Influência do diabetes mellitus sobre a perviedade da fístula arteriovenosa para hemodiálise The influence of diabetes mellitus on patency of arteriovenous fistulas for hemodialysis

Background: Failure of arteriovenous fistulas (AVFs) to meet the minimum requirements for hemodialysis (HD) is the greatest cause of morbidity in patients on renal replacement therapy. Identifying risk factors associated with failure of vascular access is crucial to management and success of hemodialysis treatment. Objective: To compare mean duration of patency and survival of arteriovenous fistulas created in HD patients with and without diabetes mellitus (DM). Methods: This was a retrospective observational study of the medical records for all patients on HD at the Hospital Santa Casa de Misericórdia de Ponta Grossa (Brazil) in February 2014. We analyzed clinical data relating to creation, maintenance and use of AVF for dialysis, comparing mean duration of patency of fistulas currently in use for HD and analyzing survival of previously occluded AVFs. Patient data was allocated to one of two groups for analysis, according to presence or absence of DM. Results: Individuals in the DM group had higher mean age (59.97 ± 10.12), shorter time on hemodialysis treatment (25.42 ± 3.21 months), lower mean time before occlusion of arteriovenous fistulas (3.09 ± 11.60 months) and a lower mean rate survival of vascular access to 24 months (50.25%). Conclusions: This study concluded that diabetic patients had shorter mean duration of AVF patency and lower rate of access survival to 24 months.


INTRODUCTION
At the start of the 1960s, Scribner et al. 1 revolutionized nephrology when they developed a Teflon device to create an arteriovenous shunt that could be continuously used for dialysis treatment. 1,2The Scribner shunt, as it came to be known, caused great interest in the scientific community, which went on to develop other vascular access techniques for chronic hemodialysis (HD) and, as a result, offered better life support for people with chronic end stage kidney disease (ESKD). 3he vascular access methods currently available are arteriovenous fistulas (AVFs), which may be autologous or prosthetic, and central venous catheters (CVCs). 4ccording to the 2012 Brazilian Chronic Dialysis Census, it is estimated that more than 95,000 patients are on dialysis treatment in the country, 91.6% of whom are being given HD as standard renal replacement therapy, demonstrating the overwhelming predominance of this modality. 5Invariably, these patients need vascular access for the dialysis procedure.The ideal vascular access should provide adequate blood flow, allow dialysis sessions lasting many hours, tolerate frequent use, have the capacity to survive for a long period of time and exhibit low rates of complications (thromboses, infections and aneurysms). 3,6ne major cause of dialysis-related morbidity is vascular access that fails to meet the minimum conditions for successful treatment. 6,7This is clearly demonstrated by the observation that vascular access complications are the most prevalent of the major causes of hospital admission. 8][12] Globally, DM is the most prevalent chronic disease among patients with ESKD, with systemic arterial hypertension (SAH) in second place. 13In Brazil, these figures are reversed, and 35.1% of patients with ESKD have SAH, while 28.5% have DM. 5 However, it should be acknowledged that DM associated with ESKD has been becoming increasingly predominant within the Brazilian epidemiological profile and if the trend continues it will reach worldwide prevalence rates in the next few years. 14,15onsidering the increasing role of diabetes mellitus as a cause of ESKD in our country, and the challenges involved in constructing AVFs in certain groups of patients, the primary objective of this study was to compare the mean duration of patency of occluded AVFs before this event, and the survival rates of arteriovenous fistulas constructed in patients with diabetes mellitus, with the same outcomes in patients who do not have diabetes mellitus, in patients given hemodialysis treatment at the Hospital Santa Casa de Misericórdia de Ponta Grossa (Parana, Brazil).

MATERIALS AND METHODS
Data were collected from the medical records of all patients on hemodialysis at the Hospital Santa Casa de Misericórdia de Ponta Grossa in February 2014.Patients with the following characteristics were included: (1) diagnosed with end stage kidney disease; (2) using hemodialysis as renal replacement therapy method; (3) current or prior use of an AVF as vascular access for dialysis treatment.
Patients were divided into two groups, depending on presence or absence of diabetes mellitus.Patients were assigned to the DM Group if they were on treatment with insulin or oral hypoglycemics or if they had a prior diagnosis of DM on their patient medical record.Patients were assigned to the NDM Group if they were on dialysis treatment but did not have DM as a comorbidity.
Sociocultural data were collected using an epidemiological questionnaire covering the following information: age, sex, ethnicity, educational level, place of residence and smoking habits.
Clinical data were collected using a structured research protocol covering the following information that was harvested from medical records: (1) time on dialysis treatment; (2) number of AVFs created since starting treatment; (3) mean duration of patency of previous AVFs, defined as cumulative or secondary patency (time elapsed from the date of creation to the date access was abandoned); 9 (4) mean duration of patency of AVFs currently in use up to the study cutoff; (5) time taken for AVF to mature (from creation until first puncture for HD); (6) anatomic site of AVF creation; (7) presence of infectious processes involving AVF since starting treatment; (8) prior use of a central venous catheter (CVC) for dialysis (9) use of CVC as access for initial dialysis treatment; and (10) presence of systemic arterial hypertension as an associated comorbidity.
The term premature occlusion was used to describe fistulas that occluded before 30 days, without attaining the necessary maturity for HD use.Results are first given for patent fistulas that were still in use for HD up to the study cutoff, and then the results for fistulas that had already occluded by that point are listed.
This study was analyzed and approved by the Research Ethics Committee at the Hospital Santa Casa de Misericórdia de Ponta Grossa under number 561.520/2014 (COEP).Patients were given free and informed consent forms, which they read and then signed to indicate their agreement to study participation.
The single-tailed Student's t test was used to detect statistical differences between means for groups and Fisher's test was used for dichotomous statistical differences.Results are expressed as mean ± standard deviation (SD).The Kaplan-Meier test was used to analyze AVF survival and the log-rank test was used to compare rates.Differences for which p < 0.05 were considered significant.Results were analyzed using MedCalc 13 (Belgium).

RESULTS
A total of 160 patients were recruited, 49 of them were allocated to the DM Group and 99 patients were allocated to the NDM Group, while 12 patients did not meet the inclusion criteria, making a total sample of 148 patients.Mean age differed between the two groups, at 59.97 years (± 10.12) for the diabetic patients and 52.54 years (± 14.83) for non-diabetic patients (p = 0.0010).There were no significant differences in educational level or smoking habits.Both groups exhibited a predominance of males, accounting for 69.39% in the DM Group and 51.52% in the NDM Group (p = 0.0510) (Table 1).
There was a significant difference between the groups in terms of time on hemodialysis treatment.The group of non-diabetic patients had a mean duration of 63.09 (± 53.19) months of treatment, which was considerably longer than the diabetic patients, who had mean hemodialysis duration of 25.42 (± 21.03) months (p = 0.0001).Although systemic arterial hypertension is an important risk factor associated with chronic kidney disease (CKD), its prevalence was similar between the groups at 87.86% of the DM Group patients and 88.89% of the patients in the NDM Group.There were no significant differences between the groups in terms of prior use of CVCs or the number of patients who started dialysis treatment via this type of access (Table 1).
For analysis of patent AVFs, 137 individuals had a fistula for HD access and in 11 patients a CVC was used as access route.The mean duration of patency for AVFs currently in use was 18.96 (± 13.40) months in the DM Group (n = 46) and 44.29 (± 43.77) months in the NDM Group (n = 91) (p = 0.0002).When fistulas were categorized by duration of patency into 1, 12 and 24-month groups, there was no significant difference between DM and NDM groups in terms of the prevalence of AVFs with less than 12 months' patency (32.61% in the DM Group vs. 22.08% in the NDM Group; p = 0.3040).Analysis of AVFs that remained patent for 12 and 24 months revealed greater prevalence in the DM Group (39.13%) (p = 0.0268).However, analysis of the rate of AVFs that remained patent for more than 24 months revealed that the proportion in the DM Group (28.26%) was significantly lower than the proportion in the NDM Group (56.04%) (p = 0.0020).
Another notable difference between the groups was related to the time taken for AVFs to mature, since 25 (54.35%) of the 49 patients in the DM Group had a vascular access puncture performed before the full 30 days' maturation period had elapsed, compared to just 31 (34.07%) of the 99 patients in the NDM Group (p = 0.0277).The remaining analyses of data on patent AVFs did not detect significant difference between the groups, in terms of current use of CVC, prosthetic grafts, autologous AVF or anatomic site of vascular access (Table 2).
The data on AVFs occluded prior to the study cutoff showed that there was no significant difference in the prevalence of patients who had had occluded fistulas (p = 0.1493), since 26 (53.06%) patients in the DM Group, and 66 (66.67%) patients in the NDM Group had had occlusions previously, including premature and late AVF losses (Table 3).There were a total of 49 occluded AVFs in the DM Group, 29 (59.18%) of which were late occlusions and 20 (40.82%) of which were premature occlusions.There were 121 occluded AVFs in the NDM Group, 71 (58.68%) late occlusions and 50 (41.32%)premature occlusions.Analysis of the time elapsed until AVF occlusion revealed that the mean time was 9.03 (± 11.60) months in the DM  Group and 15.97 (± 27.92) months in the NDM Group and the difference between them was not significant (p = 0.0952).However, excluding the premature occlusions from the analysis revealed that AVFs that underwent late occlusion exhibited significant difference between groups in terms of mean time before occlusion, which was 14.62 (± 12.39) months in the DM Group and 26.15 (± 32.58) months in the NDM Group (p = 0.0338) (Table 3).
When late-occluded AVFs were further broken down by patency at 12 and 24 months, it was found that the 12-month patency rate was 51.72% among diabetic patients and 53.52% for non-diabetic patients (p = 1), but that 24-month patency was significantly different between the groups, since 39.44% of the late-occluded AVFs in the NDM Group were still patent after 2 years, whereas in the DM Group just 17.24% survived to 24 months (p = 0.0368) (Table 3).
Analysis of the results of the Kaplan-Meier survival test showed that in the DM Group the AVFs exhibited 78.95% likelihood of patency after 1 month.In the NDM Group this probability was 76.42%.Extending the analysis to 12 months revealed that the DM Group AVFs exhibited a 64.21% likelihood of patency, compared with 60.85% of the AVFs in the NDM Group.Notwithstanding, the 24-month patency rates showed that AVFs in DM Group patients were less likely to be patent, with 50.25% patency, compared to 55.21% for the NDM Group (p = 0.3800) (Figure 1).

DISCUSSION
With regard to the prevalence of DM among ESKD patients, the national scenario was illustrated by the 2012 Brazilian Chronic Dialysis Census, 5 revealing that 28.5% of patients on dialysis treatment also have diabetes as an associated comorbidity, which is a slightly lower figure than was found in the present study (33.10%).A study conducted in 2009 in the South of Brazil by Burmeister et al. 15 reported that 37.9% of the hemodialysis patients studied also had DM.These epidemiological data suggest that there are significant regional differences in DM rates among hemodialysis patients.
Comparison of epidemiological data between groups with and without DM revealed that the mean of age of the DM patients was higher, which has also been observed in other studies in the literature, 12,14 which have identified DM as the most prevalent comorbidity among older patients using AVFs for hemodialysis. 16owever, the duration of hemodialysis treatment was significantly shorter in the DM Group, which might be explained by the higher mortality rate among diabetic patients on HD. 17,18 On the other hand, the longer duration of treatment in the NDM Group may have its causes in the earlier onset of ESKD cases that are related to causes of CKD other than diabetes 7 (Table 1).
According to the recommendations in the National Kidney Foundation -Kidney Disease Outcomes Quality Initiative (NKF -KDOQI) guidelines, 6 an autologous arteriovenous fistula is the approach that comes closest to an ideal access for dialysis treatment, since it is associated with lower rates of complications, lower costs and greater durability.In this study we observed greater than 90% utilization of autologous AVFs as access in both groups, with no distinction between them, showing that DM did not prove to be a limiting factor to choosing "fistula first", as the literature recommends. 19,20Notwithstanding, it was also observed that more than 50% of the DM patients had their AVFs punctured for use before 30 days had elapsed since creation (p = 0.0277), which is the minimum period recommended by the NKF-KDOQI to allow an autologous AVF to mature, since premature puncture of the access can result in increased incidence of infiltration and compression of the anastomoses, causing permanent loss of the AVF. 6he morbidity and mortality linked with employing a CVC for dialysis access figures among the principal motives related to premature puncture of AVFs, whether because of the risk of developing complications, such as infection of the catheter, or because of the increased discomfort attributed to employing this method. 21,22s an alternative, it is recommended that patients with CKD should be referred to a specialist as early as possible to discuss methods for renal replacement therapy, 23 particularly individuals who have chronic comorbidities, since they invariably exhibit greater chances of progression to ESKD.When the treatment chosen is HD, an AVF should be created when the patient reaches stage 4 CKD (glomerular filtration rate <30mL/min/1.73m 2 ), thereby providing sufficient time for the access to mature, so that it is available when dialysis treatment is started. 6][26] However, the data collected in this study did not reveal differences between the rates of premature occlusion in accesses created in diabetic and non-diabetic patients (Figure 1), since accesses attained maturity in more than 70% of cases in both groups, confirming data published elsewhere in the Brazilian literature. 10he restricted number of premature occlusions of vascular accesses among the diabetic patients may be the result of good management of DM treatment. 25lthough they had been on treatment for shorter periods, patients in the DM Group exhibited similar prevalence rates of later occlusions (Table 3) when compared with non-diabetic patients, showing that the occurrence of occlusion of accesses is more frequent among the diabetic patients, allowing for the length of time on dialysis treatment. 22he data on survival rates of accesses, illustrated by the Kaplan-Meier curve (Figure 1), demonstrate that at 12 months the AVFs in the diabetic patients in this study did not have lower patency rates, in contrast with what was reported in a meta-analysis published in 2014 by Al-Jaishi et al. 27 This can be explained by the fact that the mean time elapsed before late occlusion of AVFs in the DM Group (which was approximately 14 months) was beyond the 12-month analysis cutoff.
However, the univariate analysis of cumulative patency at 24 months shows that there was a significant reduction in patency among the patients in the DM Group, following the pattern that is generally described in the literature. 27This result is related to the greater number of vascular access occlusions observed from 12 to 24 months after creation of the AVFs in this group.
This study suffers from certain limitations, including the small number of patients, which did not provide significant results for AVF survival according to the Kaplan-Meier test, although it did show that accesses in the DM Group had lower survival rates at 24 months and this might have been significant with a larger sample size.Another probable limiting factor is the lack of standardization of institution of surgical treatment to create the AVFs, which is the result of the fact that these procedures were conducted by different teams of professionals over the years.
In terms of conclusions, it was observed that in the sample studied diabetic patients had lower duration of use, lower patency of AVFs that later occluded and also lower rates of access survival at 24 months, when compared with non-diabetic patients.

Table 1 .
Sociocultural and clinical patient data.

Table 2 .
Characteristics of patent arteriovenous fistulas currently in use for HD.

Table 3 .
Analysis of arteriovenous fistulas occluded prior to study cutoff.
AVF -arteriovenous fistulas.*Occlusion of access before it was used for hemodialysis (primary failure).† Occlusion of access that had successfully been used for hemodialysis.