1. BACKGROUND AND INTRODUCTION
Traditional risk factors for CV disease (CVD) derived from the Framingham Heart Study do not predict all deaths due to cardiovascular events or stroke [Stenvinkel P 2006]. Biomarkers can supplement the information provided by traditional risk factors and help identify patients at risk of CV disease and death. A biomarker can be defined as ‘a biochemical feature or facet that can be used to measure the progress of disease or the effects of treatment’ [MedicineNet.com, Ref 2].
The inclusion of biomarkers should be considered beginning in phase II and throughout phase III development program for any new drug. They include either biomarkers that allow selection of sub-populations likely to respond to the study drug (e.g. genotyping) or those that identify early changes associated with serious adverse events or death in the study population (risk stratification biomarkers). A separate informed consent is required for the use of biomarkers.
Due to a high prevalence of cardiovascular disease in the CKD population, the inclusion of biomarkers that can predict CVD and mortality has been proposed in randomized clinical trials in this patient population. The following biomarkers have been relatively well characterized: homocysteine, high–sensitivity C-reactive protein, cardiac troponin I (cTnI) and troponin T (cTnT), B-type natriuretic peptide (BNP), NT-proBNP, asymmetric dimethyl arginine (ADMA), and cystatin C. Additional biomarkers, particularly those related to genetic polymorphisms are being discovered at a rapid pace. This article describes the currently proposed biomarkers that may be included in studies of patients with CKD and anemia.
2. HIGH SENSITIVITY C-REACTIVE PROTEIN
C-reactive protein (CRP) is an acute phase reactant which is elevated during infections and inflammation. CKD patients, especially those receiving dialysis treatments have a microinflammatory state [Kaysen 2001]. High levels of CRP have been associated with increased mortality from cardiovascular complications in the general population. Compared to individuals without CKD, baseline CRP levels are much higher in CKD patients both in those not yet on dialysis and in those receiving dialysis. Increased CRP levels have been shown to be a reliable marker of morbidity and mortality in CKD Patients.
3. B-TYPE NATRIURETIC PEPTIDE (BNP) AND N-TERMINAL PRO-BNP
BNP is a peptide released from ventricles in response to wall tension. Its levels are increased in patients with congestive heart failure and in acute coronary syndromes such as unstable angina [Jenberg 2002]. Increased levels of both tests correlate with increased risk of death from cardiovascular complications in patients with chronic kidney disease [Austin 2006]. Measurement of NT pro-BNP is a useful tool for risk stratification in patients with a variety of conditions including those with chronic kidney disease [Costello-Boerrigter 2005].
4. CARDIAC TROPONIN T (CTNT)
Troponin T is a cardiospecific, highly sensitive marker of myocardial damage [Ohman1996]. Myocardial cell injury leading to elevated serum cTnT concentrations can occur not only after myocardial infarction but also in congestive heart failure, cardiomyopathy, acute coronary syndromes and heart contusion [Ohman 1996]. Cardiac troponin T may also be used as a biomarker for the assessment of mortality in ESRD patients. Elevated cTnT levels can identify ESRD patients who have poor survival and are at a high risk of cardiac death [Khan 2005].
The use of a multi-biomarker panel including hsCRP, NT pro-BNP, and cTnT or cTnI has been shown to increase the ability to predict the relative risk for all cause mortality in ESRD patients, compared to the risk prediction when each biomarkers is used separately [Apple FS, 2004].
5. HEPCIDIN AND PRO-HEPCIDIN
This test allows the determination of the influence of inflammation and cytokines in resistance to erythropoietic stimulating agents. Hepcidin is an iron-regulatory peptide that is increased during inflammation [Deicher 2004]. It can block intestinal absorption of iron and the release of iron from macrophages. High hepcidin levels are expected in ESRD patients and may be correlated with resistance to iron and to ESA therapy.
6. ASYMMETRIC DIMETHYLARGININE (ADMA)
ADMA is an endogenous inhibitor of nitric oxide (NO) synthase. High levels of ADMA can result in endothelial dysfunction and atherosclerosis. ADMA levels are markedly increased in patients with CKD [Zoccali 2006], suggesting that it may play a role in atherosclerotic complications in these patients. ADMA levels correlate with left ventricular mass and with intima-media thickness of the carotid artery [Zoccali et al. 2006]. Therefore, studies are needed to explore its usefulness as a biomarker of CVD progression in CKD patients.
7. CYSTATIN C
Serum Cystatin C measurements have been advocated as a more accurate measure of kidney function. Recent studies in an elderly population with no evidence of CKD showed that elevated cystatin C ((≥ 1.0 mg/L) can be used as a biomarker to predict the risk of death, heart failure, stroke and myocardial infarction [Shlipak MG, 2006]. In contrast, serum creatinine or GFR, calculated by the MDRD formula, could not predict death and only showed a weak correlation with CV death. Subjects with elevated cystatin C had a 4-fold increased risk of progression of CKD.
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