Amer Rajab

The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation

Abstract: Background:  Mycophenolate mofetil (MMF) has proven to be a very effective drug for the prevention of acute rejection following renal transplantation when dosed as prescribed at 2 or 3 g/d. However, circumstances arise in clinical transplantation where the dose must be lowered, either to avoid drug toxicity or because of concurrent infection. The impact on the incidence of acute rejection and graft survival when the MMF dose must be lowered has not previously been investigated.

Islet Transplantation: Alternative Sites

The portal vein is currently the site of choice for clinical islet transplantation, even though it is far from being an ideal site. Low oxygen tension and the induction of an inflammatory response impair islet implantation and lead to significant early loss. Even if enough islets survive the early implantation period to render insulin independence, few patients maintain it. Therefore, the search for an ideal site for islet transplantation continues. Experimentally, islets have been transplanted into the portal vein, kidney subcapsule, spleen, pancreas, peritoneum, omentum, gastrointestinal wall, testis, thymus, bone marrow, anterior chamber of the eye, cerebral ventricles, and subcutaneous and intramuscular spaces. Some of these sites are suitable for gathering scientific data, whereas others have potential clinical application. Varying degrees of success have been reported with the use of all these transplant sites in an experimental setting. However, the optimal transplant site remains to be finally established.

Excellent clinical outcomes in primary kidney transplant recipients treated with steroid‐free maintenance immunosuppression

Abstract:  Steroid‐free maintenance immunosuppression is desirable to eliminate the side effects of chronic corticosteroid use. Complete steroid avoidance or rapid post‐transplant steroid withdrawal has recently been used in renal transplant recipients with encouraging results. The present study evaluated the outcome of a steroid‐free maintenance immunosuppressive protocol in kidney transplant recipients with at least one‐yr follow up. Between April 2002 and October 2004, a total of 301 primary kidney transplant recipients received steroid‐free maintenance immunosuppression. The regimen consisted of induction with thymogobulin and prednisone for the first five d. Patients were maintained on Sirolimus and Neoral. Neoral dose was adjusted to target C2 levels and the Sirolimus dose was adjusted to a target rapamycin trough level. All primary kidney transplants (n = 502) performed in the two yr (starting January 2000) prior to institution of the steroid‐free regimen and thus maintained on a steroid‐based immunosuppressive protocol were used for comparison. One‐year patient and death censored graft survival were 93.1% and 98.1% for the steroid‐free group vs. 95.2% and 95.2% for the comparator groups (p = ns). The incidence of biopsy‐proven acute rejection was 4.9% in the steroid‐free group vs. 9.4% in the comparator group (p < 0.01). Two (0.7%) of 301 patients in the steroid‐free group lost their grafts because of acute rejection compared with nine (1.8%) patients in the comparator group (p < 0.05). At one‐yr post‐transplant the mean serum creatinine level was not different between the two groups. There were no significant differences in mean serum cholesterol and triglycerides levels as well as the percentage of patients on lipid lowering agents between the groups. White blood cell counts, daily doses of Neoral and weight gain were significantly lower in the steroid‐free group vs. the comparator group. However, more patients in the steroid‐free group required erythropoietin and iron therapy for anemia (p < 0.001). We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid‐free maintenance immunosuppressive protocol consisting of Neoral and Sirolimus.

Steroid-free maintenance immunosuppression with rapamune and low-dose neoral in pancreas transplant recipients

Background. Steroid-free immunosuppression is an attractive option because it avoids the many side effects of chronic corticosteroid use. It is especially attractive in pancreas recipients because it avoids the diabetogenic effects of steroids. Methods. We evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in pancreas transplant recipients. Between August 2003 and May 2006, a total of 97 pancreas transplant recipients received steroid-free maintenance immunosuppression, consisting of induction with thymoglobulin and prednisone for the first 5 days. Patients were maintained on sirolimus adjusted to a target rapamycin trough level and reduced-dose cyclosporine adjusted to target C2 levels. All pancreas transplants (n=124) performed in the previous 3 years and maintained on a steroid-based immunosuppressive protocol with cyclosporine and mycophenolate mofetil were used for comparison. Results. One-year patient and death censored pancreas graft survival were 93.8% and 94.8% for the steroid free group versus 95.2% and 87.9% for the comparator group, respectively. The incidence of acute rejection was 9.3% in the steroid-free group versus 28.3% in the comparator group (P<0.01). No pancreas loss in the steroid-free group was caused by acute rejection, whereas seven (5.6%) patients in the comparator group lost their pancreases because of acute rejection (P<0.05). At 1 year after transplant, the mean serum glucose and creatinine levels were not different between the two groups. Conclusion. We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of sirolimus and cyclosporine.

Comparison of the portal vein and kidney subcapsule as sites for primate islet autotransplantation.

To date, the portal vein has been the primary site for clinical islet transplantation. Despite success, potential complications such as portal vein thrombosis still exist. The kidney subcapsule has been used successfully in rodent models of islet transplantation. We hypothesized that the kidney subcapsule as a site for islet transplantation in the nonhuman primate model would be as effective as the portal vein. Diabetes was induced in the primate Macaca fascicularis via a total pancreatectomy. Animals were kept under anesthesia during the isolation procedure. Islet isolation was performed using intraductal infusion with Liberase™ HI and mechanical digestion in the Ricordi chamber, and were purified using a continuous Ficoll gradient. Purified islets were autotransplanted either into the portal vein (n = 6) or the left kidney subcapsule (n = 5) of pancreatectomized animals. Intravenous glucose tolerance tests were performed prior to pancreatectomy and 10 days following transplantation. Three animals underwent pancreatectomy and served as diabetic controls. Of the six animals receiving islets in the portal vein, one developed portal vein thrombosis. All remaining autotransplanted animals in this group remained normoglycemic with glucose-induced insulin secretion that was not different from that prior to pancreatectomy. Of the five animals undergoing transplantation into the kidney subcapsule, only one maintained normoglycemia and elicited insulin secretion in response to glucose stimulation. The other four animals remained hyperglycemic. We conclude that the portal vein is superior to the kidney subcapsule as a site for islet transplantation in nonhuman primates 10 days posttransplantation.

Twenty years of renal transplantation at Ohio State University: the results of five eras of immunosuppression

Over the past 20 years, more than 4,000 patients have undergone an abdominal solid organ transplant at Ohio State University. The 20-year period can be divided into five eras, each defined by an immunosuppressive protocol used during that period. With each successful era came a new immunosuppressive protocol that produced an incremental improvement in outcomes of patients and graft survival resulting from the application of the newest and most sophisticated combination of immunosuppressive drugs. The incidence of acute rejection episodes and graft survival from each era are compared and demonstrate the substantial improvement in results that has been achieved over the past 20 years.

The use of basiliximab in solid organ transplantation

The risk of acute rejection is at its highest early post-transplant. The use of various antibodies early after transplant achieves potent immunosuppression to prevent acute rejection, allowing the clinician the opportunity to optimise baseline immunosuppressive management and to delay the use of nephrotoxic agents (calcineurin inhibitors), while the graft reaches a baseline function. Basiliximab (Simulect™, Novartis) is a monoclonal antibody that binds specifically to the α-subunit of the human high-affinity interleukin-2 receptor (IL-2r) complex, consequently inhibiting interleukin-2 (IL-2) binding. IL-2 receptors are selectively expressed on the surface of the activated lymphocytes. Administration of basiliximab inhibits IL-2 mediated activation of lymphocytes, a critical pathway involved in allograft rejection. Several clinical studies have shown that basiliximab administration as an induction agent significantly reduces the incidence of acute rejection, even in high risk patients. In addition, basiliximab is well-tolerated with minimal side effects.

The safety of hand-assisted laparoscopic living donor nephrectomy: The Ohio State University experience with 1500 cases

Hand‐assisted laparoscopic donor (HALD) nephrectomy has been performed at our institution since December 1999. Through May 2014, a total of 1500 HALD procedures have been performed. We have evaluated the outcomes of HALD. The HALD procedure consists of a hand‐port incision as well as two 12‐mm ports. Mean donor age was 40.8 ± 10.8 yr, BMI was 27.9 ± 5.0, there were 541 males, 1271 Caucasians, and the left kidney was removed in 1236 patients. All procedures were successfully completed. Four donors (0.27%) were converted to an open technique due to bleeding. Four donors required blood transfusions. 53 donors (3.5%) were readmitted in the first month post‐donation; almost half were due to gastrointestinal complaints. Six donors required reoperation; three for SBO and three for wound dehiscence. 27 patients (1.8%) developed incisional hernias. Seven donors (0.47%) developed bowel obstruction. All donors recovered well with a mean hospital stay after donation of 2.1 ± 0.3 d. All except one kidney were successfully implanted. Twenty‐one recipients (1.4%) experienced DGF. Ureter complications occurred in 17 (1.1%) recipients. Early graft loss occurred in 13 patients (0.9%). In conclusion, HALD is a safe procedure for the donor with good recipient outcomes.

An Anti‐CD103 Immunotoxin Promotes Long‐Term Survival of Pancreatic Islet Allografts

Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft‐versus‐host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103+ cells from wild type hosts. To circumvent this problem, we conjugated the nondepleting anti‐CD103 monoclonal antibody, M290, to the toxin, saporin, to produce an immunotoxin (M290‐SAP) that efficiently depletes CD103+ cells in vivo. Herein, we show that M290‐SAP dramatically reduces the frequency and absolute numbers of CD103‐expressing leukocytes in the blood, spleen, mesenteric lymph nodes and intestinal epithelium of treated mice. We further demonstrate that M290‐SAP promotes indefinite islet allograft survival in a fully MHC mismatched mouse model. The prolonged islet allograft survival resulting from M290‐SAP treatment was associated with multiple effects in the host immune system including not only depletion of CD103‐expressing leukocytes, but also an increase in CD4+CD25+FoxP3+ T regulatory cells and a predominance of effector‐memory CD8 T cells. Regardless of the underlying mechanisms, these data document that depletion of CD103‐expressing cells represents a viable strategy for therapeutic intervention in allograft rejection.

Clinical outcomes of renal transplant recipients treated with enteric-coated mycophenolic acid vs. mycophenolate mofetil as a switch agent using a primary steroid-free rapamune and microemulsion cyclosporine protocol

Abstract:  Since 2002 our transplant program has utilized a steroid free, cyclosporine (CSA)‐ and rapamycin (RAPA)‐based maintenance immunosuppression regimen. In cases where it has been desirable to avoid the potential nephrotoxicity with this regimen we have used mycophenolic acid (MPA) as our “switch” drug of choice. Both mycophenolate mofetil (MMF) (Roche Inc., Nutley, NJ, USA) and enteric‐coated MPA (ECM) (Novartis, East Hanover, NJ, USA) have been used. In this study, we retrospectively compared the tolerability of the two formulations of MPA. Thus we compared 103 recipients switched to RAPA/MMF (RMM group) to 114 switched to RAPA/ECM (REC group). There was a significantly higher incidence of patients requiring dose changes and drug discontinuation in the RMM group, as well as an increased frequency of dose changes. There were significantly more acute rejection episodes and kidney losses in the dose adjustment vs. no dose adjustment patients. However, when comparing the incidence of acute rejection and kidney loss between the RMM and REC groups, there was no significant difference. We conclude that in this cohort of recipients, the ECM formulation of MPA was better tolerated than the MMF formulation, resulting in fewer patients requiring dose adjustments or drug discontinuation.