While intermittent hemodialysis for the treatment of patients with acute renal failure was introduced by Kolff in 1943, the development of chronic hemodialysis therapy for end-stage renal disease was not feasible until the introduction of the external arteriovenous shunt by Quinton and colleagues in 1960. In an era characterized by rapid technical development, Brescia and colleagues developed the endogenous arteriovenous fistula in 19661, and prosthetic subcutaneous interpositional "bridge" grafts were developed shortly thereafter2. Since these pioneering days, the pace of technical improvements in permanent hemodialysis vascular access has slowed to a crawl (Table 1). While there have been minor refinements in the biomaterials and contours of prosthetic bridge grafts, no major advances in permanent hemodialysis access have been made over the past three decades.
During this time, the rapid growth of end-stage renal failure programs in the United States and worldwide has been accompanied by a tremendous increase in hemodialysis vascular access-associated morbidity. In its latest report, the USRDS estimates that in 1995, the cost of access morbidity was approximately $7,871 per patient per year at risk, and the annual global cost to Medicare represents 14 to 17% of total spending for hemodialysis patients per year at risk3. This access-related morbidity, and its attendant costs, may be accelerating. For example, Feldman et al reported that access related morbidity accounted for approximately 15% of hospital stays prior to 1989; however, the most recent evidence suggests that access-related morbidity accounts for at least 25% of all hospital stays, and in the first year of dialysis may constitute up to 50% of all patient care costs3,4,5. These data become even more relevant to nephrology practice in the face of a major interest by Medicare and some Health Maintenance Organization (HMO) to capitate medical care to end-stage renal disease (ESRD) patients.
In addition to this enormous financial burden, for patients, dialysis staff, nephrologists and surgeons, the frequency and unpredictability with which hemodialysis vascular access thrombosis develops is an enormous frustration. Vascular access-related morbidity also contributes significantly to a reduction in the delivered dose of dialysis (a major factor in the relative risk of mortality of chronic dialysis patients) through the use of temporary catheters or reduced blood flow. Additionally, this access related morbidity leads to a significant reduction in the quality of life of dialysis patients. Finally, in our opinion, vascular access "grief" (as it is referred to in our institutions) has been responsible for turning off more graduates of internal medicine residency programs from a potential career in nephrology than any other aspect of nephrology, at a time when several reports point to an impending shortage of nephrologists.
MAGNITUDE OF THE PROBLEM
Epidemologic data analyzed by the USRDS from HCFA data and other sources clearly demonstrate that lack of appropriate timing of vascular access placement substantially contributes to subsequent access failure.
In 1993, approximately half of the patients starting ESRD therapy in the U.S. have had no permanent access placed or attempted before initiation of dialysis therapy for ESRD, and 27% have a temporary catheter 30 days after initiation of therapy. In fact, only 25% of patients have had a permanent access placed 30 days before initiation of dialysis therapy6.
These percentages need to be examined in the context of substantial data that early placement of the access, particularly A-V fistulae, generally correlates with improved outcome of the access6. In addition, Collins et al have recently shown that not only access outcome, but patient outcome strongly correlates with the timing of access placement7. The relative risk of mortality in patients who had accesses placed six months or more before initiation of therapy was one half the mortality risk of patients who have had accesses placed less than one month before ESRD therapy. Whether these glaring differences in patient outcomes relates to the more frequent use of temporary catheters (with its attendant risk of infection, sepsis and underdialysis) has not been explored8,9,10.
A number of patients do indeed present in advanced stages of uremia with minimal or no prior medical care, and need to be initiated on hemodialysis therapy with temporary catheters; however, it is unlikely that such patients account for the 50% of all patients starting dialysis therapy without a permanent access. One must presume that a certain percentage are patients who have been followed by primary care physicians ("gatekeepers"), internists or other medical subspecialties and referred to nephrologists' care late in the course of their illness. A substantial number of these patients were probably followed by nephrologists who have not adequately planned their access for initiation of dialysis6.
In an analysis by Woods and colleagues, 70% of incident hemodialysis patients knew their renal function was abnormal but only 58% had seen a nephrologist four months before ESRD therapy11. Patients who have had nephrology contact more than four months prior to ESRD therapy were significantly more likely to have a permanent access at the time of initiation, more likely to have an A-V fistulae (versus a PTFE graft) and more likely to have been told to avoid venipuncture in one arm. On the other hand, 14% of patients had seen a nephrologist only three months before ESRD therapy and 25% had seen a nephrologist one month or less before initiation of hemodialysis. These data suggest that there is a high prevalence of delayed nephrology referral on a national level.
A related problem is that in 1996, 19% of patients were using a cuffed permanent catheter (compared to 10% in 1993) at 60 days after start of hemodialysis6. Furthermore, despite well documented concerns about development of subclavian stenosis with its attendant chronic problems, the subclavian vein was used as the access site in an alarming 21.6% of incident patients in 1993, and 9% in 19963,6.
TYPES OF VASCULAR ACCESS
Arteriovenous fistulae and polytetrafluoroethylene graft
The predominant types of permanent vascular access in use for chronic hemodialysis currently are the primary arteriovenous (A-V) fistulae and the polytetrafluoroethylene (PTFE) A-V graft. The results of most, but not all, previous studies have suggested an improved survival of primary A-V fistulae compared to PTFE grafts. A recent study by the USRDS, analyzing data from a cohort of 784 patients starting dialysis in 1990, has shown that the relative risk of access failure for a patient with an A-V fistula compared with a patient with a PTFE graft was 67% lower risk at the age of 40 years, 54% lower at the age of 50 years and 24% lower risk at the age of 65 years12. These data are supported by the only previous large multicenter prospective cohort study of first permanent vascular access survival among incident patients, the Canadian Hemodialysis Morbidity study. This study demonstrated a 71% lower risk for failure of an A-V fistula compared to PTFE graft, after adjustment for the effect of age, gender, and co-morbid conditions13. Although one retrospective study has shown that if primary failures of A-V fistulaes are included in the analysis, the survival of the A-V fistulae and PTFE may be comparable14, what is clear is that the number of procedures and revisions to maintain graft patency are twice as high in PTFE grafts as in developed A-V fistulaes6.
Despite these studies, the prevalence of PTFE graft use in the U.S. has steadily increased from 51% in 1986 to 65% in 1990 of all ESRD patients starting dialysis with permanent accesses15. In 1993, the last year for which data are currently available, the percentage of permanent hemodialysis accesses made of PTFE had increased to 73% of incident patients3. However, there were substantial regional variations, ranging from only 23% of incident patients with PTFE grafts in the New England region, to 85% in the Southeastern states15. The magnitude of these regional variations in PTFE use is not likely to be due solely to differences in prevalence of co-morbid conditions or their severity, but may reflect differences in patient referral pattern and surgical practice patterns (see below).
Similarly, Hirth and colleagues have found that neither the increase in the prevalence of co-morbidities of patients presenting to dialysis nor the widespread use of high flux dialyzers (which ostensibly require higher blood flows) can account for the declining use of fistulaes relative to grafts15. The wide regional variation in the types of vascular access also suggests that other factors aside from increased co-morbidity account for this shift in types of vascular accesses. Finally, it must be noted that in Europe the percentage of patients with endogenous arterio-venous fistulas exceeds 70 to 80% and in Japan is reported to reach 90%.
ROLE OF VASCULAR SURGEONS
A common "conversation piece" among most nephrologists is the frustration they face in feeling at the mercy of the vascular surgeon(s) in their institution with regard to the timeliness, interest, quality control and follow-up data of hemodialysis access procedures. Despite its financial rewards, the formation of new vascular accesses appears to be of little interest, and is often performed by surgical residents with minimal support or supervision by the attending surgeons. Similarly, the urgency of treatment of access thrombosis that is felt by the patient and nephrologist is often not shared by the surgeon. Thrombectomies of the vascular access and the surgical treatment of the attendant venous stenosis is often delayed, necessitating the placement of temporary catheters with their attendant short-term (discomfort to the patient, bleeding, pneumo or hemothorax) and long-term (infection, sepsis, subclavian stenosis and inadequate dialysis) complications.
In the only published study that examined this issue, the results of a multivariate analysis showed that the outcome of the vascular access was more dependent on the specific surgeon than on any other parameter studied. Three-year patency rates varied from 34% to 62% depending on the surgeon16. In a more recent study, Feldman and colleagues have shown that the patency of new vascular access grafts was associated with the level of training of the surgeons performing the procedure. Not having an attending surgeon present at the time of graft placement was associated with a 2.4-fold increase in relative risk of access failure from any cause. This finding was consistent when examining non-infective and infective failures separately, and highlights the importance of having surgeons with a high degree of training and experience perform vascular surgery17. These variations in the standard of surgical practice may be one of the factors that explain regional variations, not only in the preference for PTFE grafts but also in the rates of PTFE access failures, which ranges from 45% below the reference to 33% above the reference region in the U.S.18.
Surgeons' attitude toward the types of vascular access has also been suggested as a potential explanation for the rapid shift from A-V fistulas to PTFE grafts. In their analysis of the USRDS data, Held and colleagues found that in 1991 the 10% of the surgeons who created the most fistulae accounted for 72.0% of all fistulae, while the 10% who created the most grafts accounted for 44% of all grafts. Based on this, Held et al suggest that "the distribution of surgeons proficient in performing different vascular access techniques, differences and changes in the subspecialties of the surgeons performing access procedures and the training received in surgical residency and fellowship program, and the rate of reimbursement for different types of access procedures relative to the effort and difficulty involved may influence the use of fistulas and grafts"15.
ROLE OF NEPHROLOGISTS
In the face of these data, there has been a lack of active efforts to find appropriate solutions by the nephrology community. This practical abandonment of the decision making process in the formation and treatment of vascular access complications by nephrologists has been mirrored by a paucity of clinical and biochemical research on the causes and preventive measures of vascular access stenosis. To our knowledge, despite the enormous cost of vascular access care, there has not been a National Institutes of Health (NIH) sponsored effort to develop a "consensus conference" or an organized "Request For Proposal" on the subject of vascular access in dialysis patients, although one may be in the planning stages currently at the NIH. Until recently, the priorities assigned to the USRDS special studies did not place this topic high enough to warrant a focused review.
LESSONS LEARNED IN VASCULAR ACCESS
Nevertheless, the magnitude of the problem of hemodialysis vascular access has not gone unnoticed and individual research over the past decade by Schwab et al19,20,21, Besarab et al22,23,24,25, Beathard26,27,28, Sands et al29,30,31, Sherman et al32,33,34 and others35,36,37 has led to a greatly improved understanding of the pathophysiology and appropriate treatment for vascular access morbidity. From these and other investigators, we have learned a number of lessons about hemodialysis vascular access (Table 2). These generalizations include the understanding of the process of central vein stenosis, its devastating consequence and the role that temporary subclavian catheters have played in this process38,39,40. Another learned lesson is that, once mature, autologous fistulae maintain better patency and require less salvage procedures than prosthetic grafts; however, the failure rate of autologous fistulaes in the first year after formation is high and these failures are often related to lack of time for "maturation" of these fistulae14. Other lessons include the need to monitor access function prospectively in order to detect incipient access malfunction21,32,41,42, and once diagnosed, the need to improve the natural history of such grafts by angioplasty and/or surgical intervention43,44,45.
Despite these hard-won achievements, progress to date in maintaining and improving hemodialysis vascular access primary and secondary patency has been incremental at best. While it varies from center to center, cumulative graft patency for prosthetic grafts over a two year period is approximately 30%, even with a large number of salvage procedures. In addition to the costs of salvage procedures, the costs associated with routine vascular access monitoring for stenosis and for diagnosis and treatment of established venous stenosis in PTFE grafts are difficult to ascertain, but undoubtedly are escalating enormously in an effort to maintain access patency.
PREDICTIVE TESTS OF ACCESS FAILURES
Research over the past decade has led to a better understanding of processes or measures that may be helpful in predicting the severity of vascular access venous stenosis. In an elegant conceptual breakthrough Schwab et al proposed monitoring the venous pressure at a set blood flow rate of 200 ml/min during the dialysis procedure as a non-invasive method for detecting the formation of stenosis at the venous anastomosis, a harbinger of access thrombosis19. Refinements to the method of measurement of these intra-access "venous" pressures have been proposed by Besarab and Van Stone24,25,35. However, the physiologic principle upon which such measurement has been advocated (that is, distal "venous" stenosis results in elevation of hemodynamic pressures proximal to the stenosis) may not apply to a large number of accesses for reasons listed in Table 3. In a recent angiographic study the presence of critical high-grade stenosis at the venous anastomosis was found in 38 out of 84 (45%) of grafts, while a critical stenosis was found in the central vein in 34% of grafts, 15% had a mid-graft stenosis and 4% had stenosis at the arterial anastomosis, with many grafts having multiple stenoses46. The stenosis at sites other than the venous anastomosis attenuates the usefulness of "venous" pressure monitoring as a predictive measure of access failures47.
Several additional methods for the detection of incipient prosthetic graft failures have been advocated, ranging from the measurement of venous pressures under static (zero dialyzer flow) conditions24, measurements of access recirculation28,33, acute decrements of dialysis dose or "negative" arterial pressures that develops as the pump speed exceeds the blood flow that can be obtained from the access. The limitations of studies of "venous" pressures as well as arterial pressures have already been alluded to (Table 3). Furthermore, while "venous" pressures, or measures of recirculation or negative arterial pressures may be useful, they are often late manifestations of this problem. Recent studies have also demonstrated that recirculation only occurs when access blood flow is lower than prescribed dialysis blood flow. Since this occurs very late in the life of an access, tests of recirculation have been deemed not useful in the detection of early access stenosis48.
Recent evidence suggests that detection of low access blood flow rates is an early, sensitive and specific predictor of both venous stenosis and subsequent thrombosis49,50. This concept appears to be gaining increased acceptance41. A major advantage of intra-access blood flow measurement is that, in contrast to "venous pressures," flow is affected by stenoses irrespective of their localization. Measurement of intra-access blood flow has been technologically difficult until recently, but is now readily available by Doppler ultrasound measurements51,52,53, magnetic resonance angiography, or with a technologically more user-friendly and less expensive device, based on the Fick principle, the so-called "ultrasound dilution technique" developed by Krivitski36. Krivitski has recently validated this new approach, whereby measurement of recirculation with the blood lines reversed, can accurately measure access blood flow in a practical, convenient and reproducible way.
In a recent study in a large ESRD population, several parameters were simultaneously measured to define their value in predicting the development of access thrombosis. The results of this prospective study have confirmed that intra-access blood flow determination, either by Doppler ultrasound or the ultrasound dilution technique, is the most predictive of these measures, and in prosthetic grafts, blood flows of less than 800 ml/min is associated with stenosis of greater than 50% in cross section and a progressively higher risk of thrombosis in the ensuing three months49. A follow-up to that study suggests that sequential monitoring of blood flow is potentially even more useful, since decrements of intraccess blood flow by more than 25% was associated with a relative risk of thrombosis of 10 times the risk in accesses without a decrement in blood flow. A 50% decrease in blood flow resulted in a 30-fold increase in relative risk of thrombosis compared to those that do not have a decrease in blood flow. It should be noted that while the criteria of blood flow less than 800 ml/min applies to grafts (and not native A-V fistulae), the predictive power of a decrease in blood flow by more than 25% applies to both grafts and fistulae54. Using the same physiologic principles, a recent study by Lindsay et al demonstrated that measuring hemodialysis access flow rate by differentiated conductivity also predicts access thrombosis55.
If other studies support this concept, it is clear that the measurement of blood flow in the access may need to become a routine measurement in the dialysis unit. Once these blood flows are below a "threshold" of 800 ml/min, and particularly those accesses that have a rapid drop in blood flow rates over time (for example, greater than 25% decrease in blood flow over three months) may need to have their anatomical structure studied. Ideally, the Doppler ultrasound should provide such a diagnosis, and may be less costly and less invasive than an arteriogram56. Whether these studies are sufficient for surgical or radiological intervention remains to be determined29.
The high predictive value of a drop in intraccess blood flow for thrombosis has two major implications: The first is that the degree of venous stenosis is often progressive, and a significant drop in blood flow (20 to 30%) carries higher relative risk of thrombosis than a low flow in and by itself. This is consistent with flow dynamics across a constriction whereby flow is maintained (albeit at the risk of higher pressures) until a critical stenosis is reached (usually >70% stenosis), and afterwards flow is progressively reduced. The second implication is that serial measurement of access blood flow provides sufficient early warning of the "criticality" of the stenosis so that early intervention may be helpful54.
While such research on predictors of incipient access failure has been helpful (and to our knowledge, not supported by NIH), it can be argued that such research is similar to the proverbial "closing the barn after the horse is gone." Except for one relatively old study, there has been no prospective, randomized (double blind) study of ways in which the development of the vascular access venous stenosis may be retarded or abolished57.
SALVAGE OF FAILING OR THROMBOSED ACCESS
While the availability of screening tests for incipient access thrombosis with high sensitivity and specificity will be helpful in diagnosing problems and providing an early warning of access failure, the next step is to find out if these "early warning signs" can be translated into an effective method of correcting the problem and, most importantly, whether such salvage procedures prolong access life. Several retrospective or non-randomized studies suggest that angioplasty or surgical revision of a stenotic lesion increases the lifetime of a vascular access14,45,55,58,59,60. However, a recent study of prophylactic balloon angioplasty (for >50% venous stenosis) versus observation alone did not demonstrate benefit for angioplasty for either 6 or 12 month patency rates61. However, the lack of access flow measurements before or after intervention, and important differences in patient (that is, access) characteristics between the two groups of patients severely limits the generalization of such findings. In the most recent study of 115 patients who developed thromboses in PTFE grafts, assigned to surgical or radiological interventions, post-operative graft function was found to be significantly better in the surgical group62. However, the study did not compare the success of repeat radiological interventions (secondary patency) or the comparative costs of each of these procedures. Studies of the effectiveness of prophylactic interventions for treatment of low grade stenosis (50 to 75% of venous stenosis) before thrombosis occurs are also needed, particularly with development of predictive assessment tools based on sequential measurement of access blood flow. Clearly, more studies and with a higher number of patients are needed to address these important issues.
PROPOSED SOLUTIONS
Solving the problems of vascular access morbidity in the 21st century will require some of the ingenuity and resourcefulness demonstrated by the generation of health care providers in the 1960's that paved the way for chronic hemodialysis therapy to become a reality for so many patients. A recent publication by the National Kidney Foundation (DOQI) has outlined a series of clinical recommendations related to vascular access, and recommended several important areas for improvement of access outcome63. The following is our list of focus areas in the hopes that true breakthroughs can occur in reducing hemodialysis vascular access morbidity (Table 4). Because these are recommendations that we need to focus on, each will be discussed more extensively below.
Early placement of native A-V fistulae
Despite the almost universal acceptance of its long-term superiority as a vascular access method, the frequency of placement of A-V fistulae in the U.S. is small and declining64,65,66,67,68. This has been attributed to the increased co-morbidities of patients nearing end-stage renal disease, although as discussed earlier, this may not be such an overwhelming factor15. Nevertheless, there are other factors more amenable to modification that we believe may result in a higher percentage of native A-V fistulae in incident patients.
Early start for access planning
In all patients who do not have a living related transplantation available and planned, we advocate the placement of an A-V fistula no later than at a time the creatinine reaches 4 to 5 mg/dl or when creatinine clearance is approximately 25 ml/min. While it is difficult to predict rates of progression in individual patients, several studies have pointed out that progression occurs faster in diabetic and proteinuric patients, who constitute more than 50% of all patients starting ESRD therapy and, therefore, earlier access placement may be necessary in such patients.
This early placement not only allows time for fistulae to develop, but even if it does not mature, it may dilate the venous system sufficiently to improve the eventual success of the PTFE graft. Importantly, having the A-V fistula (with appropriate education and instruction) preserves that arm from repeated venipuncture for blood drawing that leads to sclerosis of the veins. Frequent monitoring of the "maturity" of the fistulae, along with exercises (such as, tourniquet placement) to develop the fistulae and ligation of run-off veins if necessary should help in the development of these accesses. The use of anti-platelet medications for the first month after fistula formation may help prevent early thrombosis, giving the access the chance to mature (Table 5). It is reasonable, in our view, that a target of at least 70% of patients with attempted and 50% developed autologous A-V fistulae should be set as a goal for patients presenting to dialysis by the year 2000. A microsurgical technique of side to side anastomosis of the radial artery and cephalic vein (with ligation of distal veins if necessary) appears to be more successful in development of A-V fistulae than end-to-side anastomosis, which is more commonly utilized (personal communication, S. O'Regan). Upper arm brachio-cephalic fistulae as the initial access have also been proposed to improve primary fistulae survival (personal communication, S. Schwab). These targets are in accordance with the recently issued DOQI vascular access clinical practice guidelines63.
Part of this planning should include educating the patient and heath care workers (nurses, physicians, etc.) about "saving" the vasculature of patients with chronic renal failure, particularly in the non-dominant arm. Placement of the i.v. for "keep vein open" or placement of intra-arterial lines to monitor blood pressure in intensive care units should be restricted to true medical needs rather than a reflex action or for convenience.
Early referral to the nephrologist
We believe that there are sufficient data that early referral of patients with chronic renal failure to nephrologists leads to reduced morbidity (that is, hospitalization and costs) than if the patient is managed by a primary care physician until uremia develops64,69. Although this concept has not been well presented to managed care organizations, it may be time for organizations such as the American Society of Nephrology, National Kidney Foundation and Renal Physician Association to actively become engaged in this process so vital to patients with advanced renal disease.
Abolishing subclavian vein cannulation
The complications of these temporary HD catheters are devastating and prohibit future placement of vascular accesses in the side of cannulation Thus, placement of these HD catheters in the subclavian vein should only be a last resort, and limited in duration to a few days, particularly when other veins such as the internal jugular or femoral veins are available38,39,40,70.
Similarly, the cannulation of the subclavian vein for other uses, such as Swan-Gantz catherization or i.v. access for non-dialysis purposes should be discouraged for patients with any degree of renal failure.
Peritoneal dialysis as bridge therapy
Except in emergent situations where uremic symptoms or biochemical parameters (such as, hyperkalemia) need to be treated acutely with hemodialysis, nephrologists should consider the use of peritoneal dialysis (PD) as temporary or "bridge" therapy in patients who present with advanced stages of uremia but who are otherwise not ideal candidates for long-term PD therapy. The initiation of chronic therapy with PD, while allowing an A-V fistulae (or PTFE graft) to mature, may lead to improved long-term outcome of accesses and patients71.
Effective pharmacological inhibition of intimal hyperplasia
It is clear that vascular access generally fails within the first few weeks due to a thrombotic process, or thereafter due to the development of intimal hyperplasia and venous stenosis72. Despite the obvious importance of maintaining primary access patency, there have been remarkably few in vitro and ex vivo experiments and even fewer clinical trials addressing the prevention of access stenosis and thrombosis (Table 5).
Early studies clearly demonstrated that antiplatelet agents are effective in preventing thrombosis of external shunts and in preventing early native arteriovenous fistula thrombosis. On the other hand, despite the extensive use of PTFE grafts there is to date only one relatively large prospective, randomized, placebo-controlled clinical trial that examined pharmacologic approaches to decreasing the rate of graft thrombosis57. The results of this study demonstrated a significant decrease in the rate of thrombosis in patients with new PTFE grafts taking dipyridamole (relative risk 0.35, P = 0.02) and a trend toward a higher rate of thrombosis in patients taking aspirin (relative risk 1.99, P = 0.18). Differences between the groups became manifest only after six months, probably reflecting differing rates of intimal hyperplasia development at the venous anastomosis, although this was not checked with Doppler ultrasound or angiography. The results of this study were surprising, since aspirin is generally considered to be a more potent antiplatelet therapeutic agent than dipyridamole.
Recent work by our laboratory may provide an improved pathophysiologic understanding of the results of this clinical trial73,74. It is well known that the process of intimal hyperplasia formation involves medial smooth muscle replication, migration to the intima, followed by further proliferation and extracellular matrix deposition75. Ross has formulated a "response to injury" hypothesis, in which a prominent role is given to the effects of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in stimulating both smooth muscle replication and migration76. Using human aortic smooth muscle cells in culture, we have recently demonstrated that dipyridamole profoundly inhibits both PDGF- and bFGF-induced vascular smooth muscle cell proliferation. The effects of dipyridamole on smooth muscle cell proliferation are reversible over time and occur at concentrations comparable to plasma concentrations obtained after oral administration of conventional doses74.
In a series of related experiments, we have demonstrated that aspirin enhances PDGF-induced vascular smooth muscle cell proliferation74. In smooth muscle cell cultures activated with PDGF, aspirin results in an increase in 12-HETE production, an important intracellular messenger and mitogen during smooth muscle cell activation, in contrast to prostaglandin E2, the major cyclooxygenase-derived product of arachidonic acid in smooth muscle cells that is an inhibitor of activation and proliferation of these cells77. Thus, aspirin may have a direct positive effect on proliferation and mitogenesis of vascular smooth muscle cell by inhibiting cyclooxygenase and stimulating lipoxygenase pathways of arachidonic acid metabolism.
Further work is clearly needed to better define the mechanisms by which dipyridamole and similar drugs may affect intimal hyperplasia formation. Clinical trails are also clearly needed to corroborate the findings of this one relatively small trial. Nevertheless, the recommendation "to take one baby aspirin a day" in an attempt to reduce PTFE graft thrombosis is no longer an adequate recommendation, and may in fact be counterproductive. There are also a number of novel potential pharmacologic approaches to preventing intimal hyperplasia formation that have been elegantly summarized by Sukhatme78. We join Dr. Sukhatme in the plea that efforts in both basic science as well as clinical trials aimed at reducing formation of intimal hyperplasia associated with vascular access grafts be sponsored by the NIH.
Predictive tests of access failure and their costs
Based on the evidence discussed earlier, the measurement of access blood flow is an early and sensitive test for incipient access failure. This test can currently be performed in the dialysis unit, either by the ultrasound dilution technique or by Doppler ultrasound. The latter has the additional advantage of localizing the site(s) and magnitude of the attendant stenosis. We propose that these tests become an important adjunct to dialytic care.
The implementation of such a recommendation is hampered by several regulatory issues related to the U.S. health care system. HCFA denies reimbursement for tests and procedures it considers "screening" or "preventive." In addition, the considerable lag between emerging technologies and their integration into a reimbursable CPT code has made it economically difficult to acquire the necessary equipment for ultrasound dilution (currently $10,000 including a portable computer), when such tests are not reimbursed. More recently, HCFA has even attempted to disqualify reimbursement for Doppler ultrasound on the grounds that these tests are part of access monitoring that is integrated in the hemodialysis "composite" reimbursement, and because the frequency of such tests has been inconsistent in different regions of the U.S. Although timely intervention by the Renal Physician Association and the National Kidney Foundation has led HCFA to withhold implementation of their blanket denial for reimbursement of Doppler ultrasound, a more active dialogue is needed between physicians and Medicare intermediaries to highlight the medical and economic benefits of such tests and other emerging technologies.
Subject to the limitations outlined in Table 3, the measurement of venous pressures sequentially is a test that may yield information on venous stenosis and is available at no additional cost. In cases where the venous pressure is rising and there are no other intra-access stenoses, this test may be a sensitive and cost-effective, albeit late index of impending access thrombosis.
Multidisciplinary approach to vascular access management
Nephrologists need to be more proactive in the planning, management and salvage of fistulas for hemodialysis access. It is not clear why such a vital issue to the welfare of ESRD patients has been delegated to having the dialysis nurse call the secretary of the surgeon to arrange for a surgical procedure. Direct communication at the planning stage is vital and its practical implementation in a large academic center has led to a steady improvement in the number of autologous A-V fistulae and in frequency of thrombosis79. Reliance on PTFE grafts as a first access is a "learned practice" by many surgeons, and can only be changed by persistent requests for placement of A-V fistulaes. More importantly, short-term and long-term follow-up and documentation of such by each surgeon should be routine and demanded by the nephrologist. Such documentation should include a clear description of the anatomical relationship of the graft, and as well as a description of the surgical technique, sutures, etc., in addition to the usual demographic data. Equally important, and as an integral part of a CQI team led by nephrologists and including surgeons and radiologists, specific information to track access outcome needs to be organized. Several parameters related to access material, configuration, surgical technique, as well as the attending surgeon needs to be organized in a database80,81,82. In addition, any subsequent salvage procedure by the radiologist or nephrologist needs to be documented in a way that allows further analysis and plans for improvement of outcome. Although these requests for quality control information from radiologists and surgeons is not likely to be welcomed by them, it is important to be persistent in pursuing the information even at the risk of changing referral patterns to surgeons who are willing to participate in an effective quality improvement process. As the cost of nephrological care is being capitated, it may also be worthwhile to consider capitating the surgeons for access care, and the radiologist for salvage procedures.
It must also be mentioned that there is anecdotal evidence that peritoneal dialysis accesses placed by nephrologist appears to have a better outcome than surgically placed catheters. Whether this information is evidence-based or speculative, it is important that nephrologist become more intensely involved in this area so vital to their patients. Such involvement needs to start at the fellowship training level by incorporating radiological intervention techniques used in the care of accesses, as part of the fellowship program. Examples of such an involvement is clearly provided by cardiology fellows who train in ultrasound evaluation, angiography and angioplasty of coronary stenotic lesions.
Finally, as part of this multidisciplinary approach, and as an important element for improved outcome, an "access" database should include the use of antiplatelet drugs and low molecular weight heparin in a prospective, if not randomized study. The lessons learned from such databases can be a substrate for an effort by the NIH to organize a multi-center basic science research to define approaches to this vexing problem of neointimal hyperplasia and clinical research to define approaches to salvage procedures of failed or failing PTFE accesses83,84,85.
Development of better biomaterials
The ideal prosthetic materials for vascular access grafts must possess a number of characteristics to be biocompatible Figure 1. The luminal wall of the graft must be thromboresistant, while the external wall should be rapidly incorporated into surrounding tissues. The tendency toward thromboresistance versus thrombogenicity of biomaterials used in vascular access grafts is largely determined by the surface characteristics, types of proteins that selectively and actively adsorb to the graft, and by the cells that tend to adhere to the graft material86.
While PTFE has been developed after experience with other materials, there has been no other material that has been proposed as an alternative. Since the introduction of e-PTFE graft materials in 1973, there have been minimal advances in developing biomaterials for vascular access; even for PTFE, different weaving patterns and architectural support may impact on outcome. Such studies are few and far between.
There are also a number of biocompatibility disadvantages to the use of e-PTFE biomaterials, which need to be studied further87. Inflammation at the host-biomaterial interface as a result of bioincompatibility may contribute to the development of intimal hyperplasia in PTFE grafts. For example, PTFE catheters used as venous access devices are associated with a very high rate of development of thrombophlebitis during peripheral intravenous nutrition when compared to biomaterials such as silicone88,89. A potential mechanism for this is that PTFE is strongly hydrophobic, which may increase platelet activation86,90,91. Furthermore, macrophages adhere readily to PTFE and become activated with the production of reactive oxygen species and membrane-associated interleukin-1 and tumor necrosis factor-
(TNF-)87,92. Finally, endothelial cells adherent to PTFE bind human leukocytes more readily than control endothelial cells93.
A major biological problem with PTFE grafts is the failure to achieve in vivo endothelialization throughout the length of the graft90. This leads to repetitive episodes of platelet deposition and inflammatory cell (platelet, neutrophils, macrophages) activation94. It has been suggested that there may be better peri-graft tissue in-growth and endothelialization using high porosity, non-reinforced PTFE grafts (compared to the standard lower porosity reinforced PTFE grafts in clinical use) and with the use of vascular endothelial growth factor (VEGF)14,95,96. Recently, experimental approaches such as application of shear stress to endothelial cells or retroviral transduction of endothelial cells97,98 have been shown to increase retention of endothelial cells on graft material in vitro. Further research into methods to increase graft endothelialization is clearly needed.
CONCLUSION
It has been said that "insanity is doing the same thing, in the same way, and expecting a different result" (Roger Milliken). As far as hemodialysis access, we can no longer continue doing the same thing (very little indeed), the same way (tabulating data on small scale studies), and expect that the lives of our ESRD patients will be better or that the costs of access care will diminish. It is time to change the paradigm to work proactively and cooperatively to improve the outcomes of hemodialysis access care. Beginnings are half of the journey.
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Acknowledgments
The authors acknowledge the support for this project by NIH grants, R01-HL36015-12 and NIH DK45610-05. We also gratefully acknowledge the assistance of Ms. Jane McLaughlin. Finally, we acknowledge the lessons learned from all of our patients.
