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Biological markers or ‘biomarkers’ of organ damage and dysfunction occupy a central position in the armamentarium of the clinician that is used for the screening, diagnosis and management of disease. Our knowledge of the pathophysiological basis of individual diseases continues to increase inexorably and the discoveries emanating from the Human Genome Project are set to enhance this knowledge immeasurably. Understanding the aetiopathogenesis of changes that take place in individual tissues, organs or compartments of the body can help in the search for markers that reflect these changes. Some of these changes may be directly related to the pathological abnormality while others might be a secondary consequence of the abnormality.
Basic research into the pathophysiology of a disease provides the foundation of knowledge that can lead to the discovery of valuable biomarkers. This foundation can also act as the starting point for the discovery of pharmaceutical interventions. Increasingly, with a more systematic approach to biomarker development and drug discovery, we are seeing the measurement of the biomarker playing a greater role in monitoring the efficacy and/or side effects of the therapeutic intervention. From a clinical standpoint, this can have a major benefit in assessing compliance with therapy, which is acknowledged to be one of the key determinants of efficacy, especially when there is no other ready means to judge the patient's response.
The discovery of a new biomarker is complemented by the development and validation of appropriate analytical technology.
Immunosuppressive drug therapy is used to prevent acute or chronic rejection of organ allografts in patients who have received a transplant. As with most prophylactic treatments, it only becomes apparent that the treatment has failed when the unwanted event happens. If there is a large safety margin between the dose of drug that prevents the unwanted event and the dose at which unacceptable drug toxicity occurs then the drug dose given can be sufficiently high to ensure treatment effectiveness. However, in transplant patients, the consequences of under- or over-immunosuppression can be equally catastrophic. On the one hand, underimmunosuppression can result in organ rejection that may, in turn, lead to graft loss and even death, while, on the other hand, overimmunosuppression can result in life-threatening infections, carcinoma and a range of drug-related adverse events such as nephrotoxicity. At present, we use plasma or blood drug concentrations as a surrogate measure of immunosuppression in the belief that there is a tight relationship between drug concentration and effect . However, interindividual variation in pharmacological response can make drug concentration data difficult to interpret. For this reason, the use of biomarkers for monitoring the response to immunosuppressive drug therapy has been investigated.
Choice of biomarker
The choice of biomarkers for monitoring the response to immunosuppressive drug therapy is wide. Monitoring the effect of therapy on the primary intracellular drug targets offers the most promise, but these targets are also the most difficult to measure (Table 45.1).
This publication takes a critical, evidence-based look at the efficacy of diagnostic tests which are increasingly being used to evaluate organ damage and dysfunction. The use of biomarkers is growing, with a steady stream of products being brought out by the pharmaceutical industry. Some of these assist in diagnosis, others provide a means of monitoring the state of progression of disease and the effectiveness of therapeutic options. However, in many cases the evidence which supports the use of these methods as opposed to traditional biochemical tests has not yet been demonstrated, and it is intended that this volume will help clarify the strengths and weaknesses of using these biomarkers across a wide range of applications and in the various organs of the body. This approach will provide pathologists, clinical biochemists and medical laboratory scientists with an invaluable overview of the diverse applications of biomarkers in medicine.