Injury-response biomarkers

Those involved in individual health assessment are concerned with the early detection of specific organ kidney injury. With regard to acute kidney injury (AKI), biomarkers may serve several additional purposes. That is, they may determine AKI subtypes (prerenal, intrinisic renal, or postrenal), identify the etiology of AKI (ischemia, toxins, sepsis, or a combination), differentiate AKI from other forms of acute kidney disease (urinary tract infections, glomerulonephrihs, intershtial nephritis), predict the AKI severity (risk stratification for prognostication as well as guide to therapy), monitor the course of AKI, and monitor the response to AKI interventions. For chronic kidney disease (CKD), they provide both evidence and severity of exposure and may be used to assess response to removal of offend-... 

O Qualified biomarkers O Tissue injury leakage markers O Tissue injury response markers O Functional markers... 

A number of commercial antibody-based microarrays for multiplexed cytokines analysis are now available (Beckman Coulter BD Biosciences Panom-ics Pierce S S Zyomyx and others). Cytokines are essentially biomarkers of cell injury, inflammation, and apoptosis. They are released by cells in culture in response to drug action (Turtinen et al., 2004) or are elevated in serum in various disease states. Moreover, numerous cytokines are involved in cellular response and many serve as dual effectors (Asao and Fu, 2000). As a result, anticytokine microarrays are being evaluated in drug discovery for off-target toxicity testing to replace standard ELISA plate formats. 

Changes in serum ALT may not aWays be indicative ofa true hepatotoxic response. Mild dose-related ALT elevations (2x to 3x ULN) are observed in some patients taking lovastatin as a result of an adaptive response [139]. As another example, isoniazid, an anti-tuberculosis agent, leads to a high incidence of ALT and AST elevations, but is tolerated chronically without severe hepatotoxicity. This suggests that more specific and sensitive biomarkers are still needed to predict serious liver injury. 

The development of new biomarkers is based on an understanding of the physiologic functions of the liver and its response to injury. Drug exposure can alter the function of the liver and elicit injurious effects through different mechanisms. These mechanisms are becoming better understood and have been reviewed [3-5, 150,... 

These biomarkers represent a response to injury and may reflect the degree of ischemia. In a substudy of the platelet receptor inhibition for ischemic syndrome management (PRISM) trial, Heeschen et al. found that ACS patients with low... 

As increases in cardiac troponin detect any form of myocardial injury, nonischemic mechanisms of injury are also responsible for cardiac troponin release from the heart, causing increases in circulating troponin. Table 5-3 shows a list of potential etiologies that have been responsible for increases in non-ischemic damage to the heart. Thus, whenever cardiac troponin is monitored, it is important to follow the serial pattern of a rising or a falling pattern of the biomarker. An increased cTn pattern that remains relatively unchanged and is not indicative of this serial trend is likely not an MI. 

A biomarker of susceptibility can be defined as "an indicator of an inherent or acquired limitation of an organism to respond to the challenge of exposure to a specific xenobiotic substance" [4]. These markers indicate differences in individuals or populations that affect the body s response to xenobiotic exposure. They may include variations in the balance between enzymes that detoxify or enhance the toxicity of chemicals, genetic differences in the capacity of cells to recover from injury, inherited genetic defects that increase the risk of cancer. 

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

Cells are equipped with a large number of defence mechanisms, or stress response pathways, to protect themselves and their surrounding tissue from injury. The majority of these defence mechanisms are turned on to redress a specific homeostatic imbalance and are turned off again when homeostasis has been restored. Such pathways include the p53 stress response, which senses amongst other things DNA damage, Nrf2 oxidative stress response, HIF-1 alpha hypoxia stress response, unfolded protein response, and inflammatory stress responses [34], In this chapter we aim to demonstrate how some of these pathways have contributed to the identification of excellent mechanistic biomarkers. In Chap. 19 we describe these pathways in much more detail. 

One thing that is clear from the table is that in vivo assessments of renal function in humans are limited due to the need for them to be noninvasive. In contrast, in vitro cell culture models enable processes to be examined at the cellular and molecular levels where they occur. Additionally, many of the responses and processes that are measured in vivo can be similarly measured in the in vitro model. Notable among these is the measurement of sensitive biomarkers of renal injury in urine in the in vivo model and in the extracellular medium in the in vitro cell culture model. Kidney injury molecule-1 (Kim-1) is an excellent example that has been characterized by Bonventre and colleagues (Ichimura et al., 1998,2004 Han et al., 2002 Vaidya et al., 2006 Hoffmann et al., 2010). Kim-1 is a type 1 transmembrane protein that is undetectable in normal kidney tissue but is expressed at very high levels in dedifferentiated PT epithelial cells of human and rodent kidneys after either ischanic or chemically induced injury. It appears to satisfy several of the criteria for being an ideal biomarker of effect for renal injury Kim-1 is stable in urine for prolonged periods of time, it is specific to the kidneys, its expression increases markedly from a baseline of essentially zero, and its increased expression occurs early... 

The categories for outcomes of DIVI are used to group phenotypic vascular findings according to histomorphologic similarities and candidate sensitive and specific biomarker response independent of etiology, mechanisms, and sites of injury (Zhang et al., 2012 Bendjama et al., 2014). 

As novel assays become available, the overlap between the clinical and nonclinical biomarkers may further increase. For instance, DIVI and some vasculitides have been associated with changes in levels of circulating endothelial microparticles (EMPs). EMPs are a type of small membrane vesicle (0.1-1 mm in diameter) that is released from cells in response to activation, injury, inflammation, and/or apoptosis and can serve as a means of intercellular communication (Rautou et al, 2011). The use of EMPs for biomarker qualification in drug development may gain broader acceptance with the advent of newer technologies such as... 

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