Kidney transplant: New opportunities and challenges

LIVING-DONOR ORGAN TRANSPLANT

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

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 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 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% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, 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 (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 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.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing 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 3 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 2).

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%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% 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.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

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.