Published: August 2010
Renal transplantation is the best treatment for most patients with end-stage renal disease and is associated with significant improvements in quality of life and survival of patients with successful kidney grafts. Because patient and graft survival rates 1 year after transplantation are currently higher than 90% for living and deceased donor kidney recipients, there will be large numbers of successful recipients requiring long-term care in the context of chronic immunosuppression. Primary care physicians and internists are becoming increasingly involved in the care of these patients and will need basic information about immunosuppression and the medical management of these patients.
Calcineurin inhibitors (CNIs), including cyclosporine (CSA) (Neoral, Gengraf, or the earliest form, Sandimmune) and tacrolimus (TAC; Prograf) have been the cornerstones of an immunosuppressive regimen, which usually includes two or more additional agents, such as glucocorticoids, a purine antagonist (mycophenolic acid [CellCept] or azathioprine [Imuran]). Sirolimus (SRL; Rapamune) has been used as a substitute for CNIs. The choice of agents is often protocol driven but is usually adapted to each recipient’s risk profile. High-risk recipients treated with more intensive immunosuppression include those with increased levels of preformed antibody (panel-reactive antibody [PRA] >20%-50%), repeat transplantation after early immunologic loss of a previous graft, and African Americans. High-risk recipients typically receive induction therapy consisting of monoclonal or polyclonal antibodies administered intravenously beginning in the perioperative period. The mechanisms of action of these and other immunosuppressants have recently been reviewed.1, 2
Polyclonal IgG antibodies are derived from horse (Atgam) or rabbit (Thymoglobulin) sera after injecting the animals with human lymphocytes or human thymocytes, respectively. They target several T cell surface epitopes (CD2, CD3, CD4, and CD25) and, in the case of Thymoglobulin, induce long-term depletion of T lymphocytes. Thymoglobulin’s major early side effect is the cytokine release syndrome: fever, chills, myalgias, and shortness of breath. Late side effects include prolonged (up to years) depletion of T lymphocytes, thereby increasing the potential risk of opportunistic infections, post-transplantation lymphoproliferative disorder (PTLD), and possibly autoimmune disease.
Daclizumab (Zenapax) and basiliximab (Simulect) are monoclonal antibodies modified to be humanized or chimeric antibodies that bind to the alpha chain of the interleukin-2 receptor (IL-2R) on T cells and thereby impair lymphocyte proliferation. They typically have minimal side effects and do not increase the recipient’s susceptibility to infection or malignancy. Alemtuzumab (Campath), originally approved for the treatment of chronic lymphocytic leukemia, is a humanized murine monoclonal antibody directed against the surface protein CD52 expressed on T and B lymphocytes, monocytes, and macrophages. It can cause prolonged T lymphocyte depletion, with risks for opportunistic infection, PTLD, and possibly autoimmune disease.
Basic maintenance immunosuppression for many years consisted of three types of drugs in combination: glucocorticosteroid (GC) (prednisone), a purine antagonist (azathioprine or mycophenolate mofetil) and a CNI (CSA) or TAC. Because of numerous potential glucocorticoid (GC) toxicities (Box 1) and CNI toxicities (Table 1), many new regimens have been developed that incorporate rapid GC elimination, or CNI dose reduction or elimination. Rapid GC withdrawal within the first few days after transplantation is usually achieved with antibody induction. Late withdrawal of GC has a high risk of rejection.3 CNI withdrawal has been attempted by conversion to less nephrotoxic SRL. Alternatively, careful dose reduction can be successfully achieved in select patients.4 Combined use of a CNI and SRL has the potential for severe nephrotoxicity.
|Box 1 Important Glucocorticoid Side Effects|
|Increased susceptibility to infection|
|Replication of hepatitis B and C viruses|
|Weight gain (increased appetite)|
|Easy bruising, striae, acne|
|Poor wound healing|
|Fatal ventricular arrhythmias (rapid bolus)|
|Arthralgia with rapidly decreasing dose|
|Hyperosmotic nonketotic coma|
|Behavioral changes, psychosis|
|Posterior subcapsular cataracts|
|Tremor, neuropathy, convulsion||+||++|
|Susceptibility to malignancy||++||+|
|Susceptibility to viral infection||+||+|
|Nausea, vomiting, diarrhea||+||+|
GCs are used for both induction and maintenance immunosuppression. Their immunosuppressant actions are mediated through a number of pathways, mainly directed toward redistribution of lymphocytes and macrophages to the lymphoid tissue and inhibition of the production of cytokines (e.g., IL-1, IL-2, IL-6), tumor necrosis factor α (TNF-α), and interferon gamma (IFN-γ). Prednisone dosage is gradually decreased after transplantation to 5 to 7.5 mg daily unless the patient has been on a rapid GC withdrawal protocol.
CNIs include CSA and TAC; each functions as a base immunosuppressant agent around which additional agents are added to construct the complete immunosuppressant regimen. Initiation of CSA in the post-transplantation period usually requires signs of renal recovery because of potential nephrotoxicity. The usual starting dosage is about 5 to 6 mg/kg/day, divided into two doses. Many CSA formulations are now available. The original formulation (Sandimmune) has been largely replaced by the newer CSA formulations (Neoral) or modified CSA (e.g., Gengraf, Eon, other generics) that exhibit better absorption and bioavailability. These CSA preparations should not be casually substituted for each other because of increased risk of rejection or toxicity. The interval for monitoring CSA blood levels remains controversial. Monitoring trough levels (C0) is the appropriate way to monitor Sandimmune, but the newer formulations may be better monitored with levels determined 2 hours after the dose is taken (C2). The approximate CSA level is determined by the type of CSA being used, the assay method, the time after transplant, and the clinical status of the patient.5
TAC is a macrolide antibiotic somewhat more potent than CSA and has side effects that are distinct from and overlap with those of CSA (see Table 1). TAC has high bioavailability and thus its trough levels correlate with dose. The maintenance dosage is usually approximately 0.1 mg/kg/day divided into two doses, with target trough levels of 5 to 15 ng/mL in the initial 12 months after transplantation and 5 to 10 ng/mL beyond 12 months. Both CSA and TAC are metabolized by the hepatic enzyme system cytochrome P-450 3A4 (CYP 3A4), which is responsible for the metabolism of numerous drugs (Box 2). Consequently, for these drugs and those described later, it is worthwhile to consider the treatment approaches shown in Table 2.
|Box 2 Calcineurin Inhibitors and Other Drug Interactions*
The drugs listed here are only a partial list.†
|Medications that Increase Calcineurin Levels|
|Calcium Channel Blockers|
|Medications that Decrease Calcineurin Levels|
|St. John's wort|
* The safest procedure is to specifically check any drug added to or eliminated from those taken by a transplant recipient to determine its effect on calcineurin levels.
† Calcineurins can significantly increase the levels, effects, and toxicity of other drugs, notably many statins7 and sirolimus. Careful dosing and monitoring are necessary.
|Transplant Drug||Second Drug||Mechanism||Effect||Strategy|
|Azathioprine||Allopurinol||Xanthine oxidase inhibition||Increased azathioprine effects||Dose reduction or substitute mycophenolate mofetil (CellCept)|
|CSA or TAC or SRL||Azoles, most CCBs, erythromycin, statins||P4503A4||Increased levels of CSA, TAC, SRL, statin||Dose reduction or substitute nifedipine; substitute azithromycin; use ezetimibe (Zetia)|
|SRL||CSA or TAC||P4503A4||Increased nephrotoxicity; increased CSA and TAC levels||Dose reduction or avoid|
CCB, calcium channel blockers; CSA, cyclosporine; SRL, sirolimus; TAC, tacrolimus.
Purine antagonists include azathioprine and mycophenolate mofetil. Azathioprine is a prodrug converted in the body via a nonenzymatic reaction to 6-mercaptopurine, a purine analogue that acts as an antimetabolite and blocks the synthesis of nucleotides, thereby inhibiting T and B cell proliferation.1 Its major side effects are leukopenia and possible myelosuppression, increased susceptibility to infection, increased susceptibility to cancer, particularly PTLD and skin cancer, hepatotoxicity, and alopecia. The usual dosage varies from 1 to 2 mg/kg/day. The concomitant use of azathioprine with allopurinol, a xanthine oxidase inhibitor used to lower serum uric acid levels, typically in patients with gout, increases the risk of side effects and requires dose adjustments (see Table 2.). Mycophenolate mofetil has largely replaced azathioprine.
Mycophenolate mofetil (MMF) is converted to mycophenolic acid, which inhibits inosine 5′-monophosphate dehydrogenase, a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, thereby inhibiting DNA synthesis for replication of T and B cells.1 The usual dose is 1 to 2 g/day in two divided doses. Its major side effects are diarrhea, leukopenia, anemia, and tissue-invasive cytomegalovirus (CMV) disease. Often, diarrhea can be avoided by dosing three times daily rather than twice daily using the same total daily dose.
The immunosuppressants SRL (Rapamune) and everolimus bind to the same immunophilin (FKBP12) as TAC and modulate the intracellular protein mammalian target of rapamycin (mTOR), resulting in cell cycle arrest in the G1-S phase.1 The maintenance dosage is usually 2 to 5 mg/day, with target trough levels of 5 to 15 ng/mL. SRL has a very long half-life (approximately 65 hours), so that trough level monitoring should be done 5 to 7 days after initiating the medication. It should be noted that although mTOR inhibitors and reduced doses of TAC or CSA may be used together, they can be more nephrotoxic and have inferior graft survival. Initially, mTOR inhibitors alone were not believed to be nephrotoxic. However, SRL may prolong acute tubular necrosis and cause proteinuria, certain glomerulopathies, and thrombotic microangiopathy. SRL, as well as CSA and TAC, also can cause renal magnesium wasting and potentially significant hypomagnesemia. Other side effects, typically dose-related, include hypercholesterolemia, hypertriglyceridemia, edema, hypertension, anemia, thrombocytopenia, leukopenia, interstitial pneumonitis, delayed wound healing, skin rash, mouth ulcers, and myalgia. More frequent acute rejections and inferior allograft survival have been reported with SRL than with CNI.
The frequency of outpatient visits at the transplantation center is generally determined by the individual post-transplantation course of each recipient. Follow-up is focused on monitoring the recipient for acute rejection—an otherwise unexplained rise in serum creatinine level of 20% to 25% and varying clinical signs of decreased urine output, weight gain, edema—and cardiovascular disease, malignancy, infectious complications, usually pulmonary or urinary tract, delayed technical complications (e.g., renal artery stenosis, lymphocele, obstruction), worsening hypertension, new-onset or poorly controlled diabetes mellitus, hyperlipidemia, excessive weight gain, fluid retention and CHF, excessive diuresis and volume contraction, and immunosuppressant management for appropriate blood levels and toxicities. Concurrent management with the primary care physician or local nephrologists may vary among centers but will usually be a joint effort, with continuing contact with the transplantation center’s nephrologists.
The advent of new and more potent immunosuppressive agents has reduced the frequency of acute rejection but has introduced other complications of renal transplantation. The differential diagnosis of an acute rise in serum creatinine level of more than 20% to 25% is similar to that for acute renal failure (prerenal, renal arterial, renal parenchymal, postrenal), with special emphasis on the time interval from transplantation, and awareness that the CNI immunosuppressants being used can themselves be nephrotoxic (Fig. 1). Major considerations are acute rejection, CNI nephrotoxicity, uncontrolled hypertension, recurrence of the original kidney disease, infections, and prerenal causes, such as volume depletion (e.g., through gastrointestinal losses, excessive diuretics, uncontrolled hyperglycemia) or hemodynamic alterations (e.g., often caused by combinations of medications, including angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers [ARBs], nonsteroidal anti-inflammatory drugs [NSAIDs], and CNIs even with mild volume depletion), and congestive heart failure. Although the frequencies of obstruction and transplantation artery stenosis are low, these need to be evaluated promptly with graft ultrasound or other techniques, because their treatment would usually require a transplantation surgeon or interventional radiologist.
Historical clues to allograft dysfunction include changes in weight and urine output, conditions leading to and symptoms of volume depletion, fever, chills, pain over the allograft, significantly higher or lower blood pressures, failure to adhere to the prescribed immunosuppressant medications, and the addition of a new medication, such as a diuretic, NSAID, ACE inhibitor or ARB, nephrotoxin, or a CYP 3A4 enzyme inhibitor that can increase or a medication that can decrease CNI levels (see Box 2). The physical examination should focus on volume status with orthostatic hypotension, significantly higher or lower blood pressures, allograft tenderness or bruit, swelling in the allograft area, diminished femoral pulses, particularly on the side of the allograft kidney, and evidence of congestive heart failure or infection. Laboratory studies should include a complete metabolic panel, serum phosphorus magnesium and uric acid, complete blood count (CBC) with differential, immunosuppressant blood levels, urinalysis, urine culture, and other studies based on the patient’s presentation. An imaging study, including a graft ultrasound to detect evidence of obstruction and evaluate graft arterial and venous blood flow, should be performed promptly. A renal allograft biopsy is essential for determining the full extent of acute rejection.
Acute cellular rejection (ACR) is the most common type of rejection. With current immunosuppression regimens, clinical symptoms including allograft pain, fever, and oliguria, are uncommon. Typically, ACR occurs between 1 and 3 months after transplantation and less commonly after 6 months. Mild ACR (tubulitis) may be successfully reversed with corticosteroids alone, whereas moderate or severe ACR with endotheliitis may require the use of anti–T cell antibodies. Humoral or antibody-mediated rejection (AMR) caused by post-transplantation development of antidonor antibodies is a more serious form of rejection that usually requires plasmaphereses and intravenous immunoglobulin (IVIg) in addition to increased immunosuppression. Acute CNI nephrotoxicity may manifest as the hemolytic-uremic syndrome (HUS) manifested by thrombocytopenia, anemia, elevated lactic dehydrogenase (LDH) levels, and a peripheral blood smear with schistocytes. The definitive diagnosis is made by renal allograft biopsy. Recurrent renal disease in kidney transplant recipients accounts for less than 5% of all graft losses, but some diseases have a higher risk of recurrence, such as focal segmental glomerulosclerosis, immunoglobulin A (IgA) nephropathy, HUS, and membranoproliferative glomerulonephritis. Diabetic nephropathy can recur in renal allografts and has a more rapid onset than that seen in native kidneys, but it still is an uncommon cause of graft loss. Graft pyelonephritis can occur at any time after transplantation, with a clinical presentation ranging from asymptomatic pyuria to severe allograft pain and tenderness, fever, and leukocytosis; graft function usually returns to its baseline with appropriate antibiotics and volume repletion. Acute interstitial nephritis can also be encountered at any time after transplantation and usually responds to removal of the offending agent. BK virus nephropathy has become a more significant problem with the use of more potent immunosuppressant protocols. Full evaluation of BK infection and possible nephropathy should be done in a transplantation center, because treatment involves reduction in immunosuppressants and selection of additional therapy, as well as transplant biopsy with special studies. Similarly, acute rejection and recurrent disease should be managed in the transplantation center with biopsy of the transplanted kidney.
Late allograft dysfunction is usually a slow and progressive process resulting from chronic allograft injury. Biopsies of these kidneys show varying degrees of glomerulosclerosis, vascular damage, tubular atrophy, and interstitial fibrosis caused by both immunologic and nonimmunologic factors.
Medical complications create the most common cause of graft loss, namely, death of the recipient with a functioning graft. The primary causes of recipient death are cardiovascular disease (CVD), infection, and malignancy.6-8
CVD remains the leading cause of death in kidney transplant recipients. Cardiovascular risk factors, often existing before transplantation, include hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, peripheral vascular disease, long duration on dialysis, obesity, physical inactivity, older age, smoking, and male gender.7, 9 Cardiovascular risk reduction includes tight control of blood pressure (to <130/80 mm Hg), hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] level <100 mg/dL), and diabetes mellitus, if present; smoking cessation, physical activity, and weight control or reduction are also important. Evidence of carotid or peripheral arterial occlusive vascular disease should be checked at least annually on physical examination and followed with duplex ultrasound and pulse volume recordings, respectively. Stress testing is often needed for asymptomatic individuals who are also at high risk but may not experience chest pain because their underlying disease, diabetes mellitus with its neuropathy, can blunt symptoms of angina pectoris.
Approximately 60% of renal transplant recipients develop hyperlipidemia by 1 month after initiation of immunosuppressive therapy. SRL, CSA, and corticosteroids are major factors contributing to hyperlipidemia, in addition to other more usual factors (e.g., obesity, genetic predisposition, hypothyroidism, diabetes mellitus, nephrotic-range proteinuria, and allograft dysfunction). Recommendations include maintaining total cholesterol level lower than 200 mg/dL, LDL-C level lower than 100 mg/dL, and triglyceride levels lower than 150 mg/dL. First-line therapy should include both a low-fat diet and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin). There is an increased risk of myopathy or rhabdomyolysis because of the pharmacokinetic interaction of statins with CSA, TAC, and SRL. It has been recommended that the maximum dose of statins be reduced in patients receiving either CSA or TAC. Consequently, creatine kinase (CK) enzyme and alanine aminotransferase (ALT) levels should be monitored regularly. If diet and statin treatment fail to control the hypercholesterolemia, other treatment measures include switching from SRL or CSA to TAC, and adding ezetimibe (Zetia).
Hypertension is present in about 90% of kidney transplant recipients. It is well known that increasing levels of hypertension contributed to progressive graft loss. The basis of post-transplantation hypertension is often multifactorial and includes one or a combination of several factors, such as continued renin output from native kidneys, immunosuppressants (CNI, GC), graft renal artery stenosis, chronic allograft injury, liberal sodium intake, excess weight, hyperaldosteronism, and genetic factors. The Seventh Joint National Committee (JNC 7) has recognized the greater risk of hypertension in kidney transplant recipients and recommends a blood pressure goal of 130/80 mm Hg or lower. First-line therapy consists of lifestyle modification. Each class of antihypertensives has advantages and risks in a particular patient. ACE inhibitors and ARBs may be useful to help preserve renal function, particularly in diabetics, but generally should not be used when transplantation renal artery stenosis is present. Other potential side effects include angioedema, cough, hyperkalemia, anemia, and hemodynamic effects that cause a rise in the serum creatinine level. Diuretics may cause hypovolemia, leading to a rise in the serum creatinine level, hypokalemia, hypomagnesemia, and hyperuricemia. Blood levels of CNIs may be increased by some calcium channel blockers (e.g., verapamil, diltiazem, amlodipine), so appropriate monitoring of blood levels is advised with initiation of these calcium channel blockers (see Box 2 and Table 2).
The cumulative incidence of post-transplantation new-onset diabetes mellitus (NODM) at 12 and 36 months after transplantation has been reported to be approximately 16% and 24%, respectively,10 but the true incidence is difficult to assess because of the absence of a uniform definition of NODM. Risk factors for NODM are age older than 50 years, obesity, African American and Hispanic ethnicities, family history of DM, hepatitis C, and use of CSA, TAC, and GC. The use of MMF, azathioprine, statins, and ACE inhibitors does not increase the risk for developing NODM. Initial therapy focuses on diabetes education, diet, exercise, and weight reduction. Selection of medications should take into consideration drugs affected by impaired renal function and interaction with immunosuppressants. Because of the surge in new drugs for diabetes treatment, NODM often requires management by an endocrinologist. Modification of the immunosuppressive regimen, if necessary, should be done with the aid of a transplantation nephrologist. GC tapering or discontinuation should be avoided or done with extreme caution because of the high risk of acute rejection.
Calcium and phosphorus disorders are common after transplantation. Hypophosphatemia may be seen even in the early post- transplantation period and may be caused by residual secondary hyperparathyroidism and impaired proximal tubular phosphate reabsorption because of GC use, and is usually asymptomatic. The phosphorus level should be kept between 2.5 and 4.5 mg/dL, with phosphorus supplementation. Hypercalcemia is most often caused by persistent hyperparathyroidism but may resolve with a longer period of good graft function. However, in some cases of hyperparathyroidism, hypercalcemia may persist, and treatment with the calcium-sensing drug cinacalcet should be considered. Subtotal parathyroidectomy may be needed. Other causes of hypercalcemia should also be evaluated, particularly excessive vitamin D and calcium intake, hyperthyroidism, and malignancies such as lymphomas and multiple myeloma.
Hyperkalemia can be associated with the use of ACE inhibitors and ARBs, beta blockers, CNI, type IV renal tubular acidosis (RTA), and significant renal failure, especially with high-potassium diets. Hyperkalemia requires treatment that begins with the treatment of any drug or diet cause and, according to the degree of elevation, the use of diuretics, exchange resin, or even dialysis, if extreme.
Hypomagnesemia is commonly the result of the magnesuric effect of SRL and CNI, and may be associated with tremors. Magnesium supplementation should be started when the serum magnesium level falls below the lower level of the reporting laboratory, or kept within the upper normal range if the patient has tremors not due to other causes.
Female and male kidney recipients lose up to 8% of their bone mass during the first 18 months after transplantation. An assessment of kidney transplant recipients at a mean of 6 years after transplantation has shown that bone loss, in the form of osteopenia or osteoporosis, affects 88% of recipients. Corticosteroid use is a major factor in bone loss, along with persistent hyperparathyroidism. Hypothyroidism and hypogonadism are other possible factors that need to be evaluated and treated if indicated.
Guidelines from the American Society of Transplantation recommend a baseline dual-energy x-ray absorptiometry (DEXA) scan at the time of transplantation, at 6 months after transplantation in all patients, and then annually in patients with abnormal results. Prevention and treatment of osteoporosis include appropriate daily elemental calcium (1200 mg/day) and vitamin D (800 U/day) intake, along with daily exercising and avoidance of smoking, caffeine, and alcohol use. The use of bisphosphonates will often depend on the level of renal function. The emerging regimen of GC avoidance may be promising for limiting osteoporosis, whereas GC withdrawal creates a significant risk of rejection.
Gout occurs in 10% to 20% of kidney recipients at any time after transplantation. Hyperuricemia occurs in a larger number of CNI-treated recipients, primarily those receiving CSA, because of decreased glomerular filtration of uric acid. In addition to the typical site of acute gout in the first metatarsophalangeal joint, post-transplantation gout may occur in the upper extremities and larger joints (e.g., wrists, shoulders, elbows, knees, hips). Acute attacks may be treated with low-dose colchicine or oral GCs. NSAIDs should be avoided.
Allopurinol should be avoided in patients who are taking azathioprine or used in a reduced dosage with lower dose azathioprine because of the high risk of interaction leading to severe myelosuppression, hepatotoxicity, or other adverse effects (see Table 2). Conversion from azathioprine to MMF avoids the problem and usually permits doses closer to those for nontransplantation patients. However, both colchicine and allopurinol can have serious side effects in patients with reduced renal function, and careful consideration must be given to monitoring or even avoiding their use. Major adverse effects of colchicine include diarrhea, myopathy, nausea, vomiting, myelosuppression, teratogenicity, hepatocellular toxicity, and seizures.
Immunosuppression creates a greater risk of infection, especially in the current era, because many potent immunosuppressants and antibody induction therapies are now used in broad combinations. The spectrum of infections in a renal transplant patient varies over time. In the first few months after transplantation, infections are usually caused by common bacterial and fungal infections associated with the surgical wound, vascular catheters and ureteral stents, organisms transmitted with the donor organ, nosocomial urinary tract infections (UTIs) and pneumonias, and Clostridium difficile–associated diarrhea. Infections beyond 4 months often include opportunistic pathogens because of the cumulative effects of intensive immunosuppressive therapy after transplantation. The important pathogens include viruses (CMV, Epstein-Barr virus [EBV], BK polyoma), fungi (Aspergillus, Cryptococcus), bacteria (Listeria monocytogenes), and other organisms (Pneumocystis jiroveci, Nocardia). Beyond 6 months, community-acquired bacterial and viral infections, recurrent urinary tract infections, opportunistic infections, parvovirus B19, and persistent hepatitis B or C virus (HBV, HCV) infections can develop.
CMV infections represent one of the most common and serious infections in renal transplant recipients. Before prophylaxis programs were used, these infections occurred 1 to 6 months after transplantation, with a peak at approximately 6 weeks. Most transplantation programs now use at least 3 months of prophylactic antiviral therapy. However, experience has shown that CMV may occur within a few weeks after cessation of antiviral prophylaxis. The risk of CMV infection is highest in CMV antibody-negative recipients with CMV antibody-positive donors (CMV D+/R-). CMV prophylaxis programs in CMV D+/R- pairs may use oral valacyclovir or valganciclovir for 6 months or longer after transplantation.
The clinical presentation ranges from a subtle flulike syndrome to life-threatening pneumonia. It can be tissue invasive and affects the gastrointestinal tract, liver, retinas, central nervous system (CNS), and myocardium. The primary diagnostic test is quantitative CMV DNA determined by the polymerase chain reaction (PCR) assay. CMV infection is usually treated with intravenous ganciclovir for 2 to 4 weeks and reduction of immunosuppression (especially MMF).
Polyoma BK virus is a more recently recognized viral infection that can affect the renal allograft early and late after transplantation. Its detection and treatment are best managed in a transplantation center. It is a ubiquitous virus that remains in a latent state in up to 90% of the general population. About 30% to 60% of kidney transplant recipients develop BK viruria after transplantation, and 10% to 20% develop BK viremia. Among those who develop BK viremia, 5% to 10% develop BK nephropathy; of these, approximately 70% lose the allograft and the remainder exhibit some kidney dysfunction. BK infection may be associated with ureteral stenosis and possible obstruction, tubulointerstitial nephritis, and a progressive rise in the serum creatinine level, with ultimate allograft failure. BK infection must be evaluated in any episode of renal dysfunction and prospectively evaluated approximately every 3 to 6 months in the first year after transplantation.
Quantitative measurements of BK virus in the blood can strongly suggest BK nephropathy, but a graft biopsy with in situ hybridization or immunohistochemical techniques is required for a definitive diagnosis. Because there is no proven drug treatment for BK nephropathy, current therapy relies on careful reduction of immunosuppression (with the unavoidable risk of rejection) and options to use intravenous gamma globulin (IVIg) and/or low-dose cidofovir.
Prophylaxis of P. jiroveci pneumonia for recipients not allergic to sulfa includes single-strength trimethoprim-sulfamethoxazole for at least 1 year or indefinitely, depending on the perceived susceptibility of the transplant recipient and transplantation center practice. For sulfa-allergic patients, prophylaxis is achieved with oral dapsone or monthly inhaled pentamidine for up to 1 year.
Vaccinations should be administered before transplantation. There are no data regarding timing of vaccines after transplantation. Live or attenuated virus vaccines are contraindicated after transplantation; these include measles-mumps-rubella (MMR), varicella, live oral poliomyelitis (Sabin), oral typhoid, bacillus Calmette-Guérin (BCG), smallpox, yellow fever, and the new varicella zoster virus vaccine. Permitted vaccines include influenza, inactivated injectable poliomyelitis (Salk), pneumococcal (Pneumovax), tetanus, and polysaccharide typhoid vaccines.
The 10-year prevalence of post-transplantation malignancy in the United States is reported to be as high as 30%. There is a twofold increase in common cancers (e.g., lung, colon, stomach, esophagus, pancreas, prostate, breast, and ovary), fivefold increase in melanoma, leukemia, hepatobiliary, cervical, and vulvovaginal cancers, a 15-fold increase in kidney cancer, and a 20-fold increase in Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and nonmelanoma skin cancers.11 In addition to the roles of immunosuppression and oncogenic viruses, clinical contributors to the risk of cancer include increasing age, cigarette smoking, and sun exposure.
Skin cancers—squamous cell carcinoma more often than basal cell carcinoma—remain the most common cancers in kidney recipients and are more aggressive than in the general population. The interval between transplantation and diagnosis is age dependent, 8 years for recipients 40 to 60 years of age, and 3 years for those older than 60 years. A dermatologist should be part of the long-term transplant care team for prompt evaluation of suspicious lesions and full skin examinations annually.
PTLD represents a spectrum of tumors, most often in the form of non-Hodgkin’s lymphoma (NHL). The incidence of NHL peaks in the first year after transplantation and is associated with EBV virus infection in more than 90% of the cases. It differs from that in the general population by its extranodal, CNS, and allograft involvement. Therapy involves major reduction or complete elimination of nonglucocorticoid immunosuppressants and, in some cases, chemotherapy, surgical excision, and radiotherapy. It may be aggressive and respond poorly to therapy, especially if there is CNS involvement.