Todd K. Howard

Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients.

BACKGROUND Treatment with prophylactic oral acyclovir, intravenous ganciclovir, or immunoglobulins to prevent cytomegalovirus (CMV) infection and disease in renal transplantation is associated with variable efficacy and significant expense. We studied control of CMV in renal transplant recipients using either prophylactic oral ganciclovir or deferred therapy with intensive monitoring with polymerase chain reaction (PCR) analysis. METHODS Forty-two recipients were followed for 6 months after transplantation. Ganciclovir (1000 mg p.o. t.i.d.; n=19) or acyclovir (200 mg p.o. b.i.d.; n=23) was begun at transplantation and continued for 12 weeks. PCR for CMV was performed on buffy-coat specimens every week for 15 weeks and at months 5 and 6. RESULTS No patients in the ganciclovir group, compared with 14 of 23 patients (61%) in the deferred-therapy group (P<0.0001), developed CMV disease during the first 12 weeks. In the ganciclovir group, 4 of 19 patients (21%) subsequently experienced 5 episodes, whereas 14 patients in the deferred-therapy group experienced 18 episodes (P=0.013 for subjects and P=0.026 for episodes). The time to disease was also delayed in the ganciclovir group compared with the deferred-therapy group (133+/-17 days vs. 51+/-7 days; P<0.0001). Oral ganciclovir also prevented CMV viremia during prophylaxis (2/19 patients [11%] vs. 23/23 patients [100%]). Time to CMV viremia was delayed in the ganciclovir group; however, 13/19 patients (68%) ultimately showed PCR evidence for CMV viremia (P=0.005). CONCLUSIONS An initial 12-week course of oral ganciclovir prevents CMV disease and infection in renal transplant recipients during prophylaxis, and the benefits persist after discontinuation.

Fulminant hepatic failure resulting from lamivudine-resistant hepatitis B virus in a renal transplant recipient: durable response after orthotopic liver transplantation on adefovir dipivoxil and hepatitis B immune globulin.

BACKGROUND Mutations in the hepatitis B virus (HBV) genome may occur during therapy. METHODS We report an asymptomatic HBV carrier who underwent transplantation for end-stage renal disease. She developed an HBV flare 6 months after transplantation and was placed on lamivudine. After initial rapid improvement, she relapsed clinically and virologically. She decompensated with jaundice, peripheral edema, ascites, encephalopathy, coagulopathy, and hepatorenal syndrome. A liver biopsy specimen revealed submassive necrosis. RESULTS Emergency liver transplantation was performed: lamivudine was discontinued. Hepatitis B immunoglobulin and adefovir dipivoxil were initiated. Sixteen months after orthotopic liver transplantation, she is HBV DNA seronegative with normal liver enzymes. Sequencing of HBV polymerase gene from preliver transplantation sera did not detect the usual lamivudine resistance mutations in the YMDD motif but instead two other mutations (F514-->L, L528-->M). Lamivudine resistance was demonstrated in vitro. CONCLUSIONS Asymptomatic HBV carriers may reactivate following renal transplantation after immunosuppression. Resistance to lamivudine may result in severe hepatic damage in immunocompromised patients.

Short course induction immunosuppression with thymoglobulin for renal transplant recipients

BACKGROUND The aim of this study was to demonstrate that 3-days of induction immunosuppression with thymoglobulin was as effective and safe as a 7-day course and reduced initial hospitalization after transplantation. METHODS This was a prospective, nonrandomized trial of 40 consecutive patients receiving thymoglobulin induction for 3 days and followed for 1 year. An historical group of 48 patients that received 7 days of thymoglobulin served as controls. RESULTS At 1 year, acute rejection (5 vs. 4%), graft survival (95 vs. 98%) and patient survival were similar; a composite end point of freedom from death, rejection, or graft loss, the event-free graft survival, was similar as was the safety profile. In the 3-day group, lymphocyte depletion was more sustained and initial hospitalization was significantly shorter (6 vs. 8 days). CONCLUSION Three-day induction with thymoglobulin is as effective and safe as seven days, decreases initial hospitalization and causes more sustained lymphocyte depletion.

Peripheral blood microchimerism in human liver and renal transplant recipients : Rejection despite donor-specific chimerism

BACKGROUND Development of donor-specific microchimerism (DSM) has been proposed as one of the possible mechanisms for induction and maintenance of allograft tolerance. The aim of this study was to determine: (1) the state of DSM in liver transplant (LTx) and renal transplant (RTx) recipients, (2) whether the persistent presence of an allograft is a requirement for maintenance of chimerism, and (3) whether donor-specific blood transfusions (DST) facilitate chimerism development in RTx recipients and whether this correlates with allograft function. METHODS Qualitative and quantitative analysis of DSM in peripheral blood of LTx and RTx recipients was assessed by polymerase chain reaction and competitive polymerase chain reaction using HLA-DR probes for mismatched antigens between the donor and recipient. RESULTS LTx recipients (11 of 12) who had or were having rejection were positive for DSM in circulation compared with 4 of 11 with normal allograft function (P<0.01). The number of donor cells did not correlate with allograft function. LTx recipients (4 of 4) who lost their first allograft and underwent retransplantation retained DSM for the first donors. RTx recipients who received DST (8 of 8) were positive for DSM compared with 6 of 12 of nontransfused recipients (P<0.045). CONCLUSIONS The results suggest that LTx and RTx recipients undergo rejection despite DSM. The development of DSM may not be a prerequisite for normal allograft function. Once DSM is established, the presence of the allograft is not required for maintenance of chimerism. DST facilitated the development of DSM in RTx recipients. Direct correlation was not observed between the development of DSM and allograft function in either DST or nontransfused RTx recipients.

Recognition of porcine major histocompatibility complex class I antigens by human CD8+ cytolytic T cell clones.

To evaluate the nature of the human cellular immune response to porcine xenoantigens, cytolytic T lymphocyte (CTL) cell lines were generated against porcine aortic endothelial cells (PAEC). After four stimulations, the phenotypes of the T cell lines were primarily CD8+ (79.7+/-19.6%). Natural killer cells were not detected. Functional analysis of the T cell lines showed specific cytotoxicity against syngeneic porcine targets with no lysis of unrelated porcine cells, human cells, or K562, a natural killer target. The major histocompatibility complex (MHC) specificity of this response was confirmed when T cell lines established against PAEC from partially inbred SLAdd miniature swine lysed only PAEC and phytohemagglutinin-stimulated lymphocytes from SLAdd origin but not SLAgg targets. Both CD8+ (7/12) and CD4+ (5/12) T cell clones were generated from the bulk cell lines. All of the CD8+ T cell clones specifically lysed stimulator PAEC and swine leukocyte antigen (SLA)-matched, phytohemagglutinin-stimulated lymphocyte targets but not unrelated porcine targets. CD4+ T cell clones, as expected, showed no lysis of any porcine target cells. The lysis of porcine targets by the human CD8+ cytotoxic T lymphocyte clones was inhibited by monoclonal antibodies against SLA class I antigens and human CD8, which indicates that human CD8+ T cells recognize porcine MHC class I molecules. These results, which show that human T cells differentiate between porcine MHC alleles, have relevance in the clinical application of xenografts.

Posttransplant Lymphoproliferative Disease in Children: Correlation of Histology to Clinical Behavior

Purpose To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. Patients and Methods We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. Results Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. Conclusions We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.

Living-unrelated renal transplantation provides comparable results to living-related renal transplantation: A 12-year single-center experience

BACKGROUND The increasing success of renal transplantation is paralleled by the increased size of the waiting list. Efforts to increase the donor pool have included the use of living-unrelated kidney donors (LURDs). METHODS During a 12-year period our center performed 309 transplantation from living donors; 279 patients received living-related donor (LRD) transplants, and 30 patients received LURD transplants. During the same period 543 patients received cadaveric renal donor transplants. A total of 86.7% of LURD transplants were spousal transplants. A total of 29% of the patients who received LRDs were human leukocyte antigen-identical with their donors and 53% were haploidentical, versus 0 human leukocyte antigen-identical or haploidentical in the LURD group. RESULTS Twenty-seven (90%) Of 30 LURD recipients are alive, as are 240 (86%) of 279 LRD recipients. Mean current creatinine is 1.6 mg/dl for the LURD group and 1.7 mg/dl for the LRD group Kaplan-Meier 1- and 5-year graft survival was 94.9% and 82.9% for the LRD group, 93.1% and 85.9% for the LURD group (p = not significant), and 84.6% and 70.7% for the cadaveric renal donor group (p < 0.05). CONCLUSIONS LURD patient and graft survival is comparable to LRD transplants despite inferior human leukocyte antigen matching. LURD transplant survival is superior to that of cadaveric renal donor transplants. LURDs are an excellent but underused source of organs for renal transplant recipients.

Improved method for the isolation and purification of human islets of Langerhans using Liberase™ enzyme blend

To determine the effects of procedural modifications, 23 human islet isolations were analyzed. Isolations were divided into two groups based on the enzyme used. The influence of Liberase, with an improved method of mechanical disassociation of pancreas, was compared to an automated method using Sevac collagenase. Pancreases were processed within 10 h of cross clamping. Following ductal injection of the enzyme, tissue was placed in the digestion chamber for disassociation. Purification was accomplished using a COBE 2991 cell processor and continuous gradients of 1Hypaque EuroFicoll. Isolations in Group I (Sevac) had an average yield of 138,602 +/- 128,364 islet equivalents (IE) (2083 +/- 1679 IE/g) with a purity of 85 +/- 11%. Group II (Liberase) showed an average yield of 389,586 +/- 191,161 IE (5,958 +/- 3,083 IE/g) with a purity of 90 +/- 6.8%. Viability was confirmed by fluorescein diacetate and propidium iodide staining, static incubations, and perifusions. In conclusion, the combination of the enzyme blend, Liberase, and a more gentle system of disassociation has proven to be a more productive method of islet isolation with higher purity than the previously published methods.

Cadaveric versus living donor kidney transplantation: A medicare payment analysis.

BACKGROUND We found previously that the clinical advantages of living donor (LD) renal transplantation lead to financial cost savings compared to either cadaveric donation (CAD) or dialysis. Here, we analyze the sources of the cost savings of LD versus CAD kidney transplantation. METHODS We used United States Renal Data System data to merge United Network for Organ Sharing registry information with Medicare claims data for 1991-1996. Information was available for 42,868 CAD and 13,754 LD transplants. More than 5 million Medicare payment records were analyzed. We calculated the difference in average payments made by Medicare for CAD and LD for services provided during the first posttransplant year. RESULTS Average total payments were

HLA antibodies present in the sera of sensitized patients awaiting renal transplant are also reactive to swine leukocyte antigens.

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