Medical Evaluation of the Living Donor

7

Medical Evaluation of the Living Donor MATTHEW J. ELLIS, BRADLEY HENRY COLLINS, BRIAN EZEKIAN, and STUART J. KNECHTLE

CHAPTER OUTLINE

History of Living Donation and DonorRelated Ethics The Rationale for Living Donation Matching Donor and Recipient Global Variations in Living Donor Kidney Transplantation Organ Supply Problem Quality of the Living Donor Kidney Types of Living Donors

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.1 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.2 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 104

Kidney Paired Donation ABO Incompatibility Medical Evaluation Surgical Evaluation Long-Term Outcomes After Living Donation Financial Considerations Living Donor Quality Initiatives

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.3 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 2015.4 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. 

7 • Medical Evaluation of the Living Donor

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.5 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.4 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.6 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.7,8 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.5 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.9 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 2004.10

MATCHING DONOR AND RECIPIENT Optimal human leukocyte antigen (HLA) matching of a living kidney donor with a recipient influences longterm 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,

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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.11 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).12–15 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.16,17 

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.18 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.19 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.20 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

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unrelated kidney donation program, which accounts for about 75% of all its kidney transplants.21 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.10 This observation has been attributed to a combination of factors, including implementation of the kidney allocation system (KAS).4 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).10 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 5629.10 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.22 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.23 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.4 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.4,10 

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).24–26 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.27 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.28 

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.29 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.30 Some centers take the patient out of the role of soliciting for a kidney and transfer that responsibility to an advocate or “champion.”31 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.32 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, twoway swaps performed at the same location. However, the demonstrated safety of shipping living donor kidneys from

7 • Medical Evaluation of the Living Donor

one center to another33 and the addition of nondirected donors to the donor pool has allowed feasibility of KPD across much larger geographic areas.34 The US is unique in that single-center, multicenter, and national programs that operate independently of one another coexist.35 Programs have uniformly reported at least equivalent graft survival rates compared with traditional non-KPD living donor transplants.36–38 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,39 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 transplantation40 (see Chapter 23 for more details). 

ABO INCOMPATIBILITY 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.”41 However, the increasing organ shortage has stimulated the development of strategies to allow transplantation across this immunologic barrier. Current ABOi immunomodulation

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protocols variably include recipient treatment with one or more of the following: (1) plasmapheresis to remove antiA/B antibodies, (2) intravenous immunoglobulin, and (3) B cell–depleting therapies such as rituximab or splenectomy, which are combined with powerful maintenance immunosuppression posttransplantation.42 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).43 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.14,15 

Medical Evaluation 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

BOX 7.1  Components of the Living Donor Evaluation 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 HbA1c 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 Electrocardiograph Chest x-ray 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 Colonoscopy Mammogram Pregnancy test if indicated Echocardiography and cardiac stress testing as indicated Pulmonary function studies and computed tomography scanning of the chest as indicated

Modified from kidney transplantation, 7th ed., Chapter 7, MacConmara and Newell.

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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. 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.44 

Surgical Evaluation The surgeon’s unique role is to assess the operative risk of the donor. Factors that can contribute to increased morbidity include prior abdominal operations and elevated BMI. Transplant centers have various thresholds for maximum BMI in donors, with some extending their upper limit to 35 kg/m2.45 In this population, consideration should be given to the increased risk of hypertension, diabetes, heart disease, and renal disease before acceptance as a donor. The Scientific Registry of Transplant Recipients (SRTR) obesity rate for living donors in 2015 was 20% with a BMI range of 30 to 35 kg/m2 and 3% over 35 kg/m2.4 Elevated BMI is also a risk factor for prolonged surgical time and wound complications.

The primary surgical approach to living kidney donation is laparoscopic, and 97% of living donor kidneys in 2015 were retrieved by this method.4 Many surgeons prefer the hand-assisted technique. However, almost 40% of cases are performed completely laparoscopically. The kidney is extracted from the abdomen via either a periumbilical or Pfannenstiel incision. The choice of the kidney is usually driven by anatomic considerations, with preference for the left because of the longer, more substantial renal vein (for more details on donor nephrectomy see Chapter 8). The presence of multiple renal arteries may present challenges at implantation, so both the recovering and implanting surgeons should review preoperative imaging. Small upper pole arteries can be ligated should they pose undue risk during implantation (prolonged warm ischemia); however, every effort should be made to preserve lower pole arteries, because they usually provide blood supply to the ureter. Techniques include anastomosis to the main renal artery on the back table or separate arterial anastomoses in the recipient. To minimize warm ischemia time, some surgeons reperfuse the kidney once the main arterial anastomosis has been completed, then perform the second anastomosis at a more distal site on the native iliac artery. Immediate complications of living kidney donation that may require reoperation include injury to intraabdominal viscera, bleeding, and wound dehiscence (Table 7.1).46 Potential donors should also be made aware of other complications including lymphatic leak (chylous ascites), wound infection, hernia, and deep venous thrombosis. Death resulting from donor nephrectomy is rare; however, donors should be counseled that it is possible. Between 2011 and 2015 in the US, 7 out of 28,291 living kidney donors died (approximate incidence of 1 in 4000) because of what was termed “donation-related” causes.4 Most living donors are discharged within 2 days of surgery. In an attempt to decrease hospital stay prolonged by TABLE 7.1  Donor Complication Risks Risk (Percentage of Donations Unless Stated) Mortality MAJOR COMPLICATION Bleeding Bowel obstruction Vascular injury Open conversion Reoperation Blood transfusion Wound infection Urinary tract infection Readmission (including nausea, vomiting, gastroenteritis, abdominal pain, ileus, bowel obstruction) Hernia repair End-stage renal failure Hypertension

0.02–0.03 2.2 1.0 0.27 0.7–1.1 0.52 0.4 2.1 4.5 2–5 0.8 Hazard ratio 11.38 Additional risk in obese, elderly, and African American donors 15–25

Data from OPTN/SRTR 2015 Annual Data Report. In: Scientific registry of transplant recipients 2017; Mjøen G, Hallan S, Hartmann A, et al. Long-term risks for kidney donors. Kidney Int 2014;86:162–7; Lam NN, Lentine KL, Levey AS, et al. Long-term medical risks to the living kidney donor. Nat Rev Nephrol 2015;11:411–9.

7 • Medical Evaluation of the Living Donor

gastrointestinal complications (constipation, etc.), some centers have applied an enhanced recovery after surgery (ERAS) protocol to living donors. This includes preoperative bowel preparation, measured use of crystalloids in the operating room, and narcotic-free pain control. Convalescence for donors follows that of most major abdominal operations and includes avoiding driving and weight-lifting restrictions. However, walking is encouraged. Return to work depends on clinical assessment of recovery and the type of employment (desk job vs. construction). The rehospitalization rate for living donors is 5% at 1 year.4 Given the thorough medical evaluations that living donors are subjected to, the incidence of renal failure is low. However, as living donor criteria are extended, the incidence may increase. There are calculators that clinicians should employ to determine each candidate’s lifetime risk for renal failure.47 

Long-Term Outcomes After Living Donation Follow-up after living donation and characterization of the long-term outcomes have historically been limited by the short duration of follow-up, the high number of donors lost to follow-up, and the small number of minority donors; these limitations interfere with living donor programs accurately describing the inherent risks of kidney donation.48 One of the most worrisome outcomes after living donation is the development of ESRD. Current estimates in the US and Norway document a 7- to 11-fold increase in risk of ESRD after donation.49,50 White donors have up to a 6.1% increased risk for proteinuria development (a known risk factor for chronic kidney disease), whereas as many as 30% of donors will develop GFRs less than 60 mL/min/1.73 m2.51 The risks for proteinuria and “low” GFR are augmented by elevated systolic and/or diastolic predonation blood pressure, increased age, decreased predonation kidney function, and higher BMI (for each unit increase in BMI over 30, there is a 3% to 10% increase rate of new proteinuria and decreased GFR, respectively).51 In addition to renal-specific outcomes, donors may experience a number of other long-term risks. Matas and colleagues recently summarized what is known about postdonation, non-ESRD risks.52 Although many of these outcomes are known to be only associations, several risks have concrete, causal connections.    Cardiovascular risk: In the first few years after donation, a donor’s GFR most often increases, which is independently associated with increases in left ventricular mass, decreased aortic distensibility, and increased troponin measurements. These changes are all associated with increased rates of future cardiovascular events, including cardiac ischemia and heart failure. □  Pregnancy: Postdonation pregnancy does not carry an increased risk of maternal or fetal complications. However, donors tend to experience higher than expected rates of gestational hypertension and preeclampsia, similar to what is expected in women with prepregnancy hypertension, diabetes, and higher BMI. □ 

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Rehospitalizations: Patients who donate a kidney are at increased risk of subsequent hospitalizations in the 3 years after donation; some of these are related to donation, whereas other admissions are not. □  Mortality: Fortunately, there have been no clear signals for changes in mortality compared with the general population, with the caveat that most studies’ duration is not long enough to credibly state that there is no change. □ 

  

In 2013 the United Network of Organ Sharing (UNOS) mandated that centers report on patients’ laboratory and clinical outcomes and follow-up at 6, 12, and 24 months postdonation. Before the 2013 UNOS mandate, fewer than 50% of patients had clinical data reported, which has more recently improved to approximately 65%; similarly, less than 40% of patients had laboratory data reported, which has also improved to 56%.53,54 Patient factors associated with higher rates of follow-up include female gender, younger age, college or higher education level, and residence in the same state as the performing transplant center. Center characteristics associated with limited follow-up include lack of reimbursement and a lack of transplant center resources to accomplish follow-up.54 Donor surveys suggest that followup would be better if postdonation communication was more regular, predonation education about the need and effect of follow-up was improved, and more resources were available to assist in covering donation-related followup expenses.55 Although follow-up is commonly lacking, increased follow-up success can be achieved. Single-center reports describe living donor program improvement projects that resulted in dramatic (14-fold) increases in completed 2-year follow-up and reporting,56 with modest financial impact to the center (less than $200 per patient), despite increased services offered to the patient. An important consideration related to postdonation medical complications includes the timing of these events. Whereas 2-year follow-up is required after donation in the US, very few of the important complications, namely increased blood pressure, increased urinary protein excretion, or a fall in GFR, occur during that time. Furthermore, long-term follow-up is challenging, even in countries with universal, single-payer health insurance.57 Importantly, follow-up care is even more important in the current donation climate, in which transplant centers seek more living donors and allow more comorbid condition(s), as attention is paid to narrowing the gap between the increasing number of waitlisted patients and the relatively flat number of transplants performed each year. Currently, donors more often tend to be unrelated to the recipient, older, insured, employed, college educated, have a history of smoking and/ or hypertension, lower GFR pretransplant, and living outside of the US. An important component to medical and/or psychological follow-up is having reliable access to the healthcare system, principally a primary care provider (PCP). However, close to 25% of patients who donate have either never had a PCP or visit with a PCP irregularly before donation.58 The rate of follow-up after donation continues to be low, with only about 20% of donors seeking regular care with a PCP; this is particularly true among men who have completed less than a college education and who did not have a regular PCP before donation.58 The importance of having a PCP is highlighted

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by the fact that a donor is 14 times more likely to not have any follow-up in the first year after transplant if they had no regular PCP before transplant.53 Finally, the demographic risk factors for not having a PCP mirror those risk factors for not completing required follow-up and for increased risk of lower GFR, higher blood pressure and proteinuria, and other deleterious outcomes after donation.53,58 This suggests that screening for these factors may be as important as other, more traditional laboratory, physical examination, or medical history elements of a donor’s workup. Because the donor-derived benefits of living donation are psychological and not medical, specific attention to psychological outcomes is important. Additionally, donors are required to undergo extensive pretransplant psychological screening to understand their motivations for donation, to rule out any type of coercion, and to assure that each patient is free from any significant mental health issues that might influence the donation decision or complicate postdonation recovery. In general, there is a low rate of mental health issues among donors compared with the general population. However, the risk for postdonation depression and anxiety is real, along with its potential to negatively affect a donor’s quality of life. Up to 20% of donors report decreased postdonation quality of life; this is particularly true for nonrelated, nonspouse donors who experience a medical complication or who witness their graft fail in the recipient.52,59 Furthermore, if the donor is ambivalent before transplant or has a longer recovery (related to or independent of complications), they have a higher risk of postdonation psychological complications, specifically anxiety.59 

Financial Considerations Long-term donor outcomes can also be measured financially, from a number of different perspectives, related to both direct and indirect costs. Understanding the financial impact of donation is critical from both patient and societal

perspectives. Most would argue that a donor who has altruistically undergone nephrectomy for no direct medical benefit should incur as few negative consequences (including financial) as possible. Furthermore, when patients undergo financial hardship, including time away from activities of daily living and/or work, there is a significant societal strain. Finally, financial constraints and concerns may contribute to limiting enthusiasm for donation, a concept cited frequently for the recent stagnation in living donor rates. Pretransplant, more than 9 of 10 donors state that they incurred a cost related to their donation workup. These costs include travel, lodging, or other health-related costs.60 Whereas the demographic characteristics of donors vary across the country, data suggest that a high percentage of donors (85%) work outside of the home, with approximately 30% of these donors in professional lines of work. After donation, about 75% of donors indicate that they were out of work for 4 weeks, with approximately 20% stating that they were unable to perform their activities of daily living for this same time period.61 Impaired function translates into costs not commonly considered: 30% of donors stated that they spent money on child care or help covering required house maintenance, and so on.60 Attempts to place a financial value on direct and indirect costs is challenging and convoluted. However, after taking a number of factors into consideration, just less than 40% of donors will spend up to $500 related to their donation in the 12 months after the event, with 20% spending more than $5000 during that same time period.60 A similar effect is noted in other countries around the world, including Canada.62 Another consideration for donors pretransplant is the effect of donation on the attainment of postdonation insurance (health, life, or other). As many as 57% of transplant centers indicate that a lack of predonation insurance is an absolute (15%) or relative (42%) contraindication to donation (Table 7.2; Figs. 7.1 to 7.4).60 Although the rate of insurance among donors in the US is proportional to the rate of uninsured people in the general population,

TABLE 7.2  Absolute and Relative Contraindications to Living Kidney Donation Age Informed consent Substance abuse Hypertension

Diabetes Obesity Renal disease Renal stones Inherited renal disease Infection Cancer Cardiovascular disease Renal anatomic abnormalities

Absolute

Relative

Less than 18 years Impaired ability to make an autonomous decision because of mental or psychiatric condition Active substance abuse Multiple agents or high doses of single agents for control Evidence of end-organ damage End-organ injury Additional strong risk factors for cardiovascular disease Diabetes mellitus Morbid obesity (BMI >35) with comorbid conditions Evidence of renal disease with reduced creatinine clearance (GFR <80 mL/min), proteinuria (>250 mg), or hematuria Multiple or recurrent renal calculi of a metabolic condition that predisposes to the recurrence of renal calculi ADPKD, SLE, Alport’s syndrome, IgA nephropathy HIV, hepatitis B, hepatitis C, West Nile virus, Chagas’ disease Cancer current or treated but at significant risk for recurrence Coronary or peripheral vascular disease, or heart valve disease Significant discrepancy in the kidney sizes

Over 65 excluded from many programs

Borderline or control with single agents

Impaired glucose tolerance Obesity (BMI >30) with comorbid conditions Borderline creatinine clearance, microscopic hematuria low levels of proteinuria (<30 mg/24 h) Single renal stone TBMD, mutations in APOL1 Hepatitis B core antibody Vascular anomalies (see Figs. 7.1 to 7.4)

ADPKD, adult polycystic kidney disease; APOL1, apolipoprotein L1; BMI, body mass index; GFR, glomerular filtration rate; HIV, human immunodeficiency virus; IgA, immunoglobulin A; SLE, systemic lupus erythematosus; TBMD, thin basement membrane disease. Modified from kidney transplantation, 7th ed., Chapter 7, MacConmara and Newell.

7 • Medical Evaluation of the Living Donor

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Fig. 7.1  Duplication of the renal collecting system. (A) Image from a computed tomography angiogram demonstrating a left kidney with duplicated ureters. (B) Magnetic resonance imaging demonstrating duplication of the collecting systems of both the right and left kidneys. Arrows in each panel identify the duplicated ureters.

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Fig. 7.2  Renal venous anomalies—retroaortic left renal vein. (A) Image from a computed tomography angiogram demonstrating a retroaortic left renal vein (arrow identifies the retroaortic left renal vein). Note the characteristic inferior course of the retroaortic left renal vein relative to the left renal artery. (B) Reconstructed image clearly demonstrating the left renal vein coursing posterior to the aorta.

there are disparities among black and Hispanic donors. This is concerning, because these groups of donors are more likely to experience hypertension, proteinuria, or other outcomes that would require subsequent medical diagnostic and therapeutic attention after donation.60 This is further complicated by the fact that nearly 10% of donors indicate that they had trouble obtaining health insurance after donation, either because insurance companies would not insure them or because the premium to do so was too high, even after the Affordable Care Act was passed in the US.60 Most recipient insurance plans cover the costs of the donation evaluation, nephrectomy, and associated hospitalization

for the donor. However, coverage for postdonation complications is not always uniformly and durably covered. Additionally, postdonation coverage becomes even more unclear when donors have preexisting health issues, an increasingly common problem, because as the acceptable donor age rises, so do potential health issues, such as a history of hypertension, obesity, and kidney stones. Although a great deal of additional data is needed to understand how to maintain kidney donation as cost neutral, having a clear framework for understanding what costs a donor may encounter is helpful, including being specific about what outcomes are affected by donation; this allows for more straightforward attribution of risk to the act of donating.63 

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Fig. 7.3  Renal venous anomalies—duplication of the inferior vena cava and circumaortic left renal vein. (A) Duplication of the inferior vena cava (arrow identifies the duplicated, left-sided inferior vena cava and double arrow demonstrates the left-sided inferior vena cava crossing the aorta to join the main, right-sided inferior vena cava). (B) Circumaortic left renal vein (arrows indicate the component of the left renal vein that cross anterior and posterior to the aorta and the relationship to the left renal artery).

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Fig. 7.4  Anatomic abnormalities of the renal arteries. (A) Left kidney with two renal arteries with a small-caliber lower pole artery arising from the aorta immediately inferior to the main left renal artery (arrow indicates the position of the two renal arteries). (B) Reconstructed image from a computed tomography angiogram demonstrating a left renal artery with an early bifurcation (arrow indicates the larger, superior and smaller, inferior branches of the left renal artery).

Living Donor Quality Initiatives Because potential health consequences follow kidney donation, and because the long-term effect of donation is not completely known, a comprehensive quality program at each transplant center is increasingly important. Public reporting of transplant outcomes includes reporting of living donor outcomes. Living donor quality programs are a particular emphasis as donors become more medically complex. Furthermore, with the growth of paired exchange programs, the logistics of living donation have become increasingly complicated. Finally, because living donor rates have plateaued over the last several years, providing quality data may help in understanding impediments to growth.

A number of factors influence living donor rates in the US, including donor and recipient demographics, cultural beliefs about transplantation, the number of unrelated versus related donors available (particularly as the donor/ recipient relationship affects HLA and blood type compatibility), and the availability of the laparoscopic approach to nephrectomy. Many centers track the success of their living donor program based on the percentage of the total number of transplants performed from living donors, a ratio that hovers around 30% in the US. However, the rate of living and deceased donation may not be related; a more reflective measure may be the number of living donor transplants performed (or donors who register for evaluation) as a percentage of the number of new waitlist registrants.64 Measuring the living donor transplant rate in this way allows

7 • Medical Evaluation of the Living Donor

programs to more precisely understand barriers (race, socioeconomic status, age, HLA, or ABO incompatibility) in the regional donor pool. It also allows a different, and perhaps more accurate way to compare centers across a region or a country. Whereas more than 90% of donors say they would donate again, more than 25% say that their quality of life was affected negatively and 44% indicate that the donation experience could be improved, citing the time in evaluation was too long; too many required visits to complete in-person assessments and testing; and the number of postdonation encounters was not enough, leading to donors’ perceptions of feeling “lost to follow-up.”55 Toward this end, transplant centers’ quality programs should consider a focus on the patient experience, including the duration and number of visits required to complete a donor workup, and how many postdonation encounters are completed (either associated with or independent of mandated UNOS requirements). Quality of life after donation is critical to any definition of donor success and there is no doubt that donation can have a dramatic direct and indirect financial impact on a donor.61 Transplant centers should track time back to normal activities of daily living, time back to work, and costs incurred by donors. Certain groups of donors are particularly important to understand their course: donors who are female, have attained lower education, are related to the recipient, and have suffered complications at the time of donation are at the highest risk for prolonged return to daily activities and work.61 Additionally, as centers encourage more medically complex and racially diverse donors, attention must be paid to the financial impact of donation. Helping track insurance rates postdonation would help future donors better understand posttransplant risks and liabilities. Finally, in light of the fact that quality programs and initiatives, including improved donor follow-up, cost money,56 transplant centers should prospectively track the amount of effort directed toward these initiatives to quantify their effort and expenses to better understand the “value” of the donor experience.

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