Newsletter 4:2019

November 1, 2019

Dear Colleague

First of all, I would like to thank those of you who have already filled out and returned this year’s cancer questionnaire. The CTS cancer analyses underline the importance of international cooperation, allowing, in spite of low incidence rates, reliable statements about neoplasms that occur in transplant recipients. The last CTS report on this topic appeared in the March 2019 issue of Transplantation (Unterrainer et al. Pretransplant cancer in kidney recipients in relation to recurrent and de novo cancer incidence post transplantation and implications for graft and patient survival. Transplantation 103:581–7, 2019, doi: 10.1097/TP.0000000000002459).

In this newsletter we address another frequently discussed topic, namely the impact of cold ischemia time in deceased-donor kidney transplantation. Figure 1 illustrates the distribution of cold ischemia times in transplantations that were performed during 2000–2017 and reported to the CTS. The arithmetic average of ischemia time was 16.4, the median 16 and the inter-quartile range 12–20 hours.

In the literature, statements about the impact of the duration of cold storage and its influence compared to that of other confounders contradict each other. Debout et al. reported an increase in the risk of graft loss with each additional hour of cold ischemia time (Kidney Int. 87: 343–9, 2015, doi: 10.1038/ki.2014.304) whereas in several other studies no major effects were observed below a certain number of hours. The last large-scale CTS analysis of this topic was published in 2007 (Opelz G and Döhler B. Multicenter analysis of kidney preservation. Transplantation 83:247–53, 2007; doi:10.1097/01.tp.0000251781.36117.27). In this paper, in which kidney transplantations from 1990 to 2005 were analyzed, cold storage up to 18 hours did not show a detrimental effect on outcome and, importantly, even short ischemia in this range did not diminish the beneficial effect of HLA-A+B+DR matching.

Another 12 years have passed and, stimulated by ongoing discussion, we found it of interest to investigate whether the statement that the influence of cold ischemia time is marginal below a certain time interval is still valid or whether, as maintained by others, the impact of ischemia on graft survival is superior to that of HLA matching.

137,653 kidney transplantations from the years 2000–2017 were analyzed. Pediatric recipients and transplantations in which the recipient as well as the donor were ≥65-year-old were not included to avoid the interference of age-related allocation algorithms in the univariate Kaplan-Meier analyses. Also, multi-organ transplantations and transplants with cold ischemia times exceeding 48 hours (a small fraction of the total) were excluded.

Already in the 2007 publication, we had pointed to the general trend of declining cold ischemia times over the years. As illustrated in Figure 2, this continuing trend is evident also during the 2000–2017 period. The mean ischemia time decreased from 18.5 hours in 2000 to 16.1 hours in 2008 and to 14.8 hours in 2017. The fraction of patients with an ischemia time exceeding 24 hours dropped from 16.1 % in 2000 to 7.9 % in 2017.

The influence of equidistant 3-hour intervals of cold ischemia time is illustrated in Figure 3. In this univariate analysis, a linear increase of graft loss with longer ischemia was evident during the 4–24-hour interval. Remarkable was the inferior outcome with an ischemia time below 4 hours and the lack of significant differences from 22 hours upwards.

Cold ischemia time was associated with important confounders, such as age, sex, transplant year, graft number, country, panel reactive antibodies and HLA mismatches. For example, among recipients of transplants with 4–6 hours ischemia time, only 8.8 % had 0–1 and 22.4 % 5–6 HLA mismatches, whereas among recipients of transplants with 13–15 hours ischemia time, 15.7 % had 0–1 and 16.6 % 5–6 mismatches. To take these effects into account, we performed multivariable Cox regression analyses. The 4–6-hour interval, which was associated with the best survival rate, was chosen for reference. The cold ischemia time, HLA match, panel reactive antibodies, recipient and donor race, age and sex, transplant year, graft number, country, time on dialysis, recipient treatment for diabetes, recipient history of smoking, original disease, CMV status and prophylaxis, donor history of hypertension, marginal donor, cause of donor death, immunosuppressive medication (cyclosporine, tacrolimus, mTOR inhibitors, mycophenolates, azathioprine, steroids, induction therapy) and preservation technique were considered as confounders.

As shown in Figure 4, an approximately linear progression of the influence of cold ischemia time was visible for the 4–24-hour interval. However, the differences associated with the intervals 7–9, 10–12, 13–15 and 16–18 were small and did not reach significance. When the 4–24-hour interval was analyzed as a whole, a 29 % increase of graft loss was observed from 4–6 to 22–24 hours (hazard ratio [HR] 1.29, 95 % confidence interval [CI] 1.17–1.42, P<0.001).

HLA-A+B+DR matching had a stronger influence on outcome than cold ischemia time (Figure 5). As compared to the above mentioned 29 % increase of graft loss from 4–6 to 22–24 hours cold ischemia time, a 41 % increase of graft loss was found from zero to six mismatches (HR 1.41, 95 % CI 1.29–1.54, P<0.001).

In previous CTS publications we reported repeatedly on the continuously increasing donor age and the growing number of expanded criteria donors. It is widely believed that the influence of cold ischemia time is stronger on transplants from expanded criteria donors. As illustrated in Figure 6, no major differences exist regarding the impact of cold ischemia time and HLA matching on kidneys from expanded or standard criteria donors. On the contrary, the influence of cold ischemia time as well as HLA matching appeared to be even weaker on kidneys from expanded criteria donors when patients with the best outcome, namely 4–6 hours of cold ischemia or zero HLA-A+B+DR-mismatches, were excluded.

The next shipping date for the DNA and Serum Studies is

November 18/19, 2019.

As we are approaching the end of another year, on behalf of our team I would like to thank you all for your support of the Collaborative Transplant Study. Please continue contacting us with ideas for CTS analyses. Based on suggestions from your side, several important publications could be accomplished during the last years using the comprehensive database of CTS.

Sincerely yours,

Caner Süsal