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Kidney Week

Abstract: TH-PO330

Perivascular Administration of Sirolimus During Arteriovenous Access Surgery: Delivering Therapeutic Outcomes Minimizing Risk of Systemic Side Effects

Session Information

  • Vascular Access - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

  • 704 Dialysis: Vascular Access

Authors

  • DeVita, Maria V., Lenox Hill Hospital- Northwell Health System, New York, New York, United States
  • Iyer, Sriram, Lenox Hill hospital , New York, New York, United States
Background

Unmitigated cell proliferation at and around the vascular anastomosis resulting in flow limiting stenosis is an important cause of access dysfunction. mTOR (mammalian target of rapamycin), controls cell growth, proliferation and survival. Oral sirolimus is an immunosuppressant. Sirolimus (cytostatic) delivered locally to site(s) of vascular injury downregulates mTOR and inhibits cell proliferation by causing cell cycle arrest between G1 & S phases. Perivascular delivery of sirolimus is a novel method of harnessing its anti-proliferative effect with the intent of improving access outcomes. A prior Paclitaxel (cytotoxic; anti-mitotic) perivascular AVG study was prematurely terminated because of excessive infections.

Methods

Data from 56 AVF pts (includes open label subset of a US Phase 3 randomized, data safety monitored study; 55 ESRD) and 12 AVG pts (Paulson NDT 2012) treated with perivascular sirolimus at & around the anastomosis (AVF) & venous anastomosis (AVG) delivered from a collagen matrix (SirogenTM Vascular Therapies, Cresskill NJ) were analyzed. Access functional outcomes were evaluated using 2 needle cannulation for dialysis. Blood drawn at protocol specified time points yielded pharmacokinetic (PK) data.

Results

One AVF wound dehiscence required secondary suturing & local treatment with subsequent healing & preserved 12 mo. fistula primary functional patency; no cases of local infection. PK: Sirolimus levels peak ~6 hrs. after start of drug delivery (4-5ng/ml), declines to <1ng/ml by 96 hrs. PK profile for AVF and AVG are similar. Key efficacy metrics are tabulated.

Conclusion

1. Perivascular sirolimus delivery with targeted high local concentrations of sirolimus achieves therapeutic effectiveness without increasing risk of problems with wound healing and infection.
2. Systemic release of sirolimus is negligible and levels are sub-therapeutic for systemic immunosuppression.
3. The US Phase 3 study is nearing enrollment completion.

Access TypeNMaturationPrimary PatencySuitability for Dialysis
6 mos.12 mos.6 mos.12 mos.
AVF5686%62%52%78%72%
AVG12-82%73%82%73%

Funding

  • Commercial Support