Congenital nephrotic syndrome (CNS) is a rare kidney disorder characterized by heavy proteinuria, hypoproteinemia, and edema starting soon after birth. The majority of cases are caused by genetic ...defects in the components of the glomerular filtration barrier, especially nephrin and podocin. CNS may also be a part of a more generalized syndrome or caused by a perinatal infection. Immunosuppressive medication is not helpful in the genetic forms of CNS, and kidney transplantation is the only curative therapy. Before the operation, management of these infants largely depends on the magnitude of proteinuria. In severe cases, daily albumin infusions are required to prevent life-threatening edema. The therapy also includes hypercaloric diet, thyroxin and mineral substitution, prevention of thrombotic episodes, and prompt management of infectious complications. The outcome of CNS patients without major extrarenal manifestations is comparable with other patient groups after kidney transplantation.
Renal transplantation (RTx) is the only curative treatment for most cases of congenital and infantile nephrotic syndrome (NS) caused by genetic defects in glomerular podocyte proteins. The outcome of ...RTx in these children is usually excellent, with no recurrence of nephrotic syndrome. A subgroup of patients with the Finnish type of congenital nephrosis (CNF), shows, however, a clear risk for post-RTx proteinuria. Most of these patients have a homozygous truncating mutation (Fin-major mutation) in the nephrin gene (
NPHS1
), leading to total absence of the major podocyte protein, nephrin. After RTx, these patients develop anti-nephrin antibodies resulting in nephrotic range proteinuria. Plasma exchange combined with cyclophosphamide and anti-CD20 antibodies has proved to be successful therapy for these episodes. NS recurrence has also occurred in a few patients with mutations in the podocin gene (
NPHS2
). No anti-podocin antibodies have been detectable, and the pathophysiology of the recurrence remains open. While most of these episodes have resolved, the optimal therapy remains to be determined.
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 × 10
9
/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 & Aims The pathogenesis of intestinal failure (IF) associated liver disease (IFALD) is uncertain, we therefore investigated the role of FGF19 and pro-inflammatory cytokines has on this ...disease state. Methods Serum FGF19, IL-6 and, TNF-α were measured in 52 IF patients at median age 6.0 years (IQR 2.2–13) after 10 months (4.1–39) on parenteral nutrition (PN). Thirty-nine patients underwent liver biopsies. Results In IF patients, FGF19 concentrations were lower and those of IL-6 and TNF-α higher compared to healthy matched controls ( p ⩽0.001 for all). FGF19 concentrations were further decreased in patients without a remaining ileum 37 pg/ml (IQR 30–68) vs. 74 (35–135) p = 0.028, and correlated with remaining ileum length (r = 0.333, p = 0.018) and markers of cholesterol synthesis (r = −0.552 to −0.643, p <0.001). Patients with histological portal inflammation 30 pg/ml (28–45) vs. 48 (33–100), p = 0.019 or fibrosis 35 pg/ml (30–66) vs. 99 (38–163), p = 0.013 had lower serum FGF19 concentrations than others. FGF19 negatively correlated with portal inflammation grade (r = −0.442, p = 0.005), serum TNF-α (r = −0.318, p = 0.025), METAVIR fibrosis stage (r = −0.441, p = 0.005) and APRI (r = −0.328, p = 0.028). IL-6 was higher during PN 6 pg/ml (2–31) than after weaning off PN 2 pg/ml (1–5), p = 0.009, correlated weakly with cholestasis grade (r = 0.328, p = 0.044), and tended to associate with histological cholestasis n = 5, 5 pg/ml (5–267) vs. n = 34, 2 pg/ml (1–7), p = 0.058. Conclusions In pediatric onset of IF, total or partial loss of ileum decreases serum FGF19 concentration corresponding to hepatic inflammation and fibrosis, along with increased cholesterol synthesis. In contrast, serum IL-6 increases during PN and may associate with concurrent cholestasis. These data suggests that FGF19 may contribute to the pathogenesis of IFALD.
Biliary atresia is the most common reason for newborn cholestasis and pediatric liver transplantation. Even after normalization of serum bilirubin after portoenterostomy, most patients require liver ...transplantation by adulthood due to expanding fibrosis. We addressed contemporary outcomes of biliary atresia in the Nordic countries.
Data on center and patients characteristics, diagnostic practices, surgical treatment, adjuvant medical therapy after portoenterostomy, follow-up and outcomes were collected from all the Nordic centers involved with biliary atresia care during 2005–2016.
Of the 154 patients, 148 underwent portoenterostomy mostly by assigned surgical teams at median age of 64 (interquartile range 37–79) days, and 95 patients (64%) normalized their serum bilirubin concentration while living with native liver. Postoperative adjuvant medical therapy, including steroids, ursodeoxycholic acid and antibiotics was given to 137 (93%) patients. Clearance of jaundice associated with young age at surgery and favorable anatomic type of biliary atresia, whereas annual center caseload >3 patients and diagnostic protocol without routine liver biopsy predicted early performance of portoenterostomy. The cumulative 5-year native liver and overall survival estimate was 53% (95% CI 45–62) and 88% (95% CI 83–94), respectively. Portoenterostomy age <65days and annual center caseload >3 patients were predictive for long-term native liver survival, while normalization of serum bilirubin after portoenterostomy was the major predictor of both native liver and overall 5-year survival.
The outcomes of biliary atresia in the Nordic countries compared well with previous European studies. Further improvement should be pursued by active measures to reduce patient age at portoenterostomy.
Level II.
Mulibrey nanism (MUL) is a disorder with growth delay and congestive heart failure determining prognosis. We aimed to delineate arterial and venous morphology, and arterial stiffness in a ...representative pediatric MUL cohort. Twenty-three MUL and 23 individually sex and age-matched healthy controls were prospectively assessed in a cross-sectional study with ultra-high frequency ultrasound (48-70 MHz). Heart failure was present in 7 MUL patients, with severe congestive heart failure in 2. Pericardiectomy had been performed in 6 MUL. Arterial lumen diameters and arterial wall layer thickness (intima-media thickness and adventitia thickness) were smaller in MUL patients, but appropriate for body size when compared with controls. Systolic and diastolic blood pressure, aortic and carotid compliance, stiffness as well as central aortic pulsed wave velocity were all similar in MUL compared with controls. Plasma pro-BNP levels were variably elevated (>300 ng/L) in 9/23 MUL patients and in 4/18 MUL patients older than 5 years of age. Internal jugular vein (mean difference 0.054 mm, CI95% 0.024-0.084) and cubital vein (0.046 mm, CI95% 0.013 - 0.078) total wall thickness was elevated in MUL compared with controls. There were no statistically significant relations between vascular parameters and clinical or laboratory signs of heart failure or pericardiectomy. Arterial lumen, wall layer thickness and stiffness are appropriate for body size in MUL, and like healthy controls. Mild venous wall thickening in the upper body region may be due to increased venous pressures related to remodelling caused by diastolic heart failure.
Abstract
Background and aims.
Effects of caseload and organization of care on outcomes of biliary atresia (BA) remain unclear. We compared outcomes before and after national centralization of BA ...treatment in Finland with a population of 5.4 million people and 60,000 live births/year.
Methods.
All children born in Finland from 1987 to 2010 with BA were included. Complete patient identification was ascertained from the national Register of Congenital Malformations. Hospital records were reviewed for confirmation of the diagnosis, treatment, and follow-up data. Clearance of jaundice (serum bilirubin ≤20 μmol/l) and survival modalities were compared before and after centralization from five centers to Helsinki.
Results.
The incidence of BA was 1 in 20,100 live births. A total of 72 BA patients of whom 64 had undergone surgery for BA were identified. After centralization, the median caseload per center increased from 0 (range, 0-3) to 4 (2-5) patients/year (p < 0.001), clearance of jaundice rate increased from 27% to 75% (p = 0.001), 2-year jaundice-free native liver survival from 25% to 75% (p = 0.002), transplant-free survival from 27% to 75% (p = 0.005), and overall survival from 64% to 92% (p = 0.082). Baseline patient characteristics including type of BA and age at portoenterostomy remained unaltered. In a logistic regression analysis including treatment era, operating center, BA splenic malformation syndrome, and age at portoenterostomy as variables, only treatment in Helsinki after centralization predicted clearance of jaundice (odds ratio 4.2; 95% confidence interval 1.05-16.5; p = 0.043).
Conclusions.
In small countries, BA treatment should be centralized to appointed multidisciplinary teams allowing high quality results with a median of four cases/year.
Background
The prevalence of malignancies after pediatric solid organ transplantation was evaluated in a nationwide study.
Methods
All patients who had undergone kidney, liver, or heart ...transplantation during childhood between the years 1982 and 2015 in Finland were identified. The inclusion criteria were age under 16 years at transplantation and age over 18 years at the last follow-up day. A total of 233 (137 kidney, 53 liver, and 43 heart) transplant recipients were enrolled. Controls (
n
= 1157) matched by the year of birth, gender, and hometown were identified using the Population Register Center registry. The cancer diagnoses were searched using the Finnish Cancer Registry.
Results
Altogether 26 individuals diagnosed with cancer were found, including 18 transplant recipients. Cancer was diagnosed at a median of 12.0 (IQR 7.8–17.8) years after the transplantation. The transplant recipients’ risk for cancer was significantly higher when compared with the controls (HR 14.7; 95% CI 6.4–33.9). There was no difference for different graft types. Sixty-one percent of cancers among the transplant recipients were diagnosed at age older than 18 years.
Conclusion
The risk for cancer is significantly higher among young adults having undergone solid organ transplantation during childhood in comparison with population controls. Careful follow-up and attention to prevent cancers throughout adulthood are warranted.
BACKGROUND:Biliary atresia is the most common indication for childhood liver transplantation. The effects of successful portoenterostomy (PE) on native liver histology remain unclear.
AIMS:We ...assessed changes in native liver histology after a successful PE in relation to liver function and clinical outcomes.
METHODS:In total, 70 native liver biopsies of 44 biliary atresia patients were obtained at PE (n=30), 4.2 years after successful PE (n=23) and 1.1 years after failed PE (n=17), and reviewed for cholestasis, fibrosis, inflammation, and cytokeratin 7 (CK7) immunopositivity (chronic cholestasis). Ten transplant donor livers served as controls.
RESULTS:After a successful PE serum bilirubin 11 (2 to 35) μmol/L at biopsy, histologic native liver cholestasis completely resolved in 83% of the patients and portal inflammation significantly decreased. Nevertheless, enhanced fibrosis Metavir stage 2 (1-4) vs. 4 (1-4), bile duct proliferation grade 2 (1-2) vs. 1 (0-2), and periportal CK7 immunostaining grade 1 (0-2) vs. 1 (0-4) persisted in 100%, 87%, and 61% of subjects, respectively. Metavir fibrosis stage corresponded cirrhosis (stage 4) in 52% of the patients, associated with the presence of portal hypertension, and correlated with serum-conjugated bilirubin (r=0.601, P=0.002), bile duct proliferation (r=0.657, P=0.001), and CK7 positivity (r=0.657, P=0.001). Aspartate transferase to platelet ratio index predicted native liver fibrosis and development of esophageal varices. The degree of fibrosis and portal inflammation at PE were unrelated to native liver survival.
CONCLUSIONS:Despite resolution of cholestasis and decreasing inflammation, bile duct proliferation, periportal CK7 immunostaining, and fibrosis persist after successful PE. Fibrosis is associated with biochemical cholestasis, bile duct proliferation, CK7 immunopositivity (chronic cholestasis), and development of portal hypertension.
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