Newsletter 1:2002

March 1, 2002

Because of the good success rate observed with kidney transplants from living unrelated donors, there is renewed discussion concerning the importance of minimizing cold ischemic preservation of cadaver kidneys. The hypothesis has been advanced that ischemic damage of kidneys induced by prolonged cold storage may increase the immunogenicity of donor organs. Consequently, minimal cold ischemia, presumably associated with less ischemic damage, is believed to render donor organs less immunogenic. According to this reasoning, HLA matching would not be necessary for donor kidneys subjected to only short preservation times. If confirmed, the implications would be far reaching, both from a practical as well as from a conceptual point of view.

Surprisingly, when graft survival of transplants reported to CTS was analyzed in relation to the duration of cold ischemia, the result did not show the expected "the shorter, the better" association. While there was a strong general trend towards decreased graft survival with prolonged kidney preservation, the shortest ischemia category (0-6 hours) did not have the best outcome. Statistically, graft survival in this group was significantly inferior to transplants after 7-12 or 13-24 hours of ischemia (p<0.0001, Figure 1).

A likely reason for the difference was found in the distribution of HLA matches. Among the 0-6 hour transplants, there were only 8% grafts with 0-1 HLA-A+B+DR mismatches and 23% with 5-6 mismatches. In contrast, among transplants after 7-24 hours of cold ischemia, there were 15% 0-1 mismatches and 13% 5-6 mismatches (p<0.0001).

An analysis of HLA matching in first cadaver kidney transplants with donor kidney exposure to 0-12 hours of cold ischemia is shown in Figure 2.

The result clearly contradicts the hypothesis that short cold ischemia makes HLA matching unnecessary. In spite of a short ischemic preservation time, the impact of HLA compatibility on graft outcome was highly significant (p<0.0001).

The report in the last newsletter on HLA anti-class I and anti-class II antibodies generated numerous inquiries. As follow up, we would like to present two graphs which depict an important difference between the effect of presensitization in first transplants and retransplants. As shown in Figure 3, in recipients of first kidney grafts the effect of presensitization was deleterious only if antibodies against both HLA class I and class II (I+II+) were present.

Interestingly, in retransplants, presensitization against HLA class I in the absence of antibodies against HLA class II (I+II-) also had a damaging effect (Figure 4).

This points to an important qualitative difference between anti-class I antibodies produced in response to transfusions or pregnancies (first graft recipients) and antibodies produced as a result of rejection of a previous kidney graft (retransplants). The surprisingly good success rate in first graft recipients with I+ II- antibodies was based on an analysis of 159 patients and appears quite solid (Figure 3). Equally surprising is the absence of any deleterious effect in first or retransplants when preformed anti-HLA antibodies were directed exclusively against class II and not class I (I-II+).

It is highly unlikely that the poor graft outcome observed in patients with anti-class I and anti-class II reactivity (I+II+) was due to the use of insensitive crossmatch techniques. Sera containing both classes of antibodies usually react strongly in the standard lymphocytotoxicity assay. It therefore appears more likely that the presence of antibodies against both classes signals a state of high immunologic responsiveness. Rather than concentrating on the use of more sensitive crossmatch techniques, providing these patients with HLA well-matched kidneys promises to be more effective. As pointed out in the previous newsletter, we did not observe a deleterious effect if class I+II+ antibody-positive patients received kidneys with only 0 or 1 HLA-A+B+DR mismatch.

A good two-dozen centers are currently using the CTS TaXi software for maintaining their transplant records and reporting to CTS. We are pleased that no major problems have occurred. Please contact us if you have suggestions for improvements. I would like to repeat that even centers reporting to CTS in the traditional way can obtain data downloads to a local PC using TaXi. This allows data export to Excel or other analysis software for the preparation of annual center statistics, etc. If you are interested in this option, request a data download by e-mail. There is no charge for this service.

Although the CTS website has become very popular, many participants have remarked that the generation of PowerPoint presentations from website graphs was awkward and time consuming. The situation has now been improved. A new download mode allows the direct inclusion of CTS website graphs into your PowerPoint presentations. The new function is available for the more than 400 general website graphs as of March 1. For your individual center-specific analyses, it will become operational starting from the June 1, 2002, CTS update cycle. Instructions for use of this new feature are provided on the website.

The next shipping date for the DNA typing project is

May 21, 2002

As usual, be sure to indicate on the shipping papers that the samples are intended for an international research study, not hazardous, and free of viral infection. Please inform us of the shipping details by fax or e-mail.

If you would like to send sera for the sCD30 and anti-HLA class I/class II project, these can be included with your DNA study shipment. If you intend to exclusively send material for the serum project and not for the DNA study, we would appreciate it if you would post your parcels earlier in order to avoid a logistical overload at our end.

These CTS laboratory projects are very interesting and productive. They are unique in that complicated analyses are performed that would be impossible without the generous collaboration of many transplant centers. Credit is due to all those who are contributing. Because the projects are ongoing, it is not too late to join. If you have questions, please call or send me an e-mail.

Last but not least, I would like to make my yearly appeal for honest and accurate reporting. This is meant primarily for new staff members who may not be familiar with the CTS philosophy. Our objectives are strictly scientific and we depend on data input that is as accurate as possible. Please do not jeopardize the sincere efforts of all other study participants by not following this important guideline. Thank you for your support!

Sincerely yours,

Gerhard Opelz