- Email: [email protected]
Donors With Malignancies-Risk or Chance?
Donors With Malignancies-Risk or Chance? M. Giessing ABSTRACT The disparity between organ demand and organ supply in renal transplantation has led transplant physicians to pursue a variety of options for increasing the number of donor kidneys. One option is to use kidneys from living or deceased donors who have been diagnosed with a malignant tumor, either of the kidney itself or of other origin. Today, there is an increasing body of evidence in favor of accepting kidneys from donors with renal or ureteral malignancy. This review article, based on a Medline and PubMed search, presents options and strategies for deciding under which circumstances these kidneys may be considered for transplantation. The decision depends on donor tumor characteristics and recipient issues but also on surgical and urological knowledge. HE PERSISTENT shortage of donor organs leads to longer waiting times for renal transplantation (RTX). Knowing that renal transplantation is the best renal replacement therapy and knowing at the same time that the risk of death on the waiting list increases with patient age,1,2 the transplant community makes every effort to increase the number of donors. For living donors, these measures include ABO-incompatible RTX, cross-over donation, and strategies to expand the living donor pool. For deceased donors, numbers of RTX have been increased by performing non-heart-beating donation or duplex RTX and by accepting kidneys from expanded criteria donors.3 In the Eurotransplant area a specific program has been installed for the allocation of kidneys from aged donors to aged recipients (Eurotransplant Senior Program, ESP).4 A yet underutilized source of postmortem organ donations may be donors with malignancies, which includes donors with known past or current malignancy and donors with malignancy diagnosed at the time of or after transplantation of the organs.
T
RISK OF TUMOR TRANSMISSION
Reluctance to accept kidneys from donors with a malignant tumor stems from known cases of tumor transmission to organ recipients. Nevertheless, differences exist as to whether malignancy is known, either past or current, or is discovered during or after transplantation. In the early years of renal transplantation donors with tumors were widely accepted, which lead to frequent tumor transmission. In 1967 Israel Penn founded the “Denver Transplant Tumor Registry,” which, after he became Professor of Surgery at the University of Cincinnati Medical Center in
1982, was renamed “Cincinnati Transplant Tumor Registry” (CTTR). This registry aims at documenting all cases of assumed tumor transmissions to organ recipients. After his death and under the guidance of Prof. Buell the registry was named “Israel Penn International Transplant Tumor Registry” (IPITTR). In a large retrospective analysis of the period from 1965–2003, Buell et al5 identified almost 300 transplantations of organs from donors with a history of malignancy or a malignant tumor detected at autopsy following donation. In this series, they identified 124 transmissions of donor tumors to recipients. The transmission rate was found to strongly vary with the organ transplanted (kidney 45%, liver 37%, heart 30%) and with the tumor type (chorion carcinoma 93%; central nervous system (CNS) tumor 20%; melanoma 74%; renal cell carcinoma (RCC) 63%; breast cancer 29%). Feng et al,6 evaluating data from UNOS, the Penn registry, and publications on this topic, found that 9 out of 35,503 donors transmitted cancer to 12 of 109,749 recipients. The tumors transmitted were melanoma and chorion carcinoma, and the transmission rates were 0.006% for kidney, 0.025% for liver, and 0.013% for heart. Kaufmann et al7 evaluated voluntarily reported data from the OPTN registry for the period of 1994 –2001 and found that 35,000 deceased donors for 108,000 recipients transmitted 5 From the Department of Urology, Heinrich Heine University Hospital Duesseldorf, Germany. Address correspondence to Markus Giessing, MD, PhD, F.E.B.U. Vice Director, Department of Urology, University Hospital, Heinrich Heine University, Düsseldorf, Germany. E-mail: markus. [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.06.005
© 2012 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
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DONORS WITH MALIGNANCIES
tumors with liver transplants, 8 tumors with kidney transplants, and 2 tumors with heart transplants. Summing up the results of available studies, the risk of transmission of donor tumors is 0.006 – 0.2%, and the risk of tumor growth in the recipient is 0.01– 0.03%. A new mandatory reporting system for transmittable disease in transplantation was installed in the US. Ison et al found8 164 potential transmissions between 2005 and 2007 (109 infections, 55 tumors). In 2007, 4 donor tumors were transmitted to 7 recipients in a total of 28,000 donors. Five recipients died, 2 of them of a transmitted lymphoma after RTX. The overall tumor transmission risk in renal transplantation is about 1 transmission in approx. 8,000 RTX performed.9 For donors with CNS tumors such as astrocytoma, glioblastoma, or medulloblastoma, a high transmission rate of up to almost 30% has been reported,6 but the risk can be reduced to approximately 7% if donors with risk factors for transmission such as high-grade CNS tumors, ventriculoperitoneal or ventriculoatrial shunts, or craniotomy prior to donation are not accepted.10 In contrast, Watson11 reported no tumor transmission in 177 donors with primary CNS malignancy donating organs to 448 recipients (including 281 kidneys), even though 85 organs were transplanted from donors with grade IV glioma/ medulloblastoma. How high is the risk of transmission if the donor has a history of malignancy but is tumor-free at the time of donation? Kauffmann et al12 studied 1069 donors of whom 2,508 organs were transplanted and who had a history of malignant tumor (CNS ⬃ 30%; skin ⬃ 35%; urogenital 5%; breast 5%). The interval to donation was less than 5 years for 60% of the donors. There were only two transmissions in this series, 1 from a donor with a history of glioblastoma multiforme (to 3 recipients of kidney, liver, lung) and 1 from a donor with a melanoma cured 32 years prior to donation to one recipient (lung). GUIDELINES
While EBPG (European Best Practice Guideline) and ERBP (European Renal Best Practice) simply recommend to “not accept a donor with malignant tumor,”13 KDIGO (Kidney Disease Improving Global Outcome) guidelines14 do not address evaluation and selection of kidney donors at all. Deceased donors with a current tumor are not generally excluded from kidney donation according to the Guidelines of the European Association of Urology (EAU). They accept kidney donors with basal cell carcinoma, non-metastasized spinocellular carcinoma of the skin, carcinoma in situ of the cervix uteri and of the vocal cords, and benign and low-grade malignant CNS tumors.15 For urological tumors, EAU guidelines state that kidneys with a small RCC can be accepted after local excision, while for TaG1 bladder cancer no consensus exists. Donors with low-grade brain tumors may be accepted if they have no ventriculo-peritoneal shunt and have not had a brain biopsy.
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Deceased donors with a history of malignancy may be accepted after a recurrence-free interval of at least 10 years. Potential donors with a history of breast cancer, melanoma, leukemia, or lymphoma should not be accepted at all. For living donors the Amsterdam Consensus Conference16 stated that candidates with a current tumor should not be accepted, except for non-melanoma skin tumor and carcinoma in situ of the cervix uteri. British guidelines make the same recommendations with identical exception,17 but only accept donors with non-melanoma skin tumor if the tumor is low grade. For living donors with a history of malignancy, the Amsterdam Consensus Conference asks for a 10-year recurrence-free period (except for low-stage and low-grade colon cancer, for which a period of at least 5 years is accepted), as do the British guidelines. Living donors with a history of breast cancer or melanoma are not acceptable. Also, the Amsterdam guidelines exclude donors with a history of lymphoma or carcinoma of the testis, kidney, bronchial system or chorion. None of these tumors are mentioned by the British guidelines, but the latter also excludes donors with a history of sarcoma. Donor Tumor Found Unexpectedly After Transplantation
If a tumor is detected for example by donor autopsy after the kidney has already been transplanted, several options exist depending on the tumor and the individual recipient situation. Either the kidney of the recipient (and of the recipient of the other kidney) is explanted or taken under close surveillance. Immunosuppression may be altered, meaning a reduction to allow the immune system to become active against tumor cells and/or a switch to mTOR inhibitor therapy with antiangiogenetic activity.7,18 –20 Donor Tumor Known at the Time of Transplantation: Prostate Cancer (PCa)
Transmission of prostate cancer from organ donors is very rare. No case of PCa transmission in renal transplantation has been described, and only one case of transmission to a recipient of a heart transplant from a deceased donor has been reported.21 Furthermore, the kidney as a vehicle for prostate cancer is very rare. Only 1 case of a renal metastasis of prostate cancer has been described in a patient with hormone-refractory prostate cancer and a high PSA level (150 ng/mL).22 Yin et al23 performed prostate biopsies in 340 male deceased donors and found an overall prostate cancer rate of 12 %, with prevalence increasing with age. Tumors were incidental, but almost 50% of male donors ⬎ 70 years were diagnosed with prostate cancer. Applying this finding one would have to expect transplantation of about 3000 – 4000 kidneys from prostate cancer-bearing male donors in Europe each year and, if transmission takes place, a high number of recipients diagnosed with transmitted PCa would have to be expected. As this is not the case, transmission must be rare. This was proved in a study in Italy where 18 recipients on a specific list received kidneys from
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donors with known PCa after informed consent. Follow-up for 28 months revealed no transmitted prostate cancer.24 Overall, the literature describes about 20 cases of recipients receiving a kidney from a donor with known prostate cancer and no transmission was detected. Therefore, the value of determining PSA in a deceased donor is not clear. PSA was found to be elevated to ⬎ 8 ng/mL in a deceased donor population,25 which may have been due to catheterization.26 Also, prostate cancer prevalence was found to be as low as 1% even in deceased donors with a PSA ⬎ 6 ng/mL.27 In summary, a practical approach may be as follows: if digital rectal examination (DRE) is suspicious or PSA is ⬎ 20 ng/mL, evaluation for PCa should be done. If DRE is not suspicious and PSA is ⬍ 10 ng/mL, donor kidneys should be accepted.20 If PCa is suspected or detected, the kidney should only be accepted for a specific waiting list and with informed consent from the recipient.28,29 Renal Cell Cancer in Kidney Donors
According to the EAU guidelines,15 a kidney may still be transplanted if a small renal tumor is detected in a deceased donor, as long as the tumor can be excised completely. Also for living-donor renal transplantation, no tumor growth was found after local excision of renal masses up to 4 cm in size with a follow-up of ⬎ 5 years while graft survival was 93%.20,30 This finding offers a potential new strategy for overcoming organ shortage as kidneys from patients diagnosed with a renal mass may be accepted for undirected living donor transplantation. Nicol et al31 asked patients with a renal mass after extensive information about partial vs. radial nephrectomy, which operation they would prefer. In a second step patients who had opted for complete nephrectomy were asked whether they would agree if this kidney were transplanted after excision of the mass. Of 38 kidneys retrieved in this way 26 were found to have RCC and were transplanted into a specific subgroup of recipients (aged 60 years an older/HLA mismatch ⱖ 5). After a median follow-up of 25 months only 1 RCC recurred locally after 9 years. Similar data were reported from another study by Mannami et al.32 Given that despite guidelines small renal masses ⬍ 4 cm are still treated with nephrectomy in ⬎ 50% of cases, this may be a large, yet underutilized source of kidneys for transplantation.33,34 Nevertheless, as guidelines recommend partial nephrectomy for small renal masses this attempt is ethically doubtful. Ureter: Distal Urothelial Cancer in Kidney Donors
A small but undoubtedly acceptable donor pool may be patients with urothelial cancer of the distal ureter. Guidelines recommend nephroureterectomy for these patients. Mannami et al32 performed transplantation of 8 kidneys with distal ureteral cancers after resection of the distal ureter. After a follow-up of 5 years no transmission of urothelial cancer was detected and only one recurrence was observed, which was successfully treated by local excision in accordance with the recipient’s wish. Kidneys from patients
GIESSING
with distal ureteral tumors therefore could well be accepted for renal transplantation in recipients who give informed consent. CONCLUSION
Guidelines exclude donors with current non-CNS tumors (except for cervical carcinoma in situ/non- melanoma skin tumors), while donors with a history of non-CNS tumors are accepted if curative therapy has been successfully performed ⬎ 10 years prior to donation (except for breast cancer/melanoma). Donors with CNS tumors may be accepted if they have low-grade tumors and no biopsy or shunt operation has been performed. Tumor-bearing kidneys, either from deceased or living donors or from non-transplant-associated patients, can be accepted if the tumor is small and excised completely. In a non-living-donor scenario, such kidneys should preferably be transplanted into patients on a specific waiting list (increased age, high number of mismatches) after informed consent has been given. This holds true especially for donor kidneys with a distal ureteral tumor, which have been found to be transplantable successfully after distal ureteral resection. This group of patients as well as patients with renal masses opting for complete nephrectomy may represent an underutilized donor source that may help overcome the shortage of kidneys for transplantation. REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725, 1999 2. Oniscu GC, Brown H, Forsythe JL: Impact of cadaveric renal transplantation on survival in patients listed for transplantation. J Am Soc Nephrol 16:1859, 2005 3. Metzger RA, Delmonico FL, Feng S, et al: Expanded criteria donors for kidney transplantation. Am J Transplant 3(Suppl 4):114, 2003 4. Cohen B, Smits JM, Haase B, et al: Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 20:34, 2005 5. Buell JF, Beebe TM, Trofe J, et al: Donor transmitted malignancies. Ann Transplant 9:53, 2004 6. Feng S, Buell JF, Cherikh WS, et al: Organ donors with positive viral serology or malignancy: risk of disease transmission by transplantation. Transplantation 74:1657, 2002 7. Kauffman HM, McBride MA, Cherikh WS: Transplant tumor registry— donor related malignancies. Transplantation 74:358, 2002 8. Ison MG, Hager J, Blumberg E, et al: Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee. Am J Transplant 9:1929, 2009 9. Gandhi MJ, Strong DM: Donor derived malignancy following transplantation: a review. Cell Tissue Bank 8:267, 2007 10. Buell JF, Trofe J, Sethuraman G, et al: Donors with central nervous system malignancies: Are they truly safe? Transplantation 76:340, 2003 11. Watson CJ, Roberts R, Wright KA, et al: How safe is it to transplant organs from deceased donors with primary intracranial malignancy? An analysis of UK Registry data. Am J Transplant 10:1437, 2010
DONORS WITH MALIGNANCIES 12. Kauffman HM, Cherikh WS, McBride MA, et al: Deceased donors with a past history of malignancy: an organ procurement and transplantation network/united network for organ sharing update. Transplantation 84:272, 2007 13. Zoccali C, Abramowicz D, Cannata-Andia JB, et al: European best practice quo vadis? From European Best Practice Guidelines (EBPG) to European Renal Best Practice (ERBP). Nephrol Dial Transplant 23:2162, 2008 14. Kasiske BL, Zeier MG, Craig JC, et al: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 9(Suppl 3):S1, 2009 15. Guidelines on renal transplantation of the European Association of Urology (EAU) http://www.uroweb.org/gls/pdf/25_Renal_ Transplant_LR.pdf 16. Delmonico F: Council of the Transplantation Society. A Report of the Amsterdam Forum On the Care of the Live Kidney Donor: Data and Medical Guidelines. Transplantation 79:S53, 2005 17. http://www.bts.org.uk/transplantation/standards-and-guidelines/ 18. Morath C, Schwenger V, Schmidt J, et al: Transmission of malignancy with solid organ transplants. Transplantation 80:S164, 2005 19. Geissler EK, Schlitt HJ: The potential benefits of rapamycin on renal function, tolerance, fibrosis, and malignancy following transplantation. Kidney Int 78:1075, 2010 20. Buell JF, Hanaway MJ, Thomas M, et al: Donor kidneys with small renal cell cancers: can they be transplanted? Transplant Proc 37:581, 2005 21. Loh E, Couch FJ, Hendricksen C, et al: Development of donor-derived prostate cancer in a recipient following orthotopic heart transplantation. JAMA 277:133, 1997 22. Gunlusoy B, Arslan M, Selek E: A case report: renal metastasis of prostate cancer. Int Urol Nephrol 36:555, 2004 23. Yin M, Bastacky S, Chandran U, et al: Prevalence of incidental prostate cancer in the general population: a study of healthy organ donors. J Urol 179:892, 2008
1785 24. Taioli E, Mattucci DA, Palmieri S, et al: A population-based study of cancer incidence in solid organ transplants from donors at various risk of neoplasia. Transplantation 83:13, 2007 25. Salomon L, Feuillu B, Petit J, et al: Evaluation of serum PSA in brain-dead subjects over the age of 50 before organ harvesting: organ donation and the risk of transmission of prostate cancer. Survey of the transplantation committee of the Association Francaise d’Urologie. Prog Urol 17:828, 2007 26. Kravchick S, Bunkin I, Peled R et al: Patients with elevated serum PSA and indwelling catheter after acute urinary retention: prospective study of 63 patients with 7-year follow-up. J Endourol 21:1203, 2007 27. Frutos MA, Daga D, Ruiz P, et al: Prostate-specific antigen in the assessment of organ donors. Transplant Proc 35:1644, 2003 28. Sfoungaristos S, Perimenis P: PSA density versus risk stratification for lymphadenectomy-making decision in patients with prostate cancer undergoing radical prostatectomy. Int Urol Nephrol 43:1073, 2011 29. Roobol MJ, van Vugt HA, Loeb S: Prediction of prostate cancer risk: the role of prostate volume and digital rectal examination in the ERSPC risk calculators. Eur Urol 61:577, 2012 30. Sener A, Uberoi V, Bartlett ST, et al: Living-donor renal transplantation of grafts with incidental renal masses after ex-vivo partial nephrectomy. BJU Int 104:1655, 2009 31. Nicol DL, Preston JM, Wall DR, et al: Kidneys from patients with small renal tumours: a novel source of kidneys for transplantation. BJU Int 102:188, 2008 32. Mannami M, Mannami R, Mitsuhata N: Last resort for renal transplant recipients, ‘restored kidneys’ from living donors/patients. Am J Transplant 8:811, 2008 33. Breau RH, Crispen PL, Jenkins SM, et al: Treatment of patients with small renal masses: a survey of the American Urological Association. J Urol 185:407, 2011 34. Cooperberg MR, Mallin K, Ritchey J, et al: Decreasing size at diagnosis of stage 1 renal cell carcinoma: analysis from the National Cancer Data Base, 1993 to 2004. J Urol 179:2131, 2008
T
RISK OF TUMOR TRANSMISSION
Reluctance to accept kidneys from donors with a malignant tumor stems from known cases of tumor transmission to organ recipients. Nevertheless, differences exist as to whether malignancy is known, either past or current, or is discovered during or after transplantation. In the early years of renal transplantation donors with tumors were widely accepted, which lead to frequent tumor transmission. In 1967 Israel Penn founded the “Denver Transplant Tumor Registry,” which, after he became Professor of Surgery at the University of Cincinnati Medical Center in
1982, was renamed “Cincinnati Transplant Tumor Registry” (CTTR). This registry aims at documenting all cases of assumed tumor transmissions to organ recipients. After his death and under the guidance of Prof. Buell the registry was named “Israel Penn International Transplant Tumor Registry” (IPITTR). In a large retrospective analysis of the period from 1965–2003, Buell et al5 identified almost 300 transplantations of organs from donors with a history of malignancy or a malignant tumor detected at autopsy following donation. In this series, they identified 124 transmissions of donor tumors to recipients. The transmission rate was found to strongly vary with the organ transplanted (kidney 45%, liver 37%, heart 30%) and with the tumor type (chorion carcinoma 93%; central nervous system (CNS) tumor 20%; melanoma 74%; renal cell carcinoma (RCC) 63%; breast cancer 29%). Feng et al,6 evaluating data from UNOS, the Penn registry, and publications on this topic, found that 9 out of 35,503 donors transmitted cancer to 12 of 109,749 recipients. The tumors transmitted were melanoma and chorion carcinoma, and the transmission rates were 0.006% for kidney, 0.025% for liver, and 0.013% for heart. Kaufmann et al7 evaluated voluntarily reported data from the OPTN registry for the period of 1994 –2001 and found that 35,000 deceased donors for 108,000 recipients transmitted 5 From the Department of Urology, Heinrich Heine University Hospital Duesseldorf, Germany. Address correspondence to Markus Giessing, MD, PhD, F.E.B.U. Vice Director, Department of Urology, University Hospital, Heinrich Heine University, Düsseldorf, Germany. E-mail: markus. [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.06.005
© 2012 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 44, 1782–1785 (2012)
DONORS WITH MALIGNANCIES
tumors with liver transplants, 8 tumors with kidney transplants, and 2 tumors with heart transplants. Summing up the results of available studies, the risk of transmission of donor tumors is 0.006 – 0.2%, and the risk of tumor growth in the recipient is 0.01– 0.03%. A new mandatory reporting system for transmittable disease in transplantation was installed in the US. Ison et al found8 164 potential transmissions between 2005 and 2007 (109 infections, 55 tumors). In 2007, 4 donor tumors were transmitted to 7 recipients in a total of 28,000 donors. Five recipients died, 2 of them of a transmitted lymphoma after RTX. The overall tumor transmission risk in renal transplantation is about 1 transmission in approx. 8,000 RTX performed.9 For donors with CNS tumors such as astrocytoma, glioblastoma, or medulloblastoma, a high transmission rate of up to almost 30% has been reported,6 but the risk can be reduced to approximately 7% if donors with risk factors for transmission such as high-grade CNS tumors, ventriculoperitoneal or ventriculoatrial shunts, or craniotomy prior to donation are not accepted.10 In contrast, Watson11 reported no tumor transmission in 177 donors with primary CNS malignancy donating organs to 448 recipients (including 281 kidneys), even though 85 organs were transplanted from donors with grade IV glioma/ medulloblastoma. How high is the risk of transmission if the donor has a history of malignancy but is tumor-free at the time of donation? Kauffmann et al12 studied 1069 donors of whom 2,508 organs were transplanted and who had a history of malignant tumor (CNS ⬃ 30%; skin ⬃ 35%; urogenital 5%; breast 5%). The interval to donation was less than 5 years for 60% of the donors. There were only two transmissions in this series, 1 from a donor with a history of glioblastoma multiforme (to 3 recipients of kidney, liver, lung) and 1 from a donor with a melanoma cured 32 years prior to donation to one recipient (lung). GUIDELINES
While EBPG (European Best Practice Guideline) and ERBP (European Renal Best Practice) simply recommend to “not accept a donor with malignant tumor,”13 KDIGO (Kidney Disease Improving Global Outcome) guidelines14 do not address evaluation and selection of kidney donors at all. Deceased donors with a current tumor are not generally excluded from kidney donation according to the Guidelines of the European Association of Urology (EAU). They accept kidney donors with basal cell carcinoma, non-metastasized spinocellular carcinoma of the skin, carcinoma in situ of the cervix uteri and of the vocal cords, and benign and low-grade malignant CNS tumors.15 For urological tumors, EAU guidelines state that kidneys with a small RCC can be accepted after local excision, while for TaG1 bladder cancer no consensus exists. Donors with low-grade brain tumors may be accepted if they have no ventriculo-peritoneal shunt and have not had a brain biopsy.
1783
Deceased donors with a history of malignancy may be accepted after a recurrence-free interval of at least 10 years. Potential donors with a history of breast cancer, melanoma, leukemia, or lymphoma should not be accepted at all. For living donors the Amsterdam Consensus Conference16 stated that candidates with a current tumor should not be accepted, except for non-melanoma skin tumor and carcinoma in situ of the cervix uteri. British guidelines make the same recommendations with identical exception,17 but only accept donors with non-melanoma skin tumor if the tumor is low grade. For living donors with a history of malignancy, the Amsterdam Consensus Conference asks for a 10-year recurrence-free period (except for low-stage and low-grade colon cancer, for which a period of at least 5 years is accepted), as do the British guidelines. Living donors with a history of breast cancer or melanoma are not acceptable. Also, the Amsterdam guidelines exclude donors with a history of lymphoma or carcinoma of the testis, kidney, bronchial system or chorion. None of these tumors are mentioned by the British guidelines, but the latter also excludes donors with a history of sarcoma. Donor Tumor Found Unexpectedly After Transplantation
If a tumor is detected for example by donor autopsy after the kidney has already been transplanted, several options exist depending on the tumor and the individual recipient situation. Either the kidney of the recipient (and of the recipient of the other kidney) is explanted or taken under close surveillance. Immunosuppression may be altered, meaning a reduction to allow the immune system to become active against tumor cells and/or a switch to mTOR inhibitor therapy with antiangiogenetic activity.7,18 –20 Donor Tumor Known at the Time of Transplantation: Prostate Cancer (PCa)
Transmission of prostate cancer from organ donors is very rare. No case of PCa transmission in renal transplantation has been described, and only one case of transmission to a recipient of a heart transplant from a deceased donor has been reported.21 Furthermore, the kidney as a vehicle for prostate cancer is very rare. Only 1 case of a renal metastasis of prostate cancer has been described in a patient with hormone-refractory prostate cancer and a high PSA level (150 ng/mL).22 Yin et al23 performed prostate biopsies in 340 male deceased donors and found an overall prostate cancer rate of 12 %, with prevalence increasing with age. Tumors were incidental, but almost 50% of male donors ⬎ 70 years were diagnosed with prostate cancer. Applying this finding one would have to expect transplantation of about 3000 – 4000 kidneys from prostate cancer-bearing male donors in Europe each year and, if transmission takes place, a high number of recipients diagnosed with transmitted PCa would have to be expected. As this is not the case, transmission must be rare. This was proved in a study in Italy where 18 recipients on a specific list received kidneys from
1784
donors with known PCa after informed consent. Follow-up for 28 months revealed no transmitted prostate cancer.24 Overall, the literature describes about 20 cases of recipients receiving a kidney from a donor with known prostate cancer and no transmission was detected. Therefore, the value of determining PSA in a deceased donor is not clear. PSA was found to be elevated to ⬎ 8 ng/mL in a deceased donor population,25 which may have been due to catheterization.26 Also, prostate cancer prevalence was found to be as low as 1% even in deceased donors with a PSA ⬎ 6 ng/mL.27 In summary, a practical approach may be as follows: if digital rectal examination (DRE) is suspicious or PSA is ⬎ 20 ng/mL, evaluation for PCa should be done. If DRE is not suspicious and PSA is ⬍ 10 ng/mL, donor kidneys should be accepted.20 If PCa is suspected or detected, the kidney should only be accepted for a specific waiting list and with informed consent from the recipient.28,29 Renal Cell Cancer in Kidney Donors
According to the EAU guidelines,15 a kidney may still be transplanted if a small renal tumor is detected in a deceased donor, as long as the tumor can be excised completely. Also for living-donor renal transplantation, no tumor growth was found after local excision of renal masses up to 4 cm in size with a follow-up of ⬎ 5 years while graft survival was 93%.20,30 This finding offers a potential new strategy for overcoming organ shortage as kidneys from patients diagnosed with a renal mass may be accepted for undirected living donor transplantation. Nicol et al31 asked patients with a renal mass after extensive information about partial vs. radial nephrectomy, which operation they would prefer. In a second step patients who had opted for complete nephrectomy were asked whether they would agree if this kidney were transplanted after excision of the mass. Of 38 kidneys retrieved in this way 26 were found to have RCC and were transplanted into a specific subgroup of recipients (aged 60 years an older/HLA mismatch ⱖ 5). After a median follow-up of 25 months only 1 RCC recurred locally after 9 years. Similar data were reported from another study by Mannami et al.32 Given that despite guidelines small renal masses ⬍ 4 cm are still treated with nephrectomy in ⬎ 50% of cases, this may be a large, yet underutilized source of kidneys for transplantation.33,34 Nevertheless, as guidelines recommend partial nephrectomy for small renal masses this attempt is ethically doubtful. Ureter: Distal Urothelial Cancer in Kidney Donors
A small but undoubtedly acceptable donor pool may be patients with urothelial cancer of the distal ureter. Guidelines recommend nephroureterectomy for these patients. Mannami et al32 performed transplantation of 8 kidneys with distal ureteral cancers after resection of the distal ureter. After a follow-up of 5 years no transmission of urothelial cancer was detected and only one recurrence was observed, which was successfully treated by local excision in accordance with the recipient’s wish. Kidneys from patients
GIESSING
with distal ureteral tumors therefore could well be accepted for renal transplantation in recipients who give informed consent. CONCLUSION
Guidelines exclude donors with current non-CNS tumors (except for cervical carcinoma in situ/non- melanoma skin tumors), while donors with a history of non-CNS tumors are accepted if curative therapy has been successfully performed ⬎ 10 years prior to donation (except for breast cancer/melanoma). Donors with CNS tumors may be accepted if they have low-grade tumors and no biopsy or shunt operation has been performed. Tumor-bearing kidneys, either from deceased or living donors or from non-transplant-associated patients, can be accepted if the tumor is small and excised completely. In a non-living-donor scenario, such kidneys should preferably be transplanted into patients on a specific waiting list (increased age, high number of mismatches) after informed consent has been given. This holds true especially for donor kidneys with a distal ureteral tumor, which have been found to be transplantable successfully after distal ureteral resection. This group of patients as well as patients with renal masses opting for complete nephrectomy may represent an underutilized donor source that may help overcome the shortage of kidneys for transplantation. REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725, 1999 2. Oniscu GC, Brown H, Forsythe JL: Impact of cadaveric renal transplantation on survival in patients listed for transplantation. J Am Soc Nephrol 16:1859, 2005 3. Metzger RA, Delmonico FL, Feng S, et al: Expanded criteria donors for kidney transplantation. Am J Transplant 3(Suppl 4):114, 2003 4. Cohen B, Smits JM, Haase B, et al: Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 20:34, 2005 5. Buell JF, Beebe TM, Trofe J, et al: Donor transmitted malignancies. Ann Transplant 9:53, 2004 6. Feng S, Buell JF, Cherikh WS, et al: Organ donors with positive viral serology or malignancy: risk of disease transmission by transplantation. Transplantation 74:1657, 2002 7. Kauffman HM, McBride MA, Cherikh WS: Transplant tumor registry— donor related malignancies. Transplantation 74:358, 2002 8. Ison MG, Hager J, Blumberg E, et al: Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee. Am J Transplant 9:1929, 2009 9. Gandhi MJ, Strong DM: Donor derived malignancy following transplantation: a review. Cell Tissue Bank 8:267, 2007 10. Buell JF, Trofe J, Sethuraman G, et al: Donors with central nervous system malignancies: Are they truly safe? Transplantation 76:340, 2003 11. Watson CJ, Roberts R, Wright KA, et al: How safe is it to transplant organs from deceased donors with primary intracranial malignancy? An analysis of UK Registry data. Am J Transplant 10:1437, 2010
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