Selection of Prospective Kidney Transplant Recipients and Donors

Timing of Referral

Both mortality and graft outcomes are improved with early transplantation. Patients who receive a preemptive kidney transplant have a superior outcome compared with patients who undergo dialysis treatments before receiving a transplant. Similarly, the length of exposure to dialysis affects transplant outcomes and mortality. Improved outcomes are inversely related to the duration of dialysis. Thus, to allow adequate time to complete the required medical tests before transplantation and to facilitate potential preemptive transplantation, patients with CKD should be referred to a kidney transplant center early in their disease course. Many potential transplant recipients are medically complex. Determining their suitability for transplantation may require multiple specialist visits and medical tests. This process may take 6 to 12 months to complete and should be factored into the overall referral time. For patients with potential living donors, appropriate time should be allocated for donor work-up as well.

In the United States, the United Network for Organ Sharing (UNOS) allows listing for transplantation when a patient’s estimated glomerular filtration rate (eGFR) falls below 20 mL/min, whereas organizations in other countries have established stage 5 CKD (eGFR below 15 mL/min) as the upper limit for listing. Therefore, patients should be referred for transplantation evaluation when they have stage 4 CKD (eGFR below 30 mL/min) that is progressing. In some regions, transplantation assessment is initiated with referral to a multidisciplinary kidney replacement therapy planning clinic. In these clinics, transplant eligibility is considered and teaching is provided alongside planning for dialysis initiation. Education and identification of potential living kidney donors should be prioritized. It is important to recognize that certain barriers to transplant referral have been identified. Access to transplantation may be decreased for patients of certain ethnicities, those with lower socioeconomic status and/or education level, or those living a greater distance from a transplant center. Communication between a patient’s primary nephrologist and the transplant program is essential to ensure eligible recipients are efficiently evaluated and wait-listed.

General Considerations

Advanced age is not a contraindication to transplantation. At present, patients over 65 years of age are the fastest growing group of wait-listed potential recipients. Death-censored graft outcomes are similar or better in these older adult recipients. With advanced age, special attention should be paid to pretransplant medical comorbidities, functional status, and quality of life. The cost of maintaining a proposed recipient on the waiting list is not insignificant. A patient’s capacity to survive beyond current waiting list times to transplantation and beyond must be considered. Standardized tests of frailty, history of falls, and hospital admission days while wait-listed predict wait-list and posttransplant mortality. The technical aspects of the transplant surgery limit transplantation in extremely young children. However, this should not delay transplant work-up, and preemptive transplantation should be considered when possible.

Obesity

Patients with extreme obesity are susceptible to an increased risk for transplant-related complications, including delayed graft function, wound complications, and infections, as well as an increased risk for new-onset diabetes after transplantation. In some studies, long-term graft failure rates and mortality are higher among obese recipients when compared with otherwise comparable recipients. There is variability among transplant programs in the willingness to transplant extremely obese individuals, and individual programs may limit transplantation to individuals under a certain body mass index (BMI), usually 40 kg/m ² . In patients with a BMI between 30 and 39 kg/m ² , weight-loss counseling should be provided, and bariatric surgery may be considered in individuals with a BMI greater than 40 kg/m ² .

Kidney Disease Etiology

Many kidney diseases recur after transplantation. Recent analyses suggest that allograft failure secondary to recurrent disease is now the third most common reason for graft failure, behind rejection and death with a functioning graft. In an analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), allograft loss due to recurrent disease occurred in 8.4% of patients with biopsy-proven glomerulonephritis who received a kidney transplant. Similarly, when the Mayo Clinic retrospectively analyzed specific causes of kidney allograft loss, recurrent disease was diagnosed in 14.3% of all lost allografts. An additional 6.5% of graft loss was due to glomerular pathology that could not be classified as recurrent because of incomplete clinical information. Despite this, the risk for recurrence rarely precludes transplantation, and allograft failure from recurrence is rare in the first 5 years posttransplant. In the ANZDATA analysis, the overall 10-year incidence of allograft loss was similar among transplant recipients with glomerulonephritis versus those with other causes of kidney failure, and no risks were identified that would preclude transplantation. It is important to counsel prospective transplant recipients about the risk for recurrent disease. Table 59.2 shows the incidence of recurrence of different forms of kidney disease.

Immunoglobulin A (IgA) nephropathy may recur in up to 60% of allograft biopsies; however, clinically significant recurrence (with elevated creatinine or proteinuria) develops in only 30% of kidney transplants. Furthermore, clinical recurrence tends to be late, and graft loss due to IgA nephropathy occurs in only 10% of patients. Focal segmental glomerulosclerosis (FSGS) can recur in up to 30% of transplant recipients and is more common in those with primary FSGS. In patients with a previously failed allograft due to recurrent FSGS, the risk for recurrence rises to as high as 50%–80%. In many cases, recurrence appears to be secondary to a circulating permeability factor that affects podocyte foot process and glomerular slit diaphragm integrity. Plasma exchange may reduce proteinuria and prolong the life of the allograft. Membranous nephropathy can recur in up to 40% of cases posttransplant. Unlike in the nontransplanted kidney, spontaneous remission is rare, and graft failure can occur in as many as 50% of cases by 10 years. Anti-phospholipase A2 receptor (anti-PLA2R) antibody titer can be used to inform the risk of recurrence, and anti-CD20 therapy may limit proteinuria and allograft damage after recurrence.

Membranoproliferative glomerulonephritis (MPGN) has a variable rate of recurrence posttransplantation depending on the underlying etiology. Monoclonal immune complex-mediated (IC-) MPGN, even in the absence of a detectable paraprotein, has a high risk of recurrence and poor graft outcome, whereas treated polyclonal IC-MPGN has a much lower rate of recurrence and improved outcome. Complement C3 glomerulopathy (C3G), including dense deposit disease and C3 glomerulonephritis, has a high rate of recurrence (∼75%) and a 5-year graft survival of only 50%. The presence of serum monoclonal proteins and low complement levels at the time of transplantation are risks for MPGN recurrence. Recurrence of MPGN is usually early in the transplant course and is associated with proteinuria. Recurrence of rapidly progressive glomerulonephritis is rare if disease is quiescent at the time of transplantation. In patients with anti-glomerular basement membrane (anti-GBM) disease, the absence of circulating anti-GBM antibodies should be confirmed before considering transplantation. Although the presence of antineutrophil cytoplasmic antibodies (ANCA) does not preclude transplantation, patients should achieve a period of clinical remission in which they are not taking immunosuppressive medications before transplantation. Similarly, a positive serostatus in patients with systemic lupus erythematosus (SLE) does not preclude transplantation; however, disease should be quiescent. Recurrence of lupus nephritis is rare (<20%), possibly because of protection from immunosuppressive transplant medications. Glomerular diseases with organizing deposits, such as amyloidosis, fibrillary, and immunotactoid glomerulonephritis, can all recur with rates greater than 50%. With both primary and secondary forms of amyloidosis, transplantation is often limited by severe cardiac disease; early death from cardiovascular disease or infection is quite high. Patients with AL-amyloidosis should be excluded from transplantation unless they have minimal extrarenal disease and have undergone potentially curative therapy. Patients with AA-amyloidosis can be considered if the underlying cause of amyloidosis has been adequately treated.

Genetic forms of kidney disease may affect the transplanted allograft. Rarely, patients with Alport disease can develop antibodies against type IV collagen leading to a condition similar to anti-GBM disease. Patients with primary oxalosis are highly susceptible to rapid oxalate deposition in the transplanted kidney without treatment. These patients are best managed with concurrent liver transplantation and supplementation with orthophosphate and pyridoxine. Patients with atypical hemolytic uremic syndrome (aHUS) due to complement mutations have a rate of recurrent disease and graft failure of up to 60% to 70% at 2 years posttransplantation. Treatment with the complement C5 inhibitor, eculizumab, should strongly be considered. Patients with kidney failure secondary to sickle cell nephropathy can be safely transplanted with good results, providing their overall health allows transplantation.

Infection

The presence of an active infection—bacterial, fungal, or viral—is a contraindication for transplantation. All potential recipients should be screened for chronic infections during the transplant evaluation and assessed for acute infection at the time of transplantation. Clinical and occult dialysis access-related infections in indwelling peritoneal dialysis catheters and tunneled hemodialysis catheters need to be fully treated before transplantation.

Efforts to protect immunosuppressed recipients should occur before transplantation. Transplant candidates should be immunized against seasonal influenza, hepatitis B virus (HBV), and pneumococcal pneumonia. In addition, vaccination against human papillomavirus and primary (chickenpox) and secondary (shingles) varicella-zoster infection and repeat vaccination with the measles, mumps, rubella (MMR) vaccine should be considered in appropriate recipients. Although efficacy of immunization is notably poor in the ESKD population, risk for infection posttransplant is high.

Cytomegalovirus (CMV) can be transmitted via kidney transplant, and commonly leads to disease if untreated. Measuring a potential recipient’s CMV serostatus is important before transplantation, but a negative serostatus does not preclude receipt of a kidney transplant from a CMV-positive donor. In addition, potential recipients and donors should be screened for Epstein-Barr virus (EBV) and herpes simplex virus (HSV) before transplant. Those recipients with an EBV-mismatched kidney transplant should undergo EBV virus surveillance for posttransplant lymphoproliferative disorder (PTLD), whereas HSV-mismatched patients may be offered acyclovir for prophylaxis.

Screening for nonviral infections should be tailored to local infection risk. Syphilis, Strongyloides, Chagas disease, and malaria should be screened for and treated in endemic areas. Tuberculosis (TB) infection is common in immunosuppressed kidney transplant patients, and may approach 15% in TB-endemic areas. Risk factors for developing TB after transplant include a positive tuberculin skin test reaction before transplant, prior residence in a TB-endemic area, a chest radiograph suggestive of prior TB, and older age. Before transplantation, all potential recipients should undergo tuberculin skin testing or interferon-gamma release assay and a chest radiograph. High-risk patients should undergo prophylactic TB treatment before or immediately after transplantation in the absence of documented prior treatment.

Kidney transplantation of human immunodeficiency virus (HIV)–positive recipients is possible in the current era of antiretroviral therapy (ART). In general, patients should be compliant with ART therapy, HIV RNA should be undetectable, and the CD4 count should be greater than 200 mm ³ before consideration for transplant. Patient and allograft survival in this population is acceptable, although the incidence of acute rejection is increased. Patients with HIV should be referred to a transplant center with experience managing this infection.

In the modern era of immunosuppression, allograft loss due to BK (polyoma) virus has emerged as an important threat to graft survival. Polyoma virus infection is ubiquitous in the general population, with over-immunosuppression thought to be responsible for clinically evident disease. Limited evidence suggests that retransplantation in patients who have suffered a previous allograft failure from the BK virus may be successful; thus, the BK virus should not preclude retransplantation.

Malignancy

The immune system plays a role in suppressing malignancy, and immunosuppression may promote tumor growth and increase the risk for cancer recurrence. This is best illustrated by the potent antitumor response after administration of immune checkpoint inhibitors, medications that nonspecifically enhance immune responses. As allograft survival lengthens, death from malignancy increases. Thus, active malignancy is an absolute contraindication to transplantation, with the exception of superficial squamous cell and basal cell skin cancers or low-grade prostate cancers (Gleason score ≤6). In patients with a history of malignancy, a waiting period between successful treatment of cancer and transplantation is recommended. The length of this waiting period should be made collaboratively with the patient’s oncologist and depends on the type of malignancy and the risk of recurrence. Previously, a waiting period of 2 years was recommended for most types of cancers, while a 5-year waiting period for high-risk cancers was recommended. With improved knowledge of cancer biology and new cancer therapies, many cancers now have an improved prognosis and survival. Genomic profiling assays can now be used to provide a more individualized granular assessment of cancer recurrence risk. In cases with low-risk profiles, a wait of 2 years may not be necessary after completion of potentially curative therapy. Small, incidentally discovered renal cell cancers, in situ cervical cancer, DCIS breast cancer, superficial bladder cancers, and low-grade thyroid cancers do not require any waiting period. Multiple myeloma is a contraindication for transplantation unless considered concurrently with an allogeneic bone marrow transplant.

Although life expectancy is shortened in dialysis-dependent prospective kidney transplant recipients, most programs perform pretransplant malignancy screening. This screening should be based on clinical practice guidelines for the general population as part of a periodic health examination. All patients should receive a chest radiograph, abdominal ultrasound, and age-appropriate colon cancer screening as part of their work-up. Women should undergo breast examination, pelvic examination, and Pap smear as dictated by their age. Men should receive a prostate examination and prostate-specific antigen (PSA) screening as dictated by their age or if symptomatic. Patients with a heavy smoking history should undergo a chest CT. In addition, patients who have received cyclophosphamide in the past should be considered for urine cytology and cystoscopy to rule out bladder malignancy.

Prospective transplant recipients should be counseled about the risk of malignancy posttransplant. The risk of nonmelanoma skin cancer and lymphoma is much higher than similarly matched dialysis controls. The risk of squamous cell cancer increases with advancing age, lighter skin tones, a prior history of skin cancer, and cumulative lifetime sun exposure. Recipients should be counseled to avoid prolonged direct sun exposure and should wear ultraviolet A (UVA) and ultraviolet B (UVB) sunscreens along with protective clothing. The posttransplant lymphoma risk is much higher in EBV-naïve recipients. Transplant recipients should continue to receive ongoing cancer screening as per clinical practice guidelines.

Cardiovascular Disease and Risk Factors

Cardiovascular disease is the leading cause of death in patients on dialysis and in kidney transplant recipients, with diabetics at particular risk. Therefore, all potential transplant recipients should be carefully assessed for the presence of heart disease before listing. Evaluation for cardiac disease helps risk-stratify perioperative risk as well as informing life expectancy and transplant outcome. At a minimum, patients should be assessed for signs and symptoms of cardiovascular disease and undergo an electrocardiogram (ECG) and an echocardiogram. Patients with progressive anginal symptoms should not be offered transplantation without additional evaluation and treatment. Transplantation should be delayed in patients following recent myocardial infarction or revascularization, as recommended by the patient’s cardiologist. In patients with severe and irreversible coronary artery disease, projected life expectancy must be balanced against the risks of transplant surgery. It is worth noting that left ventricular dysfunction due to uremic cardiomyopathy is not a contraindication to transplantation and frequently improves after surgery. In patients at high risk for underlying coronary disease (including men over age 40, women over age 50, patients with diabetes, patients with multiple traditional cardiovascular risk factors), noninvasive testing may be performed to identify underlying disease. Patients with positive noninvasive stress test results may be referred for angiography and potential revascularization before transplantation.

At present, cardiac risk stratification of potential kidney transplant candidates is guided by little supporting evidence. Although data demonstrate that noninvasive testing can accurately diagnose coronary artery disease in patients with diabetes and in CKD patients without diabetes, subsequent management varies widely from center to center. Current guidelines from the American College of Cardiology (ACC)/American Heart Association (AHA) recommend revascularization only in symptomatic patients with high-risk cardiac lesions. In two clinical trials that examined preoperative revascularization versus medical management in moderate- to high-risk individuals, perioperative event rates and mortality did not differ. The recent ISCHEMIA-CKD trial did not show a reduction in myocardial infarction or death after revascularization in patients with advanced CKD and moderate-to-severe ischemia on stress testing. Therefore, preoperative revascularization should only be considered in symptomatic individuals, or in selected high-risk individuals in collaboration with cardiology. The question of life expectancy after organ transplant in individuals with a significant burden of coronary artery disease has not been directly addressed. With prolonged waiting times, cardiovascular disease in high-risk individuals may progress. Many programs perform periodic noninvasive rescreening in wait-listed patients; however, the value of this practice is unknown, and current evidence suggests that revascularization of asymptomatic individuals should not be performed. Trials to address this strategy are ongoing.

Modifiable risk factors for cardiovascular disease should be managed appropriately in prospective kidney transplant recipients. Physical activity and dietary modification should be encouraged. Blood pressure potentially should be treated to a target of at least 140/90 mm Hg if tolerated without significant intradialytic hypotension, and smoking cessation should be encouraged. The utility of treating dyslipidemia in patients undergoing dialysis has recently come into question (see Chapter 54); however, control of low-density lipoprotein (LDL) cholesterol should be considered in high-risk individuals. Maintenance anti-ischemic medication, including aspirin and beta-blockers, should be continued while on the waiting list and perioperatively.