EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Living donor transplant is a safe practice but is not completely risk free. Although both infection and malignancy transmissions have occurred through living organ donation, in the global view, the number of these events is negligible in contrast to the successful lifesaving transplants performed each year; however, an event can be devastating for the recipient, donor, and treatment team if it occurs. Each living donor is unique, and the donor evaluation is multifactorial, taking into the account the medical, social, and family history of individual donors, needs of the recipient, and determination of the anatomic and functional suitability of the donor organ. These considerations can be further complicated by geographical and temporal components. Although the balancing of all practical considerations can be complex, a thorough medical assessment for infection and malignancy of a potential living donor is central in protecting the donor and the intended transplant recipient. Good medical practice requires consistent donor evaluation and reasonable follow-up.

Key words : Infection, Living donor screening, Malignancy, Transplant

Introduction
The intent of a living organ donation is to remove an organ from a person (the donor) for the benefit of another (the recipient), with as few adverse consequences to either as feasible. Evaluation of the living donor is divided into 2 important and distinct elements. First, the potential donor must be screened for conditions that will impact his/her mortality and morbidity risks during and after the organ donation procedure; the conclusions of this assessment should be clearly reflected in the consent prior to proceeding with donation. Second, the donor’s organ must be assessed to ensure that the recipient will receive adequate function, that the organ is anatomically feasible to implant, and that the risk of disease transmission through the organ to the recipient is small.¹

The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing has developed policy requirements that address the evaluation of organs from living donors and deceased donors and the mandatory reporting of potential disease transmissions after an organ transplant (http://optn.transplant.hrsa.gov/media/1140/policy_notice_12-2014.pdf). Reports made through the patient safety portal about potential disease transmissions are much less frequent with living donor in contrast to deceased donor organ transplants.

Donor History and Risk Assessment Before Donation

Both donor and recipient should be provided information about the organ and pertinent details about the other individual (donor/recipient) that may affect their benefit-to-risk analysis and personal decision to proceed with the donation and/or transplant. If there is information that the potential donor is reluctant to share, the decision to proceed with evaluation should be reconsidered. The disclosure issue is becoming more complex with increasing numbers of nondirected, paired exchange, and chain donations, where donor-recipient pairs have no close relationship. An important element of the donor evaluation is to detect diseases that the potential donor may be unaware of or may not consider relevant to the donation process. Inquiry about prior diagnoses of bacterial, fungal, and viral infections, including their sequelae such as hepatitis, should be pursued. Confirmed or suspected malignancies, including information on mole removals and age-appropriate cancer screening history, are important for donor and recipient risk stratification prior to donation. Additionally, the family and social history can give insight into potential exposures to diseases such as tuberculosis and malaria, travel to or immigration from endemic areas (strongyloidiasis, coccidioidomycosis, Chagas disease, etc), and inquiry for genetic predisposition to malignancies.

Fortunately, malignancy transmission through living donor organs has proven to be very infrequent. However, an age-appropriate cancer risk evaluation and thorough examination of family history are warranted as elements for donor and recipient risk stratification. Despite emphasis on infection transmissions, malignancy has been the most common unexpected living donor potentially derived disease transmission event reported to the Disease Transmission Advisory Committee (DTAC). This experience reinforces the differences between living and deceased organ donors, in that biologic processes continue to occur in living organ donors after medical evaluation and subsequently after donation.

In 2011, the DTAC Malignancy Subcommittee published 6 risk categories for donor tumor transmission, assigning a specific risk category to the individual tumor types and including recommendations on the clinical use of organs based on these risk categories.² Stratification of tumors into different risk categories was based on individual literature reports, cancer registry review, and OPTN registry data. These recommendations provided a framework based on best available data to guide clinical decision making regarding the suitability of potential donors with a history of malignancy and need of specific screening to identify donors with a high risk of tumor transmission. No significant risk category was defined to benign tumors where malignancy has been excluded.

The minimal risk category includes tumors with 0% to 0.01% of transmission events per organ transplant from donors with specific tumors, which include nonmelanoma skin cancers, noninvasive carcinoma of the bladder (for nonrenal transplants only), small papillary or follicular carcinoma of the thyroid, and solitary well-differentiated (<1 cm) renal cell carcinoma (RCC). The low-risk category (0.1%-1% of transmission events) includes small RCC (1-2.5 cm), low-grade central nervous system (CNS) tumors, primary CNS mature teratoma, solitary papillary thyroid carcinoma (0.5-2.0 cm), minimally invasive follicular carcinoma (1.0- 2.0 cm), and history of treated non-CNS malignancy (>5 years prior) with >99% probability of cure. The intermediate risk category (1%-10% of transmission events) includes breast and colon carcinoma in situ, resected well-differentiated RCC (4-7 cm), and a history of treated non-CNS malignancy (>5 years prior) with a probability of cure between 90% and 99%. The high-risk category is defined by >10% of transmission events and comprises the following: current or past history of melanoma, leukemia/lymphoma or neuroendocrine tumors; breast or colon cancer of more than stage 1; choriocarcinoma; any CNS tumor with ventriculoperitoneal or ventriculoarterial shunt, metastasis, or high-grade (III/IV) histology; any treated non-CNS malignancy with insufficient follow-up to predict behavior, incurable, or with <90% probability of cure; metastatic carcinoma; sarcoma; stages I to IV lung cancer; RCC tumors >7 cm; or any other active cancer. The final category proposed by the DTAC includes tumors of unknown risk category. This review suggested that donors in the no significant risk category are considered to have standard, minimal risk category organs, which can be used based on clinical judgment with informed consent of the recipient; low-risk category organs could be considered for recipients at significant risk of mortality without transplant and with detailed informed consent.²

In general, any active malignancy in the potential living donor is considered to be a contraindication to donation, as organ donation is secondary to health maintenance of the potential donor. However, there have been reports of living donor kidney transplants from patients with <3 cm RCC that were excised on the back table with subsequent successful transplant. In a study of 43 transplants (5 deceased donors and 38 living donors), there was only 1 recurrence of RCC within a transplanted kidney 9 years after the original operation.^3,4 Although the risk of RCC transmission appears to be low after resection, the unknown but additional risks should be reflected in the informed consent process.

The risk of malignancy transmission will vary depending on whether the potential transplanted organ harbors the malignancy versus whether the organ is from the donor but with a malignancy from a different organ of origin. The risk assessment in this situation should be made by a multidisciplinary team, including oncologic consultation. Even a remote history of certain malignancies among potential living donors is considered to be an absolute contraindication to donation; these include melanoma, choriocarcinoma, hematological malignancy, monoclonal gammopathy, and testicular, lung, and breast cancers.⁵ Although mostly based on the deceased donor experience, choriocarcinoma and melanoma carry very high transmission rates (93% and 74%, respectively) and mortality rates among recipients (64% and 58%).⁶ Lung cancer and hematologic malignancies also carry high transmission rates and in previous reports were associated with high rates of death among recipients, whereas donors with a history of breast cancer are avoided because of the potential late metastasis and aggressive biology of the tumor.^5,7

In summary, most of the current knowledge on malignancy transmission from living donors is extrapolated from deceased donor data. Breast and lung carcinoma transmissions through living donation have been reported.⁸ However given the younger age of most living donors, in contrast to deceased donors, and the thorough preoperative assessment before donation, the event of malignancy transmission through a donation is extremely rare.⁹ However, long-term follow-up after donation may reveal a new diagnosis of malignancy in the donor, which may affect the management of the transplant recipient in the future.

Cancer Screening/Family History

Common cancers in the general population should be specifically considered among living donors, and appropriate screening should be performed before donation based on guidelines for the jurisdiction where the donation will occur. The most frequently reported transmission of a non-CNS tumor has been RCC; however, this report is primarily based on deceased donor experience.¹⁰ In light of thorough living donor evaluations and modern imaging, it is unlikely that RCC would remain undetectable on preoperative evaluations. Furthermore, attention should be given to recipients with end-stage renal disease secondary to specific etiologies such as bilateral RCC, who could have a familial predisposition. Therefore, even with normal imaging of a living related donor before donation, donor-derived de novo RCC could be diagnosed in recipients in the future. The fact that some malignancies will go undetected before donation should be taken into the consideration; therefore, living donors must be monitored after donation for a new diagnosis of malignancy.

Infection Testing

Policy and rationale knowledge of preexisting infections and diseases in a donor will allow more complete assessments of donor safety and morbidity from the donation procedure and will allow for rational planning of pre- and posttransplant recipient care and for possible donor exclusion if the risk to the recipient is high.

The OPTN living donor evaluation policy requires that the living donor be screened for all pathogens required for deceased organ donation, including cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), as well as other possible geographic and/or seasonal pathogens. A unique aspect for living organ donors is that the initial donor testing may occur significantly before the time of donation, in contrast to deceased donations, when testing is performed at the time of death and organ retrieval. In fact, this time difference was an important issue for a recipient who developed HIV after kidney transplant from a living donor. The donor had tested HIV negative 2 months before donation. This case brought into focus that living organ donors continue to have environmental exposures before and after a specific testing event.¹¹ The consequence of this transmission is behind the recommendation in the revised US Public Health Services (PHS) guidelines that HIV, HBV, and HCV testing be performed as close to the donation as possible, but certainly within 1 month of the donation event. It was also recommended that donors with increased risk behaviors be counseled about avoidance of risky behaviors before donation.

In 2013, the PHS revised the guidelines specific for organ donors; “increased risk” donors are now defined as those with 1 or more risk factors for HIV, HCV, or HBV infection. The OPTN policy stipulates that all potential (living and deceased) donors be assessed for the increased behavioral risks identified by the PHS guidelines. The presence of each risk factor indicates an increased risk of all 3 pathogens as there is an overlap of associated risk; the 11 risk factors are listed in Table 1.¹²

It is incumbent that transplant centers incorporate questions about sexual activity, drug use, incarceration time, and recent infectious exposures to identify donors who are at increased risk for HIV, HBV, and HCV and document that the recipients have been informed about the donor risk, irrespective of donor testing results.

Human immunodeficiency virus

The National Organ Transplant Act (1984) precluded the use of organs from a donor infected with HIV. Medical advancements in HIV therapy have led many to query the relevance of this exclusion, and the law has recently been amended to allow the use of organs from HIV-positive donors under yet to be defined research restrictions. However, it should be feasible for an HIV-positive individual to be a living organ donor in the future. Multiple tests have been developed over the years to detect the virus with variable levels of sensitivity and reliability. The oldest and most commonly used test has been the detection of antibodies directed against HIV antigens (anti-HIV+). This has been the only mandated test by OPTN policy to determine whether a donor has an HIV infection. A positive test would stop the evaluation process for organ donation. However, it can take up to 3 weeks after virus infection to generate an antibody response, and HIV has been transmitted from organs obtained during the “window period.” To decrease the possibility that a recent, undetected HIV infection has occurred, direct detection of viral nucleic acid with poly-merase chain reaction (PCR) (detection within 5 to 6 days of infection) or antigen/antibody combination tests (positive within 7 to 14 days after infection) have been recommended by the PHS for individuals with increased risk.¹³

Hepatitis B virus

This DNA virus is globally ubiquitous with disparate prevalence rates in people from different geographic regions. Infection with HBV is most commonly controlled by the immune response but can cause a chronic infection/hepatitis in some people with the virus. The commonly used tests to detect active HBV infection are viral products, hepatitis B surface antigen (HBsAg), and HBV DNA. The more relevant test is probably HBsAg, as it remains detectable even when viral replication is suppressed by either immunity or antiviral medications. Immune response to prior HBV exposure is typically detected by antibody generation to structural HBV antigens and HBsAb and HBcAb (which are antibodies reacting with surface and core proteins). Detection of prior HBV (contained) infection is important predominantly for liver donors. Because HBV is a DNA virus, persistence of viral genetic material is common in its dominant reservoir (ie, the liver). Liver transplant recipients of HBcAb-positive livers have a significant risk for developing active HBV infection after transplant in the absence of antiviral therapies. Recipients of nonhepatic organs from an HBcAb-positive, HBsAg-negative donor appear to have little risk of acquiring active HBV infection.¹⁴ The OPTN policy states that HBsAg and HBcAb tests should be performed on organ donors to assess the risk of HBV transmission. Active HBV infection (HBsAg-positive) is usually a reason to exclude an organ from a living donor because of the potential increased risk to the donor and the recipient. Latent HBV infection (HBcAb-positive) in the donor must be weighed as a risk for all liver transplant recipients; however, this is much less of an issue in kidney transplant recipients.

Hepatitis C virus

All organ donors must be tested for infection with HCV, an RNA virus that is a common cause of chronic infection and hepatitis. Hepatitis C virus has been transmitted to naïve organ transplant recipients through organ donations from living and deceased donors as well as through the use of isolated vascular grafts from infected deceased donors.^13,15 Multiple tests are available to discern the presence of the virus. The most common test has been the detection of antibodies generated against structural and nonstructural viral proteins. The new PHS guidelines stipulate that all donors should be tested using HCV-RNA PCR. Similar to HIV, antiviral therapies can make viral RNA undetectable in the blood, so antibody testing should not be omitted as a screening test. However, to be consistent with PHS guidelines, the final test assessed in the living donor during the month before donation should be HCV-RNA PCR.

Cytomegalovirus and Epstein-Barr virus

The herpes viruses are common within the general population, and testing is typically used to discern the risk for recipient disease and use/length of chemoprophylaxis. The presence of anti-cytomegalovirus or anti-Epstein-Barr virus (antiviral capsular antigen or anti-Epstein Barr nuclear antigen) signifies prior donor infection, with the potential that the latent virus will reactivate and cause infection, particularly in the virus-naïve recipient. Although it is rare that detection of these viruses will preclude donation, knowing that an organ comes with a latent virus is an important factor in posttransplant recipient care.16 The most commonly used tool for investigation of prior infection is the detection of antibodies directed against viral proteins.

Chronic or recurrent bacterial infections typically exclude an individual from donation. Acute symptomatic disease is also a reason to postpone the donation event. However, detection of asymptomatic bacteriuria is not infrequent, especially in female donors. Although there are no randomized studies that can confirm the safety of transplanting these kidneys, the literature is relatively silent about adverse sequelae. Donor testing for syphilis is mandated by the OPTN policy, although there have been no reported cases of disease transmission from transplant of organs from deceased or living donors with infections.

In the modern transplant practice, living donor organ transplant is a safe alternative to deceased donor organ transplant, but it is not risk free for either the donor or recipient. Assessment of the living organ donor is a dual-purpose process. The primary goal is to ascertain any underlying medical issues that would add undue risk to the organ donor.

Clinical practice guidelines provide a backbone for the evaluation of living donors; however, each living donor is unique and requires additional considerations based on his/her medical, social, and family history. Recent events in deceased organ donors (rabies, West Nile virus, Balamuthia), as detailed in a rare case of rabies acquired through kidney transplant from a deceased donor,¹⁷ have considerably influenced the living organ donor workup and emphasized the importance of environmental exposure of the donor. However, given the very low prevalence of these infections and absence of widely available testing for some of these pathogens (eg, Balamuthia serology), universal donor screening would not be practical.^18-20 Furthermore, in the case of living donations, the time period between testing and donation should be taken into consideration as the transmissible disease may be contracted by a donor during this period. Only the performance of HIV, HCV, and HBV testing, as close as possible but within 28 days of donation, is mandated in the United States; the timing of other infectious workups remain center specific.

Although both infection and malignancy transmissions have occurred through living organ donations, the number of these events is negligible in contrast to the successful life-saving transplants performed each year. However, because the risk of the transmission is not zero, good medical practice requires a consistent donor evaluation and reasonable follow-up so that our care can be improved using good medical information.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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