The utility of biomarker excretion rates in acute kidney injury

INTRODUCTION: The concentration of urinary biomarkers of acute kidney injury (AKI) is influenced by variation in urinary concentration within and between individuals.1 Normalisation to urine creatinine concentration is commonly used to account for this variation.2 The accuracy of this method is compromised by tubular secretion of creatinine, and variations in urine creatinine excretion in non-steady state when glomerular filtration rate (GFR) changes.1 Alternatives to normalisation to creatinine include using the absolute biomarker concentration or quantifying the biomarker excretion rate. Intuitively, the excretion rate may also account for variation in water reabsorption and urine flow rate. In addition, total biomarker excretion in AKI might more accurately reflect the mass of injured tubular cells, a function of both severity and duration, parameters associated with long-term mortality.3 OBJECTIVE: To compare the performance of biomarker excretion rate and the absolute and normalized biomarker concentration in diagnosis of AKI, prediction of AKI, death and the need for renal replacement therapy (RRT) in adult intensive care patients. This will assists in the comparison of biomarkers between trials and guide clinicians on how it should be utilized in clinical practice. METHODS: Urinary concentrations of alkaline phosphatase (AP), γ-glutamyl transpeptidase (GGT), cystatin C (CysC), neutrophil gelatinase-associated-lipocalin (NGAL), kidney-injury molecule-1 (KIM 1), and interleukin-18(IL-18) were measured on ICU admission, at 12 and 24 hours in the EARLYARF trial.4, 5 The average urine flow rate was calculated from 4-hour creatinine clearance measurements obtained at the same time points, which allowed calculation of biomarker excretion rate. The normalised biomarker concentrations were derived by dividing the biomarker concentration by the urinary creatinine concentration. The total excretion over 24 hours for each biomarker (i.e. integration of excretion rate with respect to time) was determined using the trapezoidal rule. The performance of absolute and normalised biomarker concentration, and biomarker excretion rate on admission to the ICU in diagnosis or prediction of outcome was assessed by comparison of the area under the curve (AUC) of receiver-operator characteristic curves (ROC) for each parameter using the DeLong method.6, 7 The association of total biomarker excretion with AKI severity (maximum AKIN stages within 48 hours), and 1-year survival were assessed with one-way ANOVA and Kaplan Meier survival analysis. RESULTS: Of 528 recruited patients, 484 had 4h-creatinine clearance measurements on ICU admission from which urine output volumes could be obtained for the calculation of biomarker excretion rates. For diagnosis of AKI on ICU admission, biomarker concentration performed better than normalised concentration or excretion rate. Normalised concentrations performed best in prediction of 7-day mortality and the need of RRT. Excretion rate did not diagnose or predict outcomes better than absolute or normalised concentration. In the cohort of patients without AKI on ICU admission (n=339), there were no differences in performance between absolute and normalised biomarker concentration in prediction of development of AKI within 48 hours (AKIN48) or sustained AKI within 7 days of admission (RIFLE 24). However, here also the normalised concentrations had higher AUCs than excretion rates (Figure 1). The total biomarker excretion in the first 24 hours increased with severity of injury for all biomarkers except AP. For NGAL alone, post-hoc analysis also demonstrated significant differences between successive AKIN stages of increasing severity AKI (p≤0.02) (Figure 2). Patient survival was assessed according to extent of biomarker excretion ranked by tertiles Only NGAL demonstrated a significant association between total excretion and survival over 365 days (log-rank test, p=0.04). After adjusting for age, gender, sepsis, APACHE II and SOFA scores, patients with higher excretion of NGAL (higher tertile, total excretion >184µg) had a higher 1-year mortality compared to those with a lower tertile of NGAL excretion (total excretion of <40µg) (Hazard ratio of 2.15 (95% CI: 1.23 to 3.73), p=0.007) (Figure 3). . CONCLUSIONS: Normalisation to urine creatinine provides no advantage in diagnosis of AKI, but improves prediction of AKI and outcome. Periodic excretion rates did not improve performance, but total excretion in the first 24hr was strongly associated with AKI severity, and for NGAL with survival. The ideal method for standardizing urinary AKI biomarkers depends on the outcome being assessed

Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion

Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine samples from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)]; 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning.NHMRC project grant 101177

Complicações da infecção por EBV em doentes transplantados

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2016Paralelamente à crescente utilização de transplantes de órgão sólido ou de células estaminais no tratamento de uma miríade de doenças, tem crescido a investigação de patologias relacionadas com a imunossupressão associada. As doenças linfoproliferativas pós-transplante (PTLD, do inglês post-transplant lymphoproliferative disorders), frequentemente associadas à reactivação do vírus de Epstein-Barr nestes doentes, podem representar uma complicação grave da imunossupressão. Nesta revisão pretende-se sumarizar o mecanismo de desenvolvimento destas patologias, apresentar as classificações, enumerar os factores de risco, assim como os sinais e sintomas de apresentação de PTLD. Para orientação clínica, expõem-se ainda os exames complementares de diagnóstico úteis para o seu rastreio e monitorização, terminando por discutir os principais esquemas terapêuticos usados com intenção preventiva ou curativa, segundo as guidelines mais actuais.The rising usage of solid organ transplants and stem cell transplant in the treatment of various diseases has been accompanied by a growing research into the consequences of the associated imunossupression. Post-Transplant Lymphoproliferative Disorders (PTLD), frequently linked to the reactivation of the Epstein-Barr virus, may represent a serious complication of immunossupression. This review summarizes the mechanism inherent to the development of these disorders, describes their current classification system, lists the risk factors and the signs and symptoms associated with PTLD. To guide the clinical approach to these disorders, this review scrutinizes the most important diagnostic tests for screening and monitoring the development of PTLD, and also discusses the main therapeutic approach to prevention or cure, according to the most recent guidelines

TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages

Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMPinduced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases

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

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion.

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD

De novo implantation vs. upgrade cardiac resynchronization therapy: a systematic review and meta-analysis

Patients with conventional pacemakers or implanted defibrillators are often considered for cardiac resynchronization therapy (CRT). Our aim was to summarize the available evidences regarding the clinical benefits of upgrade procedures. A systematic literature search was performed from studies published between 2006 and 2017 in order to compare the outcome of CRT upgrade vs. de novo implantations. Outcome data on all-cause mortality, heart failure events, New York Heart Association (NYHA) Class, QRS narrowing and echocardiographic parameters were analysed. A total of 16 reports were analysed comprising 489,568 CRT recipients, of whom 468,205 patients underwent de novo and 21,363 upgrade procedures. All-cause mortality was similar after CRT upgrade compared to de novo implantations (RR 1.19, 95% CI 0.88-1.60, p = 0.27). The risk of heart failure was also similar in both groups (RR 0.96, 95% CI 0.70-1.32, p = 0.81). There was no significant difference in clinical response after CRT upgrade compared to de novo implantations in terms of improvement in left ventricular ejection fraction (DeltaEF de novo - 6.85% vs. upgrade - 9.35%; p = 0.235), NYHA class (DeltaNYHA de novo - 0.74 vs. upgrade - 0.70; p = 0.737) and QRS narrowing (DeltaQRS de novo - 9.6 ms vs. upgrade - 29.5 ms; p = 0.485). Our systematic review and meta-analysis of currently available studies reports that CRT upgrade is associated with similar risk for all-cause mortality compared to de novo resynchronization therapy. Benefits on reverse remodelling and functional capacity improved similarly in both groups suggesting that CRT upgrade may be safely and effectively offered in routine practice. CLINICAL TRIAL REGISTRATION: Prospero Database-CRD42016043747

Implementation of Novel Biomarkers in the Diagnosis, Prognosis, and Management of Acute Kidney Injury: Executive Summary from the Tenth Consensus Conference of the Acute Dialysis Quality Initiative (ADQI)

Detection of acute kidney injury is undergoing a dynamic revolution ofbiomarker technology allowing greater, earlier, and more accuratedetermination of diagnosis, prognosis, and with powerful implication formanagement. Biomarkers can be broadly considered as any measurablebiologic entity or process that allows differentiation between normalfunction and injury or disease. The ADQI (Acute Dialysis QualityInitiative) had its Ninth Consensus Conference dedicated to synthesisand formulation of the existing literature on biomarkers for thedetection of acute kidney injury in a variety of settings. In the papersthat accompany this summary, ADQI workgroups fully develop key conceptsfrom a summary of the literature in the domains of early diagnosis,differential diagnosis, prognosis and management, and concurrentphysiologic and imaging measures