Assessment and Management of the Kidney Transplant Patient

A successful kidney transplant offers enhanced quality of life and increased life expectancy and is more effective (medically and economically) than long-term dialysis therapy for patients with chronic or end-stage kidney disease. ^[1] Transplantation is the renal replacement modality of choice for patients with end-stage renal disease, especially those with diabetic nephropathy and pediatric patients. This article provides an overview of the evaluation of a potential kidney transplant candidate and the management of a kidney transplant recipient.

Pretransplantation evaluation

Candidates for kidney transplantation undergo an extensive evaluation to identify factors that may have an adverse effect on outcome. Virtually all transplant programs have a formal committee that meets regularly to discuss the results of evaluation and select medically and surgically suitable candidates to place on the waiting list.

Emphasize identifying and treating all coexisting medical problems that may increase the morbidity and mortality rates of the surgical procedure and adversely impact the posttransplant course. In addition to a thorough medical evaluation, evaluate the psychosocial issues of the patient to determine conditions that may jeopardize the outcome of transplantation, such as financial and travel restraints or a pattern of noncompliance.

Laboratory testing in transplant candidates is extensive and includes:

• Blood chemistries
• Liver function tests
• Complete blood count (CBC)
• Coagulation profile

An infectious profile includes the following:

• Hepatitis A, B, and C serologies
• Epstein-Barr virus (EBV) serologies (IgG)
• Cytomegalovirus (CMV) serologies (IgG)
• Varicella-zoster virus (VZV) serologies (IgG)
• Rapid plasma reagin (RPR) test for syphilis
• HIV
• Interferon-gamma release assay for tuberculosis (eg, QuantiFERON Gold In-Tube)

Urinalysis and urine culture may be ordered when indicated.

Cardiac evaluation and other diagnostic procedures

A complete cardiac workup, including angiography, is not necessary in every transplant candidate, but patients with a significant history, symptoms, diabetes mellitus, or hypertensive kidney disease should undergo a thorough evaluation to rule out significant coronary artery disease (CAD). The following procedures are indicated:

• 12-lead ECG
• Chest radiography (posteroanterior [PA] and lateral views)
• Exercise and dipyridamole thallium scintigraphy or a nuclear regadenoson (Lexiscan) stress test
• 2-dimensional echocardiography with Doppler (with or without dobutamine)
• Coronary arteriography (if indicated)

Special procedures may be indicated in selected patients on the basis of findings revealed in the history and physical examination.

Studies in transplant recipients:

• Blood and urine studies
• Infectious workup as necessary
• Transplant ultrasonography to identify urinary obstruction, as well as fluid collections suggesting urine extravasation, abscess, pyelonephritis, or wound infection
• Color flow Doppler ultrasonography to evaluate vascular occlusion or stenosis
• Kidney biopsy usually required for definitive diagnosis of most renal graft dysfunction
• Lumbar puncture in cases of suspected meningitis, particularly that believed to be caused by Listeria species

Immunologic evaluation

Potential recipients of kidney transplants undergo an extensive immunologic evaluation that primarily serves to avoid transplants that are at risk for antibody-mediated hyperacute rejection. The immunologic evaluation consists of the following 4 components:

• ABO blood group determination
• Human leukocyte antigen (HLA) typing
• Serum screening for antibody to HLA phenotypes
• Crossmatching

Kidney transplant candidates with preformed, donor-specific antibodies may undergo a pretransplant desensitizing protocol. If successful, this protocol reduces antibody levels to the point where kidney transplantation becomes feasible. To avoid the increased risk of desensitization and ABO-incompatible transplants, patients with incompatible living donors may chose to participate in kidney paired exchange (KPD) or donor swap programs.

Pretransplant surgical interventions

The medical workup may reveal circumstances that necessitate surgical intervention to prepare the patient for kidney transplantation. Such interventions may include the following:

• Native kidney nephrectomy or nephroureterectomy - Reserved for specific indications, such as large polycystic kidneys, significant proteinuria, or chronic reflux disease
• Cholecystectomy - For patients with gallstones
• Splenectomy – May be indicated for ABO-incompatible kidney transplantations

Management

In addition to the surgical transplantation procedure itself, management includes the following:

• Organ procurement
• Provision of immunosuppressive therapy to the recipient
• Short- and long-term follow-up to look for indications of renal allograft dysfunction and other complications

Organ procurement

• Identification of potential donors
• Assessment of donor suitability
• Determination of donor brain death
• Medical management of donor

Immunosuppressive therapy

All kidney transplant recipients require life-long immunosuppression to prevent an alloimmune rejection response. The goals are as follows:

• Prevent acute and chronic rejection
• Minimize drug toxicity and rates of infection and malignancy
• Achieve the highest possible rates of patient and graft survival

Immunosuppressive agents may be divided into 2 broad categories, as follows:

• Antirejection induction agents (polyclonal antisera, mouse monoclonals, humanized monoclonals)
• Maintenance immunotherapy agents (prednisone, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, belatacept)

Complications

The critical considerations in medical follow-up are as follows:

• Rejection
• Nephrotoxicity of calcineurin inhibitors (ie, cyclosporine, tacrolimus)
• Recurrence of native kidney disease

Anatomic complications of surgery are as follows:

• Renal artery thrombosis
• Renal artery stenosis
• Urine leaks from disruption of the anastomosis
• Ureteral stenosis and obstruction (relatively late complications)
• Lymphocele

Allograft dysfunction and rejection may occur as follows:

• Hyperacute rejection of the renal allograft occurs within hours of the transplant; nephrectomy is indicated
• Acute rejection appears within the first 6 months after transplantation (15% of cases)
• Chronic rejection occurs more than 1 year after transplantation and is a major cause of allograft loss

Other complications include the following:

• Infection
• Malignancy
• Liver disease
• Hypertension
• Cardiovascular disease

Kidney transplantation should be strongly considered for all patients with chronic and end-stage renal disease (ESRD) who are medically suitable. ^[2] A successful kidney transplant offers enhanced quality and duration of life and is more effective (medically and economically) than long-term dialysis therapy. ^[1] Transplantation is the renal replacement modality of choice for patients with diabetic nephropathy and pediatric patients.

A number of diseases are capable of destroying kidney function in all age groups. According to the US Renal Data System (USRDS) 2018 report, the following diseases most commonly lead to kidney transplantation ^[3] :

•   Diabetes mellitus – 39%
• Hypertension – 26%
• Chronic glomerulonephritis – 15%
• Polycystic kidney disease and other causes – 15%

Understanding the etiology of kidney disease is important because the primary renal pathology may influence the outcome with respect to the propensity for recurrence of disease and the association of comorbidities.

To date, more than 518,000 kidney transplants have been performed in the United States alone. Of the 24,670 kidney transplants performed in the US in 2021, 5971 were from living donors and 18,699 were from deceased donors. ^[4] Currently, 786,000 people in the United States, or 2 in every 1,000 people, are living with ESRD: 71% are on dialysis and 29% are living with a kidney transplant. ^[5]

In 1973, Congress enacted Medicare entitlement for ESRD treatment to provide equal access to dialysis and transplantation for all patients with ESRD in the Social Security system by removing the financial barrier to care. ^[6] As of March 2022, there were 90,029 patients waiting for a kidney transplant. ^[4]

According to the Organ Procurement and Transplantation Network, both short-term and long-term graft survival have increased. ^[7] Between 2008 and 2015, 1-year graft survival was 93.2% for deceased donor transplants and 97.5% for living donor transplants. ^[4]

Kidney graft failure occurs because of chronic rejection, graft dysfunction, and nephrotoxicity, causing the patient to need dialysis and often a new organ. The development of new therapeutic approaches to prevent chronic rejection is needed to prolong the long-term survival of kidney transplants.

History

Transplant candidates

Candidates for kidney transplantation undergo an extensive evaluation to identify factors that may have an adverse effect on outcome. Virtually all transplant programs have a formal committee that meets regularly to discuss the results of evaluation and select medically suitable candidates to place on the waiting list. Most programs perform the evaluation in the outpatient setting and possess a relatively uniform approach to the diagnosis and treatment of the pertinent medical and psychosocial issues affecting candidacy.

Preexisting comorbid conditions in transplant candidates with renal disease may include the following:

• Hematologic abnormalities (eg, anemia and platelet-hemostatic dysfunction)

• Upper and lower gastrointestinal (GI) tract abnormalities (eg, gastritis, peptic ulcer disease, diverticulosis, diverticulitis, spontaneous colonic perforation, and prolonged adynamic ileus [pseudo-obstruction])

• Hepatic abnormalities (eg, hepatitis B and C)

• Cardiovascular abnormalities – The cardiovascular system is profoundly affected in patients with chronic or end-stage renal failure; the increased mortality is related to hypertension, atherosclerotic heart disease with myocardial infarction, congestive heart failure, and left ventricular hypertrophy

• Bone and joint disease – This is common in these patients because of low calcium levels, high phosphorus concentrations, and elevated serum parathyroid hormone (PTH) levels

Transplant recipients

The following factors are of particular importance in the history of any patient with an organ transplant who presents to a medical setting:

• Current symptoms, especially fever
• Transplant age (ie, time since transplant)
• Organ source (ie, living or deceased donor)
• Previous episodes of rejection (which may have necessitated increased immunosuppression)
• Current medications, including over-the-counter (OTC) drugs
• Recent medication changes
• Immunosuppressive therapy
• Compliance with therapy
• Previous infections
• Recent exposure to ill patients

In transplant recipients, many of the specific causes of infection can be correlated with the age of the graft. Most opportunistic infections occur after the first posttransplant month and through the first year, but such infections are especially common between months 1 and 6, when immunosuppression is maximized. ^[8]

Patients with deceased-donor allografts have significantly lower graft survival rates and increased infectious complications.

Patients with multiple rejection episodes requiring more aggressive immunosuppression are at significantly higher risk for infectious complications than patients who have experienced little or no rejection. Noncompliance with antirejection medications is the leading cause of late acute rejection. A complete medication history must include all OTC and herbal medications and supplements. Calcineurin inhibitors such as tacrolimus or cyclosporine are especially important agents to consider because of their wide range of drug interactions.

Also important to note are recent exposures to patients with infections (eg, COVID-19, chickenpox, cytomegalovirus [CMV] infection, or tuberculosis) or a history of chronic infections (eg, with cytomegalovirus [CMV], Epstein-Barr virus [EBV], hepatitis virus, or HIV). Reactivation of chronic infections and exposures are the most common sources of infections in transplant patients.

Other information necessary in the evaluation of any illness includes blood pressure, body weight, and serum creatinine level. Patients with kidney transplants or their families usually are very knowledgeable about their baseline status and are valuable sources of important clinical data. ^{[9, 10]}

Physical examination

Fever is the most common presentation of an infection in patients with a transplant. ^[11] Be aware that uremia, hyperglycemia, and immunosuppressants (including steroids) commonly suppress or mask fever. ^[12]

In patients with a kidney transplant, assessment of volume status is paramount. Hypotension and tachycardia are obvious clues to hypovolemia. Edema is a less reliable finding, as chronic hypoalbuminemia from malnutrition, nephrotic syndrome, and chronic liver disease is common in these patients. Often, invasive hemodynamic monitoring is the only reliable means of determining volume status in patients with kidney transplants.

The renal graft generally is placed in the right or left iliac fossa in an extraperitoneal position and is most often anastomosed to the internal or external iliac artery. It should be inspected, palpated, and auscultated. The graft insertion site should be inspected for signs of wound infection. Graft tenderness and swelling are often observed in cases of acute rejection, outflow obstruction, pyelonephritis, or renal vein occlusion. A bruit often can be heard in cases of renal artery stenosis and arteriovenous malformation.

Transplant candidates

Emphasize identifying and treating all coexisting medical problems that may increase the morbidity and mortality rates of the surgical procedure and adversely impact the posttransplant course. In addition to a thorough medical evaluation, evaluate the social issues of the patient to determine conditions that may jeopardize the outcome of transplantation, such as financial and travel restraints or a pattern of noncompliance.

Pertinent components include the following:

• Blood chemistries
• Liver function tests
• Complete blood count (CBC)
• Coagulation profile

An infectious profile should include the following:

• Hepatitis A, B, and C serologies
• Epstein-Barr virus (EBV) serologies (immunoglobulin G [IgG])
• Cytomegalovirus (CMV) serologies (IgG)
• Varicella-zoster virus (VZV) serologies (IgG)
• Rapid plasma reagin (RPR) test for syphilis
• HIV
• Purified protein derivative (PPD) - Tuberculosis skin test with anergy panel or interferon-gamma release assay for tuberculosis (eg, QuantiFERON Gold In-Tube), when indicated

Urinalysis and urine culture should be ordered when indicated.

Transplant recipients

Transplant recipients have routine blood and urine tests done regularly, with additional testing conducted if concerns arise that need further evaluation. Some of the following studies are obtained:

• Chemistry panel
• Complete blood cell count (CBC)
• Urinalysis with microscopy
• Urinary protein-to-creatinine ratio
• COVID-19 testing
• Cultures (ie, mouth, sputum, urine, blood, stool, intravenous access sites, as appropriate)
• CMV polymerase chain reaction (PCR) testing
• EBV PCR
• BK virus monitoring in urine and serum
• Lipid panel
• Intact parathyroid hormone level, 25-hydroxyvitamin D levels

Urinary tract infections (UTIs) from indwelling catheters are the most common source of bacterial infections in this patient population and account for as many as 69% of bacterial infections. Leukocytosis with a left shift commonly is observed with bacterial infections unless immunosuppressive agents have suppressed the bone marrow. Leukopenia with an increase in atypical lymphocytes is commonly observed with viral infections.

Patients may present with pneumonia from bacterial or viral agents. Interstitial infiltrates commonly are observed with Pneumocystis jiroveci pneumonia (PJP) and other atypical pneumonias. Tuberculosis may present as typical upper-lobe distribution in reactivation forms; however, tuberculosis also may present atypically as a primary infection.

Patients with acute allograft dysfunction

Renal allograft dysfunction or acute kidney injury in patients with transplants is defined as a 20% rise in serum creatinine level (as opposed to a 50% rise in nontransplant patients). In the workup, estimate the patient’s volume status. Hypovolemia should be corrected rapidly in all patients. Obtain the following studies:

• Urinalysis
• Electrolyte levels
• Blood urea nitrogen (BUN) and creatinine levels
• Tacrolimus or cyclosporine level

Urinalysis showing red blood cells (RBCs) suggests possible glomerulonephritis; white blood cells (WBCs) suggest infection and obstruction. Hyperkalemia is a common complication of renal graft rejection and tacrolimus use. Elevated tacrolimus or cyclosporine levels are associated with increased nephrotoxicity.

Transplant candidates

A complete cardiac workup, including angiography, is not necessary in every patient. However, individuals with a significant history, symptoms, type 1 diabetes, or hypertensive renal disease should undergo a thorough evaluation to rule out significant coronary artery disease (CAD). One study indicated that diabetic candidates with kidney insufficiency frequently have cardiovascular risk factors with a high likelihood of CAD. ^[13] In that study, angiographic findings of CAD were predictive of major adverse cardiac events.

The following procedures are indicated:

• 12-lead electrocardiography (ECG)
• Chest radiography (posteroanterior [PA] and lateral views)
• Exercise and dipyridamole thallium scintigraphy or a nuclear regadenoson (Lexiscan) stress test
• 2-dimensional echocardiography with Doppler (with or without dobutamine)
• Coronary arteriography (if indicated)

Special procedures may be indicated in selected patients on the basis of findings revealed in the history and physical examination, as follows:

• Upper gastrointestinal (GI) endoscopy
• Ultrasonography of native kidneys
• Peripheral arterial Doppler studies
• Pulmonary function tests
• Carotid duplex studies
• Voiding cystourethrography
• Urodynamic pressure-flow studies

Transplant recipients

In transplant recipients, test selection is based on the presenting complaint or concern.Transplant ultrasonography is performed to identify urinary obstruction, as well as fluid collections suggesting urine extravasation, abscess, pyelonephritis, or wound infection. Color flow Doppler ultrasonography is necessary to evaluate vascular occlusion or stenosis. Kidney biopsy represents the ultimate diagnostic modality and usually is required for definitive diagnosis of most cases of renal graft dysfunction. Lumbar puncture may be done in cases of suspected meningitis, particularly that believed to be caused by Listeria species.

Cancer surveillance

Because long-term immunosuppression carries an increased risk of malignancy, transplant candidates need to be screened appropriately for malignancy, based on age, demographics, and other risk factors, in accordance with current cancer screening guidelines. Tests may include:

• Colonoscopy
• Papanicolaou (Pap) smear
• Mammogram
• Prostate-specific antigen (PSA) measurement, with or without digital rectal examination (DRE)

Similarly, screening tests in transplant recipients may include:

• Colonoscopy
• Pap smear
• Mammogram
• PSA measurement, with or without DRE
• Skin cancer screening annually
• Periodic ultrasonography of native kidneys to evaluate for any suspicions lesions

Transplant candidates

Potential recipients of kidney transplants undergo an extensive immunologic evaluation that primarily serves to avoid transplants that are at risk for antibody-mediated hyperacute rejection. The immunologic evaluation consists of the following 4 components:

• ABO blood group determination
• Human leukocyte antigen (HLA) typing
• Serum screening for antibody to HLA phenotypes
• Crossmatching

ABO blood group determination is used to determine if the patient is a potential target of recipient circulating preformed cytotoxic anti-ABO antibody. Transplantation across incompatible blood groups may result in humoral-mediated hyperacute rejection.

All transplant recipients undergo tissue typing to determine the HLA class I and class II loci; 6 HLA antigens are determined. The kidney donors also undergo HLA typing, and the degree of incompatibility between the donor and the recipient is defined by the number of antigens that are mismatched at each of the HLA loci.

All transplant candidates are screened to determine the degree of humoral sensitization to HLA antigens. Sensitization to histocompatibility antigens is of great concern in certain candidate populations. This occurs when the recipient is sensitized because of receiving multiple blood transfusions, a previous kidney or other solid organ transplant, or from pregnancy. Transplantation of a kidney into a recipient who is sensitized against donor class I HLA antigens puts the recipient at high risk for hyperacute antibody-mediated rejection.

Crossmatching is an in vitro assay method that determines whether a potential transplant recipient has preformed anti-HLA class I antibodies against the antigens of the kidney donor. This immunologic test is conducted before transplantation. A negative crossmatch must be obtained before a kidney is accepted for transplantation.

Kidney transplant candidates with preformed, donor-specific antibodies may undergo a pretransplant desensitizing protocol, which, if successful, reduces antibody levels to the point where kidney transplantation becomes feasible. The short- and long-term results for patient survival rates are promising in comparison with those seen in patients staying on dialysis. ^[14]

To avoid the increased risk of rejection and the risk of intensification of immunosuppression, and to facilitate transplantation among non-compatible living donor and recipient pairs, patients may choose to participate in Kidney Paired Donor (KPD) programs or living donor exchanges.

The medical workup may reveal circumstances that necessitate surgical intervention to prepare the patient for kidney transplantation. Such interventions may include the following:

• Native kidney nephrectomy or nephroureterectomy
• Cholecystectomy
• Splenectomy
• Multiple random blood transfusions

Pretransplant native kidney nephrectomy/nephroureterectomy is no longer a routine pretransplant procedure. The native kidneys are left in place because they may still produce significant volumes of urine, secrete erythropoietin, and activate vitamin D. Nephrectomy/nephroureterectomy is reserved for specific indications, such as large polycystic kidneys, significant proteinuria, and chronic reflux disease.

Ultrasonographic evidence of symptomatic or asymptomatic gallstones is an indication for pretransplant cholecystectomy. The mortality and morbidity of acute cholecystitis is significant in transplant recipients who are immunosuppressed.

Splenectomy is no longer a required pretransplant surgical procedure. However, it may be indicated as part of a protocol for ABO-incompatible kidney transplantations.

In the pre-cyclosporine era, multiple random blood transfusions were associated with improved kidney transplant graft survival. Currently, however, transfusion offers no clinical benefit, and the risk of sensitization is significant. In the setting of living kidney transplantation, donor-specific transfusion therapy also has been almost completely eliminated. Because of the risk of transmitting infection by transfusion, immunosuppressed transplant recipients who receive transfusions should be given CMV-negative blood.

In addition to the surgical transplantation procedure itself (see Kidney Transplantation), management includes organ procurement, the provision of immunosuppressive therapy to the recipient, and short- and long-term follow-up to look for indications of renal allograft dysfunction and other complications.

For pregnant women, there are special obstetric considerations associated with renal disease necessitating transplantation. There are also special considerations for newborns, who are more often born premature and have lower birth weights for expected ages. Severely ill transplanted patients who are on long-term steroid therapy are at risk for adrenal insufficiency and should be treated with stress doses of hydrocortisone (100 mg IV every 8 hours).

In a population-based retrospective cohort study of 264 pregnant women with a functional kidney transplant and 267 pregnant women with ESRD on dialysis, kidney transplant recipients were less likely to have placental abruption, less likely to receive blood transfusions, and were less likely to have growth-restricted and small-for-gestational-age infants. Kidney transplant recipients were more likely to undergo an instrumental delivery and there was a trend toward an increase in delivery by cesarean section. Fetal death was less likely among women with a kidney transplant. Four maternal deaths occurred among the women with ESRD on dialysis and no maternal deaths occurred among kidney transplant patients. ^[15]

Organ procurement

In the United States, 90,029 patients were waiting for a kidney transplant as of March 2022. ^[4] Many of those patients will die before receiving a kidney. It is hoped that heightened attention to the task of identifying potential donors in emergency settings can help meet the escalating need for solid organ transplantation.

Identification of potential donors

The warm ischemia time (ie, the time from cessation of circulation to removal of the organ and its placement in cold storage) should be no longer than 30 minutes. This reality and other practical and logistical factors prevent “code victims” in the emergency department (ED) from becoming solid-organ donors, though these patients may still be considered for donation of other tissues (eg, bone, skin, veins, heart valves, and ocular components).

The role of ED physicians and other providers is to identify moribund patients who are appropriate candidates for transplantation and to set into motion the process of acquisition by contacting the local organ procurement organization (OPO). A list of OPOs in the United States can be found on the AOPO website.

The task of discussing organ donation with a patient’s family is best left to the OPO representative, who is highly trained for such discussion, is not involved in the acute care of the patient, and therefore does not have to weigh competing obligations. The ED physician and other healthcare providers should focus on providing the family with a realistic prognosis for the patient.

Assessment of donor suitability

Increasing demand for donor organs and improvements in transplant immunology have greatly expanded the pool of patients eligible to donate organs. Absolute contraindications for organ donation include COVID-19 infection, sepsis, and non–central nervous system (CNS) malignancy. Advanced age is a relative contraindication; most OPOs do not harvest solid organs from individuals older than 75 years. However, rejection of questionable transplant donations should be deferred to an OPO representative.

The pretransplantation workup of a potential donor should include screening for transmissible infectious agents such as herpesvirus (CMV, herpes simplex virus [HSV], EBV); HIV; hepatitis viruses A, B, C, D and E; and COVID-19. ^[16]

An investigation by Peters et al of the influence of age, sex, obesity, and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects who were potential kidney donors found the following ^[17] :

• GFR declined with age, significantly faster in women than men.
• Young women (< 30 years) had higher GFR than young men but the reverse was true in the elderly (> 65 years).
• Obesity did not affect GFR in men, but obese women had lower GFR than non-obese women.
• Obesity did not affect the age-related decline in GFR.

Determination of donor brain death

The Uniform Determination of Death Act provides guidelines outlining neurologic criteria for brain death, which is defined as complete and irreversible loss of brain and brainstem function. Criteria include the following:

• Cerebral unresponsiveness
• Brainstem areflexia
• Apnea in the absence of hypothermia and drug intoxication

Because of the lengthy process required for actual organ procurement, the ED physician or team looking after the patient should not wait for the formal declaration of brain death before involving the transplant team. If a potential donor may meet brain death criteria in the near future, a transplant coordinator should be called early on.

Patients with brain death and preserved cardiovascular function who are identified as potential donors should be quickly admitted to an intensive care unit (ICU); only in this setting can their cardiorespiratory status be maintained against the onslaught of physiologic insults that ensue once neurologic function has ceased. Once stabilized, the organ donor may officially be designated as brain-dead and transferred to the operating room for organ procurement. ^[18]

In certain situations, patients may be considered donors after circulatory death (DCD). This practice has increased the availability of life-saving organs.

Medical management of donor

After brain death, a number of physiologic changes ensue that necessitate medical intervention if donor organ perfusion is to be preserved. Increasing cerebral edema after a trauma or stroke initially results in elevated catecholamine release and hypertension. With brainstem necrosis, catecholamine levels rapidly drop to a fraction of normal values, causing hypotension. Such hypotension should be corrected with fluids and vasopressors.

Approximately three fourths of organ donors develop diabetes insipidus as a consequence of pituitary necrosis. If this condition goes untreated, significant hypovolemia may result. Systemic thermal control is often lost because of hypothalamic ischemia. This occurs in most donors and results in detrimental effects on potential donor organs, including coagulopathy, hypoxia, hepatic dysfunction, and cardiac dysfunction.

Patients who are brain-dead require invasive hemodynamic monitoring and aggressive fluid and pressor management to keep mean arterial pressure (MAP) above 60 mm Hg and urine output above 0.5 mL/kg/h. ^[19]

Immunosuppressive therapy

All kidney transplant recipients require life-long immunosuppression to prevent an alloimmune rejection response. The goals are to prevent acute and chronic rejection, to minimize drug toxicity and rates of infection and malignancy, and to achieve the highest possible rates of patient and graft survival. There is no consensus as to which immunosuppressive protocol can best meet those goals, and each transplantation program uses various combinations of agents slightly differently.

Several immunosuppressive agents have been approved by the US Food and Drug Administration (FDA), and several others are in clinical trials. Immunosuppressive agents may be divided into 2 broad categories: antirejection induction agents and maintenance immunotherapy agents.

Antirejection induction agents

Induction immunotherapy consists of a short course of intensive treatment with intravenous (IV) agents. Such agents include polyclonal antisera, mouse monoclonals, and so-called humanized monoclonals. Polyclonal antisera (eg, antilymphocyte globulin [ALG], antilymphocyte serum [ALS], and antithymocyte globulin [ATG]) are equine, goat, or rabbit antisera directed against human lymphoid cells. They significantly lower, and sometimes almost abolish, the circulating lymphoid cells that are critical to the rejection response.

The agents are very effective at prophylaxis against early acute rejection, which is especially beneficial in managing the recipient with delayed graft function. The agents provide an effective immunologic cover during a period in which the calcineurin inhibitors are either delayed or given in subtherapeutic doses until graft function improves. Induction agents are used less often if immediate graft function occurs, as in recipients of kidneys from living donors, especially human leukocyte antigen–identical (HLA-ID) grafts.

The most commonly used induction agents are basilixumab, rabbit antithymocyte globulin, and alemtuzumab. A 2011 prospective, randomized, multicenter evaluation of induction demonstrated that in low-risk patients, alemtuzumab yielded significantly lower rejection rates than basilixumab, without any significant differences in safety outcomes. ^[20]

Maintenance immunotherapy agents

Several immunosuppressive agents are currently in use for maintenance immunotherapy in kidney transplant recipients, including prednisone, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, and belatacept. An optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for the patient’s entire life.

A single-center, randomized trial of 3 distinct maintenance immunosuppression protocols found the combination of tacrolimus plus mycophenolate mofetil to be superior with respect to graft function and rejection rates, compared with tacrolimus plus sirolimus and with cyclosporine plus sirolimus. ^[21]

Dose requirements and trough levels are essentially the same for generic tacrolimus as for brand-name tacrolimus; cost savings can be realized with the use of generic tacrolimus. However, post-conversion monitoring is important because patients may require dose titration. ^[22]

Primary use of mechanistic target of rapamycin inhibitors (mTORI: sirolimus and everolimus) without calcineurin inhibitors (CNI; tacrolimus or cyclosporin) is associated with greater risks of allograft failure and death compared with a CNI-based regimen. ^[23]

Belatacept has shown promise for enhancement of kidney graft function. If this promise is borne out in further studies, this drug may help reduce the current dependence on calcineurin inhibitors (eg, tacrolimus and cyclosporine) for immunosuppression. ^[24] Belatacept gained full FDA approval in June 2011.

In the Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial (BENEFIT) and the extended BENEFIT trial (BENEFIT-EXT), belatacept-based regimens maintained better renal function and improved cardiovascular and metabolic risk profiles when compared with cyclosporine regimens. Patient and graft survival rates were comparable with the two regimen types. ^[25]

A study in six kidney transplant recipients with presumed acute calcineurin inhibitor toxicity and/or interstitial fibrosis/tubular atrophy found that conversion from tacrolimus to belatacept resulted in improved kidney function with no concurrent increase in risk of rejection. After the switch, which took place a median of 4 months after transplantation, the peak mean estimated glomerular filtration rate (eGFR) improved from 23.8 ± 12.9 to 42 ± 12.5 mL/min/1.73 m² (P = 0.03) at a mean follow-up of 16.5 months postconversion. ^[26]

No new rejection episodes were diagnosed despite a prior history of rejection in two of the six patients. Surveillance biopsies performed in five of the six patients did not show subclinical rejection. No patient developed donor-specific antibodies. ^[26]

Medical follow-up

The primary goal of short-term and long-term medical follow-up is to enable surveillance for signs and symptoms of renal allograft dysfunction. ^[27] Renal parenchymal dysfunction has many causes, and the differential diagnosis must be approached systematically. The clinical manifestation is typically an increase in serum creatinine level. The critical considerations are as follows (see Complications of Transplantation):

• Rejection
• Nephrotoxicity of calcineurin inhibitors
• Recurrence of native kidney disease

The time interval between transplantation and the rise in serum creatinine level is often helpful in determining the etiology of graft dysfunction. For example, delayed graft function immediately after transplantation is usually due to acute tubular necrosis (ATN), related to warm and cold ischemic time. The frequency is variable among the different transplant centers and is approximated at roughly 20-30% of deceased donor transplants.

The nephrotoxicity of the calcineurin inhibitors cyclosporine and tacrolimus is dose-related. Occasionally, performing a renal allograft biopsy is necessary if the serum creatinine level does not respond to a reduction in dose.

Hemolytic uremic syndrome (HUS) and thrombotic microangiopathy (TMA) may occur in the setting of endothelial injury associated with calcineurin inhibitors and the development of CMV infection. ^[28] A systemic process reveals anemia, reduced haptoglobin levels, rising lactic dehydrogenase (LDH) levels, and a peripheral blood smear with schistocytes, all of which are consistent with the diagnosis.

At times, HUS and TMA are confined to the kidney and do not give rise to any systemic findings. The definitive diagnosis, whether local or systemic, is made with the aid of renal allograft biopsy that shows glomerular microthrombi.

Recurrent renal disease in renal kidney transplant recipients accounts for fewer than 2% of all graft losses, though it affects as many as 10% of recipients. A few diseases are associated with a high risk of renal allograft loss, including focal segmental glomerulosclerosis, HUS oxalosis, and membranoproliferative glomerulonephritis. Diabetic nephropathy can recur in renal allografts, but the time to onset is similar to that seen in native kidneys, and in general, this condition is an uncommon cause of graft loss.

Improvements in surgical technique and the advent of more potent immunosuppressive agents have reduced early complications of kidney transplantation. Greater emphasis is now placed on preventing late complications. This is accomplished in the outpatient setting through routine assessment of patients who have received transplants.

Chronic systemic immunosuppression is a double-edged sword. The same immunosuppressive effects that prevent rejection of the allograft pose a risk for development of malignancy and infectious diseases. Routine cancer surveillance is mandatory to assure rapid diagnosis and treatment of any malignancy.

Anatomic complications of surgery

In patients who have undergone transplantation, risk factors for wound complications are significant, and the associated morbidity can be substantial.

Although kidney transplantation is a vascular surgery procedure, it is not associated with a great deal of blood loss. Postoperatively, life-threatening bleeding complications are very rare, but such bleeding could result from rupture of the arterial anastomosis from a mycotic aneurysm.

Renal artery thrombosis is a complication most commonly seen in the hospitalization period immediately after transplantation. It is caused by a low-flow state from hypotension or vascular kinking due to surgical error and is typically diagnosed by means of color flow Doppler ultrasonography. The presenting symptom is sudden cessation of urine output. The likely outcome is graft loss, though salvage of the renal allograft is possible if the problem is diagnosed within 30 minutes of its occurrence.

Renal artery stenosis is typically a later complication. It presents as uncontrolled hypertension, allograft dysfunction, and peripheral edema. It is diagnosed by means of color flow Doppler ultrasonography or magnetic resonance angiography (MRA).

Venous thrombosis is rare, but if it occurs, the kidney is usually unsalvageable. Often, the cause is never satisfactorily identified. Renal vein thrombosis is typically an early complication presenting as graft tenderness and edema. The patient develops pain and swelling over the graft site, as well as dark hematuria and diminished urine volume. It is diagnosed by means of color flow Doppler ultrasonography.

Urine leaks occur at the ureterovesical junction or through a ruptured calyx secondary to acute ureteral obstruction. They result from disruption of the anastomotic connection of the ureter to the graft, generally within the first 2 months after transplantation. Often, early urine leak is due to necrosis of the tip of the ureter. Urine leaks manifest as diminished urine output, an increase in creatinine levels, fever, and lower abdominal or suprapubic discomfort. Ultrasonography demonstrates perigraft fluid collection.

Repair of urine leakage with minimal intervention may be attempted either by means of percutaneous nephrostomy and drainage with internal stenting or by means of a cystoscopic retrograde approach. More aggressive treatment involves operative intervention with either reimplantation of the ureter or ureteroureterostomy utilizing the ipsilateral native ureter.

Ureteral stenosis and obstruction are relatively late complications, occurring months or years after transplantation. Potential causes include hematuria or chronic fibrotic changes at the anastomosis site, a tight ureteroneocystostomy, or extrinsic compression from a urinoma, hematoma, or lymphocele. Ureteral stenosis is manifested by elevated creatinine and hydronephrosis. Typically, the graft becomes distended and edematous, creatinine levels are elevated, and ultrasonography reveals hydronephrosis.

Lymphocele, a circumscribed collection of retroperitoneal lymph originating from lymphatic vessels around the iliac vasculature and the hilum of the kidney, can occur in as many as 15% of transplant recipients as a result of operative trauma to lymphatics. It presents as a mass at the graft site that can impinge on and obstruct the ureter. Significant secondary problems may arise if external compression of the iliac vein (causing leg swelling and discomfort) or compression of the transplant ureter (causing hydronephrosis and renal dysfunction) occurs.

The standard principle of treatment is that intraperitoneal drainage of the lymphocele should be accomplished with either a laparoscopic or an open surgical approach, with marsupialization of the edges of the lymphocele.

Allograft dysfunction and rejection

Renal allograft failure is one of the most common causes of end-stage renal disease (ESRD), accounting for 25% of all patients awaiting kidney transplants. Transplanted kidneys can fail for all the same reasons that native kidneys do, as well as for reasons unique to transplant patients. Complications of surgery (see above) are common causes of graft failure within the first 12 weeks after transplantation. Recurrent kidney disease results in fewer than 4% of graft failures but may be an important concomitant etiology of kidney failure. ^{[29, 30]}

Rejection is related primarily to activation of T cells, which, in turn, stimulate specific antibodies against the graft. Various clinical syndromes of rejection can be correlated with the length of time after transplantation. ^[31]

Hyperacute rejection

Hyperacute rejection of the renal allograft happens in the operating room within hours of the transplant, when the graft becomes mottled and cyanotic. This type of rejection is due to unrecognized compatibility of blood groups A, AB, B, and O (ABO) or to a positive T-cell crossmatch (class I human leukocyte antigen [HLA] incompatibility). No treatment exists, and nephrectomy is indicated.

Acute rejection

Acute rejection appears within the first 6 months after transplantation and affects approximately 15% of transplanted kidneys. Rejection is secondary to prior sensitization to donor alloantigens (occult T-cell crossmatch) or a positive B-cell crossmatch. Roughly 20% of patients with transplants experience recurrent rejection episodes.

Patients present with decreasing urine output, hypertension, and mild leukocytosis. The expected rise in the creatinine level may be delayed in acute rejection. Fever, graft swelling, pain, and tenderness may be observed with severe rejection episodes. Donor-derived cell-free DNA is a noninvasive blood test used to assess the probability of allograft rejection.The final diagnosis depends on a graft biopsy. Acute rejection is treated with a 3- to 5-day course of high-dose intravenous (IV) steroids.

Accelerated acute rejection is a very early, rapidly progressive, aggressive rejection reaction that is dependent on T cells. ^[2] It can occur within the first week after transplantation. Immediate therapy with anti–T-cell antibodies and pulse corticosteroids may reverse the process. Approximately 50% of cases can be salvaged.

Acute tubular interstitial cellular rejection is the most common type of rejection reaction, with an incidence of approximately 20-25%. Typically, it occurs between 1 and 3 months after transplantation. It is T-cell mediated, and injury is directed to the renal tubules. The standard for diagnosis is renal allograft biopsy. Mild rejections may be successfully reversed with corticosteroids alone, whereas moderate or severe rejections may require the use of anti–T-cell antibodies, either polyclonal or monoclonal.

Late acute rejection is strongly correlated with scheduled withdrawal of immunosuppressive therapy 6 months after transplantation.

Chronic rejection

Chronic rejection occurs more than 1 year after transplantation and is a major cause of allograft loss. It is a slow and progressive deterioration in renal function characterized by histologic changes involving the renal tubules, capillaries, and interstitium. Its precise mechanism is poorly defined and is an area of intense study. Diagnosis is by renal biopsy, and treatment depends on the identified cause, if any. Application of conventional antirejection agents (eg, corticosteroids or anti–T-cell antibodies) does not appear to alter the progressive course.

Infection

Infection is the most common cause of first-year posttransplantation mortality and morbidity. During the first year after transplantation, 40-80% of transplant recipients experience at least 1 infection; however, these numbers are decreasing as more transplant recipients receive preoperative immunizations and posttransplantation antibiotic prophylaxis. ^[32]

Infection most commonly occurs in mucocutaneous areas (41%), the urinary tract (17.2%), and the respiratory tract (13.9%). The most common infective agents are bacteria (45.9%), viruses (40.6%), fungi (12.5%), and protozoa (1%). Cytomegalovirus (CMV; 31.5%), herpes simplex virus (HSV; 23.4%), and varicella-zoster virus (VZV; 23.4%) are the most frequent viral pathogens. ^[33] Infection (32%) is the most common cause of death; pneumonias account for 50% of patient deaths from infection.

In a study of 1044 kidney transplant recipients from the Nationwide Inpatient Sample 2009-2011, urinary tract infections (UTIs) were most common among patients with hypertension (53%), The prevalence of UTIs was 28.2 cases per 1000 men and 65.9 cases per 1000 women. Patients with UTIs had an increased risk of transplant complications, higher total hospital charges, and increased length of hospital stay. ^[34]

Infectious agents can often be identified on the basis of the time interval from transplantation to presentation. Posttransplantation month 1 is dominated by infections directly related to the surgical procedure, including urinary tract infection (Escherichia coli), line infection (Staphylococcus aureus and viridans streptococci), wound infection (S aureus and viridans streptococci), and pneumonia (Streptococcus pneumoniae).

Months 1-6 after transplantation are associated with the highest levels of immunosuppression and thus the greatest risk of viral and opportunistic infections. CMV is responsible for more than two thirds of febrile episodes during this period. Patients often present with fever, malaise, lymphadenopathy, arthralgias, and myalgias. Leukopenia with atypical lymphocytes and mild hypertransaminasemia may be noted. Diagnosis is based on isolation of virus or antibody titers. Untreated CMV infection is associated with a mortality as high as 15%. BK virus infection with BK nephropathy can lead to graft loss in immunocompromised kidney transplant patients.

Other opportunistic infections include P jiroveci pneumonia (PJP), listeriosis meningitis, COVID-19, and sepsis caused by Aspergillus fumigatus.

After the first 6 months, patients with kidney transplants may be divided into the following three subgroups with regard to infection risk:

• Patients with good graft function on minimal immunosuppressants – These patients have the same risk of infection as the general population

• Patients chronically infected with latent viruses (eg, CMV, EBV, and hepatitis B or C virus) – These patients often have significant and ongoing end-organ damage (eg, cirrhosis) as a consequence of such infections

• Patients with poorly functioning grafts who have sustained multiple episodes of rejection and who require large dosages of immunosuppressants – These patients commonly have bouts of acute and chronic opportunistic infections (eg, PJP and candidal infections)

Malignancy

Transplant recipients are at significantly higher risk for many cancers than members of the general population are, as a result of the following factors ^{[35, 36]} :

• Chronic immunosuppression
• Chronic antigenic stimulation
• Increased susceptibility to oncogenic viral infections
• Direct neoplastic action of immunosuppressants

Transplant recipients are at particularly high risk for infection-related malignancies, such as non-Hodgkin lymphoma, Hodgkin lymphoma, and Kaposi sarcoma, as well as cancers of the liver, stomach, oropharynx, anus, vulva, and penis. The risk is not increased for uterine, ovarian, cervical, vaginal, nasopharyngeal, brain, and leukemic cancers. The risk is decreased for breast, prostate, and, possibly, testicular cancer, 3 cancers screened for when patients are evaluated for transplantation. ^[36]

Liver disease

Chronic liver disease is an important cause of morbidity and mortality for kidney transplant recipients. Causes of hepatic dysfunction include viral hepatitis and antirejection therapy. Of the viral infections, CMV infection is the leading cause of hepatic dysfunction, followed by hepatitis C and B. Of the antirejection medications, azathioprine and cyclosporine are known to cause cholestatic jaundice. ^{[37, 38]}

Calcineurin inhibitor nephrotoxicity

The nephrotoxicity of the calcineurin inhibitors cyclosporine and tacrolimus is related to hemodynamic factors. Acute tacrolimus or cyclosporine toxicity causes vasoconstriction and renal ischemia, which can be reversed by reducing the drug dosage. Chronic toxicity results in fixed vascular lesions and irreversible renal ischemia. ^[39] Tacrolimus and cyclosporine are noteworthy for their many interactions with other medications, such as the following:

• Calcium channel antagonists (eg, diltiazem, verapamil, and nicardipine) and certain antibiotics (eg, erythromycin, doxycycline, and ketoconazole) increase levels of tacrolimus or cyclosporine and predispose to nephrotoxicity

• Certain antibiotics (eg, nafcillin, trimethoprim-sulfamethoxazole, isoniazid, and rifampin) and certain anticonvulsants (eg, phenytoin, phenobarbital, and carbamazepine) decrease levels of tacrolimus or cyclosporine and thereby increase the risk of rejection

• Drugs that enhance the nephrotoxicity of tacrolimus or cyclosporine without altering blood levels include amphotericin B, acyclovir, and nonsteroidal anti-inflammatory drugs (NSAIDs)

Hypertension

Approximately 50% of all kidney transplant patients have hypertension. Possible causes of hypertension include graft rejection, cyclosporine toxicity, glomerulonephritis, graft renal artery stenosis, essential hypertension from native kidneys, hypercalcemia, and steroid use.

Cardiovascular complications

The risk of cardiovascular disease after transplantation is as much as 10 times that reported for age- and sex-matched controls. Recommendations are for all post-transplant recipients to be on a cholesterol-lowering agent if they are able to tolerate it, irrespective of their lipid profile, to reduce cardiovascular risk. ^[40] Risk factors for such disease include the following:

• Pretransplant cardiac disease
• Hyperlipidemia (primary or secondary to antirejection medications)
• Hypertension
• Steroid use
• Diabetes mellitus
• Erythrocytosis
• Smoking history
• Multiple previous rejection episodes
• Sedentary lifestyle
• Obesity

The standardized mortality for patients on dialysis who are awaiting kidney transplantation is 6.3/100 patient-years, and the standardized mortality with each treatment per 100 patient-years is as follows:

• Dialysis - 6.3
• Cadaveric transplant - 3.8
• Living donor transplant - 2.0

Predictably, recipients from living related donors have a lower mortality than recipients from cadaveric donors, probably because of a lower incidence of rejection episodes and thus reduced immunosuppression requirements. ^[41] According to the Organ Procurement and Transplantation Network, in 2015, 5-year survival for patients who received a deceased-donor kidney in 2010 was 86.8%; survival for living-donor recipients was 93.5%; survival was lower in recipients age 65 years and older and in recipients with diabetes as cause of kidney failure. ^[7] Within this category, recipients of sibling HLA-identical grafts do best.

Some of the most useful data on kidney transplantation have been collected by the Scientific Registry of Transplant Recipients (SRTR) of the United Network for Organ Sharing (UNOS). These data confirm that the outcome of kidney transplantation is superior in recipients receiving a kidney from a living donor. ^{[42, 4]}

Kidney transplant recipients aged 65 years and older have a marked reduced mortality rate following transplant with a living donor organ compared to a standard criteria or expanded criteria deceased donor organ. ^[43]

Common causes of death after kidney transplantation include coronary artery disease (CAD; 30.4%), sepsis (27.1%), neoplasm (13%), and stroke (8%). During the first year after the transplant procedure, most deaths are due to infectious causes. ^[44] Long-term mortality is more closely related to the development of CAD. ^{[45, 46, 47]}

In addition to complications of transplantation, such as infection and graft failure, the major causes of morbidity after kidney transplantation are hypertension (occurring in 75-85% of all kidney transplant recipients), hyperlipidemia (60%), cardiovascular disease (15.8-23%—a 10-fold increase over the general population), diabetes mellitus (16.9-19.9%), osteoporosis (60%), and malignant neoplasms (14%). ^[48]

Cardiovascular disease is increased 10-fold compared with the general population, and the rate of malignancies appears to be related to the degree of immunosuppression. Diabetes is more likely to be present prior to transplantation, and new-onset diabetes is related to tacrolimus or corticosteroid use after transplantation. ^{[49, 50]}

Transplant recipients tend to be highly experienced patients. Many have dealt with their chronic illness for years, have been treated and examined by innumerable doctors, have undergone dialysis and its attendant intrusions on their lifestyle, have managed a complicated regimen of medications, and in many cases have developed a certain expertise related to their own care.

Such patients are invariably grateful for any recognition or acknowledgment of their ordeal. In view of their expertise, it is appropriate that they be educated about and encouraged to participate actively in their disease management to the fullest possible extent. That said, these patients’ problems are often deceptively complex, and decisions regarding their care should be made in conjunction with the appropriate transplant team.

For patient education resources, see Kidney Transplant

.