Consequence Of Immunosuppressive Therapy Research Articles

Review of anaesthetic management for cataract surgery in transplant recipients.

The prevalence of transplantation is on the increase worldwide. Corneal transplantation is the most common form of human donor transplantation. Transplantation of other organs and bone marrow is established treatment for various end-organ failure and many haematological conditions, respectively. Success and survival of these patients have increased with advances in immunosuppression. Unfortunately, these patients are susceptible to cataract formation as a consequence of immunosuppressive therapy and accelerated progression of several diseases. Topical anaesthesia and regional ophthalmic blocks are ideal for cataract surgery in cooperative adults. General anaesthesia may be required in children, for extremely anxious or claustrophobic adults and for complex surgery such as simultaneous cataract and corneal transplantation. The perioperative anaesthetic management of cataract surgery in a transplant recipient is no different to a standard technique in a healthy adult, but additional challenges are posed by the underlying pathology necessitating transplantation, function of the transplanted organ, physiological and pharmacological problems of allograft denervation, side-effects of immunosuppression, risk of infection and potential for rejection. This narrative review summarises optimal anaesthetic management in transplant recipients undergoing cataract surgery.

Chagas Disease, Leishmaniasis, and Malaria in Solid Organ Transplant Recipients

Solid organ transplantation (SOT) is increasingly employed worldwide to treat several diseases causing either acute and chronic organ failure. Recipients of SOT are at increased risk to develop infections as a consequence of immunosuppressive therapy. Sometimes such infections may be acquired by the transplanted organ or by reactivation of previously acquired latent infection. The globalization and the increase of international travel poses a risk for exposure to infections such as Chagas disease (CD), leishmaniasis and malaria endemic in tropical and subtropical areas of the world. We have reviewed the literature regarding risk factors , clinical presentation , diagnosis and treatment of CD, leishmaniasis and malaria in the setting of SOT

Gastrointestinal Side Effects of Post-Transplant Therapy.

Modern immunosuppressive therapy has produced a real revolution in renal and organ transplantation but it comes with the price of multiple side effects. There are many gastrointestinal (GI) complications that are the consequence of transplant immunosuppressant medication. In fact, for any immunosuppressant therapy, certain standardized precepts and attitudes that aim to reduce the incidence and the impact of the medication side effects must be applied. Many patients undergo renal transplantation and the physicians have to be aware of the advantages and the risks associated. This article reviews the main GI complications that may arise as a consequence of immunosuppressive therapy after solid organ transplantation, focusing on renal and renal/pancreas transplantation, as well as the ways in which the incidence of these complications can be reduced. Management of the post-transplant therapy is mandatory in order to increase not only the grafts' and the patients' survival, but also their quality of life by the occurrence of fewer complications.

CD11c+ Dendritic Cells Rather than Langerhans Cells are Reduced in Normal Skin of Immunosuppressed Renal Transplant Recipients

The increased risk of squamous cell carcinomas (SCC) in renal transplant recipients (RTR) is related to impaired immunosurveillance as a consequence of immunosuppressive therapy. Since dendritic cells (DC) play an important role in immunosurveillance, we investigated the quantity of DC subsets and macrophages in normal skin of RTR and immunocompetent controls by immunohistochemistry. In this comparative study Langerhans' cells (LC) were present in similar numbers in RTR and controls. The number of CD11c+ DC was significantly reduced in RTR, particularly in patients on triple treatment therapy, compared with controls. Macrophages were significantly increased. Plasmacytoid DC were not detected in normal skin. The reduced quantity of CD11c+ DC and increased number of macrophages in normal skin of immunosuppressed RTR may contribute to the increased incidence of SCC in RTR. This finding underlines the role of DC subsets in immunosurveillance, and may have implications for our understanding of the effect of immunosuppression on DC subsets.

Costs and consequences of immunosuppressive therapy in children with aplastic anemia

Acquired aplastic anemia (AA) is the most common form of bone marrow failure, generally defined by the effective mismatch between blood cell production in the bone marrow and peripheral demand. While an occasional association with exposure to environmental factors and drugs, or hepatitis is well

Plasma cell myeloma in a renal transplant recipient: A case report and review of literature

Post-transplant lymphoproliferative disorders are mostly B-cell neoplasms that develop as a consequence of immunosuppressive therapy. Plasma cell myeloma occurring after solid organ transplant is rare. We report here a case of plasma cell myeloma variant of post-transplant lymphoproliferative disorders developing after 15 months of live related renal transplant in a 41-year-old female. We compare clinicopathological features of this case with few cases reported in literature.

Post-transplant plasmacytoma without Epstein–Barr virus infection occurring rapidly after unrelated allogeneic bone marrow transplantation

Post-transplant lymphoproliferative disorders (PTLD) represent a heterogenous group of lymphoid proliferations that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow (BM) transplantation (BMT). PTLD range from benign hyperplastic lesions to lymphoid neoplasm including plasma cell tumors, and they are mostly Epstein–Barr virus-related [1, 2]. In contrast to the high incidence of post-transplant lymphomas, PTLD manifesting as plasma cell tumors such as multiple myeloma and extranodal plasmacytoma are extremely rare [3]. We report a case of plasmacytoma without evidence of Epstein–Barr virus (EBV) infection which developed rapidly after bone marrow transplantation. A 45-year-old Japanese male with myelodysplastic syndrome (MDS, RAEB-1) received myeloablative allogeneic bone marrow transplantation due to progressive pancytopenia and episodes of recurrent infection. Pretransplant evaluation did not detect plasma cell proliferation in bone marrow aspirate and clot sections, monoclonal gammopathy on serum protein electrophoresis, or splenomegaly on the computed tomography (CT) scan (Fig. 1a). The serum IgG, IgA and IgM values were 1,160, 188, and 123 mg/dl, respectively. These were within the normal range. The conditioning regimen comprised conventional TBI and CY. He had no available HLA-identical family donors. He received an infusion of unmanipulated bone marrow containing 3.6 9 10/kg nucleated cells from a minor ABO-incompatible, one allele-mismatched (HLA DRB1) (disparities in the rejection direction), unrelated male donor. Tacrolimus and short-term MTX were administered for GVHD prophylaxis. Treatment with G-CSF was initiated on day ?5. On day ?7, severe stomatitis and febrile neutropenia (FN) developed. Immediate treatment was started with broad-spectrum antibiotics and an anti-fungal agent. The patient engrafted (ANC[500/mm) on day ?18 after the transplant. However, a platelet count above 5 9 10/mm was not observed. Along with recovery of the neutrophil count, stomatitis and FN improved. Cytomegalovirus (CMV) antigenemia developed on day ?28. Treatment with ganciclovir was started and CMV antigenemia disappeared. The patient did not develop acute graft-versus-host disease (GVHD). On day ?36, a fever of unknown origin and bilateral lower limb pain developed. Radiograph of bilateral lower limb did not show any abnormality including osteolytic lesion. These symptoms did not resolve despite the administration of broad-spectrum antibiotics and an anti-fungal agent. The neutrophil count began to decrease on day ?42. On day ?49, the serum IgG was 1,028 mg/dl, which was within the normal range. K. Kawakami (&) H. Mitani M. Nakao Division of Hematology, Suzuka General Hospital, Yasuzuka-cho, Suzuka, Mie 1275-53, Japan e-mail: Kawakei@cocoa.ocn.ne.jp

Acute acquired toxoplasmic retinochoroiditis in a patient with anterior uveitis, amplified by immunosuppressive therapy

A 24-year-old immunocompetent man with anterior uveitis developed a bilateral multifocal retinochoroiditis after an acute febrile multisystemic illness. Because of his history of idiopathic uveitis the multisystemic illness was treated with oral prednisone. When a retinochoroiditis occurred cyclosporine was added. This was followed by an extensive flare-up of the retinochoroiditis. The diagnosis of toxoplasmosis was then established by a positive polymerase chain reaction (PCR) from aqueous humour and confirmed by isolation of the parasite in several organs. On the base of kept frozen sera the acute febrile episode was found to be an acquired toxoplasmosis. On re-examination all evidence of pre-existing Fuchs' uveitis was gathered. The immunosuppressive therapy was discontinued and the patient was kept under anti-toxoplasmic maintenance therapy for 1 year without recurrence of the retinochoroiditis. The case illustrates a possible consequence of immunosuppressive therapy in infection with toxoplasmosis and the importance of the diagnosis of a pre-existing noninfectious uveitis.

IRS-1 Serine Phosphorylation and Insulin Resistance in Skeletal Muscle From Pancreas Transplant Recipients

Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal IRS-1 Ser (312) and Ser (616) phosphorylation was also increased in nondiabetic kidney transplant recipients. Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia.

Cryptococcus neoformans Isolates from Transplant Recipients Are Not Selected for Resistance to Calcineurin Inhibitors by Current Immunosuppressive Regimens

The immunosuppressants tacrolimus (FK506) and cyclosporine A inhibit calcineurin and have potent antifungal activity. In this study, 24% of Cryptococcus neoformans isolates from solid-organ transplant patients exhibited altered sensitivity to these drugs, which may have an impact on the infectious course but does not appear to be the consequence of immunosuppressive therapy.

Primary Cutaneous Plasmacytoma after Rejection of a Transplanted Kidney: Case Report and Review of the Literature

Immunosuppressed organ allograft recipients are at risk of developing lymphomas and lymphoproliferative disorders as a consequence of immunosuppressive therapy and long-term antigenic stimulation from both the graft and possible viral infections. No more than 4% of the malignant tumors detected in organ recipients are plasmacytomas. Primary cutaneous plasmacytoma is a rare type of cutaneous B-cell lymphoma arising primarily in the skin. It is derived from clonally expanded plasma cells with various degrees of maturation and atypia. We report the occurrence of a solitary cutaneous plasmacytoma in a 56-year-old male patient undergoing hemodialysis after rejection of a grafted kidney. The diagnosis was made a few months after the kidney had been surgically removed. A thorough examination showed no evidence of systemic disease. Skin lesions were successfully treated with local radiotherapy. After 2 years of follow-up there were no local or systemic recurrences.

Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients

Post-transplant lymphoproliferative disorders are mostly Epstein–Barr virus-related, B-cell tumors that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow transplants. These disorders range from reactive, polyclonal plasmacytic hyperplasia to those that are morphologically and genotypically indistinguishable from typical non-Hodgkin's lymphomas. Plasma cell myeloma occurring after solid organ transplantation is rare. We report three plasma cell myeloma post-transplant lymphoproliferative disorder cases and one polymorphic, monoclonal post-transplant lymphoproliferative disorder case associated with a monoclonal serum protein. All three plasma cell myeloma post-transplant lymphoproliferative disorder cases had clinical, radiologic, and pathologic features of conventional plasma cell myeloma. The one polymorphic post-transplant lymphoproliferative disorder case was associated with an IgM monoclonal serum protein and was morphologically indistinguishable from a lymphoplasmacytic lymphoma. Three of the four cases, including the one polymorphic post-transplant lymphoproliferative disorder case, were positive for Epstein–Barr virus encoded small RNA by in situ hybridization. One patient died of plasma cell myeloma post-transplant lymphoproliferative disorder. The remaining three patients are alive: two are completely free of post-transplant lymphoproliferative disorder, and one has shown partial response to therapy. We compare the clinicopathologic features of these cases with those in the literature.

Successful islet transplantation: continued insulin reserve provides long-term glycemic control.

Clinical islet transplantation is gaining acceptance as a potential therapy, particularly for subjects who have labile diabetes or problems with hypoglycemic awareness. The risks of the procedure and long-term outcomes are still not fully known. We have performed 54 islet transplantation procedures on 30 subjects and have detailed follow-up in 17 consecutive Edmonton protocol-treated subjects who attained insulin independence after transplantation of adequate numbers of islets. Subjects were assessed pretransplant and followed prospectively posttransplant for immediate and long-term complications related to the procedure or immunosuppressive therapy. The 17 patients all became insulin independent after a minimum of 9,000 islets/kg were transplanted. Of 15 consecutive patients with at least 1 year of follow-up after the initial transplant, 12 (80%) were insulin independent at 1 year. In 14 subjects who have maintained demonstrable C-peptide secretion, glucose control has been stable and glycemic lability and problems with hypoglycemic reactions have been corrected. After 2 of the 54 procedures, some thrombosis was detected in the portal vein circulation. Five subjects had bleeding related to the percutaneous portal vein access procedures: three required transfusion alone, and in one subject, who had a partial thrombosis of the portal vein, an expanding intrahepatic and subscapular hemorrhage occurred while on anticoagulation, requiring transfusion and surgery. Elevated liver function test results were found in 46% of subjects but resolved in all. Complications related to the therapy have been hypercholesterolemia requiring statin therapy in 65%; a rise in creatinine in two patients, both of whom had preexisting renal disease; a rise in protein in four, all of whom had preexisting proteinuria; and antihypertensive therapy increased or started in 53%. Three of the 17 patients have required retinal laser photocoagulation. There have been no cases of posttransplant lymphoproliferative disorder or cytomegalovirus infection, and no deaths. The acute insulin response to arginine correlated better with transplanted islet mass than acute insulin response to glucose (AIR(g)) and area under the curve for insulin (AUC(i)), but the AIR(g) and AUC(i) were more closely related to glycemic control. The AUC(i) directly posttransplant was lower in those who eventually became C-peptide deficient. Our results, with a maximum follow-up of 34 months, indicate that prolonged insulin independence can be achieved after islet transplantation. There are some risks associated acutely with the procedure, and hypercholesterolemia and hypertension are treatable concerns on longer-term follow-up. All patients with persisting C-peptide secretion have had a resolution of both glycemic lability and problems with hypoglycemic reactions. Apart from the rise in serum creatinine in two subjects, no serious consequences of immunosuppressive therapy have been encountered. Islet transplantation is a reasonable option in those with severe problems with glycemic lability or hypoglycemia.

Pemphigus vulgaris: the manifestations and long-term management of 55 patients with oral lesions.

Perhaps surprisingly, the manifestations and management of patients with pemphigus vulgaris and oral lesions have been detailed only infrequently. The present study has examined the clinical features, diagnosis and management of a cohort of 55 patients, including three adolescents, with pemphigus vulgaris predominantly affecting the oral mucosa. There was about a 6-month delay from the onset of symptoms until presentation for diagnosis, longer in men than in women. Patients typically had multiple lesions affecting mainly the buccal and/or palatal mucosae, and over half the patients had lesions affecting non-oral mucosal sites. Nearly one-quarter (24%) had cutaneous involvement. Most patients were otherwise healthy with no other autoimmune disorders. Classical histopathological features of pemphigus vulgaris were present in all patients, as well as IgG intraepithelial deposits in all patients tested and circulating epithelial antibodies in most. Thirty-two patients were treated in the clinic, four responding to topical immunosuppressive therapy, the remainder needing and responding, at least in part, to systemic immunosuppression. Systemic corticosteroids often with adjunctive immunosuppressives, particularly azathioprine, were required in 87% of patients. In 18% of the patients, the disease resolved in 3 months, but 76% had recalcitrant disease. Adverse effects were seen in 78%, and two patients died, at least one as a consequence of immunosuppressive therapy. It is concluded that pemphigus vulgaris affecting the oral mucosa is still diagnosed only after considerable delay because patients, especially men, present late; it has a chronic course; it is often associated with lesions in other mucosae and/or skin; it can be resistant to currently available therapies; and immunosuppressive therapy frequently produces adverse effects, occasionally lethal.

Drug-Induced Granulocytopenia with Natural Killer Lymphocytosis after Renal Transplantation

Following renal transplantation, a patient developed life-threatening granulocytopenia secondary to a specific combination of drugs which are commonly utilized in this setting. Coincident with the depression of granulocytes, an expansion of natural killer cells was seen, which may have been a consequence of immunosuppressive therapy required for allograft retention. Infection with cytomegalovirus may have contributed to both phenomena.

Rhabdomyolysis and Renal Injury With Lovastatin Use

Hyperlipidemia, particularly hypercholesterolemia, occurs in cardiac transplant recipients both as a preexisting condition and as a consequence of immunosuppressive therapy. Lovastatin (Mevacor) has emerged as an agent that may effectively manage this condition. Few serious side effects of this drug have been observed. We describe two cardiac transplant recipients treated with lovastatin in conjunction with their other medications, including cyclosporine, who developed acute renal failure and rhabdomyolysis. Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy. We postulate that hepatic dysfunction secondary to cyclosporine predisposed these patients to lovastatin-induced muscle damage. Use of this drug in cardiac and other organ transplant recipients should be accompanied by close surveillance of creatine kinase, hepatic transaminases, and cyclosporine levels.

Kaposi's Sarcoma in a Patient With Dermatomyositis Receiving Immunosuppressive Therapy

Kaposi's sarcoma occurred in a 65-year-old Mexican woman who had been treated for dermatomyositis with prednisone for 2 1/2 years and with azathioprine for four months. Kaposi's sarcoma, a malignant neoplasm not usually associated with dermatomyositis, may be a consequence of immunosuppressive therapy in this patient.