Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS.

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD n = 151, SD n = 141) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, n = 141) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; P = 0.02); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.

Alemtuzumab (Campath 1H) induction with tacrolimus monotherapy is safe for high immunological risk renal transplantation.

Immunosuppression for immunologically high-risk renal transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, has shown promise in tolerogenic induction protocols, requiring minimal maintenance immunosuppression. In this prospective, open-label, randomized, controlled trial, we enrolled 21 high immunological risk patients (i.e., panel reactive antibody>20% or previous transplant). Patients received either single-dose alemtuzumab given before graft reperfusion, with tacrolimus monotherapy, or four doses of Thymoglobulin with tacrolimus, mycophenolate, and steroids. Median follow-up was 377 days. One patient in the Thymoglobulin group who suffered primary graft nonfunction died. One-year cumulative graft survival was 85.7% for the alemtuzumab group and 87.5% for the Thymoglobulin group. Two alemtuzumab and three Thymoglobulin patients suffered rejection episodes. Infection rates were similar. Early results of this ongoing study indicate that a tolerogenic protocol with alemtuzumab induction and tacrolimus maintenance monotherapy is safe in immunologically high-risk renal transplant patients.

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

BACKGROUND: Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. METHODS: This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. RESULTS: FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. CONCLUSIONS: While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

A multicenter, prospective study of C2-monitored cyclosporine microemulsion in a U.S. population of de novo renal transplant recipients.

BACKGROUND: Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. METHODS: In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. RESULTS: Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/1.73 m. Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. CONCLUSIONS: The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.

Campath and renal transplant rejection.

No clear guidelines exist for the treatment of acute vascular rejection following renal transplantation. This report documents one patient who was treated with plasmapheresis, immunoglobulin and Campath with good initial response. However, rejection recurred resulting in graft loss and, in addition, the patient developed post-transplant lymphoma.

Successful transplantation of donor organs from a hemlock poisoning victim.

BACKGROUND: The poison hemlock plant (Conium maculatum) has been a known poison since early in human history, most notably as the agent used for the execution/suicide of Socrates in ancient Greece. No experience has been reported regarding the suitability of a hemlock victim's organs for transplantation. METHODS AND RESULTS: This report documents successful transplantation of the liver, kidney, and pancreas from a 14-year-old girl who died of anoxic encephalopathy from asphyxia after the accidental ingestion of fresh hemlock while on a nature hike. Predonation laboratory values were not remarkable, and liver and kidney biopsy results were normal. All organs in the three recipients had immediate function, and no recipient had any clinical evidence of transmitted toxin. All recipients are well, with functioning transplants at greater than 6 months after transplantation. CONCLUSIONS: Poison hemlock intoxication does not seem to be a contraindication to organ donation.

Renal cortical adenoma incidentally found during living donor nephrectomy.

We report a living related kidney donor incidentally found to have a renal cortical adenoma at nephrectomy. The patient is a 53-year-old man accepted for living related kidney donation. Predonation workup revealed a solitary left renal artery and, on the right kidney, a main artery with a small accessory artery in theupper pole. No other abnormalities were found in the medical history, physical examination, or laboratory and radiological studies. A left laparoscopic nephrectomy was planned. However, during dissection of the upper pole, a 5-mm mass was noted. The nephrectomy was completed, and the organ was preserved in cold University of Wisconsin solution. Permanent section histology showed that the lesion was mostly likely a renal cortical adenoma. As the risk of malignant transformation with immunosuppression could not be adequately determined, the kidney was not transplanted into the recipient. The donor elected not to have the kidney replaced, and the organ was discarded.

Late renal allograft rupture in a patient with small vessel vasculitis following discontinuation of immunosuppression.

We report the case of a 21-year-old man with antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis who experienced spontaneous renal allograft rupture 21 months after engraftment. Because of chronic allograft nephropathy, the patient's immunosuppressive regimen had been discontinued approximately 3 weeks prior to his presentation with abdominal pain and evidence of internal hemorrhage. He was emergently taken to the operating room, where a ruptured allograft was found and transplant nephrectomy was performed. Postoperatively, the cause of rupture was determined to have been acute cellular rejection. This case may be the longest interval reported between renal transplant and spontaneous allograft rupture.

Use of kidneys from hepatitis C seropositive donors shortens waitlist time but does not alter one-yr outcome.

Utilization of hepatitis C seropositive kidney donors remains controversial. We examined the use of hepatitis C seropositive donors for renal transplantation. Data for creatinine, liver function tests, cold ischemia time, and graft and patient survival were analyzed from 20 hepatitis C seropositive recipients receiving cadaveric renal allografts from seropositive donors and were compared with 20 hepatitis C seropositive recipients receiving allografts from seronegative donors. Recipients receiving a kidney from a hepatitis C seropositive donor were on the waitlist for 9.9 +/- 1.8 months, compared with 17.8 +/- 3.3 months for those receiving a kidney from a seronegative donor (p < 0.05). There were no significant differences in graft or patient survival. Incidences of acute cellular rejection and acute tubular necrosis were similar. There were no significant differences in creatinine, alanine aminotransferase, alkaline phosphatase, or bilirubin values. While there was a significant difference in aspartate aminotransferase at 2 wk and 6 months, these differences were of questionable clinical importance. In conclusion, donor seropositivity for hepatitis C should not preclude renal transplantation into a hepatitis C seropositive recipient and utilization of these organs decreases waitlist time for hepatitis C seropositive recipients.

Safe administration of a humanized murine antibody after anaphylaxis to a chimeric murine antibody.

BACKGROUND: Basiliximab and daclizumab are potent and relatively safe immunosuppressive induction agents used in transplantation. These chimeric or humanized monoclonal antibodies, respectively, act by binding to the alpha chain of interleukin-2 receptors on activated T lymphocytes. Herein, the authors describe successful transplant induction therapy with a humanized murine antibody in a patient with a history of anaphylaxis to a chimeric murine antibody. METHODS: The authors report a 42-year-old woman who received a dose of basiliximab without adverse reaction before an anticipated renal transplant that was canceled. Two weeks later, she received a second dose of basiliximab. Within 10 min of receiving the second dose, she developed chest tightness, shortness of breath, tongue swelling, diffuse pruritic rash, and skin flushing. RESULTS: The authors hypothesized that her anaphylaxis was mediated by immunoglobulin (Ig) E antibodies to basiliximab. Consistent with this hypothesis, intradermal administration of a 1:100 dilution of basiliximab induced a 10 x 10-mm flare. The authors sought to find an alternative immunosuppressive agent for this patient. The patient elicited prick and intradermal skin testing responses to horse and rabbit polyclonal antithymocyte antibody preparations. However, she mounted neither a prick nor an intradermal response to daclizumab. The patient was administered daclizumab without any adverse effects. CONCLUSIONS: The negative skin test and safe administration of daclizumab is surprising because the similarity of these hybrid antibodies would have predicted similar IgE responsiveness and clinical outcome. The authors propose that patients who develop anaphylaxis to basiliximab or other chimeric antibodies may be candidates for treatment with a humanized antibody preparation such as daclizumab in the presence of a negative skin test to the humanized agent.