Michael J. Armbrust

Withdrawal of steroid immunosuppression in renal transplant recipients.

The complications of long-term steroid immuno-suppression are well known. During a 12-month period, 52 living-donor renal transplant recipients were entered into a protocol of intentional early steroid withdrawal. Selection criteria were primary living-related renal transplants in HLA-identical (12) or one-haplotype match (40) patients. The study population consisted of 25 diabetics (48.1%) with a mean age of 32.4 years. All patients received preoperative blood transfusions (3 donor-specific in haplotype-matched, 3 random in HLA-identical recipients). Immunosuppression consisted of cyclosporine, azathioprine, and corticosteroids, with deliberate steroid withdrawal after two weeks. Forty-six patients (88.5%) were successfully tapered off steroids, while the six protocol failures (11.5%) were due to early rejection or leukopenia that prevented steroid withdrawal. Twenty-three patients (50%) subsequently were returned to steroid therapy for rejection (21) or leukopenia (2). Inadequate immunosuppression precipitated six rejection episodes and were preventable, while the remaining 15 were true breakthrough crises. The overall rejection rate was 50%, with 92.3% of initial rejection episodes occurring within five weeks of steroid withdrawal. Rejection episodes were responsive to steroid therapy alone in 73.2% of cases. No graft loss from rejection has occurred after a mean follow-up interval of 8.5 months. At present, 33 patients (63.5%) are off steroids. In HLA-identical recipients, all but one successfully completed the protocol and 75% are currently steroid-free. In haplotype-matched patients, 87.5% completed the protocol and 60% are steroid-independent. Comparison with well-matched control groups on steroids failed to reveal any difference in graft or patient survival, rejection, infection, or mean serum creatinine level. No discriminating risk factors could be identified that were predictive of steroid withdrawal success or failure. In select patients, early steroid withdrawal can be accomplished without jeopardizing graft function. Long-term follow-up is required to assess the risk-benefit ratio of steroid withdrawal upon immunosuppressive morbidity.

Cadaveric renal transplantation with cyclosporine in patients more than 60 years of age.

Advanced age has been a relative contraindication to kidney transplantation because of the likelihood of increased morbidity and mortality in the geriatric population. However, the introduction of cyclosporine has improved renal allograft survival rates dramatically, and higher-risk patients are now being successfully transplanted. With the introduction of cyclosporine in 1983, we have performed 36 cadaveric renal transplants in 34 recipients 60 years of age or older, including 34 primary and 2 retransplants. Most of the patients (88%) were on dialysis prior to transplantation and 29% had ASCVD. Three-year actuarial patient and allograft survival are 91% and 74%, respectively. Surgical complications were infrequent, and postoperative rejection episodes were less frequent than in younger patients but were more likely to lead to graft loss. Medical complications, especially infection, were common after transplantation but easily managed. Cadaveric renal transplantation with cyclosporine immunosuppression is a safe and effective therapeutic modality that is no longer contraindicated in elderly patients.

Orthotopic liver transplantation in patients 60 years of age and older.

Cyclosporine appears to have abrogated age as a contraindication to kidney transplantation in the elderly, although it is unclear whether this is true for other types of solid organ transplantation. We performed a retrospective analysis of liver transplant recipients who were 60 years of age and older (n = 23) versus recipients of primary transplants who were 18 to 59 years of age (n = 84). Indications in recipients over 60 included alcoholism (6), postnecrotic cirrhosis (6), cancer (4), primary biliary cirrhosis (3), sclerosing cholangitis (2), and one patient with polycystic liver disease. There were no important differences in the initial transplant hospitalization or the incidence of infection and rejection between the two groups. No patient in the over-60 population required retransplantation. Actuarial patient survival is 83% at 2 years for recipients 60 years of age and above compared to 76% patient survival in adult recipients who are under the age of 60. Liver transplant recipients over the age of 60 years have excellent patient and graft survival and the same postoperative morbidity as recipients who are under 60 years of age. Therefore, advanced age does not appear to be a contraindication to orthotopic liver transplantation.

Sequential antilymphocyte globulin/cyclosporine immunosuppression in cadaveric renal transplantation. Effect of duration of ALG therapy.

Recent studies have documented the efficacy of quadruple immunotherapy with sequential ALG/cyclosporine in cadaveric renal transplantation. However, the exact role of ALG in this regimen is controversial. Over a four-year period, we performed 429 cadaveric renal transplants (367 primary, 62 retransplants) with prednisone, azathioprine, and the sequential use of Minnesota antilymphoblast globulin (MALG) and CsA. ALG therapy was divided into three protocols: true sequential (n = 259, mean no. days of ALG = 8.2); extended (defined as sequential MALG/CsA continued for 14 days irrespective of renal function or CsA level, n = 103, mean no. days of ALG = 14.1); and therapeutic (continued MALG therapy for early breakthrough rejection, n = 67 [15.6%], mean no. days of ALG = 17.2). The study groups were comparable and retrospectively analyzed in multivariate fashion for 15 variables. Requirement for postoperative dialysis was equivalent (14%) in both sequential and extended ALG groups. Extended ALG therapy failed to reduce the incidence of acute rejection (46.5% vs. 40.4% with true sequential therapy). Prolonging the duration of ALG treatment (greater than 10 days) was associated with a higher risk of infection. Logistic regression analysis revealed that the use of OKT3 after ALG accounted for the higher infection rate. Duration of ALG therapy had no impact on patient or graft survival after a mean follow-up interval of 20 months. We recommended a quadruple immunosuppressive strategy in cadaveric renal transplantation with sequential MALG/CsA to minimize early allograft dysfunction and to achieve excellent patient and graft survival. MALG therapy should be stopped after renal function is documented and CsA levels are therapeutic. Further ALG therapy offers no immunologic advantage and may place the patient at high risk for infection if OKT3 rescue therapy is required.

Living-Unrelated Renal Transplantation: Results in 40 Patients

Kidney transplantation for the treatment of end-stage renal disease has been limited by an inadequate number of donor organs. Because of the enormous impact kidney transplantation can have for patients, the authors have performed 40 living-unrelated donor renal transplantations using a donor-specific transfusion protocol since 1981. Ten additional patients were entered but became sensitized. Donors included 23 wives, seven husbands, six friends, and four individuals related by marriage. Type I diabetes was the most common indication for transplantation (45%). Despite 36 rejections in 24 patients (27 of 36 [75%] in the early postoperative period), only two grafts failed because of rejection. Twenty-one of these rejections responded to high-dose prednisone alone; the remainder required antilymphocyte globulin therapy or plasmapheresis. Sixteen patients had no acute rejections. Three other grafts were lost, including two deaths: one myocardial infarction (with a functioning graft), and one death secondary to a postoperative cecal perforation. One graft was lost from infarction after percutaneous nephrostomy placement. Of 40 grafts, 34 were functioning with a mean serum creatinine of 1.7 mg/dL (at a mean follow-up time of 27 months). Actuarial patient and graft survival were 94% and 89%, respectively, at 3 years. Living-unrelated renal transplants are an acceptable alternative to cadaver transplants, with excellent graft and patient survival.

Surgical portosystemic shunts for treatment of portal hypertensive bleeding: outcome and effect on liver function.

BACKGROUND Since the advent of liver transplantation and transjugular intrahepatic portosystemic shunts (TIPS), the role of surgical portosystemic shunts in the treatment of portal hypertension has changed. However, we have continued to use portosystemic shunts in patients with noncirrhotic portal hypertension and in patients with Childs A cirrhosis. METHODS We performed 48 surgical portosystemic shunt procedures between 1988 and 1998. The outcomes of these patients were evaluated to assess the efficacy of this treatment. Data from 39 of 48 patients were available for analysis. The average follow-up was 42 months. RESULTS Liver function generally remained stable for the patients; only 2 patients had progressive liver failure and required transplant procedures. Gastrointestinal bleeding (3 patients), encephalopathy (3 patients), and shunt thrombosis (3 patients) were rare. Patient survival was 81% at 4 years, similar to survival with liver transplantation (P = .22). CONCLUSIONS Surgical shunts remain the treatment of choice for prevention of recurrent variceal bleeding in patients with good liver function and portal hypertension.

Pretransplant immune regulation predicts allograft outcome: bidirectional regulation correlates with excellent renal transplant function in living-related donor-recipient pairs.

Background. Tolerance to noninherited maternal antigens has provided clinical advantage when kidney transplants are exchanged between siblings but not when mother herself is the donor. This paradox prompted us to revisit the “two-way” hypothesis of transplant tolerance—that the immune status of both the organ recipient and the organ donor critically influences allograft outcome. Methods. We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions. Results. We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001). Conclusions. Contrary to the belief that only the recipients immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome.

MULTIVARIATE ANALYSIS OF DONOR-SPECIFIC VERSUS RANDOM TRANSFUSION PROTOCOLS IN HAPLOIDENTICAL LIVING-RELATED TRANSPLANTS

A total of 127 haploidentical living-related transplants have been performed at our institution since March 1986. A donor-specific transfusion plus azathioprine protocol was used until July 1988 (n = 74) and a random transfusion (RT) protocol without AZA used thereafter (n = 53) in an effort to decrease risk of recipient sensitization and reduce the burden on the prospective donor. All patients were given cyclosporine 8 mg/kg/day orally beginning 1 week prior to transplantation. Immunosuppression was similar in both groups and consisted of triple induction therapy with prednisone, CsA, and AZA. A positive T cell crossmatch eliminated the potential donor. Seven individuals (9.6%) were sensitized in the DST group and 1 (1.9%) in the RT group, leaving 67 and 52 patients in the two groups of the study, respectively. Groups were similar with respect to age, sex, history of pregnancy in female patients, peak and baseline panel-reactive antibody (PRA), DR match, and prior transplants. The groups differed slightly with respect to AB antigens shared, with an advantage in the RT group. Actuarial graft survival was not statistically significantly different between the two groups, with 2-year graft survival of 95% in the DST and 91% in the RT group (log rank, P = 0.16). Patients in the RT group had significantly more rejection episodes and had them sooner than their counterparts in the DST group. At the end of 1 year, 50% of patients in the DST group had at least 1 rejection episode, compared with 75% of patients in the RT group (P = 0.0008). Multivariate (Poisson) analysis of 10 variables was performed, with an overall model P-value of 0.0001. Only DST (P = 0.0001) and pregnancy (P = 0.015) were significant predictors of rejection episodes, both protective. The difference in rejection episodes and the timing with which they occur has not yet translated into a significant difference in graft survival between DST and RT groups.

Renal Replacement Therapy in Diabetic Nephropathy

The case of a patient with diabetes mellitus and renal failure is presented and discussed. This case represents the very successful course of a diabetic patient who received peritoneal dialysis for 14 years. Not all patients with end-stage renal disease (ESRD) from diabetic nephropathy are this fortunate. The success and complications of dialytic modalities are discussed by a nephrologist and nurse dialysis coordinator. Renal transplantation, the preferred treatment for most diabetic ESRD patients, is discussed by a nurse transplant coordinator. Simultaneous pancreas kidney transplantation, with its potential benefits in the future is discussed by an experienced transplant surgeon. In addition, the psychosocial issues of renal failure, dialysis, and transplantation in the diabetic patient are addressed by clinical social workers. Lastly, the very important issue of foot care and treatment, and prevention of vascular-related morbidity is discussed by a practicing podiatrist. With such a multidisciplinary approach, medical and psychosocial outcomes can be optimized for diabetic patients with renal failure.

A TRIAL OF MYCOPHENOLATE MONOTHERAPY IN HLA IDENTICAL SIBLING RENAL TRANSPLANTATION: 3138

W.J. Burlingham1, E. Jankowska-Gan1, L. Haynes1, M. Armbrust1, A. Djamali2, J. Pirsch3, R.M. Hofmann4, H. Sollinger1 1Surgery, University of Wisconsin, Madison/WI/UNITED STATES OF AMERICA, 2Medicine And Surgery, University of Wisconsin, Madison/Wisconsin/UNITED STATES OF AMERICA, 3Pathology And Laboratory Medicine, University of Wisconsin, Madison/UNITED STATES OF AMERICA, 4Medicine, University of Wisconsin School of Medicine and Public Health, Madison/WI/UNITED STATES OF AMERICA