Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics

Carlos A. Vieira, Avinash Agarwal, Benita K. Book, Richard A. Sidner, Christopher M. Bearden, Howard M. Gebel, Anthony L. Roggero, Naomi S. Fineberg, Tim Taber, Michael Kraus, Mark D. Pescovitz

Research output: Contribution to journalArticle

219 Citations (Scopus)

Abstract

Background. Preformed HLA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong patient waiting time for kidney transplantation. We hypothesized that rituximab (RTX) could reduce PRA via B-cell depletion. This initial study reports the safety, pharmacokinetics, and pharmacodynamics of RTX in patients with end-stage renal failure. Methods. The study was an investigator-initiated single-dose, dose-escalation phase I trial of RTX in chronic dialysis patients (PRA >50%). It was approved by the Institutional Review Board and the Food and Drug Administration. Nine subjects were treated with a single dose of RTX (n=3 per group) at 50, 150, or 375 mg/m2. Peripheral lymphocyte cell surface markers and HLA Ab levels (%PRA and titers) were tested using flow cytometry. Results. There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7°C) during infusion. At 2 days after RTX therapy, there was depletion of CD19+ cells (pre-RTX 181±137 vs. post-RTX 12±5.6, P=0.006). In 2 (22%) of 9 subjects, there was no appreciable change in PRA. Among the other seven patients, one had a decrease in PRA from 87% to 51% with a concurrent decrease in fluorescence intensity; five patients had changes in histogram architecture suggesting loss of antibody specificity; and one patient had a fourfold decrease in PRA titer from 1:64 to 1:16 at 6 months after treatment. In addition, one of the seven patients converted a donor-specific crossmatch to negative and underwent a successful living donor kidney transplantation. Conclusions. RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.

Original languageEnglish
Pages (from-to)542-548
Number of pages7
JournalTransplantation
Volume77
Issue number4
DOIs
StatePublished - Feb 27 2004

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Kidney Transplantation
Anti-Idiotypic Antibodies
Pharmacokinetics
Safety
Antibodies
Dialysis
Rituximab
Histoplasmosis
Antibody Specificity
Living Donors
Research Ethics Committees
United States Food and Drug Administration
Infection
Chronic Kidney Failure
Flow Cytometry
B-Lymphocytes
Fever
Catheters
Fluorescence
Research Personnel

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation : 1. Safety, pharmacodynamics, and pharmacokinetics. / Vieira, Carlos A.; Agarwal, Avinash; Book, Benita K.; Sidner, Richard A.; Bearden, Christopher M.; Gebel, Howard M.; Roggero, Anthony L.; Fineberg, Naomi S.; Taber, Tim; Kraus, Michael; Pescovitz, Mark D.

In: Transplantation, Vol. 77, No. 4, 27.02.2004, p. 542-548.

Research output: Contribution to journalArticle

Vieira, CA, Agarwal, A, Book, BK, Sidner, RA, Bearden, CM, Gebel, HM, Roggero, AL, Fineberg, NS, Taber, T, Kraus, M & Pescovitz, MD 2004, 'Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics', Transplantation, vol. 77, no. 4, pp. 542-548. https://doi.org/10.1097/01.TP.0000112934.12622.2B
Vieira, Carlos A. ; Agarwal, Avinash ; Book, Benita K. ; Sidner, Richard A. ; Bearden, Christopher M. ; Gebel, Howard M. ; Roggero, Anthony L. ; Fineberg, Naomi S. ; Taber, Tim ; Kraus, Michael ; Pescovitz, Mark D. / Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation : 1. Safety, pharmacodynamics, and pharmacokinetics. In: Transplantation. 2004 ; Vol. 77, No. 4. pp. 542-548.
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abstract = "Background. Preformed HLA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong patient waiting time for kidney transplantation. We hypothesized that rituximab (RTX) could reduce PRA via B-cell depletion. This initial study reports the safety, pharmacokinetics, and pharmacodynamics of RTX in patients with end-stage renal failure. Methods. The study was an investigator-initiated single-dose, dose-escalation phase I trial of RTX in chronic dialysis patients (PRA >50{\%}). It was approved by the Institutional Review Board and the Food and Drug Administration. Nine subjects were treated with a single dose of RTX (n=3 per group) at 50, 150, or 375 mg/m2. Peripheral lymphocyte cell surface markers and HLA Ab levels ({\%}PRA and titers) were tested using flow cytometry. Results. There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7°C) during infusion. At 2 days after RTX therapy, there was depletion of CD19+ cells (pre-RTX 181±137 vs. post-RTX 12±5.6, P=0.006). In 2 (22{\%}) of 9 subjects, there was no appreciable change in PRA. Among the other seven patients, one had a decrease in PRA from 87{\%} to 51{\%} with a concurrent decrease in fluorescence intensity; five patients had changes in histogram architecture suggesting loss of antibody specificity; and one patient had a fourfold decrease in PRA titer from 1:64 to 1:16 at 6 months after treatment. In addition, one of the seven patients converted a donor-specific crossmatch to negative and underwent a successful living donor kidney transplantation. Conclusions. RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.",
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T1 - Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation

T2 - 1. Safety, pharmacodynamics, and pharmacokinetics

AU - Vieira, Carlos A.

AU - Agarwal, Avinash

AU - Book, Benita K.

AU - Sidner, Richard A.

AU - Bearden, Christopher M.

AU - Gebel, Howard M.

AU - Roggero, Anthony L.

AU - Fineberg, Naomi S.

AU - Taber, Tim

AU - Kraus, Michael

AU - Pescovitz, Mark D.

PY - 2004/2/27

Y1 - 2004/2/27

N2 - Background. Preformed HLA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong patient waiting time for kidney transplantation. We hypothesized that rituximab (RTX) could reduce PRA via B-cell depletion. This initial study reports the safety, pharmacokinetics, and pharmacodynamics of RTX in patients with end-stage renal failure. Methods. The study was an investigator-initiated single-dose, dose-escalation phase I trial of RTX in chronic dialysis patients (PRA >50%). It was approved by the Institutional Review Board and the Food and Drug Administration. Nine subjects were treated with a single dose of RTX (n=3 per group) at 50, 150, or 375 mg/m2. Peripheral lymphocyte cell surface markers and HLA Ab levels (%PRA and titers) were tested using flow cytometry. Results. There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7°C) during infusion. At 2 days after RTX therapy, there was depletion of CD19+ cells (pre-RTX 181±137 vs. post-RTX 12±5.6, P=0.006). In 2 (22%) of 9 subjects, there was no appreciable change in PRA. Among the other seven patients, one had a decrease in PRA from 87% to 51% with a concurrent decrease in fluorescence intensity; five patients had changes in histogram architecture suggesting loss of antibody specificity; and one patient had a fourfold decrease in PRA titer from 1:64 to 1:16 at 6 months after treatment. In addition, one of the seven patients converted a donor-specific crossmatch to negative and underwent a successful living donor kidney transplantation. Conclusions. RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.

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