A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis.

OBJECTIVE: Arteriovenous fistulas created in patients with chronic kidney disease often lose patency and fail to become usable. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in promoting radiocephalic fistula patency and use for hemodialysis. METHODS: PATENCY-1 was a double-blind, placebo-controlled trial that enrolled 349 patients on or approaching hemodialysis and being evaluated for radiocephalic arteriovenous fistula creation. Of these, 313 were randomized and 311 treated. Patients were assigned to vonapanitase (n = 210) or placebo (n = 103). The study drug solution was applied topically to the artery and vein for 10 minutes immediately after fistula creation. The primary and secondary end points were primary patency (time to first thrombosis or corrective procedure) and secondary patency (time to abandonment). Tertiary end points included use of the fistula for hemodialysis, fistula maturation by ultrasound, and procedure rates. RESULTS: The Kaplan-Meier estimates of 12-month primary patency were 42% (95% confidence interval [CI], 35-49) and 31% (95% CI, 21-42) for vonapanitase and placebo (P = .25). The Kaplan-Meier estimates of 12-month secondary patency were 74% (95% CI, 68-80) and 61% (95% CI, 51-71) for vonapanitase and placebo (P = .048). The proportions of vonapanitase and placebo patients were 39% and 25% (P = .035) with unassisted use for hemodialysis and 64% and 44% (P = .006) with unassisted plus assisted use. CONCLUSIONS: Vonapanitase treatment did not significantly improve primary patency but was associated with increased secondary patency and use for hemodialysis. Further research is needed to evaluate these end points.

Arteriovenous fistula patency in the 3 years following vonapanitase and placebo treatment.

OBJECTIVE: This study explored the long-term outcomes of arteriovenous fistulas treated with vonapanitase (recombinant human elastase) at the time of surgical creation. METHODS: This was a randomized, double-blind, placebo-controlled trial of 151 patients undergoing radiocephalic or brachiocephalic arteriovenous fistula creation who were randomized equally to placebo, vonapanitase 10 µg, or vonapanitase 30 µg. The results after 1 year of follow-up were previously reported. The current analysis occurred when the last patient treated was observed for 3 years. For the current analysis, the primary end point was primary patency; the secondary end points included secondary patency, use of the fistula for hemodialysis, and rate of procedures to restore or to maintain patency. RESULTS: There was no significant difference in the risk of primary patency loss with vonapanitase 10 µg or 30 µg vs placebo. When seven initial patency loss events related to cephalic arch and central vein balloon angioplasty were excluded, the risk of patency loss was reduced with vonapanitase overall (hazard ratio [HR], 0.63; P = .049) and 30 µg (HR, 0.51; P = .03). In patients with radiocephalic fistulas (n = 67), the risks of primary and secondary patency loss were reduced with 30 µg (HR, 0.37 [P = .02] and 0.24 [P = .046], respectively). The rate of procedures to restore or to maintain fistula patency was reduced with 30 µg vs placebo (0.23 vs 0.72 procedure days/patient/year; P = .03) and also reduced in patients with radiocephalic fistulas with 30 µg vs placebo (0.17 vs 0.85 procedure days/patient/year; P = .048). CONCLUSIONS: In this study, vonapanitase did not significantly improve primary patency in the primary analysis but did significantly improve primary patency in an analysis that excluded patency loss due to cephalic arch and central vein balloon angioplasty. In patients with radiocephalic fistulas, 30 µg significantly improved primary and secondary patency. Vonapanitase 30 µg decreased the rate of procedures to restore or to maintain patency in the analysis that included all patients and in the subset with radiocephalic fistulas.

The Venous Window Needle Guide, a hemodialysis cannulation device for salvage of uncannulatable arteriovenous fistulas.

BACKGROUND: Arteriovenous fistulas (AVFs) are recommended for hemodialysis access when possible. A noncannulatable but otherwise well functioning AVF leads to prolonged catheter dependency and frustration for the patient and the renal health care provider team. Difficult cannulation patients include obese individuals in whom cannulation sites are too deep, and others with vein segments that are short, tortuous, or otherwise difficult to palpate. The Venous Window Needle Guide for Salvage of AV Fistulae (SAVE) trial was designed to evaluate the efficacy and safety of the Venous Window Needle Guide (VWING; Vital Access Corp, Salt Lake City, Utah) device for salvage of such noncannulatable AVFs that are otherwise functional. METHODS: The SAVE study included patients with an established and otherwise mature AVF, in whom an additional procedure would otherwise be necessary to establish reliable cannulation. The VWING is a single-piece titanium device that allows repeated access of an AVF through a single puncture site (buttonhole technique). Inclusion criteria included mature AVFs 6.0 to 15.0 mm in depth with multiple failed attempts at cannulation or where the access could not be palpated. The devices were implanted subcutaneously and sutured to the anterior wall of the mature fistula. Study end points were reliable and successful cannulation and avoidance of adverse events during the 6-month follow-up, implant technical success, and clinical cannulation success. RESULTS: Enrollment included 54 patients at 11 trial sites with implantation of 82 VWING devices. Body mass index was 26 to 50 (median, 36), 40 (74%) patients were female, and age was 17 to 84 (median, 59) years. Forty (74%) individuals were diabetic. Thirty-three (61%) patients were white, 16 (30%) black, and 10 (18%) patients were Hispanic, Pacific Islander, or Native American. Three patients were excluded from data analysis for reasons unrelated to the device. Successful AVF access was achieved using the VWING in 49 (96%) of the 51 patients evaluated. The rate of device-related serious adverse events was 0.31 per patient-year; each event was resolved leaving the AVF functional. The rates of sepsis and study-related interventions were 0.04 and 0.65 per patient-year, respectively. There were no study-related deaths. One device was removed because of infection. The AVF survival rate at 6 months was 100%. The total number of study days was 9497 and the estimated number of device cannulations was 4238. CONCLUSIONS: The VWING was safe and effective in facilitating AVF cannulation for patients with an otherwise mature but noncannulatable fistula. Successful AVF access was achieved using the VWING in 49 (96%) of the 51 patients evaluated. The AVF survival rate at 6 months was 100%.

Human type I pancreatic elastase treatment of arteriovenous fistulas in patients with chronic kidney disease.

OBJECTIVE: This study explored the safety and efficacy of recombinant type I pancreatic elastase (PRT-201) topically applied once to the external surface of an arteriovenous fistula. METHODS: This was a randomized, double-blind, placebo-controlled trial. Adults with kidney disease undergoing creation of a radiocephalic fistula (RCF) or brachiocephalic fistula were randomized to treatment with placebo (n = 51), PRT-201 at 10 µg (n = 51), or PRT-201 at 30 µg (n = 49). The primary efficacy measure was unassisted primary patency (PP) over 1 year. Secondary efficacy measures were secondary patency (SP), unassisted maturation by ultrasound interrogation, use for hemodialysis, and hemodynamically significant lumen stenosis. RESULTS: Median PP was 224 days for placebo and >365 days for the PRT-201 groups. At 1 year, 45%, 54%, and 53% of placebo, 10-µg, and 30-µg patients retained PP. The risk of PP loss was nonsignificantly reduced for 10 µg (hazard ratio [HR], 0.69; P = .19) and 30 µg (HR, 0.67; P = .17) vs placebo. In the subset (44% of patients) with a RCF, the median PP was 125 days for placebo and >365 days for the PRT-201 groups. At 1 year, 31%, 50%, and 63% of placebo, 10-µg, and 30-µg RCFs retained PP. The risk of RCF PP loss was nonsignificantly reduced by 10 µg (HR, 0.59; P = .18) and significantly reduced by 30 µg (HR, 0.37; P = .02) vs placebo. At 1 year, 77%, 81%, and 83% of placebo, 10-µg, and 30-µg patients retained SP. The risk of SP loss was nonsignificantly reduced for 10 µg (HR, 0.79; P = .61) and 30 µg (HR, 0.76; P = .55) vs placebo. In the subset with RCFs, 65%, 82%, and 90% of placebo, 10-µg, and 30-µg patients retained SP at 1 year. The risk of RCF SP loss was nonsignificantly reduced for 10 µg (HR, 0.45; P = .19) and 30 µg (HR, 0.27; P = .08) vs placebo. At month 3, 67%, 87% (P = .03), and 92% (P < .01) of the placebo, 10-µg, and 30-µg group fistulas had unassisted maturation by ultrasound interrogation. At month 3 in the subset with an RCF, 47%, 74% (P = .17), and 93% (P < .01) of placebo, 10-µg, and 30-µg group fistulas had unassisted maturation by ultrasound interrogation. Adverse event reports were not meaningfully different between groups. CONCLUSIONS: PRT-201 appeared safe. The primary efficacy end point was not met. However, both PRT-201 doses were associated with improved unassisted maturation. The 30-µg dose was associated with increased PP in the subset with RCF.

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency.

OBJECTIVE: Arteriovenous fistulas created for hemodialysis often fail to become usable and are frequently abandoned. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in increasing radiocephalic fistula use for hemodialysis and secondary patency. METHODS: PATENCY-2 was a randomized, double-blind, placebo-controlled trial in patients on or approaching the need for hemodialysis undergoing radiocephalic arteriovenous fistula creation. Of 696 screened, 613 were randomized, and 603 were treated (vonapanitase n = 405, placebo n = 208). The study drug solution was applied topically to the artery and vein for 10 min immediately after fistula creation. The primary endpoints were fistula use for hemodialysis and secondary patency (fistula survival without abandonment). Other efficacy endpoints included unassisted fistula use for hemodialysis, primary unassisted patency, fistula maturation and unassisted maturation by ultrasound criteria, and fistula procedure rates. RESULTS: The proportions of patients with fistula use for hemodialysis was similar between groups, 70% vonapanitase and 65% placebo, (p = 0.33). The Kaplan-Meier estimates of 12-month secondary patency were 78% (95% confidence interval [CI], 73-82) for vonapanitase and 76% (95% CI, 70-82) for placebo (p = 0.93). The proportions with unassisted fistula use for hemodialysis were 46% vonapanitase and 37% placebo (p = 0.054). The Kaplan-Meier estimates of 12-month primary unassisted patency were 50% (95% CI, 44-55) for vonapanitase and 43% (95% CI, 35-50) for placebo (p = 0.18). There were no differences in the proportion of patients with fistula maturation or in fistula procedure rates. Adverse events were similar between groups. Vonapanitase was not immunogenic. CONCLUSIONS: Vonapanitase treatment did not achieve clinical or statistical significance to meaningfully improve radiocephalic fistula surgical outcomes. Outcome in the placebo group were better than in historical controls. Vonapanitase was well-tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov: NCT02414841 (https://clinicaltrials.gov/ct2/show/NCT02414841).

The impact of cytomegalovirus infection ≥1 year after primary renal transplantation.

We studied the impact of a first post-transplant cytomegalovirus (CMV) infection greater than one year after primary kidney transplantation. Risk factors for developing late CMV were acute rejection and donor-recipient CMV status. Of those developing late CMV, 35% were donor (D) positive, recipient (R) negative; however, 23% were D+R+, 22% D-R+, and 15% D-R-. Late CMV was associated with significantly decreased patient and graft survival.

Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kidney disease.

PURPOSE: To explore the safety and efficacy of PRT-201 applied to the outflow vein of a newly created arteriovenous graft (AVG). METHODS: Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.01 to 9 mg) applied to the graft-vein anastomosis and adjacent outflow vein immediately after AVG placement. The primary outcome measure was safety. The efficacy measures were intraoperative increases in outflow vein diameter and blood flow rate, primary unassisted patency, and secondary patency by dose groups (placebo, low, medium, high and All PRT-201). RESULTS: A total of 89 patients were treated (28 placebo and 61 PRT-201). There were no significant differences in the proportion of placebo and PRT-201 patients reporting adverse events. Intraoperative outflow vein diameter increased 5% (p=0.14) in the placebo group compared with 13% (p=0.01), 15% (p=0.07) and 12% (p<0.001), in the low, medium and high groups, respectively. The comparison between the high and placebo groups was marginally statistically significant (p=0.06). The intraoperative blood flow did not change in the placebo group, and increased in the low, medium and high groups by 19% (p=0.34), 36% (p=0.09) and 46% (p=0.02), respectively. The low group had the longest primary unassisted and secondary patency and the fewest procedures to restore or maintain patency; however, the differences between groups were not statistically significant. CONCLUSIONS: PRT-201 was well tolerated and increased AVG intraoperative outflow vein diameter and blood flow. Low dose tended to increase secondary patency and decrease the rate of procedures to restore or maintain patency. Larger studies with these doses will be necessary to confirm these results.

A comparison of cryopreserved vein allografts and prosthetic grafts for hemodialysis access.

In hemodialysis patients with insufficient vasculature for creation of a native arteriovenous fistula (AVF), a polytetrafluoroethylene (PTFE) graft is commonly utilized. Because of PTFE complications, our group and others have used cryopreserved cadaver femoral vein allografts (Synergraft [SYN], CryoLife, Marietta, GA) in selected patients. Based on our experience with these allografts, we hypothesized that they were more resistant to thrombosis than PTFE grafts. The purpose of this study was to compare the thrombosis rates of SYN and PTFE grafts in a prospective, randomized fashion. Our study was interrupted when the FDA ordered CryoLife, Inc. to retain certain vascular tissue products, and patient accrual stopped in 2003. Most patients referred for hemodialysis access are evaluated with bilateral, upper extremity Doppler ultrasound. Starting in 2001, those with insufficient vasculature for native AVF were offered randomization into the PTFE or SYN groups. All accesses were placed in the upper extremity, above the elbow. Access patency and complications were recorded, and failure was defined as access removal, abandonment, or replacement of > 50% with a new conduit. Prior to FDA interruption of the study, 27 patients were randomized into each group. Patient characteristics were similar, but there were significantly more males and African-Americans in the SYN group. No significant differences were seen in primary or secondary patency, number of thrombectomies, revisions, or total interventions. Significantly more fistulagrams were performed in the SYN group (p < 0.05). No infections were seen in either group, but 2 aneurysms occurred in the SYN group. Nine (33%) patients in each group died with functioning access. Access failures: In the SYN group, 8 of 27 (30%) failed, with 5 failing from multiple access stenoses unresponsive to balloon angioplasty; in the PTFE group 4 of 27 (18%) failed, with 2 failing from multiple stenoses. In conclusion, for initial hemodialysis access in patients without sufficient vasculature for native AVF, our results do not support the routine use of SYN allografts in the general dialysis population.

Experience with cryopreserved cadaveric femoral vein allografts used for hemodialysis access.

The purpose of this study was to review the patency and complications of cryopreserved vein allografts used for hemodialysis access, and to compare them to a group with polytetrafluoroethylene (PTFE) grafts. Patients without adequate vasculature for native fistula were implanted with vein allografts or PTFE grafts at the surgeon's discretion. Only cryopreserved (CRY) veins were used until January 2001, when decellularized, cryopreserved Synergraft (SYN) veins became available. The CRY group had 48 patients; the SYN group, 42 patients; the PTFE group, 100 patients, who were selected from billing records listing PTFE graft insertion. Patient demographics were similar. Primary and secondary patencies were not significantly different at 1 or 2 years between groups. Complications in PTFE versus CRY and SYN groups were as follows: infection, 10 % vs. 0% (p < 0.01); aneurysm, 2% vs. 18% (p < 0.001); and steal syndrome, 12% vs. 12% (p = NS). Significantly more vein allograft patients lost their accesses to aneurysm (p < 0.01) and multiple stenoses (p < 0.05), whereas PTFE patients lost significantly more accesses to infection (p < 0.01) and recurrent thrombosis (p < 0.05). We conclude that cadaver vein allografts have similar patency to PTFE grafts. These allografts are more resistant to infection but significantly more susceptible to aneurysms. When used, vein allografts should be monitored aggressively for the development of aneurysms.

Delayed graft function may not adversely affect short-term renal allograft outcome.

INTRODUCTION: Delayed graft function (DGF) is commonly believed to adversely impact both short- and long-term renal allograft function. Because immunosuppressive therapy is commonly altered after DGF is identified, retrospective analyses are difficult to interpret. We therefore prospectively sought to examine the natural history of DGF in a controlled patient population under identical immunosuppressive protocols. METHODS: Adult patients undergoing cadaveric renal transplantation were treated with sequential triple drug immunotherapy. High-dose steroids were administered in the operating room and rapidly tapered to 20 mg prednisone by post-operative day (POD) 6. Cyclosporine (CsA) microemulsion was begun on POD 1, and dosed asymmetrically at 12-h intervals to reach a daytime Cav of 650 ng/mL (utilizing 2-h and 6-h levels), while PM doses were adjusted to an AM trough of 300 ng/mL. Mycophenolate (1000 mg q12 h) was added on POD 3 in most patients and discontinued after 3 months. No induction agents were used. All patients were followed for at least 6 months. RESULTS: Sixty consecutive patients received 64 allografts (four double grafts). In all, 17 patients required dialysis and were considered to have DGF. Eight of these patients received marginal organs turned down by at least one other centre. Cold ischaemia time was significantly longer in patients with DGF (24 h vs. 19 h, P < 0.01) All patients were treated as planned and there were no major protocol violations. One patient had primary non-function and was excluded from analysis. CsA trough and Cav values were similar between groups. Mean serum creatinine levels (mg/mL) fell more slowly in patients with DGF but there was no significant difference by 3 months (1.7 vs. 1.5) and the creatinine clearance was not significantly different between the groups after 1 year (71 cm3/min in DGF vs. 61 cm3/min, P = 0.13). Our data demonstrate that alterations in routine immunosuppressive strategies may not be necessary to achieve equivalent outcomes in patients with DGF.

Can a pharmacokinetic approach to immunosuppression eliminate ethnic disparities in renal allograft outcome?

Although renal allograft outcome correlates more closely with area under the concentration time curve (AUC) for cyclosporin (CsA) compared with the 12-h trough level (C0), few studies have prospectively evaluated pharmacokinetic monitoring in kidney transplantation. This paper describes a study designed to evaluate the impact of a novel approach to CsA-based immunosuppression on ethnic differences in renal allograft outcome. Sixty (32 African Americans and 28 Caucasians) renal transplant recipients were treated with cyclosporin-based triple therapy. Morning and evening doses were independently adjusted to reach an AUC0-12 of 6600-7200 ng h/mL and a C0 of 250-325 ng/mL, respectively. AUCs were measured within 48 h of starting CsA, and as often as necessary to maintain target levels. Only two patients experienced significant adverse events related to immunosuppression. One (Caucasian) developed haemolytic uremic syndrome and was converted to tacrolimus, while another (African American) developed acute vascular rejection. One graft was lost (Caucasian) due to death with a functioning graft. An average of 8 AUCs (range 5-13) were measured in the first 3 months. AUCs were significantly higher in African Americans compared with Caucasians only in the first and second month. C0 values were similar in both groups throughout the study period. A pharmacokinetic approach to immunosuppression allows individualization of CsA exposure, and appears to reduce ethnic disparities in renal allograft outcome.

Effect of cyclosporin pharmacokinetics on renal allograft outcome in African-Americans.

African-Americans (A-As) experience inferior outcome after transplantation compared with other ethnic groups. Bioavailability of cyclosporin (CsA) has been implicated as a possible contributing factor. This paper describes the outcome of 32 A-A recipients of de novo renal allograft who received CsA-based triple immunotherapy according to individual pharmacokinetic profiles. Patients received CsA-microemulsion q 12 h, dosed initially at 3.5 mg/kg (8 am) and 3.0 mg/kg (8 pm). The am and pm doses were independently adjusted to achieve a 12-h area under the concentration-time curve (AUC0-12) of 6600-7200 nghr/mL and morning trough level (C0) of 250-325 ng/mL, respectively. Mean age was 43 +/- 12 yr, 37% (12) female. Mean AUC0-12 in 1 wk, 1, 3, 6, and 12 months were 7810 +/- 1880 nghr/mL, 9057 +/- 2097 nghr/mL, 7674 +/- 1912 nghr/mL, 7132 +/- 2040 nghr/mL, and 6503 +/- 1410 ngl/h with corresponding C0 of 301 +/- 79 ng/mL, 316 +/- 66 ng/mL, 275 +/- 59 ng/mL, 273 +/- 66 ng/mL, and 224 +/- 49 ng/mL, respectively. Acute rejection occurred in two patients (6%) 1 yr after transplantation. Prospective use of CsA pharmocokinetic profiles improves renal allograft outcome in A-As.