The Arteriovenous Fistula

The ground-breaking article by Brescia and Cimino in 1966 (1) revolutionized the creation of the vascular access, and the Cimino fistula was soon used in almost all dialysis patients. Unfortunately, subsequent wide-spread use of PTFE grafts instead of AV fistulae occurred because of the ease of the surgical technique, the immediate availability of the graft for puncture, the need of high blood flow for high-efficiency, short-duration hemodialysis sessions, and because of financial disincentives against the AV fistula. PTFE grafts currently account for 80% of primary vascular accesses created in the United States (2,3), but they are less frequently used in other countries. It has been increasingly recognized that outcomes of PTFE grafts are poorer. In the DOQI guidelines (4), this has led to the recommendation that AV fistulae should be the first option; however, this advice has not been followed uniformly. One impediment may be the astonishingly high rate of primary failures of AV fistulae, up to 50% in some centers (4). The DOPPS study (Figure 1) documented substantial differences between survival of PTFE grafts and AV fistulae and differences of survival of AV fistulae between the United States and other countries (3). On the basis of our experience, we are of the opinion that primary failure rates can be substantially improved by attention to small but important details of surgical technique. The DOQI guidelines state that AV fistulae are feasible only in 50% of the patients, but we (5) and others (6) found that construction of native AV fistulae is feasible in up to 90%. Figure 1. : Fistula versus graft survival in patients starting hemodialysis with a permanent vascular access comparing DOPPS results from Europe and United States. Reprinted with permission from reference 4.It is the purpose of this article (a) to provide some insights into the fascinating cellular biology and pathophysiology underlying the vascular adaptation to the creation of an AV fistula and (b) to describe some small, often neglected, but important technical details that determine the success of the procedure. It is the intention to improve results and to influence patterns of practice. Vascular Remodeling and Adaptation to High Flow Wedgewood et al. (7) measured flow rates in the radial artery before and immediately subsequent to the creation of an end-to-side fistula. Flow increased from 21.6 ± 20.8 ml/min to 208 ± 175 ml/min immediately after operation. In well-developed fistulae, flow rates may ultimately reach values of 600 to 1200 ml/min. Flow increases as a result of both vasodilation and vascular remodeling. The latter has been studied using echo-tracking techniques (8). It was found that the diameter of the proximal antecubital vein increased progressively while the intima media thickness remained unchanged. Venous dilation caused reduction of mean shear stress, which had returned to normal values by 3 mo. The venous limb of the AV fistula underwent excentric hypertrophy as documented by increased wall cross-sectional area. In parallel, remodeling of the radial artery was seen without arterial hypertrophy, despite a marked increase in diameter and blood flow (9). The changes in blood flow after creation of an AV fistula initiate compensatory responses that have been elegantly elucidated in experimental models (10). Apart from primarily NO-mediated vasodilation, adaptive remodeling of the vessel wall is induced by reorganization of cellular and extracellular components, ultimately altering wall geometry. Elevated flow after creation of an AV fistula enlarges the arterial diameter (10). Kamiya and Togawa (11) documented that after creation of a carotid to jugular anastomosis the flow-loaded artery enlarged until wall shear stress had returned to baseline values. This response usually occurred rapidly, but when extremely high shear stress was induced, it required up to 6 mo (12), for example in the monkey iliac artery subjected to a 10-fold increase of flow. Endothelial cells play a central role in adaptive remodeling (13). Shear stress, i.e., the frictional force generated by blood flow, acts on the apical cell surface to deform the cell in the direction of blood flow, thus eliciting rapid cytoskeletal remodeling and activating signaling cascades with the consequent acute release of nitric oxide (NO) and prostacyclin followed by activation of transcription factors, including NF-κB, c-fos, c-jun, and SP-1. The mediators of the adaptive response include integrins, focal adhesion–associated proteins, and stretch-sensitive calcium channels. The crucial importance of endothelial cells is illustrated by the observation (14) that de-endothelialization eliminates the dilation resulting from an increase of flow. Acute flow-induced endothelial release of nitric oxide (NO) (15) as well as increased vessel wall cGMP content (16) have been documented in high flow models. Inhibition of NO by L-NAME interfered with flow-induced vascular enlargement (17). The first step of remodeling involves controlled removal of preexistent vessel wall constituents. The arterial wall of an AV fistula exhibits early tears and fragmentation of the internal elastic lamina (18) and enlarged fenestrae (19), increasing arterial distensibility. The loss of the internal elastic lamina results from degradation by metalloproteinases, which are released from endothelial cells (20). A role for oxidative stress is suggested by the observation that endothelial cells of flow-loaded carotid arteries stain positive for nitrotyrosine, which is indicative of the presence of peroxynitrite (21), and this is abrogated by administration of L-NAME. The urokinase type of plasmin activator is also upregulated. This observation is important, because the plasminogen-plasmin system activates pro-metalloproteinases. It is therefore not surprising that nonselective inhibitors of metalloproteinases diminish flow-mediated arterial enlargement in a rat AV fistula model (22). The involvement of the above systems raises the issue whether remodeling is normal or not in uremia. It is well known that generation of NO is reduced in uremia (22), and numerous specific abnormalities have been described in endothelial cell monolayer cultures (HUVEC) exposed to uremic serum: increased ELAM-1 and VCAM expression, increased presence of von Willebrand factor on the extracellular matrix (23), abnormal cell morphology, accelerated growth, and increased expression of tissue factor mRNA (24). Platelet deposition on extracellular matrix, which had been synthesized in the presence of uremic serum, is also increased. Interestingly an antibody to human tissue factor prevented the increase in platelet deposition observed on “uremic” extracellular matrix, a finding potentially relevant for the genesis of fistula stenoses. There are few formal analyses of vascular remodeling in uremia. Amann et al. (25) investigated remodeling in first-order branches of the mesenteric arteries exposed to high-flow or low-flow conditions. A highly significant increase in intimal thickness and intimal cell proliferation was noted in arteries of uremic compared with sham-operated animals when exposed to low-flow conditions, and this was abrogated by endothelin receptor antagonists. Under high-flow conditions, there was an increased number of PCNA-positive cells in the media, which again was abrogated by endothelin receptor antagonists. Obviously the responses of the intima to low flow and of the media to high flow are exaggerated. Against this background, it is remarkable that remodeling is largely appropriate in uremic patients (8,9). Although not directly related to uremia, the processes underlying the development of stenoses in coronary saphenous vein grafts are of interest for understanding the development of fistula stenoses. It is thought that the changes provoking delayed stenoses are initiated during surgery and consist of denudation of the surface endothelial cells and insudation of granulocytes and monocytes with deposition of fibrin and thrombocyte-containing thrombi (26). CRP induces a pro-inflammatory phenotype of saphenous vein endothelial cells, which is reversible with the administration of endothelin receptor antagonists (27); of interest in view of the microinflammatory state of uremia and the role of endothelin receptor antagonists in experimental models of uremia (25). Interventions interfering with smooth muscle cell accumulation in the neointima further suggest a role of PDGF (28), angiotensin subtype AT-1 receptors (29), VEGF (30), and leptin (31), among others. One important aspect in the evolution of the AV fistula of uremic patients is iatrogenic remodeling resulting from puncture of the AV fistula (32). Puncture displaces tissue, and the defect caused by the cannulation is replaced by a thrombus causing a slight increase in tissue mass. Even after healing, the edges of the puncture hole stay apart as shown by applying tattoo marks. This causes cumulative and progressive enlargement of the fistula depending on the number of punctures per unit area. This holds true if the cannula does not punch out tissue, but rather displaces tissue as seen with anti-coring cannulas, in which only the anterior half of such cannulas makes sharp cuts. There are three options for cannulation (Figure 2); (a) the rope ladder pattern, (b) the area puncture pattern, and (c) the In the rope ladder pattern, the punctures are the of the In with the area puncture they are to a small area. the technique, punctures are the This displaces the thrombus with a wall is by the tissue and the venous Figure : The three of cannulation and on of cannulation area Reprinted with permission from reference the rope ladder technique, the frequently progressive dilation is induced the of the fistula. The i.e., of wall and is usually a result of the area puncture technique. are a of true and of the wall with of the wall of the vein causes progressive enlargement of the because wall stress increases progressively with increasing diameter to the of the It is important to the in and to that are Puncture of a vein a a fistula is such with dilation and flow, and to The of both not only of the should the of the of the should be used as an the should be by a There is on the of fistula The guidelines to vascular access when the and the is ml/min 3 to mo before the of One impediment to creation of an AV fistula is the high rate of et al. an between of and the of the of dialysis with central for vascular There has been the when a fistula is for The DOQI guidelines puncture after 3 to mo. This may be measured fistula flow and found that there is an immediate and increase of blood flow rate in the radial which progressively increases during the first (7) and This is in with the in experimental (10). It is therefore the of the to puncture the fistula after operation. not however, that there is a to there are specific such as One we and others to use and as for an fistula. It has been however, that this is also for (Figure that provide to the The primary is the to the whether an anastomosis the above the be and whether a is a Figure : of the radial artery by flow a flow with a and a flow after release low with a causing high The of the radial artery and the vein should be measured It is well known that a of the blood flow in the fistula is by the artery the in up to of patients. 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One of the to flow in a fistula is to acute when the are but when the radial artery is acute be with the technique. A is that if venous it into the arterial limb of the fistula. (Figure Although techniques for anastomosis are the anastomosis has the used technique. 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The the of the the blood flow for area of the and the should the anastomosis not 6 in the of the The by is extremely and is for the small of The in the of the wall of the and is the with the as shown in Figure Figure : of the surgical to a AV anastomosis to This is when artery the it is important to that the uremic the uremic is high of that as a use only and the by the edges with using the above we have to a rate of per substantially the DOQI of per for AV One has three or is and well but it has the of causing increasing the of arterial and venous are and with or by of the or has the of the of vascular It also from to The is that an is is required when in proximal of the are or when patients have against use of In patients and other patients high of however, a of an an with for is administration of is if an fistula or graft is There is also need for use of platelet inhibitors surgical techniques are important surgical be however, it may be to in a of and There is that of is of use before the primary surgical has however, a for such as abnormalities factor and and is The DOPPS that of the primary fistula is less when calcium are used This finding is not in view of the of calcium to fistula it is of interest that patients on inhibitors have less delayed fistula when PTFE grafts are used This observation that vascular remodeling on endothelin and angiotensin (25). It whether use of venous in the for fistula A it that an increase in by of wall remodeling of the vein which is primarily the result of increased shear There is of a on the of such as a documented It increase venous blood flow, however, and thus to be on of the Fistula should be to fistula and to attention to a progressive increase of venous and are i.e., and of the fistula 6 or The purpose is to development and of stenoses in to that is not to an The pathophysiology underlying is of blood flow (Figure which activates and endothelial In this a role has been for factor Figure : a of an AV fistula created by a PTFE graft to a native vein the of with proliferation is flow in the of an are seen resulting from endothelial and the graft anastomosis mo after causing is a reduction of fistula blood flow. that low fistula flow is the of The flow rate is in PTFE grafts and in AV fistulae the we found that all fistulae in which the flow rate was ml/min. This is of less is required for blood flow during a result of low blood flow, dialysis and but of are less to fistula and of fistula flow rates The is important the values. Figure the when a flow in dialysis number of and of fistula have been in the such as but has which be for of low blood flow rates and stenoses the the of of the venous and of the after removal of the from the puncture Elevated venous during hemodialysis sessions, progressively increasing venous during dialysis a low fistula flow and have been has or Although this is we as a of that using dilation with high and is in the of for central stenoses the of the vein and while of stenoses should primarily be by surgical The for this recommendation is that the acute blood flow rates after dilation are but the and or rates are not because to endothelial cells to of and this primary rates of for and for AV fistulae have been The primary rate was only and the rate of results after surgical are and of the is usually also increasingly of patients other the Cimino fistula the of the because an increasing of and patients are to high flow rates for fistula when the radial artery is used for The may be anastomosis a proximal compared the primary fistula rate in and patients In to we found between and patients. The is that we had created a primary anastomosis the of the in of the patients compared with in patients. the high fistula has and this because the of the type patients on dialysis is low A use of the with or without of has also been by others are to use the artery for primary anastomosis out of of provoking and This can be if the of The of this is to use the vein for It the and in the The vein can and only to a thus a between the artery and the This the blood flow. this we have not seen a of from high in a of 600 patients. of flow the of a and is reduced as In patients, the vein a has to be up often in a step into a The first of the vein in the of the is in patients, only a of the vessel for again the of the vein the aspect of the can It is important to the proximal of the vein to venous during surgical PTFE numerous are for fistula The type of should be on that that if with the use of a PTFE of a fistula and fistula and a PTFE graft instead and to the surgical in we also to a of Figure : of the of the vein to a relevant of the vein of an caused by before the of the the need of a : This and a the surgical was initiated with of the venous and of the arterial as well as of a venous followed by anastomosis and of a with central venous was because cannulation was the of the of the AV Fistula In resulting from an arterial have in the of highly patients with vascular and the it is important to high-flow i.e., when fistulae with low blood flow from the and the thus of the In this type of should be to by the of the anastomosis and fistula flow the with the of the to only reduction of the be an is however, and the of low flow and but increasing in is the in patients with low fistula flow. It is primarily the result of arteries that normal blood flow in the fistula in vascular to the of low-flow from the vasodilation of the arteries as by low flow after Figure There are only a few One is to the fistula and use a central has been by and The is illustrated in Figure The artery to the anastomosis is that the fistula blood from In a the artery is an of saphenous vein or PTFE graft to the issue is whether for such patients, in to in patients with arterial low values should be to and whether high values are by and tissue may be by increasing the from tissue into of the Figure : The of an fistula and artery with artery In this the artery was the of the fistula. A anastomosis between vein graft and artery was Reprinted with permission from reference One of the native AV fistula is that and failure from high fistula flow are in with is seen with PTFE grafts if is in other when the anastomosis is This is with PTFE grafts and artery The only is to fistula flow. i.e., of the anastomosis have been but the result is Apart from the of the the is to a The results of are often for above of A central venous may be before the vascular access and only when flow is increased. a is to increased flow the result be of the and as well as of on the stenoses are usually the result of but causes have to be primary in patients with or by One is to the anastomosis and use the other after appropriate to A is to the by dilation with or by surgical The latter involves however, and a surgical It is therefore the less of the AV fistula are usually the result of of the vessel wall and by have the of that there is a to because wall stress with increasing diameter of the is by of the vessel wall by tissue after puncture of the vessel A for of an is usually a and a of are is by and in or using is for of of the of and of the The surgical or of the of and of an as illustrated in Figure It is the intention of this to out that the biology of the AV fistula is fascinating and that of the fistula and should be on There is and surgical be One to success is early and early of a vascular access after using of the fistula is and fistula flow should be in as the important of fistula It be the to rather to on as well as that native AV fistulae can be in 80% of the patients. The results are to of PTFE are that there are disincentives against the AV fistulae, but we that can be to a native AV fistula in all dialysis patients.