Evaluation of Donors and Recipients

36 Evaluation of Donors and Recipients Heidi M. Schaefer, MD, and Beatrice P. Concepcion, MD OUTLINE Evaluation of the Living Donor, 570 Clinical Assessment of the Living Donor, 570 Kidney Function, 571 Proteinuria, 571 Microscopic Hematuria, 572 Cardiovascular Risk, 572 Hypertension, 572 Diabetes, 572 Obesity, 572 Inherited Renal Disease, 572 Nephrolithiasis, 573 Psychosocial Evaluation and Informed Consent, 573 Surgical Techniques and Risks, 573 Long-Term Risks to the Donor, 573 End-Stage Renal Disease, 573 Pregnancy, 573 Quality of Life, 574 Long-Term Medical Care, 574 Conclusions, 574

EVALUATION OF THE LIVING DONOR Living kidney donation has become an increasingly important option because of the ongoing disparity between the number of end-stage renal disease (ESRD) patients listed for kidney transplantation and the availability of deceased donor kidneys. Each year, nearly 6000 transplants are made possible by living donors. As outlined in Box 36.1, living kidney donation has advantages and disadvantages for both the recipient and the donor.1 Recipients of live donor kidneys have better graft and patient survival compared with deceased donor recipients because donors are healthier, cold ischemia times are shorter, and ischemia-reperfusion injury is minimal. Waiting times for deceased donors organs are typically many years long, so living donation also minimizes or avoids dialysis time for the recipient. Over the years, the population of living kidney donors has evolved to include biologically unrelated donors and medically complex donors with increasing prevalence. More than 25% of donors are unrelated to the recipient, encompassing spouses, friends, coworkers, and even altruistic donors.2 With studies showing favorable outcomes related to surgery

570

Evaluation of the Recipient, 574 Clinical Assessment of the Recipient, 574 History, Physical Examination, and Diagnostic Testing, 574 Selected Issues in the Recipient Evaluation, 576 Cardiovascular Disease, 576 Diabetes Mellitus, 577 Pulmonary Disease, 577 Cancer, 578 Obesity, 578 Infections, 578 Systemic Diseases, 579 Emerging Risk Factors That May Affect Kidney Transplant Candidacy, 580 History of a Failed Allograft, 580 High Sensitization to Human Leukocyte Antigens, 581 Psychosocial Issues, 581 Counseling and Education, 581 Management of the Waiting List, 581 Conclusions, 581

and long-term health and survival, many centers have relaxed their criteria for living donation and are willing to consider donors with isolated medical abnormalities, including controlled hypertension, obesity, and glucose intolerance, as well as a glomerular filtration rate (GFR) around the lower limits of the normal range. Because living kidney donors are undergoing a surgical procedure without any medical benefit to their own health, it is important that the evaluating physician carefully explain the known risks to the donor during the evaluation process to ensure that informed consent is achieved. 

CLINICAL ASSESSMENT OF THE LIVING DONOR The medical evaluation of the living kidney donor consists of laboratory and radiological studies to confirm excellent health and adequate kidney function. A thorough assessment of the results of these tests, as well as a comprehensive history and physical examination, should be performed by a physician not involved in the care of the recipient to avoid

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BOX 36.1  Advantages and Disadvantages

BOX 36.3  Contraindications to Living

Advantages to Recipient • Scheduled operation during daytime hours • No waiting time on the deceased donor waiting list • Minimal cold ischemia time • Usual immediate allograft function • Overall better long-term survival compared with deceased donor kidney transplantation • Emotional benefits between the donor and recipient 

Age <18–25 or >70–75 years Mentally incapable of making informed decision Obesity with body mass index >30–35 Hypertension (uncontrolled, end organ damage, non-Caucasian race) Diabetes (gestational, prediabetes, glucose intolerance) Significant cardiovascular disease Low measured GFR or creatinine clearance <80–85 mL/min Significant proteinuria or microalbuminuria Malignancy Nephrolithiasis with high risk for recurrent stones High risk for infectious disease transmission Significant psychiatric illness likely to interfere with donation High suspicion of donor coercion or financial exchange Withdrawal of donor consent

of Living Donation

Advantages and Disadvantages to Donor • Emotional benefits between the donor and recipient • Sense of altruism and magnanimity for donor • Potential discovery of unknown health issues • Invasive operation with potential short- and long-term complications • Lost wages because of time off from work • Psychological stress on donor and family

BOX 36.2  Evaluation of the Living Donor Blood group, HLA typing, and cross-match testing Complete medical history and physical examination Chest radiograph Electrocardiogram Stress test and echocardiogram as required by the transplant center Laboratory evaluation with focus on fasting glucose, kidney function, and urinalysis for microscopic hematuria Hemoglobin A1C and oral glucose tolerance test if high risk for diabetes Evaluation of GFR • 24-hour urine for creatinine clearance • Nuclear medicine renal scan Estimation of proteinuria Assessment of renal anatomy usually through computed tomography angiography Infectious disease screening Age-appropriate cancer screening Psychosocial evaluation Nutritional education GFR, Glomerular filtration rate; HLA, human leukocyte antigen.

potential bias. Most centers require the donor to be at least 18 years of age and able to provide informed consent. The upper limit of age varies among transplant centers and may not be as important as the overall general health of the donor. Multiple guidelines are available to assist clinicians in the complex process of donor evaluation and selection.3-5 Recently Kidney Disease: Improving Global Outcomes (KDIGO) has published updated clinical practice guidelines on the evaluation and care of living kidney donors.6 The history, physical examination, and testing (Box 36.2) should focus on excluding contraindications to donation, ensuring that selected donors are at minimal risk for postdonation complications. It is important that infection and malignancy screening be performed in the potential donor to

Donation

GFR, Glomerular filtration rate.

prevent inadvertent transmission to the intended recipient as a result of the transplant. For the donor candidate, this workup occasionally results in the early detection of diseases that the donor was otherwise unaware of and allows for appropriate treatment and follow-up. Box 36.3 lists the absolute and relative contraindications to living kidney donation.

Kidney Function An accurate assessment of predonation kidney function allows physicians to estimate the likely level of residual kidney function that donors would have after donor nephrectomy. Most transplant centers obtain at minimum an estimated GFR (eGFR), although guidelines recommend confirmatory testing either through 24-hour creatinine clearance or radioisotope testing.3-6 Despite its limitations, measured creatinine clearance is usually the confirmatory test obtained because isotope testing is more costly, more time consuming, and less readily available. If the 24-hour creatinine clearance is marginal, it is recommended that a nuclear study be performed to ensure adequate kidney function before donation. Although previous guidelines recommended a GFR ≥80 mL/ min to proceed with kidney donation, KDIGO guidelines have recommend a GFR ≥90 mL/min/1.73 m2 as the acceptable threshold; most importantly, GFR < 60 mL/min/1.73 m2 is not acceptable.7 For GFRs that fall between 60 to 89 mL/ min/1.73 m2, KDIGO recommends that the decision to allow donation should be individualized, taking into account the donor age and other clinical risk factors in relation to the transplant center’s risk threshold. 

Proteinuria Proteinuria is usually a sign of renal disease and should be estimated either by 24-hour urine protein excretion or urine protein-to-creatinine ratio. We agree with most guidelines that recommend exclusion of potential live donors with a urine protein excretion of >300 mg/day or >30 mg/mmol on spot protein ratio.8 

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Microscopic Hematuria

Diabetes

Urinalysis and urine microscopy are routinely performed as part of the donor evaluation. Persistent microscopic hematuria, defined as more than 3 to 5 urinary red blood cells per high-power field, can result from many causes, such as infection, glomerular disease, nephrolithiasis, and urothelial carcinoma. To exclude urological disease, investigations can include urine culture, urine cytological testing, imaging of the kidneys and urinary tract through ultrasound or computed tomography (CT) scan, and cystoscopy. If the urological workup is unremarkable, a kidney biopsy should be considered to rule out glomerular disease, which precludes donation with the possible exception of isolated thin basement disease. It is important to distinguish thin basement membrane disease from immunoglobulin A (IgA) nephropathy because progressive renal disease is rarely observed with the former condition but occurs in 15% to 40% of patients with IgA nephropathy.9 It is important to discuss with prospective donors the additional, albeit small, risk conferred by microhematuria evaluation, in the context of their overall risk and commitment to donate. Although short-term outcomes for donors with persistent microscopic hematuria and no contraindication to donation are reassuring, the long-term outcomes remain to be determined. 

Because type 2 diabetes is a major cause of ESRD, most transplant centers do not accept potential donors with glucose impairment or overt diabetes or those with a strong family history of diabetic kidney disease, although it is unclear whether in these settings, donor nephrectomy leads to higher risk for diabetic nephropathy or faster progression of nephropathy. All potential donors should have a fasting plasma glucose, and in those with additional risk factors for diabetes, including first-degree relatives with diabetes, history of gestational diabetes, or body mass index (BMI) >30 kg/m2, a glucose tolerance test and hemoglobin A1C should be performed. Recently revised American Diabetes Association guidelines should be applied to diagnose diabetes and prediabetes.13 

Cardiovascular Risk Cardiovascular risk factors, including assessment for hypertension, diabetes, obesity, hyperlipidemia, tobacco abuse, and family history of early coronary artery disease, should be identified during the initial donor evaluation. Chest x-ray examination and electrocardiogram are also standard. For low-risk donor candidates, further cardiovascular evaluation is not recommended. It is suggested that stress testing should be performed in men aged 50 years or older, women aged 60 years or older, and donor candidates with more than one cardiac risk factor.10 However, no available evidence exists to support more rigorous cardiac testing than is recommended for nondonors undergoing surgery. 

Hypertension Donors should be screened for hypertension with two or more properly measured seated blood pressure (BP) readings. If there is concern for white-coat hypertension, ambulatory BP monitoring should be performed. Some centers allow for donation in the setting of mild hypertension controlled on one or two agents based on good short-term outcomes in selected donors.11 Selection criteria of these donors should include absence of end organ damage related to hypertension (left ventricular hypertrophy and retinopathy), absence of proteinuria and microalbuminuria, and normal GFR. The safety of donation under such circumstances has predominantly been studied in Caucasian donors.11 Available data indicate that hypertensive African American donors should be excluded because of the increased risk for postdonation kidney disease.12 

Obesity The majority of transplant centers exclude obese donors with a BMI >35 kg/m2 because of concern that excess weight is a known risk factor for ESRD.14 Despite this, the rates of obesity in living donors have increased with >25% considered obese at the time of donation.15 Obesity may be a risk factor for longer postdonation hospital length of stay and increased rates of postoperative wound complications. Although previous studies have suggested that obesity was not a risk factor for postdonation chronic kidney disease,16,17 a recent evaluation of Scientific Registry of Transplant Recipients (SRTR) data noted that donor obesity was independently associated with an increased risk for ESRD 20 years after kidney donation.18 Compared with nonobese living donors, obese donors had a 1.9-fold increased risk for postdonation ESRD.18 It is prudent to discuss weight loss management strategies and provide informed consent regarding potential short- and long-term risks in obese individuals considering living donation. 

Inherited Renal Disease Potential kidney donors, especially those considering donation to biological relatives, need to be assessed for hereditary kidney disease. It is important to be aware of the cause of the intended recipient’s kidney disease and whether other family members are affected. The most common scenario encountered is a family history of autosomal dominant polycystic kidney disease (ADPKD). If the potential donor is older than age 30 years, renal ultrasound or computed tomography of the abdomen and pelvis is highly sensitive in ruling out cystic disease. In younger donors, genetic testing either by linkage analysis or direct deoxyribonucleic acid should be obtained. Alport syndrome is a genetically heterogeneous disease with X-linked, autosomal recessive, and autosomal dominant variants, with the majority of cases being X-linked. Persons being evaluated for donation with a family history of Alport syndrome need to be screened for hematuria, hypertension, and hearing and eye abnormalities. Male siblings older than age 20 are unlikely to have the disease if hematuria is absent. Sisters of affected male recipients with X-linked disease have a 50% chance of being carriers; a small percentage of such women carrying the abnormal gene do develop renal failure. If hematuria is present, a kidney biopsy should be performed with immunostaining and consideration of genetic consultation. 

CHAPTER 36  Evaluation of Donors and Recipients

Nephrolithiasis A history of urinary tract stones has historically been a relative contraindication to donation because stones tend to recur and obstruction of a solitary kidney could adversely affect function. Despite this risk, there has been increasing acceptance of donors with a history of nephrolithiasis as long as stones are no longer present and no obvious metabolic abnormalities are identified that would increase future stone risk. Although data have shown no difference in the rate of kidney stones requiring surgical intervention or hospitalization in donors compared with nondonors,19 more studies are needed to evaluate the outcome of stone formers who donate and to identify those in whom donation may contribute to accelerated loss of kidney function or other stone complications. 

Psychosocial Evaluation and Informed Consent Current policy in the United States dictates that an independent live donor advocate (ILDA) must work with potential donors to ensure that they are informed and understand the process, are appropriately motivated, are free from coercion, and can make decisions autonomously, independent of family members or the intended recipient. The donor should not feel overt pressure or undue anxiety about proceeding and must be allowed to stop the evaluation process at any time. In addition, a careful psychosocial evaluation should be conducted by a social worker or psychiatrist. Significant psychiatric illnesses that would either impair the person’s ability to give informed consent or that might be negatively affected by the stress of surgery are contraindications to living donation. It is important that the donor have appropriate social support to assist in the postoperative period. If there are signs of secondary gain or financial reimbursement, the donor should be excluded from the process. 

SURGICAL TECHNIQUES AND RISKS The introduction of laparoscopic-assisted kidney donation has been a significant advance in organ donation with most major transplant centers performing this procedure. Before the advent of laparoscopic nephrectomy, donor kidneys were removed through the traditional method of open nephrectomy involving a large flank incision. The advantages of laparoscopic versus open nephrectomy include smaller incision, lower rates of incisional hernia, better wound cosmetics, less postoperative pain, shorter hospitalization, and less time away from work. However, the rates of early allograft dysfunction may be higher with this technique because of higher intraabdominal pressures required during the procedure, longer warm ischemia times, less experience with the technique, a learning curve, and more manipulation of the renal vessels. Despite slower early graft function, a recent Organ Procurement and Transplantation Network (OPTN) database analysis indicated equivalent short- and long-term adult recipient outcomes with either retrieval technique.20 There are data to suggest that in pediatric recipients, outcomes are inferior with laparoscopically retrieved kidneys.

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Despite newer retrieval techniques and changes to the living donor population, including older donors, the surgical mortality has not changed over the past 15 years, with perioperative mortality after donor nephrectomy of approximately 3 per 10,000 cases.21 Surgical mortality has been noted to be higher in men, African American individuals, and donors with baseline hypertension. These factors are also associated with higher risk for long-term death. Rates of early postoperative complications are low but may include perioperative bleeding requiring blood transfusion, wound complications, and early hospital readmissions. 

LONG-TERM RISKS TO THE DONOR Although many healthy adults are eager and willing to accept the risk for donor nephrectomy to help those in need, the medical community must quantify those risks as best as possible and make this information available during the initial donor evaluation. Fortunately, data have indicated that longterm death rates among living donors are no higher than in a healthy matched cohort,21 but there are other long-term risks to the donors that must be conveyed.

End-Stage Renal Disease The overall incidence of ESRD among living kidney donors during the first 10 years after donation is low, with rates of 0.2% to 0.5% reported.22 Despite this, two studies have suggested that the relative risk for ESRD may be higher in certain populations. A single-center study out of Norway found that 0.47% of donors and 0.07% of nondonors developed ESRD, with all affected donors biologically related to their recipient.23 In another study performed in the United States comparing living kidney donors to healthy controls, 0.10% of living kidney donors and 0.04% of healthy matched nondonors developed ESRD during follow-up.24 The incidence of ESRD was noted to be higher among donors aged 60 years and older and African American donors. Although both studies had limitations, it is worthwhile to emphasize that although the absolute risk for postdonation ESRD is low, there may be a slightly higher risk compared with a matched, healthy cohort. 

Pregnancy Multiple studies have found an increased risk for gestational hypertension and preeclampsia after kidney donation in women of childbearing age.25-27 This raises some concern because preeclampsia may have long-term renal consequences, including increased prevalence of proteinuria and hypertension. Despite these increased risks, maternal and fetal outcomes are comparable to that of the general population, with most having uncomplicated pregnancies. Because women of childbearing age are the largest group of kidney donors, the effects of donation on postdonation pregnancies should be a routine part of the discussion of risks during the initial donor evaluation. Most centers discourage donation in women with a history of pregnancy-induced hypertension or preeclampsia. 

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SECTION IV  Transplantation

Quality of Life In general, most studies on quality of life after donation report that the majority of donors experience no change or an improvement, with very few experiencing adverse outcomes, including depression and anxiety.28 On standardized quality-of-life scales such as the Short Form 36 Health Survey, donor and nondonors have scored similarly, even those donors whose recipients had poor outcomes. Most donors would donate again if given the opportunity. 

Long-Term Medical Care In the United States, United Network for Organ Sharing (UNOS) policy requires that the transplant center must maintain contact with the donor for at least 24 months after nephrectomy. Beyond that, recommendations for future medical care and risk modification for a kidney donor are similar to the general population. After donation, kidney donors should undergo routine checkups with a focus on BP and kidney function. Urinary protein excretion should be measured as part of routine follow-up care. Patients should undergo age-appropriate cancer screening and be counseled on the need for weight control, smoking cessation, and abstinence from excessive alcohol. Emphasis should be placed on avoidance of high-protein diets, protein supplements for body building, herbal medications, and excessive use of nonsteroidal antiinflammatory pain medications, all of which may lead to kidney injury. 

CONCLUSIONS Living kidney donation is now commonly practiced worldwide with excellent long-term outcomes and low risk for ESRD. With increasing acceptance of medically complex live donors, including those that are older and those with metabolic abnormalities, obesity, and hypertension, it is important that information regarding the risks of donation is shared with donors during the evaluation process. Ongoing efforts to improve the follow-up of living donors through the development of national registries should continue, with the primary goal to protect their long-term health and survival. 

EVALUATION OF THE RECIPIENT Kidney transplantation is the treatment of choice for patients with advanced kidney disease who have a reasonable mediumterm life expectancy and who are medically and surgically fit to undergo the procedure. Transplantation confers a survival advantage over remaining on dialysis even for higher-risk patients such as diabetics and the elderly.29,30 Evaluation of the patient for transplantation should ideally begin well before the initiation of dialysis.31 This allows for preemptive transplantation if a living donor is available. Even if living donation is not an option, completion of the evaluation before initiation of dialysis allows the patient to be added to the deceased donor waiting list and begin accruing predialysis waiting time. The initial evaluation must be thorough, and the patient must be educated about the risks and benefits of transplantation. 

BOX 36.4  Contraindications to Kidney

Transplantation

Absolute Contraindications Active cancer Active infection Active psychiatric illness Active substance abuse Ongoing noncompliance with dialysis or medical regimen Primary hyperoxaluria without liver transplantation Relative Contraindications* Major morbidity that would be worsened by transplant or would lead to very short posttransplant survival High operative risk Immunological incompatibility† Severe obesity (e.g., body mass index >40 kg/m2) Multiple myeloma without stem cell transplantation AL amyloidosis without stem cell transplantation Severe sickle cell disease Severe scleroderma Thrombotic thrombocytopenic purpura * Eligibility varies by transplant center. † Protocols are available to facilitate transplantation across these barriers.

CLINICAL ASSESSMENT OF THE RECIPIENT The patient’s primary nephrologist usually makes the first assessment as to whether a patient is a potential candidate for transplantation. This most often occurs once renal replacement therapy is expected to be required within the next 12 months32; however, in the United States, patients are eligible for listing once the GFR is less than 20 mL/min. Several scoring systems have been proposed to help guide providers in selecting patients who are appropriate for referral to a transplant center,33,34 and multiple guidelines are available to assist clinicians in the process of evaluating candidates.5,32,35 Box 36.4 lists absolute and relative contraindications to kidney transplantation. Relative contraindications vary among different transplant centers; therefore it is reasonable for patients who are excluded by one center to seek a second opinion regarding transplant eligibility.32 There is no widely accepted age cutoff as far as transplant eligibility is concerned,5,32,35 though some centers may choose to set an arbitrary age limit, especially for older patients who have no potential living donors and have an expected long waiting time. Ultimately an individualized assessment is ideal because chronological age alone does not necessarily correlate with an individual’s overall health status. In general, patients with nonrenal organ failure that is not amenable to intervention are excluded. Other factors that are also considered include a patient’s social support and ability to adhere with medical therapy.

History, Physical Examination, and Diagnostic Testing

Once referred to a transplant center, a potential recipient undergoes a thorough medical and psychosocial evaluation to

CHAPTER 36  Evaluation of Donors and Recipients

575

Interested in transplantation Yes Preliminary screening (no severe comorbidity etc.) No obvious CI Education and counseling

Complete evaluation (history, physical examination, tests) Relative CI Judge on caseby-case basis

Absolute CI

No CI Optimize medical status

Proceed with living donor transplant if available

No transplant

If no living donor, place on list

Review every 1-2 years

FIG. 36.1  Typical steps in the evaluation of a patient for kidney transplantation. CI, Contraindication.

determine suitability for transplantation. The process of evaluating a patient varies among centers but in general includes an education session, a visit with a transplant nephrologist and/or surgeon, a meeting with a social worker and a financial coordinator, and routine diagnostic testing such as bloodwork, a chest radiograph, and an electrocardiogram. The typical steps in the evaluation of a patient for kidney transplantation are shown in Fig. 36.1. During the physician visit, several important elements in the history should be obtained. This includes establishing the cause of the patient’s renal failure if it is known, and if a biopsy was performed, the results should be retrieved and reviewed. Details regarding prior therapy such as immunosuppression should be elicited. For patients who are on dialysis, it is important to ask about current urine output because this will serve as a posttransplant baseline and can also give information regarding a patient’s bladder capacity. A thorough investigation of the patient’s medical history and comorbidities such as diabetes, cardiovascular disease, chronic lung disease, and chronic liver disease should be elicited, including the duration of each condition and any associated complications. Any history of blood transfusion, pregnancy, venous thrombosis, cancer, infections such as tuberculosis (TB) or fungal infections, hypotension on dialysis, and any prior abdominal or vascular surgeries should be obtained. Review of medications should include a search for drugs that are metabolized by the cytochrome P450 system and thus have a potential drug interaction with calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR)

inhibitors. The use of midodrine, usually used for patients with hypotension on dialysis, has recently been identified as a marker for poor outcomes.36 A thorough review of systems should be performed specifically asking about symptoms of cardiovascular disease and chronic infection. A patient’s functional status is also important, and this should include an inquiry on the patient’s ability to perform activities of daily living. Finally, the patient’s social support system should be evaluated as well as any history of medical nonadherence. The physical examination should include accurate BP measurements, including a standing BP to screen for orthostatic hypotension. Attention should be given to the cardiovascular examination and should note any signs of fluid overload or murmurs that may suggest congestive heart failure, pulmonary hypertension, or valvular heart disease. To evaluate for peripheral vascular disease, peripheral pulses—particularly the femoral pulses—should be palpated and auscultated and the lower extremities examined for foot ulcerations or ischemic changes. The abdominal examination is important in determining whether obese patients are eligible for transplant, particularly those with a BMI >35 kg/m2, because distribution of body fat and the size of the pelvis vary among different individuals. For patients with markedly enlarged polycystic kidneys, the abdominal examination can also determine whether there is enough room for a transplant or if a nephrectomy is necessary before transplantation. Finally, a patient’s dentition must be examined to ensure there is no active infection that may pose a risk after transplantation.

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SECTION IV  Transplantation

BOX 36.5  Routine Tests for Potential

Kidney Transplant Recipients

ABO blood typing, human leukocyte antigen (HLA) typing, anti-HLA antibodies Complete blood cell count Comprehensive metabolic panel Intact parathyroid hormone Urinalysis and urine culture if not anuric Prothrombin time, partial thromboplastin time Chest radiograph Electrocardiogram Tests for human immunodeficiency virus, hepatitis B, hepatitis C, cytomegalovirus, Epstein-Barr virus, syphilis, tuberculosis If older than 50 years: colonoscopy Women: Papanicolaou smear; mammogram if older than 40 years Men: PSA if older than 50 years PSA, Prostate-specific antigen.

Routine diagnostic testing as listed in Box 36.5 should be obtained in all patients. Based on a patient’s history and physical examination, comorbid conditions, and results of the routine testing, supplementary diagnostic tests may be warranted as listed in Table 36.1. Each patient is required to have updated age-appropriate cancer screening such as a colonoscopy, mammogram, Papanicolaou (pap) smear, and prostate-specific antigen, according to conventional guidelines. Based on the results of the evaluation and testing, a determination is then made by a kidney transplant selection committee at each center regarding a patient’s suitability for kidney transplantation. The committee is usually composed of transplant nephrologists and surgeons, psychiatrists, pharmacists, nurses, coordinators, social workers, and financial coordinators. Patients who are approved are then activated on the deceased donor waiting list, and for those with available living donors, planning for living donor transplantation can then commence. 

SELECTED ISSUES IN THE RECIPIENT EVALUATION Cardiovascular Disease The high prevalence of cardiovascular disease in patients with chronic kidney disease is well known and among kidney transplant recipients, it remains the leading cause of allograft loss and death after transplantation.1 An evaluation for cardiovascular disease is imperative before transplantation to determine the risk for perioperative adverse cardiac events and to optimize cardiac function. In addition, detection of a severe burden of cardiovascular disease may render a patient an unacceptable candidate for transplantation because of overall poor life expectancy.

Coronary Artery Disease A proposed algorithm for the screening of kidney transplant candidates for coronary artery disease is shown in Fig. 36.2. The screening process may vary depending on the transplant center.

TABLE 36.1  Supplementary Tests

Sometimes Required for Potential Kidney Transplant Recipients Indication Congestive heart failure or valvular heart disease Risk factors for (or known) coronary artery disease Moderate to severe pulmonary hypertension Peripheral vascular disease Chronic obstructive pulmonary disease Cerebrovascular disease Venous or arterial thrombosis or access clotting Systemic lupus erythematosus or history of first trimester spontaneous abortions Polycystic kidney disease

Anti-GBM disease History of treatment with cyclophosphamide Failed transplant because of BK nephropathy End-stage renal disease >5 years Multiple prior kidney transplants

Diagnostic Test Echocardiogram Noninvasive stress testing and/or left-sided heart catheterization Right-sided heart catheterization CT or MR imaging of iliac arteries Pulmonary function testing Carotid arterial doppler Hypercoagulable workup Lupus anticoagulant; assessment of disease activity Brain imaging for aneurysms if with family history, native kidney imaging to evaluate kidney size if physical examination is inconclusive Anti-GBM antibody titer Urine cytology or cystoscopy Serum BK quantification Native kidney imaging for renal cell carcinoma screening CT or MR angiogram of abdomen/pelvis

CT, Computed tomography; GBM, glomerular basement membrane; MR, magnetic resonance.

In general, low-risk patients can proceed without additional testing if they have no risk factors, the electrocardiogram is normal, and they are asymptomatic. For patients who are at moderate risk, noninvasive stress testing is performed whether by nuclear or echocardiographic imaging depending on center expertise. For those with an abnormal stress test or for patients who are at high risk (e.g., known coronary artery disease with prior revascularization or longstanding diabetes), coronary angiography is pursued. Revascularization is determined by current guidelines. Patients with active ischemia and a culprit coronary artery lesion that is not amenable to intervention are often excluded from transplantation. In addition, if there is severe burden of disease found on catheterization (e.g., three-vessel disease), a patient may similarly be excluded especially when revascularization is not feasible and other comorbidities are present. It must be noted, however, that many uncertainties exist regarding pretransplant coronary artery disease screening and management.34 This is due to the suboptimal sensitivity and specificity of noninvasive cardiac stress testing in patients with chronic kidney

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577

History, examination review of previous tests

Low risk

abnormal Electrocardiogram normal

High risk

Moderate risk Meets ANY of the following: • Age >40 but <70 years • Dialysis duration >2 years • Diabetes <20 years • Known CAD with last angiogram <3 years ago OR CABG <5 years ago • >2 Cardiac risk factors*

Meets ALL of the following: • Age <40 years • Dialysis duration <2 years • ≤ 2 Cardiac risk factors*

Non-invasive stress test

Meets ANY of the following: • Age ≥ 70 years • Diabetes >20 years • Known CAD with last angiogram ≥ 3 years ago OR CABG ≥ 5 years ago

abnormal

Coronary angiogram

normal

Coronary artery disease evaluation complete

No significant disease or successfully revascularized

Severe burden of disease or unable to revascularize

Medically unsuitable

FIG. 36.2 Suggested algorithm for pretransplant cardiovascular screening. *Hypertension, hyperlipidemia, body mass index >35 kg/m2, smoking. CABG, Coronary artery bypass grafting; CAD, coronary artery disease.

disease and end-stage renal disease, the conflicting data from observational studies regarding the prognostic value of noninvasive testing and coronary angiography in predicting major adverse cardiac events, and the lack of evidence that revascularization in asymptomatic patients improves outcomes.37-40 

Congestive Heart Failure and Valvular Heart Disease In patients who have signs or symptoms of volume overload or an abnormal cardiac examination, an echocardiogram is usually obtained to evaluate for systolic heart failure and valvular heart disease and to screen for the presence of severe pulmonary hypertension. Patients with markedly reduced ejection fractions and no evidence of coronary artery disease can still be considered for transplantation if the cardiomyopathy is thought to be due to the uremic milieu because cardiac function would be expected to improve after transplantation. Patients with severe ischemic cardiomyopathy are excluded unless they are also candidates for heart transplantation. Patients with significant valvular dysfunction may need intervention before transplantation.  Peripheral Vascular Disease Imaging of the aortoiliac vessels through a CT angiogram or magnetic resonance angiogram (MRA) without contrast to

evaluate for peripheral vascular disease is warranted for patients with poor femoral pulses on examination or who have a history of leg claudication or foot ulcerations. For patients who have had long-standing diabetes or are of advanced age (e.g., 70 years or older), a noncontrast CT scan of the abdomen and pelvis may be obtained to screen for severe or circumferential iliac calcifications that would exclude a patient from transplantation. 

Diabetes Mellitus It is important to note that diabetic patients gain a significant survival advantage with transplantation compared with those diabetics remaining on dialysis on the waiting list.30 All diabetic transplant candidates should undergo careful screening particularly for cardiovascular disease, and this should be aggressively treated. Patients with type 1 diabetes should also be considered for pancreas transplantation—either simultaneous kidney-pancreas or pancreas after kidney transplantation.41 

Pulmonary Disease Obstructive and Restrictive Lung Disease Patients with a history of chronic lung disease should be evaluated with pulmonary function testing and oximetry. Patients

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SECTION IV  Transplantation

who have a forced expiratory volume 1 that is less than 25% of predicted are generally excluded. Similarly, patients on home oxygen or those who have hypoxia (Sao2 <90% on room air) are not candidates for kidney transplantation.32 All patients should be counseled to stop smoking. 

Pulmonary Hypertension The presence of severe pulmonary hypertension in a kidney transplant recipient may portend a poor posttransplant outcome.42,43 Patients with echocardiographic findings of right ventricular pressure overload or a right ventricular systolic pressure more than 45 mmHg may need further evaluation by right-sided heart catheterization to help characterize the type of pulmonary hypertension that is present.38,44 If volume overload is found to be the driver, aggressive ultrafiltration or diuresis and correction of the pulmonary hypertension before transplantation should be pursued. If a secondary cause for pulmonary hypertension such as obstructive sleep apnea is identified, this should be aggressively treated as well. Transplant centers vary in their cutoffs for acceptable pulmonary artery pressures, and if the severe pulmonary hypertension is not amenable to correction, a patient is usually excluded from transplantation. 

Cancer The presence of an active malignancy is an absolute contraindication to transplantation. Age-appropriate screening tests used in the general population such as a colonoscopy, pap smear, mammogram, and prostate-specific antigen are obtained as part of the pretransplant evaluation. Patients who have had ESRD for several years may benefit from radiographic imaging of the native kidneys to screen for renal cell carcinoma. Those who have a risk factor for bladder cancer such as history of prior treatment with cyclophosphamide can be screened by obtaining urine cytological testing or, if anuric, undergoing cystoscopy. Several guidelines exist on the appropriate waiting time required before pursuing a kidney transplant for patients with a history of cancer.32,35,45 Patients with small incidentally diagnosed renal cell carcinomas, basal cell skin cancers, and in-situ cervical cancers that have been adequately treated do not require a waiting period. For most other malignancies, however, a waiting period of 2 to 5 years is required. This is to ensure the absence of cancer recurrence or progression and to establish that the patient is essentially cured of the malignancy and has a reasonable life expectancy. For certain malignancies, particularly lymphoproliferative disease, there is also a concern that immunosuppression can promote cancer recurrence or progression. 

Obesity Obesity is a risk factor for surgical complications such as impaired wound healing, delayed graft function, cardiovascular disease, higher mortality, and inferior posttransplant allograft function.46,47 Nevertheless, obese patients derive a survival benefit from transplantation as opposed to remaining on dialysis, though this may be less in patients with a BMI ≥40 kg/m2.48-50 Severe obesity can also make it physically impossible for a surgeon to implant a kidney into a recipient. Centers

vary on the upper limit of BMI that they would consider transplantable, and this usually ranges from 35 to 40 kg/m2, with some centers considering those between 40 to 45 kg/m2 on an individual basis. An abdominal examination is important when evaluating obese candidates because fat distribution may vary significantly among individuals. For patients who are deemed ineligible for transplantation because of obesity, they should be counseled on available medical or surgical weight loss therapeutic options that if effective could assist in ultimately getting them to transplantation. Regardless of eligibility, all obese patients should be strongly encouraged to lose weight, with a goal BMI of less than 30 kg/m2.32 

Infections Hepatitis C Kidney transplantation is associated with superior outcomes compared with dialysis in hepatitis C virus (HCV)–infected ESRD patients. The suggested algorithm for the pretransplant evaluation and management of an HCV-infected kidney transplant candidate is shown in Fig. 36.3.51 All kidney transplant candidates in high-prevalence regions should be screened for hepatitis C by nucleic acid (HCV RNA) testing. In areas where HCV has a low prevalence, hepatitis C antibody (HCV Ab) testing, followed by HCV RNA testing for seropositive individuals, is recommended. Liver biopsy has traditionally been a requirement for patients with confirmed infection to ensure the absence of cirrhosis; however, the emergence of noninvasive techniques may render this unnecessary for most patients in the future. HCV genotyping has similarly been necessary to guide treatment options. However, it remains to be seen whether this will still be needed going forward given the advent of pangenotypic direct-acting antivirals (DAAs) to treat hepatitis C. Moreover, the option of safely using DAAs posttransplant affords HCV-positive kidney transplant candidates the option to receive a kidney from an HCV-infected donor and be treated for infection after transplantation. By doing so, patients can reduce their waiting time by several years. Emerging data indicate that HCV cure rates greater than 95% after transplantation are being achieved.52  Hepatitis B Kidney transplant candidates are screened for hepatitis B virus (HBV) by checking a hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (HbsAb), and hepatitis B core antibody (HbcAb). Those who have no evidence of exposure to the virus (HBsAb and HbcAb negative) and have not been vaccinated should be vaccinated. For patients with a positive HbsAg or HbcAb, hepatitis B DNA polymerase chain reaction testing should be performed to evaluate for active viremia. Patients with confirmed active infection should undergo a liver biopsy to ensure the absence of cirrhosis and a need for simultaneous ­liver-kidney transplantation. Liver imaging and an α-fetoprotein level should also be obtained to screen for hepatocellular carcinoma. Patients with active viremia should be treated with antiviral agents such as lamivudine, entecavir, or tenofovir before transplantation because of the risk for developing fulminant

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CHAPTER 36  Evaluation of Donors and Recipients HCV Ab+ HCV RNA-

HCV RNA+

No liver biopsy

Liver biopsy

EVALUATION

Fibrosis Stage 0-3 WAITLIST Live donor

No Live donor

DAA pre-transplant SVR

Transplant with HCVkidney

DAA pre-transplant • Short expected waiting time • Patient preference • Fibrosis stage 3*

SVR

No DAA pre-transplant

1-3 years

4-8+ years

No SVR

Transplant with HCV+ or HCV- kidney DAA post-transplant Transplant with HCVkidney

SVR

FIG. 36.3  Management of the hepatitis C–positive patient being considered for kidney transplant. *For patients listed in transplant centers with long wait times. Ab, Antibody; DAA, direct-acting antiviral; HCV, hepatitis C; RNA, ribonucleic acid; SVR, sustained virological response. (Adapted from Sawinski D, Bloom RD. Novel hepatitis C treatment and the impact on kidney transplantation. Transplantation. 2015;99:2458-2466.)

hepatitis with immunosuppression. Antivirals should be continued indefinitely after transplantation and an annual HBV DNA PCR should be obtained to ensure appropriate viral suppression. 

Human Immunodeficiency Virus Patients infected with HIV derive benefit from transplantation compared with remaining on the waiting list.53 Longterm allograft outcomes in these patients are excellent and comparable to noninfected counterparts,54,55 though patients coinfected with HCV seem to do worse.56 In addition, an increased rate of acute rejection has been reported,54 though the reason for this is unknown. Some have posited that avoidance of depleting antibody induction, cautious dosing of maintenance therapies resulting in underimmunosuppression, or drug-drug interactions between antiretrovirals and CNIs may be contributory.56 To be eligible for transplantation, patients must have an undetectable HIV viral load and a CD4 count of more than 200/mm3 for at least 3 to 6 months on stable antiretroviral therapy with no intercurrent opportunistic infections. 5,54 Protease inhibitors have a potent inhibitory effect on the cytochrome P450 system; hence a thorough review of the patient’s antiretroviral therapy should be performed so that adequate planning regarding posttransplantation CNI or mTOR dosing can be made. Some centers elect to transition patients to protease inhibitor-free regimens to allow for more traditional CNI or mTOR dosing.56 

Tuberculosis All kidney transplant candidates should be screened for TB through a careful history of exposures, risk factors, and symptoms.57 Diagnostic testing using either tuberculin skin testing (TST) (positive if there is ≥5 mm of induration at 48 to 72 hours) or interferon-γ release assays (IGRA) is performed as a screening test, and a chest radiograph is also reviewed for findings that are suggestive of old or active TB infection.58 Patients who have a positive TST or IGRA should be referred to the local health department and evaluated for active TB because these tests cannot differentiate between active and latent TB infection. If a patient is diagnosed with latent TB, he or she should be treated for latent TB with 9 months of isoniazid or other alternative regimens ideally before transplantation. A patient can generally proceed to transplantation while on latent TB therapy or can also begin treatment posttransplant. However, if a patient is diagnosed with active TB, transplantation should be postponed until the patient completes adequate therapy, which usually consists of at least three drugs and a 9-month course of therapy. 

Systemic Diseases Table 36.2 summarizes the considerations for transplant eligibility for specific systemic diseases not discussed earlier.32 

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SECTION IV  Transplantation

TABLE 36.2  Considerations for Transplant

BOX 36.6  Definition of Frailty*

Systemic Disease Primary hyperoxaluria

Component Shrinking Weakness Exhaustion Low physical activity Slowed walking speed

Eligibility of Specific Systemic Diseases

Fabry disease Sickle cell disease Systemic lupus erythematosus Vasculitis

Scleroderma

Antiglomerular basement membrane (anti-GBM) Thrombotic thrombocytopenic purpura Atypical (complementmediated) hemolytic uremic syndrome

Cystinosis Congenital nephrotic syndrome Autosomal recessive polycystic kidney disease

Considerations Consider isolated renal transplantation if pyridoxine sensitive and minimal oxalate deposition; Combined liver-kidney transplantation if with severe systemic disease Consider if systemic disease not severe Consider if systemic disease not severe Consider if clinically quiescent disease for at least 6 months off cytotoxic agents Consider if quiescent disease for at least 12 months off cytotoxic agents; pretransplant antineutrophil cytoplasmic antibodies are not predictive of outcome and may be positive at time of transplantation Consider if clinically quiescent disease for at least 6 months off cytotoxic agents and have limited extrarenal disease Consider if anti-GBM antibody is undetectable and quiescent disease off cytotoxic agents for at least 6 months posttreatment Consider if quiescent disease Consider renal transplantation after evaluation for genetic mutations or culprit antibodies, consider concurrent use of eculizumab* Consider for renal transplantation Consider after undergoing bilateral nephrectomy Consider after screening for evidence of portal hypertension and evaluation for unilateral or bilateral nephrectomy

*Authors’ recommendation. Adapted from Knoll G, Cockfield S, Blydt-Hansen T, et al. Canadian Society of Transplantation consensus guidelines on eligibility for kidney transplantation. CMAJ. 2005;173(10):1181-1184.

Emerging Risk Factors That May Affect Kidney Transplant Candidacy Hypotension on Hemodialysis Patients with a history of hypotension on dialysis requiring midodrine use are at increased risk for allograft thrombosis, primary nonfunction, delayed graft function, and inferior allograft outcomes.36 It is prudent to review BPs on dialysis flowsheets for all candidates who are on hemodialysis,

*The presence of three or more components signifies frailty. Adapted from Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-M156.

especially those on midodrine, or with low or low-normal BP at the time of evaluation. At times, resolution of hypotension can be achieved simply by adjustment of the dry weight. If patients with persistent hypotension are deemed to be suitable transplant candidates, careful selection of a donor kidney may be required, specifically avoiding those at higher risk for developing delayed graft function. 

Frailty and Functional Status Frailty has emerged as a risk factor for inferior kidney transplantation outcomes, including an increased risk for early hospital readmission, mycophenolate mofetil (MMF) intolerance, delayed graft function, and mortality.59-61 The definition of frailty62 is shown in Box 36.6. Similarly, a patient’s self-reported functional status has also been correlated with transplant outcomes.63 These studies support the notion that evaluation of physiological age through these nontraditional measures may have an important role in risk-stratifying potential candidates. For patients who are found to be frail or have suboptimal functional status, there may be a role for rehabilitation before transplantation, termed prehabilitation. How this affects posttransplant outcomes remains to be determined. 

History of a Failed Allograft Patients with a history of a failed allograft have improved survival with retransplantation compared with remaining on the waiting list.64 In evaluating these patients, the reason for graft loss must be determined and risk factors identified, and if a biopsy was performed, the results should be reviewed. A transplant nephrectomy is usually not required before retransplantation unless there is an anatomical indication or a patient has symptoms suggestive of acute allograft rejection such as gross hematuria and allograft pain. If graft loss was due to acute rejection, factors that may have contributed to this, including medical nonadherence, should be investigated. Rejection treatment that the patient received must be ascertained, particularly lymphocyte-depleting agents such as antithymocyte globulin, because this may have implications for the choice of induction agent for the subsequent transplant. If the graft was lost due to polyoma virus nephropathy, a patient’s serum BK must be undetectable before retransplantation. There is no consensus as to the benefit of a transplant nephrectomy before retransplantation in these patients. For patients with prior grafts lost because of disease recurrence, counseling is important due to the high risk for a similar

CHAPTER 36  Evaluation of Donors and Recipients outcome, particularly in cases where there is no planned alteration in pre- or posttransplant management from the prior transplant. The decision to proceed with retransplantation may depend on the rapidity by which the prior graft was lost and any available interventions that could be employed to improve outcomes. For patients with rapid failure of an allograft because of recurrent disease, the decision to proceed with retransplantation should be based on shared decision making between the patient and the transplant center. In general, living donor transplantation is avoided in these patients. 

High Sensitization to Human Leukocyte Antigens Human leukocyte antigen (HLA) typing and measurement of class I and class II panel reactive antibodies (PRA) are performed during the transplant evaluation, and PRAs are thereafter periodically measured. Patients who are highly sensitized are less likely to find an immunologically compatible donor and historically have experienced long waiting times. Patients who have an immunologically incompatible living donor can enroll in a paired donor exchange program, undergo desensitization if the levels of HLA antibody are permissible, or wait for a compatible deceased donor.65 Paired donor exchange can occur within a single transplant center or through kidney exchange programs to increase the chances of finding a compatible pair. Desensitization is another option, and it has been reported that transplantation with an immunologically incompatible live donor offers superior survival compared with waiting on the deceased donor list for a compatible donor.66 The new Kidney Allocation System, however, has been successful in increasing the number of deceased donor transplants for patients with a PRA of 98% to 100%.67,68 With this new system, it is difficult to estimate how long patients with PRA 98% to 100% will need to wait on the deceased donor list, because immunological compatibility and not dialysis vintage is the main driver for organ allocation in these patients. 

Psychosocial Issues Psychiatric illness is only a contraindication if it is severe enough to impair understanding of the risks and benefits of transplantation and to prevent normal posttransplant follow-up and adherence. Addiction to alcohol or other drugs should be successfully treated before transplantation. Intellectual disability is not a contraindication if adequate posttransplant support is available. The issue of informed consent for surgery, however, can be difficult. The recipient evaluation should also examine a patient’s ability to adhere to medical therapy and a patient’s social and financial support. This may involve probing into a patient’s history of dialysis and medication adherence. It is also important to evaluate a patient’s ability to travel to the transplant center not only for the transplant procedure but also for posttransplant clinic visits. Patients must understand the costs associated with pursuing a transplant, including potential copays for medications, travel and lodging costs, and costs related to time away from work for both the patient and the support person. 

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Counseling and Education All patients who undergo a medical evaluation for transplantation also receive counseling and education. This is often carried out in a formal education class usually conducted in groups. During the physician visit, it is important to address any concerns or questions that may arise from the class. In addition, counseling should be individualized and include a discussion on the specific risks a patient faces in pursuing transplantation, such as rejection, infection, and disease recurrence. These risks must be weighed against the risk for remaining on dialysis. Also, specific transplant options should be discussed. This must include education about the benefits of undergoing preemptive and living donor transplantation as opposed to deceased donor transplantation, including the expected waiting time at the patient’s transplant center. In addition, an individualized discussion should take place regarding the risks and benefits of listing for a deceased donor kidney with a kidney donor profile index >85%. Finally, counseling should take place regarding the risks and benefits of listing for Public Health Services increased-risk donor kidneys and A2 to B transplantation (for eligible patients). 

Management of the Waiting List Patients who have no living donor options must wait on a deceased donor kidney, which usually takes several years. In the United States the median waiting time to deceased donor transplant was 5.5 years in 2003 and 7.6 years in 2007.2 Transplant centers face the challenge of ensuring candidates are medically and surgically suitable for transplantation once an acceptable donor kidney becomes available. While waiting on the list, a patient’s medical condition may deteriorate such that he or she may require additional testing or may no longer be eligible for transplantation. The processes for reevaluating candidates and managing the waiting list vary among transplant centers. Some centers ask patients to return for a reevaluation once they are predicted to be close to being called for a transplant, whereas others elect to see patients every 1 to 2 years. Regardless of the process, it is important for the patient, the primary nephrologist, the dialysis unit, and the transplant center to maintain close communication at all times. 

CONCLUSIONS The evaluation of kidney transplant candidates aims to identify patients who would do well with a kidney transplant and ultimately derive a survival benefit and improvement in quality of life. The evaluation also identifies patients who may need medical optimization before transplantation, thus giving them the best chance at a successful outcome. An evaluation must include a thorough medical, surgical, and psychosocial assessment of the patient. Importantly, it should be used as a venue to facilitate shared decision making by educating and counseling patients regarding the risks and benefits of kidney transplantation and discussing the advantages and disadvantages of the different transplant options that are available to them.

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