Protocols for apheresis in treating heart/kidney transplant rejection

A physician in Michigan is wanting to gather data regarding apheresis practices in treating heart/kidney transplant rejection. She is particularly looking for any institutions that may be willing to share their protocols that she can compare to what she calls a "rather loose set of rules" at her own institution. Her facility does require biopsy-proven humoral rejection prior to initiating plasmapheresis. The initial plan is made for 5 treatments every other day, followed by re-evaluation. Their clinicians appear to be in her opinion very conservative, sometimes requiring 2-3 negative biopsies before discontinuing treatment. More troubling to her is the initiation of ATG during apheresis. Despite their objections and concerns, ATG is given concurrently during the course of apheresis. Each of their last 2 patients received 7 days of ATG and 4 apheresis procedures during the course of the same week. She knows of at least one other institution in which a course of 3 apheresis procedures is performed, followed by a course of ATG, which seems more reasonable to her.

The Michigan colleague's questions are:

• What are the criteria for initiating and stopping apheresis?
• What is the frequency of apheresis and number of procedures?
• If ATG is given, is it given concurrently, or are there protocols stipulating a short course of apheresis, followed by ATG?

The following responses have been received.

ADDENDA July 13, 2004

1. Ronald E. Domen, MD, Medical Director, Blood Bank and Transfusion Medicine, Milton S. Hershey Medical Center at Penn State University College of Medicine (attribution used with permission) reports that their post-transplant heart protocol for humoral rejection is three plasma exchanges over one week, then maintenance plasmapheresis with each biopsy for 1-3 months. HLA panel reactive antibody (PRA) screening is also performed. Dr. Domen states, "As an example, our most recent case had plasma exchanges performed on May 4, 5, and 7 (post-transplant); then, with each followup biopsy on May 17, 24, and June 2 (patient is doing well). I am not aware of any routine use of ATG but, in general, our colleagues in transplant (and other services) usually follow our recommendations when it comes to concerns related to concurrent drug administration and removal."

2. Richard S. Newman, M.D., Associate Clinical Professor of Pathology, University of California Irvine Medical Center (attribution used with permission) states that he has been most impressed by the protocols developed at Johns Hopkins for treating kidney transplant rejection. Dr. Newman reports, "These protocols are the most detailed I have seen, and they seem to be backed by the highest success rate of any centers whose publications I have seen.  Recently published data indicates that these patients often develop DONOR-DIRECTED HLA antibodies in their serum (detected by ELISA or flow cytometry) at least a week before their biopsies even become positive by C4d staining (Zachary AA, et al. Transplantation. 2003 Nov 27;76(10):1519-25). I am now trying to encourage all of our nephrologists and our kidney transplant surgeons, as well as our pathologists that read out our kidney biopsies, to request tests for HLA antibodies on any patient being considered for a kidney biopsy to rule out rejection. I especially encourage this in any patient with a rising creatinine, which may indicate rejection. If a donor-directed antibody is detected in the face of an unexplained rising creatinine, I would seriously consider plasmapheresis even before a biopsy has been completed. The frequency of plasmapheresis is every other day, followed by IV cytogam. (Montgomery RA, Zachary AA, et al. Transplantation. 2000; 70(6):887-95; and Sonnenday CJ, et al. Transplant Proc. 2002 Aug;34(5):1614-6.). In Hopkins' short report from 2000, rescue required anywhere from 2 to 31 procedures. In Hopkins' 2003 report, three end points were used to stop plasmapheresis: 1) elimination of (serological) donor-directed HLA antibody, 2) establishment of good graft function, or 3) graft failure. At our medical center, we recently had a case of acute graft rejection 2 years post-transplant which we treated until the creatinine returned to the patient's baseline pre-rejection; only 3 procedures were required in this particular case. Hopkins only uses ATG in cases in which there is significant rejection ("Banff 2B (I suspect they really mean IIB) or worse" in the biopsy specimen according to a handout from one of their most recent writings on the subject. (For the Banff classification, please see Racusen LC, et al. Am J Transplant 2003; 3(6):708-14). I believe Hopkins gives ATG concurrently with plasmapheresis."

ADDENDA Aug. 2, 2004

3. A colleague at Johns Hopkins reports that they have extensive experience in supporting kidney transplantation with plasmapheresis. She adds that Dr. Newman (#2 above) did a wonderful job of summarizing their experience. As confirmation on the ATG issue, indeed on occasion ATG may be given during a course of plasmapheresis. However, she cautions that ATG should be given soon AFTER a pheresis procedure, and NOT immediately before.

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Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator