Mycophenolate mofetil, with cyclosporine and prednisone, reduces early rejection while allowing the use of less antilymphocytic agent induction and cyclosporine in renal recipients with delayed graft function.

Antilymphocytic agent induction (ALAI), with antithymocyte globulin or monoclonal antibody, is generally used in renal transplantation (TX) to spare renal allografts with poor initial function from the toxic effects of cyclosporine (CsA) and/or to augment immunosuppression (IS) in the patient at a high risk for early rejection. ALAI, unfortunately, increases the cost of TX and the risk to the patient, having been associated with many adverse side effects. An IS protocol, which results in a low incidence of early rejection while using less CsA and ALAI, is a worthwhile goal. We compare our experience with mycophenolate mofetil (MMF), CsA, and prednisone (MMFCP; n = 62) to our azathioprine (AZA), CsA, and prednisone (AZACP; n = 50) triple-drug IS, with and without ALAI. The patient characteristics for age, race, first TX, cadaveric donor, pediatric recipient, and dialysis in the first post-op week (DGF) were not different for the MMFCP versus AZACP groups. There were more females in the MMFCP group (51.6% versus 30.0%, p = 0.022). We report that rejection-free survival at 6 months (RF6) was better in the MMFCP versus AZACP group (83.9% versus 60.0%, p = 0.005). Less ALAI and CsA were used in the MMFCP patients. At 1 year, actuarial graft survival was 91.9% in the MMFCP group and 81.9% in the AZACP group (p = 0.116). Actuarial 1-year patient survivals were not different in the two patient groups. In the sub-population of patients with DGF, the RF6 in the MMFCP (n = 13) group was 92.3% versus 57.1% in the AZACP (n = 14) group (p = 0.041). The reduction in early rejection episodes in the patients on MMFCP with DGF was accomplished while using half as much ALAI and lower CsA doses and levels. The African-American recipient sub-population on MMFCP also demonstrated an improvement in RF6 while using less ALAI and CsA (78.6% versus 48.0%, p = 0.022). We conclude that the use of MMF-based triple-drug IS results in fewer rejection episodes while allowing for lower CsA levels and less ALAI, even in patients with delayed graft function.

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.

BACKGROUND: Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS: Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS: A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION: Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

The high-grade match program of the South-Eastern Organ Procurement Foundation: status at four years.

In summary, the HGM program is a voluntary, multicenter, prospective study of the SEOPF that is open to all transplant centers. The program extends mandatory sharing beyond the UNOS zero-antigen mismatch obligation, and uses preliminary crossmatching via ROP trays to try to facilitate transplantation of the highly sensitized patient. The program encompasses less than 7% of the cadaver kidney transplant activity of the participating centers, so it does not impact the majority of recipients. After 49 months of operation, it has significantly improved access to transplantation for blood group O patients, patients awaiting re-grafts, and those who are highly sensitized (PRA > or = 40%). Additionally, 92% of the HGM recipients have received an allograft with 2 or less antigens mismatched. Enrollment will continue until there is sufficient power to test the null hypothesis of equality of HGM and non-HGM transplants.

The high grade match kidney sharing algorithm of the South-Eastern Organ Procurement Foundation (SEOPF): altering recipient demographics through improved matching.

BACKGROUND: Studies of kidneys shared through the South-Eastern Organ Procurement Foundation (SEOPF) have shown that regional organ procurement (ROP) trays can predict negative crossmatch in highly sensitized patients when the HLA match is of a high grade. In an attempt to offer more well-matched kidneys to highly sensitized patients, SEOPF organized the High Grade Match (HGM) Program. METHODS: This United Network for Organ Sharing (UNOS)-approved allocation variance requires mandatory sharing of all kidneys by participating centers after UNOS mandatory sharing requirements have been met. The HGM levels of sharing are: (1) 0 A,B mismatch (MM); panel-reactive antibody (PRA) > or = 40%; negative ROP crossmatch; (2) 0 B,DR MM with > or = 40% PRA; negative ROP crossmatch; (3) 0 B,DR MM with PRA < 40%. Non-HGM cadaveric transplants at the same participating centers--locally or distally procured--serve as the control group. RESULTS: During the first 18 months of this program, the 23 participating centers shared 124 kidneys of the 1592 that were available. Well-matched kidneys (two mismatches or less) accounted for 91.1% in the HGM group, but only 19% of the controls (P<0.0001). Highly sensitized patients (PRA > or = 40%) represented 13.8% of the HGM group, but only 3.3% of the non-HGM group (P<.0001). With HGM kidneys, there was a shift in recipient demographics. Patients with blood group O, female patients, older patients, and retransplanted patients all accounted for significantly larger percentages of the HGM group compared with the non-HGM control group. The racial composition of the recipients of high-grade matches was, however, no different than that of the control recipients at the same centers. CONCLUSION: The HGM Program resulted in longer ischemia times, but graft survival was not affected. The 1-year actuarial graft survival rate (Kaplan-Meier) for HGM kidneys was not different from the control cadaveric graft survival rate. By sharing kidneys based on improved HLA matches with consideration for high PRA, the HGM Program offered more transplant opportunities to women, blood group O recipients, retransplants, and older patients.

Kidney sharing by centers of the South-Eastern Organ Procurement Foundation.

1. SEOPF centers historically have shared kidneys at a higher rate than the rest of the United States. 2. SEOPF centers transplanted better-matched kidneys than the rest of the nation despite transplanting a significantly larger percentage of "hard-to-match" black recipients. 3. Within SEOPF centers, a shared kidney was almost twice as likely to be a good match (zero-3 HLA antigen mismatches) as was a local kidney. 4. Within SEOPF centers, well-matched kidneys (zero-3 HLA antigen mismatches) had significantly better graft survival than did poorly-matched (4-6 HLA antigen mismatches) kidneys. 5. SEOPF centers had one-, 2- and 3-year graft survival rates comparable to those of the rest of the nation. 6. SEOPF centers have proven the efficiency of ROP trays in predicting final crossmatch results for shared kidneys. 7. The SEOPF High Grade Match (HGM) algorithm has been successful in transplanting highly sensitized (current PRA > 40%) recipients. 8. The use of ROP trays in well-matched, highly sensitized recipients resulted in improved kidney availability. 9. Graft survival of HGM recipients was comparable to that of non-HGM recipients. 10. Despite longer cold ischemia times for HGM kidneys, there was no increased incidence of delayed graft function in these kidneys. 11. The HGM program accounted for 8.1% of the participating centers' activity and, thus, has not adversely impacted the majority of the centers' other patients. 12. The one- and 2-year graft survival data for HGM transplants were in accordance with the expected rates and were not statistically different from those of non-HGM transplants.

The effect of polyimmune gammaglobulin for prophylaxis against reactivation cytomegalovirus infection in kidney and kidney/pancreas transplant recipients.

Cytomegalovirus (CMV) remains the most important infection in the renal transplant recipient. Few data are available that provide guidance for approaches that seek to reduce the reactivation of latent disease after transplantation. To test the efficacy of polyimmune gammaglobulin in kidney and kidney/pancreas transplantation, consenting recipients with serologic evidence of previous CMV disease were randomized to receive i.v. polyimmune gammaglobulin (500 mg/kg) within 3 days of transplant with 250 mg/kg at weeks 1, 2, 4, and 6 or no prophylaxis. Both groups received identical induction and rejection immunosuppressive therapy. Polyimmune gammaglobulin prophylaxis reduced CMV reactivation infections. The incidence of reactivation infections was half in patients receiving Nashville/rabbit antithymocyte serum (N/R-ATS) compared with those receiving monoclonal anti-CD-3 therapy. Patients receiving polyimmune gammaglobulin along with N/R-ATS had an incidence of infection of only 10%. Reactivation infections were twice as common in patients who had primary nonfunction and nearly three times as common in patients with acute rejection. Both risk factors were associated with longer anti-T-cell therapy. Polyimmune gammaglobulin prophylaxis should be considered in transplant patients with previous CMV exposure who will be receiving prolonged anti-T-cell therapy because of acute rejection or primary nonfunction.

Colonic screening prior to renal transplantation and its impact on post-transplant colonic complications.

Colonic complications after renal transplantation are uncommon but have a high mortality rate. Some have recommended colonic screening in patients over 50 years of age prior to transplantation to lessen the impact of colonic diverticular disease. We report our 9-year experience of colonic screening for diverticular disease in potential recipients over the age of 50 and compare these results to the overall colonic complication rate in the same time period. From 1981-1990, 1186 renal transplants in 1019 patients were performed, during which time all potential recipients over the age of 50 yr were required to undergo colon evaluation prior to transplantation. Twenty cases of diverticular disease were found with more than a quarter of the cases in patients with adult polycystic disease. All underwent renal transplantation without a pre-transplant colectomy, and none had post transplant symptomatic colon disease. During that same time period a total of 14 colonic complications requiring surgical intervention were encountered with a mortality rate of 40%. Acute diverticulitis occurred in 5 patients, all of whom were over 50 yr of age, on low-dose immunosuppression, and in most cases it occurred remotely after transplantation. Colonic dysplasia/neoplasia also occurred remotely after transplantation in 2 patients over the age of 50. Cytomegalovirus (CMV) colitis was the next most common complication, accounting for 3 cases. This complication, which occurred in younger patients, was associated with high-dose steroid immunosuppression and had a high mortality rate, in spite of surgical intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

The strong correlation of cytotoxic T lymphocyte-specific serine protease gene transcripts with renal allograft rejection.

Several immune mechanisms are likely to be responsible for renal allograft rejection. The relative importance of delayed-type hypersensitivity versus cytotoxic T lymphocytes is controversial. We analyzed human renal allografts biopsies for intragraft expression of IL-1 beta, IL-6, and TNF alpha genes--putative mediators of DTH--as well as IL-2, IL-2 receptor (R) beta, and a CTL-specific serine protease gene. Total RNA was extracted from tissue samples and the mRNA fraction was converted to cDNA using oligo dT and reverse transcriptase. Then cDNA was amplified by the polymerase chain reaction (PCR) for 35 cycles using specific oligonucleotide primers. Each PCR analysis included beta-actin oligonucleotide primers to coamplify this constitutively expressed gene as an internal control. A total of 24 core allograft biopsies were studied and classified into a 3 histological categories: acute cellular rejection, equivocal components of rejection, and no evidence of rejection. There was no statistically significant difference in beta-actin expression among these histologic categories (P greater than 0.08). Interestingly, in this sample size, no significant difference was found between rejecting and nonrejecting samples for transcripts of any of the cytokines or IL-2R beta mRNAs. Apparently, DTH-like mechanisms are present in all allografts. However, detection of CTL-specific serine protease gene expression was almost exclusive to rejecting samples (P less than 0.003). These findings suggest that activation of CTLs play an active, but hardly exclusive, role as effectors of graft dysfunction in the rejection process. While this study does not define the relative importance of the genes examined, it does suggest that evidence of CTL-specific serine protease expression may provide a means of monitoring for rejection episodes or as a diagnostic aid when conventional diagnostic criteria are not conclusive.

Page kidney: case report and review of the literature.

Page kidney is caused by the accumulation of blood in the perinephric or subcapsular space, resulting in compression of the involved kidney, renal ischemia, and high renin hypertension. Most patients are young hypertensives with a remote history of blunt trauma to the abdomen or back. We describe a case of acute Page kidney following a renal biopsy in a patient with underlying IgA nephropathy. In addition to the new-onset hypertension, this patient developed a significant decline in renal function due to the inability of the contralateral diseased kidney to compensate. Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound were valuable in making this diagnosis. Medical and surgical therapeutic options were considered. This report also reviews all previously described cases of Page kidney.