Manifestations of renal allograft rejection in small children receiving adult kidneys.

We were concerned that clinical manifestations of rejection (R) might be subtle in small children transplanted with adult kidneys. We retrospectively analyzed the first rejection episode (biopsy proven) in 22 children (R group) under age 4 years [mean age, 23.7 +/- 2.2 months (+/- SEM); mean weight, 9.4 +/- 0.4 kg] receiving an adult-related donor kidney. We matched these patients for age, date of transplant, donor source and immunosuppression with 36 children without R (control or C group). We compared both groups at similar intervals from transplantation, based on the time of R (5.38 +/- 1.2 months) in the R group and analyzed the immediate 8-week period prior to R and the corresponding interval in the C group. Hypertension occurred in 82% (18/22) of the R versus 8% (3/36) of the C group (P less than 0.01). Fever longer than 7 days occurred in 45% (10/22) of the R versus 0% (0/36) of the C group (P less than 0.01). Increased creatinine occurred in only 45% (10/22) of the R versus 3% (1/30) of the C group (P less than 0.01). Cyclosporine did not influence these manifestations of R. The clinical manifestations did not predict the R grades on biopsy, which were moderate to severe in 13 and mild in 9 of the R patients. Graft survival was higher at 3 years in the C (95%) than in the R patients (65%), (P less than 0.004). Thus, clinical manifestations of acute R can be subtle in small children with adult renal allografts. Renal biopsy should not be delayed until the creatinine is elevated in these patients.

Local immunosuppression with reduced systemic toxicity in a canine renal allograft model.

We compared the efficacy of continuous intraarterial versus intravenous 6-mercaptopurine (6-MP) infusion in a mongrel canine renal allograft model with regard to overall survival, incidence of systemic and renal toxicity, and systemic drug exposure. Arterial anastomoses were done end-to-end, and infusion catheters were placed in the iliac artery or vena cava and connected to a subcutaneously placed programmable pump. A dose of 0.5 mg/kg/day 6-MP did not prolong survival over heparin-treated or untreated controls (MST = 7 days for both groups) when administered either locally or systemically. However, 0.75 mg/kg/day 6-MP i.a. (MST = 20 days) significantly prolonged survival over both untreated (P = 0.007) and heparin-treated controls (P = 0.02), with all dogs eventually dying of rejection. In contrast, 0.75 mg/kg/day i.v. (MST = 7 days) failed to prolong survival over controls (P greater than 0.1) and produced death from systemic toxicity in 3 of 7 animals. Six of 7 dogs receiving 2.0 mg/kg/day 6-MP i.a. (MST = 12 days) developed azotemia secondary to drug-induced nephrotoxicity. Identical renal histologic changes occurred in the same time frame in autotransplants treated similarly. Of 7 animals receiving 2.0 mg/kg/day i.v. (MST = 12 days), 5 died from early, severe systemic drug toxicity and 2 from early rejection. During 6-MP infusion at 0.5 mg/kg/day, systemic exposure was significantly less in the locally treated than in the systemically treated dogs when Cr concentrations were normal or moderately elevated (P less than 0.0005 and P = 0.01, respectively) but not when renal function became severely impaired (P = 0.34). In contrast to i.v. infusion, i.a. 6-MP delivery dissociated immunosuppressive efficacy from systemic toxicity, supporting previous work demonstrating high first-pass renal elimination of 6-MP. We conclude that tightly controlled local delivery of an immunosuppressive agent can effectively prolong graft survival with reduced systemic toxicity in a large animal model employing a pump/catheter system applicable to man.

Transplant renal artery stenosis.

A group of 31 patients with transplant renal artery stenoses was identified among 2002 patients undergoing renal transplantation at the University of Minnesota; 29 of the stenoses were at the anastomosis. A total of 43 procedures were performed to correct the stenosis. Angioplasty was performed 25 times, with 3 patients cured and 2 patients improved; 20 procedures resulted in a poor result (3) or a failure (17). The failures were usually due to recurrent stenosis (7 patients) or to arterial injury that resulted in graft loss (4 patients) or successful emergency surgery to save the transplant (3 cases). Surgical repair of the stenosis was performed 18 times. No grafts were lost and 13 patients were cured or improved. These data suggest that angioplasty for anastomotic stenosis yields poor results and that a surgical repair is probably warranted. All 7 patients who had a poor results or failed a technically successful intervention did not have a rise in creatinine secondary to captopril or had a systolic pressure gradient of less than 60 mmHg across the anastomosis. These data also suggest that patients without physiological evidence of renal artery stenosis may not have improvement in their hypertension following repair.

A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts.

Cytomegalovirus is a major viral pathogen in patients who undergo renal transplantation, and cytomegalovirus disease is difficult to treat. We therefore conducted a randomized, placebo-controlled, double-blind trial of acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts from cadavers. Acyclovir was given orally in doses of 800 to 3200 mg per day, according to the patients' estimated level of renal function. Patients took the first dose of either acyclovir or placebo six hours before transplantation and continued to take the assigned medication for 12 weeks. Of 118 patients enrolled in the study, 104 completed at least 30 days on the study medication and were included in our analysis of the results. During the first year after transplantation, 4 of 53 patients (7.5 percent) in the acyclovir group had symptomatic cytomegalovirus disease, as compared with 15 of 51 (29 percent) in the placebo group (P = 0.002). There was a single case of cytomegalovirus pneumonia in the acyclovir group, as compared with nine in the placebo group. The greatest prophylactic benefit of acyclovir was observed among seronegative patients who had received a kidney from a seropositive donor; only one of six such patients in the acyclovir group had cytomegalovirus disease, as compared with all seven in the placebo group. Acyclovir decreased the incidence of documented cytomegalovirus infection (with or without symptomatic disease) to 36 percent from 61 percent among the patients who received the placebo (P = 0.011). Among the patients who received acyclovir, the rates of recovery of virus from the blood and urine were significantly reduced, but the rate of viral shedding from the pharynx was not significantly different from that in the placebo group. There were no differences between the groups in the frequency of adverse events or in the rate of survival of either grafts or patients. We conclude that the oral administration of acyclovir, beginning before the transplantation of a renal allograft from a cadaver, reduces the rate of cytomegalovirus infection and disease without affecting the survival rate of either grafts or patients.

Allograft renal vascular thrombosis--lack of increase with cyclosporine immunosuppression.

Several recent reports have demonstrated an increased incidence of allograft renal vascular thrombosis in patients receiving cyclosporine alone or as part of multiple drug regimens when compared with patients receiving azathioprine (AZA) and prednisone (P). To determine whether CsA therapy is indeed a risk factor for renal artery or vein thrombosis, we examined the incidence of these complications in 224 adult renal allograft recipients who were prospectively randomized and stratified by risk to treatment with either CsA-P (n = 117) or AZA-P-antilymphocyte globulin (n = 107) between September 1980 and October 1983, and in 452 adult and 87 pediatric patients on triple (AZA-P-CsA) or quadruple (AZA-P-CsA-ALG) therapy protocols between July 1984 and November 1987. In the randomized trial, one of 107 AZA-P-ALG patients (0.9%) and two of 117 CsA-P patients (1.7%) developed renal vein thrombosis (P = 0.94), and there were no cases of arterial thrombosis. Though CsA levels were elevated in one of the two CsA-treated patients at the time of their events, and both these patients demonstrated other predisposing factors for thrombosis. In the triple/quadruple therapy era, there were no cases of renal vein thrombosis, and the only case of renal artery thrombosis occurred in a pediatric recipient who was not receiving CsA at the time. These data, when taken together with a critical review of the conflicting literature, strongly suggest that factors other than immunosuppression with CsA, including surgical technique, allograft rejection, use of multiple artery and/or pediatric donor kidneys, and postoperative hypotension, are important in the pathogenesis of allograft renal vascular thrombosis. It seems possible, however, that high initial dosing of CsA might trigger this complication in the early posttransplant period when other predisposing factors are present.

Factors influencing early survival after liver transplantation.

The purpose of this study was to analyze data from all adult and pediatric liver transplants performed between January 1, 1983 and January 15, 1986 at the University of Minnesota Hospital and identify perioperative variables that predict patient survival and could aid in patient selection. Charts, intraoperative anesthesia records, blood bank records, flow sheets, outpatient records, and autopsy reports were examined in 45 pediatric and 15 adult patients who underwent primary orthotopic liver transplantation. Analysis of the data can be summarized as follows: (1) Pediatric patients whose coagulation parameters could not be corrected prior to operation and who consequently required preoperative exchange transfusion had poorer outcomes than those not requiring an exchange to correct coagulation parameters. (2) The rapid infusion technique for massive blood transfusion resulted in significantly decreased blood loss and intraoperative blood product replacement. (3) Twenty-four hour postoperative factor V levels were good predictors of survival. Patients with poor factor V levels required rigorous replacement of coagulation factors. (4) Pediatric patients with uncorrectable coagulopathies requiring immediate postoperative exchange transfusion had extremely high mortality.

Results of pancreas-transplant registry.

From December 1966 to March 1988, 1394 pancreas transplants were reported to the International Pancreas Transplant Registry. For the 1129 cases since 1982, the overall 1-yr graft and recipient survival rates were 46 and 82%, respectively. When analyzed according to the three most common duct-management techniques, polymer injection (n = 324), intestinal drainage (n = 282), and bladder drainage (n = 462), the 1-yr function rates were 47, 45, and 54%, respectively. The graft survival rates were also similar, whether whole (n = 492) or segmental (n = 634) grafts were transplanted (47 vs. 46% at 1 yr). Graft survival rates according to preservation times were 49, 42, and 43% at 1 yr for those stored less than 6 h (n = 694), 6-12 h (n = 237), and greater than 12 h (n = 89), respectively. Immunosuppressive regimens that included both cyclosporin and azathioprine were associated with significantly (P less than .03) higher graft survival rates than those that included only one of the drugs, with 1-yr graft survival rates for technically successful grafts of 67, 54, and 39% for patients treated with azathioprine plus cyclosporin (n = 602), cyclosporin without azathioprine (n = 201), and azathioprine without cyclosporin (n = 44). Pancreas-graft survival rates differed according to whether a kidney was or was not transplanted and according to the timing of the transplant: 53, 40, and 32%, respectively, at 1 yr for cases in which a simultaneous kidney was transplanted (n = 685), a kidney had previously been transplanted (n = 201), or a kidney had never been transplanted (n = 202).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term survival following kidney transplantation in 100 type I diabetic patients.

Between December 1966 and April 1978, 265 uremic patients with type I diabetes received primary renal allografts at the University of Minnesota. One hundred of the diabetic patients were alive with a functioning graft 10 years after transplantation. The actual 10-year patient and primary graft functional survival rates overall were 40% and 32%, respectively. For recipients of HLA-identical sibling (n = 45), mismatched living-related (n = 121), and cadaver donor grafts (n = 99), the actual 10-year patient survival rates were 64%, 33%, and 36%, respectively, and the actual 10-year graft functional survival rates were 62%, 28%, and 22%, respectively. The differences in patient and graft survival rates between HLA-identical graft recipients and recipients of mismatched related and cadaver grafts were significant (P less than 0.001). Of the 100 patients who survived into a second decade, at 15 years posttransplant 51% were alive, and 41% had functioning grafts. For recipients of HLA-identical sibling, mismatched living-related donor grafts, and cadaver donor grafts who survived 10 years, 47%, 57%, and 43%, respectively, were alive at 15 years, and 31%, 45%, and 43%, respectively, had functioning grafts. For recipients who made it to the second decade, patient and primary graft survival rates thereafter were not statistically different by donor source. Twenty-three patients died in the second decade after transplantation, 10 of cardiovascular disease. Twenty-five patients lost graft function in the second decade, 19 from death with a functioning graft. In regard to diabetic complications, recurrence of diabetic nephropathy was common, but only two patients lost graft function solely for this reason. In 21 patients (42 eyes) followed prospectively for 10 years, visual acuity deteriorated in 26%, was stable in 64%, and improved in 10% of eyes. Neurophysiological test results indicated that correction of uremia does not stop the progression of diabetic neuropathy in recipients of kidney transplants alone. Even without cyclosporine, nearly two-thirds of recipients of HLA-identical kidney grafts, more than one-quarter of recipients of mismatched living-related donor grafts, and more than one-fifth receiving cadaver grafts enjoyed an extension of life for more than 10 years.

Renal transplantation between living-related sibling pairs matched for zero-HLA haplotypes.

The functional survival rates of kidney grafts from zero-HLA haplotype-matched sibling pairs are similar to one-haplotype-matched pairs and superior to cadaver grafts. From January 1980 to March 1988, 318 primary renal transplants from sibling donors (151 matched for two, 130 for one, and 37 for zero HLA haplotypes), and 352 cadaver graft transplants were performed at the University of Minnesota. The renal graft survival rates at two years were 94%, 91%, and 94% for the 2, 1, and 0-haplotype pairs versus 75% for cadaver graft recipients (P less than 0.04). When analyzed across the different immunosuppression protocols the same trends held up, similar graft functional survivals for 1- and 0-haplotype-matched pairs both being superior to cadaver graft recipients. The graft functional survival rates at two years of recipients of 0-haplotype-matched sibling donor grafts (n = 37) was 94% versus 80% for recipients of cadaver donor grafts matched for greater than or equal to 4 HLA antigens. In addition, for recipients of 0-haplotype-matched grafts, hospital stay was shorter, fewer patients required dialysis posttransplant, and, despite a slightly higher incidence of rejection episodes (51% versus 40%, P = ns), the creatinine values one year posttransplant were significantly lower (1.5 mg/dl versus 1.9 mg/dl, P less than 0.02) than those of recipients of cadaver grafts matched for greater than or equal to 4 HLA antigens. These data support the use of cadaver grafts for patients not having a willing sibling donor, and the use of all willing sibling donors, whether or not they are a zero-haplotype match, for patients fortunate to have that family commitment.

Single-center 1-15-year results of renal transplantation in patients with systemic lupus erythematosus.

Initially, poor long-term prognosis in patients with SLE and fear of recurrent disease dissuaded renal transplantation in this group of patients. However, in 1975 the Advisory Committee to the Renal Transplant Registry reported satisfactory 1-2-year results in 56 patients with SLE from 36 institutions. Subsequently, renal transplantation for SLE patients with end-stage renal disease has become more accepted, though it has been recommended that transplantation be postponed for at least one year after initiating dialysis. Five cases of recurrent lupus nephritis have been reported in the literature. However, since the long-term outcome after transplantation in this group of patients is not well established, we have examined the long-term outcome in SLE patients who underwent renal transplantation at the University of Minnesota. Thirty-two SLE patients receiving 33 transplants between December 1969 and December 1987 were studied retrospectively and compared with controls matched for age, sex, donor source, HLA match, date of transplant, and diabetic status. A total of 69% (22/32) of patients underwent less than 1 year of dialysis prior to transplantation, and 50% (16/32) experienced biopsy-proved acute rejection, which was reversible in 67% (11/16). Actuarial graft function and patient survival rate in SLE patients were not significantly different from those in the matched control group. Duration of prior dialysis did not affect outcome. Surviving grafts have excellent function as measured by serum creatinine (1.3 +/- 0.4 mg/dl, means +/- SD). Causes of death were sepsis (5) and myocardial infarction (1). One patient lost the graft from rejection after withdrawal of immunosuppression because of a malignancy one month posttransplant. Three patients lost graft function due to chronic rejection. To date no patients have had evidence of recurrent SLE nephritis.

Hyperuricemia after renal transplantation.

Hyperuricemia is common in cyclosporine-treated renal allograft recipients. An increased incidence of gout in patients receiving both diuretics and cyclosporine has been reported, but the effect of hyperuricemia on renal allograft function has not been studied. In a prospective, randomized trial of cyclosporine and prednisone versus azathioprine, prednisone, and antilymphocyte globulin for immunosuppression in renal allograft recipients, 105 of 131 cyclosporine and prednisone-treated patients (80 percent) experienced hyperuricemia (serum uric acid level above 8 mg/dl) and 13 of 131 (10 percent) were severely hyperuricemic (serum uric acid level above 14 mg/dl). In contrast, hyperuricemia developed in 63 of 115 patients (55 percent) treated with azathioprine, prednisone, and antilymphocyte globulin (p less than 0.002). Despite the frequent occurrence of hyperuricemia, gout was rare. Clinical gout developed in six patients in the cyclosporine and prednisone group and in 0 patients in the azathioprine, prednisone, and antilymphocyte globulin group between 1 and 43 months (median 22.5 months) after transplantation. Neither severe hyperuricemia nor diuretic therapy were associated with a significantly increased incidence of gout. The mean serum creatinine concentration of severely hyperuricemic patients (all on cyclosporine and prednisone) was similar to that of normouricemic cyclosporine and prednisone patients (1.8 mg/dl versus 1.6 mg/dl, p greater than 0.2), and the severely hyperuricemic patients had a 4-year graft survival rate of 90 percent. Asymptomatic hyperuricemia after renal transplantation does not adversely affect allograft function, requires no specific therapy, and is not a contraindication to use of diuretics.

A single-center experience of renal transplantation in thirteen Jehovah's Witnesses.

The beneficial effects of pretransplant blood transfusions on the success rate of renal transplantation have been so overwhelmingly emphasized that there is virtually no information on the fate of grafts in nontransfused patients transplanted during the last decade. Since 1979, all patients who have undergone renal transplantation at the University of Minnesota have routinely received random blood transfusions except Jehovah's Witnesses. Jehovah's Witnesses refuse transfusions but will accept renal allografts. From 1979 to May 30, 1987, primary renal allografts were placed in thirteen nontransfused Jehovah's Witnesses; six patients received kidneys from mismatched living-related donors, two patients received HLA-identical sibling grafts, and five patients received cadaveric renal allografts. The range of follow-up of the thirteen patients was 3-93 months, with a mean of 45 months and a median of 50 months. The outcomes after renal transplantation in Jehovah's Witnesses were compared with those of a paired control group (n = 25) matched for age, date of transplant, donor source, and diabetic status. The overall three-year actuarial patient and graft survival rates of the Jehovah's Witnesses were 83 per cent and 66 per cent, versus 80 per cent and 77 per cent for the controls. Although the outcomes after renal transplantation in Jehovah's Witnesses were similar to those of the control group, the Jehovah's Witnesses had an increased susceptibility to rejection episodes. The cumulative percentage of incidence of primary rejection episodes was 77 per cent at three months in the Jehovah's Witnesses versus 44 per cent at 21 months in the matched control group. The consequence of early allograft dysfunction from rejection was particularly detrimental to Jehovah's Witnesses who developed severe anemia (hemoglobin (Hgb)* 4.5 g per cent)-two early deaths occurred in the subgroup with this combination of problems. The overall results suggest that renal transplantation can be safely and efficaciously applied to most Jehovah's Witnesses but those with anemia who undergo early rejection episodes are a high-risk group relative to other transplant patients.