Bernd Döhler

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200 000 organ transplant recipients. Over a 10‐year period, the risk in renal transplant recipients was 11.8‐fold higher than that in a matched nontransplanted population (p < 0.0001). The majority of lymphomas were diagnosed after the first post‐transplant year. Heart‐lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti‐IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First‐year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post‐transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post‐transplant lymphoma.

Improved Long-Term Outcomes After Renal Transplantation Associated with Blood Pressure Control

Hypertension has a negative impact on long‐term outcomes after renal transplantation. We investigated the effect of a recent decline in blood pressure among renal transplant patients in the Collaborative Transplant Study (CTS) database on long‐term graft and patient survival. CTS data were used to evaluate transplant outcomes in relation to recipient systolic blood pressure (SBP) for 24 404 first cadaver kidney recipients transplanted between 1987 and 2000. Patients whose SBP was >140 mmHg at 1 year posttransplantation but controlled to ≤140 mmHg by 3 years had significantly improved long‐term graft outcome compared with patients with sustained high SBP to 3 years (RR 0.79; CI 0.73‐−0.86; p < 0.001). Additional examination at 5 years showed that SBP lowering after year 3 was associated with improved 10‐year graft survival (RR 0.83; CI 0.72–0.96; p = 0.01), whereas even a temporary increase in SBP at 3 years was associated with worse survival (RR 1.37; CI 1.19–1.58; p < 0.001). Changes in SBP were paralleled by changes in the incidence of cardiovascular death among recipients younger than 50 but not in older recipients. Lowering SBP, even after several years of posttransplantation hypertension, is associated with improved graft and patient survival in renal allograft recipients.

Effect of Human Leukocyte Antigen Compatibility on Kidney Graft Survival: Comparative Analysis of Two Decades

Background. Based on an analysis of United Network for Organ Sharing data, it was reported that the influence of human leukocyte antigen (HLA) matching in renal transplantation has diminished in recent years, prompting the suggestion that donor kidney allocation algorithms should be revised. Methods. We compared the impact of HLA matching on kidney graft survival during the decades 1985–1994 and 1995–2004 using the data of the Collaborative Transplant Study. Results for the last 5 years (2000–2004) were analyzed separately in addition. Multivariate Cox regression analysis was used to account for the influence of confounders. Results. Our results show that, while graft survival rates have improved overall over time, the relative impact of HLA matching on the graft survival rate has remained strong and highly significant. Both the need for posttransplant rejection treatment and the graft survival rates showed statistically highly significant associations with HLA matching regardless of the interval analyzed (P<0.001). Conclusions. We conclude that HLA mismatches significantly influence the outcome of kidney transplants and that kidney exchange programs for the purpose of achieving better HLA matches continue to be meaningful.

Identification of Highly Responsive Kidney Transplant Recipients Using Pretransplant Soluble CD30

The identification of high immunologic responders is desirable for the selection of appropriate immunosuppressive regimens. With the collaboration of 29 transplant centers in 15 countries, we investigated whether the pretransplant serum content of soluble CD30 (sCD30), a marker for the activation state of Th2-type cytokine producing T cells, is a useful predictor of kidney graft outcome. Pretransplant sera of 3899 cadaver kidney recipients were tested for serum sCD30 concentration using a commercially available enzyme-linked immunosorbent assay kit. Subsequent kidney graft survival was analyzed. The 5-yr graft survival rate in 901 recipients with a high pretransplant serum sCD30 (> or =100 U/ml) was 64 +/- 2%, significantly lower than the 75 +/- 1% rate in 2998 recipients with low sCD30 (<100 U/ml) (P < 0.0001). High sCD30 was associated primarily with graft loss and not with patient death. The sCD30 effect on graft survival was evident in first transplants as well as in retransplants, in presensitized patients with lymphocytotoxic antibodies as well as in nonsensitized patients, and in patients who received HLA well-matched kidneys as well as in patients who received poorly matched grafts. Recipients with a high pretransplant sCD30 needed significantly more rejection treatment after the first posttransplant year and continued to lose grafts at a higher rate during the 5-yr follow-up period, indicating that pretransplant sCD30 predicts not only the risk of acute rejection but also of chronic allograft nephropathy.

No Improvement of Patient or Graft Survival in Transplant Recipients Treated with Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Type 1 Receptor Blockers: A Collaborative Transplant Study Report

It was reported recently that treatment of kidney transplant recipients with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) is associated with strikingly improved long-term graft and patient survival. This finding has important implications for future posttransplantation therapy recommendations. In an analysis of 17,209 kidney and 1744 heart transplant recipients, an association of treatment with ACEI/ARB with improved transplant outcome could not be confirmed. It is concluded that recommendations for a widespread use of ACEI/ARB treatment in transplant recipients are unwarranted.

Multicenter Analysis of Kidney Preservation

Background. Kidney preservation is an integral part of clinical kidney transplantation. Changes in the use of preservation methods and storage solutions, ischemic preservation times, and the relationship between ischemia time and human leukocyte antigen (HLA) match have not been extensively studied in recent years. Methods. The Collaborative Transplant Study database was used to analyze effects of kidney preservation methods and times. Graft survival and death-censored functional survival were used as endpoints. In all, 91,674 transplants from deceased donors were analyzed using univariate and multivariate methods. Results. Cold storage accounted for more than 95% of kidney preservations from 1990–2005. Increasing ischemia up to 18 hr was not detrimental for graft outcome, whereas the risk of graft failure rose with ischemia 19–24 hr to relative risk (RR) 1.09, 25–36 hr to RR 1.16, and >36 hr to RR 1.30 (P<0.001). As compared to other preservation solutions, University of Wisconsin (UW) solution was associated with significantly better outcome when ischemia exceeded 24 hr. Short ischemia did not eliminate the effect of HLA matching. Kidneys from young or old donors were affected by prolonged ischemia to similar degrees. Pulsatile machine perfusion was not superior to cold storage. Conclusion. Kidneys from deceased donors should ideally be transplanted within 18 hr. Within the 18-hr window, the time of ischemia has no significant influence on graft survival. UW solution should be used if preservation for longer periods is envisioned. HLA matching improves graft survival regardless of length of ischemia.

Long‐Term Prospective Study of Steroid Withdrawal in Kidney and Heart Transplant Recipients

A large prospective study of steroid withdrawal was performed within the framework of the Collaborative Transplant Study to analyze long‐term graft and patient outcome in renal and heart transplant recipients. Steroids were withdrawn no earlier than 6 months posttransplantation. A comparison of 7‐year outcomes in renal transplant recipients (94% receiving cyclosporine; 97% Caucasian) showed a benefit of steroid withdrawal versus steroid continuation in retrospectively matched controls, for graft survival (81.9%± 1.8% vs. 75.3%± 1.2%, p = 0.0001), patient survival (88.8%± 1.5% vs. 84.3 ± 1.0%; p = 0.0016) and death‐censored graft survival (91.8%± 1.3% vs. 87.9%± 1.0%: p = 0.0091). Steroid withdrawal was associated with improved graft survival in heart recipients also (76.2%± 2.4% vs. 66.9%± 1.7%, p = 0.0008). A total of 58.6% of renal recipients and 44.3% of heart recipients never required steroids during follow up. Rates of acute rejection and renal dysfunction did not differ between steroid‐free and steroid‐continuation groups. Steroid withdrawal was associated with significantly improved cardiovascular risk factors compared with steroid continuation. Rates of the development of osteoporosis and cataracts did not differ in the entire patient cohort, but were strikingly lower in patients taken off steroids during the first posttransplant year.

Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients.

Background. It is widely assumed that the graft-enhancing properties of antilymphocyte induction agents and their lymphoma-inducing potential are intimately related. Methods. The Collaborative Transplant Study (CTS) database was used to evaluate graft survival and non-Hodgkin lymphoma at 3 years according to type of induction in 112,122 patients receiving a deceased-donor renal transplant during 1985 to 2004. Results. The relative risk of 3-year graft loss versus no induction was 1.07 (95% confidence interval [CI], 1.01–1.13; P=0.016) with murine anti-CD3 monoclonal antibody (OKT3), 1.03 (95% CI, 0.95–1.11; NS) with antithymocyte globulin (ATG)-Fresenius, 1.18 (95% CI, 1.02–1.35; P=0.021) with ATGAM, 0.74 (95% CI, 0.68–0.81; P<0.001) with Thymoglobulin, and 0.78 (95% CI, 0.72–0.84; P<0.001) with interleukin (IL)-2RA induction. The standardized incidence ratio of lymphoma compared with a similar nontransplant population was 21.5 (95% CI, 15.7–28.8; P<0.001) with OKT3, 4.9 (95% CI, 1.6–11.5; P=0.008) with ATG-Fresenius, 29.0 (95% CI, 12.5–57.1; P<0.001) with ATGAM, 21.6 (95% CI, 14.3–31.2; P<0.001) with Thymoglobulin, 7.8 (95% CI, 4.4–12.9; P<0.001) with IL-2RAs, and 9.4 (95% CI, 8.3–10.6 P<0.001) with no induction. Conclusions. Those agents that offered the highest rates of graft survival were not necessarily associated with the highest risk of lymphoma. Graft survival was significantly improved with Thymoglobulin and IL-2RA induction, whereas lymphoma rates were highest with ATGAM, OKT3, and Thymoglobulin. IL-2RA agents seem to offer the best risk-to-benefit ratio for this patient population overall in terms of graft survival and lymphoma.

Kidney graft survival in europe and the united states: Strikingly different long-Term outcomes

Background Kidney graft survival has never been systematically compared between Europe and the United States. Methods Applying period analysis to first deceased-donor (DD) and living-donor kidney grafts from the United Network for Organ Sharing/Organ Procurement and Transplantation Network for the United States and the Collaborative Transplant Study for Europe, we compared overall and age-specific 1-, 5-, and 10-year graft survival for Europeans and white, African, and Hispanic Americans for the 2005 to 2008 period. A Cox regression model was used to adjust for differences in patient characteristics. Results For the 2005 to 2008 period, 1-year survival for DD grafts was equal (91%) between Europeans and white and Hispanic Americans, whereas it was slightly lower for African Americans (89%). In contrast, overall 5- and 10-year graft survival rates were considerably higher for Europe (77 and 56%, respectively) than for any of the three U.S. populations (whites, 71 and 46%, Hispanic, 73 and 48%, and African American, 62 and 34%). Differences were largest for recipient ages 0 to 17 and 18 to 29 and generally increased beyond 3 to 4 years after transplantation. Survival patterns for living-donor grafts were similar as those seen for DD grafts. Adjusted hazard ratios for graft failure in United Network for Organ Sharing white Americans ranged between 1.5 and 2.3 (all P<0.001) for 2 to 5 years after transplantation, indicating that lower graft survival is not explained by differences in baseline patient characteristics. Conclusions Long-term kidney graft survival rates are markedly lower in the United States compared with Europe. Identifying actionable factors explaining long-term graft survival differences between Europe and the United States is a high priority for improving long-term graft survival.

Soluble CD30 as a predictor of kidney graft outcome.

Background. In the present study, we investigated whether the soluble form of CD30 (sCD30), a marker for T helper 2‐type cytokine‐producing T cells, is increased in sera of potential kidney graft recipients. We also investigated whether the pretransplantation serum sCD30 content is related to kidney graft survival. Methods. Pretransplantation sera of 844 cadaver kidney recipients from three transplant centers in Germany were tested for serum sCD30 content using a commercially available ELISA kit. Results. Kidney graft recipients showed a significantly higher serum sCD30 content than healthy controls (P<0.0001). High sCD30 serum content was associated with graft rejection. The 2‐year graft survival rate in recipients with a high pretransplantation serum sCD30 was 68±6%, significantly lower than the 86±1% rate in recipients with a low sCD30 (P<0.0001). Importantly, high sCD30 was indicative of an increased risk of graft loss even in recipients without lymphocytotoxic alloantibodies. Conclusion. These data show that an elevated pretransplantation serum sCD30 reflects an immune state that is detrimental for kidney graft survival.