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.

Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines.

Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol(2)/l(2). The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2-3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.

The mannitol dehydrogenase gene (mdh) from Leuconostoc mesenteroides is distinct from other known bacterial mdh genes.

The N-terminal amino acid sequences of the intact protein and three tryptic peptides from a 41 kDa protein purified from a commercial mannitol dehydrogenase (MDH) enzyme preparation of Leuconostoc mesenteroides ATCC-9135 were determined. Oligonucleotides deduced from these peptide sequences were used to isolate the putative mdh gene from L. mesenteroides using the Vectorette system. Nucleotide sequence analysis revealed an open reading frame (ORF1) of 1,014 bp encoding a putative MDH protein of 338 amino acids, and another open reading frame (ORF2) encoding an unknown protein of 245 amino acids. In Northern blots, a transcript of approximately 2.2-kb was detected with an mdh-specific probe. Mapping of the 5'-end of the 2.2-kb transcript indicated that mdh was the first gene of the operon. After fusion of six histidine codons to the 3'-end of the mdh gene and expression in Escherichia coli M15, active MDH was isolated using HisTrap purification. The overexpressed enzyme showed high specificity for mannitol and fructose. In dot blot hybridisation, the L. mesenteroides mdh-specific probe bound strongly to chromosomal DNA of Leuconostoc pseudomesenteroides and weakly to DNA of some heterofermentative Lactobacillus strains, whereas no hybridisation signals were obtained with DNA derived from strains carrying characterised mdh genes. Furthermore, the amino acid sequence similarity between L. mesenteroides MDH and other known MDHs was very low, suggesting that MDHs from heterofermentative lactic acid bacteria form a structurally and functionally separate enzyme group. Interestingly, L. mesenteroides MDH shared significant sequence similarity with the medium-chain dehydrogenase/reductase protein family.

Hypertension, cardiac state, and the role of volume overload during peritoneal dialysis.

The cardiac state and the prevalence of high blood pressure (BP) were analyzed in 21 pediatric patients (mean age 5.3 +/- 5.3 years) on chronic peritoneal dialysis (CPD), the aim being to specify the impact of hypervolemia in the etiology of hypertension. C- and N-terminal atrial natriuretic peptide (ANP-C, ANP-N) were measured as possible additional markers of hypervolemia. Baseline investigations were carried out 0.2 years after initiation of PD, and repeated after 0.9 +/- 0.2 years. Fifty-two percent of the patients had high BP, and in 40% the nocturnal BP decline was decreased. Left ventricular hypertrophy was present in 45%, but the systolic and diastolic functions of the heart were not impaired. Left ventricular mass correlated significantly with the severity of hypertension and with ANP-N (r = 0.79, P < 0.01 and r = 0.66, P < 0.01, Spearman rank correlation). Significant correlations were also found between the severity of hypertension and ANP-N and ANP-C (r = 0.82, P < 0.01 and r = 0.66, P < 0.01, Spearman rank correlation). High BP and cardiac impairment were more frequent in the younger and nephrectomized patients in whom volume overload seemed to be the most-important etiological factor. Our results suggest further that an ANP-N over 3.0 nmol/l combined with hypertension is strongly indicative of volume overload in patients on PD.

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.

Clinical outcome of pediatric patients on peritoneal dialysis under adequacy control.

Clinical outcome under adequacy control was studied in 10 pediatric patients under 5 years and 11 patients over 5 years of age on continuous peritoneal dialysis (PD). Outcome was compared between the age groups and with our previous results in patients under 5 years of age. Peritoneal equilibration test and 24-h dialysate collection were performed. Laboratory data, clinical status, and diet were recorded. PD prescription was adjusted for these parameters. The mean weekly urea Kt/V was similar and stable in the two age groups (3.1+/-0.6 vs. 3.2+/-0.4 at baseline). The mean weekly creatinine clearance (C(Cr)) was at baseline significantly lower in the younger age group (58.7+/-11.9 vs. 78.0+/-14.9 l/week per 1.73 m2, P=0.004), but later similar. Urea Kt/V and C(Cr) correlated significantly. Hematological and biochemical parameters were stable, and catch-up growth was observed in 62% of the patients during 9 months of follow-up. The outcome for children under and over 5 years of age did not differ significantly. The clinical outcome in patients under 5 years of age improved under adequacy control, when compared with our previous results in patients of the same age. This suggests a positive effect of adequacy control on clinical outcome.

Adequacy of dialysis with tidal and continuous cycling peritoneal dialysis in children.

BACKGROUND: Today the major outcome measure for peritoneal dialysis is adequacy. We seek the optimal dialysis modality and prescription for each patient. Tidal dialysis (TPD) was introduced in 1990 to increase efficacy. However, studies with TPD have been inconsistent, and results in small children are lacking. METHODS: Nine patients under and eight patients over 5 years of age who were undergoing or starting maintenance peritoneal dialysis (PD) were studied. Patients were dialysed with TPD and with continuous cycling PD (CCPD), each for 6 months. To optimize TPD and CCPD modalities, we recorded urea K(t)/V, creatinine clearance (CrCl), peritoneal membrane capacity, clinical examination, biochemical values and nutrition. RESULTS: The mean nightly dialysate flow rate was significantly higher with TPD than with CCPD (46.4+/-3.7 vs 32.7+/-4.6 ml/kg/h, P:<0.001). Mean total CrCl at the baseline was significantly higher with TPD (79. 3+/-18.5 vs 72.5+/-16.0, P:=0.02), but urea K(t)/V was similar (3. 5+/-0.5 vs 3.3+/-0.4, P:=0.28). Urea K(t)/V and CrCl were higher during TPD in patients with high peritoneal membrane permeability, but similar in patients with high-average membrane permeability. Urea K:(t)/V and CrCl in CCPD and TPD did not differ significantly in the age groups. Nor did the incidence of hypertension differ in CCPD and TPD, despite a significantly lower glucose concentration during TPD. CONCLUSIONS: Both TPD and CCPD provide adequate dialysis for paediatric patients under and over 5 years of age. Because of higher costs, we recommend TPD only for paediatric patients with high membrane permeability and reduced ultrafiltration or with mechanical outflow problems or outflow pain.

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.

Long-term follow up of renal function and histology after renal allograft transplantation in early childhood.

Survival rates, renal function, and histopathology were evaluated in 49 prospectively followed patients transplanted under 5 years of age at our center. Most patients (84%) suffered from congenital nephrosis of the Finnish type. Triple immunosuppression with cyclosporine administered in three daily doses to pre-school children was used. Patient survival 7 years after transplantation was 98% and graft survival 88%. All graft losses were due to post-transplantation nephrosis. The proportion of pathological findings in the follow-up biopsies did not change substantially with time. Five years after transplantation, 47% showed a normal histology and after 7 years this rose to 67%. Mean glomerular filtration rate (GFR) was 68 and 55 ml min per 1.73 m2 5 years and 7 years, respectively, after transplantation. The decline in GFR with time was significant. We conclude that good long-term results can be achieved with individually tailored triple immunosuppression in the youngest age group, even with cadaveric donors.

Paediatric kidney transplantation.

Renal transplantation is the optimal form of renal replacement therapy leading to substantial improvement in the quality of life. It has rapidly become the standard treatment for end-stage renal disease in children. However, despite impressive short-term results significant long-term problems remain unsolved. Because of the lack of effective treatment for chronic rejection and common recipient noncompliance, allograft half-life has not improved significantly during the last decade. A paediatric recipient is likely to need several retransplantations in adulthood. Moreover, the immunosuppressive drugs used today have potentially serious side-effects including nephrotoxicity and de novo malignancy. These are especially relevant for paediatric recipients who will continue to receive therapy for several decades. Most therapeutic protocols used for children are derived from those used for adults. However, the metabolic differences between an adult and a growing and developing paediatric transplant recipient are not always adequately appreciated before these new therapies are initiated. In the near future, we are likely to see new and more efficient drugs become available. It is important that we try to understand their properties in children and use them and our current arsenal on an individual basis aiming at optimal graft survival but also at avoiding unnecessary adverse effects.

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.

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.

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.

Mechanism underlying early anaemia in children with familial juvenile nephronophthisis.

Familial juvenile nephronophthisis (NPH) is a hereditary form of chronic tubulointerstitial nephritis with onset in childhood. About one-third of patients develop anaemia before renal insufficiency. We investigated the pathogenetic mechanisms leading to anaemia by comparing 6 patients with NPH and 12 reference patients with other renal diseases. We studied their iron metabolism and measured transferrin receptor-ferritin ratios. There was no evidence for iron deficiency or haemolysis. The serum erythropoietin concentrations of the patients with NPH (12 +/- 2.3 U/I) were low compared with the 12 reference patients (25 +/- 18.9 U/I). In the 2 patients with NPH who were fully investigated, the pharmacokinetics of recombinant human erythropoietin appeared normal. Thus, anaemia in patients with NPH does not result from iron deficiency or correlate with impaired iron status. The mechanism underlying the anaemia of NPH appears to affect the function or regulation of the cells producing erythropoietin.

Provocative growth hormone testing is not required before initiation of rhGH treatment in children with renal and liver transplants.

GH provocative testing does not predict subsequent growth response, and is not therefore required before initiation of rhGH treatment in children with renal and liver transplants. However, therapeutic doses of glucocorticoids may potentially inhibit GH secretion in some patients, and determining GH secretory status by provocation tests and measuring spontaneous GH secretion is advisable at some point after organ Tx to exclude GH deficiency.

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.