Urinary TCP1-eta: A Cortical Damage Marker for the Pathophysiological Diagnosis and Prognosis of Acute Kidney Injury (original) (raw)
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International Journal of Molecular Sciences, 2022
Nephrotoxicity is a major cause of intrinsic acute kidney injury (AKI). Because renal tissue damage may occur independently of a reduction in glomerular filtration rate and of elevations in plasma creatinine concentration, so-called injury biomarkers have been proposed to form part of diagnostic criteria as reflective of tubular damage independently of renal function status. We studied whether the urinary level of NGAL, KIM-1, GM2AP, t-gelsolin, and REGIIIb informed on the extent of tubular damage in rat models of nephrotoxicity, regardless of the etiology, moment of observation, and underlying pathophysiology. At a time of overt AKI, urinary biomarkers were measured by Western blot or ELISA, and tubular necrosis was scored from histological specimens stained with hematoxylin and eosin. Correlation and regression studies revealed that only weak relations existed between biomarkers and tubular damage. Due to high interindividual variability in the extent of damage for any given bioma...
Journal of Pharmacological and Toxicological Methods, 2020
Introduction: The implementation of novel, reliable biomarkers for the early and differential diagnosis of acute kidney injury (AKI) could greatly improve the timely treatment and prevention of disease progression, particularly since the current gold standards for detecting kidney injury such as serum creatinine (SCr) and blood urea nitrogen (BUN) lack sensitivity and specificity. We evaluated novel urinary kidney injury biomarkers focusing on early detection and better prediction of AKI with higher sensitivity and specificity. Methods: In the rat, urinary biomarkers for kidney injury, i.e. albumin, beta-2-microglobulin (B2M), clusterin, cystatin C, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and total protein (TP), were investigated in an AKI model using different hyperosmolar and high-dose solutions, i.e. mannitol, sucrose, and contrast medium (CM), as acute single insults leading to kidney injury. Additionally, dose-dependency of sucrose was investigated and effects were compared to the sucrose-and ironcontaining marketed drug Venofer®. Results: Levels of excreted urinary biomarkers correlated with severity of AKI, exhibited a dose-dependent response to sucrose treatment, and demonstrated evidence of recovery from kidney injury with transient and reversible changes. The exceptions were KIM-1 and NGAL, which showed later responses following CM and ironinduced renal injury. All biomarkers outperformed plasma creatinine (PCr), BUN, and histopathology, with regard to practicability and/or detection of proximal tubular injury. Discussion: The use of a panel of urinary kidney injury biomarkers emerged as an early, sensitive, and predictive tool to detect AKI showing enhanced sensitivity compared to current state-of-the-art markers.
2021
Background. Acute kidney injury (AKI) is a risk factor for new AKI episodes and progression to chronic kidney disease, cardiovascular events and death, as under certain circumstances renal repair is maladaptive leading to proinflammatory and profibrotic signals. The definition for AKI recovery is based on increases in plasma creatinine, but it only happens when 50-70 % of nephrons have been lost. There are no studies monitoring the real state of structural and functional recovery after an AKI episode. We analysed the functional and structural sequelae after an episode of AKI in rats, whether and for how long animals retain enhanced sensibility to AKI and whether such a condition may be detected by known biomarkers of subclinical renal damage.Methods. We performed a cisplatin (5mg/kg body weight)-induced AKI in rats and, after recovery, we studied the renal susceptibility to new AKI episodes after treatment with subtoxic doses of gentamicin (50 mg/kg).Results. One week after the recu...
Biomarkers in acute kidney injury: Evidence or paradigm?
Nefrología, 2016
Acute kidney injury in the critically ill represents an independent risk factor of morbidity and mortality in the short and long terms, with significant economic impacts in terms of public health costs. Currently its diagnosis is still based on the presence of oliguria and/or a gradual increase in serum creatinine, which make the diagnosis a delayed event and to detriment of the so-called 'therapeutic window'. The appearance of new biomarkers of acute kidney injury could potentially improve this situation, contributing to the detection of 'subclinical acute kidney injury', which could allow the precocious employment of multiple treatment strategies in order to preserve kidney function. However these new biomarkers display sensitive features that may threaten their full capacity of action, which focus specifically on their additional contribution in the early approach of the situation, given the lack of specific validated treatments for acute kidney injury. This review aims to analyze the strengths and weaknesses of these new tools in the early management of acute kidney injury.
Biomarkers of acute kidney injury
Jornal brasileiro de nefrologia : ʹorgão oficial de Sociedades Brasileira e Latino-Americana de Nefrologia
Acute kidney injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant kidney injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.
Pathophysiology of Acute Kidney Injury
Comprehensive Physiology, 2011
The term "acute renal failure" (ARF) has traditionally been used to describe a syndrome with a rapid decline in glomerular filtration rate (GFR) occurring over a period of hours to weeks as the key feature. Recently, a consortium of nephrologists and intensivists, the Acute Kidney Injury Network (AKIN), representing many of the professional societies involved in the care of critically ill patients, recommended that the term "acute kidney injury" (AKI) replace ARF. This term includes the entire spectrum of ARF and recognizes that minor changes in kidney function (reflected by a change in serum creatinine [SCr] of 0.3 mg/dL) can portend worse patient outcome, 1 whereas the term "failure" is reserved for those patients whose renal functional impairment is so severe that replacement therapy is indicated, or at least considered. The previous issue of Nephrology Rounds reviewed the epidemiology, diagnosis, and treatment of AKI in various settings. This issue of Nephrology Rounds examines the pathophysiological underpinnings of AKI.
An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury
Seminars in Nephrology, 2016
Necrosis is the predominant form of regulated cell death in acute kidney injury (AKI). This type of injury results in the formation of casts that appear in the urine sedimentation, referred to as "muddy brown casts", which are part of the diagnosis of AKI. Pathologists refer to this typical feature as acute tubular necrosis. We are only beginning to understand the dynamics and the molecular pathways that underlie such typical necrotic morphology. In this review, we provide an overview of candidate pathways and summarize the emerging evidence for the relative contribution of these pathways of regulated necrosis, such as necroptosis, ferroptosis, mitochondrial permeability transition-mediated regulated necrosis, parthanatos and pyroptosis, in the pathogenesis of AKI. Inhibitors of each of these pathways are available, and clinical trials may be started following the detection of the most promising drug targets that will be discussed here. With the global burden of AKI in mind, inhibitiors of regulated necrosis represent promising means to prevent this disease.
Biomarkers for the diagnosis of acute kidney injury
Current Opinion in Nephrology and Hypertension, 2007
tests for AKI include serum creatinine (SCr) and blood urea nitrogen (BUN), two biomarkers that were identified and incorporated into clinical practice several decades ago. It is now widely appreciated that SCr and BUN are suboptimal markers for AKI, and that more sensitive, specific, and early biomarkers are needed. This review sets out to cover recent developments in the field of AKI biomarker validation in clinical studies. Injury versus Failure: Towards a Troponin for the Kidney The new term 'acute kidney injury' instead of 'acute renal failure'-by its replacement of the word 'injury' for 'failure'-hints towards a paradigm shift in nephrology. The diagnosis of 'failure' refers to the kidney's inability to perform one of its major functions, namely glomerular filtration. The diagnosis of glomerular filtration failure is made only after endogenous filtration markers (BUN or SCr) have accumulated in the blood, typically hours or even days after an inciting event. The diagnosis of 'injury', by contrast, does not presuppose a reduction in glomerular filtration. Newer biomarkers are needed to identify correlates of cellular (typically tubular) injury, which may be present well before or in the absence of a reduction in GFR. The analogy to cardiology may be instructive: clinicians diagnosing acute myocardial infarction do not wait until a reduction in cardiac output, but rather make the diagnosis of myocardial injury on the basis of elevations of tissuespecific biomarkers in the serum. The biological response of kidney tissue to ischemic or nephrotoxic injury may be utilized as early indicators of