Combined Liver-Kidney Transplantation in Children: Single-Center Experiences and Long-Term Results.

Combined liver-kidney transplantation (CLKT) is a rare procedure in pediatric patients in which liver and kidney from 1 donor are transplanted to a recipient during a single operation. The aim of our study was to analyze indications and results of CLKT in children. MATERIALS AND METHODS: Between 1990 and 2017 we performed 722 liver transplantations in children; we performed 920 kidney transplantations in children since 1984. Among them, 25 received CLKT. Primary diagnosis was fibro-polycystic liver and kidney disease in 17 patients, primary hyperoxaluria type 1 in 6 patients, and atypical hemolytic uremic syndrome-related renal failure in 2 children. Age of patients at CLKT was 3 to 23 years (median 16 years) and body mass was 11 to 55 kg (median 35.5kg). All patients received whole liver graft. Kidney graft was transplanted after liver reperfusion before biliary anastomosis. Cold ischemia time was 5.5 to 13.3 hours (median 9.4 hours) for liver transplants and 7.3 to 15 hours (median 10.4 hours) for kidney transplants. In 8 patients X-match was positive. We analyzed posttransplant (Tx) course and late results in our group of pediatric recipients of combined grafts. RESULTS: Tx follow-up ranged from 1.5 to 17 years (median 4.5 years). Two patients died: 1 patient with oxalosis lost renal graft and died 2.6 years after Tx due to complications of long-term dialysis, and 1 died due to massive bleeding in early postoperative period. Twelve patients were transferred under the care of adult transplantation centers. Six patients were dialyzed after CLKT due to acute tubular necrosis, and time of kidney function recovery was 10 to 27 days in these patients. In 1 patient with aHUS, renal function did not recover. In children with oxalosis, hemodialysis was performed for 1 month after Tx as a standard, with the aim to remove accumulated oxalate. Primary immunosuppression consisted of daclizumab or basiliximab, tacrolimus, mycophenolate mofetil, and steroids. Acute rejection occurred in 4 liver and 3 kidney grafts. One patient required liver retransplantation due to hepatitis C virus recurrence and 2 patients required kidney retransplantation. Two patients required dialysis. CONCLUSIONS: CLKT in children results in low rate of rejection and high rate of patient and graft survival.

Tumour-processed osteopontin and lactadherin drive the protumorigenic reprogramming of microglia and glioma progression.

Tumour tissue is infiltrated by myeloid cells that are reprogrammed into alternatively activated/regenerative (M2) macrophages. The contribution of major signalling pathways and their modulators/targets involved in the macrophage reprogramming is poorly known. Glioblastoma (malignant brain tumour) attracts and reprograms brain-resident microglia and peripheral macrophages into cells that increase invasion, angiogenesis and suppress antitumour immunity. Using a 'function-first' approach and glioma secretome proteomics we identified osteopontin and lactadherin as proteins that cooperatively activate amoeboid transformation, phagocytosis and motility of primary microglia cultures via integrins and FAK-Akt (focal adhesion kinase-Akt) signalling. A synthetic peptide interfering with integrin ligands blocks glioma-microglia communication, functional activation and M2 gene expression. We found that osteopontin/secreted phosphoprotein 1 (Spp1) produced by non-transformed cells acts as a proinflammatory factor inducing inflammatory signalling and M1 genes, and counteracts the action of lactadherin. Using constructs encoding functional mutants of osteopontin, we demonstrated sequential processing of Spp1 by thrombin and matrix metalloproteinase-3 and/or -7 (MMP-3 and/or -7) in glioma cells, which generates a microglia-activating form devoid of the inflammatory activity, while retaining the M2 reprogramming potential. A similar form of osteopontin is secreted by human glioma cells but not normal human astrocytes. Knockdown of osteopontin or lactadherin in glioma cells reduces intracranial glioma growth, blocks amoeboid transformation of myeloid cells and affects M2 reprogramming of microglia/macrophages. Our findings demonstrate how glioma cells misuse macrophage-activating signals and redesign primarily proinflammatory signals towards their advantage to induce M2 reprogramming of tumour-infiltrating brain macrophages.

Liver transplantation for severe hepatic graft-versus-host disease in two children after hematopoietic stem cell transplantation.

Chronic graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). After the skin, the liver is the second, most frequent target of GVHD, which presenting with hyperbilirubinemia, elevated liver enzymes, and coagulopathy. Progressive destruction of small intrahepatic bile ducts causes vanishing bile duct syndrome and leads to end-stage liver disease. We report 2 successful cases of orthotopic liver transplantation performed in children with severe GVHD after hematopoietic stem cell transplantation from a matched unrelated donor (HSCT-MUD).

Kidney transplantation in children with bladder augmentation or ileal conduit diversion.

INTRODUCTION: Various congenital and acquired diseases of the lower urinary tract can lead to chronic renal failure requiring renal replacement therapy. AIM: The aim of the study was to assess problems and results of kidney transplantation in children with significant lower urinary tract dysfunction. MATERIALS AND METHODS: Between 1984 and 2007, there were 33 kidney transplantations in children with end-stage renal disease and severe lower tract dysfunction out of 539 kidney transplantations performed in our department. The patients were 23 males and 10 females. Thirty patients received a kidney from a deceased donor, the remaining 3 from a living related donor. The age at transplantation ranged from 2.25 years to 19 years. In 26 patients an ileal conduit modo Bricker was created (in 21 patients at transplant operation). Bladder augmentation was performed in 6 patients and a continent urinary reservoir was created in 1. RESULTS: Post-transplant follow-up ranged from 7 to 88 months (mean 32 months). Overall patient survival is 100% and graft survival is 97%. Creatinine concentrations ranged from 0.3 to 3.4 mg% (mean 0.92 mg%). Surgical complications were diagnosed in 16 patients. All surgical complications were treated successfully and none of them caused graft loss. Urinary tract infections (UTI) were the most commonly observed complication, occurring in 26/33 (78%) patients, but the majority of these UTI were asymptomatic and had no influence on graft function. CONCLUSIONS: Kidney transplantation in children with lower urinary tract dysfunction and end-stage renal failure offers excellent medium term results in our experience, despite the creation of non-standard urinary drainage. Recurrent urinary tract infections are the most common complications in these patients, but in the majority of cases this does not lead to impairment of graft function.

Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients?

HCC constitutes 25-30% of primary malignant liver tumors in children. Conventional surgical excision is not possible in more than 50% of patients. LTx has recently become an important therapeutic option for adults and children with primary liver tumors. The aim of this study was a retrospective analysis of the clinical and pathological data of children with HCC treated with LTx in relation to Milan criteria assessed at diagnosis and then immediately before transplantation, in comparison with a group of patients treated conventionally. Between 1990 and 2007 we have treated 21 children diagnosed with HCC. Patients were divided into two groups: group I, 10 children treated conventionally and group II, 11 children treated with LTx regardless of previous therapy. The outcome of our patients treated conventionally with resection and chemotherapy is very poor--the disease-free survival rate is 30%. In contrast, despite that only 3 children having fulfilled adult Milan criteria, early clinical results of LTx are much superior. Total hepatectomy followed by LTx is the main treatment option for the majority of children with HCC. Decisions on the type of surgical treatment is made individually, but very early in the course of treatment.