Fistula maturation: doesn't time matter at all?
Giuliano Brunori1,
Pietro Ravani2,
Salvatore Mandolfo3,
Enrico Imbasciati3,
Fabio Malberti2 and
Giovanni Cancarini1
1 Cattedra di Nefrologia Università di Brescia, Brescia, 2 Divisione di Nefrologia e Dialisi, Cremona and 3 Divisione di Nefrologia e Dialisi, Lodi, Italy
Correspondence and offprint requests to: Dr Giuliano Brunori, Chair and Department of Nephrology, University and Spedali Civili; Piazza Ospedale 1, 25123 Brescia, Italy. Email: gcbrunori{at}hotmail.com
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Introduction
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The arterio-venous fistula (AVF) remains the gold standard access to haemodialysis, showing better survival and lower complication rates than graft and catheters. However, fistulae are not readily usable after creation, and recommendations for optimal waiting time before use are based upon observational studies. The current guidelines suggest a minimum of 1 month and preferably 23 months before utilization of an AVF [1]. However, recently published findings from two large studies, the DOPPS and an Italian multi-centre study, reached different conclusions [24]. Those investigations tested the role of the maturation time, i.e. the time period from AVF creation and the first cannulation (FCT), as prognostic factor for AVF failure. Because of substantial differences in the measurement method applied, discussion on methodological features of those prognostic studies may contribute to a more careful interpretation of their findings.
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DOPPS studies
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The most recent report on the relationship between maturation time and AVF survival has been published by Saran et al. in a previous issue of this journal [4]. These authors found a similar risk for AVF failure in a facility-level model from the DOPPS data comparing different maturation time prescriptions. These results do not support the common practice of postponing the FCT to allow adequate maturation. Conversely, from the authors' perspective, a reduced maturation time has the potential to decrease reliance on temporary vascular access (catheters) while not affecting long-term AVF survival.
No doubt the study by Saran et al. [4] is based on a well performed epidemiological study conducted in a large sample of dialysis patients [5]. However, we feel that some fundamental issues regarding AVF maturation need to be discussed, especially in the light of the available evidence.
First, as pointed out by the authors themselves, a randomized clinical trial would be the ideal method to compare the effect of early vs delayed cannulation on vascular access survival. In the present study, the statistical analysis has been based on the responses to questionnaires filled out by the nurse managers of the dialysis units. Fistulae were first cannulated <1 month after creation in 74% of Japanese facilities, 50% of European facilities and only 2% of US facilities. After 3 months of placement, only 2% of Japanese facilities and 8% of European facilities first cannulated AVF, compared with 26% of facilities in the USA. We do not know when, during the month period after creation, fistulae were first cannulated: after 2, 3 or 4 weeks? The facility level practice pattern represents the typical time from creation to FCT but does not give the real time between AVF creation and FCT.
This kind of analysis, in the authors' view, is analogous to an intention-to-treat approach used in randomized clinical trials that avoids the treatment by indication bias that a patient-level analysis potentially could suffer from. A randomized study, at present, is not available and we need our clinical daily practice to rely on well designed longitudinal cohort studies, possibly fulfilling criteria of plausibility, consistency, temporality and validity. In these studies, the sample population should consist only of incident patients, contributing to the time at risk of disease at the same time (i.e. the AVF creation or cannulation date, according to the predictor under study). The identification of this inception cohort is of particular importance for the validity of any prognostic study. Secondly, both the response and exposure variable definitions, as well as methodology criteria must be consistent with the study question.
The problem of the possible relationship between catheter use, cannulation practice and AVF outcomes had already been analysed and reported by the DOPPS investigators [2,6]. In those studies, the inception cohort was clearly identified, and the response and exposure variables defined according to the purpose of the study. Rayner et al. [2] showed that the presence of a temporary catheter at the start of dialysis was associated with increased risk of vascular access failure. The authors hypothesized that the presence of a catheter and/or its complications may affect the longevity of an autologous fistula through its earlier utilization and/or less favourable maturation. In a subsequent study, Pisoni et al. [6] showed that the presence of a temporary catheter and a nephrologist's referral within 1 month prior to starting dialysis are the two main predictors of using fistulae earlier than 28 days, and a maturation period of <2 weeks predicts shorter AVF survival. In both studies, the statistical unit was the first AVF of incident dialysis patients (>900 in the former, and 642 in the latter). The response variable was time from first use until first failure, and the exposure variable in the study of Pisoni et al. was the maturation time between creation and first cannulation. The study entry date was used as a close approximation of first AVF use. Eighty-six percent of patients entered the DOPPS within 2 days of their first ever dialysis treatment. After excluding patients starting with catheters (to avoid violation of proportional hazard assumption), the authors found that cannulation within 14 days had a significantly increased subsequent chance of failure compared with cannulation after 14 days. No significant difference in AVF failure was seen for fistulae cannulated in 1528 days compared with 4384 days. The authors concluded that the AVF should be left to mature for at least 14 days before cannulation.
Conversely, Saran et al. [4] included in their analysis AVF of both incident and prevalent patients, using the access as the epidemiological unit of observation. In this case, although previous dialysis history and previous access can be considered for adjusted analysis, important residual confounding cannot be excluded. Characteristics and factors of these prevalent patients may be associated with both (confound the relationship between) maturation time (exposure) and AVF survival (disease). Consequently, selection bias of long survivors with potentially substantial differences in co-morbid conditions and other unmeasured variables may have affected the results. In addition, the choice of the creation date as time zero for survival analysis implies a temporal overlapping of the response variable and the predictor under study (time between surgery and cannulation). The latter in this report was defined as the facility practice policy instead of a measured value (14 days, >14 days, etc.). The authors claim that the prescribed rather than actual exposure would reduce potential confounding bias resulting from non-random distribution of factors known (or unknown) to impact outcomes, as suggested by Wolfe [7]. Indeed, the assignment of patients to different groups is determined by many measured and unmeasured patient characteristics. This treatment by indication bias can be reduced substantially by comparing outcomes for groups of physicians (or facilities). However, this intention-to-treat approach, which is not under discussion for randomized studies, is of questionable benefit in the absence of an a priori defined and randomized exposure assignment, and when the available measured value of the exposure proves to be highly variable within practice facilities. In the example of Wolfe [7], the patients' exposure to dialyser reuse represents a strong, a priori sample and clearly defined centre policy. Analyses at a patient level (actual reuse vs no reuse, instead of a comparison of facility practices) would be confounded by unmeasured factors acting at a patient level (patients from a reuse centre not reusing due to infection), thus confounding reuse-associated survival estimates. Conversely, the policy of maturation time adopted by a dialysis facility is not so simple that it can be dictated by a clear guideline: it is difficult to find a centre policy more precise than a recommended range of period of maturation. Physicians' opinion and experience may vary widely within facilities.
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The Italian multi-centre study
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In a previous report from our group [3], we tried to determine the potential association between late referral, use of temporary catheters and early cannulation of AVF, and between maturation time since AVF creation (exposure variable) and AVF survival. Similarly to the DOPPS, for the purpose of the study, we enrolled incident patients only. Specifically, the study population included all consecutive incident patients in three large nephrology centres in Northern Italy, starting haemodialysis and receiving an arterio-venous access for the first time during a 6 year period. As in all incident studies, patients started contributing to the time at risk of disease at the same time (the first cannulation date in this case). All participating centres have a similar cannulation practice: nephrologists give an indication of when, where and how to perform the first venipuncture. Of interest, despite the prescription of a minimum maturation time period before the first use of 23 weeks (ideally 4 weeks) after vascular access creation, the real FCT ranged between 3 days and 28 months (median 1 month, inter-quartile range 0.62.3 months, with small differences among the centres). Thus, despite similar policies and clinical indications, the real practice appears to vary widely. Time to primary and secondary patency (response variable) was measured using the first cannulation date as time zero for analysis. In the analysis we performed, the statistical unit was the first AVF for incident patients. Of the 535 patients enrolled, 513 (96%) had an AVF and 22 had a prosthetic graft as first vascular access. Primary and secondary survival analyses were performed on the 414 and 446 patients who used their first AVF, respectively, without or after the revision procedure. It is worthy of note that of the 513 consecutive patients with an AVF, 19% did not use their AVF without further interventions: it would be difficult for us to understand the role of maturation time (either measured or prescribed) in a model of survival analysis from placement including the exposure variable under discussion. Beyond confirming the strong association between late referral, catheter use and earlier cannulation, in the same study we found both lower unassisted and assisted patency rates associated with shorter maturation time: cannulation earlier than 1 month was associated with a 94% higher risk of primary failure (P<0.001), whereas cannulation earlier than 2 weeks increased the risk of final failure by 111% (P<0.009). Other additional independent and significant predictors of failure were: nephrology referral within 3 months of starting dialysis [hazards ratio (HR) 1.55; P<0.033] and the presence of cardiovascular disease (HR 1.83; P = 0.002) in the primary survival model (independent of catheter use); and catheter utilization at the start of dialysis (HR 1.80; P = 0.012) and the presence of cardiovascular disease (HR 2.214; P<0.001) in the secondary survival model. We concluded that late referral and use of a catheter predict shorter AVF survival not only through earlier cannulation.
The main limit of our study (and those of Pisoni and Rayner) is that our analyses of time to first event disregarded AVF failures recurring in the same individual.
In fact, AVF survival data are a typical case of multiple failure time data, arising when more than one event (failure) occurs for the same subject. In these studies, failure times are correlated within a cluster (subject), violating the independence of the failure time assumption required in traditional survival analysis. The simplest way of analysing multiple failure data is to examine time to first event only, ignoring additional failures. This approach, however, is usually not adequate because it wastes possibly relevant information. On the other hand, the use of naïve statistical methods that treat recurrent events as independent observations may produce misleading results, even if the effect of the number of previous access is controlled for in the analyses, as in the study of Saran et al. [4].
However, in our study protocol, we did not include in the data collection the cannulation dates of subsequent fistulae and, therefore, we could not test the role of maturation time beyond the first access. Thus, any conclusion should be applied to the first AVF provided to the patient. Further studies are needed focusing on the outcomes since creation, thus including earlier events, and on multiple failures recurring in the same individual.
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Final remarks
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Given the data available at present from the DOPPS [2,4] and from our own study [3], a longer maturation time appears to be associated with a lower risk of failure of the first AVF. The finding that first cannulation 2 weeks after creation is not associated with worse fistula survival, as reported by Saran et al. [4], should not be used to recommend that all AVFs can be cannulated 24 weeks after creation. Clinicians, in some facilities, may be able to select appropriate patients and perform fistula cannulation in an early stage in a way that is not detrimental to fistula survival.
In our cohort, the probability of failure decreased, on average, by 5% for every 2 weeks increase of the maturation time, with break-points at 30 and 15 days, respectively, for primary and secondary patencies (Figure 1). This implies that AVFs should be left to mature for at least 30 days to reduce the risk of primary failure and that a maturation period of only 15 days may require further interventions to maintain patency. In addition, although any inference drawn from an observational study should be proven in randomized trials, the risk factors identified in recent analyses, such as the presence of cardiovascular disease, the use of a catheter, and late referral and shorter maturation times [2,3,6], appear to be causal components consistent with the mechanism of AVF failure (Figure 2). Therefore, because the effect of these risk factors could be significantly reduced through early and appropriate specialist interventions, the results of these studies provide level B evidence in support of the vascular access DOQI guidelines concerning earlier patient referral, timing of AVF placement and maturation requirements.

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Fig. 1. Linear regression of primary (black line, squares) and secondary (grey line, triangles) risk of AVF failure over maturation time since creation (in weeks).
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Further studies are needed to evaluate the impact of the role of other dialysis-related risk factors on AVF failure, especially of early failure, unsuccessful utilization and recurrent events.
Conflict of interest statement. None declared.
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References
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- National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Vascular Access: 2000. Am J Kidney Dis 2001; 37[Suppl 1]: S137S181
- Rayner HC, Pisoni RL, Gillespie BM et al. Creation, cannulation and survival of artero-venous fistulaedata from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Kidney Int 2003; 63: 323330[CrossRef][ISI][Medline]
- Ravani P, Brunori G, Mandolfo S et al. Cardiovascular comorbidity and late referral impact arteriovenous fistula survival: a prospective multicenter study. J Am Soc Nephrol 2004; 15: 204209[Abstract/Free Full Text]
- Saran R, Dykstra DW, Pisoni RL et al. Timing of first cannulation and vascular access failure in haemodialysis: an analysis of practice patterns at dialysis facilities in the DOPPS. Nephrol Dial Transplant 2004; 19: 23342340[Abstract/Free Full Text]
- Young EW, Goodkin DA, Mapes DL et al. The Dialysis Outcomes and Practice Patterns Study (DOPPS): an international hemodialysis study. Kidney Int 2000; 57[Suppl 74]: S74S81.[CrossRef]
- Pisoni RL, Young EW, Dykstra DM et al. Vascular access use in Europe and the United states: results from the DOPPS. Kidney Int 2002; 61: 305316.[CrossRef][ISI][Medline]
- Wolfe RA. Observational studies are just as effective as randomized clinical trials. Blood Purif 2000; 18: 323326.[CrossRef][ISI][Medline]
Received for publication: 15.11.04
Accepted in revised form: 13. 2.05