Chapter 53. Renal Transplantation

Recipient Evaluation

Currently, kidney transplantation is the treatment of choice for patients with end-stage renal disease (ESRD) as it improves both patient survival and quality of life when compared to dialysis. It must be noted, however, that although the risk of death in the first year after transplantation is less than 5%, not all patients qualify for the surgery due to their unacceptably high risk for complications. The transplant evaluation process requires a comprehensive assessment of each patient's medical, surgical, and psychosocial history. A systematic approach should be used in the evaluation of potential renal transplant candidates.

The Initial Evaluation Process

Prior to the formal evaluation process, all potential transplant candidates are encouraged to attend a “patient education” session. At the meeting, patients are informed about the medical and surgical risks and benefits of renal transplantation, the necessity for frequent outpatient visits in the early postoperative period, the potential adverse effects of immunosuppression, and the importance of compliance with immunosuppressive therapy. The potential advantages and disadvantages of deceased versus living donor renal transplantation are discussed with the patients and, when possible, with their family members, significant others, and/or friends. Other issues that are addressed include the prolonged waiting time for a deceased donor transplant due to the critical shortage of donor organs and the adverse effects of waiting time on patient and graft survival. In addition, patients are forewarned that various medical and psychosocial conditions may preclude a patient from being a transplant candidate. Absolute and relative contraindications to kidney transplantation are outlined in Table 53–1.

General Assessment

The routine assessment of a renal transplant candidate includes a detailed history and a thorough physical examination. In particular, it is important to determine the cause of the original kidney disease as it can help in predicting the transplant course and outcome and the risk for disease recurrence. When available, the kidney biopsy report should be reviewed. Patients with ESRD secondary to congenital or genitourinary abnormalities should undergo a voiding cystourethrogram (VCUG) and appropriate urologic evaluation, preferably by the kidney transplant surgeon. Documentation of the patient's residual urine volume from the native kidneys is invaluable in the assessment of graft function in the posttransplant period. A history of familial or hereditary renal disease must be obtained if living related kidney donation is an option. The patients's surgical history should be elicited with special emphasis on previous abdominal operations. A complete physical examination should include a careful assessment for the presence of carotid and peripheral vascular disease. Patients should preferably have a body mass index below 30–35 as obesity is associated with a higher incidence of postoperative complications. In addition to a thorough history and physical examination, patients should also undergo a number of routine laboratory testings and imaging studies as outlined in Table 53–2. Specific risk factors need to be addressed during the transplant evaluation process.

Evaluation of Risk Factors by Specific Organ System Disease

Cardiovascular Disease and Peripheral Vascular Disease

Cardiovascular disease (CVD) is the leading cause of death after renal transplantation. Deaths with a functioning graft occurring within 30 days after transplantation are due to ischemic heart disease in nearly 50% of cases. A detailed cardiovascular history not only predicts the operative risk but also helps in postoperative cardiac management to improve short-term and long-term cardiac outcomes. Although the determinants of CVD risk in ESRD patients have not been well defined, all patients with CKD should be considered increased cardiac risk candidates. Major conventional risk factors include diabetes mellitus, hypertension, dyslipidemia, obesity, a history of angina pectoris, congestive heart failure, previous cardiac events, older age, smoking, and family history. Other suggested risk factors include preexisting left ventricular hypertrophy, dialysis for a prolonged period, coronary artery vascular calcification, abnormal electrocardiogram, and hyperhomocysteinemia. Exercise tolerance should be assessed along with cardiac-related symptoms as many patients on dialysis lead sedentary lifestyles and are symptom free. Noninvasive cardiac screening such as nuclear stress test or dobutamine stress echocardiogram is probably adequate for low-risk candidates. However, for those with multiple risk factors, particularly diabetes mellitus and/or previous cardiac events, coronary angiography is warranted. If necessary, coronary angioplasty/stenting or coronary bypass surgery and cardiac rehabilitation should be performed prior to transplantation. In general, high-risk candidates should undergo a formal evaluation by cardiology.

Patients with a history of transient ischemic attacks or cerebrovascular accidents should undergo carotid Doppler studies. When carotid bruits are detected on physical examination in an asymptomatic patient, further diagnostic imaging should be performed at the discretion of the clinician. Evidence of significant stenosis requires vascular surgery consultation. If necessary, carotid endarterectomy should be performed prior to transplantation and patients should be symptom free for at least 6 months prior to transplantation. For those with milder carotid disease, a neurologic consultation and optimal medical management may be sufficient.

Peripheral vascular disease is present in a significant number of renal transplant recipients and is associated with increased morbidity and mortality. Vascular imaging with either a Doppler ultrasound or a noncontrast abdominal/pelvis CT scan is indicated in patients with a history of claudication and/or signs of diminished peripheral arterial pulses (particularly in diabetics) on physical examination. An angiogram should be considered if noninvasive studies suggest the presence of large-vessel disease. Significant aortoiliac disease requires evaluation by the surgical transplant team and may preclude transplantation.

Malignancy

Transplant recipients are at greater risk of developing both de novo and recurrent malignancy due to the use of immunosuppressants. As the incidence of malignancy increases with the intensity and duration of immunosuppression, a history of immunosuppressive therapy for the native kidneys represents an added risk for posttransplant malignancy. For patients with a history of malignancy, consultation with an oncologist is advisable. Table 53–3 provides general guidelines for minimum tumor-free waiting periods for common malignancies.

Infections

All patients should be assessed for common latent or active infections and questioned for a history of infectious exposures. Active infections including diabetic foot ulcers and osteomyelitis must be fully treated prior to transplantation. A prior history of tuberculosis or untreated tuberculosis exposure requires appropriate posttransplant prophylactic therapy. Patients with an established history of systemic coccidioidomycosis or histoplasmosis or those from an endemic area should undergo appropriate antibody testing. In addition, these patients should be informed of possible disease reactivation with immunosuppressive therapy and indefinite posttransplant azole prophylactic therapy.

A history of immunization should also be obtained to ensure adequate immunizations for common infections prior to transplantation (eg, hepatitis B, pneumovax, and other standard immunizations appropriate for age). An immunization update is mandatory for those who have undergone surgical splenectomy. Infections with the human immunodeficiency virus (HIV) was once considered a contraindication to transplantation due to early reports of serious infectious complications and death following HIV infection transmitted from a transplanted organ or inadvertent transplantation of HIV-infected patients. However, with the advent of effective highly active antiretroviral therapy (HAART) regimens, there have been changing views regarding transplantation in HIV-positive patients. Currently, a number of transplant centers would consider transplantation in stable HIV patients, defined as those with an undetectable HIV viral load, CD4 lymphocyte count >300/mm3, and absence of opportunistic infections in the previous year. Specific recommendations may vary from center to center and a formal consultation with an infectious disease specialist is recommended.

Specific Gastrointestinal Disease Evaluation

There has been no consensus on whether all asymptomatic renal transplant candidates should be screened for cholelithiasis. Screening is warranted, however, in diabetics and patients with a history of cholecystitis. Pretransplant cholecystectomy is recommended for these patients if there is evidence of cholelithiasis due to the increased risk of life-threatening cholecystitis after transplantation.

Urologic Evaluation

All renal transplant candidates on dialysis should be imaged with a renal ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to evaluate for acquired cystic kidney disease and associated renal cell carcinoma if no imaging study has been performed within the previous 3 years. Urinalysis and urine cultures should be performed in all patients with significant residual urine volume. Transplant candidates with a history of recurrent urinary tract infections, voiding symptoms, or ESRD secondary to congenital or genitourinary abnormalities should undergo a VCUG. Persistent hematuria or sterile pyuria may warrant endoscopic evaluation and/or retrograde pyelography. Urodynamic studies may be helpful in patients with a history of lower urinary tract dysfunction and/or urinary incontinence. Patients with bladder dysfunction secondary to neurogenic bladder or chronic infections can often be managed without urinary diversion. In continent patients with lower urinary tract dysfunction, intermittent self-catheterization is a safe and effective alternative to urinary diversion. However, a formal urologic evaluation and patient education during the initial transplant evaluation process are mandatory. Augmentation cystoplasty or urinary diversion procedures may be necessary in patients in whom simple reimplantation into a dysfunctional bladder is not an option. Male transplant candidates with sufficient urine volume and symptoms of outflow tract obstruction due to benign prostatic hypertrophy should undergo prostate resection before transplantation, whereas in anuric patients, the procedure should be postponed until after a successful renal transplant.

Special Urologic Considerations: Pretransplant Native Nephrectomy

For most patients with autosomal dominant polycystic kidney disease (ADPKD) pretransplant nephrectomy is not routinely recommended. However, unilateral or bilateral pretransplant nephrectomy(ies) may be necessary for those with massively enlarged kidneys, recurrent infection, bleeding, and/or intractable pain. Table 53–4 lists the special indications for pretransplant native nephrectomy. Generally, a minimum of 6 weeks after nephrectomy is recommended prior to transplantation. For transplant candidates who undergo preemptive transplantation from a living donor, simultaneous native nephrectomy and transplantation may be performed.

Evaluation of Risk Factors Related to Specific Patient's Characteristics

Advanced Age

There is no arbitrary age limit for transplantation. The United Network for Organ Sharing organ procurement and transplant network (UNOS OPTN) database reveals that the number of kidney transplants performed in patients >65 years old has more than tripled over the past 10 years. Similar to the younger population, transplantation in the older age group of 60–74 years has been shown to improve survival compared to their wait-listed counterparts. Graft loss from rejection is lower in older compared to younger recipients presumably due to the decreased immune responsiveness in the aged population. It must be noted, however, that older transplant recipients are at increased risk for infectious complications, malignancy related to immunosuppression, and deaths in the early posttransplant period, most often as a consequence of cardiovascular disease. Screening for covert cardiovascular disease and occult malignancy in older potential recipients is, therefore, crucial and mandatory.

Obesity

Obesity is considered a contraindication to transplantation by some centers as it is associated with increased risk of posttransplant complications including delayed graft function, surgical wound infection, and death, particularly from cardiovascular disease. Although there has been no consensus on an acceptable upper limit body mass index (BMI), weight reduction to a BMI of 30–35 kg/m2 or less prior to transplantation is recommended. Morbidly obese candidates may benefit from surgery referral for gastric bypass surgery or gastric banding procedure. Data on patient and graft survival in obese versus nonobese transplant recipients are variable and contradictory. Determination of transplant candidacy in obese patients should, therefore, be assessed on an individual basis rather than reliance on an absolute BMI index. Obese candidates with comorbid conditions such as known coronary artery disease and advanced age are at particularly high risk and may fare better receiving dialysis.

Donor Evaluation

This section focuses primarily on the evaluation of the living donor candidate.

Evaluation of the Living Donor

Over the past decade, the number of living donors has steadily increased whereas the number of deceased donor kidneys has remained relatively unchanged. The increased rates of living donation are in part due to excellent patient and graft survival rates achieved with living donor transplant, the advent of laparoscopic donor nephrectomy, and improved patient and public awareness and education. Living donor transplantation offers survival advantages over deceased donor transplantation and permits the prospective recipient to undergo preemptive or elective transplantation at the time of optimal medical health. General guidelines for evaluating a potential donor candidate are described.

General Assessment

Similar to the evaluation process of the potential recipient, living donor evaluation requires a complete history, physical examination, and psychosocial assessment. A formal psychiatric evaluation by the transplant center is recommended to evaluate for any significant psychiatric problem and any possibility of coercion. The presence of either of these would preclude donation. The mandatory preliminary evaluation of a potential living donor includes determination of ABO blood group compatibility, HLA typing, and cross-matching against the potential recipient. In cases in which more than one donor is available, selection of the best donor depends on the degree of HLA matching and donor age. In addition, biologically related donors are generally preferred over unrelated donors. A suggested routine evaluation and optional testing are listed in Table 53–5.

Medical Assessment of the Potential Donor

There are significant variations among transplant centers regarding the medical evaluation of living donors, but the universal goals are to ensure that the potential donor (1) is sufficiently healthy to undergo the operation, (2) has normal kidney function with minimal future risk of kidney disease, and (3) represents no risk to the recipient in terms of infection or transmission of malignancy. Absolute and relative contraindications to living kidney donation are listed in Table 53–6.

Measurement of creatinine clearance based on a 24-hour urine collection is generally adequate, although some centers prefer iothalamate or diethylenetriaminepentaacetic acid (DTPA) clearance for a more accurate estimation of the glomerular filtration rate (GFR). A minimum GFR of 80 mL/minute/1.73 m2 is required by most centers, considering that unilateral nephrectomy reduces overall renal function by about 20% at long-term follow-up. Renal imaging studies are mandatory to assess the anatomic features of the kidneys, to delineate renal vessels to select one kidney for donation, to determine the most appropriate nephrectomy technique, and to exclude potential donors with incidental masses or fibromuscular dysplasia.

The medical evaluation should specifically probe for possible hereditary renal disease, diabetes, and hypertension. The most commonly encountered hereditary renal disease is ADPKD. For potential donors over the age of 30 years, it is safe to proceed with donor nephrectomy if ultrasound or CT imaging reveals no evidence of cysts. For potential donors between the age of 20 and 30 years, genetic studies such as linkage analysis or direct deoxyribonucleic acid (DNA) sequencing can reliably exclude the presence of ADPKD. These tests, however, are not routinely available. Potential donors with a family history of Alport's syndrome should be screened for hematuria and hypertension and should undergo special hearing and ocular testing. Alport's syndrome is predominantly transmitted as X-linked and less commonly as autosomal recessive or autosomal dominant. The absence of hematuria in an adult male 20 years of age or older essentially excludes the presence of the genetic defect. Adult female siblings with normal urinalysis have a low risk of being carriers and can safely donate. However, female relatives with persistent hematuria are most likely carriers of the mutation and donation is not advisable. Although genetic testing is possible it is not readily available and generally is not performed.

All potential donors should have a fasting plasma glucose to detect diabetes mellitus or undiagnosed impaired glucose tolerance. The presence of diabetes mellitus would preclude living donation. All individuals with impaired fasting glucose and those with risk factors for developing type 2 diabetes mellitus should undergo a 2 hour oral glucose tolerance test (OGTT). The latter includes first-degree relatives of patients with type 2 diabetes mellitus, obesity, gestational diabetes mellitus, and dyslipidemia. If the OGTT test is normal (<140 mg/dL) and no other risk factors are present, it is reasonable to proceed with the donation process. Individuals with impaired glucose tolerance are at risk for the development of diabetes mellitus and risk factor modifications including exercise and weight reduction or avoidance of excessive weight gain should be emphasized. Potential donors with impaired glucose tolerance should be assessed on an individual basis. Those with mild or borderline impaired glucose tolerance and additional risk factors and those with blood sugar levels in the high range should probably not donate since the higher the blood sugar within the range of impaired glucose tolerance (140–199 mg/dL) or impaired fasting glucose (100–125 mg/dL), the greater the tendency for tolerance to deteriorate.

Risks of Donation

Donor nephrectomy is either performed via open nephrectomy or, increasingly more popular, laparoscopic nephrectomy. Acute mortality rates related to open nephrectomy are estimated at 0.03–0.04%. The incidence of postoperative complications including wound infection, pneumonia, ileus, deep vein thrombosis, or pulmonary embolism is approximately 3%. The incidence of testicular pain, paresthesia of L1, and the need for reoperation or conversion from laparoscopic to open donor nephrectomy ranges from 0% to 3% and may vary among centers. The incidence of complications is slightly higher for laparoscopic compared to open nephrectomy. However, with the refinement in surgical techniques and the increasing expertise of the surgeons performing the procedures, comparable postoperative complication rates between the two surgical operations have been reported. The potential advantages of laparoscopic versus open nephrectomy include less donor pain and shorter donor recovery time.

The risk of future development of chronic kidney disease and progression to ESRD in the remaining single kidney has always been a major concern for prospective donors. At long-term follow-up, unilateral nephrectomy reduces renal function by approximately 20%. Similar to the nondonating population, an additional 5 mL/minute loss in GFR per decade occurred after donating. Although data on the effects of nephrectomy on the progression and complications of ESRD are lacking, the UNOS database revealed that of the 48,000 living kidney donors whose donations occurred between 1987 and 2001, 20 (or 0.04%) donors were listed for transplantation. It should also be noted that the baseline lifetime risk of developing ESRD in the general population is about 2–3% for whites and about 7% for African-Americans. Annual medical evaluation of renal function, proteinuria, fasting blood sugar, and blood pressure measurements is warranted after donation.

Evaluation of the Deceased Donor

Whereas the number of patients on the transplant waiting list has steadily increased, the number of deceased donor kidneys has remained far below the growing need, leading to longer waiting times and increased wait-list deaths. One approach to increasing the pool of deceased donor organ supply has been to expand the previously defined criteria for acceptable donor kidneys, such as advanced donor age (>60 years of age), donor comorbid conditions, such as hypertension or diabetes, donor preprocured high serum creatinine level, pediatric donors (<5 years of age), donors after cardiac death (DACD), and donor kidneys with prolonged cold preservation time. Dual kidney transplantation into one recipient from an otherwise nonacceptable donor has also been performed by some centers. More recently, UNOS set forth a new expanded criteria donor (ECD) kidney policy defining donors that meet these criteria. These kidneys are defined by donor characteristics that are associated with a 70% greater risk of kidney graft failure when compared to a reference group of normotensive donors aged of 10–39 years whose cause of death was not a cerebrovascular accident (CVA) and whose terminal serum creatinine was <1.5 mg/dL. The donor factors associated with this increased relative rate of graft failure include age 60 years or older or age 50–59 years with at least one comorbid factor. The latter may include CVA as a cause of death, hypertension, and/or terminal serum creatinine greater than 1.5 mg/dL (Table 53–7). Despite inferior outcomes compared to standard criteria donor kidneys, ECD kidney transplantation offers survival advantages over “wait-listed” continued dialysis. Compared to the younger age group, older recipients (>65 years) had a significant proportional increase in longevity, and compared to patients with nondiabetic nephropathy, more patients with ESRD due to diabetic nephropathy died while awaiting kidney transplantation (4.3% versus 10.8%, respectively, p < 0.001). Acknowledging the potential benefits and risks of ECD kidney transplantation compared to maintenance dialysis has led many centers to liberalize the criteria for accepting deceased donor kidneys.

Table 53–8 lists the absolute and relative contraindications to deceased donor donation. However, it should be noted that the acceptance criteria for deceased donor kidneys may be institution specific.

Complications following renal transplantation vary over time and can be arbitrarily categorized into those occurring early (the first 1–6 months) or late (after 6 months). We concentrate more on the early complications, describe a basic approach to evaluating renal allograft dysfunction in the immediate and early postoperative period, and discuss the urologic and infectious complications commonly encountered in the first 1–6 months following renal transplantation.

Renal Allograft Complications

Delayed Graft Function and Primary Nonfunction

The term delayed graft function (DGF) has been used to describe marginally functioning grafts that recover function only after several days to weeks. In contrast, the term primary nonfunction is best applied to kidneys that never function where allograft nephrectomy is usually indicated.

The incidence of DGF may range from 10% to 50% in some centers and can often be anticipated based on both recipient and donor factors (Table 53–9). Unless these patients have adequate residual urine output from the native kidneys, most will require temporary dialysis support for volume, hyperkalemia, and/or uremia. The differential diagnoses of DGF are shown in Table 53–10. A systematic approach to the evaluation of DGF may be categorized as prerenal (or preglomerular type), intrinsic, and postrenal. Although uncommon in the early postoperative period, vascular causes of DGF must be excluded.

Prerenal Causes of Delayed Graft Function

Intravascular volume depletion and nephrotoxic drugs are the more common causes of prerenal dysfunction. Severe intravascular volume depletion is usually suggested by a careful review of the patient's preoperative history and intraoperative report. Knowing the dialysis dry weight and preoperative weight of patients may be invaluable in the assessment of their volume status in the immediate postoperative period. Both calcineurin inhibitors (CNI)—cyclosporine and to a lesser extent tacrolimus—have been shown to cause a dose-related reversible afferent arteriolar vasoconstriction and a “preglomerular type” allograft dysfunction that manifest clinically as delayed recovery of allograft function. Intraoperative direct injection of the calcium channel blocker verapamil into the renal artery may reduce capillary spasm and improve renal blood flow. Most centers have advocated the use of nondihydropyridine calcium channel blockers (ie, diltiazem) to counteract the vasoconstrictive effect of and to allow a reduction in the dose of the calcineurin inhibitors. Their use may permit the cyclosporine dose to be reduced by up to 40%. Other commonly used drugs that may potentially precipitate acute “preglomerular type” allograft dysfunction include angiotensin-converting enzyme inhibitors (ACEI), amphotericin B, nonsteroidal anti-inflammatory drugs (NSAIDs), and contrast dye.

Intrinsic Renal Causes of Delayed Graft Function

Intrinsic renal causes of DGF typically include acute tubular necrosis, acute rejection, thrombotic microangiopathy, and recurrence of glomerular diseases affecting the native kidneys.

Acute Tubular Necrosis

Posttransplant acute tubular necrosis (ATN) is the most common cause of DGF. The two terms are often used interchangeably although not all cases of DGF are caused by ATN. The incidence of ATN varies widely among centers and has been reported to occur in 20–25% of patients (range 6–50%). The difference in the incidence reported may, in part, be due to the more liberal use of organs from marginal donors by some centers but not by others and/or the difference in the criteria used to define DGF. Unless an allograft biopsy is performed, posttransplant ATN should be a diagnosis of exclusion. In the absence of superimposed hyperacute or acute rejection, ATN typically resolves over several days and, on occasion, up to several weeks (4–6 weeks), particularly in recipients of older donor kidneys. Recovery from ATN is usually heralded by a steady increase in urine output associated with a decrease in the interdialytic rise in serum creatinine and eventually in dialysis independence. Prolonged DGF should prompt a diagnostic allograft biopsy to exclude covert acute rejection or other intrinsic causes of allograft dysfunction. The administration of sirolimus in de novo renal transplant recipients may prolong DGF duration without adversely affecting 1-year graft survival.

Acute Rejection

While hyperacute or accelerated acute rejection due to presensitization may occur immediately following transplantation or after a delay of several days, classic cell-mediated acute rejection is typically seen after the first posttransplant week. Accumulating evidence suggests that there is an interactive effect between ATN and acute rejection. Ischemia reperfusion injury causes upregulation of multiple cytokines and growth factors within the allograft including interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor (TNF), interferon-α (IFN-α), and transforming growth factor (TGF)-β. The proinflammatory cytokine response may in turn trigger acute allograft rejection through upregulation of various costimulatory and adhesion molecules as well as through increased expression of MHC class I and class II antigens. It is therefore prudent to perform a diagnostic allograft biopsy with prolonged ATN.

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) is a well-recognized complication following renal allograft transplantation. It may develop as early as 4 days postoperatively and as late as 6 years posttransplantation. In most cases, calcineurin inhibitors (cyclosporine or tacrolimus) are believed to play a role in the development of this disorder.

Posttransplant TMA may be evident clinically by the typical laboratory findings of intravascular coagulation (such as thrombocytopenia, elevated lactate dehydrogenase levels, and peripheral schistocytes) or it may be covert with inconsistent laboratory findings. In renal allograft recipients, renal dysfunction is the most common manifestation. Thrombocytopenia and microangiopathic hemolysis are often mild or absent. Indeed, the diagnosis of posttransplant TMA is often made on graft biopsies performed to determine the cause of DGF or to rule out acute rejection. Although there have been no controlled trials comparing the different treatment modalities of this condition, dose reduction or discontinuation of the offending agent appears to be pivotal to management. Adjunctive plasmapheresis with fresh frozen plasma (FFP) replacement may offer survival advantages. In transplant recipients with cyclosporine-associated TMA, successful use of tacrolimus immunosuppression has been reported. However, recurrence of TMA in renal transplant recipients treated sequentially with cyclosporine and tacrolimus has been described and clinicians must remain vigilant for signs and symptoms of recurrence of TMA in patients who are switched from cyclosporine to tacrolimus or vice versa. There have been anecdotal reports of the successful use of sirolimus and/or mycophenolate mofetil (MMF) in transplant recipients with calcineurin inhibitor-associated TMA. However, recently, sirolimus has also been reported to cause TMA in renal allograft recipients. Although infrequent, the use of the monoclonal antibody muromonab-CD3 OKT3 has also been associated with the development of posttransplant TMA.

Other potential causative factors of posttransplant-associated TMA include the presence of lupus anticoagulant and/or anticardiolipin antibody, cytomegalovirus infection, and, less frequently, systemic viral infection with parvovirus B19 or influenza A virus. An increased incidence of TMA has also been described in a subset of renal allograft recipients with concurrent hepatitis C virus infection and anticardiolipin antibody positivity.

Recurrence of Glomerular Disease of the Native Kidneys

The incidence of recurrent renal disease after renal transplantation and the risk of graft loss from disease recurrence is shown in Table 53–11.

Postrenal Causes of Delayed Graft Function

Postrenal DGF is generally due to obstruction and may occur anywhere from the intrarenal collecting system to the level of the bladder-catheter drainage system. The latter is generally due to blood clots and can often be managed by flushing the catheter with saline solution. Nursing care orders should routinely include irrigation of the Foley catheter as needed for clots or no urine flow. In patients with persistent gross hematuria, continuous bladder irrigation may be helpful. However, potential serious complications such as bleeding from vascular anastomoses or graft thrombosis should be excluded. Obstructive uropathy due to perinephric fluid collections or extrinsic compression and ureteral obstruction are discussed further under surgical and urologic complications.

Vascular Complications and Renal Artery Stenosis

Arterial or venous thrombosis generally occurs within the first 2–3 postoperative days but may occur as late as 2 months posttransplant. In most series reported, the incidence of arterial/venous thrombosis ranges from 0.5% to as high as 8% with arterial thrombosis accounting for one-third and us thrombosis for two-thirds of cases. Thrombosis occurring early after transplantation is most often due to surgical complications while late-onset thrombosis is generally due to acute rejection. In patients with initially good allograft function, thrombosis is generally heralded by the acute onset of oliguria or anuria associated with a deterioration of allograft function. Clinically, the patient may present with graft swelling or tenderness and/or gross hematuria. In patients with good residual urine output from the native kidneys but with DGF and an absence of overt signs and symptoms, the diagnosis rests on clinical suspicion and prompt imaging studies. Confirmed arterial or venous thrombosis typically necessitates allograft nephrectomy. Suggested predisposing factors for vascular thrombosis include arteriosclerotic involvement of the donor or recipient vessels, intimal injury of the graft vessels, kidneys with multiple arteries, a younger recipient and/or younger donor age, a history of recurrent thrombosis, the presence of antiphospholipid antibodies (anticardiolipin antibody and/or lupus anticoagulant antibody), and thrombocytosis.

There has been no consensus on the optimal management of recipients with an abnormal hypercoagulability profile such as an abnormal activated protein C resistance ratio associated with factor V Leiden mutation (and to a lesser extent with factor II mutation, prothrombin II 20210 A), antiphospholipid antibody positivity, protein C or protein S deficiency, or antithrombin III deficiency. However, unless contraindicated, perioperative and/or postoperative prophylactic anticoagulation should be considered, particularly in patients with a prior history of recurrent thrombotic events. At our institution, patients with identifiable risk factors are observed intraoperatively for adequacy of hemostasis. If satisfactory, these patients are given a small bolus dose of intravenous heparin (usually 1000 U). Postoperatively, a heparin infusion is continued at 100–300 U/hour. Complete blood counts are checked every 6 hours for the first 24 hours and then daily thereafter. If no bleeding complications are observed, oral warfarin is begun after 48 hours and heparin is continued until a therapeutic INR level is achieved (INR 2.0–2.5). The duration of anticoagulation has not been well defined but lifelong anticoagulation should be considered in high-risk candidates. Transplant of pediatric en bloc kidneys into adult recipients with a history of thrombosis should probably be avoided.

Transplant Renal Artery Stenosis

Although transplant renal artery stenosis may occur as early as the first week, it is usually a late complication. Clinically, patients may present with new onset or accelerated hypertension, acute deterioration of graft function, severe hypotension associated with the use of ACEI, recurrent pulmonary edema or refractory edema in the absence of heavy proteinuria, and/or erythrocytosis. The latter, when associated with hypertension and impaired graft function, should raise the suspicion of renal artery stenosis (RAS) (ie, a triad of erythrocytosis, hypertension, and elevated serum creatinine). The presence of a bruit over the allograft is neither sensitive nor specific for the diagnosis of graft renovascular disease. However, a change in the intensity of the bruit or the detection of new bruits warrants an evaluation. Although noninvasive, a radionuclide scan with and without captopril is neither sufficiently sensitive nor specific for detecting transplant RAS (a sensitivity and specificity of 75% and 67%, respectively). Color Doppler ultrasound is highly sensitive and serves well as an initial noninvasive assessment of the transplant vessels. It should be noted, however, that color Doppler ultrasound is limited by its relatively low specificity. CO2 angiography avoids nephrotoxic contrast agents but its use is not without limitations. Overestimation of the degree of stenosis, bowel gas artifact, and/or patient intolerance have been reported with the use of a CO2 angiogram. Although gadolinium-enhanced MR angiography has previously been suggested to be an alternative non-nephrotoxic method in identifying transplant renal artery stenosis, its use should be avoided in those with allograft dysfuction due to the well-described association between gadolinium and the development of nephrogenic fibrosing dermopathy (NFD) and systemic fibrosis (NSF). Although invasive, renal angiography remains the gold standard for establishing the diagnosis of RAS.

Allograft Rejection

Allograft rejection can be classified as hyperacute, accelerated acute, acute, and chronic.

Hyperacute Rejection

Hyperacute rejection can occur immediately following vascular anastomosis, which can be recognized intraoperatively by the surgeon, or it may occur within minutes to hours after graft revascularization. Grossly, the kidney allograft may appear flaccid or cyanotic and hard, and graft rupture may occur within minutes after revascularization. Hyperacute rejection is mediated by preformed, cytotoxic immunoglobulin G (IgG) anti-HLA class I antibodies that are produced in response to previous exposure to alloantigens through multiple pregnancies, blood transfusions, and/or prior transplants. These antibodies bind to the graft vascular endothelium and activate complement leading to severe vascular injury including thrombosis and obliteration of the graft vasculature. Hyperacute rejection almost uniformly leads to graft loss, and prevention with meticulous cross-match is the mainstay of management. Hyperacute rejection can also occur as a result of ABO blood group incompatibility due to preformed anti-ABO blood group antibodies. With the current pretransplant cytotoxic cross-match as well as ABO-matching policy, hyperacute rejection has become almost nonexistent.

Recently “pretransplant preconditioning” with plasmapheresis and cytomegalovirus hyperimmune globulin (CMVIg) with or without rituxumab (a humanized CD20 monoclonal antibody) has allowed renal transplantation to be carried out across a positive cross-match and/or ABO blood group incompatibility without the development of hyperacute rejection. These, however, are currently performed only at experienced transplant centers and a discussion is beyond the scope of this chapter.

Accelerated Acute Rejection (Within 24 Hours to 7 Days)

Accelerated acute rejection occurs after the first 24 hours to 7 days after transplantation and may be mediated by both humoral and cellular mechanisms. Accelerated acute rejection probably represents a delayed amnestic response to prior sensitization. It may be seen after donor-specific transfusions in recipients of living-related donor transplant due to a primed T cell response. Treatment of accelerated acute rejection generally requires aggressive treatment with antibody therapy (OKT3 or antithymocyte antibody), intravenous immunoglobulin (IVIG) with or without adjunctive plasmapheresis. Despite aggressive treatment, accelerated acute rejection commonly results in early graft loss. The T cell flow cytometry cross-match (FCXM) may be useful in the pretransplant evaluation of sensitized or reallograft transplant candidates whose antibody levels may have declined but who can mount a rapid amnestic response upon rechallenge. Transplant across a positive T cell FXCM is associated with a higher rate of early acute rejection episodes. Hyperacute rejection, however, has not been reported as long as the pretransplant cytotoxic cross-match is negative. More recently, various desensitization protocols have been developed to allow successful transplantation in sensitized recipients.

Acute Rejection

Historically, approximately 30–50% of renal allograft recipients have an episode of acute rejection within the first 6 months after transplantation. With the introduction of mycophenolate mofetil (MMF) and anti-IL-2 receptor antibody (anti-IL-2R) daclizumab and basiliximab into clinical practice, acute rejection rates of 15–30% or less have now been routinely achieved by most transplant programs. In the era of cyclosporine and other potent immunosuppressive agents in general, the classic constitutional symptoms of acute rejection including fevers, chills, myalgias, arthralgias, graft swelling, and/or tenderness are often absent. Patients are usually nonoliguric and a rise in serum creatinine may be the only sign of acute rejection. Elevated blood pressure or worsening hypertension may be variably present. Noninvasive imaging studies such as renal Doppler ultrasound or renal radioisotope flow scan is neither sufficiently sensitive nor specific in the diagnosis of acute rejection. Although invasive, allograft biopsy remains the most accurate means of differentiating acute rejection from other causes of acute deterioration of allograft function.

Treatment of Acute Rejection

Because the treatment of acute rejection is a specialized area overseen by the kidney transplant team, the reader is referred to specialty reviews and textbooks for this information.

Surgical and Urologic Complications

Perinephric Fluid Collections

Symptomatic perinephric fluid collections in the early postoperative period can be due to lymphoceles, hematoma, urinoma, or abscesses. Lymphoceles are collections of lymph caused by leakage from severed lymphatics. They typically develop within weeks after transplantation. Most lymphoceles are small and asymptomatic. Generally, the larger the lymphocele, the more likely it is to produce symptoms and require treatment, although very small but strategically placed lymphoceles can result in ureteral obstruction. Lymphoceles may also compress the iliac vein leading to ipsilateral leg swelling or deep vein thrombosis or occasionally produce urinary incontinence due to bladder compression.

Lymphoceles are usually detected by ultrasound either as an incidental finding or during an evaluation of allograft dysfunction. They appear as a roundish, sonolucent, septated mass. Hydronephrosis may be present with a lymphocele adjacent to or compressing the ureter. Generally, the clinical presentation and ultrasound appearance can distinguish a lymphocele from other types of perinephric fluid collections, such as a hematoma or urine leak. Needle aspiration reveals a clear fluid with a creatinine concentration similar to that of serum in the case of a lymphocele, while that of a urine leak would have a much higher concentration.

No therapy is necessary for the common, small, asymptomatic lymphocele. Percutaneous aspiration should be performed if a ureteral leak, obstruction, or infection is suspected. The most common indication for treatment is ureteral obstruction. If the cause of the obstruction is simple compression resulting from the mass effect of the lymphocele, percutaneous drainage alone usually suffices. The ureter is often narrowed and may need to be reimplanted because of its involvement in the inflammatory reaction in the wall of the lymphocele. Repeated percutaneous aspirations are not advised because they seldom lead to dissolution of the lymphocele and often result in infection. Infected or obstructing lymphoceles can be drained externally. Sclerosing agents such as povidone-iodine, tetracycline, or fibrin-glue can be instilled into the cavity with variable results. Lymphoceles can also be marsupialized into the peritoneal cavity, where the fluid is reabsorbed.

An obstructed hematoma is best managed by surgical evacuation. Urinoma or evidence of a urine leak should be treated without delay. A small leak can be managed expectantly with insertion of a Foley catheter to reduce intravesical pressure. This maneuver may occasionally reduce or stop the leak altogether. Persistent allograft dysfunction, particularly in a symptomatic patient, often necessitates early surgical exploration and repair. Infected perinephric fluid collections should be treated by external drainage or open surgery in conjunction with systemic antibiotics.

Ureteral Obstruction

Ureteral obstruction occurs in 2–10% of renal transplants and is usually manifested by painless impairment of graft function due to the lack of innervation of the engrafted kidney. Hydronephrosis may be minimal or absent in early obstruction, whereas low-grade dilation of the collecting system secondary to edema at the ureterovesical anastomosis may be seen early posttransplantation and does not necessarily indicate obstruction. A full bladder may also cause mild calyceal dilation due to ureteral reflux and repeat ultrasound with an empty bladder should be performed. Persistent or increasing hydronephrosis on repeat ultrasound examinations is highly suggestive of obstruction. A renal scan with furosemide washout may help support the diagnosis, but it does not provide clear anatomic detail. Although invasive, the placement of a percutaneous nephrostomy tube with an antegrade nephrostogram is the most effective way to visualize the collecting system and can be both diagnostic and therapeutic.

Blood clots, a technically poor reimplantation, and ureteral slough are common causes of early acute obstruction after transplantation. Ureteral fibrosis secondary to either ischemia or rejection can cause an intrinsic obstruction. The distal ureter close to the ureterovesical junction is particularly vulnerable to ischemic damage due to its remote location from the renal artery and hence its compromised blood supply. Ureteral fibrosis associated with polyoma BK virus is a newly recognized cause of ureteral obstruction in the setting of renal transplantation. Ureteral kinking, lymphocele, pelvic hematoma or abscess, and malignancy are potential causes of extrinsic obstruction. Calculi are uncommon causes of transplant ureteral obstruction.

Definitive treatment of ureteral obstruction due to ureteral strictures consists of either endourologic techniques or open surgery. Intrinsic ureteral scars can be treated effectively by endourologic techniques in an antegrade or retrograde approach. A stent is left indwelling to bypass the ureteral obstruction and can be removed cystoscopically after 2–6 weeks. Routine ureteral stent placement at the time of transplantation may be associated with a lower incidence of early postoperative obstruction. Extrinsic strictures or strictures that are longer than 2 cm are less likely to be amenable to percutaneous techniques and are more likely to require surgical treatment, as do strictures that fail endourologic incision. Obstructing calculi can be managed by endourologic techniques or by extracorporeal shock wave lithotripsy.

Infectious Complications

Despite the routine use of prophylactic therapy against common bacterial, viral, and opportunistic pathogens in the perioperative and postoperative period, infection remains an important cause of morbidity and mortality after organ transplantation. The time to occurrence of different infections in immunocompromised transplant recipients follows a “timetable” pattern.

In the first month after transplantation, infections are most frequently caused by bacterial microorganisms. Similar to those following any major surgical procedure, the sources of infection after solid organ transplantation include surgical wounds, surgical drainage catheters, an indwelling Foley catheter, bacteremia from vascular access devices, aspiration pneumonia, and urinary tract infections (UTIs). Potential sources of infection specific to renal transplant recipients include perinephric fluid collections due to lymphoceles, wound hematomas or urine leaks, indwelling urinary stents, and anatomic or functional genitourinary tract abnormalities such as ureteral stricture or vesicoureteric reflux and neurogenic bladder. Although bacterial pathogens may vary from center to center, UTIs in renal transplant recipients are commonly caused by Enterococcus spp., Enterobacteriaceae, and Pseudomonas aeruginosa. Preventive and prophylactic measures to reduce UTIs include early Foley catheter removal and antibiotic prophylaxis. The use of trimethoprim-sulfamethoxazole or ciprofloxacin prophylaxis effectively reduces the frequency of UTIs to less than 10% and essentially eliminates urosepsis unless urine flow is obstructed. Although strict aseptic surgical techniques and the perioperative use of the first generation cephalosporins reduce the incidence of wound infections, nonmodifiable risk factors include the presence of diabetes mellitus and obesity at the time of transplant. Weight reduction prior to transplantation should therefore be encouraged.

After the first posttransplant month, infections with immunomodulating viruses including cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein–Barr virus (EBV), hepatitis B virus (HBV), and hepatitis C virus (HCV) may occur either due to the overall state of immunosuppression, exogenous infection, or reactivation of latent disease. Repeated courses of antibiotics and corticosteroid therapy increase the risk of fungal infections whereas infections with immunomodulating viruses may render the patients more susceptible to opportunistic infections. Causative opportunistic agents include Pneumocystis jiroveci, Aspergillus spp., Listeria monocytogenes, Nocardia species, and Toxoplasma gondii. Trimethoprim prophylaxis eliminates P jiroveci pneumonia (PCP) and reduces the incidence of L monocytogenes meningitis, Nocardia spp. infection, and T gondii. Beyond 6 months following transplantation, the risk of infection in patients with good allograft function is similar to that of the general population, with community-acquired respiratory viruses constituting their major infective agents. These patients are usually maintained on a relatively low level of immunosuppression. In contrast, patients who experience multiple episodes of rejection requiring repeated exposure to heavy immunosuppression are the most likely candidates for chronic viral infections and superinfection with opportunistic organisms. Causative opportunistic pathogens include P jiroveci, L monocytogenes, N asteroides, and Crytococcus neoformans. Geographically, restricted mycoses include coccidioidomycosis, histoplasmosis, blastomycosis, and paracoccidioidomycosis. In high-risk candidates, lifelong prophylactic therapy has been advocated. Suggested prophylactic therapy in renal transplant recipients in shown in Table 53–12.

Cytomegalovirus

CMV infection occurs primarily after the first month posttransplantation and continues to be a significant cause of morbidity the first 6 months after organ transplantation. CMV infection may occur in the setting of primary infection in a seronegative recipient (donor seropositive, recipientseronegative), reactivation of endogenous latent virus (donor seropositive or seronegative, recipient seropositive), or superinfection with a new virus in a seropositive recipient (donor seropositive, recipient seropositive). Primary CMV infection often results in more severe disease than reactivation or superinfection. The clinical manifestations of CMV infection span the spectrum of asymptomatic seroconversion, mononucleosis-like syndrome, or flu-like illness with fever and leukopenia, and/or thrombocytopenia to widespread tissue invasive disease. The latter may result in clinical hepatitis, esophagitis, gastroenteritis, colitis, pneumonia, and allograft dysfunction. Donor and recipient seropositive status and the use of blood products from CMV seropositive donors are well-established risk factors for CMV infection. Other factors associated with an increased risk of CMV infection include the use of antilymphocyte antibodies, prolonged or repeated courses of antilymphocyte preparations, episodes of allograft rejection, comorbid illnesses, and neutropenia. Management of CMV infection consists of preventive (prophylactic and/or preemptive therapy) and therapeutic measures. Prophylactic therapy involves antiviral therapy beginning in the immediate postoperative period whereas preemptive therapy involves treatment of those who are found to seroconvert during surveillance studies. Treatment of established CMV disease consists of 2–3 weeks of intravenous ganciclovir followed by a 2- to 4-month course of oral ganciclovir or valganciclovir. In patients slow to respond to therapy the addition of CMV hyperimmune globulin can be of therapeutic benefit. Although oral valganciclovir provides good bioavailability, its use in the treatment of CMV disease has not been well studied. A suggested CMV prophylaxis protocol is shown in Table 53–13.

Candida Fungal Infections

Candida spp. are the most common fungal pathogens encountered in the immunocompromised transplant recipients, with C albicans and C tropicalis accounting for 90% of the infections followed by C glabrata. Diabetes mellitus, high-dose corticosteroids, and broad spectrum antibacterial therapy predispose patients to mucocutaneous candidal infections such as oral candidiasis, intertriginous candidal infections, candidal esophagitis, candidal vaginitis, and candidal UTIs. Superficial infections involving the mouth or intertriginous areas can be treated with nystatin and topical chlortrimazole whereas candidal UTIs require amphotericin B bladder washing or systemic antifungal therapy with fluconazole, amphotericin B (preferably in the lipid preparation), or caspofungin for fluconazole-resistant species. Whenever possible, foreign objects such as a bladder catheter, surgical drains (such as a percutaneous nephrostomy tube), and urinary stents should be removed.

Polyomavirus Infection

The polyomaviruses are nonenveloped double-stranded DNA viruses. BK and JC viruses are the two strains associated with disease in humans and are named after the initials of the patients in whom they were first isolated. Over the past decade BK virus-associated nephropathy has emerged as an important cause of allograft failure following renal transplantation, whereas the pathogenic role of JC virus in allograft nephropathy remains to be defined.

BK virus is a ubiquitous human virus with a peak incidence of primary infection in children 2–5 years of age and a seroprevalence rate of greater than 60–90% among the adult population worldwide. Following primary infection, the BK virus preferentially establishes latency within the genitourinary tract and frequently reactivates in the setting of immunosuppression. In renal transplant recipients, the BK virus has been shown to be associated with a range of clinical syndromes including asymptomatic viuria with or without viremia, ureteral stenosis and obstruction, interstitial nephritis, and BK allograft nephropathy. In most series it has been reported that 30–40% of renal transplant recipients develop BK viuria, 10–20% develop BK viremia, and 2–5% develop BK nephropathy (BKN).

BK nephropathy most commonly presents with an asymptomatic rise in serum creatinine between 2 and 60 months (median 9 months). The diagnosis of BKN is made by allograft biopsy showing BK virus inclusions in renal tubular and glomerular epithelial cells. Variable degrees of interstitial inflammation, degenerative changes in tubules, and focal tubulitis can be seen and may mimic acute tubular necrosis (ATN) or acute rejection. In the absence of classic histologic findings, distinguishing between BKN, acute rejection, and the concomitant presence of both processes can be a diagnostic challenge. Additional ancillary studies such as immunohistochemistry, in situ hybridization, or electron microscopy are required to confirm the diagnosis. Urine cytology for decoy cells or quantitative determinations of viuria and of viral load in blood have been proposed as surrogate markers for the diagnosis of BKN. In the late stage of BKN, few characteristic intranuclear inclusions are seen and the histopathologic changes are indistinguishable from those of chronic allograft nephropathy including interstitial fibrosis and scarring.

There has been no well-defined protocol for the treatment of BKN. The current mainstay of treatment includes a reduction or discontinuation of antimetabolites in conjunction with a judicious reduction in calcineurin inhibitor therapy or other components of the immunosuppressive regimen. The level of reduction in immunosuppression, however, has not been clearly defined. Switching from tacrolimus to cyclosporine or to sirolimus has resulted in resolution of BKN and viremia/viuria in anecdotal case reports. Adjunctive antiviral therapy with cidofovir or leflunomide has been used with variable response rates. Low-dose cidifovir (0.25–0.33 mg/kg intravenously biweekly) may be of therapeutic benefit in refractory cases. Despite various treatment strategies, up to 30–50% of patients with established BKN experienced a progressive decline in renal function and graft loss. Early diagnosis and intervention may improve the prognosis. Intensive monitoring of urine and serum for BK by polymerase chain reaction (PCR) during the first year posttransplantation and preemptive withdrawal of immunosuppression have been shown to be associated with resolution of viremia and an absence of BK nephropathy without acute rejection or graft loss. More recently, an independent panel of experts have suggested that all renal transplant recipients should be screened for BKV replication in the urine (1) every 3 months during the first 2 years posttransplant, (2) when allograft dysfunction is noted, and (3) when an allograft biopsy is performed. A positive screening result should be confirmed in <4 weeks and assessed by quantitative assays (eg, BKV DNA or RNA load in plasma or urine). A definitive diagnosis of BKN requires an allograft biopsy. In the absence of active viral replication, patients with graft loss due to BKN can safely undergo retransplantation. Active surveillance for BK virus reactivation after transplantation is recommended.

In this section the mechanisms of action of various immunosuppressive agents, the basic principles of immunosuppressive protocols, the use of immunosuppressive agents in the treatment of acute rejection, and the potential adverse effects of immunosuppressive medications and important drug–drug interaction are discussed.

The Three-Signal Model of Alloimmune Responses

T cell activation requires three signals (Figure 53–1). The first signal (signal 1) is initiated by the binding of the alloantigen on the surface of antigen-presenting cells (APCs) to the T cell receptor (TCR)–CD3 complex. Signal 2 is a non-antigen-specific costimulatory signal provided by the engagement of CD80 and CD86 on the surface of APCs with CD28 on T cells. These dual signals activate the intracellular pathways that trigger T cells to activate IL-2 and other growth-promoting cytokine genes. IL-2 will in turn engage its receptor and activate the mammalian target of rapamycin (mTOR) pathway to provide signal 3, and lead to cell proliferation. If a T cell receptor is triggered without the accompanying costimulatory signal 2, the T cell is driven into an anergic state in which it is both inactivated and refractory to later activation when all necessary activation elements are present. These observations have led to the concept of induction of graft tolerance or adaptation through agents that target the costimulatory pathways.

Immunosuppressive agents that target signal 1 include the monoclonal antibody OKT3 and polyclonal antibodies such as antithymocyte globulins directed against the CD3 molecule and a variety of T cell markers. The calcineurin inhibitors cyclosporine and tacrolimus inhibit intracellular signal 1 transduction. There are currently no clinically approved agents that target signal 2, although LEA29Y, which binds CD80 and CD86 with high affinity and inhibits the costimulatory pathway, is a new promising agent that is currently in phase II clinical trials. Agents that target signal 3 include baxiliximab and daclizumab, which are humanized monoclonal antibodies targeted against the IL-2 receptor, and sirolimus, which blocks signal 3 by preventing cytokine receptors from activating the cell cycle. Lymphocyte proliferation, which requires the synthesis of purine and pyrimidine nucleotides, is inhibited by the antimetabolites azathioprine and MMF. The sites of actions of other immunosuppressive agents that are under clinical development are shown in Figure 53–1.

Immunosuppressive Drugs in the Three-Signal Model

Anti-CD3 Monoclonal Antibodies

The monoclonal antibody muromonab-CD3, also known as OKT3, is a murine IgG2 monoclonal antibody targeting the ϵ-chain of the CD3 receptor complex. The subsequent deactivation of the CD3 complex causes the T cell receptor to undergo endocytosis. The latter process renders the T cells ineffectual and within an hour of OKT3 administration the T cells disappear from the circulation as a result of opsonization and subsequent removal from the circulation by mononuclear cells in the liver and spleen. After the first dose, OKT3 can cause an initial transient T cell activation and release of several cytokines including IL-2, TNF, IFN-γ, and IL-6 that are responsible for the “first dose cytokine release syndrome.” Clinically, patients may develop fevers, chills, rigors, headaches, pulmonary edema, and, less commonly, aseptic meningitis, acute respiratory distress syndrome (ARDS), and encephalopathy. To alleviate the severity of the cytokine release syndrome patients should be kept euvolemic and premedicated with intravenous methylprednisolone, diphenhydramine hydrochloride, and acetaminophen. Repeated use of OKT3 can result in loss of efficacy due to the potential development of high titers of neutralizing human antimurine antibodies.

Polyclonal Antithymocyte Globulin: Antithymocyte γ-Globulin and Thymoglobulin

Polyclonal antithymocyte globulin (ATG) is obtained by immunizing animals with human lymphoid cells. Antithymocyte γ-globulin (ATGAM) is produced by immunization of horses with human lymphoid material whereas thymoglobulin is made by immunizing rabbits with human lymphoid tissue. The immune sera are harvested and processed to obtain purified globulin. The resultant product contains antibodies targeting against a number of T cell surface markers including CD3, CD4, and CD8. Similar to OKT3, the polyclonal antibodies are xenogeneic proteins and can induce a number of side effects including fevers, chills, and arthralgia. ATG, however, does not cause the severe first-dose reactions seen with OKT3. Other severe adverse reactions such as serum-sickness syndrome and anaphylaxis are rarely seen. Nevertheless, patients receiving ATG should also be premedicated as with OKT3.

The Calcineurin Inhibitors: Cyclosporine and Tacrolimus

Cyclosporine is a highly hydrophobic cyclic endecapeptide isolated from Tolypocladium inflatum Gams, whereas tacrolimus is a macrocyclic lactone isolated from actinomycetes. Despite their distinct chemical structures, cyclosporine and tacrolimus share a common mechanism of action. The adverse effects of cyclosporine include nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, posttransplant diabetes mellitus (PTDM), neurotoxicity, hirsutism, and, less commonly, thrombotic microangiopathy. Commonly encountered laboratory abnormalities include hyperkalemia, hypomagnesemia, and hyperuricemia. The adverse effects of tacrolimus are similar to those of cyclosporine but with a lower incidence of hypertension, hyperlipidemia, hirsutism, gingival hyperplasia, and hyperuricemia, and a higher incidence of PTDM, neurotoxicity, gastrointestinal disturbances, and alopecia. Recently, monitoring of cyclosporine levels 2 hours after administration (C2, compared to the trough level, C0) may better reflect drug exposure thereby avoiding overexposure or underexposure to the drug. The former may alleviate nephrotoxicity whereas the latter may prevent acute rejection episodes. Trough drug level monitoring is required for tacrolimus.

Target of Rapamycin Inhibitors: Sirolimus and Everolimus

Sirolimus (rapamycin) is a macrocyclic lactone isolated from Streptomyces hygroscopicus. It was discovered in 1975 in the region of Rapa Nui, Easter Island. Sirolimus was first shown to inhibit the growth of yeast and fungi and was subsequently explored as an antitumor and immunosuppressive agent. Everolimus is an analog of sirolimus with a shorter half-life but with similar immunosuppressive mechanism and side effect profile. Although sirolimus is structurally related to tacrolimus and both engage the same FKBP-12, sirolimus has a mechanism of action that is distinct from that of tacrolimus. Commonly encountered adverse effects of sirolimus and everolimus include hyperlipidemia, particularly hypertriglyceridemia, increased CNI nephrotoxicity, mouth ulcers, thrombocytopenia, and impaired wound healing. Other reported side effects include proteinuria, peripheral edema, delayed recovery from ATN or delayed graft function, reduced testosterone concentration, and pulmonary toxicity.

Humanized Anti-CD25 Monoclonal Antibodies: Basi Liximab and Daclizumab

Basiliximab (Simulect) is a genetically engineered murine—human chimeric monoclonal antibody consisting of a variable region of murine origin and a human constant region. Daclizumab (Zenapax) is a humanized monoclonal antibody consisting of a murine hypervariable antibody-binding site and a human IgG1 framework (Figure 53–2). Both agents target the α chain of the IL-2 receptor (CD25 or Tac) thereby blocking signal 3. Unlike OKT3 or ATG that target all T cells, the anti-IL-2 receptor inhibitors bind only to activated T cells that have upregulated the α chain of the IL-2 receptor, hence complementing the effect of the CNIs. In contrast to OKT3 and the ATGs, basiliximab and daclizumab have a prolonged serum half-life and lack immunogenicity, presumably due to the “more humanized” nature of the constructs. Clinical trials leading to their approval for use in renal transplantation revealed minimal toxicity.

Antimetabolite Agents: Azathioprine and Mycophenolic Acid

Azathioprine (Imuran)

The immunosuppressive mechanism of action of azathioprine (AZA) is related to its inhibition of gene replication and consequent T cell activation. It is a purine analog that is incorporated into cellular deoxyribonucleic acid (DNA) where it inhibits purine nucleotide synthesis and interferes with the synthesis and metabolism of ribonucleic acid (RNA). AZA was the first immunosuppressive agent introduced into clinical transplantation and was widely used with steroids as maintenance immunosuppression until the introduction of cyclosporine in the early 1980s. With the dramatic improvement in graft survival seen with cyclosporine, AZA became the second-line immunosuppressive agent and later became an adjunctive agent in a triple regimen that consisted of cyclosporine, prednisone, and AZA. With the advent of the newer inhibitor of nucleoside synthesis MMF, AZA has largely been replaced by MMF as adjunctive immunosuppressive therapy. The use of AZA has been associated with bone marrow toxicity, leukopenia, macrocytosis, and, less commonly, hepatotoxicity.

Mycophenolate Mofetil

MMF is a semisynthetic derivative of mycophenolic acid (MPA), a fermentation product of the fungus penicillium. After oral administration, MMF is rapidly and completely converted to MPA, which is a reversible inhibitor of the rate-limiting enzyme inosine monophosphate dehydrogenase (IMPDH) required in the de novo synthesis of purines. In contrast to other cell types that can use the salvage pathway for the production of guanosine nucleotides from guanine, lymphocytes are primarily dependent on de novo purine biosynthesis. Hence, depletion of guanosine nucleotides by MPA has relative selective antiproliferative effects on B and T lymphocytes. Three large multicenter studies have shown that MMF was more effective than AZA in the prevention of acute rejection episodes in recipients of deceased donor renal transplants when used in combination with cyclosporine and prednisone. Consequently, it was approved by the Food and Drug Administration (FDA) in 1995 for use in rejection prophylaxis in renal transplantation. The most common adverse effects of MMF are related to the gastrointestinal tract and include diarrhea, nausea, vomiting, flatulence, and dyspepsia. Dose reduction or transient discontinuation of the drug or dividing the dose into three or four times a day often results in symptomatic relief. The enteric-coated formulation of MPA (Myfortic), developed to improve gastrointestinal tolerability, has not been shown to be significantly better than the original formulation, although there tends to be fewer gastrointestinal side effects. Leukopenia and anemia are common hematologic adverse effects of MPA that often resolve with dose reduction or transient drug discontinuation.

Corticosteroids

Steroids have been used in the prevention and treatment of episodes of acute rejection since the early 1960s. The immunosuppressive effect of steroids is due to specific immunologic processes as well as to nonspecific immunosuppressant and anti-inflammatory responses. Steroids inhibit the expression of several cytokine gene including IL-1, IL-2, IL-3, IL-6, TNF, and IFN. As a result, essentially all stages of T cell activation are inhibited. Nonspecific immunosuppressive effects of steroids may include redistribution of lymphocytes from the vascular compartment back to lymphoid tissues, inhibition of monocyte migration to inflammatory sites, and inhibition of the synthesis and action of chemoattractants and vasodilators. Well-established adverse effects of steroids include growth impairment, weight gain, Cushing's facies, avascular necrosis, osteoporosis, impaired wound healing, cataracts, hyperlipidemia, and posttransplant glucose intolerance or diabetes mellitus.

Drug–Drug Interactions

Important drug–drug interactions are shown in Table 53–14.

Basic Principles of Immunosuppressive Protocols

Immunosuppression for transplantation can be classified into induction, maintenance therapy, and treatment of acute rejection. The use of immunosuppressive agents in the treatment of acute rejection is discussed under postoperative complications and management.

Induction Therapy

Induction therapy is referred to the intense immunosuppression in the first day or weeks after transplantation. Both polyclonal and monoclonal antibodies have been used for induction therapy since the 1970s after it was demonstrated that antilymphocyte globulin (ALG) reduced the episodes of acute rejection in renal transplant recipients. Their beneficial effect is derived from depleting the recipients of CD3-positive cells at the time of transplantation. Although OKT3 and thymoglobulin were initially approved for use as antirejection therapy, these agents have increasingly been used as induction agents under different contexts such as rejection prophylaxis in high-immunologic-risk recipients (such as those with high panel reactive antibodies or retransplant recipients), DGF, and, more recently, in corticosteroid avoidance or withdrawal protocols and in CNI-sparing regimens. The use of lymphocyte-depleting antibodies, however, is not without severe adverse effects. ATGAM, thymoglobulin, and OKT3 use has been associated with an increased incidence of posttransplant lymphoproliferative disease, CMV infections, and other infectious complications. Adequate CMV prophylaxis should be an integral part of the antibody treatment protocol.

Induction therapy with the anti-IL-2R monoclonal antibodies daclizumab and basiliximab, the “so-called nondepleting antibodies,” became popular in the early 2000s when phase III clinical trials revealed that patients receiving these agents had significantly lower acute rejection rates compared to those who did not receive induction therapy. Studies comparing the effectiveness and safety of basiliximab versus thymoglobulin induction therapy in low-immunologic-risk patients showed similar acute rejection rates and overall outcome. However, a higher incidence of side effects was seen in patients receiving thymoglobulin. In contrast, studies involving high-immunologic-risk patients [defined as retransplants, plasma renin activity (PRA) >20%, those with expected delayed graft function, six antigen mismatch, and African-American recipients] demonstrated a significantly lower incidence of acute rejection and graft loss in patients receiving thymoglobulin.

Although the choice of induction therapy with depleting (ATGAM, thymoglobulin, OKT3) versus nondepleting (basiliximab, daclizumab) antibodies is largely center dependent, in general, the lymphocyte-depleting antibodies are being used in high-immunologic-risk patients due to their greater efficacy, whereas the nondepleting antibodies are used in low-to moderate-risk candidates due to their more favorable side-effect profile. Thymoglobulin has essentially displaced ATGAM and OKT3 because of its greater efficacy and lack of severe first-dose reaction, respectively.

Maintenance Immunosuppression

The CNIs cyclosporine and tacrolimus have been the mainstay of maintenance immunosuppression for the past one and a half to two decades. A traditional or “conventional” immunosuppressive protocol generally consists of a CNI (cyclosporine or tacrolimus), an antimetabolite (AZA or MMF), and prednisone, with or without induction therapy. With the introduction of sirolimus and the availability of newer agents used for induction therapy, CNI-sparing or steroid-withdrawal protocols are being increasingly used by a number of transplant centers. Although the choice of immunosuppressive therapy varies widely among centers, the ultimate goal of the transplant physician is to select a regimen that will optimize graft and patient survival while minimizing adverse effects. Reducing acute rejection rates, minimizing nephrotoxicity, lowering the incidence of dyslipidemia, posttransplant diabetes mellitus, and hypertension, and minimizing cosmetic side effects are among the important factors to consider when selecting an immunosuppressive regimen.

Tacrolimus versus Cyclosporine

In general, tacrolimus is the preferred agent in adolescents and young women because of its lack of significant cosmetic changes and in higher immunologic risk recipients because of its somewhat greater immunosuppressive potency compared to cyclosporine. Several comparative studies have demonstrated that compared to cyclosporine, tacrolimus-based immunosuppression is associated with a lower incidence of acute rejection episodes, although this has not consistently been shown to translate into improving graft survival rates. Independent investigators have also suggested that steroid withdrawal may be safer for tacrolimus- than for cyclosporine-treated patients.

Compared to cyclosporine, tacrolimus has been shown to have a more favorable effect on hypertension and the lipid profile and is often preferred over cyclosporine in recipient with difficult to control hypertension or severe dyslipidemia; however, recent studies have shown that conversion from cyclosporine trough level monitoring (C0) to 2 hour cyclosporine peak level monitoring (C2) in stable renal transplant recipients results in improvement in hypertension and hyperlipidemia control. In recipients who are at increased risk for posttransplant impaired glucose tolerance or posttransplant diabetes mellitus, cyclosporine may be the preferred agent. These recipients may include African-Americans, Hispanics, and recipients who are older, obese, and/or have a strong family history of type 2 diabetes mellitus. Recent studies demonstrated that the incidence of diabetes mellitus might be reduced when lower trough tacrolimus levels are used.

Sirolimus

In low-immunologic-risk recipients, sirolimus has increasingly been used in CNI-sparing or steroid-withdrawal protocols. Complete cyclosporine withdrawal in a regimen consisting of cyclosporine, sirolimus, and a corticosteroid has been shown to increase the risk of late acute rejection, particularly among high-risk transplant recipients. Clinically significant adverse effects of sirolimus when used in combination therapy with a CNI may include an increase in CNI nephrotoxicity and worsening dyslipidemia, particularly hypertrigliceridemia. Drug level monitoring, particularly in the early posttransplant period, is mandatory. In patients with gastrointestinal intolerance to MMF, sirolimus has been used as an adjunctive agent in combination therapy with a CNI. Although sirolimus may theoretically be the drug of choice in recipients with a history of malignancy or who develop malignancy posttransplant due to its antiproliferative or “antitumor” effect, further studies are needed.

Azathioprine versus Mycophenolate Mofetil

Three phase III clinical trials have shown that MMF is more effective than AZA in the prevention of acute rejection in recipients of deceased donor kidney transplant when used in combination therapy with cyclosporine and prednisone. Hence AZA has largely been replaced by MMF as an adjunctive immunosuppressive therapy.

Table 53–15 lists some of the commonly used immunosuppressive regimens. However, it should be noted that the choice of an immunosuppressive regimen should best be individualized.