Arteriovenous Fistula Maturation Failure in a Large Cohort of Hemodialysis Patients in the Netherlands

Patient selection

Adult patients who underwent creation of an AVF or AVG as a permanent VA for maintenance HD were retrospectively identified in 5 affiliated teaching hospitals and 3 academic hospitals in the Netherlands. To prevent survivorship bias, the time frame varied per hospital and was limited to years in which medical records were available for all consecutive AVF and AVG recipients in that year (Supplemental Table 1). Overall, patients receiving their VA between 1997 and 2016 were included.

The Medical Research Involving Human Subjects Act (WMO) was not applicable. Ethical approval was granted by the medical ethics committees of the Leiden University Medical Center. Data were collected and processed in accordance with the local research code of conduct.

Data collection

Data were collected from clinical records and included demographic variables, comorbidities, medication use, laboratory results, VA configuration and surgical details, initiation and abandonment of VA use, ultrasound results, surgical and endovascular interventions and clinical adverse events. Ethnicity of patients was not registered due to objections by the ethical committee.

Outcomes and candidate predictors

Preemptively created VAs were defined as VAs created in a patient who did not receive HD within 2 weeks after VA creation. The VA was considered mature if it was successfully used for at least three consecutive HD sessions or if the Robbin’s ultrasound criteria for maturation were met [13]. The VA was considered nonmature if it was not cannulated in a patient on HD. If the patient has not started HD, a VA was considered nonmature if ultrasound or angiography demonstrated a failed VA using Robbin’s criteria or another VA was created. If maturation could not be assessed due to death, kidney transplantation or loss to follow-up before VA cannulation or ultrasound, it was considered indeterminate.

For prevalent HD patients, maturation time was defined as the time until cannulation or ultrasound demonstrating maturation, whichever came first. Assisted maturation was defined as maturation with a procedure to improve patency.

A list of candidate predictors for nonmaturation was compiled: patient age over 60 years, female gender, diabetes mellitus, a body mass index (BMI) over 25 kg/m², symptomatic coronary, cerebrovascular or peripheral arterial disease, an ipsilateral central venous catheter, hypertension, cystic kidney disease, whether the fistula was created preemptively and a preoperative diameter of the artery or vein below 2.5 mm.

Statistical analysis

Statistical analyses were performed for RCAVFs, upper arm AVFs and upper extremity AVGs. T- and χ²-tests were used where applicable. Baseline characteristics were summarized as mean with standard deviations for continuous variables and as count with percentages for categorical variables. Missing data were handled by multiple imputation methods using fully conditional specification with 10 repetitions [14, 15]. Candidate predictors, VA sidedness and maturation outcome were entered. For age, BMI, mean arterial pressure and artery and vein diameters, continuous values were entered into the multiple imputation. The imputed values were dichotomized to appropriate categories.

A prediction model for nonmaturation was created. Candidate predictors were entered in a multivariate logistic regression analysis, with nonmaturation as the dependent variable. Backward selection was used to identify the most significant independent predictors. In logistic regression analysis, candidate predictors were considered significant at a p value <0.30. p value of 0.30 was applied as conservative selection criterion to limit chances of overfitting [16]. We used the majority method to select the predictors for the final prediction model [17]. Predictors significant in at least 7 out of 10 imputation sets were entered into the final logistic regression analysis. Subsequently, forward selection was used to check stability of the results.

Sensitivity analysis was performed by repeating the logistic regression analysis with a significance level of p value <0.40, <0.25 and <0.20. The model’s predictive performance was examined by estimating calibration and discrimination. A receiver operating characteristic analysis was performed for the model, and C-statistics from all imputation sets were pooled [18]. Statistical analysis was performed using IBM SPSS Statistics version 22 (IBM Corp., Armonk, NY).

Patient characteristics and VA configurations

Data from 1656 VAs (1383 AVF and 273 AVG) in 1 221 patients were obtained (Table 1). RCAVFs and upper arm AVFs and AVGs were the most common configurations. The 51 other configurations constituted 3.1% of the cohort and were excluded from the analysis (Fig. 1). The earliest VA available in the cohort was created in 1997 (Supplemental Table 1). Baseline measurements for arterial and venous diameters were missing in 43 and 25%, respectively, in cases where diameters were only described as ‘suitable’ in clinical practice. Additionally, the perioperative mean arterial pressure was unknown for 12.1% of cases and the BMI was missing for 7.5%

Females and patients with diabetes more frequently received an AVG and females more frequently received an upper arm AVF. Fifty-five percent of RCAVFs were preemptively created, compared to 39 and 34% for upper arm AVFs and AVGs, respectively. RCAVFs were most often the first VA, with 90% created in patients without a prior VA (Table 2).

Postoperative ultrasound examinations were not routinely performed during the historical timeframe of the study and were available for 28% (448/1605) of VAs. For 1496 out of 1605 VAs (93.2%), the maturation outcome could be determined (Fig. 1 and Supplemental Table 2).

Incidence of nonmaturation

The incidence of nonmaturation was 24% for RCAVFs. This was lower than the nonmaturation incidence of upper arm AVFs and functional failure of AVGs (p <0.001 for RCAVF versus upper arm AVF, Table 3). The short-term follow-up of VAs, defined as achieving 3 months or 6 months of functional patency, was similar for upper arm AVFs (3 months: 77.8%, 6 months: 69.5%) and AVGs (3 months: 77.7%, 6 months: 68.6%) and worse for RCAVFs (3 months: 66.6%, 6 months: 59.5%) (Supplemental Table 3).

Unassisted maturation was lowest for RCAVFs, at 60% (370/617), versus 79% for upper arm AVFs. Assisted maturation could be achieved even after multiple procedures (Supplemental Table 4 and Supplemental Figure 1). Eighty percent of AVGs did not require procedures before first use.

Of RCAVFs preemptively created in patients who initiated HD within 3 months, 81% were cannulated within 3 months (Table 3). In prevalent HD patients, 61% of RCAVFs were cannulated within 3 months. AVGs were cannulated earlier than RCAVFs and upper arm AVFs, which were rarely used within 6 weeks (Table 3, Fig. 2). The 3-month cannulation rates in prevalent HD patients differed substantially between hospitals, ranging from 48 to 70% for RCAVFs and 33–80% for upper arm AVFs (Supplemental Table 5).

Over the timeframe of the study, no significant change in maturation of AVFs or primary success of AVGs was observed (Supplemental Table 6).

Fifty-nine patients received subsequent RCAVFs in both arms. Of the first RCAVFs, 34 (57%) did not mature, the remainder failed after initial successful use. Forty-one out of 59 (69%) subsequently created contralateral RCAVFs matured without procedures. As 5 RCAVFs reached maturation with procedures, the assisted maturation of these contralateral RCAVFs was 78%. Thirteen out of 59 (22%) RCAVFs failed due to nonmaturation. For 462 RCAVFs, the preoperative venous diameter and the maturation outcome were recorded (Table 1). Of RCAVFs with a recorded preoperative venous diameter of 2.5 mm or more, 225/295 (76%) were successful. From the group of AVFs with a preoperative venous diameter below 2.5 mm, 113/167 (68%) matured successfully (p = 0.045).

Prediction of nonmaturation

In the logistic regression analysis, 4 out of 13 predictor variables were significant at p <0.30 with backward selection in at least 7 of 10 imputed datasets (Table 4). In the sensitivity analysis restriction of the removal criterion for backward selection to p <0.25 removed the predictor peripheral vascular disease, while p <0.40 added the predictor arterial diameter <2.5 mm. These results were stable with forward selection. The risk equation of this model predicted RCAVF nonmaturation with a median area under the ROC-curve of 0.629 (interquartile range 0.626–0.633). Calibration of the model was assessed by comparing observed and predicted risk (Fig. 3).

Incidence of nonmaturation

The 24% rate of primary failure of RCAVFs appears lower than the rates reported by Dember et al. (65%), Huijbrechts et al. (40%) and Schinstock et al. (37%) [7, 19, 20]. In the study by Dember et al. [7], 14% of AVFs were considered nonmature as determined by ultrasound criteria, although they were being used for HD. We found no improvement of AVF maturation over time.

It is important to notice that the definition of nonmaturation in our retrospective study differs from prospective studies. As follow-up ultrasound examinations were not routinely performed and a large proportion of AVFs was created preemptively, a composite measure of functional use and ultrasound criteria was created.

Although AVGs have a lower 5.7% incidence of functional failure than the nonmaturation incidence of upper arm AVFs (10.6%), this advantage is offset by the higher loss of AVG patency after cannulation, resulting in similar rates of 3- and 6-month functional patency.

RCAVF versus other configurations

Like previous studies, we demonstrate that RCAVFs have the highest rate of delayed cannulation and nonmaturation. Over the duration of the study since 1997, no improvement of maturation has been observed. Our findings confirm the findings by Masengu, et al. [21] that age, gender and vascular disease are associated with, but do not reliably predict nonmaturation. In contrast, Lok, et al. [9] were able to predict nonmaturation in their model. Possible explanations are the different population in the USA and Canada and differences in patient selection and surgical practice, compared to Europe. Comparable to previous studies, we found a high rate of nonmaturation in females [22-24].

RCAVFs were commonly created in patients without a history of a failed VA. It is assumed that patients receiving an upper arm AVF as their first VA often had forearm vasculature not suitable for an RCAVF. It remains unclear whether this reflects local anatomical variations or a more generalized unsuitability of the patients’ vasculature. Based on our results, we hypothesize RCAVF nonmaturation is not solely explained by demographics and comorbidities. The anatomy of the RCAVF itself appears prone to nonmaturation.

If nonmaturation was strongly associated with comorbidities and demographics, one would expect a high nonmaturation rate of contralateral AVFs in individual patients with prior VA failure. In this respect, an important observation was the 22% primary failure rate of RCAVFs in patients with a non-matured contralateral RCAVF. Rather than being increased, at 22% this was similar to the overall 24% risk of RCAVF nonmaturation in our cohort. This illustrates that comorbidities do not explain nonmaturation substantially. One possible explanation is preferential creation of the first VA in the non-dominant arm, even if the vasculature of the dominant arm is more suitable (i.e., larger vessels).

Interventions to promote maturation

Out of a total of 142 RCAVFs undergoing procedures to improve maturation, 98 (69%) matured. Although it cannot be ruled out that these also would have matured spontaneously, procedures to assist maturation appeared to be a worthwhile strategy to promote AVF usability. Similar results were observed by Shin et al. [25] achieving successful cannulation in 14 out of 19 cases (74%) of balloon angioplasty for AVF nonmaturation due to localized stenosis. In a study by Miller et al. [26] extensive balloon angioplasty and side branch interruption of 75 nonmature AVFs with a diameter of 2.0–5.0 mm resulted in successful cannulation of 71 AVFs after a median of 2.6 procedures.

Variability among hospitals

In our cohort, patients from both academic and referral hospitals were included. The variability in maturation rates of AVFs among centers was remarkable. Based on the current data, it cannot be determined whether these differences result from the process of care or demographic characteristics of the patients that we did not include in our analysis.

Limitations

Due to the retrospective design, the maturation outcome could not be determined for 10% of VAs. Another limitation of the current study is the unavailability of routine 6-week ultrasound examinations. Postoperative ultrasound examinations were often performed for symptoms or suspected nonmaturation. These therefore cannot be extrapolated to the entire cohort.

The time until first cannulation in prevalent hemodialysis patients should be interpreted with caution. As Robbin, et al. [27] demonstrated, most of the maturation occurs within 2 weeks after surgery. We cannot distinguish if the differences between the 6-week and 3-month cannulation rates of 17 and 61%, respectively, reflect actual delayed maturation or clinicians’ reluctance to early cannulation. Only a prospective study in which serial ultrasound examinations or early cannulation attempts are performed can reliably assess the potential for early cannulation of AVFs.

As the weak prediction model did not result in a clinically applicable risk equation, we did not perform external validation. One limitation could be the lack of data on ethnicity, an important factor in the scoring system by Lok et al. [9].

Future directions

One approach to prevent nonmaturation is careful patient selection. New strategies are needed to identify patients at high risk of nonmaturation. A shift toward upper arm AVFs as the primary VA option seems attractive. However, losing distal VA options may not be acceptable for all patients and high-flow symptoms more often occur with upper arm AVFs. Therefore, such paradigm shift seems not to be the right solution.

Conflict of Interest

The authors declare that they have no conflict of interest.