An Organizational-Level Program of Intervention for AKI: A Pragmatic Stepped Wedge Cluster Randomized Trial.

BACKGROUND: Variable standards of care may contribute to poor outcomes associated with AKI. We evaluated whether a multifaceted intervention (AKI e-alerts, an AKI care bundle, and an education program) would improve delivery of care and patient outcomes at an organizational level. METHODS: A multicenter, pragmatic, stepped-wedge cluster randomized trial was performed in five UK hospitals, involving patients with AKI aged ≥18 years. The intervention was introduced sequentially across fixed three-month periods according to a randomly determined schedule until all hospitals were exposed. The primary outcome was 30-day mortality, with pre-specified secondary endpoints and a nested evaluation of care process delivery. The nature of the intervention precluded blinding, but data collection and analysis were independent of project delivery teams. RESULTS: We studied 24,059 AKI episodes, finding an overall 30-day mortality of 24.5%, with no difference between control and intervention periods. Hospital length of stay was reduced with the intervention (decreases of 0.7, 1.1, and 1.3 days at the 0.5, 0.6, and 0.7 quantiles, respectively). AKI incidence increased and was mirrored by an increase in the proportion of patients with a coded diagnosis of AKI. Our assessment of process measures in 1048 patients showed improvements in several metrics including AKI recognition, medication optimization, and fluid assessment. CONCLUSIONS: A complex, hospital-wide intervention to reduce harm associated with AKI did not reduce 30-day AKI mortality but did result in reductions in hospital length of stay, accompanied by improvements in in quality of care. An increase in AKI incidence likely reflected improved recognition.

Critical care in the emergency department: acute kidney injury.

Acute kidney injury (AKI) is common among emergency department patients admitted to hospital. There is evidence of inadequate management of the condition leading to adverse outcomes. We present an illustrative case of AKI complicating a gastrointestinal disorder in an older adult. We discuss the clinical presentation, assessment and management of AKI with reference to recent consensus guidelines on classification and treatment.

Relationship between patients' outcomes and the changes in serum creatinine and urine output and RIFLE classification in a large critical care cohort database.

We report the stepwise application of the RIFLE classification in 155,624 admissions in the UK Intensive Care National Audit & Research Centre Case Mix Programme database. The assumptions required to define RIFLE and their relationship with renal replacement therapy (RRT) and ICU mortality were assessed. Previous reports had not explored the method of estimating baseline creatinine, the position of class boundaries, or interactions between urine volume (AKI-U) and the peak/estimated baseline creatinine (AKI-Cr) within 24 h of ICU admission. The risk of developing AKI strongly depended on the assumed GFR increasing from 36 to 58% across the recommended range. AKI-U was often seen without AKI-Cr, and moderate oliguria (under 850 ml/24 h) was a stronger predictor of mortality than any degree of AKI-Cr partly because mortality fell when peak/estimated baseline creatinine ratios exceed fourfold. Mild oliguria (850-1500 ml/24 h) was common (38,928 admissions, 26%) and had a similar association with mortality (relative risk 1.6, 95% CI: 1.5-1.6) as did AKI-Cr defined Failure (risk ratio 1.5, 95% CI: 1.5-1.6). However, AKI-Cr was a strong predictor for RRT, which was used in 17,802 (11%) of admissions. Nearly half (48%) of the Failure patients never received RRT; nonetheless, most (66%) survived critical care. Thus, although the RIFLE classification may be attempted in large population cohorts, there is significant heterogeneity of both renal and, in particular, vital outcomes within each class.

Raising awareness of acute kidney injury: a global perspective of a silent killer.

Worldwide, acute kidney injury (AKI) is associated with poor patient outcomes. Over the last few years, collaborative efforts, enabled by a common definition of AKI, have provided a description of the epidemiology, natural history, and outcomes of this disease and improved our understanding of the pathophysiology. There is increased recognition that AKI is encountered in multiple settings and in all age groups, and that its course and outcomes are influenced by the severity and duration of the event. The effect of AKI on an individual patient and the resulting societal burden that ensues from the long-term effects of the disease, including development of chronic kidney disease (CKD) and end-stage renal disease (ESRD), is attracting increasing scrutiny. There is evidence of marked variation in the management of AKI, which is, to a large extent, due to a lack of awareness and an absence of standards for prevention, early recognition, and intervention. These emerging data point to an urgent need for a global effort to highlight that AKI is preventable, its course is modifiable, and its treatment can improve outcomes. In this article, we provide a framework of reference and propose specific strategies to raise awareness of AKI globally, with the goal to ultimately improve outcomes from this devastating disease.

Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patients with delayed graft function following renal transplantation.

Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67-0.85) for ACY-1, 0.9 (0.84-0.95) for cystatin C, and 0.93 (0.88-0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor-brain-dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation.

A systematic analysis of the effects of increasing degrees of serum immunodepletion in terms of depth of coverage and other key aspects in top-down and bottom-up proteomic analyses.

Immunodepletion of clinical fluids to overcome the dominance by a few very abundant proteins has been explored but studies are few, commonly examining only limited aspects with one analytical platform. We have systematically compared immunodepletion of 6, 14, or 20 proteins using serum from renal transplant patients, analysing reproducibility, depth of coverage, efficiency, and specificity using 2-D DIGE ('top-down') and LC-MS/MS ('bottom-up'). A progressive increase in protein number (≥2 unique peptides) was found from 159 in unfractionated serum to 301 following 20 protein depletion using a relatively high-throughput 1-D-LC-MS/MS approach, including known biomarkers and moderate-lower abundance proteins such as NGAL and cytokine/growth factor receptors. On the contrary, readout by 2-D DIGE demonstrated good reproducibility of immunodepletion, but additional proteins seen tended to be isoforms of existing proteins. Depletion of 14 or 20 proteins followed by LC-MS/MS showed excellent reproducibility of proteins detected and a significant overlap between columns. Using label-free analysis, greater run-to-run variability was seen with the Prot20 column compared with the MARS14 column (median %CVs of 30.9 versus 18.2%, respectively) and a corresponding wider precision profile for the Prot20. These results illustrate the potential of immunodepletion followed by 1-D nano-LC-LTQ Orbitrap Velos analysis in a moderate through-put biomarker discovery process.

Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. Do medical trainees receive adequate training in the management of acute kidney injury?

There has been increased interest in acute kidney injury (AKI) over the past decade following the recognition of the association of relatively small rises in serum creatinine with worse patient outcomes. This association has resulted in newly proposed definitions in AKI based on changes in serum creatinine. In 2009, the National Confidential Enquiry into Patient Outcomes and Death Adding Insult to Injury AKI study reported that only 50% of patients who died with a diagnosis of AKI received good care. The study identified multiple deficiencies and made a number of recommendations which included improving the training of undergraduate and postgraduate trainees in the management of AKI. The aim of the evaluation was to try and identify the perception of medical trainees in Leeds Teaching Hospitals of the training they had received on AKI. A simple questionnaire was used and captured the views of 73 trainees (including 13 final-year medical students). The evaluation indicated that the majority of trainees were unaware of newly proposed definitions of AKI, and many trainees felt that the training they had received in AKI was inadequate for their needs. Following this evaluation, we have made a number of changes to the training that is delivered to both undergraduate and postgraduate trainees in Leeds on the management of AKI.

The outcomes of critically ill patients with combined severe acute liver and kidney injury secondary to paracetamol toxicity requiring renal replacement therapy.

There is a paucity of outcome data for critically ill patients with combined acute liver and kidney injury secondary to paracetamol overdose (POD) requiring renal replacement therapy (RRT). We retrospectively reviewed all admissions over a 6-year period to the intensive care unit (ICU) at a university teaching hospital which supports an active liver transplant program. Of the 5582 admissions over this period, 73 patients were admitted with combined liver and kidney injury requiring RRT, and of these 10 patients went on to receive a liver transplant. Overall mortality was 58%, being lower at 20% for transplant recipients. Transplant recipients were younger than non-transplanted patients with similar global disease severity scores [Model for End-Stage Liver Disease (MELD) and Acute Physiology and Chronic Health Evaluation II (APACHE II)]. Patients with a higher MELD or APACHE II score fared worse and patients fulfilling the King's College Hospital transplant criteria on admission had an odds ratio (OR) for death of 3.8 (1.3-10.6). Logistic regression modeling found that only a higher admission bilirubin OR 1.6 (1.1-2.3) mg/dL and a lower creatinine OR 0.52 (0.3-0.9) mg/dL were predictive of mortality. Of the ICU survivors, 41% remained RRT dependant at the time of ICU discharge; all regained independent renal function by 1 month. Combined severe acute liver and kidney injury secondary to POD requiring RRT is associated with a high mortality. The majority of survivors recover independent kidney function by 1 month. Standard disease severity scores appear to reflect prognosis in these patients.

Community Health Care Quality Standards to Prevent Acute Kidney Injury and Its Consequences.

As the incidence of acute kidney injury (AKI) increases, prevention strategies are needed across the health care continuum, which begins in the community. Recognizing this knowledge gap, the 22nd Acute Disease Quality Initiative (ADQI) was tasked to discuss the evidence for quality-of-care measurement and care processes to prevent AKI and its consequences in the community. Using a modified Delphi process, an international and interdisciplinary group provided a framework to identify and monitor patients with AKI in the community. The recommendations propose that risk stratification involve both susceptibilities (eg, chronic kidney disease) and exposures (eg, coronary angiography), with the latter triggering a Kidney Health Assessment. This assessment should include blood pressure, serum creatinine, and urine dipstick, followed by a Kidney Health Response to prevent AKI that encompasses cessation of unnecessary medications, minimization of nephrotoxins, patient education, and ongoing monitoring until the exposure resolves. These recommendations give community health care providers and health systems a starting point for quality improvement initiatives to prevent AKI and its consequences in the community.

Massive aneurysmal dilatation of a depopulated ureteric hemodialysis xenograft.

Use of depopulated bovine ureteric xenografts for hemodialysis vascular access has recently been described. Cellular components have been removed, giving a connective tissue matrix which can be neocellularized, retaining native biomechanics. A 24-year-old male with end-stage renal disease from focal segmental glomerulosclerosis presented with particularly difficult vascular access. A depopulated bovine ureteric xenograft was implanted from the left subclavian artery to innominate vein. It became massively aneurysmal, requiring emergency embolization. Biopsy of the graft stained positive for alpha-gal. We believe this is the first reported case of massive aneurysmal dilatation of a depopulated bovine ureteric xenograft.

Quality Improvement Goals for Acute Kidney Injury.

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.

Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation.

Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.

Renal Transplantation From Pediatric Donors in the United Kingdom.

BACKGROUND: Significant disparity exists in the United Kingdom between the need for organ transplant and supply of deceased donor organs. In the recent years, efforts to increase donation has improved the rate of mainly deceased donors after circulatory death and from older donors. The rate of donation from pediatric population has remained low and those younger than 2 years including neonatal donation has remained largely unexplored. METHODS: A retrospective review of the outcome of renal transplantation from pediatric donor (<18 years) kidneys in the United Kingdom. RESULTS: Our results show a poor referral and conversion rate, and high discard rate (43%) of kidneys procured from donors younger than 2 years. During the 15-year study period (1997-2011), 47 donors younger than 2 years were referred (3 per year). Of these, 26 proceeded to donation resulting in 17 transplants (65% utilization). The referral rate for donors 2 years or older to younger than 5 years also remains low (76 in 15 years), but the conversion (88%) and utilization rates (73%) are better in this group. There was better utilization in donors aged 5 years or older to younger than 18 years. Overall graft and patient survival remains excellent in all 3 groups; with comparable survival of 82%, 85%, and 77% (P = 0.29) with mean follow-up periods of 9, 12.5, and 11.8 years, respectively. CONCLUSIONS: Despite excellent outcome, the referral, donation, and utilization of kidneys from donors younger than 5 years and particularly those younger than 2 years remain low. We suggest implementing improved strategies to increase donation from this group of population.

Alemtuzumab induction in renal transplantation permits safe steroid avoidance with tacrolimus monotherapy: a randomized controlled trial.

BACKGROUND: The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). METHODS: We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection. RESULTS: The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57±26 mL/min for alemtuzumab group and 53±21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy-proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months. CONCLUSIONS: Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year.

A comparison of the analytical performance of five commercially available assays for neutrophil gelatinase-associated lipocalin using urine.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for acute kidney injury that is beginning to be used in clinical practice in addition to research studies. The current study describes an independent validation and comparison of five commercially available NGAL assays, focusing on urine samples. This is an essential step in the translation of this marker to clinical use in terms of allowing valid inter-study comparison and generation of robust results. METHODS: Two CE (Conformité Européenne)-marked assays, the NGAL Test (BioPorto) on Siemens ADVIA(®) 1800 and the ARCHITECT Urine NGAL assay on i2000SR (Abbott Laboratories), and three research-use-only (RUO) ELISAs (R&D Systems, Hycult and BioPorto) were evaluated. Imprecision, parallelism, recovery, selectivity, limit of quantitation (LOQ), vulnerability to interference and hook effect were assessed and inter-assay agreement was determined using 68 urine samples from patients with various renal diseases and healthy controls. RESULTS: The Abbott and R&D Systems assays demonstrated satisfactory performance for all parameters tested. However for the other three assays evaluated, problems were identified with LOQ (BioPorto/ADVIA(®)), parallelism (BioPorto ELISA) or several parameters (Hycult). Between-method agreement varied with the Hycult assay in particular being markedly different and highlighting issues with standardization and form of NGAL measured. CONCLUSIONS: Variability exists between the five NGAL assays in terms of their performance and this should be taken into account when interpreting results from the various clinical or research studies measuring urinary NGAL.

Detection of patients with acute kidney injury by the clinical laboratory using rises in serum creatinine: comparison of proposed definitions and a laboratory delta check.

BACKGROUND: Timely detection of acute kidney injury (AKI) in hospital patients has been hampered by the multiple definitions of AKI and difficulties applying their criteria. A laboratory delta check may provide an effective means of detecting patients developing AKI. This study compared three of the proposed AKI definitions and a delta check to detect AKI using serum creatinine results of hospital inpatients. METHODS: Serum creatinine results for 2822 inpatients were gathered retrospectively from the clinical biochemistry database. All serum creatinine results within 30 d of admission were included for each patient and assessed for AKI according to four criteria: Risk, Injury, Failure (RIFLE), Acute Kidney Injury Network (AKIN), Waikar & Bonventre or a delta check (increase of >26 µmol/L between two successive values). RESULTS: A total of 149 (11.3%) patients were defined as having AKI by at least one of the four criteria. Different populations of patients were identified by each criterion. The number of patients identified and the incidence of AKI were as follows: RIFLE 94 (7.1%), AKIN 125 (9.5%), Waikar & Bonventre 100 (7.6%) and delta check 146 (11.1%). The delta check detected 132 (98%) of all 135 cases detected by the other three criteria. A further 14 patients were detected solely by the delta check. CONCLUSIONS: The different definitions proposed for AKI detect different populations of patients. A laboratory delta check detected 98% of all the patients identified by AKIN, RIFLE and Waikar & Bonventre combined and could therefore provide a practical way of detecting AKI patients.

The outcomes of critically ill patients with acute kidney injury receiving renal replacement therapy.

INTRODUCTION: Acute kidney injury (AKI) is common among critically ill patients and associated with a high mortality. We report here on the outcomes of patients with AKI who received renal replacement therapy (RRT) on our intensive care unit (ICU). We were interested in which parameters measured at the time of ICU admission were predictive of mortality and the long term renal sequelae for these patients. PATIENTS AND METHODS: All ICU patients in a large UK teaching hospital who received RRT for AKI over a 6-year period were identified and reviewed retrospectively. RESULTS: There were 5582 admissions to ICU during this period of which 821 (14.7%) received RRT for AKI. The mean age was 59 years with ICU and hospital mortality rates of 55% and 66% respectively. Logistic regression analysis indicated that being older (OR 1.02 (1.01-1.03)) or having a lower pH (OR 0.07 (0.02-0.27)) or hemoglobin (OR 0.82 (0.74-0.91)) at the time of admission were predictive of mortality. Less than 7% of survivors were RRT dependant at hospital discharge and the majority had pre-existing renal impairment. For those patients with data available, there was a significant rise in the serum creatinine by 12 months post discharge (p<0.001). CONCLUSIONS: The mortality for critically ill patients receiving RRT for AKI is high, with two-thirds dying before hospital discharge. The requirement for long-term dialysis was 6.5% of survivors in our series which is much lower than that published elsewhere. Survivors of AKI who regained independent renal function had evidence of lasting renal injury.

Acute kidney injury: how do we define it?

Over recent years, there has been welcome increased interest in acute kidney injury (AKI) and its association with patient outcome. The term AKI has replaced the term acute renal failure (ARF) and encompasses all types of ARF. New definitions and staging systems for AKI have been proposed, which have stimulated a multitude of different studies to evaluate their clinical utility. These recent advances need to be communicated to the wider health care community so that we are using a shared nomenclature. In 2009 the National Confidential Enquiry into Patient Outcome and Death AKI study ('Adding Insult to Injury') announced its findings and recommendations. The report recommended that the detection of AKI and its management should be improved. These recommendations along with the adoption of the new staging systems will potentially have an impact on clinical biochemistry departments and exert an increased demand on resources. Running in parallel with these initiatives is the quest to discover novel biomarkers to detect AKI, the development and introduction of which will require laboratory support.

The clinical significance of early proteinuria after renal transplantation.

BACKGROUND: Late-onset proteinuria after renal transplantation has been universally associated with poor allograft outcomes. However, the significance of early low-grade posttransplant proteinuria remains uncertain. METHODS: We analyzed the effect of proteinuria 3 months posttransplantation on death-censored graft loss, death with a functioning graft, vascular events within the graft's life, and estimated glomerular filtration rate at 5 years. Four hundred seventy-seven renal transplants from a single center (1988-2003) with a mean follow-up of 122 months were divided into four groups based on the median protein creatinine ratio (PCR) during the 3rd posttransplant month (PCR<0.15 [group 1, n=85]; PCR 0.15-0.5 [group 2, n=245]; PCR 0.5-1.00 [group 3, n=96]; PCR>1.00 [group 4, n=51]). Cox proportional hazards analysis was performed to study the impact of proteinuria on the various outcomes. RESULTS: Multivariate analysis revealed that even low-level proteinuria at 3 months predicted death-censored graft failure (group 1 [reference]--hazard ratio [HR]=1, group 2--HR=7.1, group 3--HR = 10.5, group 4--HR 16.0; P=0.001). The impact on death and the occurrence of vascular events was only significant for group 4 (HR: 2.6; P=0.01 for death and HR: 2.2; P=0.04 for vascular events). Estimated glomerular filtration rate at 5 years was group 1, 48.5 mL/min; group 2, 41.2 mL/min; group 3, 31.1 mL/min; and group 4, 24.5 mL/min (P<0.001). Continued observation of group 2 to 1 year revealed adverse outcomes with increasing proteinuria. CONCLUSIONS: Low-grade proteinuria at 3 months is associated with adverse clinical outcomes and identifies high-risk group of patients who may benefit from further intervention.