History of Living Donation and Donor-Related Ethics
The first long-term successful organ transplant was a living donor kidney transplant between monozygotic twin brothers performed in 1954 at the Peter Bent Brigham Hospital in Boston. This procedure marked the first time in history that a healthy person underwent a major surgical procedure that they did not need, solely for the benefit of another person, and this reality surrounded the ethical discussion of the case. The success of the procedure from an immunologic perspective was predicated on the genetic identity of the donor and recipient, by obstetric records of the donor and recipient’s birth, and by skin grafting before the kidney transplant to confirm compatibility. Because this transplant predated the development of dialysis, it was truly a life-saving procedure, given the end-stage renal disease of the recipient. The donor lived another 56 years with a single kidney without any apparent sequelae. Additional ethical considerations and unknowns at the time were whether the twin donor would develop renal failure either because of the procedure (considered very unlikely) or because of development of the same kidney disease as his genetically identical brother (unlikely but nevertheless possible). This transplant was followed by a small but growing number of similar living donor transplants between closely related family members, even while immunosuppressive drug therapy for transplantation was in its infancy.
Although living donor renal transplants initially were the only option, deceased donor renal transplantation began shortly thereafter and grew considerably with the advent of brainstem death criteria. The development of immunosuppressive drug therapy, consisting initially of Imuran, steroids, and antilymphocyte globulin, allowed the growth of deceased donor renal transplantation as an alternative to living donor renal transplants. The arrival of cyclosporine and muromonab-CD3 (OKT3) in the 1980s further enhanced outcomes with both deceased donor and living donor transplantation. Laparoscopic live donor nephrectomy, initially described by Ratner in 1995, reduced the pain and suffering associated with live donation and resulted in a substantial growth of living kidney donation in the US. Improvements in outcomes and reduction in morbidities of surgery led to a growth in living kidney donation to a maximal number in 2004 of 6647. Unfortunately, the number of living donor transplants declined to 5626 in 2015. Reasons for the decline in total numbers of living donor nephrectomy, despite the continual growth of the recipient waitlist, are difficult to attribute accurately, but may include increasing reliance on deceased donor kidney transplantation. Utilization of living donors varies by geographic region, race and culture, and transplant program. Additionally, the increasing body mass index (BMI) of the US population discourages the use of living donors.
As living donation comes under increasing regulatory scrutiny, long-term medical follow-up has been mandated for such donors. Paired kidney donation has developed as a means of maximizing benefits and possibilities of living donation. In an attempt to increase the number of people eligible to be a living donor, donors who are older, have a higher BMI, are on one antihypertensive medication, and have other more complex medical conditions have been considered. Attitudes toward covering the medical costs of living donation vary around the world (see section on Financial Considerations). The implementation of living kidney donation reflects both medical and societal attitudes toward risk and cost sharing. However, one constant reality in the field is that the best long-term outcomes have been achieved using living donors, likely because of the superior quality of the kidneys and short preservation times that minimize graft injury associated with transplantation.
The Rationale for Living Donation
Although the survival benefit of kidney transplantation is superior to any other form of renal replacement therapy, the allograft’s source confers additional benefits. For example, kidney transplantation before the initiation of dialysis, also known as preemptive transplantation, is associated with higher graft and patient survival compared with those recipients who receive their kidneys after initiating dialysis. This survival benefit is most pronounced in the living donor kidney population, because 31% of living donor transplants performed in the US in 2015 were preemptive, whereas only 9% of deceased donor kidney transplants were performed in patients before chronic dialysis. Studies have shown that renal replacement therapy by kidney transplantation is less costly than dialysis, so it is likely that the increased use of preemptive transplantation in living donation decreases the financial burden associated with renal failure. Recipients of living donor grafts do not wait as long for their organs as the recipients of grafts from deceased donors, who may wait for years, depending on the region in which they are listed and their level of preformed antibodies to the major histocompatibility complex. Another advantage of living donor kidney transplantation is virtual absence of delayed graft function (DGF) as a result of relatively short cold ischemia times and the lack of the physiologic perturbations associated with brain death that may lead to allograft dysfunction. The avoidance of DGF is advantageous as it has been associated with an increased incidence of acute rejection and linked to the development of chronic allograft nephropathy, which both lead to inferior graft survival. Kidneys obtained from living donors outperform those from deceased donors at all time points as evidenced, for example, by a 5-year graft survival rate of >85% for living donors versus 75% for deceased donors. Finally, when surgical complications, primary nonfunction, and other causes of early graft loss are excluded, the 1-year conditional half-life of living donor transplants was 15.3 years for transplants performed from 2009 to 2010, whereas the half-life of deceased donor grafts was 12.5 years during that same period.
Living donor kidney transplantation has a number of other benefits that are harder to quantify. The procedures are scheduled electively, usually at the discretion of the donor, so they are performed during the day when the operative team is rested and all ancillary services are fully staffed. Living donation allows for the optimization of any medical comorbid conditions that might affect recipient outcome adversely. Theoretically, every living donor transplant performed leaves a deceased donor kidney for another recipient on the transplant list. However, in the US, despite the growth of the waiting list, the number of living donor kidney transplants continues to decline, and there were 1000 fewer live donors in 2016 than in 2004.
Matching Donor and Recipient
Optimal human leukocyte antigen (HLA) matching of a living kidney donor with a recipient influences long-term allograft survival. A few key donor/recipient factors have emerged as predictors of long-term outcomes. Ideal HLA matching is not required for living kidney donation, because even a poorly matched living donor kidney may perform better than a deceased donor kidney. However, each additional HLA mismatch comes with a significant linear adverse effect on allograft survival. Furthermore, kidneys from deceased donors are associated with the lowest effect of HLA mismatch, kidneys from living related donors are associated with an intermediate effect from HLA mismatch, and kidneys from living unrelated donors are associated with the highest effect from HLA mismatch. ABO incompatibility (ABOi) may serve as another immunologic barrier to living donor kidney transplantation. However, 1-, 3-, and 5-year ABOi graft survival rates with peritransplant immunomodulatory therapies are now comparable to United Network for Organ Sharing data for compatible live donor kidney transplants (see section on ABO Incompatibility). Age disparity between donors and recipients also plays a role in matching. Theoretically, age matching is of considerable importance, because younger kidney transplant recipients receiving older allografts may outlive their allografts and require retransplantation, whereas older recipients may die of other causes before their allograft fails, which both lead to suboptimal organ usage. Additionally, recent data have demonstrated that increasing living donor age is associated with reduced allograft survival, particularly in longer-term follow-up.
Global Variations in Living Donor Kidney Transplantation
Comprehensive global assessments of living kidney donation have seldom been performed because of the varying transparency of practices between countries. Recently global trends of 69 countries with available national data have been examined. In 2006 about 27,000 legal living donor kidney transplants were performed worldwide, accounting for nearly 40% of all kidney transplants. In addition to legal practices, the World Health Organization estimates a significant fraction of kidney transplants worldwide involve unacceptable or illegal practices. In general, the number of living kidney donor transplants has grown, with 62% of countries reporting at least a 50% increase in volume from the preceding decade. The highest volume of living donor kidney transplants was performed in the US (6435), Brazil (1768), Iran (1615), Mexico (1459), and Japan (939).
The current proportion of all kidney transplants from living and deceased donors shows substantial geographic variation. Most European countries, such as Poland, Spain, Italy, France, and Germany, derive a majority of their kidney allografts from deceased donors; thus the proportion of living donor kidney transplantation is small (<20%). In countries such as the US, Canada, United Kingdom, Sweden, and Switzerland, the proportion of living donor kidney transplants is increasing (now 20%–50%) alongside robust deceased donor networks. In countries such as Brazil, Korea, Turkey, Japan, and Iran, the majority of kidney transplants are from living donors (>50%). Notably in Japan, laws that were in place until 2010 required family consent for organ recovery despite the documented will of a donor, a practice that significantly hampered rates of deceased donation on the basis of cultural norms. Moreover, Iran is the only country in the world with a paid living unrelated kidney donation program, which accounts for about 75% of all its kidney transplants. Finally, in countries such as Egypt, Jordan, Pakistan, Oman, and Iceland, all kidney transplants are from living donors, because there is no deceased donor program in place.
Organ Supply Problem
The need for kidney transplants continues to far exceed the demand, although the absolute number of registrants on the list has plateaued over the past few years to just under 100,000 in the US. This observation has been attributed to a combination of factors, including implementation of the kidney allocation system (KAS). Now that waiting time is calculated from the date that dialysis was initiated, there is no benefit to maintaining a patient with end-stage renal disease (ESRD) on the waitlist in an inactive status while outstanding medical, financial, or psychosocial issues are addressed. Over the past decade, the number of kidney transplants performed each year has generally increased; however, gains in the number of kidneys recovered from deceased donors have been offset by a decline in number of living donors. For example, in 2004, 16,007 patients underwent kidney transplantation (9359 from deceased donors and 6648 from living donors). The number of allografts increased to 19,060 in 2016. However, that growth was driven entirely by an increase in the number of kidneys recovered from deceased donors (13,431) as the number of living donor grafts declined to 5629. Community outreach education initiatives, and programs through state divisions of motor vehicles where millions of drivers have provided first-person donor consent, have likely led to an increase in deceased donors, but a corresponding increase in living donors has yet to be realized. The current opioid epidemic in the US has also yielded an increase in deceased organ donors despite fears of disease transmission blunting the potential. In this era of sophisticated disease detection methodologies (e.g., nucleic acid testing), the risk of dying without being transplanted is higher than the risk of unintentional disease transmission.
Another sequela of the organ donor shortage is patient mortality while on the waiting list. Of the approximately 99,000 patients waiting for kidney transplantation in 2015, almost 5000 died. The role for living donor kidney transplantation to improve waitlist mortality may be limited given the decreasing number of individuals willing to donate and the large percentage of living donor kidneys that are transplanted preemptively. Of the 31,672 patients removed from the kidney transplant waitlist in 2015 (because of transplantation, medical deterioration, psychosocial reasons, or death), 18% received kidneys from living donors whereas 39% underwent transplantation from deceased donors.
Quality of the Living Donor Kidney
The need for risk stratification of deceased donor organs has long been recognized. Accordingly, an evolution has occurred from the simplistic expanded criteria donor (ECD) classification to the more sophisticated Kidney Donor Risk Index (KDRI) and related Kidney Donor Profile Index (KDPI). In aggregate, these tools have helped shape deceased donor organ allocation and provide the best available basis for patient and provider decisions regarding accepting or declining a given kidney offer. Recently the first Living Kidney Donor Profile Index (LKDPI) was developed. The national data used in developing the LKDPI demonstrated that donor age >50 years, African American race, ABO incompatibility, and HLA-B and HLA-DR mismatches were associated with worse graft survival, whereas higher donor estimated glomerular filtration rate (eGFR), donors unrelated to the recipient, and male-to-male donation were associated with better graft survival. This system allows direct comparison between two living donor kidneys, or comparison between a living donor kidney and one from a deceased donor. The LKDPI is particularly useful in decision making for recipients fortunate enough to have multiple potential living donors, or those who receive deceased donor kidney offers while potential living donors are under evaluation. Additionally, this index is useful in kidney paired donation (KPD). Incompatible pairs entering a KPD system can use this index to decide which alternative living donors are acceptable, and, in the case of paired donation, to evaluate the possibility of receiving a deceased donor kidney in exchange for their living donor donating to another person on the waiting list.
Types of Living Donors
When educating patients and their families about kidney transplantation, it is imperative that the advantages of the living donor are emphasized: shorter waiting time, better quality kidney/function, and longer allograft survival. Many patients are still under the impression that living donors must be blood relatives; however, transplant professionals should encourage recipients to expand their searches. In this era of social media, a wider net can be cast, although the ethical considerations are still under debate. Patients should also be taught that any interested, reasonable donor should present for screening, because blood type matching is not always necessary given desensitization protocols and the expanding role of paired donation. Once judged with skepticism, altruistic donors are now coveted because the paired donation experience has demonstrated their importance in initiating transplant chains. Some centers take the patient out of the role of soliciting for a kidney and transfer that responsibility to an advocate or “champion.” The effect that these efforts will have on the living kidney donor pool is not known at this time.
Kidney Paired Donation
KPD is now an option for recipients with willing and medically fit donors who are deemed poorly compatible on the basis of immunologic (e.g., ABO or HLA incompatibility) or other factors (e.g., age, gender differences, BMI mismatch), which affects up to 30% of cases. In these circumstances, incompatible donor/recipient pairs can be entered into a pool of one or more additional incompatible pairs who are in a similar situation. Subsequently, by exchanging donors, all recipients have the potential to receive a compatible organ match. Early paradigms consisted solely of same-day, two-way swaps performed at the same location. However, the demonstrated safety of shipping living donor kidneys from one center to another and the addition of nondirected donors to the donor pool has allowed feasibility of KPD across much larger geographic areas. The US is unique in that single-center, multicenter, and national programs that operate independently of one another coexist. Programs have uniformly reported at least equivalent graft survival rates compared with traditional non-KPD living donor transplants. A single, national KPD system that includes the need for uniform tissue-typing platforms, computerized matching algorithms, and a standardized organ acquisition charge has been proposed, but faces several logistical challenges that have impeded implementation. Such a system exists in other geographic areas, including the United Kingdom, where a national sharing scheme has been established for living donor kidneys. Matching runs are undertaken every 3 months and, from January 2018, all nondirected altruistic donors in the UK are entered into the scheme unless the donor takes exception to this. This has led to a steady increase in the number of kidneys transplanted through the scheme, with results that are comparable to related living donor transplantation (see Chapter 23 for more details).
ABOi transplants had long been considered a contraindication to kidney transplantation with Hume et al. in the 1950s remarking, “[W]e do not feel that renal transplantation in the presence of blood incompatibility is wise.” However, the increasing organ shortage has stimulated the development of strategies to allow transplantation across this immunologic barrier. Current ABOi immunomodulation protocols variably include recipient treatment with one or more of the following: (1) plasmapheresis to remove anti-A/B antibodies, (2) intravenous immunoglobulin, and (3) B cell–depleting therapies such as rituximab or splenectomy, which are combined with powerful maintenance immunosuppression posttransplantation. The ultimate goal of these protocols is to decrease the level of anti-A/B antibodies below a safe threshold in the immediate posttransplant period. After an approximately 2-week period of engraftment, rebound anti-A/B antibody production inevitably occurs, but this rebound does not appear to cause significant injury to the kidney allograft (a process termed accommodation ). Increasing experience with ABOi kidney transplantation has led to outcomes that are now equivalent to ABO-compatible transplantation in both pediatric and adult patient populations.
Donors are evaluated in a multidisciplinary manner that includes an independent living donor advocate, nephrologist, surgeon, social worker, medical psychologist, and financial counselor. The medical evaluation has multiple components, some of which can start before the patient is seen at the transplant center, and culminates in the review of all data by a multidisciplinary team and a final decision regarding candidacy. These components are listed in Box 7.1 , but the broad categories include: (1) a thorough medical history and physical examination including family history focused on renal disease; (2) general health laboratory evaluation with focus on renal function, HLA typing, HLA antibody screening, ABO typing, and screening for transmissible infection; (3) age-appropriate health and cancer screening; and (4) cross-sectional imaging of kidney anatomy.
History and Physical Examination
Interview with focus on renal disease and family history of renal disease
Detailed health questionnaire
Donor education and consent
History and physical examinations by transplant nephrologist and surgeon
Multiple complete vital signs
Evaluation by mental health expert
Interview with independent living donor advocate
Laboratory Testing to Evaluate Renal Function and Determine Immunologic Compatibility
Blood pressure—two to three separate measurements
Additional 24-hour blood pressure monitoring as indicated
Urine protein assessment (via 24 h urine or spot protein to creatinine ratio)
Glomerular filtration rate assessment (via 24 h creatinine clearance, iothalamate clearance, or radioisotope clearance)
Oral glucose tolerance test and/or HbA 1c
Metabolic workup if previous history of renal stones
Donor ABO typing
Complete blood count with platelet count and differential
Comprehensive metabolic panel to include fasting serum glucose and measurement of transaminases
Fasting lipid profile
Coagulation studies to include the prothrombin time, international normalized ratio, and partial thromboplastin time
Urinalysis and culture
Crossmatch with recipient
Human leukocyte antigen (HLA) typing of the donor
Identify Transmissible Infectious Disease
Human immunodeficiency virus, hepatitis B and C
Rapid plasma reagin (syphilis screen)
Testing for tuberculosis (TB)—TB skin testing or QuantiFERON-TB Gold
Testing for Strongyloides, Trypanosoma cruzi, and West Nile virus for donors from endemic areas
Evaluation of Renal Anatomy With Cross-Sectional Imaging
Abdominal imaging using computed tomography angiography or magnetic resonance angiography
Age-Appropriate Health Screening, Including Cancer Screening
Prostate-specific antigen (recommendations based on donor age and family history)
Gynecologic examination with Papanicolaou smear
Pregnancy test if indicated
Echocardiography and cardiac stress testing as indicated
Pulmonary function studies and computed tomography scanning of the chest as indicated
The medical history focuses on possible comorbidities such as hypertension, diabetes, cardiovascular or cerebrovascular disease that must be quantified. Multiple blood pressure readings are obtained to provide a reliable baseline. Laboratory profile includes the tests shown in Box 7.1 and specifically includes urine studies to estimate renal function and to evaluate for proteinuria. In the US, measuring renal function is a requirement and can be completed by collecting 24-hour urine samples to calculate the 24-hour creatinine clearance, or glomerular filtration rate (GFR) can be measured by nuclear imaging studies.
Immunologic testing includes ABO and HLA typing of the donor to allow interpretation of compatibility with the recipient, choosing between donors, if there are more than one, or pairing the donor with the most appropriate recipient in the case of paired exchange. Measurement of possible communicable infectious diseases such as hepatitis B and C and HIV is necessary. Screening for tuberculosis (TB) is highly recommended using TB skin testing or QuantiFERON-TB Gold. Donors who test positive should be treated for 6 to 9 months before proceeding with donation. Screening for syphilis is also highly recommended, and, if there is history of travel to Central or South America, Chagas’ disease as well. West Nile virus screening is also advised.
Abdominal imaging is usually delayed until donors pass the medical and laboratory screening stages to avoid unnecessary risk and cost. Depending on local expertise, either computed tomography (CT) angiography or magnetic resonance angiography is performed to identify vascular anatomy, size of kidneys, and the anatomy of the urinary collecting system.
All donors older than 50 and those older than 40 with cardiovascular risk factors should undergo appropriate cardiovascular diagnostic studies and imaging, such as stress testing. All donors are screened with chest x-ray, and those with a history of smoking, lung disease, or abnormal chest x-ray are screened with chest CT scan as well. Guidelines for cancer screening are published by the American Cancer Society and others according to age and gender, and guide the performance of these screening tests for donors.