Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients.
BACKGROUND
Dialysis patients have higher cardiovascular events rate than patients with normal renal function. Hyperhomocysteinemia, a risk factor for cardiovascular disease, is frequently detected in dialysis patients. Vitamin B supplementation lowers hyperhomocysteinemia, but it is unknown whether it reduces cardiovascular events rate. We planned a long-term study to analyze the effects of homocysteine-lowering vitamin B therapy on cardiovascular disease in hemodialysis patients.


METHODS
We performed a single center open prospective trial. Patients, just on folate therapy at enrolment, were left out from randomization and maintained folate therapy according to study's protocol (group A). Patients, untreated with folic acid at recruitment, were randomly assigned to other 2 groups: patients submitted to folate supplementation according to study's protocol (group B), and untreated ones (group C). We instructed patients to take 5 mg oral daily folic acid or 5 mg every other day whether serum folate levels were up the normal high limit. We measured homocysteine, folate and vitamin B12 plasma levels at baseline and every 4 months. We chose the appearance of fatal and nonfatal cardiovascular events as end-points.


RESULTS
We analyzed data of 114 patients for a median follow-up time of 871 days. Stepwise regression analysis demonstrated that baseline homocysteine levels were related to folate (coefficient: -1.02; F: 64.5), creatinine (coefficient: 0.98; F: 11.3), and C reactive protein (coefficient: -0.64; F: 4.3). Patients ended the study for the following reasons: cardiovascular morbidity (n = 44), death (n = 25), renal transplant (n = 9), moved away (n = 4). Cardiovascular events occurred in 58 of 114 patients (51%), in 26 of 63 (41%) treated patients (both group A and group B) and in 32 of 51 (63%; chi2 = 6.0; p = 0.05) untreated patients (group C). Kaplan-Meier survival analysis showed that cardiovascular events were less frequent in treated patients with low homocysteine levels (chi2 24.1; p < 0.0001). Cox regression analysis showed that cardiovascular events were explained by homocysteine, dialysis vintage, past cardiovascular accidents, and age. We noticed not only lower homocysteine levels, but also higher protein catabolic rate values in events-free patients as compared with patients with nonfatal cardiovascular events. After having divided patients into 4 subgroups according to high and low, split at median, Hcy and protein catabolic rate values, we observed in Kaplan-Meier survival curves for cardiovascular events by these subgroups that patients with low Hcy and high protein catabolic rate values showed a significant lower hazard rate than patients with high Hcy and low protein catabolic rate levels (chi2 = 21.7; p < 0.0001).


CONCLUSIONS
This trial shows for the first time that homocysteine-lowering folate therapy decreases cardiovascular events in dialysis patients. It is necessary to perform large prospective studies to confirm our results.
Righetti
Marco
M
Nephrology and Dialysis Unit, Vimercate Hospital, Vimercate, Italy. righettim@hotmail.com
Serbelloni
Paola
P
Milani
Silvana
S
Ferrario
Gianmichele
G
D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006710:Homocysteine / Q000097:blood / Q000187:drug effects*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism; D012044:Regression Analysis; D006435:Renal Dialysis / Q000009:adverse effects*; D016019:Survival Analysis; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000097:blood
D015415:Biomarkers; D011506:Proteins; D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid