26 July 2008 Imaging and Cardiology Jonathan Goldman ... - ICON plc

Pg 06Patient safety is amajor issue in clinicalpractice, as it is inclinical trials.to a lesser degree by BNP. A translational biomarker of potentialinterest is fatty acid binding protein 3 (FABP3), which has anintracellular transport function for long chain fatty acids. Sincetroponin is bound to a structural component of the myocardium,the location of FABP3 in the cytosol results in higher concentrationsof FABP3 earlier than troponin, and greater sensitivity toacute myocardial injury. The major issue with FABP3 as abiomarker for cardiotoxicity is its lack of specificity in the presenceof muscle injury or renal failure.NephrotoxicityThe accurate and timely assessment of renal function is essentialto assuring the safety of subjects enrolled in clinical trials. While‘acute renal failure’ (ARF) has traditionally been utilized to describeacute renal dysfunctions, ranging from mild prerenal azotemia tosevere oliguria associated with acute tubular necrosis, the term‘acute kidney injury’ (AKI) has recently been adopted. ARF isreserved for patients who have AKI and who require renal replacementtherapy (dialysis or renal transplantation).AKI has been variably defined as an increase in serum creatininevalues of 100%, of 50% and of 0.3 mg/dL over differing timeintervals. Conventional serum renal function tests (serum creatinineand urea nitrogen) are late markers of nephrotoxicity. Theirelevations are associated with relatively advanced and severedamage to the proximal tubule on histopathologic examination.Due to their lack of sensitivity and their failure to accurately reflectrapid changes in renal function, the utilization of conventionalmarkers can result in delays in therapeutic decision making, witha potential impact on outcomes. Conventional markers also lackspecificity. For example, creatinine values vary with changes inmuscle mass and tubular secretion, have a wide reference interval,and are impacted by nonrenal factors (e.g. body weight, race, age,sex, total body volume, drugs, muscle metabolism and proteinintake; prerenal factors; and, postrenal factors).The lack of sensitive and specific renal biomarkers may haveimpaired progress in this field, with mortality rates for severe acutekidney disease stable over the past 50 years. It has also had adetrimental effect on the design and the assessment of outcomesof clinical trials. To address this, the design of panels consisting ofbiomarkers, intended to increase sensitivity and specificity and topermit the identification of AKI subtypes, are currently in thediscovery, development, translational and/or validation phase.These biomarkers include neutophil gelatinase-associatedlipocalcin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18(IL-18), and cystatin C. 9NGAL is a growth and differentiation factor found in the tubularcells of the kidney. 10 It is involved in the intracellular transport oflow molecular weight molecules and is a sensitive, specific andpredictive early marker of AKI. Following ischemic or nephrotoxicAKI, NGAP is upregulated, with serum levels increasing 10 foldand urine levels increasing 100 fold in 2-6 hours. NGAL has beenshown to be an independent predictor of clinical outcomes andduration of AKI. Cystatin C, a member of the cystatin ‘superfamily’of protease inhibitors, is freely filtered by the glomerulus. Unlikecreatinine, it is not affected by age, gender, race or muscle mass.44021 US.indd 8 12/1/08 10:19:56 AM