Douglas J. Norman

Valacyclovir for the Prevention of Cytomegalovirus Disease after Renal Transplantation

BACKGROUND Cytomegalovirus (CMV) disease is a major complication of organ transplantation. We hypothesized that prophylactic treatment with valacyclovir would reduce the risk of CMV disease. METHODS A total of 208 CMV-negative recipients of a kidney from a seropositive donor and 408 CMV-positive recipients were randomly assigned to receive either 2 g of valacyclovir or placebo orally four times daily for 90 days after transplantation, with the dose adjusted according to renal function. The primary end point was laboratory-confirmed CMV disease in the first six months after transplantation. RESULTS Treatment with valacyclovir reduced the incidence or delayed the onset of CMV disease in both the seronegative patients (P<0.001) and the seropositive patients (P=0.03). Among the seronegative patients, the incidence of CMV disease 90 days after transplantation was 45 percent among placebo recipients and 3 percent among valacyclovir recipients. Among the seropositive patients, the respective values were 6 percent and 0 percent. At six months, the incidence of CMV disease was 45 percent among seronegative recipients of placebo and 16 percent among seronegative recipients of valacyclovir; it was 6 percent among seropositive placebo recipients and 1 percent among seropositive valacyclovir recipients. At six months, the rate of biopsy-confirmed acute graft rejection in the seronegative group was 52 percent among placebo recipients and 26 percent among valacyclovir recipients (P=0.001). Treatment with valacyclovir also decreased the rates of CMV viremia and viruria, herpes simplex virus disease, and the use of inpatient medical resources. Hallucinations and confusion were more common with valacyclovir treatment, but these events were not severe or treatment-limiting. The rates of other adverse events were similar among the groups. CONCLUSIONS Prophylactic treatment with valacyclovir is a safe and effective way to prevent CMV disease after renal transplantation.

Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation

BACKGROUND Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors

Background During pregnancy and nursing, a babys developing immune system is intimately exposed to the mothers antigens. To determine whether this exposure is of clinical benefit to patients who later receive an allograft as an adult, we analyzed the outcome of primary renal transplantations from sibling donors. Methods We retrospectively studied graft survival and rejection episodes in 205 patients who had received renal transplants at nine centers between 1966 and 1996 from sibling donors bearing maternal or paternal HLA antigens not inherited by the recipient. The sibling donors were categorized by analysis of family HLA-typing data. Results In the multicenter analysis, graft survival was higher 5 years and 10 years after transplantation in recipients of kidneys from siblings expressing maternal HLA antigens not inherited by the recipient than in recipients of kidneys from siblings expressing paternal HLA antigens not inherited by the recipient (86 percent vs. 67 percent at 5 years and 77 percent vs....

Kidney and pancreas transplantation

Data from the Scientific Registry of Transplant Recipients offer a unique and comprehensive view of US trends in kidney and pancreas waiting list characteristics and outcomes, transplant recipient and donor characteristics, and patient and allograft survival. Important findings from our review of developments during 2002 and the decades transplantation trends appear below.

A Randomized Clinical Trial Of Induction Therapy With Okt3 In Kidney Transplantation

A randomized, prospective multicenter trial was conducted to compare the safety and efficacy of OKT3 as an induction therapy with that of conventional immunosuppressive therapy administered to cadaveric renal allograft recipients. Two hundred fifteen patients were treated either with OKT3 plus azathioprine and steroids for 14 days with the delayed addition of cyclosporine on day 11, or with conventional immunosuppression (steroids, azathioprine, and cyclosporine). OKT3 patients had significantly fewer rejection episodes (51% vs. 66%, P=0.032), a longer time to initial rejection (46 days vs. 8 days, P=0.001), and fewer rejection episodes per patient (0.82 vs. 1.14, P=0.014) than conventionally treated patients. Kaplan-Meier estimates of two-year graft and patient survival rates were 84% and 95%, respectively, for the OKT3-treated group, and 75% and 94%, respectively, for the conventionally treated group. Following a subsequent first rejection episode, OKT3 reversed 93% of the rejections in patients receiving OKT3 induction therapy and 94% in patients receiving conventional therapy. Adverse experiences reported during OKT3 induction therapy were similar to those seen when the drug was used for rejection. Following initial exposure, 40.3% of the patients tested were positive for anti-OKT3 antibody, only 6.7% of which were of high titer (1:1000). In the presence of low titer (1:100 or less) antibody, OKT3 was successful in reversing rejection in five of six retreated patients tested. In conclusion, treatment with OKT3 (in combination with azathioprine, steroids, and the delayed addition of cyclosporine) is an effective approach for renal allograft maintenance.

The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol.

UNLABELLED The use of cyclosporine for immunosuppression in renal transplantation allograft recipients is associated with hypertrichosis, gingival hyperplasia, and hypercholesterolemia. Conversion of patients to tacrolimus may lead to an improvement in these effects with minimal risk of rejection or allograft dysfunction. METHODS Sixteen renal transplant recipients were prospectively converted from CsA to tacrolimus and followed for 1 year. Gingival hyperplasia index, total cholesterol, and blood pressure were recorded at the outset, 4-, 8-, and 12-month intervals. Glomerular filtration rate was checked before conversion and 1 year later. Photographs documenting hypertrichosis were taken before conversion and 1 year later. Adverse effects from tacrolimus were recorded at 4, 8, and 12 months. RESULTS Twelve patients with hypertrichosis noted rapid improvement. Mean gingival hyperplasia index decreased from 24 to 6; mean total cholesterol decreased from 237 to 195. Glomerular filtration rate was essentially unchanged (56 to 54). One episode of rejection occurred, three patients developed diarrhea, three noted headaches, and one had a tremor. CONCLUSION If carefully monitored, patients suffering adverse effects secondary to cyclosporine may be converted to tacrolimus with minimal risk of allograft dysfunction or rejection.

Renal transplantation across the ABO barrier using A2 kidneys

BACKGROUND The waiting list for cadaveric kidney transplantation has continued to grow, and with the relative scarcity of cadaver donors, the median waiting time for patients in the United States increased to 824 days in 1994. The median waiting times for patients with blood groups B or O were 1329 and 1007 days, respectively. Allocation of blood group A2 kidneys (20% of group A) to blood group O and B patients expands their potential donor pool and shortens their waiting time for a kidney transplantation. METHODS Between May 1991 and June 1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B patients. Anti-A isoagglutinins were measured before transplantation, and patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). RESULTS One patient with high titer anti-A antibodies, who did not receive PP, lost her allograft because of hyperacute rejection. Allograft function was excellent in the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89) mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft survival rate was 93.3+/-6.4% and the patient survival rate was 100%. CONCLUSION We conclude that the allocation of blood group A2 kidneys for blood group O and B recipients is a practical way to expand the donor pool for these transplant candidates. PP may be important for reducing the levels of anti-A1 and anti-A2 antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems to be unnecessary.

Reduced human IgG anti-ATGAM antibody formation in renal transplant recipients receiving mycophenolate mofetil.

Exposure to the equine-derived polyclonal antithymocyte preparation, ATGAM, frequently elicits human anti-ATGAM antibody formation. The influence of concomitant immunosuppressants on this antiantibody response has not been established. We therefore evaluated IgG antibody formation to ATGAM in 47 patients receiving ATGAM as part of a prospective, randomized, double-blinded study of mycophenolate mofetil versus azathioprine for maintenance immunosuppression after primary cadaveric renal transplantation. All patients received ATGAM for induction of immunosuppression plus methylprednisolone, prednisone, and cyclosporine. In addition, patients were randomized to receive maintenance immunosuppression consisting of either azathioprine (AZA) 1-2 mg/kg/day, mycophenolate mofetil 2 gm/day (MMF2), or mycophenolate mofetil 3 gm/day (MMF3). Patient sequential sera were independently tested for IgG anti-ATGAM antibody by 2 laboratories, which were blinded to treatment arm assignments, using enzyme-linked immunosorbent assays. Both laboratories found significantly greater anti-ATGAM antibody formation in group AZA compared with groups MMF2 and MMF3: laboratory 1 reported sensitization rates in the 3 groups of 94% (AZA), 50% (MMF2) (P < 0.02 vs. AZA), and 60% (MMF3) (P < 0.05 vs. AZA); and laboratory 2 reported rates of 67% (AZA), 17% (MMF2) (P < 0.02 vs. AZA), and 10% (MMF3) (P < 0.02 vs. AZA). In addition, fewer patients formed high titer antibody in the MMF arms compared to the AZA arm: 56% (AZA), 0% (MMF2) (P < 0.02 vs. AZA), and 20% (MMF3) (P < 0.02 vs. AZA) of patients for laboratory 1; and 20% (AZA), 0% (MMF2) (P < 0.05 vs. AZA), and 0% (MMF3) (P < 0.05 vs. AZA) of patients for laboratory 2. Differences in test results between the 2 laboratories were explained by differences in the sensitivity of their respective immunoassays and in the criteria used for assigning a positive result to test specimens. In this protocol, MMF at 2-3 gm/day was associated with a reduced incidence and titer of IgG anti-ATGAM antibody formation compared with standard azathioprine dosing. Although MMF previously has been reported to inhibit T cell responses that mediate acute cellular rejection, this is the first demonstration that MMF significantly inhibits human B cell responses to antigen in vivo.

Prospective Risk Stratification in Renal Transplant Candidates for Cardiac Death

In previous studies to predict future cardiac death of patients undergoing evaluation for renal transplantation, noninvasive or invasive testing of all, or nearly all, patients has been used. In an attempt to decrease the cost of cardiac risk assessment, we prospectively used a two-tiered cardiac risk assessment algorithm on 189 consecutive patients referred for renal transplant evaluation. First, patients were stratified by clinical characteristics of age > or = 50 years, history of angina, insulin-dependent diabetes, congestive heart failure, or abnormal electrocardiogram (excluding left ventricular hypertrophy). Patients having none of these risk factors (n = 94) were considered at low risk for cardiac events and underwent no further cardiac evaluation. Patients with one or more of the cardiac risk factors (n = 95) were considered to be in a high-risk group and were required to undergo further evaluation with thallium myocardial scintigraphy. Follow-up of patients was for 46 +/- 16 months. Cardiac mortality was significantly higher in the clinical high-risk group compared with the clinical low-risk group (17% v 1%, respectively; P < 0.001). Further cardiac risk stratification was evident by thallium myocardial scintigraphy. Patients with reversible thallium defects had significantly higher cardiac mortality rates than patients with no thallium defects (23% v 5%, respectively; P < 0.05). Fixed thallium defects also had predictive value for cardiac mortality (29%,; P < 0.05), but deaths in this fixed defect group tended to occur later in the follow-up period. The initial clinical stratification obviated the need for further noninvasive or invasive testing in nearly half of the renal transplant candidates.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics

An intravenous (i.v.) formulation of mycophenolate mofetil (MMF; CellCept®, Roche Pharmaceuticals, Inc., Palo Alto, CA) that will enable its administration to patients unable to tolerate oral medication is available. Two separate studies, an open‐labeled pharmacokinetic (PK) study and a double‐blind safety study, were performed. Within 24 h after transplant, 153 (safety study) and 45 (PK study) first or second renal transplant recipients were started on i.v. MMF 1 g Q12h or placebo (used in the safety study only, 2:1 MMF:placebo), given over 2 h via a dedicated peripheral venous catheter. In the safety study, per os (p.o.) MMF (1g Q12h) or placebo was administered, starting within 72 h after transplant, whereas in the PK study, p.o. MMF was started on the evening of day 5. Sequential blood samples obtained on study days 5 (i.v. MMF) and 6 (p.o. MMF) before and up to 12 h after the AM dose were analyzed for mycophenolic acid (MPA) and MPA glucuronide (MPAG) concentrations by high‐performance liquid chromatography. The area under the concentration curve (AUC) was calculated using the linear trapezoidal rule. The MPA AUC0–12 was higher for i.v. MMF than p.o. MMF (40.8±11.4 μg·h/mL vs. 32.9±15, p<0.001). There were no other significant PK differences for plasma MPA or MPAG. In the safety study (n=98 i.v. MMF vs. n=55 placebo), 11 patients (11%, i.v. MMF) and 4 patients (7%, placebo) discontinued their use of the drug because of an adverse event (AE). Overall, AEs were similar between i.v. MMF and placebo. Injection site phlebitis (4%) and thrombosis (4%) were observed only with i.v. MMF. MMF i.v. 1 g twice daily (b.i.d.) should provide efficacy at least equivalent to p.o. MMF without increased toxicity, and it provides an acceptable alternative dose form in the immediate period after transplant.