Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Autosomal dominant hypercalciuric hypocalcaemia: the calcium-sensing receptor in renal calcium homeostasis and the impact of renal transplantation.

Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.

Kidney functional reserve and damage biomarkers in subclinical chronic kidney disease and acute kidney injury.

Significant loss of kidney function is not easily identified by serum creatinine (sCr)-based measurements. In the presence of normal sCr, decreased kidney functional reserve (KFR) may identify a significant loss of function. We evaluated KFR in experimental subclinical chronic kidney disease (sCKD) before and after brief ischemia-reperfusion injury (IRI). Using fluorescein isothiocyanate-labeled sinistrin, glomerular filtration rate (GFR) was measured transcutaneously before and after adenine-induced sCKD, and 1 and 2 wk after brief IRI, and compared with urinary kidney damage biomarkers. sCKD reduced stimulated and unstimulated GFR by ∼20% while reducing KFR by 50%. IRI reduced unstimulated GFR for 14 days, but KFR remained relatively unchanged in sCKD and transiently increased in control kidneys at 7 days. sCr increased and creatinine clearance (CrCl) decreased only immediately after IRI; sCr and CrCl correlated poorly with measured GFR except on day 1 after IRI. Heterogeneity in sCr and CrCl resulted from variation in tubular creatinine secretion. The increase in damage biomarker concentrations persisted for up to 14 days after IRI, allowing retrospective detection of sCKD before AKI by urine clusterin/urine kidney injury molecule-1 with an area under the curve of 1.0. sCr and CrCl are unreliable unless sCr is acutely elevated. Measurement of KFR and urine damage biomarker excretion detected sCKD despite normal sCr and CrCl. After IRI, the urine clusterin-to-urine kidney injury molecule-1 ratio may identify prior sCKD.NEW & NOTEWORTHY Early kidney function loss is poorly identified by serum creatinine (sCr)-based measurements. Direct kidney functional reserve (KFR) measurement before kidney injury and elevated urinary biomarkers clusterin and kidney injury molecule-1 detect subclinical chronic kidney disease (sCKD) after kidney injury despite normal range sCr and creatinine clearance. Reliance on sCr masks underlying sCKD. Acute kidney injury risk evaluation requires direct glomerular filtration rate measurement and KFR, whereas kidney damage biomarkers facilitate identification of prior subclinical injury.

Electronic alerts and a care bundle for acute kidney injury-an Australian cohort study.

BACKGROUND: Early recognition of hospital-acquired acute kidney injury (AKI) may improve patient management and outcomes. METHODS: This multicentre study was conducted at three hospitals (H1-intervention; H2 and H3-controls) served by a single laboratory. The intervention bundle [an interruptive automated alerts (aAlerts) showing AKI stage and baseline creatinine in the eMR, a management guide and junior medical staff education] was implemented only at H1. Outcome variables included length-of-stay (LOS), all-cause in-hospital mortality and management quality. RESULTS: Over 6 months, 639 patients developed AKI (265 at H1 and 374 at controls), with 94.7% in general wards; 537 (84%) patients developed Stage 1, 58 (9%) Stage 2 and 43 (7%) Stage 3 AKI. Median LOS was 9 days (IQR 4-17) and was not different between intervention and controls. However, patients with AKI stage 1 had shorter LOS at H1 [median 8 versus 10 days (P = 0.021)]. Serum creatinine had risen prior to admission in most patients. Documentation of AKI was better in H1 (94.8% versus 83.4%; P = 0.001), with higher rates of nephrology consultation (25% versus 19%; P = 0.04) and cessation of nephrotoxins (25.3 versus 18.8%; P = 0.045). There was no difference in mortality between H1 versus controls (11.7% versus 13.0%; P = 0.71). CONCLUSIONS: Most hospitalized patients developed Stage 1 AKI and developed AKI in the community and remained outside the intensive care unit (ICU). The AKI eAlert bundle reduced LOS in most patients with AKI and increased AKI documentation, nephrology consultation rate and cessation of nephrotoxic medications.

Plasma arginine metabolites in health and chronic kidney disease.

BACKGROUND: Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. METHODS: ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography-tandem mass spectrometry. RESULTS: In a healthy DMHDS subset (n = 376), mean concentrations were: ADMA (0.40 ± 0.06 µmol/L), SDMA (0.42 ± 0.06 µmol/L), L-arginine (93.5 ± 23.1 µmol/L) and L-citrulline (24.0 ± 5.4 µmol/L). In the total cohort (n = 857), SDMA correlated positively with serum creatinine (Pearson's r = 0.55) and pCYSC (r = 0.55), and negatively with eGFR (r = 0.52). A separate cohort of 38 patients with stage 3-4 CKD (eGFR 15-60 mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61 ± 0.11 µmol/L), SDMA (0.65 ± 0.25 µmol/L) and L-citrulline (42.7 ± 11.8 µmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. CONCLUSIONS: Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.

Medication use and hospital-acquired acute kidney injury: an electronic health record-based study.

BACKGROUND AND AIMS: Medications remain an important contributor to the development of acute kidney injury (AKI). This study aimed to examine associations between (i) administration of medications known to reduce glomerular filtration rate (GFR), that is, GFR modifiers and subsequent hospital-acquired AKI; and (ii) potentially medication-related AKI and patient adverse outcomes. METHODS: A retrospective cohort study utilising electronic health record data of patients admitted to a tertiary hospital in Australia in 2015. Timing of medication administration was compared with timing of AKI development. AKI cases were identified using an algorithm based on serum creatinine level changes. Multilevel regression models were applied with adjustment for relevant demographic and clinical factors. RESULTS: Among 11 503 admissions, AKI was identified in 955 patients (8.3%) and 637 (66.7% of 955) were preceded by administration of a GFR modifier. Patients without prior AKI were 17% more likely to develop AKI after administration of these medications (adjusted odds ratio 1.17, 95% confidence interval (CI) 1.003-1.37). Older age and comorbidity with diabetes, acute myocardial infarction, peripheral vascular disease, liver cirrhosis and multiple myeloma were also significant predictors. Patients with potentially medication-related AKI were 11.69 times more likely to die in hospital (95% CI 7.84-17.43) and stayed 3.49 times longer in hospital (95% CI 3.26-3.73), compared with those without AKI. CONCLUSIONS: Administration of medications contributing to the reduction of GFR is associated with an increased risk of hospital-acquired AKI and worse patient outcomes. Caution is required when prescribing these medications to patients at risk of developing AKI, and monitoring patients for deterioration is needed if administered.

Definitions, phenotypes, and subphenotypes in acute kidney injury-Moving towards precision medicine.

The current definition of acute kidney injury (AKI) is generic and, based only on markers of function, is unsuitable for guiding individualized treatment. AKI is a complex syndrome with multiple presentations and causes. Targeted AKI management will only be possible if different phenotypes and subphenotypes of AKI are recognised, based on causation and related pathophysiology. Molecular signatures to identify subphenotypes are being recognised, as specific biomarkers reveal activated pathways. Assessment of individual clinical risk needs wider dissemination to allow identification of patients at high risk of AKI. New and more timely markers for glomerular filtration rate (GFR) are available. However, AKI diagnosis and classification should not be limited to GFR, but include tubular function and damage. Combining damage and stress biomarkers with functional markers enhances risk prediction, and identifies a population enriched for clinical trials targeting AKI. We review novel developments and aim to encourage implementation of these new techniques into clinical practice as a strategy for individualizing AKI treatment akin to a precision medicine-based approach.

Comparison of SPEED, S-Trap, and In-Solution-Based Sample Preparation Methods for Mass Spectrometry in Kidney Tissue and Plasma.

Mass spectrometry is a powerful technique for investigating renal pathologies and identifying biomarkers, and efficient protein extraction from kidney tissue is essential for bottom-up proteomic analyses. Detergent-based strategies aid cell lysis and protein solubilization but are poorly compatible with downstream protein digestion and liquid chromatography-coupled mass spectrometry, requiring additional purification and buffer-exchange steps. This study compares two well-established detergent-based methods for protein extraction (in-solution sodium deoxycholate (SDC); suspension trapping (S-Trap)) with the recently developed sample preparation by easy extraction and digestion (SPEED) method, which uses strong acid for denaturation. We compared the quantitative performance of each method using label-free mass spectrometry in both sheep kidney cortical tissue and plasma. In kidney tissue, SPEED quantified the most unique proteins (SPEED 1250; S-Trap 1202; SDC 1197). In plasma, S-Trap produced the most unique protein quantifications (S-Trap 150; SDC 148; SPEED 137). Protein quantifications were reproducible across biological replicates in both tissue (R2 = 0.85-0.90) and plasma (SPEED R2 = 0.84; SDC R2 = 0.76, S-Trap R2 = 0.65). Our data suggest SPEED as the optimal method for proteomic preparation in kidney tissue and S-Trap or SPEED as the optimal method for plasma, depending on whether a higher number of protein quantifications or greater reproducibility is desired.

Peripheral nerve morphology and intraneural blood flow in chronic kidney disease with and without diabetes.

INTRODUCTION/AIMS: Sonographic alterations of peripheral nerves in pre-dialytic kidney disease are yet to be determined. We aimed to assess peripheral nerve cross-sectional area (CSA) and intraneural blood flow in patients with pre-dialytic chronic kidney disease (CKD) and diabetic kidney disease (DKD). METHODS: Subjects with CKD (n = 20) or DKD (n = 20) underwent ultrasound to assess CSA of the median and tibial nerves as well as intraneural blood flow of the median nerve. Blood flow was quantified using maximum perfusion intensity. Neuropathy was assessed using the Total Neuropathy Score. A 6-m timed walk test was also performed. Healthy controls (n = 28) were recruited for comparison. RESULTS: The DKD group had more severe neuropathy (p = .024), larger tibial nerve CSA (p = .002) and greater median nerve blood flow than the CKD group (p = .023). Blood flow correlated with serum potassium in disease groups (r = 0.652, p = .022). Disease groups had larger tibial nerve CSA than controls (p < .05). No blood flow was detected in controls. Tibial nerve enlargement was associated with slower maximal walking speeds in disease groups (r = -0.389, p = .021). DISCUSSION: Subjects with DKD demonstrated enlarged tibial nerve CSA and increased median nerve blood flow compared to those with CKD. Elevations in serum potassium were associated with increased blood flow. Sonographic alterations were detectable in pre-dialytic kidney disease compared to controls, highlighting the utility of ultrasound in the assessment of nerve pathology in these patient groups.

Cystatin C kidney functional reserve: a simple method to predict outcome in chronic kidney disease.

BACKGROUND: Kidney functional reserve (KFR), the only clinical kidney stress test, is not routinely measured because the complexity of measurement has limited clinical application. We investigated the utility of plasma cystatin C (CysC) after oral protein loading (PL) to determine KFR in Stages 3 and 4 chronic kidney disease (CKD). METHODS: Following a 24-h low-protein diet, KFR was measured after oral protein by hourly plasma CysC and compared with simultaneous creatinine clearance (CrCl) and radionuclide 99technetium diethylenetriaminepentaacetatic acid (Tc-99m-DTPA) measured glomerular filtration rate (mGFR) measurement in an observational, single-centre cohort study of adults with CKD Stages 3 and 4. Subjects were followed for 3 years for fast (F) or slow (S) CKD progression, dialysis requirement or death or a combination of major adverse kidney events (MAKEs). RESULT: CysC, CrCl and Tc-99m-DTPA mGFR measurements of KFR in 19 CKD Stage 3 and 21 CKD Stage 4 patients yielded good agreement. KFR was not correlated with baseline kidney function. Eight CKD Stage 3 (42%) and 11 CKD Stage 4 (52%) subjects reached their lowest serum CysC concentration 4 h after PL. CysC KFR and baseline serum creatinine (sCr) predicted death or dialysis or MAKE-F with a respective area under the curve (AUC) of 0.73 [95% confidence interval (CI) 0.48-0.89] and 0.71 (95% CI 0.51-0.84). Including CysC KFR, age, baseline sCr and nadir CysC predicted a decrease in sCr-estimated GFR >1.2 mL/min/year (MAKE-S) with an AUC of 0.89. CONCLUSIONS: Serial CysC avoided timed urine collection and radionuclide exposure and yielded equivalent estimates of KFR. Serial CysC may facilitate monitoring of KFR in clinical practice.

Peripheral neuropathy: an important contributor to physical limitation and morbidity in stages 3 and 4 chronic kidney disease.

BACKGROUND: Impaired physical function drives adverse outcomes in chronic kidney disease (CKD). Peripheral neuropathy is highly prevalent in CKD, though its contribution to physical function in CKD patients is unknown. This study examined the relationships between peripheral neuropathy, walking speed and quality of life (QoL) in stages 3 and 4 CKD. METHODS: This was a prospective observational study investigating neuropathy in CKD patients with an estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73 m2. A total of 109 patients were consecutively recruited. The presence and severity of peripheral neuropathy was determined using the total neuropathy score. Walking speed was assessed at both usual and maximal speed, and QoL was assessed using the Short- Form 36 (SF-36) questionnaire. RESULTS: Peripheral neuropathy was highly prevalent: 40% demonstrated mild neuropathy and 37% had moderate-severe neuropathy. Increasing neuropathy severity was the primary predictor of reduced walking speed (R2 = -0.41, P < 0.001) and remained so after multivariable analysis adjustment for diabetes. This association was evident for both usual and maximal walking speeds. Neuropathy correlated significantly with low scores on multiple domains of SF-36 including physical function (r = -0.570, P < 0.001). Subanalysis according to diabetic status revealed a high prevalence of neuropathy both with and without diabetes; relationships to walking speed remained evident in subgroup analysis. However, those with diabetes demonstrated greater severity of neuropathy, slower walking speed and lower scores in QoL. CONCLUSIONS: Moderate to severe peripheral neuropathy was common in stages 3 and 4 CKD, associated with reduced walking speed independent of diabetes status and was correlated with patient-reported QoL. This suggests that neuropathy is an important contributor to declining physical function in CKD irrespective of diabetes status. Targeted diagnosis and management of peripheral neuropathy during CKD progression may improve functional outcomes and QoL.

Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure.

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)-an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra-mass spectrometry (SWATH-MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2-2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Prevalence, types and recognition of cognitive impairment in dialysis patients in South Eastern Sydney.

BACKGROUND: In international studies, cognitive impairment is a common but underdetected issue in dialysis patients. Chronic kidney disease (CKD) shares risk factors with and is an independent risk factor for cognitive impairment. There is a lack of Australian data on cognitive impairment in this at-risk population. This has implications on service planning because cognitive impairment in CKD is associated with higher mortality, morbidity and healthcare costs. AIMS: To examine the prevalence, types and clinician recognition of cognitive impairment within an Australian dialysis population. METHODS: A cross-sectional study of haemodialysis and peritoneal dialysis patients in South Eastern Sydney screened for cognitive impairment using the Montreal Cognitive Assessment (MoCA). Participant interviews, medical records, physician and carer questionnaires, were used to determine the types of cognitive impairment and rate of recognition. RESULTS: One hundred and six participants were included (median age 66 years, median dialysis duration 2 years) and 58 (54.7%) were cognitively impaired on the MoCA, of whom old age psychiatrists sub-classified 21 (36.2%) as having dementia, and 31 (53.4%) with 'cognitive impairment, no dementia'; 36/58 (62.0%) of the cognitively impaired participants on the MoCA were suspected of having cognitive impairment by nephrologists but only 14/58 (24.1%) had this documented in medical records. CONCLUSION: Although cognitive impairment is common in dialysis patients, there are low levels of detection by clinical teams. Cognitive screening of dialysis patients should be incorporated as part of wider assessment and determination of management goals such as individuals' capacity to self-care and provide informed consent to treatments.

The kinetic estimated glomerular filtration rate ratio predicts acute kidney injury.

AIM: Kinetic estimated Glomerular Filtration Rate (KeGFR) approximates GFR under non-steady-state conditions. We investigated whether the ratio of KeGFR difference to baseline eGFR could predict acute kidney injury (AKI) earlier than a creatinine-based algorithm that triggered an AKI electronic Alert (eAlert). METHODS: This retrospective, single-centre, proof-of-concept cohort study assessed all patients diagnosed with AKI by an automated serum creatinine-based eAlert. The kinetic eGFR, the kinetic eGFR difference from baseline and the ratio of difference to baseline was calculated in subjects with at least two serum creatinine (sCr) measurements within 72 h of AKI. RESULTS: Patients in the AKI cohort (n = 140) had a significant decline in KeGFR ratio (AKI: 17% IQR 7% to 29%, Non-AKI: 0 IQR -12% to 9%; P-value <.0001). A decrease of the ratio greater than 10% predicted AKI with a sensitivity of 66%, a specificity of 77%, a positive predictive value of 63%, and negative predictive value of 80%. The median lead time between KeGFR ratio decrease and AKI was 24 h (IQR: 19-27 h). CONCLUSIONS: KeGFR ratio is a cheap, simple method that predicted AKI 24 h before laboratory detection. KeGFR may facilitate triaging patients to increased monitoring or intervention.

Targeted protection of proximal tubular cells by nanoparticle-enhanced delivery of a TLR9-antagonist.

The kidney target site for injury that leads to acute kidney injury (AKI) is the proximal tubule. Nanoparticle-encapsulation enhanced delivery of a selective Toll-like receptor 9 antagonist to mouse proximal tubules and attenuated experimental ischemia-reperfusion injury in a mouse model of AKI.

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

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

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Identification of acute kidney injury subphenotypes.

PURPOSE OF REVIEW: AKI is a complex clinical syndrome with many causes and there is a broad range of clinical presentations that vary according to duration, severity and context. Established consensus definitions of AKI are nonspecific and limited to kidney function. This reduces treatment options to generic approaches rather than individualized, cause-based strategies that have limited both understanding and management of AKI. RECENT FINDINGS: The context and the temporal phase of kidney injury are critical features in the course of AKI and critical to timing-relevant intervention. These features are missing in generic definitions and terms used to describe AKI. Subphenotypes of AKI can be identified from novel damage biomarkers, from functional changes including creatinine trajectories, from the duration of change and from associated clinical characteristics and comorbidities. Subphenotype parameters can be combined in risk scores, or by association strategies ranging from a simple function-damage matrix to complex methods, such as machine learning. Examples of such strategies are reviewed along with tentative proposals for a revised nomenclature to facilitate description of AKI subphenotypes. SUMMARY: Appropriate intervention requires refinement of the nomenclature of AKI to identify subphenotypes that facilitate correctly timed and selectively targeted intervention.

Under-detection of acute kidney injury in hospitalised patients: a retrospective, multi-site, longitudinal study.

BACKGROUND: Acute kidney injury (AKI) is a rapid deterioration of renal function, often caused by a variety of co-existing morbidities complicating its recognition and treatment, leading to short- and long-term adverse clinical outcomes. There are limited data on the incidence of AKI in Australia using the Kidney Disease Improving Global Outcomes creatinine-based consensus definition. AIM: To determine the incidence and estimate the extent of under-reporting of AKI in four hospitals in the South-Eastern Sydney/Illawarra regions of New South Wales, Australia. METHOD: A laboratory algorithm based on the Kidney Disease Improving Global Outcomes creatinine-based definition for AKI was applied retrospectively to laboratory data for adult patients admitted to the study hospitals between 2009 and 2013 to identify those with AKI. The results were compared with the incidence of AKI based on diagnostic codes for AKI reported for the same period. RESULTS: AKI was detected in 12.4% of all hospitalisations (46 101/370 969) and 16.4% of patients (31 448/192 133) across the 5-year study period using the laboratory algorithm. Of these, 72.1% were AKI Stage 1 (33 246/46101). AKI was coded in only 15.9% of hospitalisations with AKI Stage 1 (5294/33 246), 38.5% of hospitalisations with Stage 2 (2381/6185), and 46.8% with Stage 3 (3120/6670). Yearly incidence of laboratory-identified AKI trended downward between 2009 and 2013, while annual incidence determined by coding trended upward. CONCLUSION: Although coding trends suggested a continuous increase in clinician awareness of AKI across the study period, AKI in hospitalised patients remained significantly under-reported.

Chronic methyl bromide toxicity is ameliorated by haemodialysis.

Methyl bromide is an odourless, colourless, highly volatile gas, primarily used in fumigation. It can cause significant neurotoxicity, especially with chronic exposure. Haemodialysis has been used in acute toxicity, but its utility in chronic exposure has never been reported. We report the use of haemodialysis in a 20-year-old man with chronic methyl bromide toxicity affecting the optic nerves, brain and spinal cord. The patient underwent eight haemodialysis sessions with improvement in plasma bromine concentration, half-life and marked clinical recovery. The case demonstrates the utility of haemodialysis in the treatment of chronic methyl bromide toxicity.