Inferior Outcomes on the Waiting List in Low-Volume Pediatric Heart Transplant Centers.

Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low-volume centers (fewer than three annual transplantations). Of these listed candidates in low-volume centers, only 36% received a transplant versus 89% in high-volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low-volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5-5.7 in multivariate Cox regression and HR 5.6, CI 4.4-7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0-1.6 in multivariate Cox regression). During the study period, one-fourth of pediatric transplant candidates were listed in low-volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist.

Survival Outcomes Following Pediatric Liver Transplantation (Pedi-SOFT) Score: A Novel Predictive Index.

A prognostic index to predict survival after liver transplantation could address several clinical needs. Here, we devised a scoring system that predicts recipient survival after pediatric liver transplantation. We used univariate and multivariate analysis on 4565 pediatric liver transplant recipients data and identified independent recipient and donor risk factors for posttransplant mortality at 3 months. Multiple imputation was used to account for missing variables. We identified five factors as significant predictors of recipient mortality after pediatric liver transplantation: two previous transplants (OR 5.88, CI 2.88-12.01), one previous transplant (OR 2.54, CI 1.75-3.68), life support (OR 3.68, CI 2.39-5.67), renal insufficiency (OR 2.66, CI 1.84-3.84), recipient weight under 6 kilograms (OR 1.67, CI 1.12-2.36) and cadaveric technical variant allograft (OR 1.38, CI 1.03-1.83). The Survival Outcomes Following Pediatric Liver Transplant score assigns weighted risk points to each of these factors in a scoring system to predict 3-month recipient survival after liver transplantation with a C-statistic of 0.74. Although quite accurate when compared with other posttransplant survival models, we would not advocate individual clinical application of the index.

Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial.

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

Major histocompatibility complex-specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of V beta+ T cells.

The preferential usage of certain T cell receptor (TCR) V beta genes has been well established in several major histocompatibility complex (MHC)-restricted immune responses. However, V beta usage among allogeneic responses remains unclear. Because recent findings of ours and others indicate that V beta 8 predominates in certain Ld-restricted, peptide-specific responses, we examined the V beta 8 usage in allogeneic responses to Ld. To selectively recognize the Ld molecule, cells from BALB/c-H-2dm2 (dm2), the Ld-loss mutant mouse, were stimulated in vitro or in vivo with wild-type BALB/c cells. We report here that after the intraperitoneal administration of the anti-V beta 8 monoclonal antibody (mAb) F23.1, peripheral V beta 8 T cells were depleted from dm2 mice. This in vivo depletion abrogated the ability of dm2 splenocytes to mount a primary response to Ld molecules. This abrogation was specific, since the response of V beta 8-depleted dm2 cells to Kb/Db antigens was the same as that of control nondepleted dm2 cells. Furthermore, in vivo depletion of V beta 8 cells was found to cause a dramatic prolongation of Ld-disparate skin grafts (mean survival time [MST] 22.1 +/- 2.1 vs. 10.3 +/- 1.1 d for saline-treated controls, or 10.9 +/- 1.7 d for controls treated with mAb KJ23 to V beta 17). By contrast, V beta 8 depletion had no effect on recipients grafted with haplotype-mismatched skin or single Dk-locus-disparate skin. These findings demonstrate that V beta 8+ T cells predominate in allogeneic response to Ld but not other alloantigens. The effect of V beta 8 depletion was found to be even more dramatic on recipients grafted with Ld-disparate vascularized heart transplants (MST > 100 vs. 8.6 +/- 0.5 d for controls). In total, these findings establish the efficacy of using mAb to the V beta gene family to specifically and significantly enhance the survival of allografts. The implications of detecting V beta 8 usage in both alloreactive or MHC-restricted TCR responses to the same class I molecule are discussed.

Induction of immune unresponsiveness to concordant islet xenografts by intrahepatic preimmunization and transient immunosuppression.

Streptozotocin-induced, diabetic mice (C57BL/6) were preimmunized by injecting 25 low temperature, cultured Wistar-Furth (WF) rat islets into the portal vein, and the recipients received one injection of mouse and rat antilymphocyte sera. 3 wk later, fresh WF islets were transplanted under the kidney capsule of the preimmunized recipients, and normoglycemia was maintained in all 13 recipients for 60 d. Removal of the grafts at 60 d returned the mice to a diabetic state. Transplants of fresh WF islets under the kidney capsule without pretreatment of the recipients had a mean survival time of 16.5 +/- 2.5 d. These findings demonstrate that immune unresponsiveness can be achieved across a concordant, islet xenograft barrier within 3 wk after intrahepatic preimmunization with a small number of donor rat islets and transient immunosuppression with antilymphocyte sera.

Induction of allogeneic islet survival by intrahepatic islet preimmunization and transient immunosuppression.

Induction of tolerance to fully major histocompatibility complex (MHC)-mismatched rat islet allografts implanted at two different islet transplant sites (liver and kidney capsule [KC]) was examined. Streptozotocin-induced diabetic Lewis (RT1(1)) rats remained hyperglycemic (> 200 mg/dl) after intrahepatic preimmunization by injection of 200 low-temperature cultured (24 degrees C for 7 days) Wistar-Furth (WF, RT1u) rat islets into the portal vein with one injection (1 ml) of rat antilymphocyte serum intraperitoneally. Three weeks later, 1,200 WF islets that had been cultured to remove passenger lymphoid cells were transplanted into the liver via the portal vein or under the KC. The intrahepatic transplants survived 60.2 +/- 11.9 days, and all six of the KC transplants maintained normoglycemia for > 100 days after the preimmunization regimen. In contrast, survival of fresh islet transplants was not significantly improved by this preimmunization protocol at either transplantation site. This study demonstrates that indefinite islet allograft survival can be achieved across a full MHC mismatch by intrahepatic preimmunization with a small number of cultured donor islets and a brief period of immunosuppression followed by transplantation of low-temperature cultured donor islets.

Induction of tolerance to islet xenografts in a concordant rat-to-mouse model.

Induction of tolerance to concordant rat islet xenografts (150 Wistar-Furth [WF] islets) in streptozocin-induced (STZ) diabetic mice (C57BL/6) was determined at three different sites for islet implantation (thymus, kidney capsule, and liver). Islets transplanted into the thymus or kidney capsule were either fresh or cultured at 24 degrees C for 7 days, and the mice received a single injection of either anti-mouse lymphocyte serum (MALS) alone or anti-rat lymphocyte serum (RALS) and MALS. Islets transplanted into the liver via the portal vein were cultured at 24 degrees C for 7 days, and the mice received a single injection of MALS and RALS. To document the induction of tolerance, recipients with islet xenografts surviving > 100 days were made diabetic again by STZ (thymus and liver) or nephrectomy (kidney capsule) and received a second transplant of 150 fresh WF islets in the kidney capsule. Kidney capsule placement of fresh or cultured islets with MALS alone or MALS and RALS did not induce tolerance in a significant number of recipients. The intrathymic transplantation of fresh or cultured islets with MALS alone resulted in prolonged WF islet xenograft survival (mean survival time of 39.7 +/- 7.9 days) but did not result in tolerance, whereas the administration of MALS and RALS with the intrathymic placement of fresh or cultured islets induced tolerance in approximately 50% of the mice. Intrahepatic transplantation of cultured islets with MALS and RALS resulted in tolerance to donor islets in 90% of the recipients. Donor specificity was evaluated by a third major histocompatibility complex-disparate fresh Lewis islet xenograft.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pancreatic islet transplantation on progression of diabetic retinopathy and neuropathy.

INTRODUCTION: Pancreatic islet transplantation (PIT) has only become an effective treatment for type 1 diabetes mellitus within the past 4 years. As a result, the long-term effects of PIT on progression of diabetic neuropathy and retinopathy are unknown. The benefit of halting or improving diabetic neuropathy and retinopathy is of particular interest since most PIT recipients have not developed the advanced complications of diabetes. Herein, we describe the improvement and stabilization of diabetic neuropathy and retinopathy in 12 PIT recipients. PATIENTS AND METHODS: Between January 1, 2002, and June 30, 2004, there have been 12 patients who have received PIT. Currently, there are eight patients who have sufficient follow-up to assess the progression of diabetic retinopathy and neuropathy. To assess for disease progression, patients were examined by a single ophthalmologist and single neurologist throughout the study period. Eye exams were performed using a slit-lamp exam while neurological status was assessed using electromyelograms and clinical exams. RESULTS: All PIT recipients had decreases in hemoglobin A(1)C and increases in serum C-peptide. All study patients had stabilization of their retinopathic disease. One patient demonstrated improvement of retinopathy at 1 year posttransplant. Fifty percent of patients demonstrated improvement or stabilization of their diabetic neuropathy. One patient had mild reinnervation of the fingers and wrist extensors by clinical exam 1 year posttransplant. Four patients exhibited an average decrease of 19% in sural nerve conduction velocities. CONCLUSION: Our series has demonstrated that all PIT recipients have had stabilization of their diabetic retinopathy and that 50% of patients exhibited stabilization or even improvement of their diabetic neuropathy.

Gastroschisis and biliary atresia in a neonate: uncommon presentation or common precipitant.

We report here on a newborn infant who initially presented with a history of gastroschisis, abdominal distension, and jaundice. Further studies revealed that the child had findings consistent with extrahepatic biliary atresia (EHBA). The child later developed hepatic failure and subsequently expired. The purpose of this case report is to discuss the pathogenesis of each disease process and to identify any commonality between the pathogenesis of gastroschisis and EHBA.

Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model.

MCPH1, also known as BRIT1, has recently been identified as a novel key regulatory gene of the DNA damage response pathway. MCPH1 is located on human chromosome 8p23.1, where human cancers frequently show loss of heterozygosity. As such, MCPH1 is aberrantly expressed in many malignancies, including breast and ovarian cancers, and the function of MCPH1 has been implicated in tumor suppression. However, it remains poorly understood whether MCPH1 deficiency leads to tumorigenesis. Here we generated and studied both Mcph1(-/-) and Mcph1(-/-)p53(-/-) mice; we showed that Mcph1(-/-) mice developed tumors with long latency, and that primary lymphoma developed significantly earlier in Mcph1(-/-)p53(-/-) mice than in Mcph11(+/+)p53(-/-) and Mcph1(+/-)p53(-/-) mice. The Mcph1(-/-)p53(-/-) lymphomas and derived murine embryonic fibroblasts (MEFs) were both more sensitive to irradiation. Mcph1 deficiency resulted in remarkably increased chromosome and chromatid breaks in Mcph1(-/-)p53(-/-) lymphomas and MEFs, as determined by metaphase spread assay and spectral karyotyping analysis. In addition, Mcph1 deficiency significantly enhanced aneuploidy as well as abnormal centrosome multiplication in Mcph1(-/-)p53(-/-) cells. Meanwhile, Mcph1 deficiency impaired double strand break (DSB) repair in Mcph1(-/-)p53(-/-) MEFs as demonstrated by neutral Comet assay. Compared with Mcph1(+/+)p53(-/-) MEFs, homologous recombination and non-homologous end-joining activities were significantly decreased in Mcph1(-/-)p53(-/-) MEFs. Notably, reconstituted MCPH1 rescued the defects of DSB repair and alleviated chromosomal aberrations in Mcph1(-/-)p53(-/-) MEFs. Taken together, our data demonstrate MCPH1 deficiency promotes genomic instability and increases cancer susceptibility. Our study using knockout mouse models provides convincing genetic evidence that MCPH1 is a bona fide tumor suppressor gene. Its deficiency leading to defective DNA repair in tumors can be used to develop novel targeted cancer therapies in the future.

Lower extremity paralysis after use of the supraceliac aorta for hepatic arterial reconstruction of the transplanted liver.

Use of the supraceliac aorta for hepatic arterial reconstruction of the transplanted liver in the setting of inadequate recipient celiac and hepatic arterial inflow has been advocated and has resulted in a decreased hepatic artery thrombosis rate in both the adult and pediatric populations. Over the past 6 years, we have utilized the supraceliac aorta in more than 200 patients without complication. However, in this communication, we report a major neurologic complication that resulted in anterior spinal artery syndrome.

Intrathymic injection of donor alloantigens induces specific tolerance to cardiac allografts.

The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring allograft function and survival. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic, intrasplenic, s.c., or i.v. injection of 25 x 10(6) syngeneic Buffalo (RT1b) or MHC fully mismatched Lewis (RT1l), ACI (RT1a), or UV-B irradiated Lewis (RT1l) splenocytes. The Buffalo recipients were given 1 cc of rabbit antirat antilymphocyte serum (ALS) i.p. at the time of the donor antigen injection, and 21 days later received a heterotopic Lewis or ACI heart transplant. Only intrathymic alloantigen injection induced a donor-specific tolerance which allowed the cardiac allograft to survive indefinitely (mean survival time [MST] > 176.8 days) in > 86% of the recipients without the need for further immunosuppression, whereas groups receiving antigen injections at other sites rejected cardiac allografts in control time (MST approximately 7.0 days). Histologic examination of long-term tolerated Lewis cardiac allografts revealed the presence of healthy cardiac myocytes without mononuclear infiltration. Buffalo rats with a long-term surviving Lewis cardiac allograft did not reject a second Lewis cardiac allograft (MST > 100.0 days), but rejected a heterotopic ACI cardiac allograft in normal time (MST approximately 7.0 days). By limiting dilution analysis (LDA), maturation of donor-specific CTLs (pCTL) from long-term recipient splenocytes was markedly diminished, whereas third party pCTL was not altered, and T helper-precursors were moderately decreased without alteration in the peripheral CD4+ and CD8+ phenotype frequencies. MLC responses of recipients with long-term surviving cardiac allografts to donor-specific and third party stimulation were not significantly different from naive controls. Microchimerism is unlikely because Lewis allograft survival was also prolonged (MST > 96.0 days) in rats receiving UV-B irradiated Lewis splenocytes which cannot proliferate. The absence of increased allograft survival after transfer of long-term recipient splenocytes into naive animals suggests that donor-specific suppressor cells are not present. Additionally, in vitro lymphocyte proliferative responses to mitogenic or allogeneic stimulation in MLC was not diminished by the addition of these long-term recipient splenocytes. This model emphasizes the importance of exposure of T cell precursors to foreign donor alloantigen in the thymic environment for the development of unresponsiveness to a donor-specific vascularized allograft.

Successful transfer of immune unresponsiveness to concordant rat islet xenografts.

Indefinite survival of concordant xenogeneic Wistar Furth (WF) rat islet survival was obtained by intrahepatic transplants of cultured WF islets and a single injection of antilymphocyte sera in C57BL/6 mice. Adoptive transfer of splenocytes from mice with established WF islet xenografts produced a marked prolongation of survival of WF islets transplanted under the kidney capsule of diabetic irradiated (600 rads), naive C57BL/6 recipients (mean survival time = 48.9 +/- 17.1 days), and three of the recipients were still normoglycemic at 100 days after transplantation. Adoptive transfer of an equal mixture (3 x 10(7) cells each) of these splenocytes with normal splenocytes also prolonged survival of the kidney capsule islet xenografts (mean survival time = 26.5 +/- 7.8 days vs. 15.2 +/- 5.3 days for controls). In vitro studies on lymphocyte proliferation demonstrated a low rate of proliferation of splenocytes from established islet xenografts in the presence of irradiated WF splenocytes (stimulation index = 1.6 vs. 16.2 for naive C57Bl/6 mice), and mixing the cells with control splenocytes also decreased the proliferation of splenocytes as compared with controls (stimulation index = 5.4 vs. 16.2 in controls). The inhibitory effect was not species specific, since splenocytes from mice with established islet xenografts also produced a 42% inhibition of proliferation in the presence of irradiated Lewis splenocytes. These findings demonstrate that concordant, islet xenograft, immune unresponsiveness can be adoptively transferred by splencotyes from mice with established islet xenografts.

Induction of donor-specific tolerance to cardiac but not skin or renal allografts by intrathymic injection of splenocyte alloantigen.

We have recently found that donor-specific tolerance to a cardiac allograft can be achieved after the intrathymic (i.t.) injection of donor splenocytes and a single intraperitoneal injection of rabbit antirat lymphocyte serum. The present study evaluated whether the tolerance induced by splenocytes injected i.t. could also prevent the rejection of kidney and skin allografts. Male Buffalo (RT1b) rats were given 25 x 10(6) fully MHC-mismatched unfractionated Lewis (RT1l) splenocytes by i.t. injection plus 1 ml of ALS i.p. and 21 days later underwent a Lewis heterotopic cardiac, orthotopic renal, or skin transplant. Lewis i.t. injection induced a donor-specific tolerance with indefinite cardiac allograft survival (> 153.1 days) in 88% of the recipients without the need for further immunosuppression, while renal and skin allograft survival was prolonged (kidney 14.8 days vs. control 7.8 days; skin 11.6 days vs. control 9.2 days) but were still rejected. Buffalo recipients with a long-surviving Lewis cardiac allograft after Lewis i.t. injection were still able to reject a third-party heterotopic ACI (RT1a) cardiac allograft in normal time (7.0 days), but did not reject a second Lewis cardiac allograft (> 100.0 days). In contrast, however, Buffalo recipients with long-surviving Lewis cardiac allografts did reject a Lewis skin allograft in normal time (10.0 days) and a Lewis renal allograft in a prolonged manner (17.6 days) without causing the rejection of the Lewis cardiac allografts. These data support the important role tissue-specific non-MHC antigens may play in the rejection of kidney and skin allografts.

In situ splitting of the cadaveric liver for two adult recipients.

BACKGROUND: Split-liver transplantation offers a unique opportunity to expand the existing donor pool. However, it has previously been stated that due to inadequate liver volume the advantages of split-liver transplantation would be lost when attempting to split the liver for two adult recipients. In this study, we sought to determine the safety, efficacy, and applicability of split-liver transplantation in select adult liver transplant recipients. METHODS: Liver allografts for eight adult recipients were procured by in situ splitting of four adult cadaveric livers. The donor ages were 17, 19, 22, and 25 years and weights were 72, 77, 78, and 87 kg, respectively. In situ splitting resulted in three right trisegmental grafts, one right lobe graft, one left lobe graft, and three left lateral segmental grafts. The median recipient age was 49 years (range 38-61 years), whereas the median recipient weight was 84 kg (range 78-98 kg) for the right-sided grafts and 52 kg (range 51-53 kg) for recipients of the left-sided grafts. The median graft-to-recipient body weight ratio for right trisegmental, right lobe, left lobe, and left lateral segmental grafts was 1.31%, 1.26%, 1.35%, and 0.70%, respectively. RESULTS: Overall patient and graft survival in this series is 100%. All prothrombin times were normalized within 4 days of transplantation. No evidence of ascites or prolonged hyperbilirubinemia was encountered in any right- or left-sided graft recipient. The incidence of hepatic artery, portal vein, and hepatic vein thrombosis is 0%, 0%, and 0%, respectively. Hepatic arterial anastomotic bleeding and a cut surface bile leak each occurred in one patient. Median United Network for Organ Sharing (UNOS) waiting time was 242 days (range 4-454 days) for the patients to which the donor liver was allocated. In contrast, the median waiting time for the four patients receiving the extra split-liver graft was reduced significantly to 37 days (range 21-101 days) (P<0.02). CONCLUSIONS: This study demonstrates that split-liver transplantation can expand the cadaveric donor liver pool available for select adult liver transplant recipients. When both the donor organ and the transplant recipient are chosen carefully, split-liver transplantation can be safely performed without a delay in allograft function, increase in technical complications, or compromise in graft or patient survival.

Liver transplantation in polysplenia syndrome: use of a living-related donor.

Congenital anatomic anomalies often present technical obstacles during liver transplants. Biliary atresia is the most common indication for liver transplants in children, and approximately 7-10% of these patients have congenital anomalies comprising the "polysplenia syndrome." The polysplenia syndrome, which often includes abdominal situs inversus, is of particular concern in liver transplants because these anatomic anomalies result in a more complex hepatectomy, alterations in the placement of the donor grafts, and the need for additional vascular reconstruction. Earlier reports have shown mixed results for these patients who have undergone orthotopic liver transplants, reporting a high rate of postoperative complications and poor survival. The use of living-related donor grafts has produced excellent results in the general pediatric population. This is the first report of the successful use of a living-related donor graft for an orthotopic liver transplant to treat end-stage liver disease secondary to biliary atresia in a child with polysplenia syndrome.

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.

De novo hepatitis C in children after liver transplantation.

BACKGROUND: We describe the incidence, results of interferon therapy, and outcome of hepatitis C virus (HCV) hepatitis occurring de novo after pediatric orthotopic liver transplantation (OLT). METHODS AND RESULTS: Of children undergoing OLT between 1984 and September 1996, 321 children survived for more than 1 year. Of these, 13 (4.0%) developed previously undiagnosed HCV disease, as suggested by HCV antibody testing and HCV polymerase chain reaction and confirmed by liver biopsy. Of the 117 children who received transplants before HCV screening of blood products or donors, 10.2% developed de novo HCV disease. The mean age at diagnosis of HCV hepatitis was 13.2+/-5.0 years, and the mean time to diagnosis after OLT was 8.1 years (range, 4-11 years). The mean alanine aminotransferase (ALT) level at diagnosis was 108 IU/ml, and the liver biopsy specimen showed chronic active or chronic persistent hepatitis in 11 children, cirrhosis in 1 child, and nonspecific changes in 1 child. Twelve children were treated with interferon-2alpha; children who weighed > or =20 kg received 3 x 10(6) units every other day, and those who weighed <20 kg received 1.5 x 10(6) units every other day. Four patients developed rapidly progressive liver failure while receiving interferon therapy and required urgent re-transplantation. Three of the four children again developed histologic evidence of recurrent HCV 4-6 months after the second OLT, and all three subsequently died of HCV-induced liver failure. One patient remains alive and well with no evidence of HCV recurrence and a negative HCV RNA. Of the remaining eight children treated with interferon, only two have had a sustained response (normal ALT) and one is now HCV RNA negative. HCV RNA levels did not correlate with outcome or disease severity. HCV antibody levels were unreliable, with two patients having negative HCV antibody but a positive HCV RNA at diagnosis. Six patients were able to be genotyped: four were la and two were 1b. CONCLUSION: Overall mortality for de novo HCV hepatitis was 23%. Seventy-five percent of children who received a second transplant for HCV hepatitis had early histologic recurrence that led to liver failure and death. Interferon therapy resulted in a sustained improvement in ALT in only 15% of children. The time to onset and progression of clinical disease both in the original graft and the retransplant graft were accelerated compared with nonimmunosuppressed individuals.

The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complication associated with the use of chronic immunosuppression for solid organ transplantation. This study represents a retrospective analysis of UCLA's experience with PTLD in all pediatric liver transplant recipients between 1984-1997. We assessed the clinical presentation, risk factors, incidence density, immunological characteristics, management, and outcome of patients who developed PTLD when receiving either primary cyclosporin A (CsA) or tacrolimus. METHODS: A total of 251 children received primary CsA therapy of which 70 required OKT3 for steroid resistant rejection and 29 required tacrolimus rescue for OKT3 resistance and/or chronic rejection. One hundred forty one children received tacrolimus as primary therapy. Sixty patients who survived for less than 6 months after transplantation were excluded from the study. RESULTS: The total incidence density (ID) rate of PTLD was 1.8+/-0.4 per 100 patient-years (30/392). The overall ID rate of PTLD in the CsA group was 0.93+/-0.2 per 100 patient-years (15/251). Within this group of primary CsA-treated patients, the ID rate of PTLD was 0.49+/-0.1 without OKT3 or tacrolimus, 0.67+/-0.2 with OKT3, and 6.42+/-1.1 with tacrolimus rescue. The overall PTLD ID rate in the primary tacrolimus-treated patients was 4.86+/-1.2 per 100 person-years (15/141). There was a 5-fold increase in the ID rate of PTLD in the primary tacrolimus group when compared to the comparable, primary CsA group (P<0.001). The mean time to PTLD was 5-fold longer (49.7+/-20.7 months) in the CsA group when compared to the CsA/tacrolimus rescue group (9.8+/-3 months, P<0.05) or the tacrolimus primary group (12.6+/-5.1 months, P<0.05). Five patients had monoclonal disease in the CsA group, but only one in the tacrolimus group (P<0.05). Clinical presentations with enlarged lymph nodes, fevers, malaise, anorexia, weight loss, hypoalbuminemia, and gastrointestinal blood loss were common. Mortality was 20%, three patients died in each group. CONCLUSION: The use of primary tacrolimus therapy was associated with a significant 5-fold higher rate of PTLD when compared to those treated with primary cyclosporine. Early diagnosis, decrease and/or discontinuation of potent immunosuppressive agents may contribute to decrease morbidity and mortality of this entity.

Donor-specific transfusions have long-term beneficial effects for human renal allografts.

From April, 1980 to November, 1988, 163 one or two haplotype-mismatch living related (LR) or living unrelated (LUR) potential renal transplant recipients received three 200 ml aliquots of donor specific transfusion (DST) at biweekly intervals with concomitant azathioprine (2 mg/kg/day). Following transplantation, only prednisone and azathioprine were given for immunosuppression. The results for the DST group are compared with those for HLA identical living recipients (57 patients) transplanted during this same interval (1980-1988). Comparison is also made with a group of one or two haplotype-mismatched living donor recipients (54 patients) not treated with DST but with triple drug therapy (prednisone, azathioprine, cyclosporine) and antithymocyte globulin (ATG) or OKT-3 induction. Permanent T cell crossmatch sensitization occurred in 11 of 163 patients (7%). Successful DST donor transplants were performed between 121 one HLA haplotype-mismatched, 14 two HLA haplotype-mismatched LR, and 7 two haplotype-mismatched LUR pairs. Actual one- and five-year graft survivals were 94%, 100%, 100%, and 72%, 85%, and 71%, respectively, for these three subgroups of DST treated patients. The graft survival for all DST pretreated recipients at one, five, and ten years was comparable to the HLA-identical group (94%, 79%, 64% vs. 91%, 80% and 77%). At a mean follow-up of 10 1/2 years, 54% (80 patients) of the entire group of 147 patients transplanted after DST have functioning transplants with a mean serum creatinine of 1.7 mg/dl. Fifteen percent of DST patients (21 patients) died with a functioning graft 2 to 132 months after transplantation, 26% (37 patients) rejected the DST graft after 1 to 128 months, and 6% (9 patients) were lost for nonimmunological reasons. No lymphoproliferative disease developed in the DST group and the incidence of cytomegalovirus sepsis was only 2% (3 patients). The long-term beneficial effects of DST on renal allograft survival and function and the lower incidence of the complications of nonspecific immunosuppression should encourage increased utilization of DST in renal transplantation.