RELATIONSHIP BETWEEN

HOMOCYSTEINE AND MORTALITY

IN CHRONIC KIDNEY DISEASE

Circulation 2006;113:1572-1577
BACKGROUND

Prev Hyperhomocystinemia in CKD tHcy as a risk factor

for the excess risk of CVD evident

Association between levels of tHcy and CVD have yielded

inconsistent results

Levels of tHcy are correlated with GFR, proteinuria, and

nutritional status, as well as with traditional CVD risk
factors

It remains unclear tHcy is an independent risk factor for

CVD or rather a marker of severity of kidney disease in
patients with CKD
OBJECTIVES

To evaluate whether tHcy was an

independent risk factor for all-
cause and CVD mortality in a
cohort of patients with CKD
stages 3 to 4 who had precise
measures of kidney function
METHODS

MDRD Study ( 1989 to 1993) was a randomized, controlled

trial to study the effect of dietary protein restriction and BP
control on the progression of kidney disease

Participants : 840 pts

585 pts ; baseline GFR of 25 to 55 mL/min per 1.73 m2
(studyA)
255 pts; baseline GFR of 13 to 24 mL/min per 1.73 m2
(study B)

Total Hcy were measured in frozen samples ( 804 pts ) using

high-performance liquid chromatography with fluorometric
detection
 GFR was assessed by the kidney clearance of I25l-
iothalamate

Survival status and cause of death the National Death

Index

Demographic, CVD risk factors, and kidney disease factors

were compared across tertiles of tHcy
the X2 test for categoric data
ANOVA for approximately normally distributed
continuous variables
The Kruskall-Wallis test for skewed continuous variables
 Incidence rates for mortality (per 1000 person-years) were
calculated for tertiles of tHcy. Unadjusted and 3 adjusted
Cox proportional hazards models were conducted in
sequence to evaluate the association of tHcy with all-cause
and CVD mortality

To maximize statistical power to examine the relationship

between tHcy and mortality, continuous variable analyses
were conducted with hazard ratios (HR) presented per tHcy
higher by 10 jamol/L
RESULTS
Baseline Characteristics
 Outcomes

Median follow-up (10yrs)

All-cause mortality rate

was 24% (n= 195)
There were 60 (22%), 58
(22%), and 77 (29%).

CVD mortality rate was

15% (n=118);
There were 33 (12%), 37
(14%) and 48 (18%)
DISCUSSION

The results of many studies investigating Hcy as an

independent risc factor for the CVD have been conflicting

GFR is a major determinant of Hcy levels in the general

population as well as in patients with CKD

Adjustment for GFR attenuated most of the relationship

between tHcy and mortality, suggesting that GFR was the
primary confounder for the observed association of high
tHcy levels and the mortality end points

tHcy may be a risk factor for progression of kidney disease

and thereby promote the development of CVD
 In our study, we did not find a relationship between tHcy
and a composite outcome of death or kidney failure.It
could because of:
specific to the population MDRD Study
unable to assess nonfatal CVD events, which may have
different associations with Hey than mortality end
points

The major strength of this study is

the inclusion of a large cohort of patients with precise
measures of kidney function
wide range of tHcy levels,
includes a large proportion individuals with abnormal
tHcy values
a high number of outcomes during follow-up with a
relatively healthy CKD population
CONCLUSION

tHcy does not appear to be a risk

factor for all-cause or CVD
mortality in the MDRD Study
cohort. Homocysteine may be a
marker for severity of kidney
disease rather than a mediator for
the development of CVD, in patients
with CKD stages 3 to 4
CRITICAL APPRAISAL

I. Are the results in the valid study?

- Primary Guides
Was there a representative and well-defined
sample of patients at a similar point in the course
of the disease?
Yes all the patients (MDRD study with
increasing of tHcy, CKD st 3-4)
Was follow-up sufficiently long and complete?
Yes 11 years (1989 2000)
- Secondary Guides
Were objective and unbiased outcome criteria
used?
Objective : death
Was there adjustment for important prognostic
factors?
Yes GFR
II. What are the result ?
How large is the likelyhood of the outcome
event(s) in a specified period of time ?
CVD mortality in Hcy Tertile 3 = 1,2 : 1,5
The chance of dying is more during first 5 yrs

How precise are the estimates of likelyhood?

1,2 (95% CI 0,73 1.95 )
III. Will the result help me in carring for
my patients ?
Were the study patients similar to my
own ?
Yes
Will the results lead directly to
selecting or avoiding therapy?
Yes