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 workup 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. Thus patients should be referred for transplantation evaluation when they have stage 4 CKD (eGFR below 30 mL/min) that is progressing. In many programs, 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 referral center.

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. The technical aspects of the transplant surgery limit transplantation in extremely young children. However, this should not delay transplant workup, 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. As such, many transplant programs avoid transplanting patients with extreme obesity. Individual programs 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. Bariatric surgery may be considered in individuals with a BMI greater than 40 kg/m ² .

Kidney Disease

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 60.2 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. Recently, the circulating permeability factor was proposed to be soluble urokinase-type plasminogen activator receptor (suPAR); although this is unproven, this line of research gives hope for more definitive treatments for recurrent FSGS in the future. 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. Rituximab may limit proteinuria and allograft damage after recurrence.

Membranoproliferative glomerulonephritis (MPGN) has a high rate of recurrence posttransplantation, with immune complex-mediated MPGN recurring in 30% to 50% of patients and dense deposit disease recurring in over 80% of patients. 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. The risk for graft loss from immune complex-mediated MPGN is approximately 15% at 10 years, whereas it is as high as 50% after 5 years in dense deposit disease. Recurrence of rapidly progressive glomerulonephritis is rare if disease is quiescent at the time of transplantation. In patients with antiglomerular 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 clinical remission period 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. The total burden of amyloidosis needs to be considered before transplantation.

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 (HUS) 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 should be considered in high-risk 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 it 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.

Tuberculosis (TB) infection is common in immunosuppressed kidney transplant patients, and it 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 and a chest radiograph. High-risk patients should undergo prophylactic TB treatment for 6 to 12 months in the absence of documented prior treatment. It is probably safe to proceed with transplantation after beginning prophylactic TB treatment, but evidence is lacking.

Although once considered an absolute contraindication, kidney transplantation in human immunodeficiency virus (HIV)–positive recipients has become possible in the current era of highly active antiretroviral therapy (HAART). Patient and allograft survival in this population is acceptable, and no worse than other high-risk groups (e.g., older recipients), although the incidence of acute rejection is increased. Patients with HIV should be referred to a transplant center with experience managing this infection. In general, patients should be compliant with HAART therapy, HIV RNA should be undetectable, and the CD4 count should be greater than 200 mm ³ before consideration for transplant.

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 overimmunosuppression 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

Immunosuppression likely promotes tumor growth and increases the risk for cancer recurrence. 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. 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 depends on the type of malignancy and the risk of recurrence. In general, a waiting period of 2 years is recommended for most types of cancers. In high-risk malignancies, such as breast cancer, colon cancer, melanoma, and invasive and/or symptomatic renal cell cancer, a waiting period of 5 years is recommended. However, with improved knowledge of cancer biology, it has become apparent that different molecular subtypes of certain malignancies have very different outcomes. Genomic profiling assays can now be used to provide a more individualized granular assessment of cancer recurrence risk. In cases with very low risk profiles, a wait of 2 years may not be necessary, but further work in transplant candidates is needed before this becomes routine practice. Small, incidentally discovered renal cell cancers and cervical cancer in situ 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 workup. 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. 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 increased 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 and protective clothing. The posttransplant lymphoma risk is much higher in EBV-naïve recipients.

Cardiovascular Disease

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 evaluated for the presence of heart disease before listing. 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 angina symptoms or a myocardial infarction within 6 months should not be offered transplantation. 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. It should be noted that patients with advanced CKD have not been studied in this context, nor has the question of life expectancy after organ transplant in individuals with a significant burden of coronary artery disease 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 newly detected disease is only variably acted upon.

Modifiable risk factors for cardiovascular disease should be managed appropriately in prospective kidney transplant recipients. Blood pressure should be treated to a target of at least 140/90 mm Hg, and smoking cessation should be encouraged. The utility of treating dyslipidemia in patients undergoing dialysis has recently come into question (see Chapter 55 ); however, control of low-density lipoprotein (LDL) cholesterol should be considered in high-risk individuals.

Cerebrovascular Disease

After transplantation, recipients are at an increased risk for cerebrovascular disease when compared with pretransplant patients or the general population. Patients with symptomatic transient ischemic attacks or a recent stroke should be symptom free for 6 months before transplantation. Consideration of carotid endarterectomy should be given to those individuals with known carotid stenosis. The screening of asymptomatic patients is unclear. Again, modifiable risk factors, including smoking and blood pressure, should be addressed before transplant.

Liver Disease

Because progressive liver disease causes significant morbidity and mortality in transplant patients, all prospective recipients should be screened. In patients with liver disease not caused by viral hepatitis, liver function testing and a liver biopsy should be considered to assess the severity of disease. The patient’s immunosuppressed state in the posttransplantation period permits viral replication that can accelerate chronic viral hepatitis. Therefore all patients should be screened for HBV and hepatitis C virus (HCV) infection. In patients with significant liver disease and/or cirrhosis, consideration of combined liver-kidney transplant may be an option.

Patients with positive hepatitis B surface antigen (HBsAg) should undergo testing for hepatitis B viral load by protein-creatinine ratio (PCR), hepatitis B early antigen (HBeAg), and hepatitis D virus (HDV). Patients with evidence of active viral replication (HBeAg-positive, or hepatitis B viral load–positive) should forgo transplantation until HBV is effectively treated. Those with both HBV and HDV should not be considered for transplantation because of the risk of severe liver disease. In patients with chronic active hepatitis and elevated liver enzymes, liver biopsy should be performed, and posttransplant antiviral therapy (e.g., lamivudine) should be considered. Transplant outcomes are generally worse in patients who are HBsAg-positive compared with those who are not. The decision whether to transplant can be difficult, and specialist assistance will usually be required.

HCV infection can lead to accelerated liver disease after transplantation. All prospective transplant recipients who have serologic evidence of HCV exposure should undergo HCV load testing by PCR and liver biopsy. Although patients with HCV have worse outcomes after transplantation when compared with those without infection, the outcomes are improved over remaining on dialysis. Treatment outcomes of HCV infection in ESKD patients, including posttransplantation, have significantly improved after the introduction of direct-acting antivirals (DAAs). Treatment of HCV with DAAs can occur before or after kidney transplantation. Physicians should be aware of drug interactions with calcineurin inhibitors posttransplantation. Patients with HCV may be able to accept a kidney from an HCV-positive donor, especially given improved treatment outcomes.

Pulmonary Disease

Patients with pulmonary disease are at increased risk for perioperative respiratory complications. Thus patients with severe, irreversible lung disease, including severe chronic obstructive pulmonary disease (COPD), cor pulmonale, and those needing supplemental oxygen, should not be offered kidney transplantation. Current smokers and patients with known lung disease should undergo pulmonary function testing for risk stratification before transplantation. Smokers who undergo transplantation are at risk for increased perioperative events and have poor long-term outcomes compared with nonsmokers. All smokers should be offered smoking cessation aids and counseling as necessary to encourage smoking cessation.

Thrombotic Risk

Patients with a history of venous or arterial thromboembolic disease may be at risk for perioperative graft loss due to thrombosis. Screening for genetic risks of thrombosis should be considered in those individuals with a positive medical history, and a plan for perioperative anticoagulation should be constructed. Patients with a history of SLE should be screened for antiphospholipid antibodies. Inherited disorders of complement may lead to atypical HUS, with recurrent disease occurring in up to 25% to 50% of allografts. Screening for genetic abnormalities may allow for an individualized perioperative plan, including plasma exchange and/or calcineurin inhibitor avoidance, which may lessen recurrence risk.

Urologic Evaluation

Patients with a history of lower urinary tract abnormalities, bladder dysfunction, or recurrent urinary tract infections (UTIs) require urologic investigation and voiding cystourethrogram. In addition, high-risk patients, such as those with diabetes, should be screened with a postvoid residual. Efforts should be made to preserve the native bladder, and self-intermittent catheterization is preferable to urinary diversion with ureteroileostomy. Patients with significant exposure to cyclophosphamide should be screened with cystoscopy to rule out malignancy. Pretransplant nephrectomy should be considered in patients with severe reflux or recurrent nephrolithiasis with infection, difficult-to-control hypertension, severe nephrotic syndrome, and symptomatic polycystic kidneys.

Psychological Evaluation

All prospective transplant recipients should undergo screening to identify cognitive or psychological impairments that may alter their ability to provide informed consent or their ability to follow medical protocols after transplantation. Medication nonadherence remains a major cause of graft loss. However, identification of individuals at risk is difficult and not often apparent during the transplant workup. In general, one should be cautious in restricting access to transplantation in those at risk for nonadherence. Patients with addiction or a history of chemical dependency should be offered counseling and rehabilitation. Many programs require a period of abstinence before a patient is put on the waiting list. Those individuals with major psychiatric illness should receive appropriate psychiatric care with the recognition of potential medication interactions and side effects.

Immunologic Considerations Before Transplantation

Tissue compatibility between donor and recipient is determined by matching ABO blood type, human leukocyte antigen (HLA), and/or major histocompatibility complex (MHC). Blood and HLA tissue typing is performed on all suitable transplant candidates at the time of wait-listing. For the most part, the donor kidney must be ABO compatible with the recipient. In North America, ABO B blood type recipients have a longer waiting period as compared with other blood types. Many programs now allocated ABO A2 kidneys to ABO B recipients to improve equity.

Although HLA matching is desired, it is rarely achieved because of the tremendous allelic polymorphisms present in the MHC genes. In kidney transplantation, HLA A, B, and DR are thought to be most important in histocompatibility. Both early rejection and long-term allograft survival are affected by HLA matching, with a zero-antigen mismatched kidney having a decreased risk for rejection and better long-term survival as compared with a six-antigen mismatched kidney.

A major barrier to transplantation is the development of antibodies against HLA epitopes, called sensitization. Anti-HLA antibodies are formed during exposure to foreign HLA through blood transfusions, pregnancy, and prior transplantation. The presence of anti-HLA antibodies against a donor HLA type precludes transplantation in most circumstances because of the extreme risk for hyperacute rejection and graft failure. Thus all candidates on the waiting list are screened for the presence of anti-HLA antibodies at least every 3 months.

Screening for anti-HLA antibodies is performed through serologic testing (by mixing donor lymphocytes with recipient serum) or, now more routinely, through solid-phase assays, such as flow cytometry or the Luminex platform. An estimate of a recipient’s anti-HLA antibody burden can be assessed by mixing recipient serum with a panel of lymphocytes representing random donors from the general population. The percentage of lymphocytes that react to recipient antibodies is called panel-reactive antibody (PRA) and provides an estimate of the likelihood of finding a suitable donor within the population. A high PRA means it will be more difficult to find a compatible donor. In addition, a high PRA is associated with worse graft survival, even if the final cross-match against the donor is negative. Using solid-phase assays, most transplant centers are now able to determine the specificity of a recipient’s anti-HLA antibodies. A list of unacceptable HLA antigens can then be compiled for a recipient. Comparing this profile to the donor’s HLA type to assess tissue histocompatibility is termed a virtual cross-match . Solid-phase assays to detect anti-HLA antibodies are much more sensitive than serologic detection and can often identify low-titer antibodies that were previously undetectable. Even with a negative cross-match, presence of low-titer antibodies against donor HLA is associated with antibody-mediated rejection and higher rates of graft loss.

At the time of transplantation, a final cross-match is completed to ensure tissue compatibility. Recipient serum is mixed with donor tissue. A positive cross-match indicates the presence of donor-specific anti-HLA antibodies (DSAs) and predicts hyperacute rejection. Because not all positive cross-match results are due to antibodies that cause hyperacute rejection, further laboratory tests may be necessary before transplantation. In patients with a high PRA, the cross-match is often performed with historical sera that have the highest PRA value. Recipients with a current negative cross-match but a historical positive cross-match may undergo transplantation, but they are at a higher risk for antibody-mediated rejection.

Patients with a high PRA are disadvantaged and often have prolonged waiting times because of the limited number of compatible donors. Strategies to lower a patient’s PRA to increase the probability of finding a suitable donor are constantly evolving. Noninvasive strategies, such as enrollment in a living donor–paired exchange program, have increased access for mismatched living donor pairs (see later). Strategies to decrease or eliminate anti-HLA or anti-ABO antibodies may include targeting of either the antibodies or the B cell/plasma cell clones that produce the antibodies. Plasmapheresis and high-dose intravenous immunoglobulin (IVIG) have been used successfully to greatly reduce or eliminate anti-HLA antibodies. Rituximab and bortezomib (and, rarely, splenectomy) target B cells and plasma cells. Although these strategies have allowed successful transplantation with ABO-incompatible or positive cross-match donors, the risk for antibody-mediated rejection and graft loss remains increased.