Arteriovenous Fistulae for Haemodialysis: A Systematic Review and Meta-analysis of Efficacy and Safety Outcomes.

BACKGROUND: Arteriovenous fistulae are the currently recommended gold standard vascular access modality for haemodialysis because of their prolonged patency, improved durability, and low risk of infection for those that mature. However, notable disadvantages are observed in terms of protracted maturation time, associated high rates of catheter use, and substantial abandonment rates. The aim of this study was to quantitatively summarize the outcomes of fistula patency, infection, maturation, and abandonment published in the scientific literature. METHODS: This was a systematic review and meta-analyses of studies evaluating fistula outcomes. Literature searches were conducted in multiple databases to identify observational and interventional studies of mean fistula patency rates at 1 year, infection risk, maturation time, and abandonment. Digitisation software was used to simulate individual patient level data from Kaplan-Meier survival plots. RESULTS: Over 8000 studies were reviewed, and from these, 318 studies were included comprising 62,712 accesses. For fistulas the primary unassisted, primary assisted, and secondary patency rates at one year were 64%, 73% and 79% respectively, however not all fistulas reported as patent could be confirmed as being clinically useful for dialysis (i.e. functional patency). For fistulas that were reported as mature, mean time to maturation was 3.5 months, however only 26% of created fistulas were reported as mature at 6 months and 21% of fistulas were abandoned without use. Overall risk of infection in fistula patients was 4.1% and the overall rate per 100 access days was 0.018. CONCLUSIONS: Reported fistula patency rates may overstate their potential clinical utility when time to maturation, maturation rate, abandonment and infection are considered. Protracted maturation times, abandonment and infection all have a significant impact on evaluating the clinical utility of fistula creation. A rigorous and consistent set of outcomes definitions for hemodialysis access are necessary to clarify factors contributing to fistula success and the clinical consequence of fistula failure.

Multi-center experience of 164 consecutive Hemodialysis Reliable Outflow [HeRO] graft implants for hemodialysis treatment.

OBJECTIVE: To report a multi-center experience with the novel Hemodialysis Reliable Outflow (HeRO) vascular access graft. MATERIALS AND METHODS: Four centers conducted a retrospective review of end stage renal disease patients who received the HeRO device from implant to last available follow-up. Data is available on 164 patients with an accumulated 2092.1 HeRO implant months. RESULTS: At 6 months, HeRO primary and secondary patency is 60% and 90.8%, respectively and at 12 months, 48.8% and 90.8%, respectively. At 24 months, HeRO had a primary patency of 42.9% and secondary patency was 86.7%. Interventions to maintain or re-establish patency have been required in 71.3% of patients (117/164) resulting in an intervention rate of 1.5/year. Access related infections have been reported in 4.3% patients resulting in a rate of 0.14/1000 implant days. CONCLUSIONS: In our experience the HeRO device has performed comparably to standard AVGs and has proven superior to TDCs in terms of patency, intervention, and infection rates when compared to the peer-reviewed literature. As an alternative to catheter dependence as a means for hemodialysis access, this graft could reduce the morbidity and mortality associated with TDCs and have a profound impact on the costs associated with catheter related infections and interventions.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens.

Axillary to common iliac arteriovenous graft for hemodialysis access: Case report and review of 'exotic' axillary-based grafts.

A 58-year-old Caucasian male with end-stage renal disease and peripheral arterial disease was referred to us for management of his complex vascular access. His vascular access history included a left wrist primary fistula, a left upper arm access graft, a left leg loop graft, and multiple PermCaths in his jugular veins with recurrent infections. Magnetic resonance venography (MRV) of his chest revealed extensive bilateral venous occlusions due to numerous past hemodialysis access catheters. The patient was scheduled for right lower extremity arteriovenous graft placement, but intraoperatively was found to have severe peripheral arterial disease and a thromboendarterectomy was performed instead. Lower body venous imaging demonstrated patent iliac veins. Based on these anatomic considerations a right axillary artery to right common iliac vein polytetrafluoroethylene (PTFE) graft was placed. The graft required revision twice--once for graft ultrafiltration at the arterial end of the graft and once for needle stick infection--but continues to serve as sufficient access after 15 months. Grafts based off the axillary artery have become increasingly popular in recent years and several venous outflow options have been considered, each with distinct advantages. The common iliac vein offers a central location with high flow rate and low probability of infection. Axillary artery to iliac vein arteriovenous grafting may have a place in the vascular surgeon's armamentarium for complex vascular access cases.

Blocking the initiation of coagulation by RNA aptamers to factor VIIa.

The tissue factor/factor VIIa complex is thought to be the primary initiator of most physiologic blood coagulation events. Because of its proximal role in this process, we sought to generate new inhibitors of tissue factor/factor VIIa activity by targeting factor VIIa. We employed a combinatorial RNA library and in vitro selection methods to isolate a high affinity, nuclease-resistant RNA ligand that binds specifically to coagulation factor VII/VIIa. This RNA inhibits the tissue factor-dependent activation of factor X by factor VIIa. Kinetic analyses of the mechanism of action of this RNA suggest that it antagonizes factor VIIa activity by preventing formation of a functional factor VII/tissue factor complex. Furthermore, this RNA significantly prolongs the prothrombin time of human plasma in a dose dependent manner, and has an in vitro half-life of approximately 15 h in human plasma. Thus, this RNA ligand represents a novel class of anticoagulant agents directed against factor VIIa.

Six-month survival of a calf with an artificial heart.

A pneumatically powered artificial heart, constructed primarily from a polyurethane, was implanted in the chest of a calf and supported the calf for more than 6 months. The heart, which was designed to fit in the chest of a 90 kilogram calf, was able to suppor the animal when it weighed 180 kilograms. During the first 105 days the calf remained strong and healthy. The animal grew progressively weaker after day 106, and by day 160 right heart failure became apparent. The principal cause of the right heart failure was an obstructive growth between the right atrium and the right ventricle. An attempt to correct the problem on day 184 with an artificial heart resulted in the animal's death.

In vivo evaluations of a new thromboresistant polyurethane for artificial heart blood pumps.

To reduce the risk of thromboembolic complications in prosthetic blood pumps, we have developed a new segmented polyurethane elastomer. This material is unique because its mechanical properties for long-term durability and surface properties for biocompatibility have been separated and developed in two distinct materials. Improved thromboresistance is then obtained by a 1% concentration of a new polymeric surface-modifying additive blended with the base polyurethane before fabrication of the blood pump. To evaluate this material in vivo, we performed 10 implants, in calves, of the Pierce-Donachy prosthetic ventricle with blood-pumping sacs and cannulas fabricated from the new surface-modifying additive copolymer blend (Thoratec's BPS-215M). In four control implants the blood sacs and cannulas were fabricated from Ethicon's Biomer segmented polyurethane, which is the present clinical standard for most artificial hearts and circulatory support devices. The blood pumps were connected from the apex of the left ventricle to the descending aorta in male Holstein calves weighing 82 to 108 kg and were driven pneumatically in the full-to-empty mode with flows averaging 5 to 6 L/min. Each calf was medicated with aspirin and dipyridamole throughout the study period and was electively put to death after 4 weeks for evaluation of explanted blood sacs and for examination of the kidneys for infarction. All 10 explanted blood sacs made with the surface-modifying additive copolymer blend were shiny and completely free of thrombus. Three of the four explanted Biomer blood sacs showed visible red thrombus, and all four showed small areas of white thrombus. The average surface area of the Biomer blood sacs covered with thrombus was 45 +/- 32 mm2. Use of a semiquantitative scale to assess renal infarction demonstrated that nine of 10 animals with a surface-modifying additive copolymer blend blood sac had infarction less severe than the mean infarct score of the animals with a Biomer sac. The surface-modifying additive copolymer blend has excellent mechanical and physical properties necessary for use in artificial heart blood pumps. From these experiments, we conclude that the surface-modified polyurethane blend is superior to Biomer polyurethane in blood compatibility and in freedom from thromboembolic risk. This material is now approved by the Food and Drug Administration for investigational device exemption studies in the Pierce-Donachy prosthetic ventricle.

Swine lungs expressing human complement-regulatory proteins are protected against acute pulmonary dysfunction in a human plasma perfusion model.

UNLABELLED: Pulmonary transplantation is currently limited by the number of suitable cadaver donor lungs. For this reason, pulmonary xenotransplantation is currently being investigated. OBJECTIVE: Our goal was to assess the role of complement in pulmonary xenograft dysfunction. METHODS: The pulmonary function of swine expressing human decay accelerating factor and human CD59 (n = 6) was compared with that of the lungs from nontransgenic (control) swine (n = 6) during perfusion with human plasma. RESULTS: After 2 hours of perfusion, the pulmonary vascular resistance was 1624 +/- 408 dynes.sec.cm-5 in control lungs and 908 +/- 68 dynes.sec.cm-5 in transgenic lungs (p < 0.05). Control lungs had a venous oxygen tension of 271 +/- 23 mm Hg with a ratio of venous oxygen tension to inspired oxygen fraction of 452 +/- 38 at 2 hours of perfusion; transgenic lungs had a venous oxygen tension of 398 +/- 11 mm Hg and a ratio of venous oxygen tension to inspired oxygen fraction of 663 +/- 18 (p < 0.05). Control lungs showed a decrease of 79.8% +/- 3.7% in static pulmonary compliance by 2 hours, versus a 12.0% +/- 8.1% decrease by the transgenic lungs (p < 0.05). The control lungs also developed 561.7 +/- 196.2 ml of airway edema over 2 hours, in contrast to 6.5 +/- 1.7 ml in transgenic lungs (p < 0.05). CONCLUSION: Lungs from swine expressing human decay accelerating factor and human CD59 functioned better than nontransgenic swine lungs when perfused with human plasma. These results suggest that complement activation is involved in producing acute pulmonary xenograft dysfunction and demonstrate that lungs from swine expressing human decay accelerating factor and human CD59 are protected against pulmonary injury when perfused with human plasma.

The role of natural anti-Gal alpha 1-3Gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants.

Xenoreactive natural antibodies in humans and higher primates are directed predominantly at Gal alpha 1-3Gal. These antibodies are thought to initiate hyperacute rejection of porcine organ xenografts. The contribution of anti-Gal alpha 1-3Gal antibodies to the xenoractive natural antibody repertoire and to the initiation of hyperacute rejection was tested in a pig-to-baboon cardiac xenograft model. Anti-Gal alpha 1-3Gal antibodies were depleted from baboons by extracorporeal absorption of anti-Gal alpha 1-3Gal antibodies from plasma using columns with a matrix bearing Gal alpha 1-3Galb1-4GlcNAc. Specific removal of anti-Gal alpha 1-3Gal antibodies was achieved prior to transplantation as demonstrated by immunoassay. Porcine hearts were then transplanted into these baboons and the outcome of the transplants was analysed. Immunofluorescence revealed little deposition of baboon antibodies in the grafts. The porcine hearts did not undergo hyperacute rejection even though complement activity was approximately 90% of baseline at the time of transplantation. These findings demonstrate that anti-Gal alpha 1-3Gal antibodies constitute a major fraction of xenoreactive natural antibodies in primate blood and that these antibodies contribute significantly to the pathogenesis of hyperacute xenograft rejection.

Infant cardiopulmonary bypass: a procoagulant state.

BACKGROUND: Procoagulant activity after cardiopulmonary bypass (CPB) in infants may predispose to thrombotic and bleeding complications. The induction of tissue factor and prothrombinase activity on endothelial cell membranes is a primary step in the activation of the extrinsic clotting cascade. The purpose of this study is to characterize the fibrinolytic and endothelial procoagulant state in infants undergoing congenital cardiac repairs with and without CPB. METHODS: Fourteen infants (aged 1 to 12 weeks) underwent repair of congenital cardiac defects. Two patients had closed procedures (controls) and 12 had open cardiac procedures. Serum samples were taken before and after CPB, 1, 4, and 24 hours after CPB. Tissue plasminogen activator, plasminogen activator inhibitor-1, interleukin-1beta, interleukin-6, plasma tissue factor, and factor V levels were measured. Human umbilical vein endothelial cell cultures were incubated with serum taken from the above time points and assayed for induction of tissue factor and prothrombinase activity. RESULTS: Control patients had no change from preoperative values in any of the parameters examined. In experimental patients, tissue plasminogen activator levels peaked at 1 hour after CPB and then decreased to normal by 24 hours. Plasminogen activator inhibitor-1 levels peaked at 4 hours after CPB and returned to baseline by 24 hours. The plasma of all patients had no intrinsic tissue factor activity. Induction of tissue factor activity on umbilical vein endothelial cells peaked immediately and again at 24 hours, whereas prothrombinase activity peaked early and stayed elevated. Serum factor V levels were significantly reduced after CPB, but returned to near baseline levels by 24 hours. CONCLUSIONS: Cardiopulmonary bypass is associated with derangement of the coagulation and fibrinolytic systems in infants. The serum of these patients promotes the induction of endothelial procoagulant activity, suggesting that there may be a hypercoagulable state in the postbypass period.

The role of the membrane in the expression of the vitamin K-dependent enzymes.

The hemostatic response to vascular damage results in the focal generation of thrombin to produce a fibrin/platelet clot at the site of vascular injury. This regulated hemostatic response derives from the assembly and activity of enzyme complexes that are localized to surfaces presented by the vascular damage. The product of each enzymatic complex provides the serine protease component required for the assembly and activity of each successive enzyme complex, ultimately leading to the formation of thrombin. When one limits attention to those complexes clearly associated with hemostatic or thrombotic risk, the significance of the vitamin K-dependent enzyme complexes becomes apparent. Each of these complexes involves a serine protease and a cofactor protein that assemble on a membrane surface in the presence of Ca++. The expression of an active complex involves, in addition to the activation of a zymogen to an enzyme, the presentation or activation of a cofactor protein and the provision of the appropriate membrane to support the reaction. The membrane plays an essential part in the formation and expression of vitamin K-dependent complexes; thus, its regulation is vital in the expression of procoagulant activity.

The beat goes on: status of the artificial heart, 1977.

After two decades of continuous research on the artificial heart, survival times of experimental animals indicate that clinical application of such a device is definitely feasible. However, a number of problems remain to be solved. Durability of the device, infection, pannus formation at the interface between the device and natural tissue and thrombosis within the device appear to be the major problems. Development of an implantable power source is also an area of important research. Questions of efficiency, cosmetic and psychological acceptability and cost are just beginning to be considered.

Reoperative surgery in calves with a total artificial heart.

Two surgical techniques have been developed in our laboratory to deal with identifiable problems in long-term artificial heart experiments. A right throacotomy is used to deal with problems such as extensive bleeding, which occur in the immediate postoperative stage of the experiment, while a left thoracotomy is used in cases in which the original implantation is preceded by more than one week, since extensive adhesions complicate the right thoracotomy at that stage. Pulmonary problems have been eliminated as primary cause of difficulties after reoperation, but infection remains a serious problem.

Legionnaires' Disease--the Benidorm episode.

The clinical pattern of illness in 2 fatal cases of Legionnaires' Disease is described. Common factors in the 2 patients were residence in a hotel in Benidorm, Spain, a severe and progressive pneumonia unaffected by wide-spectrum antibiotics and failure to incriminate an infecting organism. The similarities with the Philadelphia outbreak, in which a bacillus known as the Legionnaire agent was isolated, led to a retrospective diagnosis in the Benidorm episode. Subsequent serological surveys indicate that Legionnaires' Disease is widespread in nature; it is not a new disease.

Challenges of hemodialysis access for high risk patients: Impact of mesenteric vein bioprosthetic graft.

OBJECTIVE: The purpose of this study is to compare in a prospective fashion the performance of a new bioprosthesis, the mesenteric vein bioprosthesis (MVB), in patients who have had multiple failed ePTFE grafts. Performance measures include primary patency rates, assisted-primary patency rates, secondary patency rates, complications, and the number of interventions required to maintain graft patency. STUDY: From October 1999 to February 2002, 276 hemodialysis access grafts were implanted in a multicenter study. Of those grafts, 74 were placed in patients with a prior history of 3 failed prosthetic grafts (mean = 3.5 grafts, range = 3-6 grafts). Fifty-nine grafts were constructed with MVB, and 15 grafts with ePTFE as a concomitant control. Mean follow-up was 11.5 months. In the MVB group, 79.7% were African-Americans, 61% were females, and 23.7% were hypercoagulable. Of the ePTFE group, 86.7% were African-Americans, 46.7% were female, and 13.2% were hypercoagulable. Results : Per Kaplan-Meier curves, the primary patency rate of the MVB group at 12 months was 33% vs the ePTFE group of 18% (p=0.120); the assisted-primary patency rates at 12 months were 45% MVB vs 18% ePTFE (p=0.011). The secondary patency rates at 12 and 24 months for the MVB group were 67% and 59%, respectively, vs 45% and 15% for the ePTFE group (p=0.006). During the follow-up time period, 80% of the ePTFE grafts were abandoned compared to 34% of the MVB group. Infection and thrombosis rates in the MVB group were lower than the ePTFE group. The infection rate for the MVB group requiring intervention was 0.07 events/graft year (gt/y) compared to 0.30 events/gt-y for ePTFE (p=0.04). A thrombosis rate of 0.69 events/gt-y occurred in the MVB group whereas 2.50 events/gt-y presented in the ePTFE group (p<0.01). CONCLUSION: In this study, high-risk patients (defined as those having multiple failed prosthetic grafts for hemodialysis) in whom the MVB conduit for hemoaccess was implanted, showed significant improvement in assisted-primary and secondary patency rates compared to the ePTFE cohort. The MVB group, however, did not have a statistically better primary patency rate compared to the ePTFE group. The MVB patient also had fewer thrombotic and infectious events and an overall reduction in the number of interventions while maintaining a permanent access site. This new bioprosthesis should be the conduit of choice in the complex group of patients as it offers assisted-primary and secondary patency rates similar to those commonly experienced by patients without a history of multiple graft failures.

A porcine model of intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts.

PURPOSE: Vascular access polytetrafluoroethylene (PTFE) graft failure is a major cause of morbidity in the hemodialysis population. The most common cause of graft failure is thrombosis secondary to stenosis at the venous outflow tract. Venous outflow stenosis is characterized by intimal-medial hyperplasia. We have developed a porcine arteriovenous (AV) graft model that may be used to investigate this proliferative response and aid in the development of new therapies to prevent intimal-medial hyperplasia and improve graft patency. METHODS: Left carotid to right external jugular vein PTFE (6 mm) grafts were implanted in the necks of swine. Immediately following anatomosis, flow rates were recorded. In one group of animals (n = 4) the venous outflow tract was harvested after 7 days and morphometric analysis of intimal and medial area was performed. In a second group (n = 8) the graft patency was monitored until 28 days. RESULTS: All porcine PTFE fistula grafts were patent at 7 days and 100% patency was maintained until 14 days. After 28 days, 75% of the grafts failed due to thrombosis. The venous outflow tract developed a significant proliferative response. After 7 days the intimal and medial areas were 469 +/- 9 microm2 and 875 +/- 26 microm2 respectively. At 28 days the intimal and medial areas were 913 +/- 55 microm2 and 1437 +/- 182 microm2 respectively. Luminal flow rate of the venous outflow tract was reduced significantly (344 +/- 11 ml/min at Day 0 to 129 +/- 14 ml/min at Day 7, p < 0.05). CONCLUSIONS: This porcine model rapidly, reliably and robustly reproduces the flow reducing stenosis and intimal-medial hyperplasia at the venous outflow tract of PTFE arteriovenous fistula. It represents a promising tool for investigating the mechanisms of intimal-medial hyperplasia, evaluating therapeutic interventions and new graft materials.