case study 8 3 drawing blood from a transplant patient

Assessment and Management of the Kidney Transplant Patient

• Author: Darshika Chhabra, MD, MPH; Chief Editor: Vecihi Batuman, MD, FASN  more...
• Sections Assessment and Management of the Kidney Transplant Patient
• Practice Essentials
• Presentation
• Laboratory Studies
• Diagnostic Procedures
• Immunologic Evaluation
• Pretransplant Surgical Interventions
• Complications of Transplantation
• Patient Education
• Media Gallery

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
• 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

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

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:

• 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)

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:

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.

Clinical Presentation

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
• 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.

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:

An infectious profile should include the following:

• Hepatitis A , B , and C serologies
• Epstein-Barr virus (EBV) serologies (immunoglobulin G [IgG])
• 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 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
• 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:

• 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.

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)

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

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
• Prostate-specific antigen (PSA) measurement, with or without digital rectal examination (DRE)

Similarly, screening tests in transplant recipients may include:

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

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.

• 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 ]

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.

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.

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.

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.

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 ]

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 m 2 (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):

• Nephrotoxicity of calcineurin inhibitors

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 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)

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 ]

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)

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)
• Steroid use
• Diabetes mellitus
• Erythrocytosis
• Smoking history
• Multiple previous rejection episodes
• Sedentary lifestyle

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

Tonelli M, Wiebe N, Knoll G, Bello A, Browne S, Jadhav D, et al. Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am J Transplant . 2011 Oct. 11(10):2093-109. [QxMD MEDLINE Link] .

Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med . 1994 Aug 11. 331(6):365-76. [QxMD MEDLINE Link] .

Chronic Kidney Disease in the United States, 2021. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/kidneydisease/pdf/Chronic-Kidney-Disease-in-the-US-2021-h.pdf . Accessed: March 16, 2022.

National Data. Organ Procurement & Transplantation Network. Available at https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/# . Accessed: March 10, 2022.

Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. Available at https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease . September 2021; Accessed: March 16, 2022.

Nissenson AR, Rettig RA. Medicare's end-stage renal disease program: current status and future prospects. Health Aff (Millwood) . 1999 Jan-Feb. 18(1):161-79. [QxMD MEDLINE Link] .

Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, et al. OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant . 2017 Jan. 17 Suppl 1:21-116. [QxMD MEDLINE Link] . [Full Text] .

Karuthu S, Blumberg EA. Common infections in kidney transplant recipients. Clin J Am Soc Nephrol . 2012 Dec. 7 (12):2058-70. [QxMD MEDLINE Link] . [Full Text] .

Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial . 2005 Nov-Dec. 18(6):505-10. [QxMD MEDLINE Link] .

Salifu MO, Tedla F, Markell MS. Management of the well renal transplant recipient: outpatient surveillance and treatment recommendations. Semin Dial . 2005 Nov-Dec. 18(6):520-8. [QxMD MEDLINE Link] .

Peterson PK, Balfour HH Jr, Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med . 1981 Sep. 71(3):345-51. [QxMD MEDLINE Link] .

Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med . 2004 Dec 23. 351(26):2715-29. [QxMD MEDLINE Link] .

Welsh RC, Cockfield SM, Campbell P, Hervas-Malo M, Gyenes G, Dzavik V. Cardiovascular assessment of diabetic end-stage renal disease patients before renal transplantation. Transplantation . 2011 Jan 27. 91(2):213-8. [QxMD MEDLINE Link] .

Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med . 2011 Jul 28. 365(4):318-26. [QxMD MEDLINE Link] .

Saliem S, Patenaude V, Abenhaim HA. Pregnancy outcomes among renal transplant recipients and patients with end-stage renal disease on dialysis. J Perinat Med . 2015 Feb 23. [QxMD MEDLINE Link] .

Calder FR, Chang RW. Panning for gold: screening for potential live kidney donors. Nephrol Dial Transplant . 2004 May. 19(5):1276-80. [QxMD MEDLINE Link] .

Peters AM, Perry L, Hooker CA, et al. Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling. Nephrol Dial Transplant . 2012 Apr. 27(4):1429-37. [QxMD MEDLINE Link] .

Black PM. Brain death (first of two parts). N Engl J Med . 1978 Aug 17. 299(7):338-44. [QxMD MEDLINE Link] .

Novitzky D. Donor management: state of the art. Transplant Proc . 1997 Dec. 29(8):3773-5. [QxMD MEDLINE Link] .

Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, et al. Alemtuzumab induction in renal transplantation. N Engl J Med . 2011 May 19. 364(20):1909-19. [QxMD MEDLINE Link] .

Guerra G, Ciancio G, Gaynor JJ, et al. Randomized trial of immunosuppressive regimens in renal transplantation. J Am Soc Nephrol . 2011 Sep. 22(9):1758-68. [QxMD MEDLINE Link] . [Full Text] .

McDevitt-Potter LM, Sadaka B, Tichy EM, Rogers CC, Gabardi S. A multicenter experience with generic tacrolimus conversion. Transplantation . 2011 Sep 27. 92(6):653-7. [QxMD MEDLINE Link] .

Isakova T, Xie H, Messinger S, Cortazar F, Scialla JJ, Guerra G, et al. Inhibitors of mTOR and Risks of Allograft Failure and Mortality in Kidney Transplantation. Am J Transplant . 2012 Oct 1. [QxMD MEDLINE Link] .

Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant . 2012 Jan. 12(1):210-7. [QxMD MEDLINE Link] .

Larsen CP, Grinyó J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation . 2010 Dec 27. 90(12):1528-35. [QxMD MEDLINE Link] .

Gupta G, Regmi A, Kumar D, Posner S, Posner MP, Sharma A, et al. Safe Conversion From Tacrolimus to Belatacept in High Immunologic Risk Kidney Transplant Recipients With Allograft Dysfunction. Am J Transplant . 2015 May 18. [QxMD MEDLINE Link] .

Meyers CM, Kirk AD. Workshop on late renal allograft dysfunction. Am J Transplant . 2005 Jul. 5(7):1600-5. [QxMD MEDLINE Link] .

Zarifian A, Meleg-Smith S, O'donovan R, Tesi RJ, Batuman V. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int . 1999 Jun. 55(6):2457-66. [QxMD MEDLINE Link] .

Jevnikar AM, Mannon RB. Late kidney allograft loss: what we know about it, and what we can do about it. Clin J Am Soc Nephrol . 2008 Mar. 3 Suppl 2:S56-67. [QxMD MEDLINE Link] . [Full Text] .

Cornell LD, Colvin RB. Chronic allograft nephropathy. Curr Opin Nephrol Hypertens . 2005 May. 14(3):229-34. [QxMD MEDLINE Link] .

Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet . 2004 Nov 13-19. 364(9447):1814-27. [QxMD MEDLINE Link] .

Sia IG, Paya CV. Infectious complications following renal transplantation. Surg Clin North Am . 1998 Feb. 78(1):95-112. [QxMD MEDLINE Link] .

Smith SR, Butterly DW, Alexander BD, Greenberg A. Viral infections after renal transplantation. Am J Kidney Dis . 2001 Apr. 37(4):659-76. [QxMD MEDLINE Link] .

Becerra BJ, Becerra MB, Safdar N. A Nationwide Assessment of the Burden of Urinary Tract Infection among Renal Transplant Recipients. J Transplant . 2015. 2015:854640. [QxMD MEDLINE Link] .

Birkeland SA, Løkkegaard H, Storm HH. Cancer risk in patients on dialysis and after renal transplantation. Lancet . 2000 May 27. 355(9218):1886-7. [QxMD MEDLINE Link] .

Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA . 2011 Nov 2. 306(17):1891-901. [QxMD MEDLINE Link] . [Full Text] .

Rao KV, Anderson WR. Liver disease after renal transplantation. Am J Kidney Dis . 1992 May. 19(5):496-501. [QxMD MEDLINE Link] .

Rostami Z, Nourbala MH, Alavian SM, Bieraghdar F, Jahani Y, Einollahi B. The impact of Hepatitis C virus infection on kidney transplantation outcomes: A systematic review of 18 observational studies: The impact of HCV on renal transplantation. Hepat Mon . 2011 Apr. 11(4):247-54. [QxMD MEDLINE Link] . [Full Text] .

Myers BD, Newton L. Cyclosporine-induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol . 1991 Aug. 2(2 Suppl 1):S45-52. [QxMD MEDLINE Link] .

Chhabra D, Doppalapudi AV, Kumbham A, Lerma EV. Dyslipidemia after kidney tranplantation. Weir M, Lerma E (Eds),. Kidney Transplantation: Practical Guide to Management . New York: Springer; 2014.

Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am J Kidney Dis . 2001 Dec. 38(6 Suppl 6):S2-9. [QxMD MEDLINE Link] .

Hart A, Lentine KL, Smith JM, Miller JM, Skeans MA, Prentice M, et al. OPTN/SRTR 2019 Annual Data Report: Kidney. Am J Transplant . 2021 Feb. 21 Suppl 2:21-137. [QxMD MEDLINE Link] . [Full Text] .

Gill JS, Schaeffner E, Chadban S, Dong J, Rose C, Johnston O, et al. Quantification of the Early Risk of Death in Elderly Kidney Transplant Recipients. Am J Transplant . 2012 Nov 21. [QxMD MEDLINE Link] .

Rubin RH. Infectious disease complications of renal transplantation. Kidney Int . 1993 Jul. 44(1):221-36. [QxMD MEDLINE Link] .

Cohen D, Galbraith C. General health management and long-term care of the renal transplant recipient. Am J Kidney Dis . 2001 Dec. 38(6 Suppl 6):S10-24. [QxMD MEDLINE Link] .

Mahony JF. Long term results and complications of transplantation: the kidney. Transplant Proc . 1989 Feb. 21(1 Pt 2):1433-4. [QxMD MEDLINE Link] .

Cantarovich M, Tchervenkov J, Paraskevas S, et al. Early changes in kidney function predict long-term chronic kidney disease and mortality in patients after liver transplantation. Transplantation . 2011 Dec 27. 92(12):1358-63. [QxMD MEDLINE Link] .

Howard RJ, Reed AI, Hemming AW, et al. Graft loss and death: changing causes after kidney transplantation. Transplant Proc . 2001 Nov-Dec. 33(7-8):3416. [QxMD MEDLINE Link] .

Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol . 1996 Jan. 7(1):158-65. [QxMD MEDLINE Link] .

Sharif A, Baboolal K. Complications associated with new-onset diabetes after kidney transplantation. Nat Rev Nephrol . 2011 Nov 15. 8(1):34-42. [QxMD MEDLINE Link] .

Kidney Disease Statistics for the United States. National Institute of Diabetes & Digestive & Kidney Diseases. Available at https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease . December 2016; Accessed: September 27, 2021.

Matas AJ, Smith JM, Skeans MA, Thompson B, Gustafson SK, Stewart DE, et al. OPTN/SRTR 2013 Annual Data Report: kidney. Am J Transplant . 2015 Jan. 15 Suppl 2:1-34. [QxMD MEDLINE Link] .

Hariharan S, Israni AK, Danovitch G. Long-Term Survival after Kidney Transplantation. N Engl J Med . 2021 Aug 19. 385 (8):729-743. [QxMD MEDLINE Link] .

Zolet, ML. US Kidney Transplants Grow in Number and Success. Medscape Medical News . August 24, 2021. Available at https://www.medscape.com/viewarticle/957168 .

Organ Donation and Transplantation Statistics. National Kidney Foundation. Available at https://www.kidney.org/news/newsroom/factsheets/Organ-Donation-and-Transplantation-Stats . Accessed: September, 25, 2021.

2020 Annual Data Report: Epidemiology of Kidney Disease in the United States. USRDS. Available at https://adr.usrds.org/2020/ . Accessed: March 16, 2022.

• Kidney transplantation ultrasonograms. (A) Normal kidney. (B) Color Doppler ultrasonogram documenting normal perfusion to the kidney. (C) Color Doppler ultrasonogram showing absence of perfusion in a patient with thrombosis. (D) Hydronephrosis. (E) Lymphocele. (F) Stone in a kidney transplant.
• Digital subtraction angiogram showing renal artery stenosis
• Histology of percutaneous kidney transplantation biopsy. (A) Normal kidney. (B) Acute rejection. Note the infiltration of lymphocytes.

Contributor Information and Disclosures

Darshika Chhabra, MD, MPH Clinical Assistant Professor, Section of Nephrology, University of Illinois at Chicago College of Medicine; Medical Director and Primary Transplant Nephrologist, Kidney Transplant Program, Advocate Christ Medical Center Darshika Chhabra, MD, MPH is a member of the following medical societies: American Society of Nephrology , American Society of Transplantation , National Kidney Foundation , Renal Physicians Association Disclosure: Nothing to disclose.

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians , American Society of Hypertension , American Society of Nephrology , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Dixon B Kaufman, MD, PhD, FACS Ray D Owen Professor and Chief, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health Dixon B Kaufman, MD, PhD, FACS is a member of the following medical societies: American College of Surgeons , American Society of Transplant Surgeons , American Surgical Association , Association for Academic Surgery , Central Surgical Association , Society of University Surgeons Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: MEDEOR Therapeutics; eGenesis<br/>Received research grant from: NIH.

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research , American Society of Nephrology , Kentucky Medical Association , and National Kidney Foundation

Disclosure: Nothing to disclose.

Enesha M Cobb, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital, State University of New York Downstate Medical Center College of Medicine

Enesha M Cobb, MD, is a member of the following medical societies: American Academy of Emergency Medicine , American College of Emergency Physicians , and Phi Beta Kappa

Mert Erogul, MD Assistant Professor of Emergency Medicine, University Hospital of Brooklyn: Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Mert Erogul, MD is a member of the following medical societies: American College of Emergency Physicians , American Medical Association , and Society for Academic Emergency Medicine

Allison J N Harriott, MD Resident Physician, Department of Emergency Medicine, State University of New York Downstate Medical Center

Allison J N Harriott, MD is a member of the following medical societies: American Academy of Emergency Medicine , American Medical Association , American Public Health Association , National Medical Association , Physicians for Human Rights , and Society for Academic Emergency Medicine

James Li, MD Former Assistant Professor, Division of Emergency Medicine, Harvard Medical School; Board of Directors, Remote Medicine

Laura Lyngby Mulloy, DO, FACP Professor of Medicine, Chief, Section of Nephrology, Hypertension, and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians and Society for Academic Emergency Medicine

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Efficacy and safety of hematopoietic stem cell transplantation for hematologic malignancies

A protocol for an overview of systematic reviews and meta-analyses.

Ji, Cong-hua MD a,b,∗ ; Dai, Rong-chen MM a ; Wu, Han-ting MM a ; Li, Qiu-shuang MD b ; Liu, Shan MM b ; He, Pei-jie MM a ; Liang, Juan MM a

a School of public health

b The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China.

∗Correspondence: Cong-hua Ji, Zhejiang Chinese Medical University, Hangzhou, China (e-mail: [email protected] ).

Abbreviations: AMSTAR-2 = Assessment of Multiple Systematic Reviews-2, GRADE = Grading of Recommendations, Assessment, Development, and Evaluation, HMs = hematologic malignancies, MAs = Meta-analysis, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RCTs = randomized controlled trials, SRs = systematic reviews.

How to cite this article: Ji Ch, Dai Rc, Wu Ht, Li Qs, Liu S, He Pj, Liang J. Efficacy and safety of hematopoietic stem cell transplantation for hematologic malignancies: a protocol for an overview of systematic reviews and meta-analyses. Med Case Rep Study Protoc . 2021;2:12(e0174).

Ethics approval are not required as no private information from individuals is collected. The results will be published in a peer-reviewed journal or disseminated in relevant conferences.

This work was supported by the Health Commission of Zhejiang Province (No.2017KY502), and the Administration of Traditional Chinese Medicine of Zhejiang Province (NO.2017ZZ007), the People's Republic of China.

The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Introduction: 

Hematopoietic stem cell transplantation is an essential and often the sole treatment strategy for relapsed and refractory hematologic malignancies (HMs). More and more systematic reviews and meta-analysis of clinical trials have investigated the effects of hematopoietic stem cell transplantation in patients with HMs. In order to systematically appraise and synthesize these results, we will conduct an overview of systematic review and meta-analysis.

Methods: 

This is a protocol for an overview of systematic reviews and meta-analysis. We will search eight databases: PubMed, Embase, Cochrane Library, Web of Science Core Collection, China Biology Medicine disc, Chinese National Knowledge Infrastructure, Chinese Scientific Journals Database and Wan Fang Data. The time is limited from the construction of the library to May 2021.Systematic reviews and meta-analysis of clinical trials evaluating the efficacy and safety of hematopoietic stem cells in patients with HMs will be included. Hematopoietic stem cells included bone marrow, peripheral blood stem cells and cord blood stem cells. Patients with HMs including leukemia, malignant lymphoma, myelodysplastic syndrome, etc. Two independent authors will screen titles and abstracts retrieved in the literature search and select studies meeting the eligibility criteria for full text review. The methodological quality of the included reviews will be assessed using A Measurement Tool to Assess Systematic Reviews-2. The efficacy and safety of different stem cell types in the treatment of the same hematological disease and the same stem cell type in the treatment of different HMs will be analyzed. Additionally, the quality of evidence will use the Grading of Recommendations Assessment, Development and Evaluation system. Our reviewers will conduct systematic reviews, qualification evaluation, data extraction, methodological quality and evidence quality screening in pairs.

Results: 

The results will be published in a peer-reviewed journal.

Conclusion: 

This overview will provide comprehensive evidence for hematopoietic stem cell transplantation in patients with HMs.

Protocol Registration: 

INPLASY202150064.

1 Introduction

Hematopoietic stem cell transplantation is an essential and often the sole treatment strategy for relapsed and refractory hematologic malignancies (HMs), [1] and it is also an important method for aplastic anemia. [2] In addition, it can also be used for some genetic diseases, congenital diseases and metabolic diseases, [3,4] such as multiple sclerosis (MS) and neuromyelitis optical spectrum disorders. [3] Hematological malignancies are a diverse group of cancers that are associated with substantial incidence and mortality in all regions of the world. Non-Hodgkin lymphoma, chronic lymphoid leukemia, acute myeloid leukemia, acute lymphoid leukemia, multiple myeloma, Hodgkin lymphoma, and chronic myeloid leukemia ranked 8th, 21st, 22nd, 25th, 26th, 28th, and 30th, respectively in the Global Burden of Cancer report. [5] Hematopoietic stem cell transplantation can improve the overall survival and relax free survival of patients to a certain extent, [6] but there are also many adverse reactions. Adverse events after hematopoietic cell transplantation include the immune reaction called graft-versus-host disease; bacterial, viral, and fungal infections; hepatic sinusoidal obstruction syndrome [7] ; and Venous thromboembolism, [8] etc.

Hematopoietic stem cells usually included bone marrow, [1,9–13] peripheral blood stem cells [1,11,14] and cord blood stem cells. [9,15–17] According the HLA matching results of donors and recipients (patients), hematopoietic stem cell transplantation was divided into two groups: Homologous hematopoietic stem cell transplantation [8,14,15,18–20] and allogeneic hematopoietic stem cell transplantation. [1,6,14,18,19] Many studies have been carried out. Different hematopoietic stem cells are used in different diseases, and their effectiveness and safety are different. There are also differences in adults and children. Different hematopoietic stem cells are used in different diseases, and their effectiveness and safety are different. There are also differences in adults and children.

Multiple systematic reviews (SRs) and meta-analysis (MAs) have already been conducted to evaluate the efficacy and safety of hematopoietic stem cell transplantation in the treatment of HMs, and as early as 1993, there was a meta-analysis of stem cell transplantation. [21] High-quality randomized control trials (RCTs) studies can provide strong evidence to guide the treatment of hematopoietic stem cell. Overview of SRs and MAs can provide a compile evidence and synthesize the results of multiple SRs and MAs. However, there is still a lack of critically designed overview of SRs and MAs of hematopoietic stem cell for HMs. Therefore, the objectives of this study are as follows: evaluate the methodological quality, report quality and evidence quality and the risk of bias of available SRs and MAs using Assessment of Multiple Systematic Reviews-2 (AMSTAR-2), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), and ROBIS; summarize the evidence for the efficacy and safety of hematopoietic stem cell transplantation in the treatment of HMs; provide more reliable, evidence-based medical references for clinical practitioners and researchers.

2.1 Study registration

This protocol was designed in accordance with the methodological guidelines for overviews provided by the Cochrane Handbook for Systematic Reviews of Interventions. [22] This protocol has been registered at INPLASY202150064 ( https://inplasy.com/inplasy-2021–5–0064/ ). Any changes will be described in our full review.

2.2 Eligibility criteria for study selection

Population, Intervention, Comparison, Outcome and Study (PICOS) strategy will be employed.

2.2.1 Types of studies

SRs and MAs of RCTs which evaluated the efficacy and safety of hematopoietic stem cell transplantation in the treatment of HMs, published in English and Chinese.

2.2.2 Types of participants

Participants who meet the diagnostic criteria of HMs, Including all kinds of leukemia, malignant lymphoma, myelodysplastic syndrome, etc. There are no restrictions on age, sex, or race of participants.

2.2.3 Type of interventions

The sources of hematopoietic stem cells include bone marrow, peripheral blood or umbilical cord blood of blood and non-blood donors, and blood donors include HLA identical or haplotype identical.

2.2.4 Type of comparator (s)/control

The control group's treatment includes conventional drugs or no treatment which are considered as comparators in SRs and MAs.

2.2.5 Types of outcome measurements

The primary endpoints are overall survival and relapse-free survival at 6 months, 1 year, 2 years and 3 years, measured from the time of hematopoietic stem cell transplantation. The secondary endpoints are the cumulative incidence of relapse and non-relapse mortality. The safety indexes are mainly the incidence of graft versus host disease and infection.

2.2.6 Study design

SRs and MAs that contain more than one RCT will be included for further study.

2.2.7 Exclusion criteria

SRs and MAs without RCTs, reviews, and other overviews will be excluded; literatures published repeatedly by the same author or with duplicate data will be excluded; the quality evaluation of SR or methodological research literatures will be excluded; The full text of the literature is not available will be excluded.

2.3 Search methods for identification of studies

We will retrieve eight electronic databases from their inception to May 31, 2021, which include four English databases: PubMed, Cochrane Library, Excerpt Medical Database (Embase), Web of science, and four Chinese databases: China Biology Medicine disc, VIP database, Wan Fang database, China National Knowledge Infrastructure. The language will be restricted to English and Chinese. References of the included literatures and PROSPERO database will be also screened to supplement the potential eligible SRs and MAs. The proposed search strategy for PubMed is presented in Table 1 .

2.4 Studies selection

Two independent reviewers (PH and QL) will screen the included databases for related studies. The eligible articles will be imported into Endnote X9 and duplicate articles will be identified and deleted. Then two reviewers will review full text independently to determine the inclusion of SRs and MAs. Any discrepancies will be solved by introducing a third researcher (CJ) for judgment. If the study has incomplete information, PH will try to contact the corresponding author of the study for full research details. Study selection will be performed in accordance with the PRISMA flowchart ( Fig. 1 ).

2.5 Data extraction

Two reviewers (PH and QL) will independently extract the following information from each included study: first author, year, country, number of RCTs enrolled, quality assessment tool for RCTs included in SRs and MAs, Stem cell types, comparisons, name of disease, outcome measures (primary, secondary and safety outcomes), data synthesis methods, main results, and conclusions. Any disagreement will also be solved by introducing a third researcher (CJ) for judgment.

2.6 Evaluate the methodological quality of included studies

Two reviewers (QL and SL) will evaluate the methodological quality of included studies independently, using AMSTAR-2, which is an update of AMSTAR. [23] AMSTAR-2 is a critical appraisal tool for SRs that include randomized or nonrandomized studies and become used commonly to assess the quality of SRs and MAs included in overviews. [24] AMSTAR-2 includes 16 items, with each of the 16 criteria given a rating of “yes” (definitely done), “no” (definitely not done), “can’t report” (unclear if completed), or “not applicable” based on information provided by the SRs. Reviewers will evaluate the methodological quality of the study when the criterion is met. Any disagreement will be solved by the third researcher (CJ) for judgment.

2.7 Evaluation of the reporting quality of the included studies

PRISMA will be applied to assess report quality of SRs and MAs. Two authors (QL and SL) will evaluate the reports’ quality of each study using PRISMA, which contains 27 item list. Each checklist item will be evaluated as yes, no, or partially Yes to indicate compliance. [25] Any disagreement will be solved by the third researcher (CJ) for judgment.

2.8 Evaluation of the evidence quality of the included studies

The evaluation of the evidence quality of the included studies will be conducted by two reviewers (PH and CD), using the GRADE approach. GRADE specifies four categories: high, moderate, low, and very low. [26] Two reviewers will evaluate the evidence quality of the outcomes of the included SRs and MAs independently, and describe the downgraded or upgraded factors that may affect the evidence quality to guarantee the reliability and transparency of results. If there are any disagreements, they will be solved by introducing a third researcher (CJ) for judgment.

2.9 Evaluation of the risk of bias of the included studies

Two authors of this review (PH and CD) will assess the risk of bias of the included studies, using ROBIS tool. [27] The ROBIS is a tool to assess the risk of bias of SRs, which involves assessment of four domains: study eligibility criteria; identification and selection of studies; data collection and study appraisal; and synthesis and findings. The evaluation of the risk of bias is associated with each domain which will be judged as “low risk”, “high risk” or “unclear risk”. Any disagreement will be solved by the third researcher (CJ) for judgment.

2.10 Dealing with lost data

If no specific or insufficient data exists in the included SRs and MAs, the author will contact the original author of the article by email or telephone to get the necessary information. Insufficient data will be discarded if we fail to obtain enough data. The analysis will be conducted based on available data, and the potential impact of missing data will be discussed.

2.11 Synthesis of data

This overview will analyze SRs and MAs for hematopoietic stem cell transplantation. General characteristics of the included studies include the total sample size of SRs and MAs, interventions, name of disease and their effect size and related 95% CIs. Data from individual studies are likely to be pooled multiple times across the reviews included in our overview. As a result, we will not conduct a meta-analysis of results; rather, we will present a narrative synthesis of the findings from the included meta-analyses reviewed. AMSTAR-2 will be used for the SRs and MRs methodological quality assessment, PRISMA will be applied to assess report quality, and GRADE for the quality of evidence and ROBIS for the bias, which will be conducted in tabular form for each review. The quality of evidence will be detailed in the form of tables. We will combine the reviews in a narrative summary, structured around the type and content of interventions and the reported results. Efficacy and safety of hematopoietic stem cell transplantation in the treatment of HMs will be assessed at SRs and MAs level. We will extract pooled relative risk (RR) or pooled odds ratio (OR) for dichotomous outcomes, and pooled weighted mean difference or standardized mean difference for continuous outcomes which will be also reported with 95% confidence interval (CI) and will be presented graphically using a forest plot. The I 2 values will be described for reporting heterogeneity across RCTs, with 0% to 25% representing low heterogeneity, 26% to 50% representing medium heterogeneity, and above 50% representing high heterogeneity. [28] We will report the findings of our study according to the Preferred Reporting Items for Overviews of SRs Checklist. [25]

2.12 Subgroup analysis

We will also investigate the sources of heterogeneity to determine the robustness and reliability of the consolidated results. If possible, we will do some extra subgroup analyses according to the results of heterogeneity and inconsistency (such as age, Source of transplantation, race, and etc.).

3 Discussion

Stem cell transplantation is an advanced medical technology, which brings hope for the treatment of some difficult and miscellaneous diseases. The process of transplantation includes transplanting stem cells into the body, differentiating into functional parenchymal cells, replacing the cells damaged by degeneration, injury, gene defect or autoimmunity, and reconstructing the structure and function of tissues and organs, which is the development and improvement of organ transplantation. Through this study, we hope to answer which HMs is best treated by bone marrow transplantation, peripheral blood stem cell transplantation or cord blood stem cell transplantation; similarly, we also hope to answer which transplantation method is most effective for leukemia, malignant lymphoma and other HMs; and whether there is any difference between children and adults.

This overview will be the first summary of existing SRs and meta-analysis. We will incorporate all other relevant potential considerations besides the findings of the included SRs when drawing conclusions about implications for practice and research. The conclusions will be based on types of interventions and finding of the included reviews. Hematopoietic stem cell resources are precious. This overview, therefore, will help healthcare policymakers to implement the most effective interventions to treat malignant blood diseases, and for researchers to design high-quality studies of the available evidence-based interventions. The study also has some defects as follows: low quality of original researches, the possible occurrence of various duration of disease, language restriction, etc. All of these will lead to some bias and influence the results of evaluation results, ultimately affecting this study's reliability.

Author contributions

Conceptualization: Conghua Ji.

Data curation: Rong-chen Dai, Han-ting Wu, Pei-jie He, Juan Liang.

Formal analysis: Han-ting Wu.

Funding acquisition: Conghua Ji, Han-ting Wu.

Investigation: Qiu-shuang Li.

Methodology: Conghua Ji, Qiu-shuang Li, Shan Liu.

Project administration: conghua ji.

Resources: Qiu-shuang Li, Shan Liu, Juan Liang.

Software: Rong-chen Dai, Shan Liu, Juan Liang.

Visualization: Shan Liu.

Writing – original draft: Conghua Ji, Pei-jie He.

Writing – review & editing: Conghua Ji.

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Article Contents

I ntroduction, pbsc m obilization, pbsc c ollection, t umor c ontrol, t umor c ontamination, c ost -e ffectiveness, f uture d evelopments, c onclusion, a cknowledgment, r eferences.

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Peripheral Blood Stem Cells: Transplantation and Beyond

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Albert K.W. Lie, L. Bik To, Peripheral Blood Stem Cells: Transplantation and Beyond, The Oncologist , Volume 2, Issue 1, February 1997, Pages 40–49, https://doi.org/10.1634/theoncologist.2-1-40

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Peripheral blood stem cells are rapidly becoming a major source of hemopoietic stem cells for transplantation in patients with various hematological and oncological conditions. Clinical results of peripheral blood stem cell transplantation (PBSCT) have shown benefits of earlier hemopoietic recovery, lower morbidity, and greater cost-effectiveness compared with conventional bone marrow transplant. Moreover, the relative ease of obtaining large amounts of stem cells has made multicycle transplantation a viable option in the treatment of malignancies, allowing further escalation of chemotherapy dose intensity. The extension of PBSCT into the use of allogeneic and cord blood cells so far has been met with encouraging results, and the latter holds promise to increasing donor availability to patients requiring transplantation. Developments in cytokine research and ex vivo manipulation of hemopoietic stem cells are enabling new approaches to anticancer treatment involving tumor purging, immunomodulation, ex vivo expansion of stem cells and gene therapy. PBSCT may also become a therapeutic option in certain nonmalignant diseases. This review will discuss the current clinical practice and future developments in PBSCT.

Hemopoietic progenitor cells circulate in low number during steady-state hemopoiesis but do not seem to serve any particularly useful purpose outside the bone marrow milieu. However, it was demonstrated that such circulating progenitor cells could be administered to rescue irradiated mice with marrow failure [ 1 ]. Even then, it was only natural to use bone marrow as a source of stem cells in the clinical setting because there are more progenitor cells, and presumably stem cells, in 200 ml of marrow than in the 5 liters of circulating blood in a human [ 2 , 3 ]. Not surprisingly, early attempts at peripheral blood stem cell transplant (PBSCT) using steady-state peripheral blood in humans had met with discouraging results due to the lower number of progenitor cells infused [ 4 , 5 ].

The important breakthrough was the discovery that the number of circulating progenitor cells dramatically increased under various conditions, especially during the recovery from cytopenic phase following chemotherapy [ 6 – 9 ]. This process of mobilization of progenitor cells into circulation made PBSCT more feasible. However, doubts remained as to the self-renewing quality of such cells [ 10 ]. Laboratory and clinical data have since provided evidence that primitive progenitor cells were indeed harvested from peripheral blood, and durable hematopoietic reconstitution after PBSCT has been reported. [ 11 – 13 ].

In recent years, there has been an increase in PBSCT performed for malignant conditions, both hematological and solid tumors. The number of PBSCTs has rapidly surpassed the number of bone marrow transplants (BMTs) performed in the autologous setting and PBSCT is also increasingly applied in the allogeneic setting [ 14 ]. The main interest in PBSCT is in its increased safety.

Early hemopoietic reconstitution with enhanced granulocyte and platelet recovery reduces the risks of infection and hemorrhage. This is reflected in shortened hospital stay, less use of antibiotics, and lower transfusion requirements, especially with platelet concentrates in PBSCT as compared with BMT [ 15 – 17 ]. A wider margin of safety also allows exploration of higher doses of chemotherapy, especially in solid tumors, which in the past was partly limited by hematological toxicity. Accumulating data also suggest an earlier reconstitution of the immune system with PBSCT which may translate into lower risk of late post-transplant infection [ 18 – 20 ].

As with autologous PBSCT, early data on the use of allogeneic sources of blood stem cells, including cord blood, for transplantation are providing encouraging results. Together with technology to process the collected cells ex vivo, PBSCT is offering new therapeutic options for malignant as well as nonmalignant diseases. The current clinical practice and future developments of PBSCT are reviewed in this article.

The higher number of progenitor cells in mobilized compared with steady-state peripheral blood enables sufficient cell harvest with fewer apheresis sessions. Furthermore, the benefits of enhanced hemopoietic recovery in PBSCT are only seen using mobilized but not steady-state collection [ 21 , 22 ]. Clinically, mobilization regimes consist of chemotherapy or hemopoietic growth factors (HGFs) or both.

Myelosuppressive Chemotherapy Alone

During recovery from the cytopenic phase after myelosuppressive chemotherapy, there is a 50-fold or more increase of granulocyte-macrophage colony-forming units (CFU-GM) in peripheral blood [ 12 , 23 , 24 ]. This phenomenon was the first employed clinically to collect mobilized PBSCs. Various chemotherapeutic agents have been used either singly or in combination to achieve an adequate harvest. Cyclophosphamide is the most common drug used as a single agent. The yield of stem cells has been shown to be dose-dependent on the chemotherapeutic regime [ 25 – 27 ].

Myelosuppressive chemotherapy mobilization has the additional effect of tumor bulk reduction before the PBSCT proper. The main drawbacks are neutropenic infection, severe thrombocytopenia, and organ-specific toxicity such as hemorrhagic cystitis [ 25 , 26 , 28 ]. The timing for hematological recovery, hence the apheresis schedule, is also much less predictable than mobilization regimes including HGF. With the introduction of various HGFs for clinical use, chemotherapy alone is rapidly falling out of favor as the method of choice.

Myelosuppressive Chemotherapy Plus HGFs

The use of HGFs, most commonly G-CSF or GM-CSF, following myelosuppressive chemotherapy has several advantages. The duration of cytopenia is shortened, reducing the associated risks and hospital stay [ 15 , 29 ]. Scheduling of apheresis is also more predictable. Furthermore, both G-CSF and GM-CSF enhance PBSC yield following chemotherapy mobilization [ 16 , 30 , 31 ]. This suggests that adequate mobilization may be attained at a lower dose of chemotherapy with a further reduction of toxicity. Alternatively, fewer apheresis sessions will be required or a larger number of stem cells can be collected for repeated cycles of treatment.

The dose of G-CSF used in combination with chemotherapy is between 3 and 6 mg/kg/d. Schwartzberg reported the largest series of 382 patients where the addition of G-CSF doubled the mononuclear cell yield with a four- to sixfold rise in CD34 + cell yield compared with chemotherapy alone [ 29 ]. GM-CSF is usually administered at 5 mg/kg/d or 250 mg/m 2 /d following chemotherapy. Higher doses are rarely used because of associated side effects. Interleukin 3 (IL-3) [ 32 ] and the hybrid molecule of GM-CSF and IL-3, PIXY321 [ 33 , 34 ], have also been used in conjunction with chemotherapy to enhance mobilization.

Most of the combination regimes commence HGF the day following chemotherapy. It is noteworthy that in a recent study where G-CSF was started from day 5 after chemotherapy, an adequate yield of CD34 + cells was obtained [ 35 ]. In another study, GM-CSF was started on either day 1 or 5 postchemotherapy with sufficient progenitor cell yield in either situation [ 36 ]. This highlights the optimal dosages and scheduling of combined chemotherapy, and HGF mobilization regimes are yet to be defined.

Using HGF alone in mobilization has the obvious advantage of avoiding the cytotoxic side effects for the patient as well as on the collected PBSCs. It would also be a suitable method for harvesting PBSCs from normal healthy donors in the appropriate setting. The time of rise in PBSCs is very predictable, in particular with G-CSF. In general, side effects are few and easily controlled.

G-CSF is the HGF most commonly used alone for mobilization. There is a dose-dependent response with G-CSF mobilization up to 10-16 μg/kg/d, beyond which further enhancement is not seen. Circulating CFU-GM increase 40 to 80 times above the steady-state level after four to five days [ 16 , 37 ]. Bone pain, myalgia, headache and a rise in serum alkaline phosphatase level are common side effects. Symptoms are usually mild, readily controlled with analgesics, and subside with termination of G-CSF administration. There is some concern about the possible long-term adverse effect of G-CSF on normal PBSC donors, such as its potential for inducing leukemia. A study on three normal donors who received short courses of G-CSF for mobilization with five years of follow-up did not reveal any hematological or cytogenetic abnormality [ 38 ]. Considering that bone marrow harvest in itself is not free from risk, HGF mobilization in normal donors is a reasonable and acceptable option.

GM-CSF used alone also increases circulating CFU-GM by a median of 18-fold in an earlier study [ 39 ]. A more recent report by Peters et al . [ 40 ] comparing the use of GM-CSF and G-CSF in mobilization suggested a lower overall efficacy with GM-CSF. IL-3 itself has little mobilizing activity [ 41 ], and PIXY321 gives a three- to sixfold increase in CFU-GM and CD34 + cells [ 42 ].

Stem cell factor (SCF) caused a 10- to 1,000-fold increase in CD34 + cells, CFU-GM and BFU-E in baboons [ 43 ]. Results in humans so far indicate that together with G-CSF, SCF enhances mobilization and, depending on the dose scheduling, the yield of CFU-GM was reported to be 70% to 250% higher than with G-CSF alone [ 44 , 45 ].

In a murine study, Brasel reported an 83-fold increase of circulating CFU-GM with Flt3 ligand only, a 2,193-fold increase when given with G-CSF, but minimal synergism with GM-CSF [ 46 ]. Other agents which have been studied in human or animal studies include erythropoietin [ 47 ], macrophage inflammatory protein-1α [ 48 ], IL-1 [ 49 ] and IL-8 [ 50 ], but none of these are in current clinical use. A comparison of the results of the described mobilization regimes is provided in Table 1 .

Comparison of mobilization regimes

PBSC collection is usually performed with a continuous-flow apheresis machine with acid-citrate-dextrose as anticoagulant. Heparin may be added, particularly when patients have high leucocyte counts. Problems common to all apheresis procedures, such as difficult vascular access, citrate toxicity and hypotension may arise. Hence, expertise in apheresis procedure is essential. In particular, thrombocytopenia may be a problem with repeated apheresis, especially when performed in the recovery phase of myelosuppression. Returning the platelet fraction of the harvest helps to alleviate this problem. Large-volume apheresis has been designed to maximize PBSC collection, achieving adequate yield in a single procedure, but patient tolerance and citrate toxicity may be a problem [ 51 ].

Timing of Collection and Monitoring of Cell Yield

With chemotherapy mobilization, collection usually begins when leucocyte count rises above 1 × 10 9 /l, especially when it is associated with a rapid rise in platelet count [ 52 ]. With combined chemotherapy and HGF regimes, most groups start when leucocyte count is between 2 - 5 × 10 9 /l [ 53 ] and others suggest commencing at a level above 10 × 10 9 /l [ 54 ]. Mobilization with G-CSF alone is usually harvested on days 5 to 7, and prolonging the schedule is of little advantage as the progenitor cell level falls despite continuation of G-CSF [ 16 , 55 ].

Total mononuclear cell yield is one of the parameters used to monitor cell yield. An arbitrary level of 3 × 10 8 /kg body weight (BW) has been used as the target end point [ 56 ]. Currently, CD34 + cell enumeration by immunofluorescence flow cytometry is more commonly performed to determine when to commence apheresis and to monitor cell yield. A minimum level of 20 - 40 × 10 6 /l is often used as the trigger level for starting apheresis. CFU-GM is the most commonly performed assay to assess the proliferative capacity of the yield. However, it cannot be used clinically to adjust the apheresis schedule because of the 14-day culture period needed to obtain a result.

Target and Thresholds

As the rate of hemopoietic reconstitution in PBSCT is correlated with the amount of progenitor cells infused, the target cell yield should be set at a point which ensures rapid and sustained engraftment [ 57 – 59 ]. A target set too low may result in slow engraftment and will thus compromise the desired benefits in safety and cost. Too high a target, on the other hand, would mean unnecessary patient discomfort with apheresis and extra cost in cell collection and storage. The target cell yield should, of course, be adjusted if multiple PBSCTs are contemplated.

There is a highly significant correlation between CFU-GM and CD34 + cells, and either assay may be used clinically. Earlier reports suggested a minimum threshold dose of 30 - 50 × 10 4 CFU-GM/kg BW [ 57 ]. More recent data, however, indicate that 15 - 20 × 10 4 CFU-GM/kg BW or 1 - 2 × 10 6 CD34 + cells/kg BW are acceptable minimum thresholds to enable rapid hemopoietic recovery [ 58 , 60 ]. In general, increasing the cell dose above the minimum threshold is associated with progressive improvement of recovery rate. However, above an upper threshold of 50 × 10 4 CFU-GM/kg BW or 5 - 8 × 10 6 CD34 + cells/kg BW, further enhancement of recovery does not seem to occur [ 61 ]. Indeed, an obligatory cytopenic phase of 7-10 days seems to be inevitable, even with large amounts of PBSC infusion or with post-PBSCT G-CSF administration [ 58 , 59 ].

Factors Affecting Cell Yield

The PBSC yield is dependent upon the mobilization regime administered. Higher dose of chemotherapy [ 25 – 27 ], addition of HGF to chemotherapy [ 16 , 27 , 30 – 34 ], and use of the appropriate combination of HGFs [ 32 , 44 , 45 ] enhance progenitor yield. With myelosuppressive chemotherapy mobilization, the severity of myelosuppression, reflected by platelet nadir and number of days with neutrophil count <0.5 × 10 9 /l, as well as the rate of leucocyte recovery, are positive features of higher yield [ 26 , 31 , 52 ].

Patient factors affecting yield include extent of bone marrow involvement by disease and amount of chemotherapy received prior to mobilization [ 53 ]. The latter factor should be taken into consideration to determine the timing of PBSC collection in the design of treatment plans for various diseases. A study by Dreger et al . [ 62 ] illustrated the adverse effects on cell yield and engraftment due to prior chemotherapy insult on stem cells.

The rapid hematological recovery with PBSCT allows higher doses of chemotherapy to be administered safely. Together with the relative ease of collecting large numbers of PBSCs, it is possible to further increase dose intensity by repeated high-dose therapy with PBSC support. The rationale for this strategy is to increase tumor kill according to Gompertzian kinetics and thereby improve tumor control and possibly cure rate.

Evidence in support is seen in a study by Bezwoda et al . [ 63 ]. Previously untreated patients with metastatic breast cancer were randomized to having either 6 to 8 courses of combination chemotherapy or double high-dose therapy with PBSC rescue. The latter group had significantly better response (53% versus 95%) and complete remission rates (4% versus 51%), as well as longer median duration of response (34 weeks versus 80 weeks) and of survival (45 weeks versus 90 weeks). Another study in myeloma patients with grade III disease by Durie-Salmon classification demonstrated significantly improved median survival in the group having high-dose therapy plus PBSC rescue than in the group receiving conventional combination chemotherapy [ 64 ].

The role of PBSCT for malignancies of earlier stages is yet to be defined. Basser et al . [ 65 ] reported the use of multiple cycles of PBSCT as adjuvant therapy for high-risk stage II and III breast cancer and demonstrated it to be feasible and safe. Long-term clinical outcomes comparing PBSCT with conventional chemotherapy will be awaited with great interest.

Detection of tumor contamination in stem cell harvest is most often by immunological methods or molecular markers with sensitivity levels between 10 −5 and 10 −6 . All these tests rely on the studied characteristics being present in tumor cells only. However, whether all cells expressing the markers are tumorogenic at all levels is a question which remains to be answered. The clonogenic assay reported by Ross et al . [ 66 ] to detect viable breast cancer cells perhaps sheds some light on this issue. Positive detection by the assay correlated with the immunocytochemical method.

Clinical studies in lymphoma and acute lymphoblastic leukemia indicate detectable residual tumor cells in harvested stem cells are associated with a higher risk of relapse [ 67 , 68 ]. Gene marking studies in acute myeloid leukemia, neuroblastoma, and chronic myeloid leukemia also demonstrated the significance of tumor contamination, confirming that infused cells do contribute to relapse after autologous bone marrow transplant [ 69 – 71 ].

PBSCT is not spared from this problem. Studies in breast cancer, lung cancer, acute myeloblastic leukemia, lymphoma, and myeloma indicated presence of tumor cells in mobilized PBSC [ 66 , 72 – 75 ]. Nevertheless, it is of interest to note that the degree of tumor contamination seems to be lower in PBSC than in bone-marrow harvest [ 76 , 77 ]. Moreover, the timing of tumor cell mobilization may be different from that of stem cell mobilization [ 72 , 78 ], in which case appropriate scheduling of apheresis may help to reduce contamination.

Ultimately, it would be ideal to be able to clear the harvest of all tumor cells. Various purging techniques, based on either negative or positive selection, take advantage of intrinsic differences between normal stem cells and tumor cells. It remains to be seen whether these differences are entirely reliable for making the separation, bearing in mind that tumor cells are known to be phenotypically heterogeneous.

As mentioned earlier, PBSCT is associated with less use of antibiotics, a lower transfusion requirement, and a shorter hospital stay. One would naturally expect PBSCT to be more cost-effective than autologous BMT. Indeed, this is confirmed in a retrospective cost-effectiveness analysis study where PBSCT was 21% less costly (US $29,000 versus US $36,800) than autologous BMT [ 79 ]. In our center, PBSCT costs 35% less.

More interesting is to consider PBSCT as a first-line treatment. Hénon et al . [ 64 ] studied Durie-Salmon grade III myeloma patients receiving high-dose therapy plus PBSC rescue (group I, n = 12), conventional combination chemotherapy (group II, n = 10), or conventional chemotherapy (group III, n = 15). The total global cost was higher in group I than in group II (US $56,700 versus US $46,555), but because of significantly better median survival in group I, the absolute cost-effectiveness (corrected for survival) was lower for every week of life gained in group I than in group II (US $350/week versus US $1,862/week). When corrected for quality-of-life assessment, costs for group I were only US $74/week extra compared with group II in qualitative cost-effectiveness. Group III patients had a lower quality-of-life index but not survival than group I. Absolute cost-effectiveness and qualitative cost-effectiveness were US $125/week less and US $966/week less, respectively, in group III than in group I.

Clearly, the cost-effectiveness issue is complex and intertwined with survival and quality of life. There is a great need for more similar studies to assess the overall impact of new forms of therapy on patients and the health system.

Allogeneic PBSCT

Allogeneic PBSCT was initially attempted in cases of graft failure requiring second infusion of stem cells and for donors unsuitable for general anesthesia [ 80 , 81 ]. Recently, allogeneic PBSCTs are being performed in greater number, and results of studies are appearing in the literature. G-CSF at a dose of 5-10 μg/kg/d for 4 to 5 days is most often employed [ 82 – 86 ]. A minimum threshold dose of 3 × 10 6 CD34 + cells/kg BW is in general associated with rapid engraftment. This target can often be reached with a single apheresis, which helps to improve acceptability by donors. Nevertheless, an occasional donor may fail mobilization, in which case marrow harvest is necessary.

From the European Group for Blood and Marrow Transplantation data on 59 patients, median times to neutrophil count >0.5 × 10 9 /l and platelet count >20 × 10 9 /l were 15 and 16 days, respectively [ 87 ]. A study by Schmitz et al . [ 83 ] suggested that the inclusion of methotrexate in graft-versus-host disease (GVHD) prophylaxis delayed engraftment compared with using cyclosporine alone.

Allogeneic PBSC harvest has a larger number of T cells than bone marrow (1-5 × 10 8 /kg versus < 0.5 × 10 8 /kg). The initial concern was a greater risk of GVHD from the larger T cell yield. Nevertheless, several reports so far indicated that the incidence of severe GVHD was not increased and that the severity of GVHD did not correlate with the number of T cells infused [ 81 , 82 , 87 , 88 ]. On the other hand, T cell depletion by CD34 + selection has been attempted to reduce the risk of GVHD.

As mentioned before, data suggested an earlier immune reconstitution with PBSCT compared with BMT [ 18 – 20 , 89 ]. Whether this will be translated into clinical benefits of reduced post-transplant infection and, perhaps, improved graft-versus-leukemia effect and survival remains to be studied.

Cord-Blood Transplant (CBT)

High levels of stem and progenitor cells with high renewable and proliferative capacities are present in cord blood. This normal physiological state of cord blood provides a unique opportunity to collect PBSCs, which otherwise would be wasted, in quantity sufficient for transplantation.

The first CBT was reported in 1989 by Gluckman et al . in a child with Fanconi's anemia using HLA-identical sibling cord blood [ 90 ]. Initial reports of HLA-matched and -mismatched sibling CBTs showed a lower incidence of GVHD, which seems to hold true for unrelated CBTs as well [ 91 – 93 ]. Incidence of primary graft failure was also low despite mismatch. Most CBTs have been performed in the pediatric population, but data on adults receiving unrelated CBTs are appearing, supporting the feasibility of this procedure in adults [ 94 ]. The full potential of CBT is yet to be explored, and interested readers are referred to an article by Broxmeyer [ 95 ].

Ex Vivo Manipulation of PBSC

Efforts to process blood or marrow cells in vitro with the aim of achieving therapeutic goals have been an ongoing quest. PBSC mobilization has provided a means of obtaining stem cells in large quantities with relative ease, compensating for the cell loss during these ex vivo manipulations. Areas of oncological interest are tumor purging, immunomodulation, expansion of hemopoietic cells, and gene therapy.

Attempts to kill or remove tumor cells include the use of chemicals, immunotoxins, and immunomagnetic separation, which rely on the expression of certain tumor markers [ 96 – 98 ]. The shortcomings of these methods are nonspecific toxicity to normal stem cells and possible nonexpression of the targeted marker by a subpopulation of tumor cells. CD34 + selection by the immunomagnetic method offers a nontoxic way of purging tumor cells that do not express the CD34 antigen. In a study by Schiller et al . [ 99 ] in advanced multiple myeloma, CD34 + selection gave a 2.7-4.5 log tumor depletion on PBSC harvest while maintaining the median time to both neutrophil and platelet recovery (>0.5 × 10 9 /l and >20 × 10 9 /l, respectively) at 12 days.

CD34 + selection has also been applied to allogeneic PBSCT in an attempt to reduce GVHD [ 100 – 102 ]. A two- to four-log depletion of T cells can be achieved. Early results from Bensinger et al . [ 101 ] and Link et al . [ 102 ] confirmed rapid engraftment and no primary graft failure. However, incidence of GVHD remained significant. Immunomodulation may also be possible to potentiate antitumor activity by utilizing the larger quantities of T and NK cells in a PBSC harvest [ 100 ].

The availability of various HGFs has made it possible to expand progenitor cells ex vivo [ 103 ]. With new cytokines being identified, the optimal combination of agents has yet to be defined. The practicality and safety of such an approach on cryopreserved PBSCs have been demonstrated clinically by Alcorn et al . [ 104 ]. Ex vivo expansion will be useful in situations of small initial harvest, multiple cycles of PBSCT and possibly abrogation of the obligatory cytopenic phase.

Gene therapy offers novel approaches to cancer therapy. One approach in a murine model was to insert the multiple drug-resistant gene ( MDR -1) into hemopoietic cells to reduce chemotoxicity and allow administration of higher doses of chemotherapy [ 105 ]. Tumor cell eradication may also be enhanced by genetic modification of chemosensitivity and immunomodulation [ 106 , 107 ].

PBSCT and Non-Malignant Diseases

Enriched CD34 + cells are a suitable source of stem cells for carrying out gene therapy in certain nonmalignant conditions. Diseases of single-gene defects in hemopoietic cells, such as adenosine deaminase deficiency, chronic granulomatous disease, and Gaucher disease would be possible candidates.

PBSCT also holds promise for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and other autoimmune diseases. In PNH, hemopoietic cells show impaired surface expression of phosphatidylinositol-linked proteins such as decay-accelerating factor (DAF) and membrane inhibitor of reactive lysis (CD59). Prince et al . [ 108 ] reported relative enrichment of DAF + CD59 + cells in the CD34 + CD38 − fraction of G-CSF- or GM-CSF-mobilized blood, suggesting a possible source of unaffected stem cells for autologous transplantation.

Multiple sclerosis is a disease which can lead to severe, intractable neurological disabilities. Therapy has included severe immunosuppression by total nodal irradiation, antilymphocyte globulin, and high-dose cyclophosphamide with some success. It has been suggested that complete lymphoid and myeloid ablation with subsequent recapitulation of immune ontogeny by marrow rescue may correct the autoimmune process [ 109 ]. Anecdotal reports also exist in the literature where autoimmune diseases such as psoriasis, ulcerative colitis, and rheumatoid arthritis went into long-term remission after BMT for coincidental hematological diseases [ 110 , 111 ]. Indeed, for aplastic anemia, which has an autoimmune basis in etiology, high-dose immunosuppression with or without stem cell rescue is an established therapeutic approach.

PBSCT is a relatively safe and cost-effective form of treatment which enables further chemotherapy dose escalation in anticancer therapy. Mobilization is now most commonly using chemotherapy plus G-CSF or GM-CSF or, alternatively, with G-CSF alone. A minimum threshold of 15-20 × 10 4 CFU-GM/kg BW or 1-2 × 10 6 CD34 + cells/kg BW enables rapid hemopoietic reconstitution in autologous PBSCT. A higher threshold of 3 × 10 6 CD34 + cells/kg BW is recommended in the allogeneic setting. The timing of PBSC collection should be taken into consideration in the overall treatment strategy to avoid excessive exposure to marrow toxic agents. Various tumor purging techniques are being studied to overcome the problem of tumor contamination in the harvest.

Together with developments in cytokine research, ex vivo processing, and gene therapy, PBSCT using autologous or allogeneic stem cells is offering new dimensions to the treatment of both malignant and nonmalignant diseases. Efforts to determine the mechanism of mobilization and to define the functional and proliferative capacities of different subpopulations of harvested cells may help to improve yield and engraftment kinetics. Standardization of stem cell measurement ensures the quality of infused product and enables proper comparison among studies. Finally, carefully designed clinical trials to compare PBSCT and present standard therapy are necessary to define the therapeutic role of PBSCT.

This article is adapted from a presentation given at the International Society of Hematology meeting held in Singapore, August 1996.

JW   Goodman , GS   Hodgson . Evidence for stem cells in the peripheral blood of mice . Blood   1962 ; 19 : 702 – 714 .

Google Scholar

A   Kessinger , JO   Armitage . Harvesting marrow for autologous transplantation from patients with malignancies . Bone Marrow Transplant   1987 ; 2 : 15 – 18 .

A   Kessinger , JO   Armitage , JD   Landmark et al. Autologous peripheral hematopoietic stem cell transplantation restores hematopoietic function following marrow ablative therapy . Blood   1988 ; 71 : 723 – 727 .

C   Hershko , RP   Gale , WG   Ho et al. Cure of aplastic anaemia in paroxysmal nocturnal haemoglobinuria by marrow transfusion from identical twin: failure of peripheral-leucocyte transfusion to correct marrow aplasia . Lancet   1979 ; I : 945 – 947 .

RA   Abrams , D   Glaubiger , FR   Appelbaum et al. Result of attempted hematopoietic reconstitution using isologous, peripheral blood mononuclear cells: a case report . Blood   1980 ; 56 : 516 – 520 .

PA   Chervenick . Increase in circulating stem cells in patients with myelofibrosis . Blood   1973 ; 41 : 67 – 71 .

CM   Richman , RS   Weiner , RA   Yankee . Increase in circulating stem cells following chemotherapy in man . Blood   1976 ; 47 : 1031 – 1039 .

MJ   Cline , DW   Golde . Mobilization of hematopoietic stem cells (CFU-C) into the peripheral blood of man by endotoxin . Exp Hematol   1977 ; 5 : 186 – 190 .

AJ   Barrett , P   Longhurst , P   Sneath et al. Mobilization of CFU-C by exercise and CTH induced stress in man . Exp Hematol   1978 ; 6 : 590 – 594 .

HS   Micklem , N   Anderson , E   Ross . Limited potential of circulating haemopoietic stem cells . Nature   1975 ; 256 : 41 – 43 .

CA   Juttner , LB   To , DN   Haylock et al. Circulating autologous stem cells collected in very early remission from acute non-lymphoblastic leukaemia produce prompt but incomplete haemopoietic reconstitution after high dose melphalan or supralethal chemoradiotherapy . Br J Haematol   1985 ; 61 : 739 – 745 .

A   Kessinger , JO   Armitage , JD   Landmark et al. Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells . Exp Hematol   1986 ; 14 : 192 – 196 .

M   Körbling , B   Dorken , AD   Ho et al. Autologous transplantation of blood-derived hemopoietic stem cells after myeloablative therapy in a patient with Burkitt's lymphoma . Blood   1986 ; 67 : 529 – 532 .

A   Gratwohl , J   Hermans , H   Baldomero . Hemopoietic precursor cell transplants in Europe: activity in 1994. Report from the European Group for Blood and Marrow Transplatation (EBMT) . Bone Marrow Transplant   1996 ; 17 : 137 – 148 .

AD   Elias , L   Ayash , KC   Anderson et al. Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer . Blood   1992 ; 79 : 3036 – 3044 .

WP   Sheridan , CG   Begley , CA   Juttner et al. Effect of peripheral-blood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high dose chemotherapy . Lancet   1992 ; 339 : 640 – 644 .

LB   To , MM   Roberts , DN   Haylock et al. Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants . Bone Marrow Transplant   1992 ; 9 : 277 – 284 .

MM   Roberts , LB   To , D   Gillis et al. Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation . Bone Marrow Transplant   1993 ; 12 : 469 – 475 .

E   Ashihara , C   Shimazaki , N   Yamagata et al. Reconstitution of lymphocyte subsets after peripheral blood stem cell transplantation: two-color flow cytometric analysis . Bone Marrow Transplant   1994 ; 13 : 377 – 381 .

MC   Rosillo , F   Ortuno , JM   Moraleda et al. Immune recovery after autologous or rhG-CSF primed PBSC transplantation . Eur J Haematol   1996 ; 56 : 301 – 307 .

A   Kessinger , JO   Armitage , DM   Smith et al. High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma . Blood   1989 ; 74 : 1260 – 1265 .

LC   Lasky , DD   Hurd , JA   Smith et al. Peripheral blood stem cell collection and use in Hodgkin's disease. Comparison with marrow in autologous transplantation . Transfusion   1989 ; 29 : 323 – 327 .

LB   To , DN   Haylock , RJ   Kimber et al. High levels of circulating haemopoietic stem cells in very early remission from acute non-lymphoblastic leukaemia and their collection and cryopreservation . Br J Haematol   1984 ; 58 : 399 – 410 .

J   Reiffers , P   Bernard , B   David et al. Successful autologous transplantation with peripheral blood hemopoietic cells in a patient with acute leukaemia . Exp Hematol   1986 ; 14 : 312 – 315 .

D   Kotasek , KM   Shepherd , RE   Sage et al. Factors affecting blood stem cell collections following high-dose cyclophosphamide mobilization in lymphoma, myeloma and solid tumours . Bone Marrow Transplant   1992 ; 9 : 11 – 17 .

PA   Rowlings , JL   Bayly , CM   Rawling et al. A comparison of peripheral blood stem cell mobilisation after chemotherapy with cyclophosphamide as a single agent in doses of 4 g/m 2 or 7 g/m 2 in patients with advanced cancer . Aust N Z J Med   1992 ; 22 : 660 – 664 .

AK   Lie , TP   Rawling , JL   Bayly et al. Progenitor cell yield in sequential blood stem cell mobilization in the same patients: insights into chemotherapy dose escalation and combination of haemopoietic growth factor and chemotherapy . Br J Haematol   1996 ; 95 : 39 – 44 .

S   Jagannath , DH   Vesole , L   Glenn et al. Low risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support . Blood   1992 ; 80 : 1666 – 1672 .

LS   Schwartzberg , R   Birch , B   Hazelton et al. Peripheral blood stem cell mobilization by chemotherapy with and without recombinant human granulocyte colony-stimulating factor . J Hematother   1992 ; 1 : 317 – 327 .

AM   Gianni , M   Bregni , S   Siena et al. Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma . J Clin Oncol   1990 ; 8 : 768 – 778 .

LS.   Schwartzberg . Peripheral blood stem cell mobilization in the out-patient setting. In EW   Wunder , PR   Henon , eds. Peripheral Blood Stem Cell Autografts , Heidelberg : Springer-Verlag , 1993 , 177 – 184 .

Google Preview

W   Brugger , K   Bross , J   Frisch et al. Mobilization of peripheral blood progenitor cells by sequential administration of interleukin-3 and granulocyte-macrophage colony-stimulating factor following polychemotherapy with etoposide, ifosfamide and cisplatin . Blood   1992 ; 79 : 1193 – 1200 .

CN   Abboud , S   Reykdal , JL   Liesveld et al. Prospective randomized trial (NCI/T92-0010), comparing the efficacy of hematopoietic growth factors for mobilizing peripheral blood stem cells (PBSC) in autologous bone marrow transplantation. II. Progenitor mobilization kinetics . Blood   1995 ; 86 ( suppl 1 ): 463a .

JN   Winter , HM   Lazarus , AF   Rademaker et al. Comparison of PIXY321 and GM-CSF for mobilization of peripheral blood progenitor cells (PBPC) in advanced breast cancer . Blood   1995 ; 86 ( suppl 1 ): 578a .

A   Haynes , A   Hunter , G   McQuaker et al. Engraftment characteristics of peripheral blood stem cells mobilised with cyclophosphamide and the delayed addition of G-CSF . Bone Marrow Transplant   1995 ; 16 : 359 – 363 .

AM   Gianni , S   Siena , M   Bregni et al. Granulocyte-macrophage colony-stimulating factor to harvest circulating haemopoietic stem cells for autotransplantation . Lancet   1989 ; II : 580 – 585 .

E   DeLuca , WP   Sheridan , D   Watson et al. Prior chemotherapy does not prevent effective mobilisation by G-CSF of peripheral blood progenitor cells . Br J Cancer   1992 ; 66 : 893 – 899 .

S   Sakamaki , T   Matsunaga , Y   Hirayama et al. Haematological study of healthy volunteers 5 years after G-CSF . Lancet   1995 ; 346 : 1432 – 1433 .

MA   Socinski , SA   Cannistra , A   Elias et al. Granulocyte-macrophage colony stimulating factor expands the circulating haemopoietic progenitor cell compartment in man . Lancet   1988 ; I : 1194 – 1198 .

WP   Peters , G   Rosner , M   Ross et al. Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy . Blood   1993 ; 81 : 1709 – 1719 .

OG   Ottmann , A   Ganser , G   Seipelt et al. Effects of recombinant human interleukin-3 on human hematopoietic progenitor and precursor cells in vivo . Blood   1990 ; 76 : 1494 – 1502 .

S   Vadhan-Raj , HE   Broxmeyer , M   Andreeff et al. In vivo biologic effects of PIXY321, a synthetic hybrid protein of recombinant human granulocyte-macrophage colony-stimulating factor and interleukin-3 in cancer patients with normal hematopoiesis: a phase I study . Blood   1995 ; 86 : 2098 – 2105 .

RG   Andrews , GH   Knitter , SH   Bartelmez et al. Recombinant human stem cell factor, a c- kit ligand, stimulates hematopoiesis in primates . Blood   1991 ; 78 : 1975 – 1980 .

CG   Begley , R   Basser , R   Mansfield et al. Randomized prospective study demonstrating a prolonged effect of SCF with G-CSF (filgrastim) on PBPC in untreated patients: early results . Blood   1994 ; 84 ( suppl 1 ): 25a .

R   Basser , CG   Begley , R   Mansfield et al. Mobilization of PBPC by priming with stem cell factor (SCF) before filgrastim compared to concurrent administration . Blood   1995 ; 86 ( suppl 1 ): 687a .

K   Brasel , HJ   McKenna , K   Charrier et al. Synergistic effects in vivo of flt3 ligand with GM-CSF or G-CSF in mobilization of colony forming cells in mice . Blood   1995 ; 86 ( suppl 1 ): 499a .

R   Pettengell , PJ   Woll , J   Chang et al. Effects of erythropoietin on mobilisation of haemopoietic progenitor cells . Bone Marrow Transplant   1994 ; 14 : 125 – 130 .

BI   Lord , LB   Woolford , LM   Wood et al. Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein-1 alpha . Blood   1995 ; 85 : 3412 – 3415 .

WE   Fibbe , MS   Hamilton , LL   Laterveer et al. Sustained engraftment of mice transplanted with IL-1 primed blood-derived stem cells . J Immunol   1992 ; 148 : 417 – 421 .

L   Laterveer , IJ   Lindley , DP   Heemskerk et al. Rapid mobilization of hematopoietic progenitor cells in rhesus monkeys by a single intravenous injection of interleukin-8 . Blood   1996 ; 87 : 781 – 788 .

CD   Hillyer . Large volume leukapheresis to maximize peripheral blood stem cell collection . J Hematother   1993 ; 2 : 529 – 532 .

LB   To , DN   Haylock , D   Thorp et al. The optimisation of collection of peripheral blood stem cells for autotransplantation in acute myeloid leukaemia . Bone Marrow Transplant   1989 ; 4 : 41 – 47 .

R   Haas , R   Mohle , S   Fruhauf et al. Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma . Blood   1994 ; 83 : 3787 – 3794 .

M   Fukuda , S   Kojima , K   Matsumoto et al. Autotransplantation of peripheral blood stem cells mobilized by chemotherapy and recombinant human granulocyte colony-stimulating factor in childhood neuroblastoma and non-Hodgkin's lymphoma . Br J Haematol   1992 ; 80 : 327 – 331 .

W   Bensinger , J   Singer , F   Appelbaum et al. Autologous transplantation with peripheral blood mononuclear cells collected after administration of recombinant granulocyte colony stimulating factor . Blood   1993 ; 81 : 3158 – 3163 .

LB   To , KM   Shepperd , DN   Haylock et al. Single high doses of cyclophosphamide enable the collection of high numbers of hemopoietic stem cells from the peripheral blood . Exp Hematol   1990 ; 18 : 442 – 447 .

LB   To , PG   Dyson , CA   Juttner . Cell-dose effect in circulating stem-cell autografting . Lancet   1986 ; II : 404 – 405 .

JG   Bender , LB   To , S   Williams et al. Defining a therapeutic dose of peripheral blood stem cells . J Hematother   1992 ; 1 : 329 – 341 .

LB   To , MM   Roberts , CM   Rawling , et al. Establishment of a clinical threshold cell dose: correlation between CFU-GM and duration of aplasia. In E   Wunder , H   Sovalat , P   Hénon , et al., eds. Hematopoietic Stem Cells: The Mulhouse Manual , Dayton, OH : AlphaMed Press , 1994 , 15 – 20 .

J   Reiffers , C   Faberes , JM   Boiron et al. Peripheral blood progenitor cell transplantation in 118 patients with hematological malignancies: analysis of factors affecting the rate of engraftment . J Hematother   1994 ; 3 : 185 – 191 .

CH   Weaver , B   Hazelton , R   Birch et al. An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy . Blood   1995 ; 86 : 3961 – 3969 .

P   Dreger , M   Kloss , B   Peterson et al. Autologous progenitor cell transplantation: prior exposure to stem cell-toxic drugs determines yield and engraftment of peripheral blood progenitor cell but not of bone marrow grafts . Blood   1995 ; 86 : 3970 – 3978 .

WR   Bezwoda , L   Seymour , RD   Dansey . High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial . J Clin Oncol   1995 ; 13 : 2483 – 2489 .

P   Hénon , B   Donatini , JC   Eisenmann et al. Comparative survival, quality of life and cost-effectiveness of intensive therapy with autologous blood cell transplantation or conventional chemotherapy in multiple myeloma . Bone Marrow Transplant   1995 ; 16 : 19 – 25 .

RL   Basser , LB   To , CG   Begley et al. Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells . Clin Cancer Research   1995 ; 1 : 715 – 721 .

AA   Ross , BW   Cooper , HM   Lazarus et al. Detection and viability of tumour cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques . Blood   1993 ; 82 : 2605 – 2610 .

JG   Gribben , AS   Freedman , D   Neuberg et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma . N Engl J Med   1991 ; 325 : 1525 – 1533 .

T   Seriu , S   Yokota , M   Nakao et al. Prospective monitoring of minimal residual disease during the course of chemotherapy in patients with acute lymphoblastic leukaemia, and detection of contaminating tumour cells in peripheral blood stem cells for autotransplantation . Leukemia   1995 ; 9 : 615 – 623 .

MK   Brenner , DR   Rill , RC   Moen et al. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation . Lancet   1993 ; 341 : 85 – 86 .

DR   Rill , VM   Santana , WM   Roberts et al. Direct demonstration that autologous bone marrow transplantation for solid tumours can return a multiplicity of tumorigenic cells . Blood   1994 ; 84 : 380 – 383 .

AB   Deisseroth , Z   Zu , D   Claxton et al. Genetic marking shows that Ph + cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML . Blood   1994 ; 83 : 3068 – 3076 .

W   Brugger , KJ   Bross , M   Glatt et al. Mobilization of tumour cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumours . Blood   1994 ; 83 : 636 – 640 .

WC   Chan , GQ   Wu , TC   Greiner et al. Detection of tumour contamination of peripheral stem cells in patients with lymphoma using cell culture and polymerase chain reaction technology . J Hematother   1994 ; 3 : 175 – 184 .

T   Miyamoto , K   Nagafuji , M   Harada et al. Quantitative analysis of AML1/ETO transcripts in peripheral blood stem cell harvest from patients with t(8;21) acute myelogenous leukaemia . Br J Haematol   1995 ; 91 : 132 – 138 .

F   Dreyfus , V   Ribrag , V   Leblond et al. Detection of malignant B cells in peripheral blood stem cell collections after chemotherapy in patients with multiple myeloma . Bone Marrow Transplant   1995 ; 15 : 707 – 711 .

JL   Passos-Coelho , AA   Ross , TJ   Moss et al. Absence of breast cancer cells in a single-day peripheral blood progenitor cell collection after priming with cyclophosphamide and granulocyte-macrophage colony-stimulating factor . Blood   1995 ; 85 : 1138 – 1143 .

JM   Henry , PJ   Sykes , MJ   Brisco et al. Comparison of myeloma cell contamination of bone marrow and peripheral blood stem cell harvests . Br J Haematol   1996 ; 92 : 614 – 619 .

Y   Gazitt , E   Tian , B   Barlogie et al. Differential mobilization of myeloma cells and normal hematopoietic stem cells in multiple myeloma after treatment with cyclophosphamide and granulocyte-macrophage colony-stimulating factor . Blood   1996 ; 87 : 805 – 811 .

PR.   Hénon . Autologous blood stem-cell versus bone marrow transplantation: comparison of cost-effectiveness and of clinical benefits. In D   Levitt , R   Mertelsmann , eds. Hematopoietic Stem Cells: Biology and Therapeutic Applications , New York : Marcel Dekker, Inc. , 1995 , 421 – 434 .

P   Dreger , M   Suttorp , T   Haferlach et al. Allogeneic granulocyte colony-stimulating factor mobilised peripheral blood progenitor cells for treatment of engraftment failure after bone marrow transplantation . Blood   1993 ; 81 : 1404 – 1407 .

JA   Russell , J   Luider , M   Weaver et al. Collection of progenitor cells for allogeneic transplantation from peripheral blood of normal donors . Bone Marrow Transplant   1995 ; 15 : 111 – 115 .

WI   Bensinger , CH   Weaver , FR   Appelbaum et al. Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor . Blood   1995 ; 85 : 1655 – 1658 .

N   Schmitz , P   Dreger , M   Suttorp et al. Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor) . Blood   1995 ; 85 : 1666 – 1672 .

M   Körbling , YO   Huh , A   Durett et al. Allogeneic blood stem cell transplantation: peripheralization and yield of donor-derived primitive hematopoietic progenitor cells (CD34 + Thy-1 dim ) and lymphoid subsets, and possible predictors of engraftment and graft-versus-host disease . Blood   1995 ; 86 : 2842 – 2848 .

AP   Grigg , AW   Roberts , H   Raunow et al. Optimizing dose and scheduling of filgrastim (granulocyte colony-stimulating factor) for mobilization and collection of peripheral blood progenitor cells in normal volunteers . Blood   1995 ; 86 : 4437 – 4445 .

M   Harada , K   Nagafuji , T   Fujisaki et al. G-CSF-induced mobilization of peripheral blood stem cells from healthy adults for allogeneic transplantation . J Hematother   1996 ; 5 : 63 – 71 .

N   Schmitz , A   Bacigalupo , M   Labopin et al. Transplantation of allogeneic peripheral blood progenitor cells—the EBMT experience . Bone Marrow Transplant   1996 ; 17 ( suppl 2 ): S40 –S46.

WM   Azevedo , FJ   Aranha , JV   Gouvea et al. Allogeneic transplantation with blood stem cells mobilized by rhG-CSF for hematological malignancies . Bone Marrow Transplant   1995 ; 16 : 647 – 653 .

HD   Ottinger , B   Scheulen , DW   Beelen et al. Immune reconstitution after allogeneic peripheral blood progenitor cell transplantation . Bone Marrow Transplant   1996 ; 17 ( suppl 2 ): S70 .

E   Gluckman , HE   Broxmeyer , AD   Auerbach et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling . N Engl J Med   1989 ; 321 : 1174 – 1178 .

J   Kurtzberg , M   Graham , J   Casey et al. The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation . Blood Cells   1994 ; 20 : 275 – 283 .

JE   Wagner , NA   Kernan , M   Steinbuch et al. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease . Lancet   1995 ; 346 : 214 – 219 .

J   Kurtzberg , M   Laughlin , ML   Graham et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients . N Engl J Med   1996 ; 335 : 157 – 166 .

JP   Laporte , NC   Gorin , P   Rubinstein et al. Cord-blood transplantation from an unrelated donor in an adult with chronic myelogenous leukemia . N Engl J Med   1996 ; 335 : 167 – 170 .

HE   Broxmeyer . Cord blood as an alternative source for stem and progenitor cell transplantation . Curr Opin Pediatr   1995 ; 7 : 47 – 55 .

SD.   Rowley . Pharmacological purging of malignant cells. In SJ   Forman , KG   Blume , ED   Thomas , eds. Bone Marrow Transplantation , Boston : Blackwell Scientific Publications , 1994 , 164 – 178 .

ML   Grossbard , LM.   Nadler . Immunotoxin therapy of malignancy. In VT   DeVita , S   Hellman , SA   Rosenberg , eds. Important Advances in Oncology , Philadelphia : JB Lippincott , 1992 , 111 – 135 .

JG   Gribben , L   Saporito , M   Barber et al. Bone marrows of non-Hodgkin's lymphoma patients with a bcl-2 translocation can be purged of polymerase chain reaction-detectable lymphoma cells using monoclonal antibodies and immunomagnetic beads depletion . Blood   1992 ; 80 : 1083 – 1089 .

G   Schiller , R   Vescio , C   Freytes et al. Transplantation of CD34 + peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma . Blood   1995 ; 86 : 390 – 397 .

P   Dreger , K   Viehmann , J   Steinmann et al. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: comparison of T cell depletion strategies using different CD34 + selection systems or CAMPATH-1 . Exp Hematol   1995 ; 23 : 147 – 154 .

WI   Bensinger , CD   Buckner , S   Rowley et al. Transplantation of allogeneic CD34 + peripheral blood stem cells (PBSC) in patients with advanced hematologic malignancy . Bone Marrow Transplant   1996 ; 17 ( suppl 2 ): S38 –S39.

H   Link , L   Arseniev , O   Bahre et al. Transplantation of allogeneic CD34 + blood cells . Blood   1996 ; 87 : 4903 – 4909 .

DN   Haylock , LB   To , S   Makino , et al. Ex vivo expansion of human hemopoietic progenitors with cytokines. In D   Levitt , R   Mertelsmann , eds. Hematopoietic Stem Cells: Biology and Therapeutic Applications , New York : Marcel Dekker, Inc. , 1995 , 491 – 518 .

MJ   Alcorn , TL   Holyoake , L   Richmond et al. CD34-positive cells isolated from cryopreserved peripheral-blood progenitor cells can be expanded ex vivo and used for transplantation with little or no toxicity . J Clin Oncol   1996 ; 14 : 1839 – 1847 .

EG   Hanania , S   Fu , I   Roninson et al. Resistance to taxol chemotherapy produced in mouse marrow cells by safety-modified retroviruses containing a human MDR-1 transcription unit . Gene Ther   1995 ; 2 : 279 – 284 .

S   Kaneko , P   Hallenbeck , T   Kotani et al. Adenovirus-mediated gene therapy of hepatocellular carcinoma using cancer-specific gene expression . Cancer Res   1995 ; 55 : 5283 – 5287 .

T   Ohira , Y   Ohe , Y   Heike et al. Gene therapy for Lewis lung carcinoma with tumour necrosis factor and interleukin 2 cDNAs co-transfected subline . Gene Ther   1994 ; 1 : 269 – 275 .

GM   Prince , M   Nguyen , HM   Lazarus et al. Peripheral blood harvest of unaffected CD34 + CD38 − hematopoietic precursors in paroxysmal nocturnal hemoglobinuria . Blood   1995 ; 86 : 3381 – 3386 .

RK   Burt , W   Burns , A   Hess . Bone marrow transplantation for multiple sclerosis . Bone Marrow Transplant   1995 ; 16 : 1 – 6 .

JA   Yin , SN   Jowitt . Resolution of immune-mediated diseases following allogeneic bone marrow transplantation for leukaemia . Bone Marrow Transplant   1992 ; 9 : 31 – 33 .

RM   Lowenthal , ML   Cohen , K   Atkinson et al. Apparent cure of rheumatoid arthritis by bone marrow transplantation . J Rheumatol   1993 ; 20 : 137 – 140 .

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“This is the wrong patient's blood!”: Evaluating a Near-Miss Wrong Transfusion Event

Barnhard S. “This is the wrong patient's blood!”: Evaluating a Near-Miss Wrong Transfusion Event. PSNet [internet]. Rockville (MD): Agency for Healthcare Research and Quality, US Department of Health and Human Services. 2020.

Case Objectives

• Identify the key aspects of the closed-loop blood delivery pathway and how they ensure transfusion recipient safety.
• Differentiate the human and technologic roles involved in delivering the correct blood to the correct patient.
• Recognize the potential system areas of risk.
• Identify areas to focus on for continuous quality improvement to ensure safe transfusion practices.

A 74-year-old male with a history of hypertension, hyperlipidemia, paroxysmal atrial fibrillation, coronary artery disease, congestive heart failure with an ejection fraction of 45%, stage I chronic kidney disease and gout presented for a total hip replacement. His home medications included lisinopril, metoprolol, colchicine, sertraline, acetaminophen and oxycodone as needed, and warfarin, which was withheld appropriately prior to the surgery.

The patient was seen by the surgical and anesthesia teams in the preoperative holding area the morning of surgery. An intravenous (IV) line was placed and a “type and cross for blood” request was sent along with baseline laboratory tests. At our institution, an initial blood sample is sent in a purple tube from the holding area and then the blood bank will request a second confirmatory sample in a pink tube. The anesthesiologist marks the first tube with a patient sticker, date, time, and initials. The blood bank then sends a pink tube with pre-made labels to the operating room (OR) for a second blood sample.

Shortly into the case, the patient became hypotensive and vasopressors were initiated. During this time, the patient's pink tube for the confirmatory blood sample was delivered to the room. The anesthesiologist filled the tube with blood and sent it back to the blood bank. About an hour into the case significant bleeding was encountered and a blood transfusion was needed. The patient information on the blood bags was checked per institution policy, which requires a witness signature. It was quickly discovered that the blood delivered contained the wrong labels. The blood bank was notified, the blood returned, and a new blood sample sent. Because the patient was persistently hypotensive and still bleeding, a massive transfusion protocol was initiated to rapidly get blood to the room. Uncrossed universal donor blood was delivered and administered, and the patient's hemodynamic parameters recovered appropriately.

The Commentary

By Sarah Barnhard, MD

Introduction: Transfusion Safety

The history of the blood supply in the U.S. is one of early, sobering frequency of disease transmission but also remarkable improvement in safety in terms of infectious agents. 1 Rates of transfusion-transmitted viral infections such as the human immunodeficiency virus (HIV) and hepatitides have plummeted over the last few decades mainly due to the highly sensitive technique of viral nucleic acid testing. According to the National Blood Collection and Utilization Survey (NBCUS), 11,349,000 (95% confidence interval, 10,592,000–11,747,000) red blood cell units were transfused in the US in calendar year 2015. 2 A case of transfusion-transmitted HIV has not been reported to the Centers for Disease Control and Prevention (CDC) since one traced to a 2008 donation 3 and this single case was the first since 2002. The estimated risk of HIV transmission due to blood transfusion is 1 in 1.5 million (based on incidence estimate data from a selected time period during 2007-2008). 4 This risk estimate is almost certainly too high because over 100 million red blood cell units have been transfused since 2008 without any documented cases of HIV transmission.

Still, in day-to-day counseling of patients regarding the risks of a red blood cell transfusion, most mention their apprehension due to the potential risk of HIV transmission. Some even recognize the risks of transfusion reactions (allergic, febrile non-hemolytic, etc.) defined by the National Healthcare Safety Network. 6 Very few patients readily recognize systemic errors in the closed-loop blood delivery pathway as a serious risk to patient outcomes.

Transfusion System Infrastructure

The pathway of blood delivery is inherently complex because multiple patient care areas are involved. The goal of the blood delivery pathway is to deliver the right product to the right patient. The pathway can be summarized by three simple steps:

1) Identify the patient with two unique identifiers.

2) Connect the patient identifiers to all prepared lab samples, tests, and blood products.

3) Deliver the right blood product to the right patient at the right time, confirming patient ID again.

These three simple steps comprise numerous processes, each with its risk of failure. The highest rates of failure are associated with processes outside of the clinical laboratory. 7

The clinical laboratory is one of the most highly regulated services in the hospital, and the transfusion service is one of the most highly regulated services within the clinical laboratory. The Centers for Medicare & Medicaid Services (CMS) regulates all laboratory testing (except research-related testing) performed on humans in the US through the Clinical Laboratory Improvement Amendments (CLIA). 7 The Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation and Research (CBER) regulates biological products for human use under applicable federal laws. 8 The AABB (formerly American Association of Blood Banks), an international non-profit transfusion medicine organization, sets standards for transfusion medicine 9 and these are incorporated into state law in California 10 and other states. The College of American Pathologists also sets standards for accreditation of clinical laboratories in compliance with CLIA. 11 This robust oversight is aimed at ensuring quality laboratory testing and processes.

The Quality Management System

The American Society for Quality defines a quality management system (QMS) as “a formalized system that documents processes, procedures, and responsibilities for achieving quality policies and objectives.” 12 For hospital-based transfusion services, a practical QMS is an essential part of meeting regulatory requirements and improving effectiveness and efficiency. AABB requires transfusion services to have documented QMSs (Standard 1.2). 13

A hospital-based transfusion service QMS must include a closed-loop process that protects patients from an ABO-incompatible (blood type-incompatible) red blood cell transfusion. The loop begins and ends at the patient bedside. Notice how the following (paraphrased) AABB Standards protect a recipient from an ABO-incompatible red blood cell transfusion: 13

• 5.11.1 All requests for blood contain two independent identifiers of the intended recipient.
• 5.11.2 All patient blood sample labels include two independent identifiers and (5.11.2.1) the label is affixed to the container before the person who obtained the sample leaves the bedside.
• 5.12 The ABO group of each donor unit of red blood cells is confirmed through serologic testing before being placed in stock inventory.
• 5.14.1 The ABO group of the patient is determined by comparing the ABO antigens detected with the presence of expected anti-A and anti-B antibodies.
• 5.16.1 Before issue, a crossmatch demonstrates ABO compatibility.
• 5.16.2 If a computer crossmatch technique is used, two determinations of the recipient’s ABO group must be made before transfusing non-group O red blood cell units.
• 5.14.5 The recipient’s historical records for ABO group are reviewed before every unit issued.
• 5.23 At the time a unit is issued, two people verify the recipient ABO group and the donor ABO group.
• 5.28.3 After issue and immediately before transfusion, two people verify the ABO group of the recipient and the donor ABO group and confirm recipient identification in the presence of the recipient. One of these two staff members must be the person transfusing the blood.
• 5.14.1 If a discrepancy is identified in the ABO testing, only group O red blood cells are transfused until resolution.

Risk of ABO-Incompatible Transfusions and Hemolytic Reactions

In the United States, reporting of fatalities to accreditors and regulators is mandatory but reporting of near-miss or system errors is not. Therefore, risk assessment is difficult due to underreporting and the fact that there is no centralized public database for tracking errors.

Employees at all hospital-based transfusion services across the US are very aware of the “Fatalities Reported to FDA Following Blood Collection and Transfusion Annual Summary”. 14 All blood transfusion- and donation-related deaths must be reported to the FDA as soon as possible after confirming a complication of blood transfusion or donation. Such notifications must be followed by an investigation report within 7 days. Fatal acute hemolytic transfusion reactions related to ABO-mismatched transfusions were reported 1-4 times each year from 2013 to 2017. 14

When combined with the NBCUS data, the risk of fatality due to an ABO-mismatched red blood cell transfusion could therefore be estimated at 1-4 per 10,000,000 for each red blood cell unit transfused. But fatal reactions represent the ‘tip of the iceberg’ as most ABO-incompatible transfusions involve small volumes due to early clinical signs/symptoms and usually patients survive. 15

The risk of a lethal hemolytic transfusion reaction was estimated at 1 per 550,000 units transfused for the time period 1976-1985 in the US. 16 Not all hemolytic reactions are ABO-related and not all wrong transfusion events result in adverse clinical outcomes. Others have estimated that 1 in every 19,000 units of red blood cells is transfused to the wrong patient each year, 1 in 76,000 transfusions results in an acute hemolytic reaction, and 1 in 1.8 million units of transfused red blood cell units results in death due to acute hemolytic reaction. 17,18

When estimating risk, the best information available indicates that most transfusions to the wrong patient occur as a result of potentially avoidable system failures. 19 The most frequent error leading to transfusion of ABO-incompatible blood occurs during patient identification/verification at the bedside; as a result, although the blood is labeled appropriately, it is transfused to someone other than the correct recipient. 15

Response to a Near-Miss High-Risk Transfusion Event

For every process in the transfusion services laboratory, control measures should be in place to ensure quality outcomes. When process variation occurs, it is important to review the methods of process control and the need for improvement. “Process control” encompasses the defined activities that ensure a process is predictable, stable and consistently operating at a target performance level. Common cause variation is inherent in a process over time and requires constant process improvement, while special cause variation arises due to unusual circumstances and requires removing the cause. 12

Per FDA, AABB and the College of American Pathologists (CAP), the response to a near-miss high-risk patient safety event in transfusion services must include:

• Notification of the appropriate accreditation and/or regulatory agencies if required; errors classified as blood product deviations (BPDs) must be reported within 45 calendar days to the FDA. 20
• Evaluate standard operating procedures to determine if revision is needed.
• Interview staff involved to determine what aspects of the system failed and why.
• Notify appropriate accreditation and/or regulatory agencies of CAPA if required.
• Retain the document for future inspections.

Root Cause Analysis of this Case

The root cause analysis of this Case (Figure 1) reveals two steps at which errors occurred: the tube was labeled incorrectly by the blood bank and was not checked at the bedside by the anesthesiologist before obtaining a blood sample. The underlying reasons for the two errors are not provided. The downstream effect of the two errors was the wrong blood reaching the patient’s bedside, a high risk near-miss event that may have led to serious patient outcomes.

Figure 1: Root cause analysis of this near-miss Case

Corrective and Preventative Action Plan (CAPA)

The underlying reasons for the two errors are not provided for this Case, but the general approach to the corrective and preventative action plan (CAPA) should include reviewing the standard operating procedures (SOP) with the involved staff to discuss whether there are any areas where the SOP is confusing or misleading. This review may include re-educating the staff on the current SOP, evaluating other samples processed by the involved staff members to ensure no other labeling errors were made, reviewing records for other deviations, assessing processes through direct observation of staff, or assessing skills with quizzes or other methods.

Re-addressing the six core elements of competency of the staff members involved, per CLIA, is required in the transfusion services laboratory when significant deviations occur. The core competency elements are: ( 1) direct observation of routine patient test performance; (2) monitoring the recording and reporting of test results; (3) review of intermediate test results, quality control records, proficiency testing results, and preventive maintenance records; (4) direct observation of performance of instrument maintenance and function checks; (5) assessment of test performance through testing of previously analyzed specimens, internal blind testing of samples, or external proficiency testing of samples; and (6) assessment of problem-solving skills. 21 A monitoring process, typically through periodic audits, should be initiated if the underlying reason for the error is systemic and especially if a process change is made to ensure compliance.

One potential corrective action is to implement bedside sample labeling for all blood-type verifications to remove the variability of labels being generated from the laboratory. Checking the labels of all blood samples against the two unique identifiers on the patient’s wristband and labeling at the bedside is standard practice. Combining this standard practice with barcode scanning significantly reduces laboratory testing errors. 22 Even without bedside labeling, barcode scanning of the patient’s wristband by the anesthesiologist at the time of sample collection should ensure the wristband and sample label match.

Approach to Urgent Transfusion Cases with Discrepancies

This Case highlights a realistic scenario in which clinical need was urgent despite system errors. It illustrates how sometimes patient care cannot await resolutions of discrepancies in the blood delivery pathway and when critical transfusions are required, emergent un-crossmatched red blood cells that are group O should be provided. Unfortunately, in this case, a massive transfusion protocol had to be initiated and un-crossmatched group O red blood cells provided to the patient in this Case, potentially causing a ‘universal blood’ shortage for a future patient. Although un-crossmatched group O units are the safest product to transfuse in emergent cases such as an unstable patient who is actively bleeding or who has significant organ dysfunction due to anemia, using un-crossmatched red blood cells increases the risk of hemolytic reaction due to non-ABO antibodies and should be avoided unless the clinical situation is truly emergent. Implementing strong systems processes as discussed in this Commentary should reduce the risk of errors in the transfusion delivery system and ensure that patients receive the correct blood product, reducing the need for un-crossmatched group O blood.

Take-Home Points

• Risk of error in the blood delivery pathway is significantly higher than the risk of transfusion-transmitted HIV or hepatitis in the U.S.
• Each step in the closed-loop blood delivery pathway is critical for transfusion safety; the highest area of risk is bedside patient identification.
• No matter how urgent, the steps in the closed-loop blood delivery pathway must always be followed to protect a patient from a fatal ABO-mismatched transfusion.
• In critically ill patients who require transfusion and cannot wait for verified, crossmatched blood to be available, only group O red blood cells should be transfused.
• Transfusion services are highly regulated services in the clinical laboratory that are under state and federal oversight.
• The appropriate response to a near-miss high-risk transfusion event includes: (1) report the event to accreditation/regulatory agencies as required, (2) perform a root cause analysis, (3) develop and implement a corrective and preventative action plan and (4) monitor the system.

Sarah Barnhard, MD Medical Director of Transfusion Services Department of Pathology and Laboratory Medicine UC Davis Health

Acknowledgements: The author acknowledges the contribution of Ying Liu, MD, and Nam Tran, PhD for their assistance on the Root Cause Analysis.

References:

• Dzik WH. Emily Cooley Lecture 2002: Transfusion safety in the hospital. Transfusion . 2003; 43:1190-1199. [ Available at ]
• Ellingson KD, Sapiano MRP, Haass KA, et al. Continued decline in blood collection and transfusion in the United States-2015. Transfusion . 2017 Jun; 57(Suppl 2):1588-1598. [ Free full text ]
• Centers for Disease Control and Prevention (CDC). HIV transmission through transfusion --- Missouri and Colorado, 2008. MMWR Morb Mortal Wkly Rep . 2010;59(41):1335-1339. [ Free full text ]
• Zou S, Dorsey KA, Notari EP, et al. Prevalence, incidence, and residual risk of human immunodeficiency virus and hepatitis C virus infections among United States blood donors since the introduction of nucleic acid testing. Transfusion 2010; 50:1495-504. [ Available at ]
• Védy D, Robert D, Gasparini D,et al. Bacterial contamination of platelet concentrates: pathogen detection and inactivation methods. Hematol Rev 2009 Mar 1; 1(1):e5. [ Free full text ]
• Centers for Disease Control and Prevention (CDC). National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol. Accessed December 26, 2019. [ Free full text (PDF) ]
• Centers for Medicare and Medicaid Services (CMS). Clinical laboratory improvement amendments (CLIA). [ Free full text ]
• U.S. Food and Drug Administration (FDA). Center for Biologics Evaluation and Research (CBER). Accessed December 26, 2019. [ Free full text ]
• AABB. Transfusion Medicine.Accessed December 26, 2019. [ Free full text ]
• California Department of Public Health (CDPH). Blood banks and biologics.Accessed December 26, 2019.[ Free full text ]
• College of American Pathologists. Laboratory accreditation program. Accessed December 26, 2019. [ Free full text ]
• American Society for Quality (ASQ). What is a quality management system (QMS)? Accessed December 26, 2019. [ Free full text ]
• Standards for Blood Banks and Transfusion Services. AABB 31 st Edition. Effective April 1, 2018. [ Available at ]
• Fatalities Reported to FDA Following Blood Collection and Transfusion. Annual Summary for Fiscal Year 2017. Accessed December 26, 2019. [ Free full text ]
• Janatpour KA, Kalmin ND, Jensen HM, et al. Clinical outcomes of ABO-incompatible RBC transfusions. Am J Clin Pathol. 2008; 129:276-281. [ Free full text ]
• Strobel E. Hemolytic transfusion reactions. Transfus Med Hemother . 2008; 35(5):346-353. [ Free full text ]
• Vamvakas EC, et al. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood 2009; 113:3406-17. [ Free full text ]
• Fung MK, Grossman BJ, Hillyer CD and Westhoff CM, Eds. AABB Technical Manual 18 th Edition 2014. Accessed January 6, 2020. [ Free full text ]
• Stainsby D, Jones H, Asher D, et al.Serious hazards of transfusion: a decade of hemovigilance in the UK. Transfus Med Rev. 2006; 20:273-282. [ Free full text ]
• Snyder SR, Favoretto AM, Derzon JH, et al.Effectiveness of barcoding for reducing patient specimen and laboratory testing identification errors: alaboratory medicine best practices systematic review and meta-analysis. Clin Biochem . 2012;45(13-14):988-998. [ Free full text ]
• FDA Blood Product Deviation Reporting for Blood and Plasma Establishments: Guidance for Industry. 2006 Oct. Accessed January 6, 2020. [ Free full text ]
• Medicare, Medicaid and CLIA programs; regulations implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA)--HCFA. Final rule with comment period. Fed Regist. 1992 Feb 28; 57(40):7002-186. [ Free full text ]

This project was funded under contract number 75Q80119C00004 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services. The authors are solely responsible for this report’s contents, findings, and conclusions, which do not necessarily represent the views of AHRQ. Readers should not interpret any statement in this report as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the authors has any affiliation or financial involvement that conflicts with the material presented in this report. View AHRQ Disclaimers

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Serious hazards of transfusion: evaluating the dangers of a wrong patient autologous salvaged blood in cardiac surgery. October 5, 2022

Factors associated with wrong blood in tube errors: an international case series - The BEST collaborative study. November 17, 2021

Emergency departments are higher-risk locations for wrong blood in tube errors. September 29, 2021

Transfusion safety: the nature and outcomes of errors in patient registration. February 20, 2019

Assessment of incorrect surgical procedures within and outside the operating room. A follow-up study from US Veterans Health Administration medical centers. December 5, 2018

Patient misidentification in laboratory medicine: a qualitative analysis of 227 root cause analysis reports in the Veterans Health Administration. February 17, 2010

Surgical specimen identification errors: a new measure of quality in surgical care. April 11, 2007

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Publication

Assessing the Impact of Transplant Case Management on Clinical Outcomes

This article examines the effect of a transplant case management program on clinical outcomes following transplant surgery.

Objectives: Case management is commonly used by health plans to attempt to improve the care received by their members who have complex needs, such as those who undergo transplantation. There are few observational studies evaluating the effects that transplant case management programs have on clinical outcomes following a solid organ transplant. This limits the understanding of the quantitative effectiveness of such programs.

Study Design: This retrospective cohort study of solid organ transplant recipients with access to a transplant case management program used a case-control study design. Propensity score 1:1 matching was used to balance the comparison groups on demographic and pretransplant clinical characteristics.

Methods: Health care claims data were used to determine whether program participation affected clinical outcomes following the transplant. A cohort of 1756 adults 18 years and older (878 cases and 878 controls) who had a solid organ transplant between 2018 and 2020 was followed beginning at the time of referral to transplant until 90 days following the transplant procedure.

Results: Transplant recipients who participated in the case management program had significantly lower 30-day and 90-day rejection rates, fewer 90-day readmissions, lower discharge mortality and 90-day mortality, and fewer bed days post transplant compared with those who did not participate in case management.

Conclusions: Patients undergoing a solid organ transplant had improved clinical outcomes when they participated in a specialized case management program sponsored by their health plan.

Am J Manag Care. 2023;29(3):e85-e90. https://doi.org/10.37765/ajmc.2023.89334

Takeaway Points

This article examines the effect of a transplant case management program on clinical outcomes following transplant surgery and whether participating in the program affects those outcomes. These findings can help to:

• Understand the role of case management programs throughout the phases of transplant care, and
• Provide important direction for transplant case management programs worldwide.

Over the past decade, there have been more than 25,000 organ transplants per year in the United States, with some years seeing more than 30,000 transplants. Since 2010, the number of kidney transplants has increased by 37%, liver transplants have increased 41%, and heart and lung transplants have increased 52%. Demand for transplants also continues to rise, as newly listed candidates added to the waitlist outpace the number of transplants performed each year, often by as much as 6 times. 1

Transplant care is highly specialized, with only 250 hospitals in the United States providing these services. 2 Patients must navigate a fragmented health care system to be referred for evaluation at a transplant center, be placed on the transplant list, finally receive a transplant, and then ultimately return home needing to adhere to a complex treatment plan that is critical to avoid organ rejection and achieve the promised benefits of this lifesaving procedure. Both transplant centers and health plans commonly offer case management to help patients navigate this complicated process, providing education and support to improve their clinical outcomes; however, there is limited evidence of the effectiveness of these programs. We conducted this study to evaluate the impact of a transplant case management program used by health plans on clinical outcomes among patients who receive a solid organ transplant.

MATERIALS AND METHODS

Program Design

Transplant Resource Services is a case management program operated by Optum for health plans for more than 30 years. The program attempts to enroll individuals upon notification by a transplant facility that they intend to proceed with evaluation or plan referrals (eg, other case management programs, employer’s human resource department). Nurses with transplant experience telephonically support each participating member throughout the transplant phases of care, from referral all the way to post transplant. These case managers work with the members to provide education about their health plan benefits and about the Centers of Excellence (a network of transplant centers that meet rigorous evaluation criteria) available to them; they also help coordinate services, plan for the transplant process, implement the discharge care plan (including facilitating filling prescriptions for immunosuppressive medications, which often must be obtained from a specialty pharmacy), and continue to provide education and support for up to 1 year post discharge. At 3 separate points throughout their case management experience, each member completes an assessment to determine gaps in care or knowledge and to gauge their needs, behaviors, and attitudes. These assessments help guide the case managers and aid in prioritizing care. Once the transplant surgery is complete, case management nurses continue to educate patients, in addition to ensuring that they make and keep all necessary doctor appointments, get laboratory work done as needed, and follow all postoperative instructions provided by the doctors and care team.

Study Design

We conducted a retrospective cohort study of patients 18 years and older in the United States who were drawn from a national health plan claims database and were identified as having received a solid organ transplant in the calendar years 2018, 2019, or 2020. Because all health plan members referred for a transplant evaluation were eligible for the program, we used a case-control design. The treatment group consisted of commercial health plan members who participated in transplant case management throughout the transplant phases of care, from the time to referral to 90 days post transplant (n = 878). The control group consisted of commercial health plan members who did not participate in case management during the transplant phases of care (n = 878). All study participants had to have been continually enrolled in the health plan from the time they were referred to transplant to 90 days post transplant. Individuals for whom the commercial health insurance was secondary to Medicare were excluded because of the potential for incomplete data.

The control group was selected by propensity score matching on demographic and pretransplant clinical characteristics, transplant organ type, and geographic region. Variables used to balance the 2 groups are shown in Table 1 . Sex, age, organ type, United Network for Organ Sharing region of their transplant center, and number of bed days prior to transplant were extracted from the members’ health care claims. United States 2020 Census data were used to measure urban/rural type, median household income by zip code, and total physician concentration by zip code for each member. Cases and controls were matched 1:1. The Charlson Comorbidity Index (CCI) score, a measure of disease burden and case mix widely used by health researchers, was calculated from the members’ claims.

The Consumer Health Activation Index (CHAI) tool has been shown to be valid and reliable in estimating a patient’s level of engagement in their own health. It considers more than 50 health decisions that are controllable by the individual, including clinical decisions, financial decisions, and the use of health resources. The index, developed in 2007 by UnitedHealthcare, measures each decision through claims data, clinical data, and other health plan activities. 3 The CHAI was used in the propensity score matching of the current study to help control for differences in health literacy, engagement, and self-care across the 2 groups. It was calculated from each member’s profile and claims.

Data Sources

We used health plan claims data that included all inpatient and outpatient data for commercial health plan members who received an organ transplant between 2018 and 2020. Claims for the transplant recipients were then aligned with a clinical case management database to determine which members participated in case management.

Clinical Outcome Measures

We compared the following clinical outcomes between the case and control groups: 30-day and 90-day readmission rates, emergency department (ED) visits within 30 days and 90 days of discharge, total number of bed days post transplant, 30-day and 90-day pneumonia rates, 30-day and 90-day organ rejection rates, discharge mortality rate, and 90-day mortality rate.

Statistical Analyses

For the binary outcomes, χ 2 tests were used to measure the significance of the difference between the groups. For the measure of total bed days post transplant, a zero-inflated binomial regression was used due to the large number of patients who had 0 bed days. All measures were assessed using a .05 significance level.

This study was approved by Optum’s Institutional Review Board.

A total of 1756 patients across 136 transplant facilities were included in the study. Cases and controls were well matched (Table 1). There were no statistically significant differences between the 2 groups for any of the variables used in the matching process. At baseline, 63.2% were aged 45 to 64 years and 62.3% were men, as shown in Table 1. Liver recipients made up 36.4% of the study population; 25.2% and 14.8% received a kidney from a deceased donor and a living donor, respectively; and 13.6% received a heart transplant. Only 2.5% of patients were registered for multiple organs. Patients had a mean CCI score of 3.4 and a mean CHAI score of 0.52, and most lived in urban areas.

Results of the clinical outcomes are summarized in Table 2 [ part A and part B ] . The 30-day readmission rate was not significantly different between participants and nonparticipants for any of the organ types. Overall, case management participants had a 16.3% 90-day readmission rate compared with 20.1% in the nonparticipants ( P  = .040). Heart transplant recipients who participated in case management had a significantly lower 90-day readmission rate (20.0%) than heart recipients who did not participate in case management (32.5%; P  = .028). Living donor kidney recipients who participated in case management also had significantly lower 90-day readmission rates compared with nonparticipants (9.5% vs 15.9%; P  = .041).

The number of ED visits within 30 days post discharge and within 90 days post discharge was significantly different only for heart transplant recipients. Among case management participants, heart transplant patients had a mean of 3.3 ED visits within 30 days, compared with 10.3 ED visits for nonparticipants ( P  = .033). Heart transplant participants had a mean of 5.0 ED visits within 90 days, compared with 13.7 visits for nonparticipants ( P  = .021).

The total number of bed days from transplant through 90 days post transplant was the outcome that demonstrated the largest differences between participants and nonparticipants. Overall, case management participants had a mean of 15.6 bed days in the 90 days following transplant surgery compared with 16.6 bed days for nonparticipants ( P  = .006). Among liver recipients, participants had a mean of 22.2 bed days compared with 25.5 days for nonparticipants ( P  < .001). Participants who underwent a lung transplant had a mean of 41.3 bed days compared with 47.6 days for nonparticipants ( P  < .001). Finally, pancreas recipients who participated in case management had a mean of 9.3 bed days compared with 13.0 days among nonparticipants ( P  = .009).

Both deceased donor and living donor kidney recipients who participated in case management had more bed days in the 90 days following transplantation than the nonparticipants. Among deceased donor kidney recipients, participants had a mean of 7.4 total bed days, whereas nonparticipants had 6.6 days ( P  = .027). Among living donor kidney recipients, participants had a mean of 5.5 total bed days compared with 4.5 days among nonparticipants ( P  < .001).

Both pneumonia measures showed significant differences among liver recipients, but no significant differences appeared in recipients of other organs. Among liver recipients who participated in case management, 1.5% developed pneumonia within 30 days, whereas 5.0% of nonparticipant liver recipients did so ( P  = .013). Just under 3% of liver recipients who participated in case management developed pneumonia within 90 days compared with 6.9% of liver recipients who did not participate in case management ( P  = .015).

Overall, members who participated in the case management program had a 5.5% 30-day rejection rate and a 9.0% 90-day rejection rate compared with 8.7% ( P  = .009) and 12.6% ( P  = .020), respectively, of members who did not participate in case management. When examined by individual organ type, case management participants who received a heart had significantly lower 30-day rejection rates (22.5% vs 35.0%; P  = .033) and 90-day rejection rates (33.3% vs 48.7%; P  = .016) compared with nonparticipants who received a heart. Case management participants who received a liver had significantly lower 30-day rejection rates (3.4% vs 7.8%; P  = .014) and 90-day rejection rates (6.5% vs 11.6%; P  = .024) compared with nonparticipants who received a liver.

Case management participants overall had lower discharge mortality rates (0.8% vs 2.6%; P  = .003) compared with nonparticipants; however, this was due to differences in the liver transplant recipients and was not observed in the other transplant types. For liver recipients, participants had a 0.6% discharge mortality rate compared with 4.4% for nonparticipants ( P  = .002).

For 90-day mortality, living donor kidney recipients who participated in case management had a 0.0% mortality rate compared with 2.3% among nonparticipants ( P  = .024). Liver recipient participants had a 2.8% 90-day mortality rate compared with 6.9% among nonparticipants ( P  = .009). The overall 90-day mortality rate was also significantly different between case management participants and nonparticipants (2.3% vs 5.0%; P  = .002).

Case management is commonly used to attempt to remove barriers to care and improve outcomes for patients who have complex needs. Although every case management program is distinct in its offerings and operations, they can all be viewed as complex interventions for the conditions they target. For instance, case management programs all have many interacting components, require a wide variety of actions and behaviors between those who deliver it and those who receive it, require flexibility in its delivery, and have diverse outcomes. 4 Further, to be successful, advanced levels of patient self-care, self-responsibility, and self-management are required. 5 Evaluating the effectiveness of case management is challenging because there is rarely a standard intervention; rather, the appropriate care model is typically tailored to match the patients’ specific needs. Further, given variable rates of engagement, determining an appropriate comparison group can often be difficult. 4 For these reasons, very few studies have been conducted that assess whether case management leads to fewer complications and better clinical outcomes.

Although there are numerous care management programs for individuals undergoing transplant, this is the first study to demonstrate an improvement in clinical outcomes with the use of such programs, to our knowledge. We found that health plan members who engaged with case management, compared with those who did not do so, appeared to do better across a range of clinical outcomes, including readmissions, pneumonia, rejection, and mortality. Although this is the first study to our knowledge on the effectiveness of a health plan case management program, our results are consistent with those of a small, randomized trial of case management in patients undergoing living-donor renal transplants. Schmid et al found that recipients who were randomly assigned to telemedically supported case management had a reduction of unplanned inpatient acute care, fewer costs, and lower nonadherence rates compared with those who did not receive case management. 5

Hospital readmissions are often used as an indicator of health care quality and a focus of case management programs because it is estimated that 75% of readmissions are avoidable. Readmissions after organ transplantation are common and differ from those following many other surgical procedures because of the severity of illness, complexity of the procedure, and complications that often arise from immunosuppression. 6 We found that participation in case management was associated with a meaningful 4% fewer readmissions over the 90 days following transplant, with the greatest impact among heart transplant recipients (12.5% difference) and living donor kidney recipients (6.4% difference). In addition, there were 1.0 fewer bed days post transplant among case management participants, with the greatest difference observed among lung transplant recipients (6.3 days). We also observed a significant difference in the clinical outcomes of ED visits, pneumonia, transplant rejection, and mortality.

Case management is a multifactorial intervention tailored to the individual participant’s unique needs, which makes it challenging to try to determine what might be the causal mechanism for an impact on these clinically important outcomes. One possible mechanism may be discerned from the aforementioned study performed by Schmid et al, who found a substantial impact of case management on medication nonadherence in patients undergoing renal transplant. 5 They reported that the prevalence of nonadherence over the 1-year study period was 17.4% in the intervention group vs 56.5% in the standard aftercare group ( P  = .013). Further research is needed to understand whether health plan–sponsored case management programs have the same impact on medication adherence, especially for the immunosuppressive medications that are critical to the long-term success of the transplants. In addition, it will be important to better understand why these effects were observed in only the kidney transplant population and whether there is opportunity to improve outcomes among other transplant recipients.

One unexpected finding was that deceased donor kidney transplant patients who participated in the program had worse clinical outcomes, by most metrics, than those with no program participation. Although most of these differences were not statistically significant, these findings warrant additional research.

Although the scope of the current analysis focuses on events following the transplant procedure, it is important to note that case management could have significant impacts on events prior to the transplant surgery that could also affect clinical outcomes. Further research is needed to evaluate whether case management has an impact on the time lags from referral to evaluation to wait-listing to transplant. Longer time periods between each phase of transplant care can also affect transplant outcomes. For instance, longer dialysis periods prior to kidney transplantation may be associated with worse outcomes post transplant.

Limitations

As already mentioned, a limitation of this study is the comparison of participants with nonparticipants, as it is the patient’s choice whether to engage in the case management program. Propensity score matching was used to ensure comparability between the cohorts on demographic and clinical characteristics, as well as health literacy and engagement. Use of the CHAI helps to ensure that the 2 cohorts are comparable on health behavior, but it is possible that there are still unmeasurable factors not considered with this tool that could be associated with participation bias.

It is also possible that the outcomes are influenced by the transplant facility itself, as each facility has its own nuances in how it manages patients. Case managers in the current study may not always integrate center-specific protocols into their case management. Further, transplant facility size could also affect clinical outcomes, but such information was not captured for this study.

CONCLUSIONS

Patients undergoing a solid organ transplant had improved clinical outcomes when they participated in a specialized case management program sponsored by their health plan. Further studies are needed to determine the effectiveness of other case management programs, including those provided by the transplant centers themselves, and whether such programs are duplicative or synergistic in supporting these complex patients. In addition, future efforts should identify the components of the case management intervention that have the greatest impact, as well as ways to increase participation in these programs. 

Author Affiliations: OptumHealth (AC, GK, WB, AB, JM), Eden Prairie, MN.

Source of Funding: OptumHealth.

Author Disclosures: Drs Crossman, Bannister, Bonagura, and Malin and Ms Krishnaswamy are currently employed by Optum, which owns and operates the case management program discussed in this article. Dr Bannister owns stock in UnitedHealth Group, of which Optum is a subsidiary.

Authorship Information: Concept and design (AC, WB, AB, JM); acquisition of data (GK); analysis and interpretation of data (AC, GK, WB); drafting of the manuscript (AC, JM); critical revision of the manuscript for important intellectual content (AC, WB, AB, JM); statistical analysis (GK); and supervision (AC, AB).

Address Correspondence to: Ashley Crossman, PhD, MPH, OptumHealth, 11000 Optum Circle, Eden Prairie, MN 55344. Email: [email protected].

1. OPTN/SRTR 2019 Annual Data Report. Scientific Registry of Transplant Recipients. Accessed November 15, 2021. https://srtr.transplant.hrsa.gov/annual_reports/2019_ADR_Preview.aspx

2. United Network for Organ Sharing (UNOS). The National Organ Transplant System. Accessed November 15, 2021. https://unos.org/solutions/research-data-analytics-transplant/

3. Wolf MS, Smith SG, Pandit AU, et al. Development and validation of the Consumer Health Activation Index. Med Decis Making . 2018;38(3):334-343. doi:10.1177/0272989X17753392

4. Lambert AS, Legrand C, Cès S, Van Durme T, Macq J. Evaluating case management as a complex intervention: lessons for the future. PLoS One . 2019;14(10):e0224286. doi:10.1371/journal.pone.0224286

5. Schmid A, Hils S, Kramer-Zucker A, et al. Telemedically supported case management of living-donor renal transplant recipients to optimize routine evidence-based aftercare: a single-center randomized controlled trial. Am J Transplant . 2017;17(6):1594-1605. doi:10.1111/ajt.14138

6. Paterno F, Wilson GC, Wima K, et al. Hospital utilization and consequences of readmissions after liver transplantation. Surgery . 2014;156(4):871-878. doi:10.1016/j.surg.2014.06.018

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• v.8; Jan-Dec 2021

Educational Case: Kidney Transplant Rejection

1 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA

Daniel Schwartz

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040 . 1

Primary Objective

Objective IM1.8: Transplantation . Discuss the consequences of tissue transplantation, including mechanisms and pathophysiology of graft versus host organ rejection, and the possible therapeutic interventions that can mitigate these effects.

Competency 1: Disease Mechanisms and Processes; Topic Immunological Mechanisms (IM); Learning Goal 1: Immune dysfunction

Patient Presentation

A 40-year-old man presents to the emergency department (ED) complaining of gradually worsening fatigue and malaise for 2 days. His medical history includes morbid obesity, hypertension, diabetes mellitus, gout, and end-stage renal disease secondary to hypertension, for which he underwent a deceased-donor kidney transplant 1 month ago. There are no other symptoms. Specifically, he denies fever, shortness of breath, myalgia, flank pain, and dysuria. He also denies any recent travel or contacts with sick individuals. The family history is positive for hypertension and diabetes but is otherwise unremarkable. He does not drink or smoke and denies any illicit drug use. Further inquiry of his post-transplant history reveals an uneventful clinical course, with a functional transplanted kidney at the time of discharge home. He also reports that he has been compliant with medications as directed by his kidney doctor, including tacrolimus and a corticosteroid.

Diagnostic Findings, Part 1

On examination, the patient’s vital signs are stable (heart rate: 74 beats per minute, temperature: 99.4 °F; respiratory rate: 16 per minute), but his blood pressure is slightly increased (145/88 mm Hg). He measures 185 cm in height and weighs 125 kg (body mass index: 36.5), appears well-nourished and in no acute distress. Review of systems and physical examination do not reveal additional relevant information. Laboratory evaluation includes a serum creatinine level of 9.9 mg/dL (reference range: <1.5 mg/dL), and the glomerular filtration rate (GFR) is markedly decreased (16 mL/min/1.73m 2 ). The patient is hypocalcemic at 7 mg/dL (8.5-10.5 mg/dL) but electrolytes are within normal limits. The hemoglobin level is 7.1 g/dL (14-17.4 g/dL) and the white blood cell count is 8400/µL (4800-10800/µL). Qualitative urinalysis shows trace blood, protein +1, and few white blood cells. Repeated tacrolimus serum levels are all within therapeutic range.

Additional serum studies show that patient does not have circulating cytomegalovirus or BK polyomavirus in the blood.

Ultrasound imaging with duplex Doppler study is performed on the allograft kidney ( Figure 1 ) and demonstrates patent renal vasculature with a normal flow rate. There is no evidence of arterial stenosis, venous thrombosis, hydronephrosis, or renal calculi. There is a known perinephric fluid collection that has been stable in size since transplantation.

Renal allograft ultrasonogram. A, The kidney is normal in appearance with no evidence of thrombosis, arterial thickening, hydronephrosis, or calculus formation. Note that there is a hypo-echoic loculated structure near the upper pole, implying fluid accumulation (arrowhead). B, Ultrasonographic enhancement by spectral imaging shows normal renal perfusion. The absence of spectral enhancement indicates the lack of fluid movement within the accumulation, which is suggestive of seroma.

Question/Discussion Points, Part 1

What is the differential diagnosis based on the clinical history and initial diagnostic findings.

The patient’s nonspecific presentation encompasses a wide range of possible diagnoses including infection, autoimmune processes, toxic or ischemic injury, nutritional deficiencies, and even psychosomatic causes. Further evaluation is necessary to establish that diagnosis. The presence of perinephric fluid also raises the concern of possible surgical complications such as hematoma and urinoma (urine leak into perinephric tissues) as well as infection with abscess formation. Other possible diagnoses include viral infection, medication-induced reaction/toxicity, and post-transplant lymphoproliferative disease. All of these should be entertained since they can present with similar findings ( Table 1 2 ).

Common Causes of Renal Allograft Dysfunction. 2 , *

* One of the important factors to consider during evaluation is the timing of presentation. A diagnosis can sometimes be established by physical examination and laboratory evaluation, but additional evaluation is frequently required.

The initial studies performed at the ED are helpful in ruling out various pathologic processes and revealing the underlying cause of the patient’s presentation. The absence of leukocytosis, negative findings in viral studies, and therapeutic-range tacrolimus serum level have made infection and drug toxicity less likely. Given the current findings, including the short post-transplantation time frame, organ rejection is a major concern and should be at the top of the differential diagnosis.

What Are the Different Types of Renal Allograft Rejection?

There are 2 main types of transplant rejection, one mediated by T lymphocytes, the other by circulating antibodies. They are not mutually exclusive and can at times be seen in the same biopsy. 3 As outlined in Table 1 , timing is usually helpful in determining the type of organ rejection, with different parts of immune system activated at different times in the post-transplant course. The classification and subcategorization of types of organ rejection continues to change as our understanding of the etiology and pathophysiology of the immune regulatory response evolves. Presently, many scholars characterize renal allograft rejection based on both temporal occurrence (hyperacute, acute, chronic) and mechanism involved (cellular- or antibody-mediated), as described in Table 2 . 4

Classification of Renal Allograft Rejection. 4

Abbreviations: DSA, donor-specific antigen; HLA, human leukocyte antigen; MHC, major histocompatibility complex; PTC, peritubular capillary.

How Is the Pathogenesis of T Cell-Mediated Rejection Different From That of Antibody Mediated Rejection?

A tremendous amount of work has been done in the field of immunotherapy and solid organ rejection, and it is still an area of extensive research. 4 Organ rejection results from a complex series of interactions between the grafted organs and the host’s immune defense.

T cell-mediated rejection, also known as acute cellular rejection, is more frequently seen during the first 6 months after transplantation. As the name suggests, the key cell type in this form of rejection is the T lymphocyte. The chain of events is initiated through the presentation and recognition of human leukocyte antigens in the donor organ that are foreign to the recipient. A special subgroup of immune cells, called the antigen presenting cell, is responsible for taking up and presenting these antigens to naïve T lymphocytes. Via interactions such as receptor binding and chemokine stimulation, a molecular signal cascade ensues, and naïve T lymphocytes undergo a maturation process to become differentiated and activated. They then migrate to and infiltrate the grafted organ and begin an inflammatory process with tissue injury. 3 , 5

Our understanding of the regulating mechanisms and molecular pathways of antibody-mediated rejection is still evolving. As in T cell-mediated rejection, exposure of antigens from the grafted organ to the immune system is believed to be the inciting event. 6 In response, allo- and auto-antibodies are expressed and released by the host’s B lymphocytes and plasma cells, leading to antibody complex formation and complement cascade activation via the classical pathway. Ultimately there is organ damage and dysfunction. As the complement cascade is activated by circulating antibodies, the breakdown product C4d is generated. It has a long half-life and covalently binds to microvascular endothelial cells and their basement membranes, allowing it to be visualized in biopsies using immunohistochemical techniques. There is a strong (although not universal) correlation between C4d staining, the presence of circulating donor-specific alloantibodies, and clinical evidence of rejection. 7 , 8 Hence, immunohistochemical staining for C4d is a routine practice in evaluation of the renal transplant biopsy.

What Additional Testing Should Be Performed?

There are no laboratory or imaging studies that will specifically point to a diagnosis of T cell-mediated rejection or cellular rejection. To evaluate for antibody-mediated rejection, an assessment for donor-specific antibodies (DSA) is important. Although there are exceptions, DSA are present in most cases of antibody-mediated rejection. In rare instances, recurrent or de novo native renal diseases can occur in the early post-transplant course, and they are important in the evaluation. Specialized laboratory studies, however, should always be selected with care and in appropriate clinical scenarios to ensure effective and cost-efficient laboratory utilization.

Usually, when renal allograft rejection is suspected, biopsy is warranted to confirm or rule out the diagnosis. Although there are limitations, such as representative and adequate sampling, renal biopsy remains the gold standard for assessing the mechanism and the severity of allograft injury. In general, a minimum of two 1-cm cores should be obtained for accurate assessment. While most of the specimen is processed and embedded in paraffin, small portions of the core biopsy will often also be sent for immunofluorescence microscopy and electron microscopy, 9 particularly for transplants in place for over 6 months.

Diagnostic Findings, Part 2

A biopsy is performed and an adequate sample containing 14 glomeruli is obtained. The findings were considered sufficient to establish the diagnosis of active T cell-mediated rejection. In the absence of clinical or laboratory evidence of other types of renal disease, it was elected to defer immunofluorescence and electron microscopy.

Question/Discussion Points, Part 2

What are the specific findings in the renal biopsy.

Routine histologic findings are illustrated in Figure 2A - ​ -D, D , with the C4d immunohistochemical stain in Figure 2E . All of the glomeruli show no histopathologic abnormality ( Figure 2A ). The tubulointerstitium is remarkable for the loss of tubules and a marked inflammatory infiltrate consisting predominantly of lymphocytes with few plasma cells and eosinophils ( Figure 2B ). Lymphocytes infiltrate into proximal tubular epithelium, in some places exceeding 10 lymphocytes per tubular cross section ( Figure 2C ). A few arteries contain lymphocytes within the intima (intimal arteritis, Figure 2D ), but there is no transmural infiltration or frank necrosis. An immunohistochemical stain for complement component C4d shows moderate staining in less than 10% of peritubular capillaries with nonspecific staining of tubular epithelium ( Figure 2E ).

Allograft kidney biopsy. A, Glomeruli are normal (periodic acid-Schiff stain, ×200). B, There is interstitial inflammation (hematoxylin and eosin stain, ×100). C, Tubulitis is present (arrowhead) (hematoxylin and eosin stain, ×400). D, Intimal arteritis is also present (arterial intima lymphocytic infiltration, arrowheads) (hematoxylin and eosin stain, ×200). E, There is focal peritubular capillary C4d staining (immunohistochemical stain, ×200).

How Do Pathologists Evaluate Renal Allograft Diseases?

Historically, pathologists described renal allograft abnormalities based on patterns of injury. 10 While this helped clinicians to understand the etiology of renal dysfunction, the lack of standardization caused significant interobserver variability as well as difficulty in creating treatment plans. A reporting schema was proposed by a group of renal pathologists, nephrologists, and transplant surgeons at an international conference in Banff, Canada, in 1991. 11 The proposed system evolved into the Banff Classification, which has been reviewed and updated every 2 years since then using evidence-based studies. It is now the gold standard for diagnosis of allograft disease in the kidney as well as other transplanted solid organs. It is widely accepted by pathologists and clinicians as it standardizes renal allograft biopsy reporting and allows meaningful comparison of clinical studies.

The Banff Classification considers several parameters, including (1) inflammation and resultant damage to any of the renal histologic compartments; (2) alterations in microscopic structure; (3) evidence of chronic injury; and (4) deposition of molecules associated with immune-mediated reactions. Numerous individual features are analyzed and assigned scores on a point-based system. The scores are then used in categorizing the overall observed lesions. The classification scheme provides a highly granular, objective method for evaluation of renal transplant biopsies.

For this patient, marked interstitial inflammation and tubulitis with mild vasculitis produces a Banff classification of active T cell-mediated rejection, Grade IIA. In addition, C4d staining may indicate additional antibody-mediated rejection. However, the staining is weak, and in the absence of microvascular injury or DSA, the finding is only suggestive.

How Is Acute Renal Allograft Rejection Treated?

Immunosuppression is crucial to prevent or mitigate damage from the recipient’s immune system. When rejection does occur, augmentation of immunosuppressive medications is the standard treatment. 12 Depending on the severity of inflammation, the dosage of the drugs will be adjusted and as renal function returns, tapered. Antithymocyte globulin may be administered in severe or nonresponsive cases of T cell-mediated rejection. This has a potent effect of T-lymphocyte depletion with resulting decrease and eventual elimination of the inflammatory reaction. 13

Treatment for antibody-mediated rejection, however, is not always as efficacious. While the primary goal is removal of cytotoxic donor-specific antibodies as well as the clonal B-cells that produce them, currently available treatment regimens have shown mixed results. 10 In addition to steroid administration and augmentation of immunosuppression, plasmapheresis and intravenous immunoglobulin may also be given to sequester donor-specific antibodies. In cases of severe rejection, anti-CD20 medication such as rituximab may also be considered.

Diagnostic Findings, Part 3

The patient is admitted to the transplant service and is promptly started on treatment with intravenous steroids and mycophenolate mofetil (an immunosuppressive agent that selectively inhibits B- and T-cell proliferation), in addition to his usual tacrolimus dose. Antithymocyte globulin is also administered when creatinine level remains markedly increased. Renal function eventually recovers over a 1-week period with creatinine levels gradually decreasing and an increasing glomerular filtration rate. The patient is discharged on a tapering dose of oral steroids, daily mycophenolate mofetil, and his previous dose of tacrolimus. At a follow-up appointment 1 week later, he feels well and both the GFR and creatinine level have returned to the normal range.

Questions/Discussion Points, Part 3

What should be the long-term management plan for this patient.

The primary goal of transplant care management is to maximize the longevity of allograft organ while minimizing possible treatment-related complications. 14 To prevent recurrent acute rejection episodes and onset of chronic organ rejection, maintaining immunosuppressant medication levels within therapeutic ranges is paramount. Additionally, other than routine laboratory testing ( Table 3 12 , 14 ), prevention of infection in these immunosuppressed patients is crucial. In this context, there is a window for opportunistic infections, leading to morbidity and in some cases mortality. Other important factors to consider as parts of long-term management include proper patient education, social support, and access to medication. Involving the patient, the family members, and even social services is vital to optimize the complex regimen and clinical outcome. As such, building a strong rapport between the patient and the transplant nephrology specialists and primary care physicians is essential to monitor renal function as well as to maintain an overall healthy lifestyle.

This Table Outlines a Set of Routine Laboratory Tests/Recommendations That Specialists or Primary care Physicians Should Monitor in Transplant Recipients. 12 , 14 , *

* Although a general clinical guideline was established by the 2009 Kidney Disease: Improving Global Outcomes (KDIGO), the types and the frequency of testing should be individualized and discussed with the patients, based on their health conditions.

† Including serum level of sodium, potassium, magnesium, calcium, and phosphates.

‡ Including levels of vitamin D and parathyroid hormone.

§ Control modifiable risk factor such as smoking, drinking, weight control, and dietary intake.

Teaching Points

• Solid organ rejection in a kidney transplant recipient, while complex and multifactorial in nature, is a result of imbalance between host immune response to the allograft and immunosuppressive therapy.
• Rejection must be differentiated from a host of other inflammatory processes that may affect the kidney, including infections, drug toxicity, and recurrent or de novo nonrejection renal disease.
• Transplant rejection may be T lymphocyte-mediated or antibody-mediated. Each has distinctive histopathological findings, but both types of rejection may occur together, complicating biopsy interpretation.
• T lymphocyte-mediated rejection is most commonly seen in the first 6 months after transplantation and has a well-elucidated pathophysiology.
• Antibody-mediated rejection more commonly occurs later in the post-transplantation course, and our understanding of its pathophysiology is still evolving.
• Although clinical findings are sensitive for detecting allograft dysfunction, kidney biopsy remains the gold standard in diagnosing organ rejection.
• The Banff classification is a detailed schema for characterizing the nature and extent of kidney transplant rejection in order to guide treatment.
• Regular follow-up and laboratory testing are essential for prolonging the longevity of the transplant kidney and maximizing the quality of life of transplant patients.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.