Nasimul Ahsan

Continued influence of preoperative renal function on outcome of orthotopic liver transplant (OLTX) in the US: where will MELD lead us?

Renal function is a component of the Model for End Stage Liver Disease (MELD), We queried the 1999–2004 OPTN/UNOS database to determine whether preoperative renal function remained an important determinant of survival in primary deceased donor liver transplant alone patients (DDLTA) or primary combined kidney liver transplant patients (KLTX). We examined preoperative creatinine, renal replacement therapy (RRT), incidence of KLTX, and patient survival in the 34 months before and after introduction of MELD and performed a multivariate Cox regression analysis of time to death.

Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: Role of percutaneous renal biopsy

The feasibility, value and risk of percutaneous renal biopsy (PRB) in liver transplant candidates with renal failure are unknown. PRB was performed on 44 liver transplant candidates with renal failure of undetermined etiology and glomerular filtration rate (GFR) <40 mL/min/1.73 m2 (n = 37) or on renal replacement therapy (RRT) (n = 7). Patients with ≥30% interstitial fibrosis (IF), ≥40% global glomerulosclerosis (gGS) and/or diffuse glomerulonephritis were approved for simultaneous‐liver‐kidney (SLK) transplantation. Prebiopsy GFR, urinary sodium indices, dependency on RRT and kidney size were comparable between 27 liver‐transplant‐alone (LTA) and 17 SLK candidates and did not relate to the biopsy diagnosis. The interobserver agreement for the degree of IF or gGS was moderate‐to‐excellent. After a mean of 78 ± 67 days, 16 and 8 patients received LTA and SLK transplants. All five LTA recipients on RRT recovered kidney function after transplantation and serum creatinine was comparable between LTA and SLK recipients at last follow‐up. Biopsy complications developed in 13, of these, five required intervention. PRB is feasible in liver transplant candidates with renal failure and provides reproducible histological information that does not relate to the pretransplant clinical data. Randomized studies are needed to determine if PRB can direct kidney allocation in this challenging group of liver transplant candidates.

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.

Antibody immunosuppressive therapy in solid organ transplant

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.

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

Pharmacotherapeutic options for the management of human polyomaviruses.

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.

Steroid avoidance: is it ready for prime time?

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.

Polyomaviruses and Human Diseases

One mark of success in organ transplantation is the attempt to reduce maintenance immunosuppression. This change in direction from maximizing therapy to exploring alternatives of minimizing drug treatment to prevent rejection is predicated on the success of current regimens to reduce rejection. This accomplishment allows investigators to focus on alternative immunosuppression to lessen undesirable side effects, some of which may be life threatening. Prime examples are the corticosteroid withdrawal trials in conventional renal transplantation. The drive behind these studies is the reduction of debilitating side effects of corticosteroids including cataract formation, osteoporosis or osteonecrosis, cosmetic changes and importantly the cardiovascular risks of hypertension, dyslipidemia, and diabetes mellitus. Some efforts of steroid withdrawal were fraught with an increased risk of rejection and graft loss (1). However, use of currently available induction drugs and maintenance therapy in addition to withdrawing corticosteroids in the first 2 weeks posttransplant has produced results with graft survival equal to those recipients using chronic corticosteroids. In this issue, Galliford et al. (2) described their experience with a rapid steroid withdrawal protocol in ABO incompatible kidney transplantation, a group at high risk for antibody-mediated rejection and early graft loss. In the past, ABO incompatibility was a contraindication to kidney transplantation. Through trial and error, investigators developed regimens to successfully remove blood group antibody and lower the risk of antibody rebound posttransplantation, permitting kidney transplantation. These regimens required significant immunosuppression, relying on combinations of plasmapheresis, double-filtration plasmapheresis, antigenspecific immunoadsorption, splenectomy, intravenous immunoglobulin, or rituxamab (anti-CD20a monoclonal antibody) in addition to various induction agents and triple maintenance immunosuppression to generate results equal to ABO compatible kidney transplantation. As noted by the authors, “ABO incompatible renal transplantation is now an accepted therapy for end-stage renal failure.” Thus, it is not surprising that this group pursued minimization of immunosuppression to reduce the detrimental side effects of corticosteroids that conventional kidney transplant candidates similarly face. In the study of Galliford et al. (2), blood group antibodies were removed by pheresis with intravenous immunoglobulin replacement preand posttransplant. Rituxamab and daclizumab were administered along with maintenance therapy using tacrolimus and mycophenolate mofetil. A 7-day steroid taper was given. Ten patients received living donor kidney transplantation with 100% patient and graft survival at a median follow-up of 21.6 months. Graft function was excellent early and at 12 months as measured by creatinine and estimated clearance. Three patients experienced biopsy-proven antibody-mediated rejection successfully responding to treatment. All three patients required chronic corticosteroid treatment. Of these three patients, two developed diabetes mellitus associated with significant weight gain. Hypertension and dyslipidemia were not reported. This is a pilot study designed to look at the safety of corticosteroid withdrawal in this high-risk group and does not address the question if there is a metabolic benefit to this change. The favorable short-term graft and patient survival call for larger randomized studies to confirm this data. These future trials should carefully document changes in weight, bone disease, blood pressure, dyslipidemia, and diabetes mellitus during long-term follow-up of the steroid maintenance and steroid withdrawal groups. Hopefully, a clearer picture of the benefits of steroid withdrawal will form. A review of the ABO compatible kidney transplant literature examining steroid avoidance or withdrawal is inconclusive with respect to metabolic advantages. A decrease in the incidence of weight gain, bone disease, hypertension, dyslipidemia, and diabetes mellitus was not apparent in all studies. One report describes a reversal of diabetes mellitus with steroid withdrawal only to see the majority of these patients develop diabetes later without steroids on board. Although total cholesterol drops after steroid withdrawal, in one study it is accompanied by a fall in high density lipoprotein which may not produce the desired cardiovascular benefit. One large randomized study still underway reported no differences at 1 year in weight, blood pressure, dyslipidemia, or diabetes between the corticosteroid versus steroid withdrawal arms. It is not certain that steroids need to be completely withdrawn to attain these benefits. Some investigators report no gain in weight, blood pressure, or diabetic control when reducing corticosteroids below 5 to 10 mg/day. Although most recent reports note equal graft survival despite an increased risk of biopsy proven rejection, the folDepartment of Transplantation, Mayo Clinic, Jacksonville, FL. Address correspondence to: Martin L. Mai, M.D., F.A.C.P., Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: mai.martin@mayo.edu Received 4 June 2008. Accepted 4 July 2008. Copyright