Newsletter 4:2022

November 1, 2022

Dear Colleague

In this newsletter, we would like to revisit the impact of pre-transplant HLA antibodies on graft survival in kidney transplantation. Due to its relevance for short- and long-term transplant outcomes, the percentage of lymphocytotoxic panel-reactive antibodies (CDC-PRA) of the last serum before transplantation has been an important component of multivariate transplant analyses for decades. In the meantime, single antigen bead (SAB) assays have become the predominant assays used for detecting HLA antibodies. Therefore, on current CTS questionnaires, the percentage of positive SAB as well as their specificities against HLA class I and II are recorded in addition to the CDC-PRA value. In studies with data collected over several decades such as the CTS, the question arises how the two test methods compare when evaluated together regarding their correlation with graft survival.

SAB test results have been recorded in the CTS database since the year 2008. All kidney transplants performed from 2008 to 2021 for which a pre-transplant CDC or SAB value was available were analyzed in this newsletter. After exclusion of multiorgan transplants, 120,676 kidney transplants could be included in the analysis: 92,244 with CDC and 40,868 with SAB; in 12,436 transplants, data on both tests were reported. Kaplan-Meier analyses with log-rank test were performed for 5-year death-censored graft survival.

Of the 92,244 patients with available CDC values, three-quarters (75.0%) had no antibodies and about one-sixth (16.0%) had a PRA value between 1% and 10%. In scientific literature, there is no uniform categorization of the ‘immunization degree’ based on CDC-PRA values. For the definition of a ‘sensitized patient’, various cut-off values of up to 50% can be found, starting from a PRA cut-off of >0%. Even for the widely discussed ‘highly sensitized patients’, there are different definitions by different centers.

Figure 1 shows how the graft failure rate increases with increasing CDC-PRA values. In the worst group with a CDC-PRA of more than 80%, there is almost a double risk of graft loss compared with the group of non-sensitized patients with 0% reactivity (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.72–2.29, P<0.001). For more in-depth analysis of sensitized subpopulations, four categories of CDC-PRA were defined based on Figure 1: non-sensitized (=0%), lowly sensitized (1–25%), moderately sensitized (26–80%), and highly sensitized (>80%) patients.

Besides blood transfusions, pregnancies and previous transplantations are well-known causes of alloimmunization in transplant recipients. Accordingly, stratification of the analyses with respect to recipient sex and first or re-transplantation was performed.

As expected, the proportion of sensitized patients with CDC-PRA >0% is higher in female recipients (29.1%) than in male recipients (22.7%), and the proportion of highly sensitized with >80% panel reactivity is twice as high in females (2.07% vs. 1.02%). Figure 2 shows that the influence of antibodies on graft survival is greater in male than in female recipients. The hazard ratios of graft loss comparing highly sensitized patients to non-sensitized patients are 2.36 (95% CI 1.95–2.85, P<0.001) in male and 1.65 (95% CI 1.33–2.05, P<0.001) in female recipients. In the absence of specific data, one might interpret this to suggest that highly reactive antibodies induced by pregnancies may not be quite as deleterious as those induced by rejected transplants.

The differences in the proportion of sensitized patients are even larger when first and retransplantations are compared. The proportion of sensitized patients with any evidence of antibodies increases from 21.3% in first graft recipients to more than half (52.7%) in retransplantations, and that of highly sensitized patients with >80% reactivity from 0.7% to 6.5%. In highly sensitized retransplanted patients, there is a 92% increase in the graft failure rate compared with the 0% non-sensitized group (HR=1.92, 95% CI 1.59–2.32, P<0.001), whereas in first transplants the increase of transplant failure from the 0% group to the >80% group is only 42% (HR=1.42, 95% CI 1.11–1.82, P=0.006; Figure 3).

SAB test results. Figure 4 illustrates that antibodies against HLA class I and class II have approximately the same detrimental effect on death-censored graft survival. Therefore, we used the mean of the percentages of HLA class I and class II positive beads for further analyses.

Although the SAB test is considered to be much more sensitive than CDC, the number of sensitized patients with reactivity >0% increases by only 2.8% percentage points and that of highly sensitized patients even decreases from 1.4% to 1.1%. The largest difference is found for the group of moderately sensitized patients with 26–80% reactivity, whose proportion almost doubles with the SAB assay (Figure 5).

Using the same categorization, Figure 6 shows the comparison of the impact of CDC and SAB values on 5-year death-censored graft survival. The two graphs (A) and (B) of Figure 6 show very similar results, although the differences appear somewhat smaller for the SAB categories. The 5-year death-censored graft survival rates are the same for the non-sensitized patients at 88.9% and differ by less than one percentage point for the highly sensitized patients. Thus, it appears quite justified to use this categorization in multivariate analyses with PRA as a confounder, regardless of whether the test technique was CDC or SAB.

Calculated/virtual PRA (cPRA/vPRA) is an important parameter in the organ allocation procedure nowadays. With approximately 4,000 cPRA/vPRA values currently being available in the CTS database, we are in the process of collecting more data to obtain a solid evaluation regarding the impact of different immunization categories of cPRA/vPRA on graft survival. An analysis of pre-transplant donor-specific antibodies (DSA) determined with SAB was already presented in CTS Newsletter 2:2020.

40 years have passed since Gerhard Opelz, Heidelberg, initially together with 20 friends from other transplant centers, launched the international Collaborative Transplant Study. Many centers have joined the CTS during this time. It is wonderful to see that at present more than 400 transplant centers in 42 countries around the world are actively participating in this voluntary scientific multicenter study. In the meantime, the database has grown to include more than 850,000 kidney, liver, heart, lung, and pancreas transplants with more than 5 million years of follow-up. However, it is not only the volume of the data that is remarkable, but especially the quality of the data thanks to the enthusiasm and dedication of all those involved. Everyone who participated in this voluntary study can be proud of it.

With your invaluable support over four decades, the CTS has been able to provide our community with numerous findings which helped to improve our understanding of the mechanisms of graft rejection and the management of transplanted patients. What are the perspectives of the CTS for the coming years? As graft and patient survival have markedly improved over the last decades due to great achievements in transplant diagnostics and treatment, infections, cancers and other late ‘side’ effects have attracted higher attention in the care of long-surviving transplanted patients. We hope that in our future work, with your continued help, we will be able to focus our data collection and analysis on these topics which definitely need to be addressed based on a very large transplant cohort with a long observation time as provided by the CTS. We are convinced that a fruitful and rewarding collaboration can be maintained as the foundation of our joint efforts in contributing to the advancement of transplantation science, as we have experienced it during the last 40 years.

The next shipping date of Serum and DNA
for the Biomarker Studies is
January 13, 2023.

Thank you all for your continued support over the last 40 years and best wishes,


Yours,

Gerhard Opelz	Caner Süsal	Hien Tran