New potent immunosuppression requires careful pretransplant assessment, posttransplant care
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Kidney transplant improves survival and long-term outcomes in patients with renal failure. But potent immunosuppression is required to maintain a successful kidney transplant, and this has several implications:
This article reviews immunotherapy issues, coronary artery disease and infectious complications in kidney transplantation. (In this article, I address issues surrounding the waiting list and source of donated organs.)
Induction therapy
Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.
Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least two to three months after a series of injections (dosage 1.5 mg/kg/day, usually for four to 10 doses).
Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.
Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30 percent relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day zero and day four, which provides receptor saturation for 30 to 45 days.
Basiliximab is also sometimes used off label for patients who need to discontinue a calcineurin inhibitor (i.e., tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for one or two doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.
Antithymocyte globulin is more effective but also more risky. Brennan et al randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16 percent rejection rate versus 26 percent in the basiliximab group. Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and longstanding immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side effect profiles are similar to those of placebo.
Maintenance therapy
The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.
Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after three months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors and hair loss.
Cyclosporine, tacrolimus and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 1).
Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40 percent, so the drug is not potent enough to be used without a calcineurin inhibitor.
Side effects include gastrointestinal toxicity in up to 20 percent of patients, and leukopenia, which is associated with viral infections.
Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85 percent of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.
Death from acute myocardial infarction occurs in about 20-30 percent of patients on dialysis versus about 2 percent of patients with normal renal function. Five years after myocardial infarction, survival is only about 30 percent in patients on dialysis.
There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.
Pretransplant evaluation for heart disease
Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.
Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.
Reduced long-term risk of myocardial infarction after transplant
Kasiske et al analyzed data from more than 50,000 patients from the US Renal Data System and found that for about the first year after transplant patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By three years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.
Kidney recipients are prone to many common and uncommon infections (Table 2). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis and tuberculosis. A positive result does not necessarily rule out transplant.
The following viral serology tests are also done before transplant:
Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.
Hepatitis C
Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease — membranous proliferative glomerulonephritis — also occurs, as do comorbidities such as diabetes.
Careful evaluation is warranted before transplant, including liver imaging, alphafetoprotein testing and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.
There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C. Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective posttransplant.
Hepatitis B
No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alphafetoprotein levels and biopsy are recommended for evaluation. All hepatitis B-negative patients should be vaccinated before transplant.
Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.
Cytomegalovirus
CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.
Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.
CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.
BK virus
BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18 percent of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10 percent of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.
Patients can develop BK nephropathy after exposure to transplant immunosuppression. Posttransplant monitoring protocols typically include PCR testing for BK virus at one, three, six and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.
The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.
Posttransplant lymphoproliferative disorder
Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.
The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80 percent of the cases occur early after transplant, within the first year.
Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (e.g., antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.
Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract) or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal or pulmonary involvement.
Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.
Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone, is usually used. Radiation therapy may help in some cases.
Cryptococcal infection
Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al found a 1 percent incidence in a series of more than 5,000 patients who had received an organ transplant.
Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than six months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ. Bird exposure is a risk factor for cryptococcal infection.
One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.
Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50 percent in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10 percent to 15 percent of cases and can be nodular, ulcerative or cellulitic.
More than 75 percent of fungal infections requiring hospitalization in U.S. patients who have undergone transplant are attributed to either Candida, Aspergillus or Cryptococcus species. Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy or rejection treatment.
Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity.
Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.
Dr. Augustine is staff in the Department of Nephrology and Hypertension, Glickman Urological & Kidney Institute.
This post is excerpted and adapted from an article that originally appeared in Cleveland Clinic Journal of Medicine. Read the full article, Kidney Transplant: New Opportunities and Challenges.
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