Use of Enalapril to Prevent Myointimal Hyperplasia in Arm ’ s Arteriovenous Fistula for Hemodialysis Access

End-point: Evaluate the effect of Enalapril in preventing Myointimal Hyperplasia (MIH) in arm’s arteriovenous fistula (AVF) for hemodialysis access. Method: Inclusion criteria consisted on patients with no ACEI, or angiotensin II receptor blockers (ARB) treatment, or no intake up to 3 months before procedure, declared suitable for AVF access, and having thrill and bruit after AVF construction procedure. Under these criteria, we selected eighty-eight patients and assigned them randomly in case group and control group. Case group received Enalapril 48 hours before AVF construction procedure and during study. We did evaluations of efferent vein diameter, myointimal complex, and flow velocities with Doppler Ultrasound (DU) during six weeks after procedure. MIH risk factors according to medical history and obtained data analysis were performed using student test. Results: After medical history analysis, the main MIH risk factors presented were diabetes, hypertension and active smoking p=0.05. Within control group, MIH was higher as three patients had AVF failure vs one patient in case group, the Enalapril group. Conclusion: We found no statistical difference in both groups (p=0.637).

of Enalapril calculated at 0.07 mg per kg [9].There are other medications, such as corticosteroids, that decrease MIH by attenuating inflammatory response, however, its combined use with ACEIs does not potentiate the protective effect, so to achieve the maximum effect of suppressing the MIH response, only one medication is required [8][9].
In our hospital, we perform an average of 150-240 AVF access construction procedures each year and we have a shortterm follow-up program of 10-12 weeks to supervise reached maturation targets before sending the patient to start HD therapy through AVF access.

Material and Method
The present descriptive, longitudinal, cross-sectional of case and control study was performed in our hospital at the vascular surgery service in collaboration with the radiology service from January to May of 2017.Patients were randomized in 2 groups, case group where Enalapril oral intake of 10mg daily, starting 2 days prior to AVF construction procedure and continued for 6 weeks and control group with no Enalapril intake.
Patients were at least 18y old, with ESRD requiring HD continuous therapy, declared suitable for AVF access, having no previous AVF and no ACEIs or ARBs intake within at least 3 months.Only patients that had immediate bruit and thrill after surgery and had agreed to informed consent were included.Excluded patients were those with ACEI allergy or contraindication for it, and those lost in follow-up.Doppler ultrasound of AVF was performed on all patients 6 weeks after procedure, in order to evaluate the myointimal complex of the efferent vein, diameter and flow velocity.
To diminish variation, all AVF were performed by the same vascular surgeon and all DU studies by the same radiologist using Toshiba Xario XG equipment and being blind to which study group each patient belonged to.Data regarding medical history and non-pathological background that could affect AVF maturation process was collected and statistical analysis using standard deviation, interquartile range, Student's T and Shapiro-Wilk tests was made with Stata13® (StataCorp, college station, Texas, USA).

Results
Both groups were homogeneous.During the study, one patient of the Enalapril group and three patients of the control group were excluded due to early AVF thrombosis.

Introduction
The end-stage renal disease (ESRD) has a high morbidmortality in Mexico and other countries [1].In the United States 62% of the patients receiving hemodialysis uses an arteriovenous fistula (AVF) as vascular access, having a 60% primary patency [2].Myointimal Hyperplasia (MIH) is one of the main causes of complications, presented in 30-50% of the cases and it has been demonstrated that steroids, calcium antagonists and angiotensin-converting enzyme inhibitors (ACEI) can diminish it [2][3].
In Mexico, ESRD has a prevalence of 337 per 1,000,000 habitants per year, and 1,142 per 1,000,000 habitants, of which 40% are under treatment and 16% receive hemodialysis as regular treatment at the Mexican Institute of Social Security [1].
On 1966, Drs.Brescia and Cimino described the arteriovenous internal fistula as vascular access [4][5][6] and today is considered the access of choice, associated with a lowrate infection, low-rate complications and high patency, on comparison with the other types of vascular access.[2,[4][5][6] In order to have a functional AVF, it has to complete a process of growth and vein wall thickening also known as maturation.Other maturation targets are parameters such as, 6mm vein diameter minimum, 6mm below skin location maximum, and over 600ml/min flow [4][5][6].
The construction of an arterial-venous abnormal shunt, (meaning from a high speed and high pressure system to a low pressure and capacitance system), originates changes at the vein wall, such as vascular smooth muscle cells proliferation and medial thickening.These due to high shear stress and flow dynamics, that tend to continue until vein lumen is reduced, and eventually thrombosis occurs [5][6].
Between 55 to 65% of AVF do not complete a successful maturation process and up to 50% of those are due to obliterative processes [7].AVF access have a primary patency of 60% in the first year, [3-5] and it is strictly related to factors such as age, diabetes, hypertension, arterial disease, active smoking and surgical technique, nevertheless, all these have similar molecular physiopathology [3].
Animal models and vein analysis have shown that the pro-inflammation response has a marked wall migration of macrophage, lymphocyte and cytokines and this exaggerated response has an inversely proportional relation to a successful maturation [4][5][6][7].Experimental studies showed that using substances such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and calciumantagonists (CA) could diminish MIH due to trauma or endothelial stress by blocking vasoconstrictors and releasing bradykinin [7][8][9][10].
Genes that encode Beta transformation growth factor (TGF-B) and platelet derivative growth factor (PDGF) are induced by angiotensin II to activate mRNA that cause cell proliferation, therefore can be suppressed by ACEIs and this reduction seems to be dose-dependent, with a maximum effect Control group (n=45) characteristics are listed in table 1.Two patients had AVF dysfunction associated with active smoking.Thirty-one patients were over the limit of 1.0 at vein intimalmedia complex, of those 31 patients, 27 of them (87%) had a significant increase in that measure, with 1.7mm associated with diabetes, renal hypoplasia and 11 patients had active smoking.MIH predominate with radio median configuration.
In 50% of patients at Enalapril group, myointimal complex basal measure, prior to surgery, was of 0.06mm and 1.16 after AVF procedure; at control group basal measure was 0.09 and 1.7 after (Figure 1).Within Enalapril group, 60% of patients (n=26) passed the 1.0mm myointimal complex limit and within control group, 75.6% (n=31) were over the limit.
No significant statistical difference was found regarding percentage of patients with MIH ( * P value: 0.137) or at the myointimal complex measurement increase between before and after AVF procedure between the groups ( * P value 0.579) (Table 1 and Figure 1).

Discussion
ESRD is a serious public health care problem in Mexico and several other countries [1].It has a very high morbidity and mortality rate in our country [1] and has a strong association with diabetes, with a prevalence of up to 7.2%, is considered the first cause of ESRD.Even when guidelines stipulate that between 65 to 85% patients with ESRD must be with continuous hemodialysis treatment, according to WHO, in Latin America only 15% are under hemodialysis.Table2: Patient characteristics with and without myointimal hyperplasia.Mexico occupies the 6 th place of countries with people with diabetes, and according to the National Health and Nutrition Enquiry (ENSAUT) and WHO, Mexico is also the 6 th place with male active smokers and the 2 nd with female active smokers [14,15].
As AVF is considered the access of choice for under hemodialysis patients [2,[4][5][6], primary patency is an important issue, considered up to 60% at first year of procedure, MIH is presented as reason of early failure in between 30 to 50% of patients.
In our study main causes of early AVF thrombosis, were diabetes and active smoking; also presenting higher MIH within those patients.Our results are non-conclusive regarding Enalapril as a protection factor against MIH, but in general, patients in Enalapril group developed lower myointimal complex measures and less AVF early failure.That, among other experimental studies, stands up for using medication against MIH in order to improve AVF useful life [2][3].

Conclusion
Active smoking and diabetes have an important role at MIH ( * P=0.05).
No statistical difference was found ( * P=0.637), associated to the number of cases.

Table 2
resumes patients and characteristics with MIH.No difference was observed between the 2 groups regarding age, number of patients with diabetes and active smoking, AVF configuration or ESRD etiology, although, a tendency was observed involving more patients with active smoking and hypertension within MIH group.Statistical difference regarding years of ESRD between the 2 groups.