In JoVE (1)

Other Publications (53)

Articles by Rita R. Alloway in JoVE

 JoVE Medicine

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

1iC42 Clinical Research and Development, University of Colorado, Anschutz Medical Campus, 2Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3Food and Drug Administration (FDA), Center of Drug Evaluation Research - Office of Generic Drugs, 4Transplant Clinical Research, University of Cincinnati

JoVE 52424

Other articles by Rita R. Alloway on PubMed

Strategies to Reduce Toxicities and Improve Outcomes in Renal Transplant Recipients

Pharmacotherapy. Mar, 2002  |  Pubmed ID: 11898890

Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.

A Multicenter, Open-label, Comparative Trial of Two Daclizumab Dosing Strategies Vs. No Antibody Induction in Combination with Tacrolimus, Mycophenolate Mofetil, and Steroids for the Prevention of Acute Rejection in Simultaneous Kidney-pancreas Transplant Recipients: Interim Analysis

Clinical Transplantation. Feb, 2002  |  Pubmed ID: 11982617

The safety and efficacy of daclizumab (1 mg/kg/dose every 14 d for five doses) has been established in kidney and heart transplant recipients. Alternative dosing regimens based on pharmacokinetic simulation and limited clinical trials are being investigated. The purpose of this ongoing multicenter study is to determine the safety and efficacy of two dosing regimens of daclizumab as an adjunctive immunosuppressive agent compared with no antibody induction in simultaneous kidney-pancreas transplant (SKPT) recipients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids as primary immunosuppression.

Impact of Hepatitis C Virus Status in Pancreas Transplantation: a Case Controlled Study

Clinical Transplantation. Aug, 2002  |  Pubmed ID: 12099979

Available data suggest that hepatitis C virus positive (HCV+) renal transplant patients may be at an increased risk of morbidity and mortality compared with HCV- patients. Limited data are available regarding the impact of HCV status in pancreas transplant patients. We compared the outcomes of 10 HCV+ patients undergoing pancreas transplantation (seven simultaneous kidney-pancreas, one pancreas after kidney, two pancreas alone) between 1/96 and 10/99 with 20 HCV- recipients that were matched for age, race, gender, timing of transplant, type of pancreas transplant, and surgical technique. Length of follow-up was not significantly different between the HCV+ group compared with the HCV- group (24 +/- 14 vs. 20 +/- 13 months; p=0.45). There was a trend toward a higher incidence of all cause mortality in HCV+ recipients compared with HCV- recipients, 30 vs. 10%, respectively (p=0.17). Additionally, the HCV+ recipients had a trend toward a higher incidence of sepsis-related mortality compared with HCV- recipients, 20 vs. 5%, respectively (p=0.19). Renal allograft survival was 50% in the HCV+ group compared with 94% in the HCV- group (p=0.02). Pancreas allograft survival was not significantly different between the groups, 60 vs. 80%, respectively (p=0.24). At 3, 6, 12 months, and end of follow-up, there were no differences in serum creatinine, amylase, C-peptide, or fasting glucose levels. However, there was a significantly higher incidence of proteinuria at last follow-up in the HCV+ recipients with a renal allograft when compared with HCV- recipients, 50 vs. 12.5%, respectively (p=0.05). In order to maintain comparable glycemic control between the groups, there was a significant increase in oral hypoglycemic requirement in HCV+ recipients compared with HCV- recipients, 33 vs. 0%, respectively (p=0.01). These data suggest that HCV+ pancreas transplant patients may be at an increased risk of graft dysfunction and morbidity. Further studies with more patients and longer follow-up are needed to fully define the impact of HCV status on pancreas graft survival and function.

Thymoglobulin for Induction or Rejection Therapy in Pancreas Allograft Recipients: a Single Centre Experience

Clinical Transplantation. 2002  |  Pubmed ID: 12372042

To review the safety and efficacy of thymoglobulin in pancreas transplant patients receiving tacrolimus and mycophenolate mofetil.

MALToma: a Helicobacter Pylori-associated Malignancy in Transplant Patients: a Report from the Israel Penn International Transplant Tumor Registry with a Review of Published Literature

Transplantation. Jan, 2003  |  Pubmed ID: 12548128

Mucosa-associated lymphoid tissue lymphoma (MALToma) is a Helicobacter pylori-related tumor of B-cell origin, the malignant potential for which remains to be defined in immunosuppressed patients.

Two-dose Daclizumab Regimen in Simultaneous Kidney-pancreas Transplant Recipients: Primary Endpoint Analysis of a Multicenter, Randomized Study

Transplantation. Apr, 2003  |  Pubmed ID: 12717213

Controversy exists about the optimal immunosuppressive regimen in simultaneous kidney-pancreas transplant (SKPT) recipients. This study determined the safety and efficacy of two dosing regimens of daclizumab compared with no antibody induction in SKPT recipients receiving tacrolimus, mycophenolate mofetil, and steroids.

The Effect of CYP3A5 and MDR1 Polymorphic Expression on Cyclosporine Oral Disposition in Renal Transplant Patients

Journal of Clinical Pharmacology. Jun, 2003  |  Pubmed ID: 12817518

Variability in CYP3A (CYP3A4/5) and P-glycoprotein (human MDR1 gene product) activity underlies interindividual differences in oral cyclosporine (CsA) bioavailability. Racial differences in polymorphic expression of CYP3A5 and MDR1 may explain observed interracial variability in oral bioavailability. Our objective was to evaluate the effect of CYP3A5 and MDR1 polymorphic expression on CsA oral disposition. Steady-state plasma concentration profiles (n = 19) were sampled in renal transplant recipients receiving concentration-adjusted CsA maintenance therapy. CsA plasma concentrations were measured by fluorescence polarization immunoassay. CYP3A5 and MDR1 genotypes were determined by real-time polymerase chain reaction. Noncompartmental pharmacokinetic analysis and nonlinear mixed-effects modeling (NONMEM) were performed to assess the effect of genotype on CsA pharmacokinetics. MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. CsA oral clearance was significantly higher in subjects who carried at least one 3435T allele compared to homozygous wild-type individuals (40.0 +/- 2.2 vs. 26.4 +/- 3.1 L/h, p = 0.007). MDR1 C3435T genotype accounted for 43% of the interindividual variability of CsA oral clearance in the study population after accounting for interoccasion variability. The authors were unable to independently assess whether CYP3A5 correlated with any CsA pharmacokinetic parameter since all CYP3A5 nonexpressors were also 3435T allele carriers. MDR1 3435T allele carriers have enhanced oral clearance compared to individuals with the CC genotype. The frequency of the 3435T allele is lower in African Americans compared to Caucasians. Thus, the MDR1 C3435T genotype offers a potential mechanistic basis to explain interracial differences in CsA oral bioavailability. Further studies are needed to explore the relationship between CYP3A5 and MDR1 genotype and phenotype.

Report of the American Society of Transplantation Conference on Immunosuppressive Drugs and the Use of Generic Immunosuppressants

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Oct, 2003  |  Pubmed ID: 14510694

Considerable economic and health-related costs are associated with the life-long maintenance immunosuppressive therapy required to prevent transplant rejection. Generic medications have the potential of providing equivalent therapeutic efficacy at a lower economic cost. In 2001, the American Society of Transplantation invited experts to review the data and issues associated with the approval and use of generic immunosuppressants. A summary of that meeting is reported here. The generic medication approval process has been in effect for more than 30 years. All marketed generic cyclosporin formulations have met FDA criteria demonstrating bioequivalence in healthy subjects, and some were also tested in transplant recipients. Most participants agreed that generic narrow therapeutic index immunosuppressive agents provide adequate de novo immunosuppression in low-risk transplant recipients. However, some participants expressed concern regarding the currently unquantified risk that may be associated with switching immunosuppressive agents under uncontrolled circumstances. There was broad agreement among the participants that generic medications should be clearly labeled and distinguishable from innovator drugs, and that patients should be educated to inform their physicians of any switch to or among generic alternatives. There was also strong support in favor of requiring studies to demonstrate bioequivalence in potentially at-risk patient populations, specifically African-Americans and pediatric patients.

The Israel Penn International Transplant Tumor Registry

AMIA ... Annual Symposium Proceedings / AMIA Symposium. AMIA Symposium. 2003  |  Pubmed ID: 14728556

The Israel Penn International Transplant Tumor Registry is literally the world's premier repository of information on patients who have developed malignancies after organ transplants. The administrators of the Registry not only collect information but also provide consulting services based on the accumulated knowledge that the Registry contains. By creating a secure Web-based front end, we have made it possible for the Registry to keep pace with its burgeoning international caseload.

Polyomavirus Nephropathy in Kidney Transplantation

Progress in Transplantation (Aliso Viejo, Calif.). Jun, 2004  |  Pubmed ID: 15264457

Polyomavirus nephropathy has become an important complication in kidney transplantation, with a prevalence of 1% to 8%. Unfortunately, the risk factors for polyomavirus nephropathy and renal allograft loss are not well defined. The definitive diagnosis is made through assessment of a kidney transplant biopsy. Recently, noninvasive urine and serum markers have been used to assist in polyomavirus nephropathy diagnosis and monitoring. Primary treatment is immunosuppression reduction, but must be balanced with the risks of rejection. No antiviral treatments for polyomavirus nephropathy have been approved by the Food and Drug Administration. Although cidofovir has shown in vitro activity against murine polyomaviruses, and has been effective in some patients, it is associated with significant nephrotoxicity. Graft loss due to polyomavirus nephropathy should not be a contraindication to retransplantation; however, experience is limited. This review presents potential risk factors, screening, diagnostic and monitoring methods, therapeutic management, and retransplantation experience for polyomavirus nephropathy.

Donor Transmitted Malignancies

Annals of Transplantation : Quarterly of the Polish Transplantation Society. 2004  |  Pubmed ID: 15478892

Early experiences in transplantation, which pre-dated brain death laws, utilized organs from donors with active malignancies. The use of organs from such donors occasionally resulted in the transmission of malignancy from the donor to an unknowing recipient. Over a period of three decades, Israel Penn, M. D. catalogued some two hundred and fifty cases of organs transplanted from donors with a history of malignancy; carefully examining each reported case for tumor histology, donor risk factors, method of tumor presentation and recipient outcome. Some recipients never developed malignancies, while others were less fortunate, developing cancers that were suspicious for donor origin. The evolution of transplantation has resulted in improved patient survival, which in turn has led to an increased demand for organ transplantation. Unfortunately, the supply of organs available for transplantation has failed to keep pace with the demand, with the worldwide deficit growing annually. In an effort to bridge the widening gap, utilization of older and more marginal donors has been suggested. However, use of older donors is accompanied by the likelihood that a significant proportion may have undiagnosed malignancies. Multiple transplant programs have considered the use of donors with tumors of non-malignant or even low-grade malignant histology, most often involving the central nervous system (CNS). According to a survey from the United Network for Organ Sharing (UNOS), central nervous system malignancies are among the most commonly identified malignancies found in potential donors. This study examines the distribution of potential donor transmitted malignancies reported to the Israel Penn International Transplant Tumor Registry. The incidence of tumor transmission is examined in the overall group as well as among individual histologies. We also seek to identify specific factors associated with the risk of malignancy transmission from donor to recipient, in an effort to minimize future transmission of donor tumors to unwitting recipients. The study is based on voluntary registry data, which some argue can be criticized for a lack of true incidence data. In reality, however, this data may provide a more accurate insight since it is based on transmissions from high-risk donors rather than from the general population.

Recurrence Risk After Organ Transplantation in Patients with a History of Hodgkin Disease or Non-Hodgkin Lymphoma

Transplantation. Oct, 2004  |  Pubmed ID: 15480161

This study defines the incidence and recurrence risk of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) after organ transplant. Patients from the United States with a history of HD or NHL before organ transplantation reported to the Israel Penn International Transplant Tumor Registry from 1968 to 2001 were analyzed. A total of 91 patients underwent organ transplantation with a lymphoma history: HD (38 patients) and NHL (53 patients). Median disease-free interval pretransplant was 99 (range 0-459.1) months, and median follow-up posttransplant was 25.7 (0.4-131.1) months. Ten patients were excluded from further analysis because of lack of follow-up information (n=9) or they never achieved remission (n=1). Recurrence incidence was 8 of 81 patients (10%) (HD=3/34 [9%] vs. NHL=5/47 [11%]). Gender, race, allograft type and source, age at lymphoma diagnosis, and immunosuppression did not influence recurrence. Patients with less than a 2-year period between diagnosis and transplant seem to be at increased risk of relapse. Median disease-free interval before transplant was longer for patients without recurrence (115 vs. 30.2 months, P=0.24), but was not statistically significant. Median time to recurrence posttransplant was 18.7 (range 1.9-82.2) months (HD=3.7 vs. NHL 23.6 months, P=0.10). Survival after recurrence was poor (HD [1/3] and NHL [1/5], median survival 6.8 [range 0-22.1] months). There is no difference in recurrence rates for HD and NHL. The outcome for recurrent lymphoma is poor. The low risk of recurrence (10%) indicates that preexisting HD and NHL need not be an absolute contraindication to transplantation.

Posttransplant Malignancy

Progress in Transplantation (Aliso Viejo, Calif.). Sep, 2004  |  Pubmed ID: 15495778

In the past few decades, great advances have been made in the field of solid-organ transplantation. A greater understanding of immune system function, the development of modern immunosuppression, and advancements in surgical technique have led to marked improvements in both recipient and graft survivals, as well as recipients' quality of life. However, improved survival rates have also led to prolonged exposure to chronic immunosuppression, which increases the risk for the development of posttransplant malignancies. In addition, older transplant candidates are being considered, carrying with them the increased likelihood of preexisting malignancy. Consequently, the potential risk of posttransplant malignancy must be considered. Moreover, as long-term transplant survivors continue to age, posttransplant malignancies will be seen more frequently. This review presents the more commonly encountered posttransplant malignancies and the measures that are currently being utilized to prevent and treat them.

Experience with 274 Cardiac Transplant Recipients with Posttransplant Lymphoproliferative Disorder: a Report from the Israel Penn International Transplant Tumor Registry

Transplantation. Dec, 2004  |  Pubmed ID: 15591959

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication that occurs in a small but significant minority of solid organ transplant recipients. Published experiences with PTLD in cardiac transplant recipients are limited to relatively small single-center reports.

Characteristics and Survival Patterns of Solid Organ Transplant Patients Developing De Novo Colon and Rectal Cancer

Diseases of the Colon and Rectum. Nov, 2004  |  Pubmed ID: 15622583

Immunosuppression used in transplantation is associated with an increased incidence of various cancers. Although the incidence of colorectal cancer in transplant patients seems to be equal to nontransplant population, the effects of immunosuppression on patients who develop colorectal cancer are not well defined. The purpose of this study was to define the characteristics and survival patterns of transplant patients developing de novo colorectal cancer.

Basic and Clinical Research in Polyomavirus Nephropathy

Experimental and Clinical Transplantation : Official Journal of the Middle East Society for Organ Transplantation. Jun, 2004  |  Pubmed ID: 15859923

Over the last decade, polyomavirus nephropathy (PVN) has emerged as an important cause of renal allograft dysfunction and graft loss. PVN occurs with a prevalence of 1%-8% in renal transplant recipients and is most commonly reported within the first 12 months posttransplant. The human polyomavirus, BK virus, is thought to be the primary etiologic agent of PVN. Risk factors for PVN are not well defined and are most likely a result of a complex interaction between multiple donor and recipient factors. Definitive diagnosis of PVN is made through histological assessment of a renal allograft biopsy. Recent studies have also evaluated noninvasive urine and serum markers for screening of BK virus replication and as adjunct tools in PVN diagnosis and monitoring. The principal treatment for PVN is immunosuppression reduction, but this must be balanced against the risks of rejection. If rejection occurs concurrently with PVN, a brief increase in immunosuppression to treat the rejection episode followed by a subsequent reduction in immunosuppression is recommended. No antiviral treatments for PVN have been approved by the Food and Drug Administration. Although the antiviral drug cidofovir has shown in vitro activity against murine polyomaviruses, and has been effective in some patients, it is associated with significant nephrotoxicity. Small series of patients treated with leflunomide and intravenous immune globulin therapy for PVN have also recently been reported. Retransplantation after graft loss due to PVN is feasible, but experience is limited. Current research is focusing on identifying PVN risk factors, refining screening, diagnostic and monitoring methods, and developing therapy for prophylaxis and treatment of PVN with the goals of decreasing the prevalence of PVN and improving allograft outcomes in renal transplant recipients diagnosed with PVN. This review will present recent advances in basic and clinical research related to PVN and renal transplantation.

African-American Renal Transplant Recipients Benefit from Early Corticosteroid Withdrawal Under Modern Immunosuppression

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Feb, 2005  |  Pubmed ID: 15643996

African-Americans (AAs) have historically been considered high-risk renal transplant recipients due to increased rejection rates and reduced long-term graft survival. As a result, AAs are often excluded from corticosteroid withdrawal (CSWD) protocols. Modern immunosuppression has reduced rejections and improved graft survival in AAs and may allow successful CSWD. Outcomes in 56 AAs were compared to 56 non-AAs. All patients were enrolled in one of four early CSWD protocols. Results are reported as AA versus non-AA. Acute rejection at 1-year was 23% and 18%; (p = NS); creatinine clearance at 1-year was 75 versus 80 mL/min (p = NS); patient and graft survival was 96% versus 98% and 91% versus 91%; (p = NS). AAs benefit from early CSWD with significantly improved blood pressure, LDL < 130 mg/dL and HDL > 45 mg/dL at 1-year, post-transplant diabetes of 8.7%, and mean weight change at 1-year of 4.8 +/- 7.2 kg. In conclusion, early CSWD in AAs is associated with acceptable rejection rates, excellent patient and graft survival, and improved cardiovascular risk, indicating that the risks and benefits of early CSWD are similar between AAs and non-AAs. Additional follow-up is needed to determine long-term renal function, graft survival, and cardiovascular risk in AAs with early CSWD.

United Network for Organ Sharing Publication on Scientific Registry of Transplant Recipients Central Nervous System Donor Cancer Transmission Data

Transplantation. Mar, 2005  |  Pubmed ID: 15753859

Analysis of Factors That Influence Survival with Post-transplant Lymphoproliferative Disorder in Renal Transplant Recipients: the Israel Penn International Transplant Tumor Registry Experience

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Apr, 2005  |  Pubmed ID: 15760401

Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1-310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.

Body Weight Alterations Under Early Corticosteroid Withdrawal and Chronic Corticosteroid Therapy with Modern Immunosuppression

Transplantation. Jul, 2005  |  Pubmed ID: 16003229

Weight gain is a known complication of corticosteroid maintenance therapy. The purpose of the present study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) with that observed under early (i.e., within 7 days posttransplant) corticosteroid withdrawal (CSWD) in renal-transplant recipients.

Multivariate Analysis of Risk Factors for Acute Rejection in Early Corticosteroid Cessation Regimens Under Modern Immunosuppression

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Nov, 2005  |  Pubmed ID: 16212635

The purpose of this study was to define risk factors for acute rejection with early corticosteroid withdrawal (CSWD; within 7 days posttransplant) in renal transplantation. Data from prospective, IRB-approved early CSWD trials were analyzed. Overall acute rejection rate in 308 patients was 17.1%. Acute rejection rates and observed risks (OR) in patients with individual risk factors were: repeat transplants 38.6%; current PRA >25%; 29.4%; African Americans 23.5%; delayed graft function (DGF) 26.1%; HLA DR mismatches >0 17.9%; female gender 19.7%; Thymoglobulin induction 15.3%; type 1 diabetes 30.8%; type 2 diabetes 11.1%; deceased donor recipients 21%; and living donor recipients 14%. Logistic regression analysis provided the following risks (OR) for acute rejection: repeat transplant 2.51; current PRA > 25% 1.53; African Americans 1.47; DGF 1.58; HLA DR mismatches > 0 1.61; female gender 1.43; Thymoglobulin induction 0.61; type 1 diabetes 2.23, type 2 diabetes 0.5, deceased donor recipients 1.11, and living donor recipients 0.9. Risk factors for acute rejection under early corticosteroid withdrawal are similar to those previously defined under chronic corticosteroid therapy. These observations provide implications for future CSWD trials including: use of T cell depleting antibody induction therapy (thymoglobulin) to reduce acute rejection risk, 2) enrollment stratification for high risk groups, and 3) modified immunosuppression for high risk groups.

Can Immunonutrients Reduce Rejection Rates in African Americans?

Experimental and Clinical Transplantation : Official Journal of the Middle East Society for Organ Transplantation. Dec, 2005  |  Pubmed ID: 16417441

African-American kidney allograft recipients have higher rates of rejection than do white patients. This study was performed to determine whether the use of immunonutrients may reduce the incidence of rejection in African Americans.

How Can Donors with a Previous Malignancy Be Evaluated?

Journal of Hepatology. Oct, 2006  |  Pubmed ID: 16919360

Monitoring of Inosine Monophosphate Dehydrogenase Activity As a Biomarker for Mycophenolic Acid Effect: Potential Clinical Implications

Therapeutic Drug Monitoring. Apr, 2007  |  Pubmed ID: 17417067

Mycophenolic acid (MPA) is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and, in combination with other immunosuppressive drugs, effectively inhibits rejection in solid organ transplant recipients. MPA has a relatively narrow therapeutic window and exhibits wide inter- and intrapatient pharmacokinetic (PK) variability. This has stimulated the use of therapeutic drug monitoring as a strategy to tailor the MPA exposure to each patient's individual needs. Despite increasing therapeutic drug monitoring use, PK-assisted dosing is not universally adopted in part because of MPA's complex PK behavior. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic (PD) marker of MPA-induced immunosuppression may allow for increased precision when used in an integrated PK-PD fashion, providing a more accurate assessment of efficacy and aid in limiting toxicity. IMPDH activity displays wide interpatient variability but relatively small intrapatient variability even after long-term administration of MPA. The advent of calcineurin and corticosteroid-sparing regimens necessitates more patient-specific PK-PD parameters, which can be used throughout the posttransplant period to optimize MPA exposure and immediate and long-term graft and patient outcomes. Quantification of IMPDH posttransplant may serve as a stable, surrogate PD marker of MPA-induced immunosuppression when combined with current PK and monitoring strategies.

Renal Transplantation in High-risk Patients

Drugs. 2007  |  Pubmed ID: 17661529

Renal transplantation in high-risk patients is a growing phenomenon. More patients are progressing to endstage renal failure, in the setting of an increased incidence of diabetes mellitus and cardiovascular disease. Current organ shortages and the use of more marginal donors have affected both patient and graft survival. Acute rejection has been minimised under modern immunosuppression; however, patient and long-term allograft outcomes have not improved concurrently. Specific understanding of donor, recipient and allograft variables associated with stratification of patients as 'high risk for renal transplantation' is necessary to facilitate appropriate peri- and post-transplant pharmacotherapy. Induction and maintenance immunosuppression choices are different for high-risk patients and must be made to ensure optimal immunosuppression, while limiting patient and allograft toxicity.

Risk Assessment of Immunosuppressive Therapy in Facial Transplantation

Plastic and Reconstructive Surgery. Sep, 2007  |  Pubmed ID: 17700117

Immunosuppression-related risks are foremost among ethical concerns regarding facial transplantation. However, previous risk estimates are inaccurate and misleading, because they are based on data from studies using different immunosuppression regimens, health status of the transplant recipients, tissue composition, and antigenicity. This review provides a comprehensive risk assessment for facial transplantation based on comparable data of immunosuppression, recipient health status, and composition and antigenicity of the transplanted tissue.

Composite Tissue Allotransplantation: a Review of Relevant Immunological Issues for Plastic Surgeons

Journal of Plastic, Reconstructive & Aesthetic Surgery : JPRAS. 2008  |  Pubmed ID: 18248779

Composite tissue allotransplantation of hand, facial and other tissues is now a clinical reality. The terminology, treatment principles, drug combinations, dosage schedules and mechanisms of the immunosuppression medications on which contemporary transplant surgery is based are unfamiliar to plastic surgeons and most healthcare providers outside the field of transplantation medicine. With this in mind, the purpose of this manuscript is to provide plastic surgeons with a comprehensive and understandable review of key immunological principles relevant to composite tissue allotransplantation.

Plastic Surgeon's Risk Acceptance in Facial Transplantation

Plastic and Reconstructive Surgery. Mar, 2008  |  Pubmed ID: 18317085

A great deal of ethical debate has accompanied the introduction of facial tissue allotransplantation into the clinical arena. Critics contend that the risks of lifelong immunosuppression do not justify the benefits of this new non-life-saving reconstructive procedure, whereas proponents argue that they do. Absent from this debate are the opinions of individuals with real-life experiences with the risks and benefits associated with this new treatment.

Cardiovascular Risk, Cardiovascular Events, and Metabolic Syndrome in Renal Transplantation: Comparison of Early Steroid Withdrawal and Chronic Steroids

Clinical Transplantation. Mar-Apr, 2008  |  Pubmed ID: 18339144

Cardiovascular disease (CVD) is the leading cause of death with a functioning graft in renal transplant recipients. The purpose of this study was to compare Framingham Risk Score (FRS), metabolic syndrome (MS), and cardiovascular events (CVE) in patients receiving early corticosteroid withdrawal (ECSWD), or chronic corticosteroid therapy (CCS).

Pharmacokinetics of Mycophenolic Acid, Tacrolimus and Sirolimus After Gastric Bypass Surgery in End-stage Renal Disease and Transplant Patients: a Pilot Study

Clinical Transplantation. May-Jun, 2008  |  Pubmed ID: 18482049

Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population.

Bortezomib Provides Effective Therapy for Antibody- and Cell-mediated Acute Rejection

Transplantation. Dec, 2008  |  Pubmed ID: 19104417

Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy.

A Prospective Trial of a Steroid-free/calcineurin Inhibitor Minimization Regimen in Human Leukocyte Antigen (HLA)-identical Live Donor Renal Transplantation

Transplantation. Feb, 2009  |  Pubmed ID: 19202447

Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transplantation exist. This prospective study evaluated a corticosteroid (CS)-free, calcineurin inhibitor (CNI) minimization immunosuppressive regimen in HLA-identical LD renal transplant recipients.

De Novo Cancers Arising in Organ Transplant Recipients Are Associated with Adverse Outcomes Compared with the General Population

Transplantation. May, 2009  |  Pubmed ID: 19424035

Transplant recipients are at increased risk of malignancy; however, the influence of transplantation on cancer outcomes has not been rigorously defined. The purpose of this study was to examine the influence of transplantation on the outcomes of individual cancers.

Proteasome Inhibition for Antibody-mediated Rejection

Current Opinion in Organ Transplantation. Dec, 2009  |  Pubmed ID: 19667989

The purpose of this review is to describe the biochemistry and physiology of proteasome inhibition and to discuss recent studies with proteasome inhibitor therapy in organ transplantation.

Bortezomib for Refractory Antibody-mediated Cardiac Allograft Rejection

Clinical Transplants. 2009  |  Pubmed ID: 20524318

This experience demonstrates that a bortezomib-based regimen provided effective therapy for late, refractory AMR in an adult heart transplant recipient and was well tolerated. This remarkably positive experience despite the refractory nature of the AMR episode argues strongly for continued evaluation of bortezomib use in this patient population.

Proteasome Inhibitor-based Primary Therapy for Antibody-mediated Renal Allograft Rejection

Transplantation. Feb, 2010  |  Pubmed ID: 20145517

Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented.

Four-year Experience with Tacrolimus Once-daily Prolonged Release in Patients from Phase II Conversion and De Novo Kidney, Liver, and Heart Studies

Clinical Transplantation. Jan-Feb, 2011  |  Pubmed ID: 21158926

This study assessed the long-term effects of prolonged-release tacrolimus (Advagraf(®) [Tacrolimus QD]), which has been developed to provide similar efficacy and safety to twice-daily tacrolimus (Prograf(®) [Tacrolimus BID]) with the added benefit of once-daily dosing.

Early and Late Acute Antibody-mediated Rejection Differ Immunologically and in Response to Proteasome Inhibition

Transplantation. Jun, 2011  |  Pubmed ID: 21617586

The efficacy of plasma cell targeted therapies for antibody-mediated rejection (AMR) has not been defined in detail. The purpose of this study was to compare early and late acute AMR in terms of immunologic characteristics and responses with proteasome inhibitor (PI) therapy.

Proteasome Inhibitor Treatment of Antibody-mediated Allograft Rejection

Current Opinion in Organ Transplantation. Aug, 2011  |  Pubmed ID: 21753709

Bortezomib is a first-in-class proteasome inhibitor that was originally Food and Drug Administration approved for the treatment of multiple myeloma. In the past few years, off-label use in solid organ transplant recipients has demonstrated its ability to provide plasma cell-targeted therapy in humans. The purpose of this review is to provide an update of recent basic science and clinical results with bortezomib in treating antibody-mediated rejection (AMR) that occurs in solid organ transplant recipients.

Clinical and Investigational Use of Proteasome Inhibitors for Transplant Rejection

Expert Opinion on Investigational Drugs. Nov, 2011  |  Pubmed ID: 21916809

The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) in patients experiencing acute cellular rejection and antibody-mediated rejection (AMR) is associated with poor renal allograft survival in kidney transplant recipients. Traditional therapies for AMR provide variable results, and do not deplete the cellular source of antibody production, that is, the plasma cell.

Proteasome Inhibitor-based Therapy for Antibody-mediated Rejection

Kidney International. Jun, 2012  |  Pubmed ID: 22336990

The development of donor-specific anti-human leukocyte antigen antibodies (DSAs) following renal transplantation significantly reduces long-term renal graft function and survival. The traditional therapies for antibody-mediated rejection (AMR) have provided inconsistent results and transient effects that may be due to a failure to deplete mature antibody-producing plasma cells. Proteasome inhibition (PI) is a novel AMR therapy that deletes plasma cells. Initial reports of PI-based AMR treatment in refractory rejection demonstrated the ability of bortezomib to deplete plasma cells producing DSA, reduce DSA levels, provide histological improvement or resolution, and improve renal allograft function. These results have subsequently been confirmed in a multicenter collaborative study. PI has also been shown to provide effective primary AMR therapy in case reports. Recent studies have demonstrated that PI therapy results in differential responses in early and late post-transplant AMR. Additional randomized studies are evaluating the role of PI in transplant induction, acute AMR, and chronic rejection in renal transplantation. An important theoretical advantage of PI-based regimens is derived from several potential strategies for achievement of synergy.

Proteasome Inhibition for Antibody-mediated Allograft Rejection

Seminars in Hematology. Jul, 2012  |  Pubmed ID: 22726550

Antibody-mediated rejection (AMR) is a major risk factor for graft loss following kidney transplantation. Traditional anti-humoral therapies provide suboptimal therapy and they do not deplete plasma cells, which are the source of antibody production. Proteasome inhibitors (PI) have been shown to deplete both transformed and nontransformed plasma cells in human transplant recipients and animal models; and therefore, offer a new paradigm for AMR, ie, plasma cell-targeted therapy. Bortezomib, a first in class proteasome inhibitor approved by the US Food and Drug Administration for treatment of multiple myeloma, has been used to treat AMR in several solid organ transplant recipients. The greatest experience with PI therapy for treating AMR is in kidney transplant recipients. Experiences to date with PI therapy have demonstrated that: (1) early AMR (within the first 6 months post-transplant) responds better than late AMR, and (2) the nature of the plasma cell clonal population influences sensitivity to PI therapy with plasma subsets greater than long-lived bone marrow niche-resident plasma cells. In conclusion, plasma cell-targeted therapy with PIs is a method for targeting plasma cells (the source of antibody production) with a well-elucidated mechanism of action and subsequent points of synergy, thereby providing an exciting new potential means for enhancing anti-humoral therapies.

Prospective Evaluation of the Toxicity Profile of Proteasome Inhibitor-based Therapy in Renal Transplant Candidates and Recipients

Transplantation. Aug, 2012  |  Pubmed ID: 22836132

A prospective intermediate-term evaluation of toxicities associated with bortezomib therapy for antibody-mediated rejection (AMR) and desensitization was conducted.

Acute Rejection Characteristics from a Prospective, Randomized, Double-blind, Placebo-controlled Multicenter Trial of Early Corticosteroid Withdrawal

Transplantation. Feb, 2013  |  Pubmed ID: 23423269

This report characterizes acute rejection and rejection outcomes in subjects randomized to continuous corticosteroid therapy (CCS) or early corticosteroid withdrawal (CSWD; 7 days after transplantation) in the Astellas Blinded CSWD Trial.

Conversion from Twice-daily Tacrolimus Capsules to Once-daily Extended-release Tacrolimus (LCPT): a Phase 2 Trial of Stable Renal Transplant Recipients

Transplantation. Jul, 2013  |  Pubmed ID: 23715050

LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability to twice-daily tacrolimus capsules and no new safety concerns.

Management of Antibody-mediated Rejection in Transplantation

The Surgical Clinics of North America. Dec, 2013  |  Pubmed ID: 24206861

Despite intensive traditional immunosuppressive therapy, rates of graft loss have approximated 15% to 20% at 1 year following antibody-mediated rejection (AMR) in solid organ transplant recipients. Therefore, the development of antihumoral therapies that provide prompt elimination of donor-specific anti-HLA antibodies and improve allograft survival is an important goal. Traditional treatment modalities for AMR deplete B-cell populations but not the cell at the source of antibody production, the mature plasma cell. Plasma cell-targeted therapies using proteasome inhibition is a novel approach to treating AMR. This review discusses current and emerging treatment modalities used for AMR.

Plasma Cell Biology: Principles for Therapeutic Design

Clinical Transplants. 2013  |  Pubmed ID: 25095519

Plasma cells represent the terminally differentiated cell population of the B-lymphocyte lineage. Plasma cells possess a unique biology, primarily as a result of their role as antibody factories. The unique features associated with the massive antibody production capacity confer upon the plasma cell a vulnerability to attack by specific targeted therapies. Over the past nine years, we have worked to develop therapies that exploit the unique features of plasma cells - therapies we have termed plasma cell targeted therapies. To date, these therapies have been almost exclusively based on proteasome inhibitor therapy, which has been used to treat antibody-mediated rejection and also to reduce chronic human leukocyte antigen antibody production via therapies commonly referred to as "desensitization." Future iterations of plasma cell targeted regimens, however, are more likely to depend on combination therapies designed specifically to achieve additivity and preferably synergy, using either small molecule inhibitors of metabolic pathways or alternatively, biologic agents. As such, these plasma cell targeted therapies provide a new approach for treating acute and chronic antibody responses in humans, not only in transplantation, but also in other disease states including autoimmune disease.

Conversion from Twice Daily Tacrolimus Capsules to Once Daily Extended-release Tacrolimus (LCP-Tacro): Phase 2 Trial of Stable Liver Transplant Recipients

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. May, 2014  |  Pubmed ID: 24493215

LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax , Cmax /Cmin ratio, percent fluctuation and swing were significantly (P<0.001) lower and Tmax significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were ≥0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough fluctuations. LCP-Tacro administered over one year was well tolerated with no new safety concerns.

Bortezomib-based Antibody-mediated Rejection Therapy and Simultaneous Conversion to Belatacept

Transplantation. Feb, 2014  |  Pubmed ID: 24531826

Desensitization in Kidney Transplantation: Review and Future Perspectives

Clinical Transplantation. Apr, 2014  |  Pubmed ID: 24621089

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg.

Review of Bortezomib Treatment of Antibody-mediated Rejection in Renal Transplantation

Antioxidants & Redox Signaling. Dec, 2014  |  Pubmed ID: 24635140

Development of donor-specific antibodies (DSA) after kidney transplantation is associated with reduced allograft survival. A few strategies have been tested in controlled clinical trials for the treatment of antibody-mediated rejection (AMR), and no therapies are approved by regulatory authorities. Thus development of antihumoral therapies that provide prompt elimination of DSA and improve allograft survival is an important goal.

A Banff Component Scoring-based Histologic Assessment of Bortezomib-based Antibody-mediated Rejection Therapy

Transplantation. Aug, 2015  |  Pubmed ID: 25803498

Histology remains a cornerstone for antibody-mediated rejection (AMR) diagnosis. Little data exist supporting histology for assessing therapeutic responses. This study evaluates histologic components in assessing AMR therapeutic responses.

Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival

Transplantation. Oct, 2015  |  Pubmed ID: 25856409

Classification of acute rejection (AR) based on etiology and timing may provide a means for enhancing therapeutic results and allograft survival. This study evaluated graft and patient survival after the first AR episodes among kidney transplant recipients with an early or late antibody-mediated rejection (AMR), acute cellular rejection (ACR) or mixed AR (MAR).

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