New apheresis techniques in transplantation

The shortage of organs for transplantation is a global problem and therefore it is of outmost importance to increase the number of donations and improve long term graft survival. As an effort to increase kidney donations, living kidney donors are being increasingly used and both patient and graft survival is superior after living donation compared with kidney transplantations using organs from deceased donors.

If ABO incompatible kidney transplantations can be done, the pool of living kidney donors can theoretically be increased with 30-40%. Until recently ABO incompatible kidney transplantations could only be performed after a reinforced immunosuppressive protocol combined with splenectomy. These reinforced immunosuppressive protocols have had very limited use due to the significant side effects with increased morbidity as well as mortality.

Therefore, in 2001 we introduced a new protocol that allows ABO incompatible kidney transplantation without splenectomy. The protocol includes rituximab to deplete B lymphocytes and to prevent rebound of antibodies post transplant, combined with a new antigen-specific apheresis technique for preoperative depletion of circulating anti-A/B antibodies. The new antigen-specific filter has been evaluated in 15 patients with the conclusion that this new technique is safe and that anti-A/B antibodies were efficiently depleted. The clinical outcome for the 15 patients was equal compared with ABO compatible kidney transplantation.

The implementation of the protocol in other transplant centers revealed significant differences regarding preoperative anti-A/B titer levels using the semi-quantitative hemagglutination technique. Collaborative analysis showed that the differences were method-related due to the high variability of the tube hemagglutination technique. We showed that by standardization of the simple gel microcolumn hemagglutination technique, titer results can be reproducible enough to allow inter-center comparison of clinical results.

Between September 2001 and September 2008, 45 patients have received ABO incompatible kidney transplantations at Karolinska University Hospital Huddinge with the new protocol. The first 20 kidney recipients were compared with a group of ABO compatible living donor kidney recipients. Mean follow-up was 3 years and the study showed that clinical outcome is similar after ABO incompatible kidney transplantation with this protocol compared with ABO compatible kidney transplantation, both short-term and long-term.

The short term graft survival after kidney transplantation has improved much over the last decades but long term graft survival is still poor. In a pilot study, seven consecutive patients with biopsy-proven ongoing acute cellular rejections, which did not respond to conventional anti rejection treatment, were successfully treated with extracorporeal photopheresis (ECP), an immunomodulatory apheresis treatment. In a case control study with a 3-year follow up we aimed to investigate if prophylactic ECP can prevent rejection and improve clinical outcome after kidney transplantation. Because our patient groups are small, we regard the study mainly as a pilot study of safety. Event-free survival time was not different in the two groups and no ECP-related side effects were noted. An adaptive immune response with a tolerogenic shift was induced during ECP treatment with a significant increase of CD4+CD25hiFoxP3+ regulatory T cells. These two approaches to combat the organ shortage a) will increase the number of living kidney donations and b) shows promise as a tolerogenic immunomodulatory therapy.

List of scientific papers

I. Tydén G, Kumlien G, Fehrman I (2003). Successful ABO-incompatible kidney transplantations without splenectomy using antigen-specific immunoadsorption and rituximab. Transplantation. 76(4): 730-1
https://pubmed.ncbi.nlm.nih.gov/12973118

II. Kumlien G, Ullström L, Losvall A, Persson LG, Tydén G (2006). Clinical experience with a new apheresis filter that specifically depletes ABO blood group antibodies. Transfusion. 46(9): 1568-75
https://pubmed.ncbi.nlm.nih.gov/16965585

III. Kumlien G, Wilpert J, Säfwenberg J, Tydén G (2007). Comparing the tube and gel techniques for ABO antibody titration, as performed in three European centers. Transplantation. 84(12 Suppl): S17-9
https://pubmed.ncbi.nlm.nih.gov/18162980

IV. Genberg H, Kumlien G, Wennberg L, Berg U, Tydén G (2008). ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up. Transplantation. 85(12): 1745-54
https://pubmed.ncbi.nlm.nih.gov/18580466

V. Kumlien G, Genberg H, Shanwell A, Tydén G (2005). Photopheresis for the treatment of refractory renal graft rejection. Transplantation. 79(1): 123-5
https://pubmed.ncbi.nlm.nih.gov/15714180

VI. Kumlien G, Genberg H, Lundahl J, Winqvist O, Tydén G (2008). Photopheresis as prevention for acute rejection after kidney transplantation a case control study with a 3-year follow-up. [Manuscript]