Martin D. Jendrisak

Prosthetic Fistula Survival and Complications in Hemodialysis Patients: Effects of Diabetes and Age

Current trends in hemodialysis include increases in patient age, prevalence of diabetes, and use of high-efficiency dialysis. These patients often require prosthetic fistulas for vascular access. Little is known about fistula survival and complications in this setting. Hemodialysis patients at our center receiving new prosthetic fistulas between January 1, 1988 and January 1, 1991 were studied. Sixty-five prosthetic fistulas were placed in 50 nondiabetic and 73 in 51 diabetic patients. There were no differences in age, sex, race, or access type or location in patients with or without diabetes. Seventeen percent of fistulas were lost in nondiabetic compared with 32% diabetic patients (P less than 0.05). Life-table analysis showed 1- and 2-year graft survivals of 88% and 77% in nondiabetic patients and 70% and 67% in diabetic patients. A significant difference in graft survivals was found for the time interval from 100 to 600 days after fistula placement. There were 188 complications in 92 of the grafts. There was no difference in the distribution of thromboses, elevated recirculations, or infections causing the first complication in patients with or without diabetes, but complications occurred earlier in diabetic patients (175 +/- 26 v 286 +/- 36 days, P less than 0.01). Nondiabetic patients with prosthetic fistula complications were significantly older than those without complications (64 +/- 4 and 56 +/- 2 years, respectively, P less than 0.05). No impact of age on complications was found in diabetic patients. The probability of a first thrombosis at 6 and 12 months was 29% and 49% in nondiabetic and 55% and 72% in diabetic patients (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Altruistic living donors: evaluation for nondirected kidney or liver donation.

A program was established within our regional procurement organization to permit evaluation of altruistic living donors (LD) interested in nondirected kidney or liver segment donation prior to transplant center referral.

RENAL TRANSPLANTATION FOR SYSTEMIC LUPUS ERYTHEMATOSUS AND RECURRENT LUPUS NEPHRITIS: A SINGLE-CENTER EXPERIENCE AND A REVIEW OF THE LITERATURE

Prior to 1975 patients with systemic lupus erythematosus were generally not considered candidates for renal transplantation because of concern that immune complex deposition would rapidly destroy the allograft. However, recent evidence suggests that good patient and graft survival rates can be achieved comparable to other renal diseases. Between September 23, 1963 and July 31, 1990, 1070 renal transplants were performed at Washington University Medical Center (WUMC). During this period, 14 patients with SLE (12 female and 2 male) received 16 renal transplants (7 living-related donor [LRD], 1 living-unrelated donor [LURD], and 8 cadaver [CAD]). The mean age at the time of the first transplant was 32.5±10.3 years. The duration of disease prior to transplant was 88.0±45.9 months and the duration of hemodialysis prior to transplant was 36.0± 33.7 months. Of these patients, 7/14 (50%) had negative and 3/14 (21%) positive SLE serology pre- and post-transplant, 3/14 (21%) had negative serology pretransplant that became positive posttransplant, and 1/14 (2%) was positive pretransplant and became seronegative posttransplant. Patient survival was 92.8% (13/14), and of the 16 kidneys transplanted 62.5% (10/16) are still functioning with a mean follow-up period of 43.7±45 months. The current mean serum creatinine was 1.4± 0.26 mg/dl. One noncompliant patient developed recurrent lupus nephritis bringing the total number of cases reported in the literature to seven. The present study demonstrates that patients with SLE can be transplanted with excellent patient and graft survival and function and a low rate of recurrent lupus nephritis. From a review of the literature, there appears to be an association between positive SLE serology pre- and posttransplant and recurrent lupus nephritis.

Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Leflunomide (LEF) is a synthetic isoxazole derivative with anti‐inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy‐proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six‐month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6 months preconversion was 2.2 ± 0.6 mg/dL, at initiation was 3.0 ± 1.1 mg/dL, and 6 months postconversion was 2.8 ± 1.3 mg/dL. The rate of change in serum creatinine was 35 ± 39%/6 months preconversion and − 5 ± 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 ± 72 ng/mL pre‐LEF vs. 132 ± 51 ng/mL post‐LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.

A significant role for histocompatibility in human islet transplantation

Background. In recent years, transplantation of islets and pancreas has become a viable option for patients debilitated with type I diabetes. The success of islet transplantation has been attributed to the ability to isolate high quality islets for transplantation and capacity to maintain the recipients immunosuppressive levels within a specific target range following transplantation. The purpose of this study was to determine the role of pretransplant sensitization to human leukocyte antigen (HLA) in islet transplantation. Methods. We retrospectively analyzed seven patients that were transplanted with islets under the auspices of the Juvenile Diabetes Research Foundation and Islet Cell Resource Center/National Institutes of Health. Humoral sensitization towards donor antigens both prior to and following islet transplantation was detected by FLOW panel reactive antibodies (PRA) and donor-specific cellular sensitization was detected by performing enzyme-linked immunospot assay analysis for cytokines interferon-γ and interleukin-2. Results. Our analysis demonstrates that humoral and cellular sensitization to histocompatibility antigens prior to and after islet transplantation are associated with the failure of transplanted islets Conclusion. Patient selection based on sensitization to donor HLA may be one of the factors crucial for the success of islet transplant. Further, in some patients, rejection of islets can be associated with sensitization to mismatched donor histocompatibility antigens.

Living donor renal transplantation in the presence of donor-specific human leukocyte antigen antibody detected by solid-phase assay

Presensitization of donor human leukocyte antigens (HLA) demonstrated through a positive crossmatch is detrimental to allograft function and best avoided through donor exclusion. The clinical significance of alloantibody detectable by sensitive solid-phase assay is not completely defined and is the focus of this study. Pretransplant sera from 64 consecutive living-donor renal transplant recipients were screened by enzyme-linked immunosorbent assay (ELISA) and Luminex assays. Results were analyzed for correlation with clinical outcome. Luminex proved more sensitive than ELISA for alloantibody detection, with three identifiable patterns. Twenty-eight patients were antibody negative, 24 had non-donor-specific antibody (non-DSA), and 12 had donor-specific antibody (DSA). The highest number of rejections (n = 4) and graft losses (n = 6) occurred in the antibody-negative group. The non-DSA group had two graft losses, as did the DSA group. The two graft losses in the DSA group were caused by recurrent focal segmental glomerulosclerosis (FSGS) at 35 months and death with a functioning graft at 32 months. Overall, there were no cases of antibody-mediated rejection and allograft function to 4 years was comparable among all three groups. Under our standard immunosuppression protocol and crossmatch criteria for histocompatibility, alloantibody detectable by Luminex was not detrimental to successful living-donor transplantation.

Failure of high-dose oral acyclovir with or without immune globulin to prevent primary cytomegalovirus disease in recipients of solid organ transplants☆☆☆

Abstract purpose: To assess the efficacy of acyclovir and intravenous immune globulin (IVIG) for cytomegalovirus (CMV) prophylaxis in high-risk recipients of solid organ transplants. patients and methods: We randomized 21 CMV-seronegative organ transplant recipients with seropositive donors (D+R−) to receive oral acyclovir, 800 mg four times daily, or, in addition to acyclovir, IVIG, 300 mg/kg, every 2 weeks for six doses. Patients were followed closely for the development of CMV infection and disease. results: All but one prophylactically treated patient (95%) developed CMV infection. Fifteen of 21 patients (71%) who received prophylaxis fulfilled criteria for CMV disease. Disease onset was delayed in those who received IVIG, but this did not reach statistical significance. Ganciclovir was used for treatment in 15 of the 21 patients (71%). conclusions: Acyclovir, with or without IVIG, did not prevent primary CMV infection or disease in D+R− solid organ transplant recipients at our institution. Moreover, most patients were treated with ganciclovir despite the use of prophylaxis. Given the ready availability of ganciclovir to treat CMV disease, we recommend a reappraisal of the role of CMV prophylaxis by these means in the solid organ transplant population.

Improved Islet Yields from Pancreas Preserved in Perflurocarbon Is Via Inhibition of Apoptosis Mediated by Mitochondrial Pathway

Islet transplantation is a treatment option for type I diabetic patients. Preservation of human pancreata prior to islet isolation using two‐layer method with perfluorocarbon (PFC) and University of Wisconsin solution (UW) results in twofold increase in islet yields. The objective of this study was to determine the mechanism by which islets undergo apoptosis and determine PFCs effects on this process. Gene array analysis was used to analyze the expression of pro‐ and anti‐apoptotic genes in islets isolated from pancreata preserved under varying conditions. A 12‐fold increase in the expression of inhibitor of apoptosis (IAP) and survivin was observed in islets isolated from pancreata preserved in PFC. This was accompanied by decreased expression of BAD (3.7‐fold), BAX (2.7‐fold) and caspases (5.2‐fold). Levels of activated caspase‐9 (77.98%), caspase‐2 (61.5%), caspase‐3 (68.3%) and caspase‐8 (37.2%) were also reduced. ‘Rescue’ of pancreata after storage (12 h) in UW by preservation using PFC also resulted in a down‐regulation of pro‐apoptotic genes and inhibition of caspase activation. Apoptosis observed in islets from all groups was mainly mitochondria‐dependent, mediated by change in redox potential initiated by hypoxia. We demonstrate that reduction in hypoxia of pancreata preserved using PFC leads to significant up‐regulation of anti‐apoptotic and inhibition of pro‐apoptotic genes.

Cytolytic T lymphocytes from human renal allograft biopsies are tissue specific.

The cytolytic activity of T lymphocytes infiltrating renal allografts from recipients undergoing episodes of acute cellular rejection was studied. These T-cell populations, composed of both CD4+ and CD8+ cells, demonstrated significant cytolytic activity against both donor-derived KCLs and B-LCLs. In five of 21 biopsy-derived lines greater cytolytic activity was measured against donor KCLs compared to donor B-LCLs, suggesting the presence of kidney antigen-specific, MHC-restricted clones. Clones developed by stimulation with donor B-LCLs lysed both donor B-LCLs and KCLs while clones developed on donor KCLs as stimulator cells showed tissue specificity. Three of 26 clones recognized tissue-specific antigens in the context of donor MHC class I antigens lysing donor KCLs but not B-LCLs. These data demonstrate that a subpopulation of T cells recognizing kidney-specific antigens are present in biopsies of renal allograft recipients undergoing acute cellular rejection. This subpopulation of tissue-specific cytotoxic T lymphocytes may prove to contribute significantly to the pathology of allograft rejection.

Vascular access in patients with arterial insufficiency. Construction of proximal bridge fistulae based on inflow from axillary branch arteries.

Patients with renal failure and underlying peripheral vascular disease pose a difficult management problem in establishing longterm angioaccess for chronic hemodialysis. This report summarizes our experience with five debilitated patients who developed acute upper extremity ischemia after forearm fistula construction corrected by fistula ligation. Successful angioaccess was achieved without ischemia recurrence by construction of proximal bridge fistulae with arterial inflow based on branch arteries of the axillary artery. The relatively small size of the branch vessel was the main factor in limiting fistula flow while permitting normal distal axillary artery flow. In four patients direct fistula flow measurements ranged from 200 mL per minute to 620 mL per minute. Axillary arterial flow distal to the fistula ranged from 120 to 200 mL per minute and did not significantly change after fistula construction or during temporary occlusion of the fistula. Four of the five patients continue to dialyze uneventfully from 4 to 8.5 months. One patient died after discontinuation of dialysis 1 month after operation.