Larva currens in a patient scheduled for renal transplant.

We present a case of larva currens in a patient scheduled for renal transplant. Larva currens is an eruption caused by Strongyloides stercoralis, characterized most often by a pathognomonic, migratory, rapidly extending, serpiginous, urticarial eruption. Infected patients who are immunocompromised are at risk for disseminated and often fatal infection. In disseminated disease, diffuse petechiae and purpura may be present, and periumbilical ecchymoses may resemble thumbprints. The dermatologist may be in a unique position to diagnose this condition and institute therapy. Although found endemically in the United States, the increasingly international nature of medical practice and transplantation medicine causes an increase in the number of patients who may present for evaluation.

The long-term management of pancreas transplantation.

Diabetes mellitus (DM) is a major health problem worldwide, which affects 18.2 million individuals (6.3% of the population) in the United States. Currently, the prevalence of Type 1 DM in the United States is estimated to be 1,000,000 individuals, and 30,000 new cases are diagnosed each year. In addition to end-stage renal disease (ESRD), DM is associated with blindness, accelerated atherosclerosis, dyslipidemia, cardio- and cerebrovascular disease, amputation, poor quality of life, and overall lifespan reduction. It accounts for more than 160,000 deaths per year in the United States alone. In 2002, the annual national direct and indirect costs of Types 1 and 2 DM exceeded $130 billion, which included hospital and physician care, laboratory tests, pharmaceutical products, and patient workdays lost because of disability or premature death. Hyperglycemia alone or in concert with hypertension is the primary factor influencing the development of major diabetic complications. From 1990 to 2001, the number of existing ESRD cases to DM increased by more than 300%, while the rate per million populations increased from 167% to 491%. The number is expected to grow 10-fold by 2030 to 1.3 million accounting for 60% of ESRD population. To date, DM is the leading indication for transplantation and is the cause of ESRD in more than 40% of all transplant recipients each year.

Polyomaviruses and human diseases.

Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature. In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency. The human polyomaviruses BKV and JCV are known to cause, respectively, hemorrhagic cystitis in recipients of bone marrow transplantation and progressive multifocal leukoencephalopathy in immunocompromised patients, for example, by HIV infection. Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure. Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden "decoy cells" in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods. Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions. While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts' immune status. In this chapter, we provide an overview of polyomaviruses and briefly introduce its association with human diseases, which will be covered extensively in other chapters by experts in the field.

Pharmacotherapeutic options for the management of human polyomaviruses.

Polyomaviruses [BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40)] have been known to be associated with diseases in humans for over thirty years. BKV-associated nephropathy and JCV-induced progressive multifocal leukoencephalopathy (PML) were for many years rare diseases occurring only in patients with underlying severe impaired immunity. Over the past decade, the use of more potent immunosuppression (IS) in transplantation, and the Acquired Immune Deficiency Syndrome (AIDS) epidemic, have coincided with a significant increase in the prevalence of these viral complications. Prophylactic and therapeutic interventions for human polyomavirus diseases are limited by our current understanding of polyomaviral pathogenesis. Clinical trials are limited by small numbers of patients affected with clinically significant diseases, lack of defined risk factors and disease definitions, no proven effective treatment and the overall significant morbidity and mortality associated with these diseases. This chapter will focus on a review of the current and future research related to therapeutic targets and interventions for polyomavirus-associated diseases.

Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years.

METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years. RESULTS: The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF. CONCLUSION: All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

Rituximab in immunologic glomerular diseases.

Experimental data suggest that the B-cell antigen CD20 may play a significant role in the pathogenesis of many diseases including glomerular diseases. These and other findings underpin the central concept of B-cell-depleting therapies that target CD20 antigen as treatments for lupus nephritis, idiopathic membranous nephropathy, focal segmental glomerulosclerosis, cryglobulinemic glomerulonephritis, antibody mediated renal allograft rejection and recurrent glomerulonephritis in renal allograft. Use of rituximab as a B-cell depleting therapy has been associated with clinical improvement and has emerged as a possible adjunct or alternative treatment option in this field of nephrology.

Antibody immunosuppressive therapy in solid organ transplant: Part II.

The use of antibodies in transplantation dates to 1986 when muromonab CD3, a monoclonal antibody (mAb) targeting CD3, was first approved for prevention and treatment of renal allograft rejection. These agents have largely been used in a brief adjunctive manner to provide immunosuppression during the initial period after solid organ transplantation or during an episode of acute rejection. Recent advances in our understanding of transplant immunology have allowed emergence of numerous new mAbs, targeting co-stimulatory signals, cell surface receptors and novel protein constructs. During the next decade, transplant professionals will increasingly require knowledge of the mechanisms and pharmacologic characteristics of these novel therapeutic agents.

Antibody immunosuppressive therapy in solid-organ transplant: Part I.

Currently, a wide variety of both polyclonal and monoclonal antibodies are being routinely utilized to prevent and treat solid organ rejection. More commonly, these agents are also administered in order to delay introduction of calcineurin inhibitors, especially in patients with already compromised renal function. While these antibody therapies dramatically reduced the incidence of acute rejection episodes and improved both short and long-term graft survival, they are also associated with an increased incidence of opportunistic infections and neoplastic complications. Therefore, effective patient management must necessarily balance these risks against the potential benefits of the therapy.

Excellent renal allograft survival in donor-specific antibody positive transplant patients-role of intravenous immunoglobulin and rabbit antithymocyte globulin.

BACKGROUND: Timely transplantation of sensitized kidney recipients remains a challenge. Patients with a complement-dependent cytotoxicity negative and flow cytometry (FC) positive crossmatch carry increased risk of antibody-mediated rejection and thus graft loss. Solid phase assays are available to confirm donor specificity for antibody identified by FC crossmatch. Treatment using induction therapy with rabbit antithymocyte globulin (RATG) and intravenous immunoglobulin (IVIG) may allow successful transplant of these high-risk patients. METHODS: A retrospective study of 264 consecutive patients after exclusions yielded 94 complement-dependent cytotoxicity anti-human globulin crossmatch-negative patients, including group 1: 58 primary transplants with panel-reactive antibody (PRA) less than 20%, group 2: 16 retransplants and PRA more than 20% who were FC crossmatch-negative, and group 3: 20 retransplants and PRA more than 20% who were FC crossmatch-positive. All were treated with RATG induction and maintenance therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. Only group 3 received IVIG at 500 mg/kg daily in three doses. RESULTS: Eighteen of 20 patients in group 3 had donor-specific antibody identified by solid phase assay. Cellular- and antibody-mediated rejections were statistically higher in group 3. Two-year serum creatinine and glomerular filtration rate along with 3-year patient and graft survival were comparable between the groups. CONCLUSIONS: Sensitized patients with positive FC crossmatch and donor-specific antibody identified by solid phase assays can be successfully transplanted using standard RATG induction, IVIG, and maintenance immunosuppression with equal renal function and graft survival to immunologically lower risk recipients. Given these results, this patient group should not be excluded from transplantation based on antibody specificities determined by virtual crossmatch techniques.

Dialysis access failure: an indication for immediate kidney transplantation.

In the United States, presently there are more than 50,000 patients with end-stage renal disease (ESRD) awaiting a cadaveric kidney and each year less than a quarter receive kidney transplantation. Although the real incidence in unknown, a significant number of these patients die due to lack of dialysis access. While various medical necessities are indications for emergent transplantation of other organs, the current kidney allocation system of the United Network for Organ Sharing (UNOS) makes no room for those ESRD patients whose death is imminent due to lack of vascular access. Local organ procurement organizations (OPOs) are allowed to make decisions based on arbitrary policies (or no policies at all) which often falter and fail to deal appropriately with a largely ignored issue. The growing wait for cadaveric kidneys makes the problem of ESRD patients dying due to lack of dialysis access increasingly important and one that must be addressed through a revision of the UNOS kidney allocation system.

Hepatobiliary diseases after kidney transplantation unrelated to classic hepatitis virus.

Multiple studies during the past decades have identified chronic liver disease as an important cause of morbidity and mortality in kidney transplant recipients. It has been reported that up to 25% of patients will have some degree of abnormal liver functions during the immediate posttransplant period. In these patients, liver failure has been implicated as the cause of death in approximately 30% of the long-term survivors. While infections from hepatitis virus remain the main cause of ongoing liver damage, many other opportunistic infections with various potential to alter liver function have also been identified. In addition, posttransplant patients are also exposed to hepatotoxic adverse effects of many pharmacotherapeutics including immunosuppressive and nonimmunosuppressive agents. Since there are numerous reports dealing with classic viral hepatitis after kidney transplantation, this review primarily focuses on post-kidney transplant liver diseases which are not due to classic hepatitis viruses.

Limited dose monoclonal IL-2R antibody induction protocol after primary kidney transplantation.

This study prospectively compared immunoprophylaxis with a single intraoperative dose (2 mg/kg) of monoclonal interleukin-2 receptor (IL-2R) antibody vs. noninduction in kidney transplant recipients treated with tacrolimus (FK 506), mycophenolate mofetil (MMF) and a prednisone-based immunosuppression regimen. One hundred recipients of first-kidney transplant were enrolled into the study to receive either anti-IL-2R monoclonal antibody, daclizumab (2 mg/kg intraoperatively, limited anti-IL-2R) or no induction (control). Each patient also received oral tacrolimus (dosed to target trough level 10-15 ng/mL), MMF (500 mg bid) and prednisone. The primary efficacy end-point was the incidence of biopsy proven acute rejection during the first 6 months post-transplant. The patients were also followed for 12-month graft function, and graft and patient survival rates. Other than the donor's age being significantly lower in the control group, both groups were comparable with respect to age, weight, gender, race, human leukocyte antigen (HLA)-DR mismatch, panel reactive antibody (%PRA), cold ischemic time, cytomegalovirus (CMV) status, causes of renal failure, and duration and modes of renal replacement therapy (RRT). During the first 6 months, episodes of first biopsy confirmed acute rejection was 3/50 (6%) in the limited anti-IL-2R group and 8/50 (16%) in the controls (p < 0.05). Twelve-month patient 100/98 (%) and graft survival 100/96 (%) were not statistically different. The group receiving limited anti-IL-2R did not have any adverse reactions. Our study demonstrates that a limited (single) 2 mg/kg immunoprophylaxis dose with monoclonal IL-2R antibody (daclizumab) when combined with tacrolimus/MMF/steroid allows significant reduction in early renal allograft rejection to the single digit level. The therapy with anti-IL-2R antibody is simple and is well tolerated.