Adverse Effects Of Immunosuppression Research Articles

Pregnancy after liver transplantation

The first known posttransplantation pregnancy was in 1958 in a renal transplant recipient who had received a kidney from her identical twin sister. The first known posttransplantation pregnancy in a liver transplant recipient was in 1978. Information available from female kidney transplant recipients helped in the decision making involved in the management of this case, as well as those that followed. Over the last 20 years, issues specific to liver transplantation and pregnancy have been identified. Similar to the kidney transplant recipient population, when prepregnancy recipient graft function is stable and adequate, pregnancy appears to be well tolerated. Also similar to kidney transplant recipients, there has been no evidence of a specific malformation pattern among the children, and although prematurity and low birth weight occur, overall newborn outcomes have been favorable. Pregnancy in the setting of recurrent liver disease, such as recurrent hepatitis C, poses a potential problem among liver transplant recipients, as well as the possible adverse effects of immunosuppression on maternal kidney function. Also of significance, peripartum graft deterioration has more severe consequences in this transplant recipient population. Therefore, pregnancy must be considered carefully in this transplant recipient group. Since 1991, the National Transplantation Pregnancy Registry (NTPR) has studied the safety of pregnancy outcomes in solid-organ transplant recipients. The purpose of this review is to catalog studies in the literature, as well as to present current data from the registry with management guidelines.

Leukocyte Suppression is Associated with Improved Clinical Outcomes in Children’s Status after Orthotopic Heart Transplantation

Leukocyte suppression is a sequela of immunosuppressive therapy after orthotopic heart transplantation and may result in discontinuation of anti-proliferative agents. Clinical outcomes in this patient population have not been well delineated. This study was a retrospective review of children who underwent orthotopic heart transplantation at our institution from 1986 to 2003. Leukocyte suppression was defined as a white blood cell count <5,000, prompting the withdrawal of anti-proliferative agents. The population was divided into 2 groups, leukosuppressed (LS) and non-leukosuppressed (NLS), and their clinical outcomes were compared. The study included 109 patients, of which 44 (40%) became leukosuppressed. The 2 groups were similar regarding demographic data and initial management. The LS Group had a significantly decreased incidence of rejection, being 7 times less likely to have recurrent rejection (p = 0.001). The median time to rejection was 0.8 +/- 0.6 years for the NLS Group, whereas the median time to rejection was not yet reached at 17 years for the LS Group. The LS Group also tended toward a decreased incidence of retransplantation or death (p = 0.06). The organ "half-life" in the NLS Group was 7.5 years vs 12.5 years in the LS Group. There was no difference between the 2 groups in regards to other adverse effects of immunosuppression. Children who have undergone orthotopic heart transplantation and subsequently become leukosuppressed have a lower incidence of rejection and a tendency toward less organ loss than children who do not become leukosuppressed, without having an increased incidence of adverse side effects.

Tolerance: Is It Worth the Risk?

The success of orthotopic liver transplantation (OLT) has been limited by the adverse effects of immunosuppression. The purpose of this study was to determine the safety and feasibility of withdrawing immunosuppression in OLT recipients to achieve tolerance. Eighteen adult OLT recipients in our steroid-free protocol without rejection were selected for this protocol. All patients chosen for this trial were on tacrolimus monotherapy with normal liver function tests (LFTs). Tacrolimus was weaned as long as LFTs remained stable. Weaning was halted for elevations of liver enzymes and tacrolimus was increased to the last dosage at which the patients had normal LFTs. Rejection was treated by increasing tacrolimus to levels of 10-15 ng/ml. Mycophenolate mofetil (MMF) or sirolimus was added if there was severe rejection by biopsy. Steroids were used if there was no improvement. One patient has been weaned off immunosuppression. Three additional patients were weaned completely off but had tacrolimus resumed because of mild elevations in LFTs. Eleven of 18 (61%) patients had rejection. Two patients required steroid therapy and one required rabbit antithymocyte globulin in addition to MMF and steroids. One of the patients with rejection developed diabetes and one patient had renal failure, which subsequently resolved. One patient died following a stroke. Clinical tolerance can be achieved in a minority of patients, even when being maintained on minimum immunosuppression. The potential benefit of achieving tolerance must be weighed against the risks of rejection therapy in patients doing well on low-dose immunosuppression.

Quality of life after lung transplantation: A cross-sectional study

Background The increase in life expectancy has raised the importance of quality of life after lung transplantation, although this issue has not yet been systematically investigated. The aim of this cross-sectional study was to provide an overview of quality of life in lung transplant patients. Methods Between April and July 2001, a set of 4 questionnaires were given to all adult, German-speaking lung transplant recipients ( n = 108; response rate 87% [ n = 94]): St. George’s Respiratory Questionnaire (SGRQ), a lung-specific health status instrument; the Short Form-36 (SF-36), a general quality of life measure; the Hospital Anxiety and Depression Scale (HADS-D) and a self-reported questionnaire concerning sexual functioning, physical symptoms, adverse effects of immunosuppression and satisfaction with outcome. Results With regard to the SGRQ, all lung transplant recipients had significantly better scores, which reflected an enhanced quality of life compared with the reference value for patients with obstructive pulmonary disease (SGRQ: p < 0.001 in all sub-scales). The Hospital Anxiety and Depression Scale and the Mental Component Summary Scale of the SF-36 did not differ significantly compared with published normative data in the healthy population. However, the side effects of immunosuppression proved to be a major factor influencing the quality of life of lung transplant recipients (11% influenced strongly and 24% moderately). Seventy-six percent of lung transplant patients were highly satisfied with the transplant outcome and 92% would opt for the procedure again. Among all lung transplant recipients, those with cystic fibrosis were most satisfied (significantly) with their quality of life. Conclusions Although lung transplant patients must cope with the side effects of immunosuppression, they report a highly satisfying quality of life with regard to physical and emotional well-being and social and sexual function.

Drug Therapy in the Heart Transplant Recipient

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. Part I of this series describes the mechanisms and types of rejection and the intravenous immunosuppressive drugs commonly used for induction or antirejection therapy. In this article, we review the commonly used oral immunosuppressive drugs. Intravenous corticosteroid methylprednisolone is included in the discussion of corticosteroids. Table 1 gives trade names, pharmacology, necessary adjustments for renal or hepatic dysfunction, and dosing and general monitoring guidelines for drugs described in this section. Table 2 lists the major adverse effects of immunosuppressive drugs described in Parts I and II of this review and provides an estimate of their relative frequency. View this table: TABLE 1. Commonly Used Oral (and Intravenous) Immunosuppressive Drugs View this table: TABLE 2. Major Adverse Effects of Immunosuppressive Drugs Steroids, among the first immunosuppressive agents used in clinical transplantation, have remained an important component of induction, maintenance, and rejection regimens. ### Mechanism of Action Glucocorticoids are potent immunosuppressive and antiinflammatory agents (the Figure). They diffuse freely across cell membranes and bind to high-affinity cytoplasmic glucocorticoid receptors. The glucocorticoid receptor–steroid complex translocates to the nucleus, where it binds to a glucocorticoid response element within the DNA.1 The glucocorticoid receptor–steroid complex may also bind to other regulatory elements, inhibiting their binding to DNA. Both actions cause transcriptional regulation, thereby altering the expression of genes involved in immune and inflammatory response. Glucocorticoids affect the number, distribution, and function of all types of leukocytes (T and B lymphocytes, granulocytes, macrophages, and monocytes), as well as endothelial cells.2 The major effect on lymphocytes appears to be mediated by inhibition of 2 transcription factors, activator protein-1 and nuclear factor (NF) κ-B.3,4 This affects the expression of a number of genes, including those for growth factors, cytokines, CD40 ligand, GM-CSF, and adhesion and myosin heavy chain molecules.2 In nonlymphoid …

Should patients with chronic hepatitis C infection be transplanted?

Chronic hepatitis C (HCV) infection affects more than 170 million people throughout the world and 2 to 3 million Americans. End-stage liver disease secondary to chronic HCV infection is the most frequent indication for liver transplantation in this country. Currently, the gold standard for treatment for immunocompetent patients is a combination of peginterferon (PEG-IFN) and ribavirin for 6 to 12 months depending on the genotype. This treatment achieves a sustained virological response (SVR) in 54% to 61% of patients overall. Almost 50% of patients do not respond or have recurrences posttreatment and progress in over 10 to 20 years into chronic liver disease and its complications. Liver transplantation is the only therapeutic modality that impacts on quality of life and survival of these patients. However, recurrence of HCV in the new allograft is universal with accelerated progression to cirrhosis in 5 to 10 years. Response to treatment is usually low (20% to 30%), and associated with significant side effects and depression. A significant percentage of patients with recurrent HCV after transplantation require retransplantation to control the complications of end-stage liver disease. Other solid organ transplants recipients already HCV-positive, or infected at the time of transplantation from blood transfusions or an infected graft, develop accelerated, progressive liver disease facilitated by the adverse effects of immunosuppression in addition to HCV replication. To prevent morbidity, mortality, and high costs related to the consequences of HCV infection, all solid organ transplant candidates should be tested for HCV infection and treated appropriately with PEG-IFN and ribavirin prior to transplantation.

Molecular Basis for the Neuroprotective Properties of FKBP-Binding Immunophilin Ligands

Non-immunosuppressive immunophilin ligands (NI-IPLs) are attracting attention as new candidate drugs for neuroprotection and / or neurorestoration, particularly, since they do not have the adverse effects of immunosuppressants. However, it is not yet enough to understand that NI-IPLs are useful drugs for treating neurological disorders. In particular, the molecular mechanism of NI-IPL activity in target cells in the brain remains obscure. In this review, we focused on the molecular basis of the neuroprotective properties of FK506 binding protein (FKBP)-binding IPLs. Our findings suggest that IPLs have neuroprotective effects mediated by multiple beneficial properties such as a GSH-activating effect, a NTF-activating effect, and an anti-apoptotic effect, but not by an immunosuppressive effect, both in cell cultures and in vivo. In particular, the GSH-activating effect and the NTF-activating effect of NI-IPLs may be essential to the expression of their neuroprotective properties. Thus, NI-IPLs might have a potentially beneficial effect by ameliorating neurological disorders, since they do not cause serious side effects such as immune deficiency. Keywords: neuroimmunophilins, non-immunosuppressive immunophilin ligand, glutathione, gdnf, bdnf, apoptosis

Possibility of Non-Immunosuppressive Immunophilin Ligands as Potential Therapeutic Agents for Parkinsons Disease

Non-immunosuppressive immunophilin ligands (NI-IPLs) are attracting attention as new candidate drugs for neuroprotection and/or neurorestoration, particularly since they do not have the adverse effects of immunosuppressants. However, it is not yet enough to understand that NI-IPLs are useful drugs for treating neurological disorders. In particular, the molecular mechanism of NI-IPL activity in target cells in the brain remains obscure. In this review, we focused on the molecular basis of the neuroprotective properties of IPLs. Our findings suggest that IPLs have neuroprotective effects mediated by multiple beneficial properties such as a glutathione (GSH)-activating effect, a neurotrophic factor (NTF)-activating effect, and an anti-apoptotic effect, but not by an immunosuppressive effect, both in cell cultures and in vivo. In particular, the GSH-activating effect and the NTF-activating effect of NI-IPLs may be essential to the expression of their neuroprotective properties. Thus, NI-IPLs might have a potentially beneficial effect by ameliorating neurological disorders, since they do not cause serious side effects such as immune deficiency.

Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study.

The North American Pediatric Renal Transplant Cooperative Study has collected clinical information on children undergoing a renal transplantation since 1987. This cooperative group now includes over 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. This report covers the years from 1987 through 2001 and includes data on 7545 renal transplants in 6878 patients. This report demonstrates changing trends in many areas of pediatric transplantation including increasing numbers of African American and Hispanic children receiving transplantation, remarkable improvements in the rate of acute rejection, rejection reversal, and short- and long-term allograft survival. In the most recent cohorts of patients, we now see that 1-yr allograft survival is no different in cadaver donor compared to living donor recipients and in infants compared to all other age groups. However, this analysis also reveals areas of continued challenges including inferior outcomes in African American and adolescent populations, chronic rejection, and the adverse effects of immunosuppression.

Strategies for optimizing immunosuppression in adolescent transplant recipients: a focus on liver transplantation.

Adolescence is a difficult time for transplant recipients; they must learn to take responsibility for their own behavior and medication, and to balance their developing sexuality in a body that has been transformed by the adverse effects of immunosuppression. More than 80% of children survive transplantation to adolescence and adulthood, thus long-term outcome and tailoring of immunosuppression is of great importance. To date, the most experience with long-term immunosuppression regimens is cyclosporine, which is well tolerated and effective. Long-term adverse effects include hypertension, nephrotoxicity, and post-transplant lymphoproliferative disease (PTLD). The recent development of tacrolimus has improved the cosmetic adverse effects related to cyclosporine, but has similar rates of hypertension and nephrotoxicity, and possibly a higher rate of PTLD. There has been a recent, welcome development in renal sparing drugs, such as mycophenolate mofetil, which has no cosmetic adverse effects, does not require drug level monitoring and is thus particularly attractive to teenagers. Recent surveys demonstrate recovery of renal function with mycophenolate mofetil, if started prior to irreversible renal dysfunction. There are currently little published data on the use of sirolimus (rapamycin) in the pediatric population, but preliminary studies suggest that the future use of interleukin-2 receptor antibodies may be beneficial for immediate post-transplant induction of immunosuppression. It is important when planning immunosuppression for adolescents to consider the effects of drug therapy on both males and females in order to maintain fertility and to ensure safety in pregnancy. Noncompliance is a problem in this age group, but adequate practical measures and support should reduce noncompliance, and allow good, long-term graft function.

Life satisfaction among kidney transplant recipients: demographic and biological factors

The Transplant Learning Center is a program providing education and support for solid-organ transplant recipients taking cyclosporine (Neoral or Sandimmune). One goal of the program is to improve patients' quality of life, which may be influenced by demographic and biological factors, and in turn influences adherence to prescribed medication regimens. We analyzed the results from the initial survey of enrollees to better understand life satisfaction and to test the validity and reliability of the satisfaction scale used in the program. Patients enter the program through self-selection: all enrollees who received a kidney transplant were included in this analysis. Satisfaction was measured using the Life Satisfaction Index, which includes 8 questions about aspects of satisfaction with the patient's life. Associations between the Life Satisfaction Index and demographic factors, comorbid medical conditions, adverse effects of immunosuppressants, and medication compliance were examined. All 3676 kidney transplant recipients who completed the initial survey were included. Mean satisfaction scores were highest in persons who were older than 64 years, men, and those who were married. Satisfaction scores were positively correlated with education and income. Mean satisfaction score was significantly lower among persons with medical comorbidities, persons who reported that adverse effects of medications were more frequent, and persons who reported noncompliance with their medication regimen. The Life Satisfaction Index is a transplant-specific measure of health-related quality of life that can be used to help detect areas of potential concern in the clinical management of kidney transplant recipients.

Life satisfaction among kidney transplant recipients: demographic and biological factors.

The Transplant Learning Center is a program providing education and support for solid-organ transplant recipients taking cyclosporine (Neoral or Sandimmune). One goal of the program is to improve patients' quality of life, which may be influenced by demographic and biological factors, and in turn influences adherence to prescribed medication regimens. We analyzed the results from the initial survey of enrollees to better understand life satisfaction and to test the validity and reliability of the satisfaction scale used in the program. Patients enter the program through self-selection: all enrollees who received a kidney transplant were included in this analysis. Satisfaction was measured using the Life Satisfaction Index, which includes 8 questions about aspects of satisfaction with the patient's life. Associations between the Life Satisfaction Index and demographic factors, comorbid medical conditions, adverse effects of immunosuppressants, and medication compliance were examined. All 3676 kidney transplant recipients who completed the initial survey were included. Mean satisfaction scores were highest in persons who were older than 64 years, men, and those who were married. Satisfaction scores were positively correlated with education and income. Mean satisfaction score was significantly lower among persons with medical comorbidities, persons who reported that adverse effects of medications were more frequent, and persons who reported noncompliance with their medication regimen. The Life Satisfaction Index is a transplant-specific measure of health-related quality of life that can be used to help detect areas of potential concern in the clinical management of kidney transplant recipients.

Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin.

Autoimmune destruction of pancreatic beta cells in type I, insulin-dependent diabetes mellitus (IDDM) results in the loss of endogenous insulin secretion, which is incompletely replaced by exogenous insulin administration. The functional restoration provided by allogeneic beta-cell transplantation is limited by adverse effects of immunosuppression. To pursue an insulin replacement therapy based on autologous, engineered human non-beta cells, we generated a retroviral vector encoding a genetically modified human proinsulin, cleavable to insulin in non-beta cells, and a human nonfunctional cell surface marker. Here we report that this vector efficiently transduced primary human cells, inducing the synthesis of a modified proinsulin that was processed and released as mature insulin. This retrovirally derived insulin displayed in vitro biological activity, specifically binding to and phosphorylation of the insulin receptor, comparable to human insulin. In vivo, the transplantation of insulin-producing fibroblasts reverted hyperglycemia in a murine model of diabetes, whereas proinsulin-producing cells were ineffective. These results support the possibility of developing insulin production machinery in human non-beta cells for gene therapy of IDDM.

Adverse effects of immunosuppressive drugs on long-term graft outcome

Adverse effects of immunosuppressive drugs on long-term graft outcome

Thymus atrophy in the nonhuman primate by FK506: An immunohistochemical study

F K 506 is a potent anti-lymphocytic and immunosuppressive agent with a totally distinct structure from the cyclic peptide cyclosporin A (CyA), but with the same selective, inhibitory action on CD4+ lymphocyte activation and cytokine gene expression.‘” FIG06 suppresses both humoral and cell-mediated immunity and is highly effective in prolonging organ allograft survival in a variety of species, including rodents, non-human primates, and man at considerably lower doses than CyA.6-“’ Concerning the adverse effects of immunosuppressive drugs on the thymus, the capacity of CyA to alter the thymic microenvironment in normal or allografted animals is well characterized.” There is evidence that the drug interferes with thymocyte differentiation and maturation both in viva” and in vitro.‘“,‘4 The effects of FKS06 on the thymus have been studied in rats and mice. Thymic medullary atrophy has been demonstrated after short term exposure (6 to 14 days) to the drug.“-*’ There are substantial interspecies differences with regard to the effects of FK.506.831” The discrepant findings concerning the immunosuppressive potency and toxicity of the drug in non-human primates indicated the need for further non-human primate studies. 20-22 Therefore, we investigated the immunotoxic effects of FK506 on the thymic environment and T lymphocyte development in young adult Cynomolgus monkeys.

Management of the adverse effects of immunosuppressants

Management of the adverse effects of immunosuppressants

Liver Disease in Kidney Transplant Patients Receiving Azathioprine

The liver disease in 24 kidney transplant patients receiving azathioprine was reviewed to determine the cause and appropriate management. Azathioprine hepatotoxicity could not be implicated in any of the 24 patients, and there was no correlation between the course of the liver disease and azathioprine administration and withdrawal. Seven patients had "nonspecific reactive hepatitis" associated with sepsis and other complications; 12 patients had viral hepatitis, based on the clinical course, histopathologic and laboratory findings, and tests for Australia antigen; and in five patients the cause of the liver disease could not be determined. The high morbidity of viral hepatitis in these patients (fulminant hepatitis in one and post-necrotic cirrhosis in two) suggested an adverse effect of immunosuppression. Liver disease is not an indication to discontinue azathioprine therapy, but rather to reduce total immunosuppression whenever possible.