The main cause of reduced long-term graft survival is chronic allograft injury.
Cardiovascular risk factors such as hyperhomocysteinemia seem to play an important
role. As atherosclerotic lesions in chronic allograft injury may be due to
hyperhomocysteinemia, we examined the hypothesis that the C677T variant of the
methylenetetrahydrofolate reductase (MTHFR) gene, which is linked to elevated
plasma homocysteine levels in patients with renal failure, determines renal allograft
dysfunction. Endothelial dysfunction probably has a role in this process. The aim of
the present work was to study the influence of the C677T MTHFR gene polymorphism
on plasma levels of homocysteine and folate in renal graft recipients, and their impact
on chronic graft dysfunction, as well as studying the relation between chronic
allograft injury and endothelial dysfunction by estimating von Willebrand factor
(vWF) and measuring endothelial dependent dilatation of the brachial artery (EDD).
The subjects included in this study were 32 renal allograft recipients (Group I) and
30 normal subjects as a control group (Group II). MTHFR genotype was determined
by PCR, subsequently the patients were further classified into three subgroups
according to the MTHFR genotypes: Group I (a): 6 allograft recipients with
homozygous- TT type. Group I (b): 8 allograft recipients with heterozygous- CT type.
Group I (c): 18 allograft recipients with wild- CC type. Estimation of total plasma
homocysteine concentration, plasma folic acid, plasma and von Willebrand factor
(vWF) were determined. Vascular responses of the brachi al artery were performed by
high resolution ultrasound imaging. This study showed significantly higher levels of
both homocysteine and von Willebrand factor (vWF) were found in renal allograft
recipients as compared to the control group. A negative correlation was found
between homocysteine levels and creatinine clearance suggesting
hyperhomocysteinemia contributes to the renal allograft dysfunction. No significant
difference was found as regards the plasma folic acid levels between the patients and
controls. Allograft recipients with MTHFR homozygous-TT type showed significantly
higher levels of homocysteine and vWF as compared to allograft recipients with
heterozygous-CT type and those with wild- CC type. Also allograft recipients with
homozygous- TT type showed lower levels of plasma folic acid and creatinine  clearance as compared to the other two subgroups. Lower endothelial dependent
dilatation of the brachial artery (EDD) was observed in renal allograft recipients as
compared to the control group. The EDD was significantly less in allograft recipients
with MTHFR homozygous- TT type than those with MTHFR heterozygous- CT type or
wild- CC type. CONCLUSION: The present study supports the hypothesis that the
C677T variant of the MTHFR gene is an important determinant of renal-transplant
survival, and that certain genotypes of MTHFR gene are associated with chronic
allograft injury. Hyperhomocysteinemia, elevated vWF, lower folic acid levels and
endothelial dysfunction together with certain genotypes of MTHFR gene increases the
risk of development of chronic allograft injury in renal transplant patients.