Jay C. Fish

Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study.

BACKGROUND Antiphospholipid antibody syndrome (APAS) is characterized by the presence of anticardiolipin antibodies (ACA) in association with thrombotic disorders of arterial and/or venus systems, spontaneous abortion(s) or thrombocytopenia. METHODS In this multicenter study, 502 end-stage renal disease (ESRD) patients awaiting renal transplants were screened to determine the frequency of APAS, the potential risk associated with APAS, and strategies for therapeutic intervention. Ninety-three patients (19%) had high titers of ACA. Twenty-three patients had documented evidence of one or more of the thrombotic disorders such as lupus, frequent abortions, frequent thrombosis of arteriovenous shunts, biopsy-proven microrenal angiopathy, or thrombocytopenia and thus were diagnosed with APAS. Of these 23 patients, 11 received kidney transplants either with (4 patients) or without (7 patients), concomitant anticoagulation therapy. RESULTS All seven of the patients with APAS not treated with anticoagulation therapy lost their allografts within 1 week as a result of renal thrombosis. In contrast, three out of four transplant patients with APAS treated with anticoagulation therapy maintained their allografts for over 2 years. The fourth patient lost his graft within a week because of thrombosis. Of the remaining 70 patients with high titers of ACA but no evidence of thrombotic disorders, 37 received kidney transplants. None lost their allografts as a result of thrombosis. Our data suggest that, although 19% of our ESRD patients exhibit high titer of ACA, only 5% of the patients have APAS. CONCLUSION In conclusion, our data suggest that the patients with APAS are at high risk of posttransplant renal thrombosis. Anticoagulation therapy could prevent patients from posttransplant thrombosis in patients with APAS.

Improved flow cytometric detection of HLA alloantibodies using pronase: Potential implications in renal transplantation

Background. Flow cytomeric crossmatch (FCXM) has grown in popularity and has become the “standard of practice” in many programs. Although FCXM is the most sensitive method for detecting alloantibody, the B cell FCXM has been problematic. Difficulties with the B cell FCXMs have been centered around high nonspecific fluorescence background owing to Fc-receptors present on the B cells and autoantibodies. To improve the specificity and sensitivity of the B cell FCXM, we utilized the proteolytic enzyme pronase to remove Fc receptors from lymphocytes before their use in FCXM. Methods. Lymphocytes isolated from peripheral blood, spleen, or lymph nodes were treated with pronase and then used in a three-color FCXM. A total of 167 T- and B cell FCXMs using pronase-treated and untreated cells were performed. Testing used serial dilutions of HLA allosera (22 class I and 6 class II), with the titer of each antibody at one dilution past the titer at which the complement-mediated cytotoxicity anti-human globulin crossmatch became negative. Results. After pronase treatment, the actual channel values of the negative control in both T cell and B cell FCXMs declined from 78±10 to 57±4 (P <0.05) and 107±11 to 49±3 (P <0.00001), respectively. Pronase treatment resulted in improved sensitivity of the T and B cell FCXM in detecting class I antibody by 20% and 80%, respectively. In no instance was a false-positive reaction observed. In this study, pronase treatment improved the specificity of B cell FCXM for detecting class II antibodies from 75% to 100% (P =0.03). In no instance was a false-negative reaction recorded. Lastly, on the basis of these observations we re-evaluated three primary transplant recipients who lost their allografts because of accelerated rejection. One of the patients was transplanted across negative T and B cell FCXM, whereas the other two patients were transplanted across a positive T cell, but negative B cell, FCXM. After pronase treatment, T and B cell FCXMs of each patient became strongly positive, and donor-specific anti-HLA class I antibody was identified in each case. Conclusion. Utilization of pronase-treated lymphocytes improves both the sensitivity and specificity of the FCXM.

Digestive function after radical pancreaticoduodenectomy

Abstract Forty-nine patients have had pancreaticoduodenectomy performed for periampullary carcinoma at the University of Texas Medical Branch Hospitals. Ten of these patients are currently alive. Six patients surviving from twenty to eighty-four months were studied to determine the degree of residual pancreatic function. Half of the patients were unable to regain their weight or resume their previous occupations. All the patients had an increased number of stools per day (three to twelve) and were receiving a small amount of pancreatic enzyme supplementation. Five of the six patients had abnormal amounts of fecal fat and three of them had an elevated fecal nitrogen excretion. A diabetic glucose tolerance curve was found in all six patients, but no treatment other than diet was required. Serum albumin, total exchangeable albumin, and albumin halflife was decreased in all patients. Liver biopsy revealed changes of fatty infiltration in three of four patients. Subjective and objective improvement was obtained by instituting adequate doses of oral pancreatic enzymes. In nine dogs elevated fecal fats and nitrogens as well as diabetic glucose tolerance curves were found after resection and implantation of the distal pancreas. At sacrifice, pancreatic atrophy was found secondary to stricture of the pancreatic duct at the site of implantation. Obstruction of the pancreatic duct followed by resection and implantation of a pancreatic remnant did not influence the subsequent results. It is concluded that implantation of the stump of residual pancreas into the bowel leads to stricture of the pancreatic duct, parenchymal atrophy, and functional insufficiency. The loss of digestive enzymes may prevent the full rehabilitation of the patients. Pancreatic enzyme supplementation in adequate dosage is useful in overcoming this deficit.

Effects of FK506 and cyclosporine on dynamic insulin secretion from isolated dog pancreatic islets

Pancreatic islet transplantation may be the most ideal treatment for patients with insulin-dependent diabetes mellitus. However, immunosuppressive agents such as cyclosporine A(CsA) and FK506, used for these transplanted patients have been reported to cause glucose intolerance. In the present study, we have compared the effects of CsA and FK506 on glucose-stimulated insulin release from the isolated dog pancreatic islets, which have been maintained in culture for 3 days after isolation. The isolated dog pancreatic islets, pretreated for 24 hr with either CsA or FK506 (1, 10, and 100 nM), were perifused with 16.7 mM glucose. Pretreatment with both drugs suppressed glucose-stimulated insulin secretion in a dose-dependent fashion. CsA (100 nM), which is a therapeutically relevant concentration, significantly suppressed both the first and second phases of glucose-stimulated insulin release compared with 100 nM FK506. These findings suggest that, with a therapeutically relevant concentration, FK506 may be less toxic than CsA against pancreatic islets in patients with organ or cell transplantation.

Serologic and molecular evidence of human herpesvirus 8 activation in renal transplant recipients.

This study was designed to determine whether there is serologic or molecular evidence of human herpesvirus 8 (HHV-8) activation in renal transplant patients, an immunocompromised population at risk for development of Kaposis sarcoma. Indirect immunofluorescence for detection of HHV-8 serum antibody and Southern blot polymerase chain reaction (PCR) for detection of viral DNA in whole blood were used. Seroprevalence and geometric mean titer (GMT) were significantly increased in the transplant group compared with healthy adults and were comparable to those in human immunodeficiency virus (HIV)-positive adults (transplant patients, 50% [GMT 1:210]; healthy adults, 7% [GMT 1:44]; HIV-positive patients, 73% [GMT 1:172]). Viral DNA was present in the blood of some renal transplant patients (3/33 PCR-positive) but in none of 20 healthy adults. Thus, there is both serologic and molecular evidence of HHV-8 activation in the renal transplant population compared with healthy adults (P<.01). The serologic results approximate those obtained for HIV-positive adults.

Hydrocortisone activation of human herpesvirus 8 viral DNA replication and gene expression in vitro

BACKGROUND Patients undergoing chronic steroid therapy for organ transplantation are at increased risk for development of human herpes virus 8(HHV-8)-associated Kaposis sarcoma (KS). It has also been reported that following steroid withdrawal, KS lesions often undergo partial or complete regression. METHODS We have examined the effect of corticosteroid treatment on HHV-8 replication, gene expression, and lytic protein expression in BCBL-1 cells in vitro. BCBL-1 cells were collected after culture for 24-72 hr with hydrocortisone (HC) 1-5 microM, phorbol ester 20 ng/ml (positive control), and culture medium only (negative control). HHV-8 genomic conformation was examined by Gardella gel analysis. mRNA expression of viral cyclin (v-Cyc), viral Bcl-2 (v-Bcl-2), viral macrophage inflammatory protein-I (v-MIP-I), viral interferon regulatory factor-1(v-IRF-1), and viral tegument protein (TP) was examined by RT-PCR Southern blot. Viral protein expression within the cells was examined by indirect immunofluorescence using 5 different HHV-8 positive antisera from 4 renal transplant recipients and 1 patient with classic KS. RESULTS Gardella gel analysis revealed that HC induced an accumulation of the linear replicative genomic form of the virus in a time-dependent fashion. Southern blot analysis of the RT-PCR products revealed that HC induced increased expression of v-IRF-1, v-Bcl-2, and TP mRNA, with little discernible effect on v-Cyc, and v-MIP-I. Immunofluorescence revealed that HC induced increased numbers of cells expressing lytic antigens. CONCLUSIONS These data indicate that hydrocortisone acts directly on BCBL-1 cells to activate the lytic cycle of HHV-8 and provide further support for the hypothesis that HHV-8 is activated in corticosteroid-treated immunocompromised patients.

The Risk of Anticoagulation in Hemodialysis Patients

The risks of intermittent anticoagulation with heparin for hemodialysis and longterm anticoagulation with warfarin to prevent clotting of arteriovenous shunts were assessed in a group of 125 home dialysis patients. Over a 7-year period, there were nine bleeding complications attributable to heparin anticoagulation for an incidence of one complication for every 40 patient year on dialysis. In contrast, 20 of 48 patients anticoagulated with warfarin for an average of 2 years each, had a total of 50 hemorrhagic complications requiring 542 days in the hospital and 15 operative procedures. Concersion to an alternative form of vascular access, the internal arteriovenous fistula, obviated the need for warfarin therapy and its unacceptably high complication rate in this population of patients.

Multivariate analysis of donor risk factors for pancreas allograft failure after simultaneous pancreas-kidney transplantation

BACKGROUND Donor and recipient selection criteria for pancreas allograft are not standardized and may vary from center to center. METHODS Simultaneous pancreas-kidney transplantations performed between April 1988 and June 1994 were reviewed (n = 61), and univariate and multivariate analyses of factors that affect pancreas graft survival were performed. Analysis of all cases and cases excluding early thrombosis were performed separately. RESULTS Pancreas graft survival when early thrombosis was excluded and in the overall group was 76% and 70%, respectively, at 1 year. Although blood group and donor gender were weak predictors of graft survival by univariate analysis, neither affected graft survival in the multivariate model. Risk factors for graft failure as determined by Cox regression analysis and in descending order of significance were (1) duration of brain death before procurement, (2) length of donor admission, and (3) donor age of 40 years or older. The risk of graft failure for each of these factors was increased 2.2-, 3.2-, and 4-fold, respectively. Prolonged brain death was the only risk factor in the overall group, suggesting an association with early thrombosis. CONCLUSIONS Center-specific donor risk factors for pancreas graft survival after simultaneous pancreas-kidney transplantation were identified in this study, the importance of which need to be better defined.

Renal allograft and patient outcome after transplantation pancreas-kidney versus kidney-alone transplants in type 1 diabetic patients versus kidney-alone transplants in nondiabetic patients

Despite recent advances and improved outcome, pancreas transplantation remains controversial. The purpose of this review was to study renal allograft outcome after simultaneous pancreas-kidney transplants (SPK, n = 61), kidney-alone transplants in type I diabetic patients (KA-D, n = 63), and kidney-alone transplants in nondiabetic patients (KA-ND, n = 80). Patients were matched for donor age, donor gender, donor race, interval from donor admission to procurement, DR mismatch, and recipient gender. The mean renal allograft cold ischemic time and recipient age were lower in the SPK group. Patient survival was highest in the KA-ND group (99% and 86% at 1 and 5 years, respectively), intermediate in the SPK group (90% and 78% at 1 and 5 years, respectively), and lowest in the KA-D group (89% and 66% at 1 and 5 years, respectively) (P = 0.004). similarly, renal allograft survival was higher in the KA-ND (89% and 63% at 1 and 5 years, respectively) and SPK (82% and 69% at 1 and 5 years, respectively) groups compared with the KA-D group (76% and 49% at 1 and 5 years, respectively) (P = 0.07). This difference disappeared when renal graft survival was censored for death, which probably reflects the selection bias. Actuarial pancreas graft survival was 76% and 62% at 1 and 5 years, respectively. Acute rejection (AR) was more frequent in the SPK group than in the KA-D and KA-ND groups (41% v 16% v 29%; P = 0.007). Delayed graft function (DGF), on the other hand, occurred more frequently in the KA-D group than in the KA-ND and SPK groups (66% v 55% v 38%; P = 0.08). Death as a result of a cardiovascular event occurred more frequently in the KA-D group. Cardiovascular death and renal graft failure occurred earlier in the SPK group. Cox regression analysis revealed a 1.6 and 1.8 times higher risk of renal graft failure in the SPK group when the donor was > or = 40 years old or female and a five times higher risk of graft failure in the KA-ND group in the presence of AR. Graft survival in patients with AR/DGF was lower than that in patients with no AR/no DGF in both the KA-D (71% and 63% v 100% and 100% at 1 and 5 years, respectively; P = 0.03) and KA-ND (90% and 56% v 100% and 100% at 1 and 5 years, respectively; P = 0.001) groups. Acute rejection did not affect graft survival in the SPK group. In the absence of AR, DGF had no effect on graft survival in any of the groups. Although the selection bias in favor of pancreas transplantation does not allow for definitive conclusions, our results show that outcome after SPK transplantation is acceptable and factors that influence the outcome after this procedure may be different from the ones affecting KA-D recipients.

Hereditary nephritis, retinitis pigmentosa and chromosomal abnormalities.

Abstract A family afflicted with hereditary nephritis, retinitis pigmentosa and pendular nystagmus is described. On the maternal side of the family, six members have had serious chronic renal disease which histologically resembles chronic pyelonephritis. The proband and a sibling also had retinitis pigmentosa and pendular nystagmus. The paternal side of the family demonstrates several chromosomal abnormalities which can best be explained as a familial tendency to nondysjunction with mosaicism.