Factors associated with access blood flow in native vessel arteriovenous fistulae

Marcello Tonelli1,2,3, David J. Hirsch4,5, Christopher T. Chan6, Joanne Marryatt5, Paula Mossop5, Colleen Wile5 and Kailash Jindal1

1 Department of Medicine, University of Alberta, 2 Department of Critical Care, University of Alberta, 3 Institute of Health Economics, Edmonton, Canada, 4 Department of Medicine, Dalhousie University, 5 Queen Elizabeth II Health Sciences Centre, Halifax and 6 Toronto General Hospital, University Health Network, Toronto, Canada

Correspondence and offprint requests to: Dr Tonelli, 7-129 Clinical Sciences Building, 8440-112 Street, Edmonton, Alberta T6G 2G3, Canada. Email: mtonelli{at}ualberta.ca



   Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Access blood flow (Qa) identifies stenosis in patients with native vessel AV fistulae (AVF), but data on factors that are associated with Qa in normally functioning accesses are sparse. Such factors could be used in conjunction with Qa to improve the diagnostic performance of screening. We examined the relationship between Qa and certain clinical characteristics in a large group of patients with AVF.

Methods. This was a retrospective study of incident and prevalent haemodialysis patients treated at a single institution, all of whom had a functioning AVF during the study period. Qa was measured bimonthly using ultrasound dilution in all subjects. Mixed models were used to explore the relationship between Qa and a group of independent variables, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), diabetes mellitus, patient age, sex, height, body mass index (BMI) and AVF location (forearm vs upper arm).

Results. A total of 4084 Qa measurements was made in 294 patients. Univariate analysis found that younger patient age, non-diabetic status, higher blood pressure (SBP, DBP, MAP, all at the time of Qa measurement), upper arm AVF location and overweight status (BMI ≥25) were significantly associated with Qa. SBP appeared to be more strongly associated with Qa than either DBP or MAP. Patient sex, height and interval between access creation and Qa measurement were not significantly associated with Qa. Tests for interaction suggested that the association between SBP and age and Qa varied significantly by access location. In a multivariate model, SBP, overweight status and diabetic status were independently associated with Qa. The strength of the association between these characteristics and Qa appeared to be clinically relevant.

Conclusions. Our findings suggest that a single Qa threshold for angiography in all patients may be simplistic, and that the optimal threshold might vary by patient subgroup. The strong association between SBP and Qa suggests that adjusting Qa for SBP may improve the specificity of access screening. Further work is required to determine whether such modifications to current practice would improve the predictive power of Qa measurements for detection of stenosis in AVF.

Keywords: arteriovenous shunt; haemodialysis; surgical shunt; vascular access



   Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Canadian clinical practice guidelines suggest performing angiography in native vessel AV fistulae (AVF) when access blood flow (Qa) is <500 ml/min, or if Qa declines >20% from baseline [1]. Following these guidelines has been shown to identify first and recurrent episodes of stenosis in patients with AVF, with a positive predictive value for stenosis of ~70–75% [2,3].

Although no controlled trials have been conducted to evaluate the benefit of using Qa to screen AVF for stenosis, a randomized study indicates that percutaneous correction of stenosis (once identified) improves AVF patency [4]. These investigators used screening angiograms to detect stenosis in study subjects. Although this method is the gold standard for detecting stenosis, it is impractical for routine clinical use. This suggests that refinement of existing non-invasive techniques for identifying stenosis in AVF is warranted.

Existing guidelines do not account for clinical variables other than stenosis which might affect Qa. While Qa might vary according to patient characteristics or access location, there are few data testing this hypothesis in AVF. If present, such differences would imply that adjustment of Qa measurements for these characteristics might improve the diagnostic performance of screening. We examined the relationship between Qa and a number of clinical characteristics in a large group of patients with AVF.



   Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We studied 294 incident and prevalent chronic haemodialysis patients at the Queen Elizabeth Health Sciences Centre with a functioning AVF. Cannulation of AVF was attempted once clinical assessment suggested that they were sufficiently well developed to support haemodialysis, and only after a minimum maturation period of 8 weeks. No access monitoring was performed prior to this first cannulation. The height of patients was measured at the time they commenced renal replacement therapy. Height and the pre-dialysis weight at the time of the first study treatment were used to calculate body mass index (BMI). BMI ≥25 was used to define overweight status, based on guidelines for the general population.

Dialysis technique
Patients were dialysed according to their usual prescription. No patients received anti-platelet or anti-coagulant agents specifically to maintain access patency. Blood pump speeds were set as high as venous pressures would allow, and fistulae were cannulated with 15 gauge needles whenever possible.

Procedure for access screening
Screening studies were performed bimonthly with a Transonic HD01 Monitor (Transonic Systems Inc., Ithaca, NY), using indicator dilution technology, where the ultrasound velocity through blood is the indicator, and dilution is provided by the bolus of normal saline. Each patient had Qa measured twice in succession during the same dialysis treatment, and the mean value was recorded. Studies were not performed during the last hour of haemodialysis or during periods of clinically significant hypotension (at the discretion of the dialysis unit nurses).

Statistical analysis
Most patients had multiple measurements of Qa, meaning that ordinary regression models would be inappropriate because of autocorrelation. Therefore, mean Qa values for the first screening study per patient were compared using t-tests in groups defined by patient and access characteristics. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), diabetes mellitus, patient age, sex, height, BMI and AVF location (forearm vs upper arm) were selected for further evaluation.

To take advantage of the increased statistical power associated with the multiple measurements per patient, mixed models were used to explore the relationship between independent variables (the same patient and access characteristics) and Qa, after correction for autocorrelation [5]. Time was entered as an independent continuous variable in these models, meaning that the relationship between Qa and patient characteristics was independent of changes in Qa over time (making our results analogous to those in a cross-sectional study). Variables which were significant at the P<0.20 level in univariate analyses were entered into multivariable mixed models. Tests for interaction between blood pressure and access type were performed by inserting a cross-product term into these models. Model fit was assessed using Akaike's Information Criterion (AIC) [5] to determine which models best fit the data. Model assumptions were tested by examining plots of residuals vs predicted values and explanatory variables, and by examining histograms of the residuals to confirm that they were normally distributed. Statistical analysis was performed using SAS 8.2 software (Cary, NC).



   Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient characteristics of the 294 study patients are shown in Table 1. The mean number of measurements per patient was 14 ± 11, resulting in a total of 4084 Qa measurements.


View this table:
[in this window]
[in a new window]
 
Table 1. Demographic characteristics of patients (n = 294)

 
Considering only the first measurement per patient, Qa was significantly lower in patients with diabetes mellitus (compared with no diabetes mellitus, 788 ± 580 vs 1054 ± 681 ml/min, P = 0.002), in patients >65 years old (compared with ≤65 years old, 883 ± 620 vs 1118 ± 706 ml/min, P = 0.004) and in patients with forearm AVF (compared with upper arm, 909 ± 547 vs 1103 ± 769 ml/min, P = 0.04). Qa was also significantly higher in overweight compared with non-overweight patients (1186 ± 691 vs 890 ± 636 ml/min, P = 0.0008). There were no differences in Qa between groups defined by patient sex (female, 979 ± 659 ml/min vs male, 973 ± 670 ml/min, P = 0.95), patient height (≥170 cm, 987 ± 664 ml/min vs <170 cm, 990 ± 685 ml/min, P = 0.97) or recent fistula creation (time from creation to Qa measurement <180 days, 1042 ± 559 vs ≥180 days, 961 ± 685, P = 0.45).

Using mixed models to correct for autocorrelation, we examined the univariate relationship between Qa and each clinical characteristic in turn, considering all 4084 measurements. We found that younger patient age, upper arm location, non-diabetic status, overweight status, years on dialysis and higher blood pressure (SBP, DBP and MAP, all at the time of Qa measurement) were significantly associated with higher Qa (Table 2). SBP was more strongly associated with Qa than either DBP or MAP (AIC 54 463 vs 54 483 and 54 470, respectively). Patient sex and the interval between AVF creation and Qa measurement were not significantly associated with Qa.


View this table:
[in this window]
[in a new window]
 
Table 2. Univariate relationships between Qa and clinical characteristics

 
We noted a statistically significant interaction between SBP and access type (P<0.0001) and between age and access type (P<0.03), so all multivariate mixed models were performed after stratification by access type. For both forearm and upper arm fistulae, SBP, overweight status and diabetic status were independently associated with Qa (Table 3). However, patient age was independently associated with Qa in those with forearm fistulae (P<0.0001) but not in individuals with upper arm fistulae (P = 0.25), and SBP appeared to be associated with Qa to a greater extent in upper arm AVF. For example, after adjustment, a 1 mmHg increase in SBP was associated with a 1.8 ml/min increase in Qa for forearm AVF, but with a 2.9 ml/min increase in upper arm AVF.


View this table:
[in this window]
[in a new window]
 
Table 3. Multivariate relationship between Qa and clinical characteristics, stratified by access location

 


   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Using data from a large series of patients with native vessel AVF, we evaluated the relationship between clinical characteristics and rates of access blood flow. We found that access location, diabetic status, SBP and BMI >25 (overweight status) were independently associated with Qa. Older patient age was apparently associated with lower Qa in forearm but not upper arm AVF, even after adjustment for potential confounders.

Each 1 mmHg increase in SBP was associated with a 1.8 ml/min increase in Qa for forearm AVF, and an increase of 2.9 ml/min for upper arm AVF. This implies that Qa in an upper arm AVF, measured when SBP was 160 mmHg, would be ~116 ml/min higher than Qa measured at an SBP of 120 mmHg. Similarly, the mean difference in Qa between overweight and non-overweight patients was between 215 and 315 ml/min, depending on access location. Finally, the mean difference between forearm and upper arm AVF was ~160 ml/min. These differences appear to be clinically relevant.

Canadian guidelines recommend that angiography be performed in AVF with Qa <500 ml/min (absolute threshold), or in which Qa declines by >20% from baseline (relative threshold), based on the findings of two small observational studies which included a total of 115 fistulae [6,7]. Although following these guidelines leads to identification of subclinical stenosis in AVF, the positive predictive value of screening is only 70–75%, suggesting that there is potential for improvement [2,3]. The intent of the current study was to identify parameters that might be used to increase the predictive power of screening. Our findings have potential implications for both the absolute and relative thresholds for angiography in AVF.

The differences in mean Qa observed between groups defined by clinical characteristics suggest that a single absolute threshold for angiography of Qa <500 ml/min may be simplistic. Although these characteristics theoretically could be used to adjust Qa, they do not vary much between screening measurements, suggesting that the predictive power of the relative threshold for angiography should not be affected. If the associations noted in the current analysis are correct, one might speculate that stenosis might occur despite relatively preserved Qa in overweight or non-diabetic subjects, especially those with upper arm AVF. We hypothesize that diagnostic accuracy might be improved by performing angiography at higher levels of Qa in subjects with these characteristics, compared with those without.

Most previous work in AVF has attempted to minimize the effect of blood pressure on Qa by making all Qa measurements during the first 1–3 h of dialysis. However, even under such conditions, SBP may vary markedly between haemodialysis sessions, and our findings imply that such fluctuations might result in clinically relevant changes in Qa. It is therefore plausible that adjusting Qa for changes in SBP between treatments would improve the performance of the relative threshold for angiography. For example, all Qa measurements could be normalized to a reference SBP value before determining whether angiography should be performed.

Consideration of some physiological principles may allow us to explain the association between changes in SBP and Qa. From a simplified haemodynamic standpoint, blood pressure could be expressed as the product of impedance and blood flow. Indeed, this haemodynamic relationship has been investigated in human models of systolic hypertension. Mitchell et al. [8] examined 128 patients with uncomplicated hypertension and determined that change in blood pressure could be uniquely attributed to an elevation in impedance and a reduction in the diameter of the aorta. Impedance per se is closely related to changes in the resistance and stiffness of the conduit vessels, which in turn is associated with SBP in patients with end-stage renal disease [9]. Our results highlight the close relationship between SBP (a composite surrogate marker of mechanical properties of blood vessels), blood flow and diameter of the conduit (AVF).

The site specificity of the association between SBP and Qa may require further explanation. It is known that brachial blood pressure is a composite of central aortic blood pressure and the augmented blood pressure exerted by the vasculature [10]. Put another way, brachial and aortic blood pressures differ because of this phenomenon of augmentation. The primary determinant of augmentation of blood pressure is due to the resistance of the vasculature. Although the determinants of intra-AVF blood pressure are not as well described, it seems reasonable that augmentation also results in a difference between brachial arterial blood pressure and blood pressures within an AVF. We hypothesize that augmentation for upper arm AVF is lower than that of forearm AVF, resulting in a lower systolic access resistance (SBP/Qa). Our data are entirely consistent with the above concept resulting in a larger correction term for SBP in upper AVF.

We believe that this is the largest study examining factors that influence Qa specifically in AVF. Previous studies that consider the relationship between blood pressure and Qa have been conducted predominantly in polytetrafluoroethylene (PTFE) grafts [11,12]. A previous publication showed that intradialytic changes in Qa (within a given haemodialysis treatment) correlated with intradialytic changes in MAP [13]. However, only 12 patients with AVF were included. A second study evaluated the relationship between MAP and Qa in 18 patients with AVF, but found no significant correlation, perhaps because of limited variation in MAP [14].

A third paper demonstrated that MAP significantly influenced Qa in 25 patients with AVF, although other patient characteristics such as access location were not considered [15]. A fourth study found that SBP was the major determinant of Qa in 10 stable haemodialysis patients with AVF [16]. These authors also noted an interaction between access type and the relationship between Qa and blood pressure in univariate analyses. However, multivariate models were not possible due to the small number of participants, and results were presented for MAP rather than SBP, making it difficult to compare their findings directly with those in the current study.

Two recent studies in AVF indicate that correcting Qa measurements for characteristics such as access location or blood pressure does not increase the performance of the absolute threshold for angiography, as defined by the area under receiver operating characteristic curves [17,18]. However, this parameter is a global measure of test performance, and may be insensitive to differences in diagnostic efficiency occurring within ranges of Qa which might plausibly be influenced by such adjustment. For example, Qa which are >1000 ml/min are unlikely to indicate stenosis with or without correction, whereas for Qa <600 ml/min, such adjustment might be critical. In addition, neither study accounted for the differential association between blood pressure and Qa by access locations, which was noted in the current work. Finally, no published study has examined the effect of adjusting Qa on the diagnostic performance of the relative threshold for angiography.

Our study has several limitations that should be considered. First, some of the AVF in our study may have had stenoses. Because access stenosis may be more common in certain patient subgroups, it is possible that the relationship between these characteristics and Qa is confounded by the presence of stenosis. While we could have reduced the potential effect of this bias by considering only AVF which did not develop stenosis during follow-up, this would have violated the general principle that studies evaluating screening tests should be conducted in populations similar to those in which they will be used in practice [19].

Secondly, our results reflect the average association between Qa and patient characteristics such as SBP. Thus, our results might not reflect the relationship between Qa and SBP for an individual patient. However, it is important to recognize that all currently available data relating to access screening in AVF are potentially subject to a similar criticism.

Thirdly, since both incident and prevalent patients are subject to access screening in clinical practice, we included both in our primary analysis. Accordingly, we cannot exclude the possibility of incidence prevalence bias. It is notable that all AVF included in the current study had matured sufficiently to permit haemodialysis treatment. It is possible that characteristics which correlate with Qa might differ if subjects with primary non-function were included, but unfortunately our study design did not permit us to address this.

Fourthly, although we did not collect data on the presence or absence of ipsilateral arteriovenous accesses, this characteristic does not exert a sustained influence on Qa in AVF [20]. Finally, we recorded weight at the time of the first study treatment rather than separately for each dialysis treatment. However, using baseline weight should have biased our results towards the null, making this unlikely to have resulted in the significant association between BMI and Qa.

Our study advances the current literature because of its large sample size and careful statistical methodology, and allows insight into factors (other than stenosis) which potentially affect Qa in AVF. However, to evaluate conclusively the benefit of varying the absolute threshold based on clinical characteristics, or adjusting Qa for SBP to apply the relative threshold, a prospective study which compared these strategies with current practice would be required.

In conclusion, Qa in native vessel fistulae is associated with clinical characteristics such as access location, diabetic status, BMI ≥ 25 and SBP. Further work is required to determine whether adjusting the relative or absolute thresholds for angiography based on these characteristics will improve the accuracy of Qa measurements for detection of stenosis in AVF.

Conflict of interest statement. Grant support: Dr Tonelli was supported by a Population Health Investigator Award from the Alberta Heritage Foundation for Medical Research.



   References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Jindal KK, Ethier J, Lindsay RM et al. Clinical practice guidelines for vascular access. Canadian Society of Nephrology. J Am Soc Nephrol 1999; 10 [Suppl 13]: S287–S321
  2. Tonelli M, Jindal K, Hirsch D et al. Screening for subclinical stenosis in native vessel arteriovenous fistulae. J Am Soc Nephrol 2001; 12: 1729–1733[Abstract/Free Full Text]
  3. Tonelli M, Hirsch D, Clark TW et al. Access flow monitoring of patients with native vessel arteriovenous fistulae and previous angioplasty. J Am Soc Nephrol 2002; 13: 2969–2973[Abstract/Free Full Text]
  4. Tessitore N, Mansueto G, Bedogna V et al. A prospective controlled trial on effect of percutaneous transluminal angioplasty on functioning arteriovenous fistulae survival. J Am Soc Nephrol 2003; 14: 1623–1627[Abstract/Free Full Text]
  5. Littell RC, Milliken GA, Stroup WW, Wolfinger RD. SAS System for Mixed Models. SAS Institute, Cary, NC;1996
  6. Bouchouareb D, Saveanu A, Bartoli JM, Olmer M. A new approach to evaluate vascular access in hemodialysis patients. Artif Organs 1998; 22: 591–595[CrossRef][ISI][Medline]
  7. Lindsay RM, Blake PG, Malek P et al. Hemodialysis access blood flow rates can be measured by a differential conductivity technique and are predictive of access clotting. Am J Kidney Dis 1997; 30: 475–482[ISI][Medline]
  8. Mitchell GF, Lacourciere Y, Ouellet JP et al. Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure–flow relationship. Circulation 2003; 108: 1592–1598[Abstract/Free Full Text]
  9. London GM. Cardiovascular disease in chronic renal failure: pathophysiologic aspects. Semin Dial 2003; 16: 85–94[ISI][Medline]
  10. Nichols WW, O'Rourke MF, Avolio AP et al. Ventricular/vascular interaction in patients with mild systemic hypertension and normal peripheral resistance. Circulation 1986; 74: 455–462[Abstract]
  11. Paulson WD, Ram SJ, Birk CG et al. Accuracy of decrease in blood flow in predicting hemodialysis graft thrombosis. Am J Kidney Dis 2000; 35: 1089–1095[ISI][Medline]
  12. Sands J, Glidden D, Miranda C. Access flow measured during hemodialysis. ASAIO J 1996; 42: M530–M532[ISI][Medline]
  13. Rehman SU, Pupim LB, Shyr Y, Hakim R, Ikizler TA. Intradialytic serial vascular access flow measurements. Am J Kidney Dis 1999; 34: 471–477[ISI][Medline]
  14. Ronco C, Brendolan A, Crepaldi C et al. Noninvasive transcutaneous access flow measurement before and after hemodialysis: impact of hematocrit and blood pressure. Blood Purif. 2002; 20: 376–379[CrossRef][ISI][Medline]
  15. Besarab A, Lubkowski T, Vu A, Aslam A, Frinak S. Effects of systemic hemodynamics on flow within vascular accesses used for hemodialysis. ASAIO J 2001; 47: 501–506[CrossRef][ISI][Medline]
  16. Polkinghorne KR, Atkins RC, Kerr PG. Native arteriovenous fistula blood flow and resistance during hemodialysis. Am J Kidney Dis 2003; 41: 132–139[CrossRef][ISI][Medline]
  17. Tessitore N, Bedogna V, Gammaro L et al. Diagnostic accuracy of ultrasound dilution access blood flow measurement in detecting stenosis and predicting thrombosis in native forearm arteriovenous fistulae for hemodialysis. Am J Kidney Dis 2003; 42: 331–341[CrossRef][ISI][Medline]
  18. Tonelli M, Jhangri GS, Hirsch DJ et al. Best threshold for diagnosis of stenosis or thrombosis within six months of access flow measurement in arteriovenous fistulae. J Am Soc Nephrol 2003; 14: 3264–3269[Abstract/Free Full Text]
  19. Mulherin SA, Miller WC. Spectrum bias or spectrum effect? Subgroup variation in diagnostic test evaluation. Ann Intern Med 2002; 137: 598–602[Abstract/Free Full Text]
  20. Begin V, Ethier J, Dumont M, Leblanc M. Prospective evaluation of the intra-access flow of recently created native arteriovenous fistulae. Am J Kidney Dis 2002; 40: 1277–1282[CrossRef][ISI][Medline]
Received for publication: 19. 4.04
Accepted in revised form: 16. 6.04





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
19/10/2559    most recent
gfh406v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Tonelli, M.
Articles by Jindal, K.
PubMed
PubMed Citation
Articles by Tonelli, M.
Articles by Jindal, K.