title: Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics.
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/m. 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 degrees 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.
authors.affiliation: Department of Surgery, Indiana University, Indianapolis, IN, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Vieira
authors.forename: Avinash
authors.initials: A
authors.lastname: Agarwal
authors.forename: Benita K
authors.initials: BK
authors.lastname: Book
authors.forename: Richard A
authors.initials: RA
authors.lastname: Sidner
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bearden
authors.forename: Howard M
authors.initials: HM
authors.lastname: Gebel
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Roggero
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Fineberg
authors.forename: Timothy
authors.initials: T
authors.lastname: Taber
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kraus
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
mesh_terms: D000328:Adult; D000906:Antibodies / Q000032:analysis / Q000187:drug effects*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D000069283:Rituximab; D018183:Transplantation Chimera / Q000276:immunology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D006680:HLA Antigens; D000069283:Rituximab