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)

ObjectiveArteriovenous 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.MethodsPATENCY-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.ResultsThe 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.ConclusionsVonapanitase 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.

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 mg, or vonapanitase 30 mg. 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 mg or 30 mg 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 mg (HR, 0.51; P =.03). In patients with radiocephalic fistulas (n = 67), the risks of primary and secondary patency loss were reduced with 30 mg (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 mg vs placebo (0.23 vs 0.72 procedure days/patient/year; P =.03) and also reduced in patients with radiocephalic fistulas with 30 mg 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 mg significantly improved primary and secondary patency. Vonapanitase 30 mg 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.

Background: The Venous Window Needle Guide (VWING; Vital Access Corp, Salt Lake City, Utah) is a surgically implanted titanium device designed to facilitate cannulation of uncannulatable dialysis access arteriovenous fistulas (AVFs) because of excessive depth, aneurysm formation, or tortuosity but that exhibit sufficient flow volume to support hemodialysis. We report the 18-month fistula patency, functionality, and complications of the use of the VWING device.Methods: This retrospective study examined AVF patency, VWING functionality, interventions, and device infections at 18 months after VWING implantation. The study population comprised the eligible patients enrolled in the VWING Salvage of AV Fistula (SAVE) trial.Results: Fifty-four patients were originally enrolled in the SAVE trial, and 35 were enrolled in the follow-up study. At 18 months, when considering surgical or percutaneous interventions at the VWING site(s) only, the primary AVF patency rate was 78%. Interventions elsewhere on the AVF, outside the boundaries of the VWING, resulted in a primary patency rate of 38%. The VWING accounted for 13% loss of AVF primary patency compared with 53% loss from the remaining AVFs. The overall AVF assisted primary patency rate was 91%, and the primary patency rate was 21%. VWING secondary functionality, the continued ability to access the fistula through the VWING using a constant site cannulation technique, was 65%. During the 12 months after the SAVE Study 80% of patients did not require the use of a central venous catheter. Eleven VWING devices were removed from eight patients, all but one for cannulation difficulties. One device was removed during the SAVE trial because of infection. No device or systemic infection was identified in the ensuing 12 months, for an overall systemic infection rate of 0.014 per device-year. An intervention rate of 0.32 per deviceyear was required to maintain device functionality during the 18-month follow-up period.Conclusions: Implantation of the VWING device is a safe and effective means of establishing hemodialysis access in an otherwise functional but uncannulatable AVF. The device infection rate is acceptably low.

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%.

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 mu g (n = 51), or PRT-201 at 30 mu g (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-mu g, and 30-mu g patients retained PP. The risk of PP loss was nonsignificantly reduced for 10 mu g (hazard ratio [HR], 0.69; P = .19) and 30 mu g (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-mu g, and 30-mu g RCFs retained PP. The risk of RCF PP loss was nonsignificantly reduced by 10 mu g (HR, 0.59; P =.18) and significantly reduced by 30 mu g (HR, 0.37; P = .02) vs placebo. At 1 year, 77%, 81%, and 83% of placebo, 10-mu g, and 30-mu g patients retained SP. The risk of SP loss was nonsignificantly reduced for 10 mg (HR, 0.79; P = .61) and 30 mu g (HR, 0.76; P = .55) vs placebo. In the subset with RCFs, 65%, 82%, and 90% of placebo, 10-mu g, and 30-mu g patients retained SP at 1 year. The risk of RCF SP loss was nonsignificantly reduced for 10 mg (HR, 0.45; P = .19) and 30 mu g (HR, 0.27; P = .08) vs placebo. At month 3, 67%, 87% (P = .03), and 92% (P < .01) of the placebo, 10-mu g, and 30-mg 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-mu g, and 30-mu g 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-mu g dose was associated with increased PP in the subset with RCF.

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.

Immunoglobulin G (IgG) subclasses IgG1 (G1) and lgG3 (G3) can induce complement dependent cytotoxicity (CDC) and bind to Fc receptors (FcR), which induces phagocytosis and antibody dependent cellular cytotoxicity. In contrast, IgG2 has low CDC activity, lgG4 (G4) has no CDC activity, and neither binds high affinity FcR. Seven transplant recipients were analyzed for G1- G4 human leukocyte antigen (HLA) donor-specific antibodies (DSAs); six had active rejection and one had stable function. Patients with rejection had equal numbers of DSAs, which were G1 and G3, but no G4. The predominant DSAs were directed against HLA Class II proteins. Even with successful anti-rejection therapy, DSA persisted, albeit in several instances with lowered levels. Our findings are consistent with the presence of CDC-inducing G1 and G3 subclass DSAs during rejection. One heart transplant recipient followed for over 42 months had consistent, continuous G4 HLA DSA and stable function. We hypothesize that the presence of G4 DSA in the heart transplant recipient is akin to the allergen specific G4 that has been found in allergic desensitization tolerance, controlled by regulatory T-cells, and that manipulating G4 class switching through HLA antigen desensitzation could produce a tolerant state.

Contrary to the way transplant surgery is portrayed on popular television shows, transplantation in the real world is less glamorous, less exciting, and when done correctly, quite routine. While the success or failure of the surgical procedure rests primarily on the shoulders of the transplant surgeon, the ingredients necessary to create a positive outcome rely on a team of specialists from a variety of fields. Matching the right patient with the right organ is an art developed by years of experience. The decisions involved in offering kidneys to patients, while highly regulated, are influenced greatly by nephrologists, surgeons, transplant coordinators, and social workers. Organ allocation is more fully discussed in Chapter 5.

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.

Nonadherence (NA) is a difficult posttransplant problem that can lead to graft loss. A retransplant is controversial because of a fear of recurrent NA. We reviewed our center's data base and identified 114 kidney recipients who lost their graft to overt NA; of this group, 35 (31%) underwent a retransplant after a thorough reevaluation. We compared this NA retransplant group to a control group of second transplant recipients who did not lose their first graft to overt NA (non-NA) (n = 552). After 8 years of follow-up, we found no significant differences between the groups in actuarial graft or patient survival rates, renal function, or the incidence of biopsy-proven chronic rejection. However, 5 of 35 (14%) NA recipients versus 10 of 552 (2%) non-NA recipients lost their retransplant to NA (p = 0.0001). Twenty of 35 (57%) of the NA group exhibited repeat NA behavior after retransplant. We conclude that prior graft loss to NA is associated with increased graft loss to NA after retransplant. However, the majority of NA retransplant recipients did well-with overall long-term outcomes similar to those of the non-NA group. With careful patient selection and aggressive intervention, prior overt NA should not be an absolute contraindication to retransplantation.

Objective The search for an effective post‐tonsillectomy analgesic has been disappointing. This study tests the hypothesis that rofecoxib improves pain scores in children for 72 hours post‐tonsillectomy when compared to hydrocodone with acetaminophen elixir. Study Design Prospective, randomized, double‐blind, active comparison of postoperatively administered rofecoxib or hydrocodone with acetaminophen in 60 healthy children scheduled for elective tonsillectomy. Subjects and Methods Sixty ASA I and II children scheduled for elective tonsillectomy were enrolled to receive either rofecoxib or hydrocodone with acetaminophen, commencing at discharge from day surgery. Active and passive pain scores and side effects were assessed for 3 days. Results and Conclusion Rofecoxib significantly reduced active pain scores at all time intervals after 6 hours following surgery when compared to hydrocodone with acetaminophen without detectable differences in adverse effects. This difference was not apparent in passive pain scores. A review of analgesic strategies is presented. Study results and review of the literature support the development of pediatric formulations of NSAIDs with greater COX‐2 selectivity to improve postsurgical pain relief for children.