The reverse epidemiology of plasma total homocysteine as a mortality risk factor is related to the impact of wasting and inflammation.
BACKGROUND
The reason(s) for the apparently paradoxical 'reverse' association in end-stage renal disease (ESRD) patients in whom a low, rather than a high, total plasma total homocysteine (tHcy) level is an indicator of poor outcome remains unclear. The aim of this study was to examine whether the inverse association maintains, mitigates or reverses after comprehensive multivariate adjustment for the presence of wasting and inflammation as well as other potential confounders.


METHODS
We studied 317 ESRD patients starting dialysis therapy. Fasting blood samples were taken for the analyses of tHcy, serum albumin, C-reactive protein (CRP), serum creatinine and plasma folate. Nutritional status was assessed by subjective global assessment (SGA). Survival was followed for up to 66 months; 105 patients died.


RESULTS
Using Kaplan-Meier analysis, a low tHcy concentration (< or =30 micromol/l) was associated with higher all-cause and cardiovascular (CV) mortality (P < 0.05). Using Cox proportional analysis adjusting for age, gender, glomerular filtration rate = GFR, cardiovascular disease = CVD, plasma folate, total cholesterol and diabetes mellitus, the all-cause and CV mortality still tended to be high for patients with low tHcy. Adding nutritional and inflammation markers (Body mass index = BMI, SGA, serum creatinine, serum albumin and CRP), a low tHcy level was no longer associated with higher mortality but a trend for high tHcy was observed.


CONCLUSIONS
The link between wasting inflammation and a low tHcy appears to be responsible for the reverse association between plasma tHcy and clinical outcome in ESRD patients. After adjustment for confounders including nutritional and inflammation markers, a trend towards increased death risk for high, rather than low, tHcy levels was apparent after adjustment.
Suliman
Mohamed
M
Renal Medicine and Baxter Novum, K56, Karolinska University Hospital Huddinge, Karolinska Institutet, S-141 86 Stockholm, Sweden.
Stenvinkel
Peter
P
Qureshi
Abdul Rashid
AR
Kalantar-Zadeh
Kamyar
K
Bárány
Peter
P
Heimbürger
Olof
O
Vonesh
Edward F
EF
Lindholm
Bengt
B
D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007249:Inflammation; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000453:epidemiology / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D052756:Nutritional Sciences; D016016:Proportional Hazards Models; D012307:Risk Factors; D016896:Treatment Outcome
D006710:Homocysteine; D002097:C-Reactive Protein