Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation.

BACKGROUND: In simultaneous kidney-pancreas (SPK) transplantation, manifestations of renal allograft rejection typically become evident before those of pancreatic rejection. This study compared mycophenolate mofetil (MMF) and azathioprine (AZA) in prevention of renal rejection after primary SPK transplantation. METHODS: In an open-label, randomized, multicenter study, patients received MMF 1.5 g twice daily (n=74) or AZA 1-3 mg/kg daily (n=76) for 1 year after transplantation. The incidence of rejection was assessed at 6 months. Adverse events were tracked through 1 year. Survival data are reported through 2 years. RESULTS: At 6 months, efficacy results for MMF vs. AZA patients, respectively, were the following: rejection (27% vs. 39%); rejection or death (34% vs. 42%); rejection, graft loss, death, or premature withdrawal (i.e., treatment failure; 41% vs. 55%). Six-month efficacy trends favored MMF, and time to rejection or treatment failure was significantly longer when compared with AZA (P=0.049). One-year efficacy results for MMF vs. AZA patients, respectively, were the following: treatment of renal rejection (35% vs. 47%); renal allograft loss or death (9% vs. 12%); pancreas allograft loss or death (15% vs. 14%). Five MMF patients (7%) and four (5%) in the AZA group died. More MMF than AZA patients developed opportunistic infections (54% vs. 38%), but the pathogens did not differ. CONCLUSIONS: Trends for most efficacy parameters favored MMF over AZA, and time to renal allograft rejection or treatment failure was statistically significantly longer for MMF. The use of MMF in the treatment of SPK recipients is a useful advance.

The effect of age and prolonged cold ischemia times on the national allocation of cadaveric renal allografts.

BACKGROUND: National sharing of cadaveric renal allografts for perfectly matched kidneys (0 antigen mismatch) has improved outcome in the recipients of these kidneys despite increasing cold storage times. However, there may be limits to outcome improvement of matched kidneys based on age and cold storage time. MATERIALS AND METHODS: To determine if national sharing of kidneys based on matching improves outcome regardless of donor age and cold storage time, we evaluated the United Network for Organ Sharing (UNOS) Scientific Registry for all recipients of cadaveric kidney transplants between January 1, 1990 and July 31, 1998. We divided the recipients into four groups based on donor age and cold storage time. Group 1 comprised young donors (donor age <55 years) with average (<24 h) cold storage time; group 2, young donors with long (>/=24 h) cold storage time; group 3, older donors (donor age >/=55 years) with average cold storage time; and group 4, older donors with long cold storage time. RESULTS: A total of 64,046 recipients were evaluated: 35,061 (55%) in group 1, 21,264 (33%) in group 2, 4308 (7%) in group 3, and 3414 (5%) in group 4. Early graft performance progressively decreased from group 1 to group 4. Delayed graft function (DGF: dialysis requirement in the first 7 days posttransplant) was 18, 29, 33, and 42% (P < 0.0001); serum creatinine at 3 years (in mg/dl) was 1.70 +/- 0.8, 1.73 +/- 0.9, 2. 31 +/- 1.0, and 2.42 +/- 1.1 (P < 0.0001); 1-year graft survival was 87, 84, 79, and 77% (P < 0.0001); and 3-year graft survival was 77, 74, 63, and 62% (P < 0.0001, for groups 1 and 2 vs groups 3 and 4, respectively). The trends in DGF persisted through the groups in 0 antigen mismatched kidneys. CONCLUSIONS: Early function is adversely affected by prolonged cold storage, despite matching, in recipients of younger and older donor kidneys. Long-term function does not appear to be affected by prolonged cold storage. Recipients of kidneys from donors >/=55 years of age have significantly worse short- and long-term outcome and may not benefit from national sharing.

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants.

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.

Arteriographic detection of renovascular disease in potential renal donors: incidence and effect on donor surgery.

PURPOSE: To determine the arteriographic incidence and severity of renal arterial disease in potential renal donors and to evaluate the effect of identifying vascular abnormalities on subsequent donor surgery. MATERIALS AND METHODS: The records of 716 potential living renal donors who underwent conventional arteriography were reviewed. Abnormal arteriograms were reexamined to characterize vascular disease, and the effect of identifying renovascular disease on subsequent donor surgery was ascertained with chart review. RESULTS: Renovascular abnormalities were noted in the dictated reports in 78 patients (10.9%). The most common causes were fibromuscular dysplasia and atherosclerosis. The arteriograms of 64 patients were available for retrospective review. Abnormalities were characterized as minimal stenosis (<30% narrowing) in 42 patients and mild stenosis (30%-50% narrowing) in 19 of 61 patients with arteriographic abnormalities at retrospective review. In three patients, no significant abnormality was seen at retrospective review. The effect of detecting renovascular disease on donor selection was determined in 74 of the 78 patients. In 73 of these 74 patients (99%), detection of an abnormality directly affected donor surgery. CONCLUSION: In this population of potential renal donors, the arteriographic incidence of renovascular disease (10.9%) was higher than previously reported. Although renovascular abnormalities were mild, their detection influenced the plan for donor surgery in almost all patients.

Simultaneous pancreas-kidney transplantation: an overview of indications, complications, and outcomes.

Simultaneous pancreas-kidney transplantation (SPK) has become an accepted therapy for the treatment of patients with insulin-dependent diabetes mellitus and renal failure from diabetic nephropathy. The procedure has evolved over the last twenty years, and refinements in technique, better organ preservation solutions, and more potent immunosuppressive therapies have improved one-year graft-survival rates to 81% for the pancreas and 88% for the kidney (International Pancreas Transplant Registry Data-1996). Proper patient selection is important, given the increased complexity of the procedure, the increased need for immunosuppression, and the need for compliance with postoperative medications and monitoring. The benefits of a successful SPK include more physiologic glucose metabolism and freedom from dialysis. This review will describe the indications and selection process for potential candidates, outline the procedure and postoperative care, and discuss the potential impact on secondary complications of diabetes mellitus. It will then discuss results and complications from the use of current protocols and immunosuppression at the University of California at San Francisco.

Ureteral obstructions and leaks after renal transplantation: outcome of percutaneous antegrade ureteral stent placement in 44 patients.

PURPOSE: To analyze the outcome of percutaneous antegrade ureteral stent placement for treatment of ureteral stenoses and leaks after renal transplantation. MATERIALS AND METHODS: Antegrade pyelography and percutaneous ureteral stent placement were performed in 45 patients with ureteral obstruction (n = 40), leak (n = 3), or both (n = 2). Obstructions were graded as mild, moderate, or complete, and as early (< or = 3 months after transplantation) or late (> 3 months). RESULTS: The outcome of stent placement was successful in 25 (57%) patients (average follow-up, 30 months). The ureteroneocystostomy (UNC) was the most common site of obstructions (22 of 41), leaks (four of five), and successful outcomes (16 of 22). Moderate obstructions were most common (29 of 41) and responded best to treatment (17 of 29). Eighteen (69%) of 26 early obstructions and five (33%) of 15 late obstructions were successfully managed percutaneously. All complications (12 of 45 patients) were minor, with infections the most common (n = 7). No mortality or allograft loss was attributable to stent placement. CONCLUSION: Ureteral stents are safe and effective for the treatment of obstructions and leaks and are particularly effective for early and UNC obstructions. These stents may also be useful for temporary drainage.

Diagnosis of duodenal leaks from kidney-pancreas transplants in patients with duodenovesical anastomoses: value of CT cystography.

OBJECTIVE: This study was undertaken to assess the value of CT cystography, using scans made with full bladder distention by a combination of iodinated contrast material and air and scans made after active voiding, for detecting duodenal segment leaks in patients with kidney transplants and pancreas transplants associated with small duodenal segments and duodenovesical anastomoses. SUBJECTS AND METHODS: 18 patients with such kidney-pancreas transplants underwent CT cystography for clinically suspected leaks from the duodenal segment. Six patients had two examinations, resulting in 24 CT cystograms. The CT protocol consisted of an initial series of pelvic scans (plain CT) without oral, IV, or bladder contrast material; CT cystogram with the bladder fully distended by iodinated contrast material and air; and, if the findings were negative, CT after voiding. If no leak was demonstrated, the remainder of the abdomen to the liver dome was examined. Diagnoses were proved by surgery or cystoscopy (n = 11) and clinical follow-up examinations (n = 13). RESULTS: Overall, bladder-duodenal segment leaks were demonstrated in 11 of 12 studies: one by plain CT, seven by full CT cystography, and four by CT after voiding following negative findings on full CT cystography. One surgically proved leak was missed by CT cystography owing to a large amount of pelvic fluid. In 12 studies without a leak, CT cystography results correlated well with clinical follow-up studies. There were no false-positive results. Sensitivity was 92%, specificity was 100%, and accuracy was 96%. CONCLUSION: CT cystography with a dedicated protocol is an accurate way to diagnose leaks of the duodenal segment in patients with bladder-drained kidney-pancreas transplants if administration of air combined with contrast material into the bladder and CT after voiding are used.

Long-term outcome in kidney transplant patients with hepatitis C (HCV) infection.

To assess the prevalence and long-term impact of HCV on kidney transplant recipients, we assayed 716 pre-transplant sera using a first-generation ELISA. The anti-HCV positive sera were confirmed by a 6-antigen radioimmunoassay (RIA). Patients were followed up for 5 years. Graft survival, function, evidence of chemical hepatitis (AST > 2x normal), patient mortality and cause of death were evaluated. The prevalence of anti-HCV antibody was 10.3%. In the 638 patients who were followed up for 5 years, there were no differences in graft function, graft survival, overall mortality, or death from sepsis or liver disease. Peak AST levels were significantly higher in anti-HCV positive patients compared to anti-HCV negative patients. At 5 years, the AST levels remained significantly higher in the anti-HCV positive group, however, this was only 6 U/1 > normal. Liver biopsies performed 3 to 7 years post-transplant in 80% of anti-HCV positive patients with chemical hepatitis showed 12% CAH, 50% mild hepatitis and 38% normal histology. Six (9.7%) patients seroconverted from anti-HCV positive to anti-HCV negative 2 to 5 years post-transplant. The presence of anti-HCV does not appear to alter long-term patient or graft survival, and histologic evidence of severe chronic liver disease was rare in anti-HCV positive patients with chemical hepatitis. From these results, the presence of anti-HCV antibody should not preclude kidney transplantation.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

Are blood transfusions beneficial in the cyclosporine era?

In patients treated with conventional immunosuppression (azathioprine and prednisone) after renal transplantation, there is a beneficial effect of pre-transplant blood transfusions on graft survival; in patients treated with cyclosporine, this effect may be lost. In 66 children who received living-related donor transplants after donor-specific transfusions (DST) and were treated with azathioprine-prednisone in our center, 1- and 5-year graft survival rates were 99% and 77% respectively. These rates were similar to those reported for children who did not receive DST but were treated with cyclosporine in other centers. There were 634 adult and pediatric recipients of cadaver transplants in our center who were treated with cyclosporine and prednisone (non-sequential therapy, n = 89) or antilymphoblast globulin, azathioprine preduisone, and cyclosporin (sequential therapy, n = 545). When all patients were considered, graft survival rates were higher in transfused than in non-transfused patients at 3-5 years, but in the sequential therapy group, there were no differences in graft survival rates between transfused and non-transfused patients. The results suggest that transfusions do not improve cadaver graft survival in patients receiving optimal cyclosporine therapy and that equally good related donor graft survival can be achieved with DST and conventional immunosuppression or no DST and cyclosporine.