H. Myron Kauffman

Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de Novo malignancies

Background. Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. Methods. A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for nonskin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. Results. The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24–0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24–0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. Conclusions. Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and nonskin solid malignancy.

Aggressive pharmacologic donor management results in more transplanted organs

Background. Brain death results in adverse pathophysiologic effects in many cadaveric donors, resulting in cardiovascular instability and poor organ perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve cardiac function in brain-dead donors. The goal of this study was to examine the effect of HR on the brain-dead donor on the number of organs transplanted per donor. Methods. A retrospective analysis of all brain-dead donors recovered in the United States from January 1, 2000, to September 30, 2001, was conducted. HR consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or L-thyroxine. Univariate analyses and multivariate logistic regression analyses were used to detect differences between the HR group and those donors who did not receive HR. Results. Of 10,292 consecutive brain-dead donors analyzed, 701 received three-drug HR. Univariate analysis showed the mean number of organs from HR donors (3.8) was 22.5% greater than that from nonhormonal resuscitation donors (3.1) (P <0.001). Multivariate analyses showed that HR was associated with the following statistically significant increased probabilities of an organ being transplanted from a donor: kidney 7.3%, heart 4.7%, liver 4.9%, lung 2.8%, and pancreas 6.0%. Extrapolation of these probabilities to the 5,921 brain-dead donors recovered in 2001 was calculated to yield a total increase of 2,053 organs. Conclusion. HR stabilizes certain brain-dead donors and is associated with significant increases in organs transplanted per donor.

Hormonal resuscitation yields more transplanted hearts, with improved early function1

Background. Brain death results in cardiovascular instability and poor organ perfusion in many brain-dead donors. Hormonal resuscitation stabilizes certain brain-dead donors and is associated with significant increases in the numbers of organs transplanted per donor. The goal of this study was to examine the quality of hearts recovered from donors treated with hormonal resuscitation. Methods. A retrospective analysis of 4,543 recipients of hearts recovered from brain-dead donors, reported to the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between November 1, 1999, and December 31, 2001, was conducted. Hormonal resuscitation consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or l-thyroxine. Univariate and multivariate analyses were used to evaluate the quality of hearts from donors who received three-drug hormonal resuscitation (3HR) treatment versus donors who did not receive all three drugs (non-3HR). Death within 30 days and early graft dysfunction were used as endpoints. Results. Hearts from 3HR donors demonstrated a 1-month survival rate of 96.2%, compared with a 92.1% survival rate for non-3HR donor hearts (P <0.01). Early graft dysfunction occurred in 5.6% of 3HR donor hearts and 11.6% of non-3HR donor hearts (P <0.01). Multivariate results demonstrated a 46% reduced odds of death within 30 days and a 48% reduced odds of early graft dysfunction. Steroids alone and steroids plus triiodothyronine/l-thyroxine also significantly reduced prolonged graft dysfunction. Conclusions. This study suggests that 3HR treatment of brain-dead donors results in increased numbers of transplanted hearts, with improved short-term graft function.

Transplant tumor registry: donor related malignancies.

Background. Transmission of donor malignancies has been intermittently reported since the early days of clinical transplantation. The incidence of United States donor related malignancies has not previously been documented. Methods. All donor related malignancies reported to the Organ Procurement and Transplantation Network/United Network for Organ Sharing from 4/1/94–7/1/01 in a cohort of 34,933 cadaveric donors and 108,062 recipients were investigated by contacting the transplant centers to verify that the reported tumors were of donor origin. Time and mode of discovery, as well as graft and patient outcome, were determined. The status of other recipients from the donor was investigated. Results. A total of 21 donor related malignancies from 14 cadaveric and 3 living donors were reported. Fifteen tumors were donor transmitted and 6 were donor derived. Transmitted tumors are malignancies that existed in the donor at the time of transplantation. Derived tumors are de novo tumors that develop in transplanted donor hematogenous or lymphoid cells after transplantation. The cadaveric donor related tumor rate is 0.04% (14 of 34,993). The donor related tumor rate among transplanted cadaveric organs is 0.017% (18 of 108,062). Among patients developing donor related malignancies, the overall mortality rate was 38%, with that of transmitted tumors being 46% and derived tumors being 33%. The cadaveric donor related tumor mortality rate is 0.007% (8 of 108,062). Conclusions. The United States incidence of donor related tumors is extremely small. The donor related tumor death rate is also extremely small, particularly when compared with waiting-list mortality.

Post‐transplant de novo malignancies in renal transplant recipients: the past and present

Post‐transplant de novo malignancies are reviewed in three time periods: (i) the azathioprine (AZA) era from 1962 to 1980–1981, (ii) the cyclosporine (CYA) era (1980 to present) in which the calcineurin inhibitors, CYA and tacrolimus (TAC), were the mainstay of recipient immunosuppression, and (iii) the TOR inhibitor era starting in the year 2000. Both transplant registry and transplant center reports on malignancies occurring in the AZA era are reviewed. Reports from transplant centers and from the Cincinnati Transplant Tumor Registry (CTTR) in both the early CYA era (1980s) and the 1900–2000 CYA era are reported. Cancer incidence associated with AZA versus CYA, CYA versus TAC, and AZA versus mycophenolate mofetil (MMF) is compared in both transplant center and registry reports including new, unreported Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 1998 to 2003. The malignancy incidence associated with lymphocyte‐depleting antibody and corticosteroid immunosuppression is discussed. Reduced malignancy incidence recently reported with TOR inhibitors is compared with that of conventional immunosuppression. Important nondrug factors influencing the incidence of post‐transplant malignancies from seven single and three registry reports are detailed. The substantial role that de novo malignancies play in post‐transplant mortality is discussed. Finally, management recommendations for recipients who develop de novo post‐transplant malignancies are briefly presented.

Increased transplanted organs from the use of a standardized donor management protocol.

The organ shortage has resulted in increasing recipient waiting lists and waiting‐list deaths. The increased use of expanded donors has been associated with increased discarding of procured organs because of poor organ function. A structured donor management algorithm or critical pathway was tested to determine its effect on the donor management and procurement process. A pilot study examined donors from 88 critical care units in 10 organ procurement organizations managed under the critical pathway and compared them to retrospective data collected at those same pilot sites. The total number of organs both procured and transplanted per 100 donors was significantly greater (p < 0.01) in the critical pathway group when compared to the control group. There was no significant difference in 1‐year graft survival for any of the organs recovered, and no significant difference in the rate of delayed graft function in the kidneys transplanted. Use of a structured donor management algorithm results in significant increases in organs procured and organs transplanted without any reduction in the quality of the organs being transplanted.

First report of the United Network for Organ Sharing Transplant Tumor Registry: donors with a history of cancer.

Background. Severe organ shortages have led to donor pool expansion to include older individuals, patients with hypertension, diabetes, and a past history of cancer. Transmission of cancer from cadaveric donors is a risk of transplantation and carries a high mortality rate. Methods. During a 33 month period, UNOS recorded 14,705 cadaveric donors of which 257 had a past history of cancer (PHC). A total of 650 organs (397 kidneys, 178 livers, and 75 hearts) were transplanted from these 257 donors. Type of cancer, tumor-free interval at organ procurement, and whether any PHC donor transmitted a tumor to the recipient were analyzed. Results. Three PHC donor tumor types (skin, brain, genitourinary) were associated with 549 of the transplanted organs (85%). Twenty-eight recipients of PHC donor organs developed posttransplantation tumors (18 skin, 2 PTLD, 8 solid cancers). During a mean follow-up of 45 months (range 30–61 months), no recipients of organs from PHC donors developed a donor derived cancer. The majority (71.5%) of all non-skin and non-CNS system cancer donors had a cancer-free interval of greater than five years. Conclusions. Risks of cancer transmission from donors with a history of non-melanoma skin cancer and selected cancers of the CNS appear to be small. Risks of tumor transmission with certain other types of cancer may be acceptable, particularly if the donor has a long cancer-free interval prior to organ procurement while certain other cancers pose a high transmission risk. Selective use of PHC donors may permit expansion of the donor pool.

Early Mortality Rates in Older Kidney Recipients With Comorbid Risk Factors

Background. There are over 60,000 candidates on the deceased donor kidney wait-list and the percentage of candidates over age 50 years continues to grow each year. National data have not previously been used to evaluate the association of comorbidities with mortality in older patients. Methods. A multivariate analysis of 30,262 deceased donor primary kidney recipients aged 18–59 years and 8,895 aged ≥60 years evaluated the association of six recipient comorbidities on 90- and 365-day patient mortality rates. The additional effects of expanded criteria donors (ECD) and development of delayed graft function (DGF) were also evaluated. Results. The 365-day mortality rate for recipients aged ≥60 years (10.5%) was more than twice that of recipients aged 18–59 years (4.4%) and comorbidities significantly increased mortality rates even higher (10.6–21.4%). The 365-day mortality rate for recipients aged ≥60 years who received an ECD kidney was 14.4% and who developed DGF was 15.9% while recipients with comorbidities but no DGF and no ECD ranged from 16.0 to 42.3%. The 365-day transplant mortality rate of recipients aged ≥60 years with comorbidities is higher than the 365-day wait-list mortality for patients with the same comorbidities, suggesting a lack of survival benefit from transplantation. Conclusions. Mortality rates for patients aged ≥60 years with comorbidities are higher than for those without comorbidities, significantly higher than for younger patients, and higher than for wait-listed patients. Thus, utility may be poorly served by allocating kidneys to older patients with comorbidities, and perhaps discussion of exclusionary listing criteria is warranted.

Utilization of extended donor criteria liver allograft : Is the elevated risk of failure independent of the model for end-stage liver disease score of the recipient?

Background. The goal of this analysis was to determine if outcomes from the use of extended criteria donor (ECD) livers were dependent upon the Model for End-Stage Liver Disease (MELD) score of the recipient. Methods. The Organ Procurement and Transplantation Network (OPTN) database as of March 4, 2006 was used for the analysis. Data from 12,056 adult liver transplant (LTx) recipients between June 1, 2002 and June 30, 2005 was analyzed. The donor risk index (DRI) was calculated as previously reported. A DRI of ≥1.7 was classified as ECD. Relative risk (RR) estimates were derived from Cox regression models adjusted for DRI, recipient MELD, age, sex, ethnicity, diagnosis, and year of transplant. Results. Data from 2,873 grafts falling in the ECD category (23.8%) and their recipients were analyzed. Recipients with low MELD scores (<15) received the highest proportion of ECD livers (33%). ECD livers were associated with a significant increase in the RR of graft failure within each MELD category. However, this effect held within each of the three MELD categories. Conclusion. The use of ECD grafts expands the organ pool at expense of increased RR of liver failure. Our analysis showed no significant interaction between DRI and MELD score of the recipient. The fact that there is no additional impact of ECD livers in recipients with high MELD scores suggests that this group of patients may benefit from this pool of grafts.

The expanded donor

D ata from the United Network for Organ Sharing (UNOS) Scientific Registry indicate that the size of the waiting list and number ofwaiting list deaths are increasing more rapidly than either the number of organs procured or the total number of living and cadaver transplants (UNOS Annual Report, 1995). Although the number of cadaveric donors increased slightly between the years 1988 and 1995, there is evidence that older donors and donors with characteristics once thought to preclude organ donation are being used more and more frequently. Although there is no single delinition of an expanded donor, it is becoming increasingly important to routinely evaluate the impact of expanded donor organs on patient and graft survival. Additionally, it is important to consider outcomes of expanded donor organ transplants in view of the substantial mortality on the waiting list.