Research and Clinical PracticeContributions to Nephrology193pp. 21-34
S. Karger AG
Darmon M., Ostermann M., Cerda J., Dimopoulos M.A., Forni Lui, Hoste E., Legrand M., Lerolle N., Rondeau E., Schneider A., Souweine B., Schetz M. (2017) Diagnostic work-up and specific causes of acute kidney injury,Intensive Care Medicine43(6)pp. 829-840
Acute kidney injury (AKI) is common in critically ill patients and associated with grim short- and long-term outcome.
Although in the vast majority of cases AKI is multifactorial, with sepsis, shock and nephrotoxicity accounting for most
episodes, specific causes of AKI are not uncommon. Despite remaining uncertainties regarding their prevalence in the
ICU, prompt recognition of specific aetiologies of AKI is likely to ensure timely management, limit worsening of renal
dysfunction, and ultimately limit renal and systemic consequences of AKI. The ability to recognize conditions that
may be associated with specific aetiologies and the appropriate use of clinical imaging, biological and immunological
tests, along with optimal assessment of the need for renal biopsies, should be part of routine ICU care. In this review,
we summarize uncertainties, current knowledge and recent advances regarding specific types of AKI. We describe the
most common specific causes as well as rare aetiologies requiring urgent management, and outline available tools
that may be used during the diagnostic work-up along with their limitations.
Peri?operative acute kidney injury is common, accounting for 30?40% of all in?hospital cases of acute kidney injury. It is associated with clinically significant morbidity and mortality even with what was hitherto regarded as relatively trivial increases in serum creatinine, and carries over a 12?fold relative risk of death following major abdominal surgery. Comorbid conditions such as diabetes, hypertension, liver disease and particularly pre?existing chronic kidney disease, as well as the type and urgency of surgery, are major risk factors for the development of postoperative acute kidney injury. As yet, there are no specific treatment options for the injured kidney, although there are several modifiable risk factors of which the anaesthetist should be aware. As well as the avoidance of potential nephrotoxins and appropriate volume balance, optimal anaesthetic management should aim to reduce the risk of postoperative renal complications. This may include careful ventilatory management and blood pressure control, as well as appropriate analgesic strategies. The choice of anaesthetic agent may also influence renal outcomes. Rather than concentrate on the classical management of acute kidney injury, this review focuses on the potential development of acute kidney injury peri?operatively, and the means by which this may be ameliorated.
Ostermann M., McCullough P.A., Forni Lui G., Bagshaw S.M., Joannidis M., Shi J., Kashani K., Honore P.M., Chawla L.S., Kellum J.A. (2018) Kinetics of urinary cell cycle arrest markers for acute kidney injury following exposure to potential renal insults,Critical Care Medicine46(3)pp. 375-383
Lippincott, Williams & Wilkins
Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure.
In an ancillary analysis of the multicenter SAPPHIRE study, we examined the kinetics of the urinary [tissue inhibitor of metalloproteinase-2]"[insulin-like growth factor binding protein 7] in association with exposure to common renal insults (major surgery, IV radiocontrast, vancomycin, nonsteroidal anti-inflammatory drugs, and piperacillin/tazobactam).
Thirty-five sites in North America and Europe between September 2010 and June 2012.
Seven hundred twenty-three critically ill adult patients admitted to the ICU.
Measurements and Main Results:
We compared the urinary [tissue metalloproteinase-2]"[insulin growth factor binding protein 7] kinetics from the day prior to exposure up to 5 days after exposure in patients developing acute kidney injury stage 2?3, stage 1, or no acute kidney injury by Kidney Disease Improving Global Outcome criteria. Among the 723 patients, 679 (94%) had at least one, 70% had more than one, and 35% had three or more exposures to a known renal insult. There was a significant association between cumulative number of exposures up to study day 3 and risk of acute
kidney injury (p = 0.02) but no association between the specific type of exposure and acute kidney injury (p = 0.22). With the exception of radiocontrast, patients who developed acute kidney injury stage 2?3 after one of the five exposures, had a clear rise and fall of urinary [tissue inhibitor of metalloproteinase-2]"[insulin-like growth factor binding protein 7] from the day of exposure to 24?48 hours later. In patients without acute kidney injury, there was no significant elevation in urinary [tissue inhibitor of metalloproteinase-2]"[insulinlike growth factor binding protein 7].
Exposure to potential renal insults is common. In patients developing acute kidney injury stage 2?3, the kinetics of urinary [tissue inhibitor of metalloproteinase-2]"[insulin-like growth factor binding protein 7] matched the exposure except in the case of radiocontrast.
Forni L.G., Darmon M., Ostermann M., Oudemans-van Straaten H.M., Pettilä V., Prowle J.R., Schetz M., Joannidis M. (2017) Renal recovery after acute kidney injury,Intensive Care Medicine43(6)pp. 855-866
Acute kidney injury (AKI) is a frequent complication of critical illness and carries a significant risk of short- and longterm
mortality, chronic kidney disease (CKD) and cardiovascular events. The degree of renal recovery from AKI may substantially affect these long-term endpoints. Therefore maximising recovery of renal function should be the goal
of any AKI prevention and treatment strategy. Defining renal recovery is far from straightforward due in part to the
limitations of the tests available to assess renal function. Here, we discuss common pitfalls in the evaluation of renal
recovery and provide suggestions for improved assessment in the future. We review the epidemiology of renal recovery
and of the association between AKI and the development of CKD. Finally, we stress the importance of post-discharge
follow-up of AKI patients and make suggestions for its incorporation into clinical practice. Summary key points
are that risk factors for non-recovery of AKI are age, CKD, comorbidity, higher severity of AKI and acute disease scores.
Second, AKI and CKD are mutually related and seem to have a common denominator. Third, despite its limitations full
recovery of AKI may best be defined as the absence of AKI criteria, and partial recovery as a fall in AKI stage. Fourth,
after an episode of AKI, serial follow-up measurements of serum creatinine and proteinuria are warranted to diagnose
renal impairment and prevent further progression. Measures to promote recovery are similar to those preventing
renal harm. Specific interventions promoting repair are still experimental.
Tumlin J.A., Murugan R., Deane A.M., Ostermann M., Busse L.W., Ham K.R., Kashani K., Szerlip H.M., Prowle J.R., Bihorac A., Finkel K.W., Zarbock A., Forni Lui G., Lynch S.J., Jensen J., Kroll S., Chawla L.S., Tidmarsh G.F., Bellomo R. (2018) Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II,Critical Care Medicine46(6)pp. 949-957
Lippincott Williams and Wilkins
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.
Post hoc analysis of the Angiotensin II for the Treatment of
High-Output Shock 3 trial.
Patients with acute kidney injury treated with renal
replacement therapy at initiation of angiotensin II or placebo (n =
45 and n = 60, respectively).
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 e 10 mm Hg or increase to e 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.
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
To summarize and extend the main conclusions and recommendations relevant to drug management during acute kidney disease (AKD) as agreed at the 16th Acute Disease Quality Initiative (ADQI) consensus conference.
Using a modi?ed Delphi method to achieve consensus, experts attending t he 16thADQI consensus conference reviewed and appraised the existing literature on drug management during AKD and identi?ed recommendations for clinical practice and future research. The group focussed on drugs with one of the following characteristics: (i) predominant renal excretion; (ii) nephrotoxicity; (iii) potential to alter glomerular function; and (iv) presence of metabolites that are modi?ed in AKD and may affect other organs.
We recommend that medication reconciliation should occur at admission and discharge, at AKD diagnosis and change in AKD phase, and when the patient ?s condition changes. Strategies to avoid adverse drug reactions in AKD should seek to minimize adverse events from overdosing and nephrotoxicity and therapeutic failure from under-dosing or incorrect drug selection. Medication regimen assessment or introduction of medications during the AKD period should consider the nephrotoxic potential, altered renal and non renal elimination, the effects of toxic metabolites and drug interactions and altered pharmacodynamics in AKD. A dynamic monitoring plan including repeated serial assessment of clinical features, utilization of renal diagnostic tests and therapeutic drug monitoring should be used to guide medication regimen assessment.
Drug management during different phases of AKD requires an individualized approach and frequent re-assessment. More research is needed to avoid drug associated harm and therapeutic failure.
Pickkers P., Ostermann M., Joannidis M., Zarbock A., Hoste E., Bellomo R., Prowle J., Darmon M., Bonventre J.V., Forni Lui, Bagshaw S.M., Schetz M. (2017) The intensive care medicine agenda on acute kidney injury,Intensive Care Medicine43(9)pp. 1198-1209
Acute kidney injury (AKI) is a common complication in the critically ill. Current standard of care mainly relies on identification
of patients at risk, haemodynamic optimization, avoidance of nephrotoxicity and the use of renal replacement
therapy (RRT) in established AKI. The detection of early biomarkers of renal tissue damage is a recent development
that allows amending the late and insensitive diagnosis with current AKI criteria. Increasing evidence suggests that
the consequences of an episode of AKI extend long beyond the acute hospitalization. Citrate has been established as
the anticoagulant of choice for continuous RRT. Conflicting results have been published on the optimal timing of RRT
and on the renoprotective effect of remote ischaemic preconditioning. Recent research has contradicted that acute
tubular necrosis is the common pathology in AKI, that septic AKI is due to global kidney hypoperfusion, that aggressive
fluid therapy benefits the kidney, that vasopressor therapy harms the kidney and that high doses of RRT improve
outcome. Remaining uncertainties include the impact of aetiology and clinical context on pathophysiology, therapy
and prognosis, the clinical benefit of biomarker-driven interventions, the optimal mode of RRT to improve short- and
long-term patient and kidney outcomes, the contribution of AKI to failure of other organs and the optimal approach
for assessing and promoting renal recovery. Based on the established gaps in current knowledge the trials that must
have priority in the coming 10 years are proposed together with the definition of appropriate clinical endpoints.
Critically appraise prediction models for
hospital-acquired acute kidney injury (HA-AKI) in general
Design Systematic review.
Data sources Medline, Embase and Web of Science until
Studies describing development of a
multivariable model for predicting HA-AKI in nonspecialised
adult hospital populations. Published
guidance followed for data extraction reporting and
14 046 references were screened. Of 53
HA-AKI prediction models, 11 met inclusion criteria
(general medicine and/or surgery populations, 474 478
patient episodes) and five externally validated. The most
common predictors were age (n=9 models), diabetes
(5), admission serum creatinine (SCr) (5), chronic
kidney disease (CKD) (4), drugs (diuretics (4) and/or ACE
inhibitors/angiotensin-receptor blockers (3)), bicarbonate
and heart failure (4 models each). Heterogeneity was
identified for outcome definition. Deficiencies in reporting
included handling of predictors, missing data and sample
size. Admission SCr was frequently taken to represent
baseline renal function. Most models were considered
at high risk of bias. Area under the receiver operating
characteristic curves to predict HA-AKI ranged 0.71?0.80
in derivation (reported in 8/11 studies), 0.66?0.80
for internal validation studies (n=7) and 0.65?0.71 in
five external validations. For calibration, the Hosmer-
Lemeshow test or a calibration plot was provided in 4/11
derivations, 3/11 internal and 3/5 external validations.
A minority of the models allow easy bedside calculation
and potential electronic automation. No impact analysis
studies were found.
AKI prediction models may help address
shortcomings in risk assessment; however, in general
hospital populations, few have external validation. Similar
predictors reflect an elderly demographic with chronic
comorbidities. Reporting deficiencies mirrors prediction
research more broadly, with handling of SCr (baseline
function and use as a predictor) a concern. Future research
should focus on validation, exploration of electronic linkage
and impact analysis. The latter could combine a prediction
model with AKI alerting to address prevention and early
recognition of evolving AKI.
The aim of this study was to investigate the influence of mild therapeutic hypothermia (MTH) on the incidence of and recovery from acute kidney injury (AKI).
Patients who had undergone successful cardiopulmonary resuscitation (CPR) were included. Serum creatinine and cystatin C were measured at baseline, daily up to 5 days and at ICU discharge. AKI was defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. MTH was applied for 24 h targeting a temperature of 33 °C. Neurological outcome was assessed with the Cerebral Performance Categories score at hospital discharge.
126 patients were included in the study; 73 patients (58%) developed AKI. Patients treated with MTH had a significantly lower incidence of AKI as compared to normothermia (NT) (44 vs. 69%; p = 0.004). Patients with less favourable neurological outcomes had a significantly higher rate of AKI, although when treated with MTH the occurrence of AKI was reduced (50 vs. 80%; p = 0.017). Furthermore, MTH treatment was accompanied by significantly lower creatinine levels on day 0?1 and at ICU discharge (day 0: 1.12 (0.90?1.29) vs. 1.29 (1.00?1.52) mg/dl; p = 0.016) and lower cystatin C levels on day 0?3 and at ICU discharge (day 0: 0.88 (0.77?1.10) vs. 1.29 (1.06?2.16) mg/l; p< 0.001).
Mild therapeutic hypothermia seems to have a protective effect against the development of AKI and on renal recovery. This may be less pronounced in patients with a favourable neurological outcome.
Oliguria is often observed in critically ill patients. However, different thresholds in urine output (UO) have raised discussion as to the clinical importance of a transiently reduced UO of less than 0.5 ml/kg/h lasting for at least 6 h. While some studies have demonstrated that isolated oliguria without a concomitant increase in serum creatinine is associated with higher mortality rates, different underlying pathophysiological mechanisms suggest varied clinical importance of reduced UO, as some episodes of oliguria may be fully reversible. We aim to explore the clinical relevance of oliguria in critically ill patients and propose a clinical pathway for the diagnostic and therapeutic management of an oliguric, critically ill patient.
Acute kidney injury (AKI) is associated with high mortality and measures to improve risk stratification and early identification have been urgently called for. This study investigated whether an electronic clinical prediction rule (CPR) combined with an AKI e-alert could reduce hospital-acquired AKI (HA-AKI) and improve associated outcomes.
Methods and findings
A controlled before-and-after study included 30,295 acute medical admissions to two adult non-specialist hospital sites in the South of England (two ten-month time periods, 2014?16); all included patients stayed at least one night and had at least two serum creatinine tests. In the second period at the intervention site a CPR flagged those at risk of AKI and an alert was generated for those with AKI; both alerts incorporated care bundles. Patients were followed-up until death or hospital discharge. Primary outcome was change in incident HA-AKI. Secondary outcomes in those developing HA-AKI included: in-hospital mortality, AKI progression and escalation of care. On difference-in-differences analysis incidence of HA-AKI reduced (odds ratio [OR] 0.990, 95% CI 0.981?1.000, P = 0.049). In-hospital mortality in HA-AKI cases reduced on difference-in-differences analysis (OR 0.924, 95% CI 0.858?0.996, P = 0.038) and unadjusted analysis (27.46% pre vs 21.67% post, OR 0.731, 95% CI 0.560?0.954, P = 0.021). Mortality in those flagged by the CPR significantly reduced (14% pre vs 11% post intervention, P = 0.008). Outcomes for community-acquired AKI (CA-AKI) cases did not change. A number of process measures significantly improved at the intervention site. Limitations include lack of randomization, and generalizability will require future investigation.
In acute medical admissions a multi-modal intervention, including an electronically integrated CPR alongside an e-alert for those developing HA-AKI improved in-hospital outcomes. CA-AKI outcomes were not affected. The study provides a template for investigations utilising electronically generated prediction modelling. Further studies should assess generalisability and cost effectiveness.
Nadim M.K., Forni L.G., Bihorac A., Hobson C., Koyner J.L., Shaw A., Arnaoutakis G.J., Ding X., Engelman D.T., Gasparovic H., Gasparovic V., Herzog C.A., Kashani K., Katz N., Liu K.D., Mehta R.L., Ostermann M., Pannu N., Pickkers P., Price S., Ricci Z., Rich J.B., Sajja L.R., Weaver F.A., Zarbock A., Ronco C., Kellum J.A. (2018) Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group,Journal of the American Heart Association7(11)e008834.
American Heart Association Inc. (Wiley)
Hodgson L.E., Congleton J., Venn R., Forni L.G., Roderick P.J. (2018) NEWS 2 - too little evidence to implement?,Clinical Medicine, Journal of the Royal College of Physicians of London18(5)pp. 371-373
Royal College of Physicians
The Royal College of Physicians (RCP) recently published the National Early Warning Score 2 (NEWS2), aiming to improve safety for patients with hypercapnic respiratory failure by suggesting a separate oxygen saturation (SpO2) parameter scoring system for such patients. A previously published study of patients (n=2,361 admissions) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) demonstrated alternative scoring systems at admission did not outperform the original NEWS. Applying NEWS2 SpO2 parameters to this previously described cohort would have resulted in 44% (n=27/62) of patients who scored e7 points on the original NEWS and subsequently died being placed in a lower call-out threshold. NEWS2 loses the benefits of a unified, standardised scoring system and we suggest prospective research in this area before applying this adjustment.
Notice of republication
An incorrect version of Fig 3 was published in error. This article was republished on August 17, 2018 to correct for this error. Please download this article again to view the correct version.
Although improving, the mortality from septic shock still remains high despite increased international awareness. As a consequence, much effort has focused on alternative treatment strategies in an effort to improve outcomes. The application of blood purification therapies to improve immune homeostasis has been suggested as one such method, but these approaches, such as high-volume continuous haemofiltration or cytokine and/or endotoxin removal, have enjoyed little success to date. More recently, the use of sorbent technologies has attracted much attention. These adsorbers are highly effective at removing inflammatory mediators, in particular, cytokines, from the bloodstream. This narrative review is the executive summary of meetings held throughout the 6th International Fluid Academy Days in Antwerp, Belgium (Nov 23?25, 2017), focusing on the current understanding regarding the use of such adsorbers in humans with septic shock. We followed a modified Delphi approach involving a combination of evidence appraisal together with expert opinion in order to achieve recommendations for practice and, importantly, future research.
Early recognition of patients developing acute kidney injury (AKI) is of considerable interest, we report the first use of a combination of a clinical prediction rule with a biomarker in emergent adult medical patients to improve AKI recognition.
Single-centre prospective pilot study of medical admissions without AKI identified as high risk by a clinical prediction rule. Urine samples were obtained and tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) ? biomarkers associated with cell cycle arrest, were measured.
Creatinine-based KDIGO hospital-acquired AKI (HA-AKI).
Of 69 patients recruited, HA-AKI developed in 13% (n = 9), in whom biomarker values were higher (median 0.43 (interquartile range (IQR) 0.21?1.25) vs. 0.07 (0.03?0.16) in cases without (p = 0.008). Peak rise in creatinine was higher in biomarker positive cases (median 30 ¼mol/L (7?72) vs. 1 ¼mol/L (0?16), p = 0.002). AUROC was 0.78 (95% CI 0.57?0.98). At the suggested cut-off (0.3) sensitivity for predicting AKI was 78% (95% CI 40?97%), specificity 89% (78?95%), positive predictive value 50% (31?69%) and negative predictive value 96% (89?99%).
Addition of a urinary biomarker allows exclusion of a significant number of patients identified to be at higher risk of AKI by a clinical prediction rule.
The mainstay of hemodynamic treatment of septic shock is fluid resuscitation followed by vasopressors where fluids
alone are insufficient to achieve target blood pressure. Norepinephrine, a catecholamine, is the first-line vasopressor
used worldwide but given that all routinely used catecholamines target the same adrenergic receptors, many
clinicians may add a non-catecholamine vasopressor where refractory hypotension due to septic shock is present.
However, the timing of this additional intervention is variable. This decision is based on three key factors:
availability, familiarity, and safety profile. In our opinion, further consideration should be potential vasopressor
response because following appropriate volume resuscitation, the response to different vasopressor classes is
neither uniform nor predictable. Critically ill patients who are non-responders to high-dose catecholamines have a
dismal outcome. Similarly, patients have a variable response to non-catecholamine agents including vasopressin
and angiotensin II: but where patients exhibit a blood pressure response the outcomes are improved over nonresponders.
This variable responsiveness to vasopressors is similar to the clinical approach of anti-microbial
sensitivity. In this commentary, the authors propose the concept of ?broad spectrum vasopressors? wherein patients
with septic shock are started on multiple vasopressors with a different mechanism of action simultaneously while
the vasopressor sensitivity is assessed. Once the vasopressor sensitivities are assessed, then the vasopressors are ?deescalated? accordingly. We believe that this concept may offer a new approach to the treatment of septic shock.
Sepsis is life-threatening organ dysfunction because of a dysregulated host response to infection. Disturbed microvascular blood flow is associated with excess mortality and is a potential future target for interventions. This review addresses the evidence for pharmacological manipulation of the microcirculation in sepsis assessed by techniques that evaluate the sublingual microvasculature.
Systematic review using a published protocol. Eligibility criteria were studies of septic patients published from January 2000 to February 2018. Interventions were drugs aimed at improving perfusion. Outcome was improvement in microvascular flow using orthogonal polarization spectral, sidestream dark field, or incident dark field imaging (Grades of Recommendation, Assessment, Development, and Evaluation criteria used).
Two thousand six hundred and six articles were screened and 22 included. (6 randomized controlled trials, 12 interventional, 3 observational, and 1 pilot, n = 572 participants). Multiple measurement techniques were described, including: automated analyses, subjective, and composite scoring systems. Norepinephrine was not found to improve microvascular flow (low-grade evidence, n = 6 studies); except in chronic hypertension (low, n = 1 study). Addition of arginine vasopressin or terlipressin to norepinephrine maintained flow while decreasing norepinephrine requirements (high, n = 2 studies). Neither dobutamine nor glyceryl trinitrate consistently improved flow (low, n = 6 studies). A single study (n = 40 participants) demonstrated improved flow with levosimendan (high). In a risk of bias assessment 16/16 interventional, pilot and observational studies were found to be high risk.
There is no robust evidence to date that any one agent can reproducibly lead to improved microvascular flow. Furthermore, no study demonstrated outcome benefit of one therapeutic agent over another. Updated consensus guidelines could improve comparable reporting of measurements and reduce bias, to enable meaningful comparisons around the effects of individual pharmacological agents.
Guzzi L.M., Bergler T., Binnall B., Engelman D.T., Forni Lui, Germain M.J., Gluck E., Göcze I., Joannidis M., Koyner J.L., Reddy V.S., Rimmelé T., Ronco C., Textoris J., Zarbock A., Kellum J.A. (2019) Clinical use of [TIMP-2]"[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: Guidance from an expert panel,Critical Care23(1)225
BioMed Central Ltd.
The first FDA-approved test to assess risk for acute kidney injury (AKI), [TIMP-2]"[IGFBP7], is clinically
available in many parts of the world, including the USA and Europe. We sought to understand how the test is
currently being used clinically.
We invited a group of experts knowledgeable on the utility of this test for kidney injury to a panel
discussion regarding the appropriate use of the test. Specifically, we wanted to identify which patients would be
appropriate for testing, how the results are interpreted, and what actions would be taken based on the results of
the test. We used a modified Delphi method to prioritize specific populations for testing and actions based on
biomarker test results. No attempt was made to evaluate the evidence in support of various actions however.
Our results indicate that clinical experts have developed similar practice patterns for use of the [TIMP-
2]"[IGFBP7] test in Europe and North America. Patients undergoing major surgery (both cardiac and non-cardiac),
those who were hemodynamically unstable, or those with sepsis appear to be priority patient populations for
testing kidney stress. It was agreed that, in patients who tested positive, management of potentially nephrotoxic
drugs and fluids would be a priority. Patients who tested negative may be candidates for ?fast-track? protocols.
Conclusion: In the experience of our expert panel, biomarker testing has been a priority after major surgery,
hemodynamic instability, or sepsis. Our panel members reported that a positive test prompts management of
nephrotoxic drugs as well as fluids, while patients with negative results are considered to be excellent candidates
for ?fast-track? protocols.
Kashani K., Rosner M.H., Haase M., Lewington A.J.P., O'Donoghue D.J., Wilson F.P., Nadim M.K., Silver S.A., Zarbock A., Ostermann M., Mehta R.L., Kane-Gill S.L., Ding X., Pickkers P., Bihorac A., Siew E.D., Barreto E.F., Macedo E., Kellum J.A., Palevsky P.M., Tolwani A.J., Ronco C., Juncos L.A., Rewa O.G., Bagshaw S.M., Mottes T.A., Koyner J.L., Liu K.D., Forni Lui, Heung M., Wu V.-C. (2019) Quality improvement goals for acute kidney injury,Clinical Journal of the American Society of Nephrology14(6)pp. 941-953
American Society of Nephrology
AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators.
Gattinoni L., Vasques F., Camporota L., Meessen J., Romitti F., Pasticci I., Duscio E., Vassalli F., Forni Lui G., Payen D., Cressoni M., Zanella A., Latini R., Quintel M., Marini J.J. (2019) Understanding lactatemia in human sepsis potential impact for early management,American Journal of Respiratory and Critical Care Medicine200(5)pp. 582-589
American Thoracic Society
Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy.
To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate.
This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2. We defined the ?alactic base excess,? as the sum of lactate and standard base excess.
Measurements and Main Results:
Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance.
Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.
Lacey J., Corbett J., Forni Lui, Hooper L., Hughes F., Minto G., Moss C., Price S., Whyte G., Woodcock T., Mythen M., Montgomery H. (2019) A multidisciplinary consensus on dehydration: definitions, diagnostic methods and clinical implications,Annals of Medicine51(3-4)pp. 232-251
Taylor and Francis Ltd
Dehydration appears prevalent, costly and associated with adverse outcomes. We sought to generate consensus on such key issues and elucidate need for further scientific enquiry.
Materials and methods:
A modified Delphi process combined expert opinion and evidence appraisal. Twelve relevant experts addressed dehydration?s definition, objective markers and impact on physiology and outcome.
Fifteen consensus statements and seven research recommendations were generated. Key findings, evidenced in detail, were that there is no universally accepted definition for dehydration; hydration assessment is complex and requires combining physiological and laboratory variables; ?dehydration? and ?hypovolaemia? are incorrectly used interchangeably; abnormal hydration status includes relative and/or absolute abnormalities in body water and serum/plasma osmolality (pOsm); raised pOsm usually indicates dehydration; direct measurement of pOsm is the gold standard for determining dehydration; pOsm >300 and d280 mOsm/kg classifies a person as hyper or hypo-osmolar; outside extremes, signs of adult dehydration are subtle and unreliable; dehydration is common in hospitals and care homes and associated with poorer outcomes.
Dehydration poses risk to public health. Dehydration is under-recognized and poorly managed in hospital and community-based care. Further research is required to improve assessment and management of dehydration and the authors have made recommendations to focus academic endeavours.
"Dehydration assessment is a major clinical challenge due to a complex, varying pathophysiology, non-specific clinical presentations and the lack of international consensus on definition and diagnosis.
"Plasma osmolality represents a valuable, objective surrogate marker of hypertonic dehydration which is underutilized in clinical practice.
"Dehydration is prevalent within the healthcare setting and in the community, and appears associated with increased morbidity and mortality.
The IDEAL-ICU study reports no mortality benefit of early versus delayed initiation of renal replacement therapy (RRT) in patients with early septic shock and acute kidney injury. In the delayed initiation group, 17% of patients required emergency RRT but more than one-third spontaneously recovered renal function and did not require RRT.
Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death.
Design: Prospective, international, Sapphire study.
Setting: Academic Medical Center.
Patients: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3.
Measurements and Main Results:
The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2?3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]"[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]"[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2?3) within 7 days.
Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]"[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.
Acute kidney injury (AKI) is the most common cause of organ dysfunction in critically ill adults, with a single
episode of AKI, regardless of stage, carrying a significant morbidity and mortality risk. Since the consensus on AKI
nomenclature has been reached, data reflecting outcomes have become more apparent allowing investigation of
both short- and long-term outcomes.
Classically the short-term effects of AKI can be thought of as those reflecting an acute deterioration in renal
function per se. However, the effects of AKI, especially with regard to distant organ function (?organ cross-talk?), are
being elucidated as is the increased susceptibility to other conditions. With regards to the long-term effects, the
consideration that outcome is a simple binary endpoint of dialysis or not, or survival or not, is overly simplistic, with
the reality being much more complex.
Also discussed are currently available treatment strategies to mitigate these adverse effects, as they have the
potential to improve patient outcome and provide considerable economic health savings. Moving forward, an
agreement for defining renal recovery is warranted if we are to assess and extrapolate the efficacy of novel
therapies. Future research should focus on targeted therapies assessed by measure of long-term outcomes.
Doyle James F., Sarnowski Alexander, Saadat Farzad, Samuels Theophilus L., Huddart Sam, Quiney Nial, Dickinson Matthew C., McCormick Bruce, deBrunner Robert, Preece Jeremy, Swart Michael, Peden Carol J., Richards Sarah, Forni Lui G. (2019) Does the Implementation of a Quality Improvement Care Bundle Reduce the Incidence of Acute Kidney Injury in Patients Undergoing Emergency Laparotomy?,Journal of Clinical Medicine8(8)
Purpose: Previous work has demonstrated a survival improvement following the
introduction of an enhanced recovery protocol in patients undergoing emergency laparotomy
(the emergency laparotomy pathway quality improvement care (ELPQuiC) bundle). Implementation
of this bundle increased the use of intra-operative goal directed fluid therapy and ICU admission,
both evidence-based strategies recommended to improve kidney outcomes. The aim of this study
was to determine if the observed mortality benefit could be explained by a dfference in the incidence
of AKI pre- and post-implementation of the protocol. Method: The primary outcome was the
incidence of AKI in the pre- and post-ELPQuiC bundle patient population in four acute trusts in
the United Kingdom. Secondary outcomes included the KDIGO stage specific incidence of AKI.
Serum creatinine values were obtained retrospectively at baseline, in the post-operative period and
the maximum recorded creatinine between day 1 and day 30 were obtained. Results: A total of
303 patients pre-ELPQuiC bundle and 426 patients post-ELPQuiC bundle implementation were
identified across the four centres. The overall AKI incidence was 18.4% in the pre-bundle group
versus 19.8% in the post bundle group p = 0.653. No significant differences were observed between
the groups. Conclusions: Despite this multi-centre cohort study demonstrating an overall survival
benefit, implementation of the quality improvement care bundle did not affect the incidence of AKI.
Native chemical ligation (NCL) employing the
N-methylbenzimidazolinone (MeNbz) linker readily provided
the linear precursor of a 16-mer peptide that is difficult to
obtain by stepwise solid-phase peptide synthesis. NCL and the
workup conditions were improved toward a protocol that
allows for quantitative removal of the 4-hydroxymercaptophenol
additive and subsequent formation of the disulfide
bridge in the NCL cocktail by oxidation in air, tolerated by the
presence of tris(hydroxypropyl)phosphine.
Purpose of review Since the adoption of the classification of acute kidney injury (AKI) through changes in serum creatinine and/or urine output, much data have accumulated as to the associated risks in terms of morbidity and mortality after the development of AKI. However, until recently, a nihilistic approach persisted which implied that little could be done to alter the clinical course of a patient with AKI even where early identification was achieved. This view is reinforced by the opinion that given the broad cause underlying the syndrome of AKI, a ?one size fits all? approach is unlikely to be successful.
Recent findings Recent evidence suggests that the management of AKI may be improved somewhat by simple measures, such as the use of care bundles particularly in the intensive care setting. Moreover, there are other interventions using common treatments, which may prove to be of benefit as well as some early evidence that specific therapeutics may be on the horizon.
Summary Although a syndrome of significantly differing causes, the application of standardized care bundles appears promising and this approach may be improved by the use of specific therapies, including recombinant alkaline phosphatase, the use of intravenous bicarbonate and remote ischaemic preconditioning may also ameliorate the effects of AKI.
Acute kidney injury (AKI), a sudden reduction in kidney
function, is seen in some people with covid-19 infection. A
subset of patients develop severe AKI and require renal
replacement therapy (RRT). As in many settings, the
development of AKI is associated with an increased risk of
mortality.1 2 Although our understanding is incomplete, a picture is emerging from case reports and autopsy series of covid-19 specific causes of AKI. Intrinsic renal pathology including thrombotic vascular processes, viral mediated tubular cell injury, and glomerulonephritis have been reported, as well as AKI resulting from extrinsic factors such as fluid depletion, multi-organ failure, and rhabdomyolysis.3-7 Anecdotal reports
have emerged of proximal tubular injury with Fanconi syndrome that manifests as hypokalaemia, hypophosphataemia, normal anion gap metabolic acidosis, and hypovolaemia from salt wasting. Importantly, AKI can occur at all stages of covid-19 infection, so clinical vigilance and consideration of risk factors for AKI alongside early detection and diagnosis are essential components of general supportive care. Fluid management is
central to this. This article summarises key points from the National Institute for Health and Care Excellence (NICE) covid-19 rapid guideline on AKI in hospital.
Douglas Ivor S., Alpat Phillip M., Corl Keith A., Exline Matthew C., Forni Lui, Holder Andre L., Kaufman David A., Khan Akram, Levy Mitchell M., Martin Gregory S., Sahatjian Jennifer A., Seeley Eric, Self Wesley H., Weingarten Jeremy A., Williams Mark, Hansell Douglas M. (2020) Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial,Chest
Background: Fluid and vasopressor management in septic shock remains controversial. In this
randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume
change during passive leg raise) to guide resuscitation and improve patient outcome.
Research Question: Will resuscitation guided by dynamic assessments of fluid responsiveness in
patients with septic shock improve patient outcomes?
Study Design and Methods: Prospective, multicenter, randomized clinical trial at 13 hospitals in
the United States and United Kingdom. Patients presented to Emergency Rooms with sepsis
associated hypotension and anticipated Intensive Care Unit (ICU) admission. Intervention arm
patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in
vasopressors. The protocol included reassessment and therapy as indicated by the PLR result.
The control arm received Usual Care. Primary clinical outcome was positive fluid balance at 72
hours or ICU discharge, whichever occurred first.
Results: In modified-ITT (mITT) analysis including 83 Intervention and 41 Usual Care eligible
patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37L favoring
Intervention arm, 0.65 ± 2.85L Intervention arm vs. 2.02 ± 3.44L Usual Care arm, p=0.021.
Fewer patients required renal replacement therapy (5.1% vs 17.5%, p=0.04) or mechanical
ventilation (17.7% vs 34.1%, p=0.04) in the Intervention arm compared to Usual Care. In the allrandomized
Intent to Treat (ITT) population (102 Intervention, 48 Usual Care) there were no
significant differences in safety signals.
Interpretation: Physiologically informed fluid and vasopressor resuscitation using passive leg
raise-induced stroke volume change to guide management of septic shock is safe and
demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for septic shock patients compared with Usual Care.
Trial Registration clinicaltrials.gov identifier: NCT02837731
In the acute hospital setting the COVID-19 pandemic presents some unique challenges to acute patient care. These include accurate recognition of cases, confirmation of both testing requests and results, establishing patient acuity and alerting to deterioration. We report our experience introducing a digital COVID-19 assessment tool with an associated live dashboard at two acute NHS hospitals, enabling accurate hospital-level reporting alongside risk stratification.