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Background and Aims Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients. Methods Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed. Results Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal1/2) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients. Conclusion Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.

Background: Mulibrey nanism (MUL) is a rare condition with profound growth delay. Congestive heart failure is a major determinant of prognosis. The aim was to delineate pericardial constriction and myocardial functional abnormalities in a pediatric MUL sample. Methods: A total of 23 MUL patients and 23 individually sex- and age-matched healthy control subjects were prospectively assessed in a cross-sectional study with echocardiography. Results: Clinical signs of heart failure were present in 7 MUL patients, with severe congestive heart failure in 2. Significant diastolic dysfunction, mainly related to constriction, was found in MUL patients without pericardiectomy (N = 18)—septal bounce, pronounced hepatic vein atrial reversal and right heart inflow–outflow variations, and decreased inferior vena cava collapse during respiration. The appearance of the pericardium was not different from that of control subjects. Longitudinal diastolic myocardial velocities were similar to those in control subjects, suggesting an absence of significant myocardial restriction. Right ventricular free wall longitudinal systolic strain and bilateral longitudinal myocardial systolic velocities were decreased in MUL patients, indicating mild biventricular systolic dysfunction. Myocardial motion abnormalities and persistent congestive heart failure were common (in 3 of 6) in MUL patients with a history of pericardiectomy. Cardiac dimensions were similar between MUL patients and control subjects when adjusting for body size, except for smaller biventricular volumes. Conclusions: MUL disease presents with significant constriction-related diastolic dysfunction and mild bilateral systolic dysfunction. Constriction–restriction assessments during follow-up could be of benefit in decision-making regarding pericardiectomy in MUL disease. Myocardial abnormalities were prevalent among MUL patients who had undergone pericardiectomy and are consistent with progression of myocardial disease in a significant proportion of patients. Résumé: Contexte: Le nanisme Mulibrey (MUL) est une maladie rare qui donne lieu à un retard de croissance marqué. L’insuffisance cardiaque congestive est un déterminant majeur du pronostic. L’objectif de cette étude était de caractériser la constriction péricardique et les anomalies fonctionnelles myocardiques dans un échantillon de cas de MUL pédiatrique. Méthodologie: Au total, 23 patients atteints de MUL et 23 sujets témoins en bonne santé ont été appariés individuellement selon le sexe et l’âge et soumis à une évaluation prospective dans le cadre d’une étude transversale avec échocardiographie. Résultats: Sept patients atteints de MUL présentaient des signes cliniques d’insuffisance cardiaque, et deux, une insuffisance cardiaque congestive sévère. Une dysfonction diastolique significative, principalement liée à la constriction, a été observée chez les patients atteints de MUL n’ayant pas subi de péricardiectomie (N = 18) – rebond septal, inversion auriculaire marquée du flux de la veine hépatique, variations prononcées du flux entrant et sortant du cœur droit, diminution du collapsus de la veine cave inférieure pendant la respiration. L’apparence du péricarde n’était pas différente de celle notée chez les sujets témoins. Les vélocités myocardiques longitudinales pendant la diastole étaient similaires à celles relevées chez les sujets témoins, ce qui suggère l’absence de restriction myocardique significative. La déformation longitudinale de la paroi libre du ventricule droit et les vélocités myocardiques longitudinales bilatérales étaient diminuées pendant la systole chez les patients atteints de MUL, ce qui indique une dysfonction systolique biventriculaire légère. Les anomalies de la cinétique myocardique et la persistance de l’insuffisance cardiaque congestive étaient fréquentes (dans trois cas sur six) chez les patients atteints de MUL ayant des antécédents de péricardiectomie. Les dimensions cardiaques chez les patients atteints de MUL étaient similaires à celles observées chez les sujets témoins après les ajustements en fonction de la taille corporelle, à l’exception des volumes biventriculaires, qui étaient plus petits. Conclusions: Le MUL entraîne une dysfonction diastolique significative liée à la constriction et une légère dysfonction systolique bilatérale. Les évaluations axées sur la constriction et la restriction effectuées au cours du suivi pourraient être utiles pour la prise de décisions concernant le recours à la péricardiectomie dans les cas de MUL. Les anomalies myocardiques étaient fréquentes chez les patients atteints de MUL qui avaient subi une péricardiectomie et concordent avec la progression de la myocardiopathie dans une proportion significative de cas.

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Introduction Low physical activity is a well-recognized problem in pediatric solid organ transplant recipients; however, little is known about the differences between transplant groups. Physical performance testing was performed in a cohort of pediatric kidney, liver, and heart transplant recipients. Methods Fifty-one patients (54.9% boys), including 17 liver, 20 kidney, 2 combined liver-kidney, and 12 heart transplant recipients, were tested at the median age of 11.5 (7.5-14.9) years. The results were compared with a control group, which consisted of 425 healthy schoolchildren. The physical performance test included six different tests of endurance, strength, flexibility, and speed. Results The transplant recipients performed worse on most tests when compared with the control subjects (leg-lift test 42.0 vs. 44.9 repetitions, p = .002; repeated squatting 21.6 vs. 23.9 repetitions, p < .001; sit-up test 9 vs. 17 vs. 9 repetitions, p < .001, back extension 20 vs. 35 repetitions, p < .001; and shuttle run test 26.5 vs. 23.7 seconds, p < .001). None of the test results differed statistically significantly between the transplant groups. Conclusion The physical performance of pediatric solid organ transplant recipients is lower than that of their healthy peers but do not differ between different transplant groups. More systematic rehabilitation programs and follow-up are needed.

OBJECTIVES The aim of the study was to examine the frequency of rickets and bone fractures and to assess areal bone mineral density (aBMD) in childhood among patients with biliary atresia (BA). METHODS We gathered data on all patients diagnosed with BA in Finland that survived to ≥1 year of age between 1 January 2000 to 30 June 2018. Data on gestational age, birth weight, postsurgical medications, and history of rickets and bone fractures were collected retrospectively. Serum levels of 25-hydroxyvitamin D [25(OH)D] postportoenterostomy (PE) were collected. Plain radiographs and dual energy X-ray absorptiometry (DXA) measurements of study subjects were reviewed. RESULTS Out of 49 patients, 7 (14%) were diagnosed with rickets during infancy. Clearance of jaundice [odds ratio 0.055, 95% confidence interval [CI] 0.00266-0.393; P

Background Data on adult sexual functioning after kidney transplantation (KTx) during childhood or adolescence are scarce. Aim To assess the long-term sexual and psychosocial quality of life after pediatric KTx. Methods 29 young men (median age 27.1 years) were examined 18.7 years (median) after KTx. 56 age-matched healthy men (median age 30.0 years) served as controls. Outcome We studied the influence of sociodemographics, previous renal replacement therapy, current reproductive hormonal serum levels, testicular size, and data on several validated mental and physical questionnaires on participants' Derogatis Interview for Sexual Functioning self-report scores. Results The KTx recipients had significantly poorer sexual functioning than their healthy peers. KTx men had less frequent sexual activity with a partner (P = .03) and poorer orgasms (P = .002) than the controls but no erectile dysfunction (P = .5). Clinical implications Depressive symptoms, relationship status, and longer dialysis duration predicted poor adult sexual functioning in KTx recipients, whereas age at transplantation or at the time of the study did not. Strengths & Limitations This study contributes extended follow-up data to the very scarce literature on adult sexual functioning in pediatric KTx recipients. Relatively small population and low participation rate limit the comprehensive data interpretation in a population-based cohort of male KTx recipients. Conclusion Sexual functioning is often impaired in young men after pediatric KTx, emphasizing the need for long-term monitoring of sexual health and sexuality as important dimensions of quality of life.

Congenital nephrotic syndrome (CNS) was primarily considered one disease entity. Hence, one treatment protocol was proposed in the beginning to all CNS patients. Today, with the help of gene diagnostics, we know that CNS is a heterogeneous group of disorders and therefore, different treatment protocols are needed. The most important gene defects causing CNS areNPHS1,NPHS2,WT1,LAMB2, andPLCE1. Before active treatment, all infants with CNS died. It was stated already in the mid-1980s that intensive medical therapy followed by kidney transplantation (KTx) should be the choice of treatment for infants with severe CNS. In Finland, early aggressive treatment protocol was adopted from the USA and further developed for treatment of children with the Finnish type of CNS. The aim of this review is to state reasons for “early aggressive treatment” including daily albumin infusions, intensified nutrition, and timely bilateral nephrectomy followed by KTx at the age of 1–2 years.

Background Unexplained graft fibrosis and inflammation are common after pediatric liver transplantation (LT). Objective We investigated the graft expression of fibrogenic genes and correlated the findings with transplant histopathology and outcome. Methods Liver biopsies from 29 recipients were obtained at a median of 13.1 (IQR: 5.0-18.4) years after pediatric LT. Control samples were from six liver-healthy subjects. Hepatic expression of 40 fibrosis-related genes was correlated to histological findings: normal histology, fibrosis with no inflammation, and fibrosis with inflammation. Liver function was evaluated after a subsequent follow-up of 9.0 years (IQR: 8.0-9.4). Results Patients with fibrosis and no inflammation had significantly increased gene expression of profibrotic TGF-beta 3 (1.17 vs. 1.02 p = .005), CTGF (1.64 vs. 0.66 p = .014), PDGF-alpha (1.79 vs. 0.98 p = .049), PDGF -beta (0.99 vs. 0.76 p = .006), integrin-subunit-beta 1 (1.19 vs. 1.02 p = .045), alpha-SMA (1.12 vs. 0.58 p = .013), type I collagen (0.82 vs. 0.53 p = .005) and antifibrotic decorin (1.15 vs. 0.99 p = .045) compared to patients with normal histology. mRNA expression of VEGF A (0.84 vs. 1.06 p = .049) was lower. Only a few of the studied genes were upregulated in patients with both fibrosis and inflammation. The gene expression levels showed no association with later graft outcome. Conclusions Altered hepatic expression of fibrosis-related genes is associated with graft fibrosis without concurrent inflammation.

Background: The appearance of human leukocyte antigen (HLA) antibodies after solid organ transplantation predisposes recipients to graft dysfunction. In theory, vascular homografts, which are widely used in children with congenital heart defects, may cause allosensitization. Material/Methods: In this single-center retrospective study, the presence of pre-existing HLA antibodies in pediatric heart trans- plant (HTx) recipients with a vascular homograft was evaluated in a cohort of 12 patients. HLA antibodies were screened before and after HTx and positive screening results were confirmed and identified using the Luminex (R) single antigen bead method. Endomyocardial biopsies (EMB) and coronary angiography studies were re-evaluated to assess the prevalence of acute rejections and coronary artery change in these patients. Results: At the time of HTx, 8 patients (67%) had HLA antibodies detected by the Luminex assay, none of which were heart donor specific (DSA). All patients had negative leukocyte crossmatch. One patient developed DSAs against homograft donor prior to HTx. After the HTx, 5 patients (42%) developed DSAs against the heart donor and 4 patients (40%) against the homograft donor. In 2 patients (17%), the antibodies were against both heart and homograft donors. The rejection rate or prevalence of coronary artery vasculopathy did not differ significantly between the homograft cohort and our historical controls. Conclusions: Our results suggest that the prevalence of DSAs against homograft donor prior to HTx is relatively rare. However, almost half of the patients developed DSAs against homograft post-HTx. The clinical importance of these antibodies warrants further studies.

We investigated noninvasive follow‐up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin 11 µmol/L in the youngest tertile (AUROC, 0.91; P < 0.001), bile acids was >80 µmol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.

Background: Subclinical graft inflammation and fibrosis after pediatric liver transplantation (LT) are common. Biomarkers are needed that precede and are associated with these changes and graft outcome. Material/Methods: We evaluated immunohistochemical expression of 6 biomarkers [alpha-smooth muscle actin (alpha-SMA), collagen I, decorin, vimentin, P-selectin glycoprotein ligand-1 (PSGL-1), and CD34] in biopsies taken intraoperatively at LT (baseline) (n=29) and at 11.3 years after LT (first follow-up) (n=51). Liver biochemistry and graft histology were assessed at the first follow-up and at final assessment (19.6 years after LT) (n=48). Second follow-up biopsies for histology were available from 24 patients. The immunostainings were correlated with liver histology, biochemistry, and outcome at these time-points. Results: Baseline levels of the biomarkers were unrelated to presence of fibrosis at follow-up. Increased a-SMA, collagen I levels, decorin, and vimentin were associated with simultaneous fibrosis at the first follow-up (p=0.001-0.027). Increased SMA, collagen I, decorin, vimentin, PSGL-1, and CD34 expression at first follow-up were associated with simultaneous portal inflammation (p=0.001-0.025). alpha-SMA, decorin, and vimentin expression were increased in patients without fibrosis at the first follow-up but who developed fibrosis in second follow-up (p=0.014 p=0.024 and p=0.024). Significant fibrosis (F2) and markedly increased alpha-SMA, collagen I, decorin, and vimentin levels at first follow-up were associated with suboptimal liver status at the final assessment (p=0.002-0.042). Conclusions: The expression of the biomarkers at LT was unrelated to later development of graft fibrosis. alpha-SMA, decorin, and vimentin were associated with later graft fibrosis and suboptimal liver status.

Background Hemolytic uremic syndrome (HUS) is a multisystemic disease. In a nationwide study, we characterized the incidence, clinical course, and prognosis of HUS caused by Shiga toxin (Stx)–producing Escherichia coli (STEC) strains with emphasis on risk factors, disease severity, and long-term outcome. Methods The data on pediatric HUS patients from 2000 to 2016 were collected from the medical records. STEC isolates from fecal cultures of HUS and non-HUS patients were collected from the same time period and characterized by whole genome sequencing analysis. Results Fifty-eight out of 262 culture-positive cases developed verified (n = 58, 22%) STEC-HUS. Another 29 cases had probable STEC-HUS, the annual incidence of STEC-HUS being 0.5 per 100,000 children. Eleven different serogroups were detected, O157 being the most common (n = 37, 66%). Age under 3 years (OR 2.4), stx2 (OR 9.7), and stx2a (OR 16.6) were found to be risk factors for HUS. Fifty-five patients (63%) needed dialysis. Twenty-nine patients (33%) developed major neurological symptoms. Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up. Age under 3 years, leukocyte count over 20 × 109/L, and need for dialysis were predictive factors for poor renal outcome. Conclusions Age under 3 years, stx2, and stx2a were risk factors for HUS in STEC-positive children. However, serogroup or stx types did not predict the renal outcome or major CNS symptoms.

Background In Henoch–Schönlein nephritis (HSN), a risk factor for unfavorable outcome is prolonged proteinuria, but the value of renal biopsies in prognosis assessment is debatable. Methods We evaluated serial renal biopsies from 26 HSN patients. Follow-up biopsy occurred at median 2.1 years after diagnostic biopsy. Patients formed two groups at the follow-up biopsy: patients without proteinuria (group I; n = 11) and with proteinuria (group II; n = 15). Biopsies underwent evaluation according to three classifications: International Study of Kidney Disease in Children (ISKDC), Oxford (MEST-C), and semiquantitative classification (SQC) including an activity and chronicity score. Analysis also included expression of pro-fibrotic (alpha-smooth muscle actin and vimentin) and inflammatory (P-selectin glycoprotein ligand-1) molecules in the diagnostic biopsy specimens. Definition of unfavorable outcome was active renal disease or reduced renal function at last follow-up. Results Between the biopsies, SQC chronicity score increased in 22 (85%) patients, whereas activity score and ISKDC grade decreased in 21 (81%) and 17 (65%), respectively. Of the MEST-C parameters, endocapillary proliferation (from 83 to 13%; p < 0.001) and crescents (from 63 to 25%; p = 0.022) showed significant reduction, and segmental glomerulosclerosis (from 38 to 79%; p = 0.006) significant increment. These changes occurred similarly in groups I and II. Expression of the pro-fibrotic and inflammatory molecules showed no clinically significant differences between groups I and II. None in group I and five (33%) patients in group II had unfavorable outcome (p = 0.053). Conclusions Our results suggest that follow-up biopsies provide limited additional information to clinical symptoms in HSN outcome prediction.

Background Mulibrey nanism (MUL) is a rare growth restriction disorder with multiple organ manifestations caused by genetic defects affecting the TRIM37 protein. A perimyocardial heart disease is the most serious manifestation. Many MUL children appear to suffer from airway obstruction related to infection or exercise, prompting use of inhaled therapies. Asthma medication is continued up to adolescence or even to adulthood due to persisting of symptoms. The pulmonary pathophysiology has previously not been evaluated in any MUL cohort. Methods Thirty three finnish MUL patients (median age 20 years) were investigated with several lung function tests: spirometry with bronchodilatation test, single-breath diffusing capacity for carbon monoxide, single-breath lung volume measurements with helium dilution, and thoracic gas volume, airway resistance and specific conductance measurements with a body plethysmograph. As MUL typically affects body proportions, all variables were compared with reference values and with predicted values calculated from sitting height. Results Total lung capacity and forced vital capacity were markedly reduced (total lung capacity [TLC] and forced vital capacity [FVC], P = 12% and >= 200 mL) was found only in one patient. Conclusion MUL patients typically have volume restriction of the lungs, but function of the pulmonary tissue remains intact. Evidence of asthma in lung function testing at adult age is rare.

Over the past 30 years, there has been an improvement in both patient and graft survival after pediatric renal transplantation (RTX). Despite this success, these patients still carry an elevated risk for untimely death, partly through premature aging of the vasculature. The aim of this study was thus to investigate the long-term outcome of individuals with RTX in childhood, as well as to explore the cardiovascular health of these adults more than a decade later. We studied 131 individuals who had undergone a RTX between the years 1979 and 2005. Furthermore, left ventricular hypertrophy (LVH), coronary artery calcifications (CAC), and related metabolic factors were investigated in a cross-sectional study including 52 individuals as part of the initial cohort. The mortality rate (n = 131) was 12.2%. The median estimated graft survival was 17.5 years (95% CI 13.6-21.3), being significantly better in children transplanted below the age of 5 years (18.6 vs. 14.3 years, P

Although liver disease is a major complication of parenteral nutrition (PN) for intestinal failure (IF), its pathogenesis remains unclear. We investigated potential molecular mechanisms of liver injury in pediatric onset IF.Liver expression of canalicular phospholipid (ABCB4), bile acid (ABCB11), and sterol (ABCG5/8) transporters, their upstream regulators LXR and FXR as well as pro-inflammatory cytokines interleukin-6 (IL6) and tumor necrosis factor (TNF) were investigated among patients with IF [age median 3.8 (IQR 1.2 to 11)] in relation to biochemical and histologic liver injury, PN, serum plant sterols, fibroblast growth factor 19, and α-tocopherol.Patients receiving PN currently (n = 18) showed more advanced liver injury than patients after weaning off PN (n = 30). Histologic portal inflammation strongly segregated PN-dependent (44%) from weaned off patients (3%, P = 0.001) and coupled with progression of cholestasis and liver fibrosis. Patients with portal inflammation demonstrated markedly induced liver RNA expression of IL6 and TNF, repression of FXR and its canalicular bile transporter target gene RNA expression, including ABCB4 and ABCB11 as well as decreased protein expression of ABCB11 and ABCB4. Furthermore, upregulation of LXR and ABCG5/8 RNA expression was suppressed in patients with portal inflammation. Current PN, increased serum levels of plant sterols stigmasterol, avenasterol, and sitosterol along with serum citrulline, a marker of enterocyte mass, predicted portal inflammation.In pediatric onset IF, current PN delivery synergistically with intestinal compromise promote liver inflammation, which associates with progression of biochemical and histologic liver injury, while reducing expression of canalicular bile transporters.

OBJECTIVES The aim of the study was to evaluate health-related quality of life (HRQoL) and parental distress in a national cohort of children with biliary atresia (BA) with their native livers in relation to BA complications and HRQoL of normal population controls. METHODS We invited all Finnish children with BA surviving with their native livers at age 2 to 18 years to participate in 2009 and in 2014. Parents filled the Pediatric Quality of Life Inventory (PedsQL) proxy questionnaire, a survey of their child's health and evaluated parental distress on a visual-analog scale from 0 to 7. Overall participation rates were 80% (12/15) for the longitudinal and 83% (20/24) for the cross-sectional assessment. A control population of 324 children matched for age and sex was randomly picked, and 108 (33%) participated. RESULTS Overall, patients and controls had comparable HRQoL. Patients reported significantly lower scores for school functioning (P = 0.004) as depicted by missing school or day care due to hospital visits. Eighty-five percent of parents reported extreme worry (7.0) when hearing their child's BA diagnosis. At 6 years after diagnosis, parents reported significantly less worry: median score 3.8 (interquartile range 3.0-5.4, P

Background Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Methods Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Results Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman's space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation, a-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2-51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Conclusions Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.

Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross-sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age-appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients' clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10-fold, both p

Aim The human leukocyte antigen (HLA) allele and haplotype frequencies of the Finnish population are unique because of the restricted and homogenous gene population. There are no published data on HLA genotype associations in paediatric autoimmune liver diseases in Scandinavia. This study characterised the HLA genotypes of children with autoimmune liver or biliary disease in Finland. Methods The study cohort comprised 19 paediatric patients (13 female) aged 3-15 years treated for autoimmune liver or biliary disease at the Children's Hospital, Helsinki University Hospital, between 2000 and 2011 and followed up for 4.3 to 14.6 years. We genotyped HLA-B and HLA-DRB1 in the children and the HLA antigen frequencies were compared with 19,807 records from the Finnish Bone Marrow Donor Registry. Results All paediatric patients with autoimmune liver or biliary disease had either autoimmune HLA haplotype B*08;DRB1*03 or DRB1*13. These were significantly more common among patients with autoimmune hepatitis, primary sclerosing cholangitis and autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome than the Finnish control population. HLA RB1*04 was not found in the study cohort. Conclusion Our study found that B*08, DRB1*03 and DRB1*13 were significantly associated with autoimmune liver and biliary diseases in Finnish paediatric patients. This article is protected by copyright. All rights reserved.

BKPyV is widely recognized in KTRs, but little is known about rates of primary and secondary JCPyV exposure in pediatric KTRs. We evaluated JCPyV exposure in pediatric KTRs using antibody responses in the first 12 months post-transplant. Of 46 children transplanted between 2009 and 2014, 6 lacked any samples for serologic testing, leaving 40 KTRs for study. JCPyV-specific IgG and IgM antibodies were measured using a normalized VLP ELISA. Significant JCPyV exposure was defined as IgG seroconversion, increasing IgG levels of >0.5 nOD units, or IgM detection. Of 40 recipients (median age 3.2 years), 11 (27.5%) were seropositive, 20 (50%) seronegative for JCPyV-IgG, while 9 (22.5%) had no specimen at the time of transplantation, but were confirmed as seronegative in post-transplant samples. Of 29 (72.5%) at risk, JCPyV-IgG seroconversion occurred in 15/29 (51.7%) including JCPyV-IgM in 6 patients (20.7%). Two patients (6.9%) developed only JCPyV-IgM. Among JCPyV-IgG-positive KTRs, six (12.5%) had significant IgG increases. Altogether 23 of 40 patients (57.5%) had serological evidence of primary or secondary JCPyV exposure. In these patients, kidney function tended to be lower during the 2 years of follow-up, but only one patient lost the graft due to JCPyV nephropathy. Thus, JCPyV exposure is common in pediatric KTR and may present serologically as primary or secondary infection. Although only one case of JC-PyVAN occurred, a trend toward lower renal function was seen. Dedicated studies of larger cohorts are warranted to define impact of JCPyV in pediatric KTR.

Pathogenesis of progressive liver fibrosis in biliary atresia after successful portoenterostomy remains unclear. We related hepatic expression of transforming growth factor beta (TGF-β) superfamily cytokines to histologic liver injury after successful portoenterostomy.Enrolled in our study were 28 patients with biliary atresia who had liver biopsies obtained during and after successful portoenterostomy, which normalized serum bilirubin (20 µmol/l). Biopsies were evaluated for cholestasis, inflammation, ductal reaction, and fibrosis and were stained immunohistochemically for transforming growth factor beta 1, transforming growth factor beta 2, connective tissue growth factor, and decorin. Respective gene expression (TGFB1, TGFB2, TGFB3, CTGF, DCN) was analyzed at follow-up using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results were compared with fibrotic and healthy control livers.After median follow-up of 3.0 years, histologic cholestasis resolved, whereas fibrosis had progressed only in isolated biliary atresia. Liver protein expression of transforming growth factor beta 1 and connective tissue growth factor (P.001 for both), but not that of transforming growth factor beta 2 or decorin, decreased after successful portoenterostomy, although expression of all four cytokines remained elevated. In accordance with postportoenterostomy changes in protein expression, follow-up ribonucleic acid expression of TGFB2 and DCN, but not that of TGFB1 and CTGF, was upregulated when compared with the controls. Both protein and gene expression of transforming growth factor beta 1 and protein expression of transforming growth factor beta 2, connective tissue growth factor and decorin correlated with METAVIR fibrosis stage. Syndromic patients (n = 12) showed milder fibrosis and lower transforming growth factor beta 1 expression than patients with isolated biliary atresia.These findings support a central role of transforming growth factor beta superfamily in mediating continuing liver fibrogenesis after successful portoenterostomy. Transforming growth factor beta pathway cytokines responded divergently to clearance of jaundice, which was reflected by differential progression of fibrosis between syndromic and isolated patients.

We addressed growth of biliary atresia (BA) patients living with native livers between ages 0–6 and effects of post-surgical corticosteroid treatment on growth. Growth charts of 28 BA patients born in Finland between 1987 and 2017 were retrospectively evaluated. Dosage and length of corticosteroid treatment and hydrocortisone substitution were reviewed. At birth, BA patients were shorter (median height − 0.6 (interquartile range (IQR) − 1.3 to − 0.1) SDS, n = 28, P 50 mg/kg) cumulative prednisolone dosage has a negative transitory impact on height gain after portoenterostomy

Aim: We herein describe the establishment of the Helsinki Vascularized Composite Allotransplantation (VCA) program and its execution in the first two face transplant cases. Methods & patients: The Helsinki VCA program initially required the fulfillment of legal, hospital, financial, and ethical requirements. Thereafter, the assembling of a multidisciplinary team commenced. A team of Plastic, maxillofacial and ENT surgeons comprise the facial VCA team. The protocol involves collaboration with the Solid Organ Transplant (SOT) team, transplant immunology, immunosuppression, microbiology, psychiatric evaluation, well-defined VCA indications and informed consent. Between 2011 and 2017 two patients were selected for transplantation. Both patients had a severe composite facial deformity involving the maxilla and mandible following earlier ballistic injury. Results: Patient 1 was a 35 year-old male who underwent successful near total face transplantation in February 2016 and at 30 months he has a good aesthetic outcome with symmetrical restoration of the central face and good sensory and symmetrical motor functional outcomes. Patient 2 was a 58 year-old male who underwent full face transplantation in March 2018 and at 5 months he has recovered without major problems. Conclusion: A successful facial VCA program requires a well-prepared research protocol, experts from multiple specialties and careful patient selection. The establishment of the Helsinki VCA program required long and thorough planning and resulted in the first two Nordic face transplantation cases. This protocol now forms the platform (as a proof of concept) for other types of vascularized composite allotransplantations. (C) 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Background. Intestinal failure is associated frequently with liver injury, which persists after weaning off parenteral nutrition. We compared features of liver remodeling in intestinal failure during and after weaning off parenteral nutrition. Methods. Liver biopsies and serum samples were obtained from 25 intestinal failure patients at a median age of 9.7 years (interquartile range: 4.6-18) and from age-matched control patients. Seven patients had been receiving parenteral nutrition for 53 months (22-160), and 18 patients had been weaned off parenteral nutrition 6.3 years (2.4-17) earlier, after having received parenteral nutrition for 10 months (3.3-34). Expression of alpha smooth muscle actin, collagen 1, proinflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) was measured. Results. Significant increases in immunohistochemical expression of alpha-smooth muscle actin and collagen 1 were observed predominantly in portal areas and were similar to increases seen in patients currently receiving parenteral nutrition and in patients weaned off parenteral nutrition. Gene and protein expressions of alpha-smooth muscle actin and collagen were interrelated. Gene expression of ACTA2, encoding alpha-smooth muscle actin, was increased only in patients who were receiving parenteral nutrition currently. Comparable upregulation of interleukin-1 (alpha and beta), epidermal growth factor, integrin-beta 6, and MMP9 gene expression was observed in both patient groups, irrespective of whether they were receiving parenteral nutrition currently. Liver expression and serum levels of TIMP1 and MMP7 were increased only in the patients on parenteral nutrition currently but were not increased after weaning off parenteral nutrition. Conclusion. Intestinal failure is characterized by abnormal activation of hepatic myofibroblast and accumulation of collagen both during and after weaning off parenteral nutrition. Persistent transcriptional upregulation of proinflammatory and fibrogenic cytokines after weaning off parenteral nutrition suggests that factors other than parenteral nutrition may contribute to intestinal failure associated liver disease.

Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by Cr-51-EDTA clearance. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (> 1 mg/L) and ESR (> 25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p

Background Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS. Methods We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease. We carried out a whole genome sequencing in two affected and two healthy family members. The function of found podocin variant was studied using co-immunoprecipitation and immunohistochemistry. Podocyte gene sequences were analyzed in a cohort of Finnish non-familial SRNS patients. Results A heterozygous de novo deletion, c. 988_989delCT in NPHS2, was found in all affected family members and in none of their healthy relatives, non-familial patients or controls. No other SRNS-related gene variant, coding or non-coding co-segregated with the disease phenotype in the family. While the truncated podocin remained able to bind nephrin, the expression of nephrin was fragmented and podocin expression reduced. The gene analysis of the non-familial SRNS patients revealed few variants. Conclusion The role of podocin variants in nephrotic syndrome may be more varied than previously thought.

OBJECTIVES: We studied the long-term survival and rejection episodes of paediatric heart transplant recipients. METHODS: We included all paediatric patients (≤18 years) who underwent heart transplantation during 1991–2014 in Finland. Data were obtained retrospectively from a paediatric cardiac surgery database. Patient status was received from the Finnish population registry. All patients underwent yearly routine postoperative endomyocardial biopsies and coronary angiographies. RESULTS: Between 1991 and 2014, 68 heart transplantations were performed. The early mortality (

The aim of this population-based observational case-control questionnaire study was to investigate the possible role of environmental risk factors associated with pediatric-onset autoimmune liver diseases.Seventy-one patients with autoimmune liver diseases (16 years) received a questionnaire with 22 items, evaluating contact with environmental factors (eg, family manners, type of housing, pets) before the diagnosis. Two age- and sex-matched control groups were used: inflammatory bowel disease (IBD; n = 91) and healthy subjects (n = 716; matched also for place of residence at birth). Univariate analysis (odds ratio [OR] and 95% confidence interval) for all variables was calculated. Fisher exact test was performed to depict associations between variables and the multivariate logistic regression to test their interactions.In the final analyses, the responses of 51 autoimmune liver diseases cases (n = 51/71, 72%), 59 IBD controls (n = 59/91, 65%), and 292 healthy controls (n = 292/716, 41%) were investigated. In univariate analysis only having a cat, a dog, and a cat or a dog were risk factors of autoimmune liver diseases (OR varying between 2.6-3.4); no other significant associations (eg, place of residence, number of siblings, family manners) were found. Multivariate logistic regression analyses showed that especially living with a cat in block of flats was a risk factor (OR 3.6, 1.2-10.8).Living in a close contact with a pet (especially a cat) was a risk factor of autoimmune liver diseases. This finding may suggest an involvement of an unidentified agent (ie, toxin/microbe) among the triggers of these diseases.

The NPRTSG has collected data on pediatric KTx since 1994. The registry archives information from all centers that perform pediatric KTx in Denmark, Finland, Norway, and Sweden and has 100% coverage. The first NPRTSG report was published in 1998 and was based on data collected in the 1982─1996 period. The present report provides data on 602 pediatric KTx in the Nordic countries from 1997 to 2012. Comparison of the patient demographics and one- and three-yr graft survivals between the two time cohorts revealed no significant change in the recipient and donor demographics. The number of transplantations increased by approximately 30%, doubling the recipients below the age of two yr. The use of Tac and mycophenolate as primary immunosuppression increased from practically 0% to 50% and 40%, respectively. The one- and three-yr graft survivals improved significantly (p < 0.001), especially among the youngest recipients with transplant from DD. In these patients, the one-yr survival improved from 70% to 94.6% and the three-yr graft survival from 60% to 94.6%, respectively. The improved graft survival may be at least partly due to changes in immunosuppression strategies, but also greater experience may also be of importance.

Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37−/−) model for MUL. Trim37−/− mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37−/− mice as compared with wild-type. Both male and female Trim37−/− mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37−/− mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37−/− mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37−/− mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37−/− mice. The most consistently seen phenotypes in Trim37−/− mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37−/− mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis., Summary: A congenic Trim37-deficient mouse model recapitulates several features of the human disorder Mulibrey nanism, and thus provides a good model to study disease pathogenesis related to TRIM37 deficiency.

Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.

Cancer after liver transplantation (LT) constitutes a threat also for young recipients, but cancer risk factors are usually absent in children and large studies on the cancer risk profile in young LT recipients are scarce. Data of patients younger than 30 years who underwent LT during the period 1982-2013 in the Nordic countries were linked with respective national cancer registries to calculate standardized incidence ratios (SIRs). A total of 37 cancer cases were observed in 923 patients with 7846 person-years of follow-up. The SIR for all cancer types, compared with the matched general population, was 9.8 (12.4 for males and 7.8 for females). Cumulative incidence of cancer adjusted for the competing risk of death was 2% at 10 years, 6% at 20 years, and 22% at 25 years after LT. Non-Hodgkin lymphoma was the most common cancer type (n = 14) followed by colorectal (n = 4) and hepatocellular cancer (n = 4). Age was a significant risk factor for cancer, and the absolute risk of most cancers (except for lymphoma) increased considerably in young adults older than 20 years. The cancer risk pattern is different in pediatric and young LT patients compared with adult recipients. The striking increase in cancer incidence in young adulthood after the second decade of life deserves further consideration in transition programs.

BACKGROUND: Different treatment policies can influence biliary atresia outcomes, but the pathophysiology of expanding fibrosis occurring even after successful portoenterostomy remains unclear. STUDY DESIGN: Clearance of jaundice (COJ) (bilirubin

While the majority of kidney transplantations in Finland have been traditionally performed from deceased donors, the frequency of living donors should be increased. Kidney donation is a safe procedure for a carefully examined donor, and for the recipient living donation enables elective surgery and preemptive transplantation. Potential risks for the donor must be minimized, but according to current recommendations, mild hypertension or obesity are not absolute contraindications for donation. Guidelines for donor selection and examination have been updated to simplify the process for all parties. Legislation in Finland requires changes to optimize the use of all potential living donors.

BACKGROUND Heart surgery requiring cardiopulmonary bypass (CPB) causes an inflammatory response which may further induce acute kidney injury (AKI). In the present randomized controlled study we evaluated whether corticosteroids can prevent CPB related AKI in neonates undergoing heart surgery. METHODS Forty neonates were randomized to receive 2 mg/kg methylprednisolone followed by hydrocortisone infusion 0.2 mg/kg/h perioperatively with tapering doses for 5 days, or placebo administered in a similar fashion. The primary outcome was the inflammatory response (plasma concentrations of interleukins 6 and 10). The correspondence of the interleukin concentrations with AKI was analysed as secondary outcome. In addition, plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin C, and urine kidney injury molecule-1 (KIM-1) levels were measured. RESULTS Six patients (15%) developed post-operative AKI. No significant difference in the AKI occurrence between the treatment (n = 2) and the placebo (n = 4) groups could be found (risk ratio 2.00, 95% confidence interval 0.41-9.71; P = .661) despite significant reduction in inflammatory response in the treatment group. One patient in the treatment group and two patients in the placebo group required acute peritoneal dialysis. Plasma creatinine and cystatin C or urine NGAL and KIM-1 concentrations did not differ between the treatment and the placebo group. CONCLUSIONS Significantly reduced inflammatory reaction induced by corticosteroid treatment in neonates undergoing cardiac surgery did not reduce the incidence of AKI defined by KDIGO classification or decrease the rise of AKI biomarkers.

BackgroundNeonatal autosomal-recessive polycystic kidney disease (ARPKD) is associated with pulmonary hypoplasia and severe respiratory distress. There is no published information on long-term lung function in ARPKD survivors.MethodsPulmonary function tests, including spirometry and diffusion capacity, were performed in a nationwide cohort of Finnish paediatric patients with ARPKD. The annual incidence of respiratory infections and the need for permanent asthma medication were also evaluated in this population.ResultsPulmonary function in 11 children surviving the neonatal period was good when measured after a median follow-up time of 10.4 years (range 5.4–16.1 years). None of the patients required oxygen supplementation, and only one patient had asthma. Patients who had received ventilator therapy during infancy had significantly lower maximal instantaneous forced expiratory flow (MEF%) (66%; 43–93% vs 105%; 63–110%; p=0.048) and forced expiratory volume/forced vital capacity (0.76; 0.7–0.81 vs 0.89; 0.77–0.91; p=0.03) than patients without a history of mechanical ventilation, suggesting tendency for airway obstruction in the former group of patients. The frequency of respiratory infections did not differ from Finnish paediatric population in general.ConclusionsThe results of pulmonary function tests were within reference values for most patients with ARPKD, which suggested good long-term lung prognosis. Lung function tests should be considered for patients with ARPKD with a history of mechanical ventilation during infancy.

Renal transplantation (RTx) has become an accepted mode of therapy in infants with severe renal failure. The major indications are structural abnormalities of the urinary tract, congenital nephrotic syndrome, polycystic diseases, and neonatal kidney injury. Assessment of these infants needs expertise and time as well as active treatment before RTx to ensure optimal growth and development, and to avoid complications that could lead to permanent neurological defects. RTx can be performed already in infants weighing around 5 kg, but most operations occur in infants with a weight of 10 kg or more. Perioperative management focuses on adequate perfusion of the allograft and avoidance of thrombotic and other surgical complications. Important long-term issues include rejections, infections, graft function, growth, bone health, metabolic problems, neurocognitive development, adherence to medication, pubertal maturation, and quality of life. The overall outcome of infant RTx has dramatically improved, with long-term patient and graft survivals of over 90 and 80 %, respectively.

A 15-year-old boy with a posterior urethral valve received a deceased donor kidney transplant (KT) in March 2011. Basiliximab induction followed by tacrolimus-based triple medication was used as immunosuppression. Eleven months after KT, the graft function deteriorated and the biopsy demonstrated interstitial nephritis suggestive of acute rejection. BK polyomavirus (BKPyV) surveillance in urine and plasma was negative. The patient received methylprednisolone pulses and anti-thymocyte globulin. Immunohistochemistry was positive for simian virus 40 (SV40) large T-antigen (LTag) in the biopsies, and quantitative polymerase chain reaction for JC polyomavirus (JCPyV) indicated high viral loads in urine and borderline levels in plasma. Immunosuppression was reduced and follow-up biopsies showed tubular atrophy and interstitial fibrosis. Two years after KT, antibody-mediated rejection resulted in graft loss and return to hemodialysis. Retrospective serologic work-up indicated a primary JCPyV infection with seroconversion first for IgM, followed by IgG, but no indication of BKPyV infection. In the SV40 LTag positive biopsies, JCPyV deoxyribonucleic acid (DNA) with archetype noncoding control region was detected, while BKPyV DNA was undetectable. To the best of our knowledge, this is the first reported case of primary JCPyV infection as the cause of PyV-associated nephropathy in KT.

Summary Data about health-related quality of life (HRQOL) in adult recipients after pediatric kidney transplantation (KTx) are scarce. In this nationwide questionnaire-based study, HRQOL and social status in young adult men having undergone KTx during childhood (n = 29) were studied and compared to age- and gender-matched healthy controls (n = 56) and survivors of childhood acute lymphoblastic leukemia (n = 52) comprising controls with another chronic disease of childhood. Altogether 41% of the KTx recipients, 50% of the leukemia survivors and 80% of the healthy controls lived in a permanent relationship. When compared with leukemia survivors, the KTx recipients reported significantly more bodily pain and worse general health (RAND-36). Older age at time of study, longer duration of dialysis, multiple transplantations and diminished graft function correlated with lower scores. The KTx recipients had a significantly higher mean Beck Depression Inventory (BDI) score than the leukemia survivors (P = 0.000) or the healthy controls (P = 0.006). BDI scores were highest in patients who lived without a partner or children had lower educational level or were unemployed. KTx recipients had significantly lower HRQOL scores than their healthy and controls with childhood chronic disease. Early detection of psychosocial problems and poor physical functioning among these patients is warranted.

Background. In biliary atresia mechanisms of progressive liver injury leading to need of liver transplantation after successful portoenterostomy remain unknown. A better understanding is a prerequisite for development of novel therapies to extend native liver survival, and we aimed to unravel molecular characteristics of liver injury after successful portoenterostomy. Methods. Liver biopsies obtained from 28 biliary atresia children during successful portoenterostomy and at median age 3.0 years were studied. Biopsies were analyzed for histology and immunohistochemical expression of collagen 1, myofibroblast marker alpha-smooth muscle actin, and cytokeratin-7 positive ductal reactions. Hepatic ribonucleic acid (RNA) expression of growth factors and inflammatory cytokines was evaluated. Intestinal failure patients with comparable liver fibrosis and nonfibrotic gallstone patients and donor livers were controls. Results. After successful portoenterostomy, histologic cholestasis resolved and portal inflammation reduced, while fibrosis along with ductal reactions and overexpression of collagen and alpha-smooth muscle actin persisted. At follow-up, liver RNA expression of collagen and platelet-derived growth factor was increased, whereas RNA expression of various inflammatory cytokines remained low. Disappearance of periductal alpha-smooth muscle actin expression after successful portoenterostomy (36% of patients) associated with contracted ductal reactions and reduced progression of fibrosis, collagen accumulation, platelet-derived growth factor RNA expression, and serum levels of bile acids and bilirubin. Fibrosis progressed less rapidly in syndromic than in isolated biliary atresia patients. Conclusion. These findings suggest that instead of inflammation, molecular signature of active fibrogenesis in association with ductal reactions prevails in long-term native liver survivors with biliary atresia. Patients should be stratified for isolated and syndromic disease forms in interventional studies.