Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries.

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 µmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

HLA associations with tubulointerstitial nephritis with or without uveitis in Finnish pediatric population: a nation-wide study.

The human leukocyte antigen (HLA) genotype has been shown to associate with tubulointerstitial nephritis (TIN) and tubulointerstitial nephritis with uveitis syndrome (TINU). The association of HLA genes with TIN was examined in this nation-wide study. HLA genotyping was performed in 31 pediatric patients with biopsy-proven TIN. All patients were examined by an ophthalmologist to diagnose possible uveitis. Class II HLA genotypes of TIN patients were compared with the Finnish reference population. We found a significant association between the HLA alleles DQA1*04:01 [risk ratio (RR) 5.0, 95% confidence interval (CI) 2.0-11.2], DQB1*04:02 (RR 2.7, 95% CI 1.4-5.3), and DRB1*08 (RR 3.8, 95% CI 1.5-8.4) and TIN. Uveitis was found in 20/31 (64.5%) patients. HLA genotyping of the TINU patients showed additional risk HLA alleles: DQA1*01:04 (RR 6.1, 95% CI 1.5-17.8), and DRB1*14 (RR 8.2, 95% CI 2.2-22.1). The alleles DQA1*01:04 (RR 8.8, 95% CI 2.2-26.5), DQA1*04:01 (RR 3.2, 95% CI 1.2-7.3), and DRB1*14 (RR 12.0, 95% CI 3.2-33.0) were more frequent in patients with TIN and chronic uveitis than in reference population. The HLA class II haplotype DQA1*04:01/DQB1:04:02/DRB1*08 was the most common combination in our study population (58.1%). None of the patients had haplotype DQA1*04:01/DQB1*06:02/DRB1*15, which is common in Finland. HLA genotype did not predict the renal outcome. We found a strong association between certain HLA genotypes both in TIN and TINU patients. The TIN/TINU-associated HLA alleles appear to vary depending on study population.

Recombinant human growth hormone improves growth in children receiving glucocorticoid treatment after liver transplantation.

Linear growth is often impaired after successful liver transplantation. The cause is multifactorial; poor graft function and long term glucocorticoid treatment are the main factors responsible. The efficacy and safety of recombinant human GH (rhGH) treatment were assessed in eight growth-retarded children (five boys and three girls) with liver transplants. Immunosuppression comprised azathioprine, cyclosporin, and methylprednisolone. rhGH was administered in a dose of 1 IU/kg x week, given by daily sc injections. The median age at the start of treatment was 9.7 yr (range, 5.9-14.9 yr). All but one of the patients remained prepubertal during treatment. The median growth rate increased from 3.2 to 7.l cm/yr (P = 0.025) and height SD score increased from -3.9 to -3.1 (P = 0.036) during the first year of rhGH treatment. Serum insulin-like growth factor I and insulin-like growth factor-binding protein-3 levels increased significantly during treatment. Graft function was normal in all except one patient, and no rejections or other serious side-effects were documented. In conclusion, rhGH treatment is effective in short, non-GH-deficient, liver-transplanted children receiving long term glucocorticoid treatment. Due to potential risk of allograft rejection, close monitoring of liver function and immunosuppression is required.

Need for riboflavin supplementation in small prematures fed with human milk.

It is the practice in Finland to feed small premature infants with human milk and with no riboflavin supplementation. In this study the riboflavin status was analyzed in 39 such premature infants, 19 with riboflavin supplementation (0.3 mg/day) and 20 without, in their mothers, and in breast-milk samples during a period of 12 wk after delivery. The mean gestational age of the infants was 30.1 wk and their birth weight 1,183 g. Stimulation of erythrocyte glutathione reductase by flavin-adenine-dinucleotide was used as the criterion for riboflavin status in the blood samples. At age 6 wk 47% of the infants without supplementation had activity coefficient values indicative of riboflavin deficiency. The riboflavin status of the infants receiving supplementation was better (p less than 0.01). The concentration of riboflavin in the human milk samples was dependent on the amount of riboflavin supplementation of the mothers during the period from two to twelve weeks after delivery (p less than 0.05-0.01). These data indicate that, in small premature infants the intake of riboflavin may be inadequate without supplementation during the first few weeks after birth.

Vitamin E supplementation in very-low-birth-weight infants: long-term follow-up at two different levels of vitamin E supplementation.

This study evaluates the need of vitamin E supplementation in very-low-birth-weight infants by long-term follow-up of plasma vitamin E status during the first 15 mo of life, with two different levels of supplementation. The subjects were 51 newborn infants with birth weights less than or equal to 1520 g. During hospitalization the infants were fed human milk. On the third day of life oral vitamin E supplementation of less than or equal to 10 mg/d was started in all infants. In addition, 23 infants selected at random were given intramuscular vitamin E (20 mg/kg/d) during the first 3 d. The data indicate that the 10 mg/d supplement resulted in an adequate plasma concentration of vitamin E. After cessation of supplementation at age 3 mo, the risk of low plasma vitamin E levels increased. Although intramuscular administration resulted in long-lasting increments in mean plasma vitamin E values, some later levels in these infants were marginal.

Kidney function after 1:1 conversion to the cyclosporine microemulsion formulation in children with liver allografts.

BACKGROUND: One-to-one (mg:mg) conversion from the conventional to the microemulsion formulation of cyclosporine (CsA) is advocated as a simple way to use the new therapeutic regimen. However, the potentially harmful effects of the conversion on kidney function in nonrenal transplant recipients are poorly known. METHODS: Renal effects of the conversion were prospectively investigated in 22 pediatric liver transplant recipients (mean age, 8.4 years; mean time from transplantation, 3.2 years). Patients were followed for 12 months. Pharmacokinetic studies were performed at baseline and 5 days and 6 and 12 months after conversion. RESULTS: Peak concentration, minimum concentration, average steady state concentration, and area under the concentration-versus-time curve increased by 60-130% after conversion. Graft losses, progressive deterioration of graft function, and acute rejection episodes did not occur. The mean glomerular filtration rate (GFR) was 103 ml/min/1.73 m2 at baseline and 100 ml/min/1.73 m2 after 12 months. However, 6 of the 22 patients showed at least a 15% (range, 16-38%) decrease in GFR between baseline and 6 months (P<0.01). They had a significantly higher increase in average steady state concentration between baseline and 6 months than the six patients with the best outcome in GFR during the same time period (164 ng/ml vs. 53 ng/ml, P<0.05). At this point (6 months), target CsA trough levels were reduced by 20-30%, while the mean area under the concentration-versus-time curve remained above that obtained at baseline. The GFR of three of the six patients subsequently improved. CONCLUSIONS: One-to-one conversion can be performed safely in liver transplant recipients if strict follow-up is feasible.

Course of renal allograft histopathology after transplantation in early childhood.

BACKGROUND: We report a long-term prospective follow-up of renal allograft histology in children <5 years of age at transplantation (Tx). METHODS: Fifty-one kidney allograft recipients were prospectively followed for renal allograft histology and function up to 7 years after Tx. Twenty patients were recipients of kidneys from living related donors, and 31 were cadaveric kidney recipients. All patients received triple immunosuppression. Biopsies were analyzed according to the Banff classification and scored semiquantitatively. The "chronic allograft damage index" (CADI) was calculated. RESULTS: Five of seven grafts were lost because of nephrosis in patients with congenital nephrotic syndrome of the Finnish type. Most of the biopsies (52-69%) were considered normal (Banff classification), and the proportion with chronic allograft nephropathy did not increase with time. The median CADI score was 2.5 (scale: 0-36) at 1.5 years and 3.5 at 7 years. Recipients with an acute rejection episode had higher CADI scores than recipients without acute rejection episode. Patients with a high CADI score at 3 years had inferior graft function at 5 years. Recipients <2 years of age had CADI scores and numbers of acute rejection episode similar to recipients between 2 and 5 years of age. However, in contrast to the older recipients, the younger recipients did not improve their absolute glomerular filtration rate with time. CONCLUSIONS: The long-term histopathological findings were mostly mild and stable with time. Acute rejection episode had an impact on these changes and CADI predicted later graft function. Nonimmunological risk factors seem to be more important in the youngest recipients.

Graft function 5-7 years after renal transplantation in early childhood.

BACKGROUND: Low recipient age is still a risk factor for graft failure after kidney transplantation (Tx). Detailed prospective reports on long-term graft function in small children after renal Tx are still lacking. METHODS: Forty-nine kidney allograft recipients who received transplants before the age of 5 years were followed prospectively. The most common disease was congenital nephrotic syndrome of the Finnish type. Twenty patients were recipients of living related donors (LRD), and 29 were cadaveric kidney (CAD) recipients. All patients received triple immunosuppression. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), sodium, urate, and potassium handling, and concentrating capacity were studied for up to 7 years after Tx. RESULTS: Patient survival 7 years after Tx was 100% for LRD and 96% for CAD recipients. Graft survival was 94% for LRD and 79% for CAD recipients (P=NS) and 89% and 83% for children >2 years and <2 years of age at Tx, respectively (P=NS). Five years after Tx, GFR was 70 vs. 64 and ERPF was 380 vs. 310 ml/min/1.73 m2 for LRD and CAD recipients, respectively (P=NS). Mean absolute GFR remained stable. GFR was lower in children who received transplants at <2 years than in children who received transplants at >2 years of age, 54 vs. 75 ml/min/1.73 m2 (P=0.02). Sodium handling remained intact, but hyperuricemia was seen in 43-67%; 17-33% showed abnormal handling of potassium; and most patients had a subnormal concentrating capacity. CONCLUSIONS: Excellent long-term graft survival and good graft function can be achieved with triple immunosuppression, even in young CAD kidney recipients.

Recombinant human growth hormone treatment. Its effect on renal allograft function and histology.

Our objective was to investigate the effects of recombinant human growth hormone (rhGH) treatment on long-term renal allograft function and histopathology. RhGH is a potent therapy for poor growth after renal transplantation. However, rhGH has proinflammatory properties and may induce acute rejection or accelerate chronic rejection. Nine prepubertal rhGH-treated renal transplanted children and nine pair-matched controls were studied 18 (before the start of rhGH) and 36 months after transplantation (mean duration of rhGH-treatment 14 months). 51Cr-EDTA- and PAH-clearances were performed. A protocol renal biopsy was done at 36 months. Growth showed significant improvement during rhGH (P<0.01). One graft loss occurred in both groups. One acute rejection was seen in the control group. There was no difference in the rate pf change in 51Cr-EDTA-or PAH-clearance between the two groups. Histopathological findings were mostly mild. One new onset chronic rejection developed in both groups. Proximal tubular atrophy was more extensive in the rhGH-treated patients (P<0.05), but there was no uniform trend toward more severe findings. RhGH improved growth, and no significant differences were seen in allograft function or histopathology; however, larger trials controlled for pretreatment renal function and immunosuppression are needed.

Fine-needle aspiration biopsy allows early detection of acute rejection in children after renal transplantation.

UNLABELLED: analysis detected rejections often before clinical signs. Half of the patients had increased serum creatinine concentration and 38% had fever at the time of rejection diagnosis. Both signs were present in only 19% of the episodes. A decrease in urine output (>20%) was seen in a third of the episodes. The rejections responded well to oral methylprednisolone (3 mg/kg/day), and lymphoglobulins were needed in only 12% of the episodes. More than 90% of the rejections were completely reversible and no transplant was lost because of acute rejection. CONCLUSION: The results indicate that FNAB is a safe and sensitive method for the diagnosis and follow-up of acute cellular rejection in pediatric recipients of different ages.

Supplementation with human milk protein improves growth of small premature infants fed human milk.

We investigated the influence of human milk protein and medium-chain triglyceride supplementations of human milk feedings on the growth of very low birth weight infants during their first weeks of life. A group of 44 preterm infants with birth weights of less than 1,520 g and a mean gestational age of 30.3 weeks was randomly divided into four groups to receive plain human milk or human milk supplemented with human milk protein (0.9 g/dL), with medium-chain triglycerides (1 g/dL), or with both. The medium-chain triglyceride oil supplementation did not influence the growth of these infants. The infants given supplementary protein gained weight faster during weeks 4 to 6 than those without (18.5 +/- 0.7 v 15.1 +/- 0.6 g/kg/d; mean +/- SEM; P = .001). After 4 weeks of age the infants given supplementary protein had a mean weight gain equal to the mean intrauterine rate, in contrast to the infants of the other groups, who grew more slowly until age 6 weeks. Furthermore, we found a correlation between serum albumin concentration and weight gain during the seventh week of life (P = .018). The length growth velocity for the infants with protein supplementation was 0.99 +/- 0.06 cm/wk (mean +/- SEM) and for those without 0.83 +/- 0.05 cm/wk (P = .043). There was no difference in growth of head circumference between the groups. We conclude that human milk protein supplementation improves the growth of small premature infants fed human milk, and that the protein concentration of bank milk is insufficient for their adequate growth.

Human milk protein and medium-chain triglyceride oil supplementation of human milk: plasma amino acids in very low-birth-weight infants.

Fifty-one very low-birth-weight infants (birth weight less than 1,520 g) randomly fed either human milk or human milk supplemented with human milk protein and/or with medium-chain triglyceride (MCT) oil were observed. Plasma amino acids from these infants were studied at 2, 8, and 10 weeks. Medium-chain triglyceride oil supplementation had minimal or no influence on plasma amino acids. Human milk protein supplementation resulted in increased concentrations of all amino acids at all ages studied. The concentrations were 1.5- to threefold as compared with values in infants not given protein supplements. However, the concentrations of methionine, tyrosine, phenylalanine, and lysine remained far below values considered harmful. The age at which maximal plasma amino acid concentrations in infants given human milk protein supplementation occur coincides with the age of the lowest serum albumin concentrations in infants fed only human milk. This suggests that high plasma amino acid concentrations may hasten albumin synthesis in very low-birth-weight infants.

Congenital nephrotic syndrome.

Congenital nephrotic syndrome (CNS) can be caused by neonatal infections, renal diseases which exceptionally occur in early infancy and syndromes with a renal histology of DMS. The most common CNS is the Finnish-type (CNF), an autosomal recessively inherited disease characterized by intrauterine onset of massive proteinuria. The CNF gene has been localized to the long arm of chromosome 19, but the pathogenesis remains unclear. Forty-six CNF patients have been treated at our institution. The diagnosis was based on family history, severe proteinuria of intrauterine onset (serum albumin < 10 g/liter at presentation and urinary protein > 20 g/liter when serum albumin was corrected to > 15 g/liter), a large placenta (> 25% of birth wt), exclusion of other CNS-types and normal glomerular filtration rate during the first six months. Treatment included i.v. albumin substitution, optimal nutrition, thyroxine and anticoagulation. Forty-one patients had been nephrectomized bilaterally at a mean age of 1.2 years and after 3 to 25 months on peritoneal dialysis renal transplantation (Tx) had been performed on 34 who were a mean age of 2.2 years. Growth and development has been normal. Patient survival after Tx was 97%, graft survival 94%, 81% and 81% one, three and five years after Tx was (50% cadaver grafts). Mean GFR was 75 ml/min/1.73 m2 after three years, mean height SDS -1.42, and the nine oldest patients attend school in a normal class.

A study on the mutagenic activity of styrene and styrene oxide.

Styrene oxide is multagenic, without metabolic activation, to S. typhimurium strains TA 1535 and TA 100, which have been devised to detect mutagens causing base-pair substitutions. Styrene seems to be mutagenic toward the same strains, but only after metabolic activation. The toxicity of both styrene and styrene oxide make the construction of reliable dose-response curves rather difficult. Diethylmaleate and 3,3,3-trichloropropene oxide enhanced the mutagenicity of styrene oxide in the presence of homogenate; this result indicates the participation of epoxide hydratase and glutathione S-oxide transferase in the metabolism of styrene oxide. These two chemicals did not influence the mutagenic activity of styrene. Styrene glycol and 4-tert-butyl-brenzcatechin were not mutagenic to any of the strains studied. Results show that further, more detailed experimental and, possibly, epidemiologic studies are warranted.

Influence of age, time, and peritonitis on peritoneal transport kinetics in children.

OBJECTIVE: To evaluate peritoneal transport kinetics and its changes over time in children with and without peritonitis, and to record possible differences between children under and over 5.0 years of age. DESIGN: A prospective study. The patients underwent a 4-hour peritoneal equilibration test (PET) comprising 2.27% dextrose with a dialysate fill volume of 1000 mL/m2 of body surface area (BSA), at baseline and after a mean of 0.8 +/- 0.4 years of uninterrupted dialysis. PATIENTS: We investigated 28 patients on maintenance peritoneal dialysis at baseline; 10 were under 5.0 years of age. The final PET was performed in 21 patients. MAIN OUTCOME MEASURES: Peritoneal equilibration rates for urea (U), creatinine (C), glucose (G), sodium, potassium, phosphate, and albumin (A) were measured. Initial and final peritoneal equilibration rates were compared. Mass transfer area coefficients (MTAC) were calculated for urea, creatinine, glucose, and albumin. Residual dialysate volume was determined. RESULTS: Median age at first PET was 7.6 years (range 0.3-16.6 yr). The mean (+/- 1 SD) 4-hour dialysate-to-plasma (D/P) ratios for U, C, and A were 0.92 +/- 0.05, 0.70 +/- 0.12, and 0.014 +/- 0.007, respectively. The mean 4-hour D/D0 ratio for G was 0.32 +/- 0.10. D/P and D/D0 results were similar in the two age groups, and peritoneal membrane function remained stable over the study period. Mean MTAC (+/- 1 SD) values were: U, 22.3 +/- 4.8; C, 10.9 +/- 4.1; G, 11.1 +/- 3.3; and A, 0.07 +/- 0.03. MTAC data were similar in the two age groups and no significant changes occurred during the study period. CONCLUSIONS: When the volume tested in children is proportional to BSA, the solute D/P ratios seem to be age-independent. Our data provide evidence that in pediatric patients MTAC is also age-independent.

Peritoneal dialysis in children under 5 years of age.

OBJECTIVE: We report our experience with maintenance peritoneal dialysis (PD) in small children. DESIGN: This is a retrospective analysis of the patient records of all children under the age of 5 years treated with continuous peritoneal dialysis (CPD) between 1986 and 1994 in Finland. SETTING: Treatment was started and the patients were seen at the outpatient clinic at the Hospital for Children and Adolescents, University of Helsinki, every 3 months. Between these visits, they had controls at their local hospital every 2-4 weeks. PATIENTS: The most common primary renal disease in these 34 patients was congenital nephrotic syndrome of the Finnish type (27 patients). Others were: congenital nephrotic syndrome (3 patients), polycystic kidney disease (1), urethral valve (1), neuroblastoma (1), and renal dysplasia (1). RESULTS: Mean age at onset was 1.6 years and median treatment time 9.3 months. Time spent in hospital decreased from 270 days/year in the 1980s to 150 days/year in the 1990s. Two children died (5.9%). The peritonitis rate on continuous cyclic peritoneal dialysis was 1:11.5 patient-months. Hernias were diagnosed in 29% of the patients. After 3 months half of the patients were on antihypertensive medication. Pulmonary edema was diagnosed once in 12 patients and twice in 2 patients. During the first 6 months on PD the mean height standard deviation score (hSDS) increased from -2.13 to -1.66 (p < 0.0001). The 6-month change in hSDS before initiation and 6 months after the start of CPD increased from -0.12 +/-0.68 to +0.59 +/- 0.64 (p = 0.0008). CONCLUSIONS: Our results indicate that peritoneal dialysis is feasible and safe in small children. Mortality was low and growth was good. The major challenges presented by CPD therapy were maintenance of optimal nutrition, avoidance of peritonitis, and control of volemia.