Uta Herden

Long-term Clinical Relevance of De Novo Donor-Specific Antibodies After Pediatric Liver Transplantation.

Background Anti-HLA antibodies and especially donor-specific antibodies (DSA) play a significant role in graft survival after solid organ transplantation. Their impact on long-term survival in adult liver transplantation (LT) is controversial, but they may be a risk factor. The effects of DSA after pediatric LT are still unclear. Methods We performed a retrospective evaluation of DSA in sera from 43 children who had received transplants at our tertiary center. Twenty-four patients had good long-term clinical and laboratory graft function (group 1), whereas 19 LT recipients suffered from histologically confirmed and clinically relevant chronic allograft rejection (group 2); 16 of these have already undergone retransplantation due to graft dysfunction. Inclusion criteria were availability of sera before the first LT to identify preformed antibodies in case of DSA positivity after LT and long-term follow-up at our institution. Sera were analyzed for anti-HLA antibodies using Luminex single antigen beads, where a mean fluorescence intensity value of more than 1500 was considered positive. Results The prevalence of DSA was 33% for group 1 and 68% for group 2. Antibodies were predominantly HLA class II. Values of mean fluorescence intensity were comparable in both groups. Only one of the DSA+ ve patients from group 1 exhibited preformed antibodies. In conclusion, pediatric patients with chronic rejection revealed a higher rate of de novo DSA, especially of HLA-class II DSA. Further studies are necessary to confirm these data with a larger pediatric cohort.

Sorafenib-induced severe acute hepatitis in a stable liver transplant recipient.

1. Sotiropoulos GC, Lang H, Nadalin S, et al. Liver transplantation for hepatocellular carcinoma: University Hospital Essen experience and metaanalysis of prognostic factors. J Am Coll Surg 2007; 205: 661. 2. Nouso K, Ito YM, Kuwaki K, et al. Prognostic factors and treatment effects for hepatocellular carcinoma in Child C cirrhosis. Br J Cancer 2008; 98: 1161. 3. Sotiropoulos GC, Malagó M, Molmenti E, et al. Liver transplantation for hepatocellular carcinoma in cirrhosis: Is clinical tumor classification before transplantation realistic? Transplantation 2005; 79: 483. 4. Sotiropoulos GC, Malagó M, Molmenti EP, et al. Liver transplantation and incidentally found hepatocellular carcinoma in liver explants: Need for a new definition? Transplantation 2006; 81: 531. 5. Eisenbach C, Merle U, Stremmel W, et al. Liver transplantation in HIV-positive patients. Clin Transplant 2009; 23(suppl 21): 68. 6. de Vera ME, Dvorchik I, Tom K, et al. Survival of liver transplant patients coinfected by recurrent Hepatitis C. Am J Transplant 2006; 6: 2983. 7. Di Benedetto F, De Ruvo N, Berretta M, et al. Hepatocellular carcinoma in HIV patients treated by liver transplantation. Eur J Surg Oncol 2008; 34: 422.

Immediate postoperative intensive care treatment of pediatric combined liver-kidney transplantation: outcome and prognostic factors.

Background. Studies reporting the immediate pediatric intensive care unit (PICU) treatment after combined liver-kidney transplantation (CLKT) are scarce, although this period is pivotal for survival and long-term outcome. Methods. We retrospectively analyzed all pediatric CLKT performed in our center between 1998 and 2010. Results. Sixteen patients underwent 17 CLKT at a median age of 5.3 years (range, 1.3–15.9 years). Median body weight at CLKT was 17.7 kg (range, 9.2–55 kg). Underlying diagnosis was primary hyperoxaluria type 1 in nine patients and autosomal recessive polycystic kidney disease in seven patients. Median time on PICU was 8.5 days (range, 3–68 days); however, patients with primary hyperoxaluria type 1 had a significantly longer stay (P=0.031). Median duration of ventilation was 1 day; however, five patients required ventilation for 25 to 52 days. Continuous veno-venous hemofiltration was applied in nine patients due to delayed kidney graft function, volume overload, or high plasma oxalate. Overall, the survival rate after CLKT was 100% and long-term outcome was very good at a mean follow-up of 3.6 years (range, 0.5–12.2 years). Waiting time, donor age, and donor-to-recipient weight ratio were found to be significant risk factors for an extended PICU stay (P=0.02, 0.0031, and 0.014, respectively). Conclusions. Immediate postoperative course after CLKT may be challenging and complex. However, excellent results can be achieved, even in small children.

Surgical aspects and outcome of combined liver and kidney transplantation in children

In children with renal insufficiency and accompanying or underlying liver disease, combined liver and kidney transplantations (CLKT) are indicated. However, because of the rare indications, the number of paediatric CLKT is low. Our aim was to analyse CLKT in children with special regard to surgical aspects and outcome. All paediatric CLKT performed at our institution between 1998 and 2009 were retrospectively analysed. Between 1998 and 2009, 15 CLKT were performed in 14 paediatric patients (median age 8u2003years, range 1–16u2003years). The indications for CLKT were autosomal recessive polycystic kidney disease (nu2003=u20037), primary hyperoxaluria type 1 (nu2003=u20037) and retransplantation because of primary liver nonfunction (nu2003=u20031). In the postoperative course, six patients showed bleeding complications, thereof three patients needed operative revision for intra‐abdominal bleeding. Eight of 15 patients (53%) needed dialysis. The 1‐ and 5‐year patient survival was 100%; and 1‐ and 5‐year graft survival was 80% for the liver and 93% for the kidney allograft. A number of different complications, especially secondary haemorrhage have to be anticipated after CLKT, requiring a timely and interdisciplinary treatment approach. With this management, our patients showed an excellent graft and patient survival.

Long‐term outcomes after liver transplantation for deoxyguanosine kinase deficiency: A single‐center experience and a review of the literature

Deoxyguanosine kinase (DGUOK) deficiency is a well‐known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life‐threatening liver failure, but the benefits of liver transplantation (LT) are controversial because of the frequently severe neurological involvement due to the underlying mitochondrial disease. We describe the long‐term clinical course of 2 patients from our institution and provide an update on their outcomes after LT with this condition. Another 12 pediatric patients were identified through a systematic search of the literature. All 14 reported patients underwent transplantation in infancy despite mild to moderate neurological impairment in some cases. The 2 DGUOK‐deficient patients from our center displayed liver failure and mild to moderate neurological involvement. At the time of this writing, they had been followed for 5 and 8 years after LT, both patients were alive, and they had only mild neurological symptoms. Three of the 12 patients identified through the literature review survived for a long time (17, 12, and 23 years); 8 died during early follow‐up; and for 1 patient, no follow‐up information was available. The 1‐year survival rate was 64%; 36% survived for more than 5 years. The long‐term survivors had good quality of life. In conclusion, although survival after LT for DGUOK deficiency is lower than survival after LT for other indications, a significant proportion of patients benefit from LT with long‐term survival and a stable neurological situation despite initial neurological abnormalities. Nevertheless, a decision to carry out LT for patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LT despite their absence before transplantation. Liver Transpl 20:464–472, 2014.

A formula to calculate the standard liver volume in children and its application in pediatric liver transplantation.

Due to a lack of available size‐matched liver grafts from children, most pediatric recipients are transplanted with technical variant grafts from adult donors. Size requirements for these grafts are not well defined, and consequences of mismatched graft sizes in pediatric liver transplantation are not known. Existing formulas for calculation of a standard liver volume are mostly derived from adults disregarding the age‐related percentual liver weight changes in children. In this study, we aimed to establish a formula for general use in children to calculate the standard liver volume. In a second step, the formula was applied in pediatric patients undergoing liver transplantation at our institution between 2000 and 2010 (n = 377). Analysis of a large number (n = 388) of autopsy data from children by regression analysis revealed a best fit for two formulas: “Formula 1,” children 0 to ≤1 year (n = 246): standard liver volume [ml] = −143.062973 +4.274603051 * body length [cm] + 14.78817631 * body weight [kg]; “Formula 2,” children >1 to <16 years (n = 142): standard liver volume [ml] = −20.2472281 + 3.339056437 * body length [cm] + 13.11312561 * body weight [kg]. In comparison with children receiving size‐matched organs, we found an elevated risk of liver graft failure in children transplanted with a small‐for‐size graft, whereas large‐for‐size organs seem to have no negative impact.

Developments in pediatric liver transplantation since implementation of the new allocation rules in Eurotransplant.

Liver allocation in the Eurotransplant (ET) region has changed from a waiting time to an urgency‐based system using the model of end‐stage liver disease (MELD) score in 2006. To allow timely transplantation, pediatric recipients are allocated by an assigned pediatric MELD independent of severity of illness. Consequences for children listed at our center were evaluated by retrospective analysis of all primary pediatric liver transplantation (LTX) from deceased donors between 2002 and 2010 (110 LTX before/50 LTX after new allocation). Of 50 children transplanted in the MELD era, 17 (34%) underwent LTX with a high‐urgent status that was real in five patients (median lab MELD 22, waiting time five d) and assigned in 12 patients (lab MELD 7, waiting time 35 d). Thirty‐three children received a liver by their assigned pediatric MELD (lab MELD 15, waiting time 255 d). Waiting time in the two periods was similar, whereas the wait‐list mortality decreased (from about four children/yr to about one child/yr). One‐ and three‐yr patient survival showed no significant difference (94.5/97.7%; p = 0.385) as did one‐ and three‐yr graft survival (80.7/75.2%; and 86.5/82%; p = 0.436 before/after). Introduction of a MELD‐based allocation system in ET with assignment of a granted score for pediatric recipients has led to a clear priorization of children resulting in a low wait‐list mortality and good clinical outcome.

Monitoring of nuclear factor of activated T-cell-regulated gene expression in de novo and long-term liver transplant recipients treated with cyclosporine a.

Pharmacodynamic drug monitoring might allow an improved use of immunosuppressive medication in transplant recipients. We assessed whether drug concentrations reflect the effect of cyclosporine (CsA) on expression of nuclear factor of activated T-cells-regulated cytokines. CsA drug concentrations and expression of interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor in stimulated blood lymphocytes were determined predose (C0) and 2 hours after (C2) CsA intake in 20 de novo (less than 3 months) and 20 long-term (3 months to 10 years) liver transplant patients. The residual cytokine expression at C2 relative to C0 was calculated. Mean CsA C0 and C2 concentrations were 236 and 776 μg/L in de novo and 100 and 573 μg/L in long-term liver transplant patients, respectively. Two hours after CsA intake, the residual cytokine expression for all cytokines was comparable in both groups (de novo patients mean 16%; long-term patients mean 17%). CsA C2 concentrations showed a significant (P < 0.01) correlation with the residual cytokine expression of interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor in both de novo and long-term patients, whereas CsA C0 concentrations did not. The data suggest that CsA C2 concentrations, but not C0 concentrations, reflect the effect of CsA on downregulation of cytokine expression in both de novo and long-term liver transplant patients.

Successful outcome of severe Amanita phalloides poisoning in children

Amanita phalloides intoxication can lead to FHF with high mortality, especially in children. There is still ongoing discussion about the optimal treatment and decision criteria for emergency liver transplantation (LTx). Here, we summarize our experience with outcomes in five children. Five children with severe A. phalloides intoxication were treated at our tertiary center from 1995 to 2010 and studied retrospectively with respect to clinical and laboratory aspects that might help to decide between LTx or conservative therapy only. The findings are discussed with regard to recommended treatment and transplantation criteria for adults. All patients survived, of whom two of five received emergency LTx. Three patients survived with conservative treatment consisting of intravenous silibinin, NAC, detoxification measures, and intensive care. Indications for LTx in two children were progressive brain edema and cardiovascular failure. Children with FHF due to A. phalloides intoxication should be considered early for emergency LTx but should be monitored closely for the necessity of definite LTx. Early detoxification with active charcoal as well as silibinin and NAC seems to improve the outcome. Late recovery of liver function after day 4 post‐ingestion is possible.

Early Initiation of Everolimus After Liver Transplantation: A Single-Center Experience

BACKGROUNDnEvidence relating to early everolimus use after liver transplantation remains limited.nnnMATERIAL AND METHODSnNinety-one adult patients undergoing liver transplantation at our center during 2007-2012 in whom everolimus therapy was initiated <3 months post-transplant were analyzed retrospectively. Everolimus was started on days 1-5 in 50 patients (group 1) and after day 5 in 41 patients (group 2). Most patients continued to receive low-dose cyclosporine (59.3%, target 50-80 ng/ml) or low-dose tacrolimus (25.3%; target 3-5 ng/ml). Mean follow-up was 4.6 years.nnnRESULTSnOne-, three- and five-year patient survival rates were 80.5%, 74.2%, and 70.5%, respectively, and did not differ between groups 1 and 2. Six patients (6.6%) developed biopsy-proven acute rejection after a median of 47 days (range 27-356 days). Everolimus was discontinued due to adverse events in 21 patients (23.1%). Incisional hernia repair occurred in 14.0% and 9.4% of patients in group 1 and 2, respectively. Renal function remained stable during follow-up, despite poor baseline function.nnnCONCLUSIONSnEverolimus with very low-dose calcineurin inhibitor given immediately after liver transplantation appears safe and effective, achieving a low rejection rate with well-preserved renal function.