This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Patients with chronic renal disease occupy the highest risk stratum for subsequent arteriosclerotic cardiovascular disease (CVD) events. The excess risk of CVD in chronic renal disease is due in part to a higher prevalence of established arteriosclerotic risk factors, including older age, hypertension, diabetes, dyslipidemia, and physicial inactivity. However, unique renal insufficiency/'uremia'-related risk factors likely also contribute to this excess CVD risk. Prominent among these unique risk factors in the chronic renal disease population are elevated levels of the putatively atherothrombotic sulfur amino acid homocysteine. Homozygous genetic disorders (i.e., the 'homocystinurias') resulting in marked hyperhomocysteinemia (total homocysteine levels of 100 to 500 umol/L) are clearly associated with precocious atherothrombotic events, and total homocysteine (tHcy)-lowering treatment appears to reduce the incidence of such outcomes among these patients. In addition, pooled data from prospective observational studies suggest that mild to moderate hyperhomocysteinemia (tHcy levels of 12 to 99 umol/L) may also be a significant risk factor for arteriosclerotic CVD among general populations of men and women. However, randomized, controlled clinical trial data confirming these reported associations are unavailable. Moreover, the impact of cereal grain flour fortification with folic acid on plasma tHcy levels within the general population may obfuscate the results from any such trials conducted in the United States. Chronic renal disease patients, including renal transplant recipients, have an excess prevalence of mild to moderate hyperhomocysteinemia, which has been independently linked to their development of CVD outcomes in recent prospective observational studies. These investigators hypothesize that lowering tHcy levels in patients with chronic renal disease will reduce their excess incidence of arteriosclerotic CVD outcomes.
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