Clinical Characteristics and Outcomes of Drug-Induced Acute Kidney Injury Cases.

Introduction: Drug-induced acute kidney injury (DI-AKI) is a frequent adverse event. The identification of DI-AKI is challenged by competing etiologies, clinical heterogeneity among patients, and a lack of accurate diagnostic tools. Our research aims to describe the clinical characteristics and predictive variables of DI-AKI. Methods: We analyzed data from the Drug-Induced Renal Injury Consortium (DIRECT) study (NCT02159209), an international, multicenter, observational cohort study of enriched clinically adjudicated DI-AKI cases. Cases met the primary inclusion criteria if the patient was exposed to at least 1 nephrotoxic drug for a minimum of 24 hours prior to AKI onset. Cases were clinically adjudicated, and inter-rater reliability (IRR) was measured using Krippendorff's alpha. Variables associated with DI-AKI were identified using L1 regularized multivariable logistic regression. Model performance was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: A total of 314 AKI cases met the eligibility criteria for this analysis, and 271 (86%) cases were adjudicated as DI-AKI. The majority of the AKI cases were recruited from the United States (68%). The most frequent causal nephrotoxic drugs were vancomycin (48.7%), nonsteroidal antiinflammatory drugs (18.2%), and piperacillin/tazobactam (17.8%). The IRR for DI-AKI adjudication was 0.309. The multivariable model identified age, vascular capacity, hyperglycemia, infections, pyuria, serum creatinine (SCr) trends, and contrast media as significant predictors of DI-AKI with good performance (ROC AUC 0.86). Conclusion: The identification of DI-AKI is challenging even with comprehensive adjudication by experienced nephrologists. Our analysis identified key clinical characteristics and outcomes of DI-AKI compared to other AKI etiologies.

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.

The use of peritoneal dialysis in heart failure: A systematic review.

Heart failure (HF) is a major cause of morbidity and mortality. Extracorporeal (EC) therapy, including ultrafiltration (UF) and haemodialysis (HD), peritoneal dialysis (PD) and peritoneal ultrafiltration (PUF) are potential therapeutic options in diuretic-resistant states. This systematic review assessed outcomes of PD and compared the effects of PD to EC. A comprehensive search of major databases from 1966 to 2017 for studies utilising PD (or PUF) in diuretic-resistant HF was conducted, excluding studies involving patients with end-stage kidney disease. Data were extracted and combined using a random-effects model, expressed as odds ratio (OR). Thirty-one studies (n = 902) were identified from 3195 citations. None were randomised trials. Survival was variable (0-100%) with a wide follow-up duration (36 h-10 years). With follow-up > 1 year, the overall mortality was 48.3%. Only four studies compared PD with EC. Survival was 42.1% with PD and 45.0% with EC; the pooled effect did not favour either (OR 0.80; 95% confidence interval (CI): 0.24-2.69; p = 0.710). Studies on PD in patients with HF reported several benefits. Left ventricular ejection fraction (LVEF) improved after PD (OR 3.76, 95%CI: 2.24-5.27; p < 0.001). Seven of nine studies saw LVEF increase by > 10%. Twenty-one studies reported the New York Heart Association status and 40-100% of the patients improved by ≥ 1 grade. Nine of 10 studies reported reductions in hospitalisation frequency and/or duration. When treated with PD, HF patients had fewer symptoms, lower hospital admissions and duration compared to diuretic therapy. However, there is inadequate evidence comparing PD versus UF or HD. Further studies comparing these modalities in diuretic-resistant HF should be conducted.

Toward Precision Medicine in the Cardiorenal Syndrome.

Although the field of oncology has made significant steps toward individualized precision medicine, cardiology and nephrology still often use a "one size fits all" approach. This applies to the intersection of the heart-kidney interaction and the cardiorenal syndrome as well. Recent studies have shown that the prognostic implications of worsening renal function (WRF) in acute heart failure are variable; thus, there is a need to differentiate the implications of WRF to better guide precise care. This may best be performed with biomarkers that can give the clinician a real-time evaluation of the physiologic state at the time of developing WRF. This review will summarize current cardiac and renal biomarkers and their status in the evaluation of cardiorenal syndrome. Although we have made progress in our understanding of this syndrome, further investigation is needed to bring precision medicine into routine clinical practice for the care of patients with cardiorenal syndrome.

Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.

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.

We Use Permcaths Instead of Peritoneal Catheters for Acute Kidney Injury and Urgent-Start Dialysis.

The rising tide of severe acute kidney injury requiring dialysis (AKI-D) and unplanned dialysis initiation for advanced CKD patients remains a major problem for the nephrology community worldwide. Hemodialysis (HD) through a central venous catheter remains the most common practice for both. Peritoneal dialysis (PD) remains greatly underutilized despite mounting evidence of equipoise with HD for a significant proportion of patients. PD is technically simpler, requires less infrastructure, and costs less. However, the structure of our healthcare system, hospital logistics, and the current state of nephrology training all contribute to the reflexive consult for a central venous catheter. As clinicians, we must ask ourselves if we are doing our patients and our healthcare system a disservice by not offering PD in AKI and urgent-start situations.

A comparison of three commercial platforms for urinary NGAL in critically ill adults.

BACKGROUND: Early biomarkers for acute kidney injury (AKI) diagnosis are needed since an increase in serum creatinine levels is a late marker. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising AKI biomarkers. Prior to routine clinical use, it is necessary to evaluate and validate a high-throughput commercially available method for NGAL detection. The aim of this study was to do an independent validation and comparison of the analytical performance of three different commercially available urine NGAL (uNGAL) assays. METHODS: Urine samples (n=110) were obtained from various patient groups with and without AKI. All urine samples were processed using Architect NGAL assay, Siemens Advia® 2400 NGAL test, and Siemens Dimension Vista® NGAL Test™, based on the three different platforms. RESULTS: Overall, there was good agreement among the three assays: Spearman's rank correlation coefficient between Architect and Vista was 0.989 (95% confidence interval [CI], 0.983-0.993), between Architect and Advia, 0.962 (95% CI, 0.937-0.977), between Vista and Advia 2400, 0.975 (95% CI, 0.961-0.984). We observed a negative bias of Architect compared with the other assays: comparing Architect to Vista, the mean bias was -55.7 ng/mL (95% CI, -74.3 to -37.0 ng/mL); comparing Architect to Advia 2400, the mean bias was -40.9 ng/mL (95% CI, -56.4 to -25.4 ng/nL). The bias is proportional to the concentration of uNGAL and is more pronounced at higher levels, while irrelevant near the tested cutoff levels of 100 and 190 ng/mL. Comparing Vista and Advia 2400, the mean bias was 10.1 ng/mL (95% CI, 1.5-18.8 ng/mL). Intra-assay imprecision was generally acceptable across all assays; coefficient of variation ranged from 0.8% to 5.3%. CONCLUSIONS: All three methods for uNGAL showed acceptable performance for the tested parameters and are comparable with each other at clinically relevant cutoffs. However, Architect yields lower results than the other two methods, with a bias more pronounced at higher uNGAL concentrations, suggesting additional standardization efforts will likely be necessary to better harmonize the uNGAL methods at various clinically relevant cutoffs.

Pro-Apoptotic Effects of Plasma from Patients with Cardiorenal Syndrome on Human Tubular Cells.

BACKGROUND: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. METHODS: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. RESULTS: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). CONCLUSION: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis.

Promoting Kidney Function Recovery in Patients with AKI Requiring RRT.

AKI requiring RRT is associated with high mortality, morbidity, and long-term consequences, including CKD and ESRD. Many patients never recover kidney function; in others, kidney function improves over a period of many weeks or months. Methodologic constraints of the available literature limit our understanding of the recovery process and hamper adequate intervention. Current management strategies have focused on acute care and short-term mortality, but new data indicate that long-term consequences of AKI requiring RRT are substantial. Promotion of kidney function recovery is a neglected focus of research and intervention. This lack of emphasis on recovery is illustrated by the relative paucity of research in this area and by the lack of demonstrated effective management strategies. In this article the epidemiologic implications of kidney recovery after AKI requiring RRT are discussed, the available literature and its methodologic constraints are reviewed, and strategies to improve the understanding of factors that affect kidney function recovery are proposed. Measures to promote kidney function recovery are a serious unmet need, with a great potential to improve short- and long-term patient outcomes.

Outpatient Dialysis for Patients with AKI: A Policy Approach to Improving Care.

The rate of AKI requiring dialysis has increased significantly over the past decade in the United States. At the same time, survival from AKI seems to be improving, and thus, more patients with AKI are surviving to discharge while still requiring dialysis. Currently, the options for providing outpatient dialysis in patients with AKI are limited, particularly after a 2012 revised interpretation of the Centers for Medicare and Medicaid Services guidelines, which prohibited Medicare reimbursement for acute dialysis at ESRD facilities. This article provides a historical perspective on outpatient dialysis management of patients with AKI, reviews the current clinical landscape of care for these patients, and highlights key areas of knowledge deficit. Lastly, policy changes that have the opportunity to significantly improve the care of this at-risk population are suggested.

Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.

PURPOSE: Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients. METHODS: The Acute Kidney Injury-Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge. RESULTS: A total of 1032 ICU patients out of 1802 [57.3%; 95% confidence interval (CI) 55.0-59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95% CI 0.890-3.169; p = 0.109), stage 2 = 2.945 (95% CI 1.382-6.276; p = 0.005), and stage 3 = 6.884 (95% CI 3.876-12.228; p < 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) in 47.7% (95% CI 43.6-51.7) versus 14.8% (95% CI 11.9-18.2) in those without AKI, p < 0.001. CONCLUSIONS: This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.

[Plasma NGAL and ADPKD progression]. / Ruolo di NGAL nella progressione dell'insufficienza renale determinata da ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease with variable rate of progression. It is associated with inter- and intra-familial variability. Neutrophil gelatinase-associated lipocalin (NGAL) has been implicated in pathological conditions and it is proposed as a biomarker for CKD progression. Our aim was to evaluate whether NGAL could be a good marker for progression of ADPKD, as we hypothesized. ADPKD patients with confirmed mutations (PKD1 n=33; PKD2 n=17) were enrolled and followed in a prospective study. Creatinine (sCr) and NGAL values were measured at baseline and on follow-up. Plasma NGAL was measured by Triage point of care test. CKD progression was defined as 15% decrease in eGFR from baseline to follow-up. Patients were divided into 2 groups based on median baseline NGAL and compared by the Kaplan-Meier curve. We enrolled 50 ADPKD pts (60%M age 41 yrs); mean sCr 1.30.7 mg/dl and median eGFR was 62 mL/min/1.73 m2. NGAL values are inversely correlated with baseline eGFR (r=-0.64, p<0.001). There was weak correlation between baseline NGAL and subsequent change in eGFR (r=0.28, p=0.05). 9/50 of patients had NGAL below limits of detection (60 pg/ml); median NGAL level was 79 pg/ml. At follow-up, 12 patients (24%) had progression as defined. No statistically significant relationship between higher NGAL and ADPKD progression was observed. We did not observe a relationship between NGAL and CKD progression in ADPKD patients; however 18% of patients had undetectable plasma NGAL levels. This raises doubt about the utility of the current NGAL assay as a biomarker for CKD progression in this population.

The forgotten role of central volume in low frequency oscillations of heart rate variability.

The hypothesis that central volume plays a key role in the source of low frequency (LF) oscillations of heart rate variability (HRV) was tested in a population of end stage renal disease patients undergoing conventional hemodialysis (HD) treatment, and thus subject to large fluid shifts and sympathetic activation. Fluid overload (FO) in 58 chronic HD patients was assessed by whole body bioimpedance measurements before the midweek HD session. Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. Time domain and frequency domain analyses were performed on HRV signals. Patients were retrospectively classified in three groups according to tertiles of FO normalized to the extracellular water (FO/ECW%). These groups were also compared after stratification by diabetes mellitus. Patients with the low to medium hydration status before the treatment (i.e. 1st and 2nd FO/ECW% tertiles) showed a significant increase in LF power during last 30 min of HD compared to dialysis begin, while no significant change in LF power was seen in the third group (i.e. those with high pre-treatment hydration values). In conclusion, several mechanisms can generate LF oscillations in the cardiovascular system, including baroreflex feedback loops and central oscillators. However, the current results emphasize the role played by the central volume in determining the power of LF oscillations.

Variation in risk and mortality of acute kidney injury in critically ill patients: a multicenter study.

BACKGROUND: Despite standardized definitions of acute kidney injury (AKI), there is wide variation in the reported rates of AKI and hospital mortality for patients with AKI. Variation could be due to actual differences in disease incidence, clinical course, or a function of data ascertainment and application of diagnostic criteria. Using standard criteria may help determine and compare the risk and outcomes of AKI across centers. METHODS: In this cohort study of critically ill patients admitted to the intensive care units at six hospitals in four countries, we used KDIGO criteria to define AKI. The main outcomes were the occurrence of AKI and hospital mortality. RESULTS: Of the 15,132 critically ill patients, 32% developed AKI based on serum creatinine criteria. After adjusting for differences in age, sex, and severity of illness, the odds ratio for AKI continued to vary across centers (odds ratio (OR), 2.57-6.04, p < 0.001). The overall, crude hospital mortality of patients with AKI was 27%, which also varied across centers after adjusting for KDIGO stage, differences in age, sex, and severity of illness (OR, 1.13-2.20, p < 0.001). The severity of AKI was associated with incremental mortality risk across centers. CONCLUSIONS: In this study, the absolute and severity-adjusted rates of AKI and hospital mortality rates for AKI varied across centers. Future studies should examine whether variation in the risk of AKI among centers is due to differences in clinical practice or process of care or residual confounding due to unmeasured factors.

Understanding acute kidney injury in low resource settings: a step forward.

Attention has recently been focused on addressing the problem of acute kidney injury in both the developed and developing world. Little information is actually available on the incidence and management of AKI in low resource settings. Thus, the paper by Bagasha in the current issue of BMC Nephrology makes an important contribution to our understanding of this serious and potentially remediable problem.

Neutrophil gelatinase-associated lipocalin: ready for routine clinical use? An international perspective.

Acute kidney injury (AKI) remains a challenge in terms of diagnosis and classification, its morbidity and mortality remaining high in the face of improving clinical protocols. Current clinical criteria use serum creatinine (sCr) and urine output to classify patients. Ongoing research has identified novel biomarkers that may improve the speed and accuracy of patient evaluation and prognostication, yet the route from basic science to clinical practice remains poorly paved. International evidence supporting the use of plasma neutrophil gelatinase-associated lipocalin (NGAL) as a valuable biomarker of AKI and chronic kidney disease (CKD) for a number of clinical scenarios was presented at the 31st International Vicenza Course on Critical Care Nephrology, and these data are detailed in this review. NGAL was shown to be highly useful alongside sCr, urinary output, and other biomarkers in assessing kidney injury; in patient stratification and continuous renal replacement therapy (CRRT) selection in paediatric AKI; in assessing kidney injury in conjunction with sCr in sepsis; in guiding resuscitation protocols in conjunction with brain natriuretic peptide in burn patients; as an early biomarker of delayed graft function and calcineurin inhibitor nephrotoxicity in kidney transplantation from extended criteria donors; as a biomarker of cardiovascular disease and heart failure, and in guiding CRRT selection in the intensive care unit and emergency department. While some applications require further clarification by way of larger randomised controlled trials, NGAL nevertheless demonstrates promise as an independent biological marker with the potential to improve earlier diagnosis and better assessment of risk groups in AKI and CKD. This is a critical element in formulating quick and accurate decisions for individual patients, both in acute scenarios and in long-term care, in order to improve patient prognostics and outcomes.