Search

Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear.In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mutsup0/sup-type MMAemia, one patient had a mutsup-/sup-type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0-15.1 years).Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 μmol/L) was 7.8-fold higher than in LTx (176 ± 103 μmol/L; Plt; 0.001) and 6.4-fold higher than in LKTx (215 ± 110 μmol/L; Plt; 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 msup2/sup, in LTx 99.8 ± 29.9 mL/min/1.73 msup2/sup, and in LKTx 31.5 ± 21.2 mL/min/1.73 msup2/sup. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 msup2/sup) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 msup2/sup; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 msup2/sup; P = 0.0403).In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.

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: The present study aimed at investigating long-term mortality of patients who underwent solid organ transplantation during childhood and at identifying their causes of death. Methods: A cohort of 233 pediatric solid organ transplant recipients who had a kidney, liver, or heart transplantation between 1982 and 2015 in Finland were studied. Year of birth-, sex-, and hometown-matched controls (n = 1157) were identified using the Population Register Center registry. The Causes of Death Registry was utilized to identify the causes of death. Results: Among the transplant recipients, there were 60 (25.8%) deaths (median follow-up 18.0 years, interquartile range of 11.0–23.0 years). Transplant recipients' risk of death was nearly 130-fold higher than that of the controls (95% CI 51.9–1784.6). The 20-year survival rates for kidney, liver, and heart recipients were 86.1% (95% CI 79.9%–92.3%), 58.5% (95% CI 46.2%–74.1%), and 61.4% (95% CI 48.1%–78.4%), respectively. The most common causes of death were cardiovascular diseases (23%), infections (22%), and malignancies (17%). There were no significant differences in survival based on sex or transplantation era. Conclusion: The late mortality is still significantly higher among pediatric solid organ recipients in comparison with controls. Cardiovascular complications, infections, and cancers are the main causes of late mortality for all studied transplant groups. These findings emphasize the cruciality of careful monitoring of pediatric transplant recipients in order to reduce long-term mortality. publishedVersion

Publisher Copyright: © 2021 Annals of Cardiac Anaesthesia. Background: Cardiopulmonary bypass (CPB) may lead to tissue hypoxia, inflammatory response, and risk for acute kidney injury (AKI). We evaluated the prevalence of AKI and inflammatory response in neonates undergoing heart surgery requiring CPB with or without antegrade cerebral perfusion (ACP). Methods: Forty neonates were enrolled. The patients were divided into two groups depending on the use of ACP. AKI was classified based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Inflammatory response was measured using plasma concentrations of interleukins 6 (IL-6) and 10 (IL-10), white blood cell count (WBC), and C-reactive protein (CRP). Results: Eight patients (20%) experienced AKI: five (29%) in the ACP group and three (13%) in the non-ACP group (P = 0.25). Postoperative peak plasma creatinine and urine neutrophil gelatinase-associated lipocalin were significantly higher in the ACP group than in the non-ACP group [46.0 (35.0-60.5) vs 37.5 (33.0-42.5), P = 0.044 and 118.0 (55.4-223.7) vs 29.8 (8.1-109.2), P = 0.02, respectively]. Four patients in the ACP group and one in the non-ACP group required peritoneal dialysis (P = 0.003). Postoperative plasma IL-6, IL-10, and CRP increased significantly in both groups. There were no significant differences between the ACP and non-ACP groups in any of the inflammatory parameters measured. Conclusions: No significant difference in the AKI occurrence or inflammatory response related to CPB modality could be found. In our study population, inflammation was not the key factor leading to AKI. Due to the limited number of patients, these findings should be interpreted with caution.

Background For 10 consecutive years, the ESPN/ERA-EDTA Registry has included data on children with stage 5 chronic kidney disease (CKD 5) receiving kidney replacement therapy (KRT) in Europe. We examined trends in incidence and prevalence of KRT and patient survival. Methods We included all children aged Results Incidence of children commencing KRT Conclusions We found a stable incidence and increasing prevalence of European children on KRT 2007–2016. Five-year patient survival was good and was unchanged over time. These data can inform patients and healthcare providers and aid health policy makers on future resource planning of pediatric KRT in Europe.

Gastrointestinal symptoms are common among solid organ transplant (SOT) recipients. Information about colonoscopy findings after pediatric SOT is limited. This retrospective study reports endoscopy findings in a nationwide pediatric transplant recipient cohort.All pediatric recipients (kidney, liver, or heart) transplanted between 2010 and 2020 at our institution (n = 193) who had undergone ileocolonoscopy and upper gastrointestinal endoscopy after SOT were enrolled. Sixteen patients were identified. A meticulous search on clinical data including transplantation, gastrointestinal symptoms, endoscopy findings, and follow-up data was performed.Endoscopy was performed at a median of 2.6 years (0.4-13.3) after the first transplantation (median age at SOT 1.2 years). Gastrointestinal symptoms leading to endoscopy did not differ between the different transplant groups. The leading endoscopy indications were prolonged diarrhea and anemia. PTLD was found in 8 (50%) patients. Five were histologically early PTLD lesions and three were monomorphic large B-cell PTLDs (two EBV-positive and one EBV-negative), one having previously been diagnosed with autoimmune enteropathy. One patient had EBV enteritis. De novo inflammatory bowel disease was found in one patient, eosinophilic gastroenteritis in another, and in one patient with several episodes of watery diarrhea, the histological finding was mild non-specific colitis. In four patients, the endoscopy finding remained unclear and the symptoms were suspected to be caused by infectious agents or mycophenolate.PTDL with various stages is a common finding after pediatric SOT in patients with gastrointestinal symptoms. Endoscopy should be considered in transplant recipients with prolonged diarrhea, anemia, and/or abdominal pain.

publishedVersion Non

Background History of chronic kidney disease and kidney transplantation is known to influence physical performance capacity. The aim of this study was to compare the physical performance of pediatric kidney transplant recipients to healthy controls and to find possible correlations between clinical parameters and physical performance capacity. Methods Twenty-four pediatric kidney transplant recipients (62.5% boys) were tested at a median age of 10.8 years. Physical performance capacity was tested with a test set including six different components assessing muscle endurance, strength, speed, and flexibility. The control group consisted of 273 healthy age-matched schoolchildren. Clinical parameters were collected as part of routine follow-up protocol. The majority of patients (62.5%) had congenital nephrotic syndrome of Finnish type (CNS) as primary diagnosis, and therefore, the results of CNS recipients were compared to the other disease groups. Results The physical performance capacity in pediatric kidney transplant recipients was lower compared to healthy controls. Surprisingly, no statistically significant correlation was found between graft function and physical performance capacity. The CNS patients scored worse than patients with other diagnoses in all test domains except for sit-and-reach and shuttle run, but the differences did not reach statistical significance. Conclusion The physical performance of pediatric kidney transplant recipients is reduced, especially in those with congenital nephrotic syndrome. Clinical parameters, including graft function, did not predict physical performance capacity, suggesting that the reduced physical performance seems to be of multivariable cause. Graphical abstract

BACKGROUND AND AIMS ANCA-associated vasculitis (AAV) is rare among children but leads to kidney failure (KF) in almost 30% of cases with renal involvement [1]. Kidney transplantation (KT) is the treatment of choice in adults with AAV and KF, while data among children are limited to small case series [2, 3]. We report the outcomes of KT in a multicentre cohort of patients with childhood-onset AAV. METHOD Patients with AAV diagnosed before the age of 18 years who had undergone KT were identified at one Canadian and 20 European centres. We analysed patient and graft survival and the rates of rejection, AAV relapse and infections. Eighteen patients from this cohort had already been reported in previous articles [1, 2]; their follow-up was extended and further relevant data were retrieved. RESULTS We included 55 patients, of whom 38 (69%) had microscopic polyangiitis (MPA) and 17 (31%) granulomatosis with polyangiitis (GPA). Their median age at diagnosis and transplantation was, respectively, 12 (interquartile range, IQR 9–14) and 14 (IQR 12–16) years (Table 1). Living donor transplantation was performed in 20 cases (36%) and deceased donor transplantation in 35 (64%). At the time of transplantation, all patients were in clinical remission and ANCA was positive in 14/54 (26%). As immunosuppressive therapy, 46 patients (84%) received glucocorticoids, tacrolimus and either mycophenolate mofetil or azathioprine. The median follow-up after transplantation was 54 months (IQR 21–91). Acute rejection was reported in 22 patients (40%), 12 of whom experienced it during the first post-transplant year, while chronic rejection was established in two (4%). AAV relapsed in five cases (9%) and involved the graft in 4/5. Positive ANCA at transplantation was significantly associated with relapse (29% versus 2%; P = 0.02). Infections occurred in 34 patients (62%), and were mainly bacterial infections of the urinary tract or viral infections due to CMV (8/34), EBV (5/34) and BK virus (4/34). No patient developed malignancy. At last visit, all patients were alive and 48 (87%) had a functioning graft. Graft function impairment (eGFR CONCLUSION KT in childhood-onset AAV has a relatively good graft and patient survival, while the rate of complications and the risk of vasculitis relapse appear low. Positive ANCA at the time of transplantation may be a risk factor for both AAV relapse and graft function impairment.

One of the main objectives of the European health policy framework is to ensure equitable access to high-quality health services across Europe. Here we examined country-specific kidney transplantation and graft failure rates in children and explore their country- and patient-level determinants. Patients under 20 years of age initiating kidney replacement therapy from January 2007 through December 2015 in 37 European countries participating in the ESPN/ERA-EDTA Registry were included in the analyses. Countries were categorized as low-, middle-, and high-income based on gross domestic product. At five-years of follow-up, 4326 of 6909 children on kidney replacement therapy received their first kidney transplant. Overall median time from kidney replacement therapy start to first kidney transplantation was 1.4 (inter quartile range 0.3-4.3) years. The five-year kidney transplantation probability was 48.8% (95% confidence interval: 45.9-51.7%) in low-income, 76.3% (72.8-79.5%) in middle-income and 92.3% (91.0-93.4%) in high-income countries and was strongly associated with macro-economic factors. Gross domestic product alone explained 66% of the international variation in transplantation rates. Compared with high-income countries, kidney transplantation was 76% less likely to be performed in low-income and 58% less likely in middle-income countries. Overall five-year graft survival in Europe was 88% and showed little variation across countries. Thus, despite large disparities transplantation access across Europe, graft failure rates were relatively similar. Hence, graft survival in low-risk transplant recipients from lower-income countries seems as good as graft survival among all (low, medium, and high risk) graft recipients from high-income countries.

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.

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.

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.

OBJECTIVES The aim of the study was to evaluate the neurocognitive and motor development of biliary atresia (BA) patients in childhood and adolescence and to identify risk factors for impaired outcome. METHODS We invited all BA patients between ages 1 and 20 years followed up at Helsinki University Children's Hospital in Finland between 1 January 2019 to 31 January 2020 to participate. All participants underwent age-appropriate validated neurocognitive tests. Participants between 3.0 and 16.9 years of age were assessed with the Movement Assessment Battery for children, version 2. Guardians of participants between ages 5 and 17 years filled the Five-to-Fifteen-Revised (5-15R) parental questionnaire. RESULTS The mean (±standard deviation [SD]) total intelligence quotient (IQ) of the 39 participants was 91 ± 15, lower compared with test norms (mean IQ 100 ± 15, P

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. Many centers accept a minimum body weight of 10 kg as threshold for kidney transplantation (Tx) in children. As solid evidence for clinical outcomes in multinational studies is lacking, we evaluated practices and outcomes in European children weighing below 10 kg at Tx. Methods. Data were obtained from the European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry on all children who started kidney replacement therapy at

Background The pathophysiology of Henoch-Schönlein purpura (HSP) is still unclear, but several findings suggest that genetic factors may influence disease susceptibility. We aimed to perform a genome-wide association study (GWAS) in pediatric HSP patients with an emphasis on severe HSP nephritis. Methods The study included 46 HSP patients, 42 of whom had undergone kidney biopsy. Forty-nine pediatric patients with an inflammatory bowel disease (IBD) served as an autoimmune disease control group while Finnish bone marrow and blood donors represented the general reference population (n = 18,757). GWAS was performed for HSP and IBD samples in a case-control manner against the reference population. The analysis also included imputation of human leukocyte antigen (HLA) alleles. Results GWAS analysis in HSP revealed several polymorphisms from the HLA region that surpassed the genome-wide significance level. Three HLA class II alleles were also significantly more frequent in HSP than in the reference population: DQA1*01:01, DQB1*05:01, and DRB1*01:01. Haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 occurred in 43.5% of HSP patients, whereas its frequency was 8.2% in IBD patients and 15.0% in the reference population. HSP patients with this haplotype showed similar baseline clinical findings and outcome as HSP patients negative for the haplotype. In IBD patients, no polymorphism or HLA allele appeared significant at the genome-wide level. Conclusions Our results suggest that haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 is associated with susceptibility to HSP, but not with the severity of the kidney involvement. These HLA associations did not occur in IBD patients, suggesting that they are specific to HSP and not related to susceptibility to autoimmune diseases in general. Graphical abstract

BackgroundOnly a few studies reporting the long-term outcome of children with idiopathic tubulointerstitial nephritis (TIN) and uveitis syndrome (TINU) are available. We studied the long-term kidney and ocular outcome in a nationwide cohort of children with TIN or TINU.MethodsAll patients followed up for a minimum of 1 year by a paediatrician and an ophthalmologist were enrolled. The data on plasma creatinine (P-Cr), estimated glomerular filtration rate (eGFR), proteinuria, hypertension and uveitis were collected retrospectively.ResultsFifty-two patients were studied. Median age at time of diagnosis was 13.1 (1.8–16.9) years and median follow-up time was 5.7 (1.1–21.2) years. Forty-five (87%) patients were initially treated with glucocorticoids. The median of the maximum P-Cr was 162 μmol/l (47–1,016) and that of eGFR 47 ml/min/1.73m2(8–124). Uveitis was diagnosed in 33 patients (63%) and 21 (40%) patients developed chronic uveitis. P-Cr normalised in a median of 2 months. Eleven (21%) patients had nephritis recurrence during or after discontinuation of glucocorticoids. At the latest follow-up, 13 (25%) patients had eGFR < 90 ml/min/1.73m2(median 83; 61–89 ml/min/1.73m2). Six patients had tubular proteinuria; all presented with TIN without uveitis. Seven (13%) patients were hypertensive. Eleven (21%) patients had uveitis. One patient developed uraemia and was later transplanted.ConclusionsOur study questions the previously reported good long-term kidney and ocular outcome of patients with TIN/TINU. Decreased kidney function and/or ocular co-morbidities may persist for several years; thus, both kidney and ocular follow-up for at least 1 year is warranted.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Podocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.

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.

OBJECTIVE To analyze renal glomerular and tubular function and their association in patients operated for posterior urethral valves and to prognosticate the risk for end-stage kidney disease (ESKD) METHODS Sixty-three previously treated patients were evaluated for renal function during 1987-1991. The patients' age at evaluation was 11 years (range 2-24). Glomerular function was assessed by measuring glomerular filtration rate (GFR) and urine albumin excretion. Tubular function was determined by measuring urine concentration capacity and excretion of electrolytes (Na, K, Cl, Ca, P, Mg) and 0-2-microglobulin. Additionally, the prevalence of hypertension and serum parathyroid hormone and aldosterone values were registered. Tubular function was compared with GFR and the risk of developing ESKD before November 2018. RESULTS Twenty of the study patients (32%) had decreased GFR. In addition, 19% had proteinuria and 56% were hypertensive. Those without proteinuria or hypertension had better GFR values (P < .01 for both). There was a significant correlation between GFR and all the tubular function (P < .05) variables (except excretion of chloride) measured. Compared to the patients with favorable renal outcome, the patients (n = 10) who later developed ESKD had significantly (P < .01) lower GFR and reduced urinary excretion of all measured electrolytes except calcium. Consistently, urine 0-2 microglobulin and serum parathyroid hormone and aldosterone values were significantly higher in the patients who developed ESKD (P CONCLUSION Both glomerular and tubular function decline was common and several parameters were likely to predict ESKD in posterior urethral valves patients. UROLOGY (C) 2020 Elsevier Inc.

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 Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function. PROCEDURE Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated. RESULTS No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P

Aim To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017. Methods Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method. Results During follow-up, liver malignancy incidence remained stable at 1.1:10(6). Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged >= 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1). Conclusion Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality.

Objectives Knowledge of the vitamin and mineral intake and status of children on dialysis is scarce. Guidelines suggest supplementation of water-soluble vitamins, but the need for supplementation of minerals is less clear. We evaluated vitamin and mineral intake and status of children on chronic dialysis in our center. Methods We reviewed patient records of all 33 children aged 0-16 years who were treated with chronic dialysis at a University Hospital between December 2014 and August 2019. Dietary intake was estimated from feed prescriptions and 3-day food records. Vitamin and mineral determinations were performed as part of routine care. Results Food records or adherence to dietary prescription of feeds were available for 29 children. Dietary intake of most nutrients was sufficient in children on feeds, but children not on feeds had low intakes of vitamins D, B1, B2, and B6 as well as zinc, iron, and calcium from their diet. Insufficient intake was corrected with supplementation. We discovered some children with blood concentrations below the reference range for vitamins D (3.1%) and C (15.4%) and copper (16.7%) and selenium (3.1%). In contrast, various proportions of children with blood concentrations above the reference range were detected for all nutrients apart from vitamin D. Conclusions In our study, children receiving sufficient amounts of renal-specific feeds to meet at least 100% of age-specific requirements do not appear to need multivitamin-mineral supplementation, apart from vitamin D and calcium; in addition, children on PD usually need a sodium supplement and, on rare occasions with low intake from feeds, a phosphate supplement is needed. This study further revealed that other children at our center are more prone to deficient intakes of several vitamins and minerals, requiring supplementation based on dietetic review and, in some instances, laboratory measurements.

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 and objectives Data on recovery of kidney function in pediatric patients with presumed ESKD are scarce. We examined the occurrence of recovery of kidney function and its determinants in a large cohort of pediatric patients on maintenance dialysis in Europe. Design, setting, participants, & measurements Data for 6574 patients from 36 European countries commencing dialysis at an age below 15 years, between 1990 and 2014 were extracted from the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry. Recovery of kidney function was defined as discontinuation of dialysis for at least 30 days. Time to recovery was studied using a cumulative incidence competing risk approach and adjusted Cox proportional hazard models. Results Two years after dialysis initiation, 130 patients (2%) experienced recovery of their kidney function after a median of 5.0 (interquartile range, 2.0–9.6) months on dialysis. Compared with patients with congenital anomalies of the kidney and urinary tract, recovery more often occurred in patients with vasculitis (11% at 2 years; adjusted hazard ratio [HR], 20.4; 95% confidence interval [95% CI], 9.7 to 42.8), ischemic kidney failure (12%; adjusted HR, 11.4; 95% CI, 5.6 to 23.1), and hemolytic uremic syndrome (13%; adjusted HR, 15.6; 95% CI, 8.9 to 27.3). Younger age and initiation on hemodialysis instead of peritoneal dialysis were also associated with recovery. For 42 patients (32%), recovery was transient as they returned to kidney replacement therapy after a median recovery period of 19.7 (interquartile range, 9.0–41.3) months. Conclusions We demonstrate a recovery rate of 2% within 2 years after dialysis initiation in a large cohort of pediatric patients on maintenance dialysis. There is a clinically important chance of recovery in patients on dialysis with vasculitis, ischemic kidney failure, and hemolytic uremic syndrome, which should be considered when planning kidney transplantation in these children.

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

Objective Corticosteroids attenuate an inflammatory reaction in pediatric heart surgery. Inflammation is a source of free oxygen radicals. Children with a cyanotic heart defect are prone to increased radical stress during heart surgery. The authors hypothesized that high-dose methylprednisolone reduces inflammatory reaction and thereby also oxidative stress in infants with a univentricular heart defect undergoing the bidirectional Glenn procedure. Design A double-blind, placebo-controlled, randomized clinical trial. Setting Operating room and pediatric intensive care unit of a university hospital. Participants The study comprised 29 infants undergoing the bidirectional Glenn procedure with or without aortic arch or pulmonary arterial repair. Interventions After anesthesia induction, the patients received intravenously either 30 mg/kg of methylprednisolone (n = 15) or the same volume of saline as placebo (n = 14). Measurements and Main Results Plasma interleukin-6, interleukin-8, interleukin-10 (biomarkers of inflammation), and 8-hydroxydeoxyguanosine concentrations (a biomarker of oxidative stress) were measured at the following 4 time points: preoperatively, during cardiopulmonary bypass, after protamine administration, and 6 hours postoperatively. The study parameters did not differ between the study groups preoperatively. Methylprednisolone reduced the proinflammatory cytokines interleukin-6 and interleukin-8 and increased the anti-inflammatory cytokine interleukin-10 postoperatively. Despite reduced inflammation, there were no differences in 8-hydroxydeoxyguanosine between the methylprednisolone and placebo groups. Conclusions The proinflammatory reaction and increase in free radical stress were not interrelated during congenital heart surgery in cyanotic infants with a univentricular heart defect undergoing the bidirectional Glenn procedure. High-dose methylprednisolone was ineffective in attenuating free radical stress.

Progression of fibrosis and ensuing complications determine the postoperative course of patients operated on for biliary atresia. We evaluated predictors of the progression of fibrosis in the native liver after operative treatment.Among patients whose bilirubin decreased to34 µmol/L after portoenterostomy (n = 41), predictors of follow-up cirrhosis and the progression of fibrosis were analyzed with logistic regression and survival of their native liver was evaluated with the Kaplan-Meier method. Areas under receiving operating characteristic were used to define optimal cutoffs.After median follow-up of 5.2 years (interquartile range 1.6-10.2) after portoenterostomy, liver biopsies showed cirrhosis in 53% of patients, and the Metavir stage remained stable or decreased in 38%. The development of cirrhosis was predicted by total or conjugated bilirubin ≥170/120 µmol/L at the time of portoenterostomy (P ≤ .009); normalization of bilirubin within 1.9 months (P = .002); total or conjugated bilirubin ≥ 12.5/7.5 µmol/L (P = .002) and aspartate aminotransferase-to-platelet ratio ≥ 0.55 at 3 months postoperatively (P = .001); and total or conjugated bilirubin ≥ 7.5/2.5 µmol/L (P ≤ .001), aspartate aminotransferase-to-platelet ratio ≥ 0.63 (P = .004), and gamma glutamyl transferase ≥ 266 U/L (P = .007) at 6 months postoperatively. In multiple regression analysis, conjugated bilirubin ≥ 2.5 µmol/L at 6 months increased the risk of cirrhosis 35-fold (P = .020), and other predictors were not predictive. Total or conjugated bilirubin12.5/7.5 µmol/L (P ≤ .014), aspartate aminotransferase-to-platelet ratio0.55 at 3 months (P = .006), and total or conjugated bilirubin7.5/2.5 µmol/L at 6 months postoperatively (P ≤ .014) were the strongest predictors of a stable, nonprogressive fibrosis. Decreases in total or conjugated bilirubin to12.5/7.5 µmol/L by 3 months and to7.5/2.5 µmol/L by 6 months improved survival of the native liver (log-rank P ≤ .025). Age at follow-up or at portoenterostomy, anatomic type of biliary atresia, use of postoperative steroids, and episodes of cholangitis were unrelated to the progression of fibrosis or the development of cirrhosis (P = not significant).Among patients whose serum bilirubin normalizes after portoenterostomy, its rapid decrease to very low levels prolongs the survival of their native liver by delaying the progression of fibrosis.

Background Tubulointerstitial nephritis (TIN) and uveitis syndrome (TINU) are likely to be autoimmune diseases. Based on previous studies, adults with isolated idiopathic uveitis have polymorphisms in interleukin 10 (IL-10) and tumor necrosis factor a (TNF-alpha) genes. We aimed to evaluate the presence of IL-10 and TNF-alpha polymorphisms in a nationwide cohort of pediatric TIN/TINU patients. Methods Single nucleotide polymorphisms in IL-10 (+434T/C, +504G/T, -1082G/A, -2849C/T) and in TNF alpha (-308G/A, -238G/A, -857C/T) genes were genotyped in 30 well-defined pediatric patients with idiopathic TIN/TINU syndrome. Control group frequencies for these SNPs were obtained from 393 independent Finnish subjects. Results The homozygous minor allele in IL-10 +434T (rs2222202) and IL-10+504G (rs3024490) was found in all patients with TIN or TINU syndrome while the frequency of these minor alleles in the control population was 44% and 23%, respectively (p

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 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.

OBJECTIVES Plasma neutrophil gelatinase-associated lipocalin is a kidney injury marker used in pediatric heart surgery. Neutrophil gelatinase-associated lipocalin is also a constituent of specific granules of neutrophils. Corticosteroids are widely used in pediatric heart surgery. Methylprednisolone inhibits degranulation of neutrophil-specific granules. Use of corticosteroids has not been taken into account in studies of neutrophil gelatinase-associated lipocalin in pediatric heart surgery. We studied the influence of systemically administered methylprednisolone on plasma neutrophil gelatinase-associated lipocalin concentrations in pediatric heart surgery. DESIGN Two separate double-blinded randomized trials. SETTING PICU at a university-affiliated hospital. PATIENTS Forty neonates undergoing open-heart surgery and 45 children undergoing ventricular and atrioventricular septal defect correction. INTERVENTIONS First trial (neonate trial), 40 neonates undergoing open-heart surgery received either 30 mg/kg IV methylprednisolone (n = 20) or placebo (n = 20). Second trial (ventricular septal defect trial), 45 children undergoing ventricular or atrioventricular septal defect correction received one of the following: 30 mg/kg of methylprednisolone IV after anesthesia induction (n = 15), 30 mg/kg methylprednisolone in the cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). MEASUREMENTS AND MAIN RESULTS Plasma neutrophil gelatinase-associated lipocalin and creatinine were measured in both series. Lactoferrin levels were measured as a marker of neutrophil-specific granules in the ventricular septal defect trial only. No differences in creatinine levels occurred between the groups of either trial. Preoperative, neutrophil gelatinase-associated lipocalin did not differ between the study groups of either trial. Preoperatively administered methylprednisolone in the neonate trial reduced neutrophil gelatinase-associated lipocalin by 41% at 6 hours postoperatively (p = 0.002). Preoperatively administered methylprednisolone in the ventricular septal defect trial reduced neutrophil gelatinase-associated lipocalin by 47% (p = 0.010) and lactoferrin by 52% (p = 0.013) 6 hours postoperatively. Lactoferrin levels in the ventricular septal defect trial correlated with neutrophil gelatinase-associated lipocalin (R = 0.492; p = 0.001) preoperatively and after weaning from cardiopulmonary bypass (R = 0.471; p = 0.001). CONCLUSIONS Preoperatively administered methylprednisolone profoundly decreases plasma neutrophil gelatinase-associated lipocalin levels. Neutrophil gelatinase-associated lipocalin seems to originate to a significant extent from activated neutrophils. Preoperative methylprednisolone is a confounding factor when interpreting plasma neutrophil gelatinase-associated lipocalin levels as a kidney injury marker in pediatric heart surgery.

Optimal treatment of Henoch-Schonlein purpura nephritis (HSN) remains unclear. We evaluated outcome of pediatric HSN patients treated initially with either methylprednisolone (MP) or cyclosporine A (CyA) in Finland between 1996 and 2011. Outcome of 62 HSN patients was evaluated by screening urine and blood samples (n = 51) or by collecting clinical parameters from medical charts until last follow-up visit (n = 11). Sixty (97%) patients had nephrotic-range proteinuria and/or ISKDC grade ≥ III before initial treatment. Patients were initially treated with either MP pulses (n = 42) followed by oral prednisone or with CyA (n = 20). Fifty-nine (95%) patients received angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. Mean follow-up time was 10.8 years (range 3.2–21.2 years). One patient developed end-stage renal disease and another had decreased renal function (eGFR 0.5 g/day at end of follow-up. Sixteen (38%) MP-treated and two (10%) CyA-treated patients needed additional immunosuppressive treatment (RR 3.81, 95% CI 1.16–14.3, p = 0.035). Late initiation of treatment was associated with an increased risk for persistent proteinuria. Long-term outcome was relatively good in both treatment groups. However, since urinary abnormalities may persist or develop, long-term follow-up of HSN patients is mandatory. Early initiation of treatment had a favorable effect on proteinuria.

Background Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children. Despite severe outcomes, their genetic background is still poorly characterized. Objectives The purpose of this study was to characterize the genetics of severe childhood cardiomyopathies in a countrywide cohort. Methods The authors collected a countrywide cohort, KidCMP, of 66 severe childhood cardiomyopathies from the sole center in Finland performing cardiac transplantation. For genetic diagnosis, next-generation sequencing and subsequent validation using genetic, cell biology, and computational approaches were used. Results The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation. The authors identified the pathogenic variants in 39% of patients: 46% de novo, 34% recessive, and 20% dominantly-inherited. The authors report NRAP underlying childhood dilated cardiomyopathy, as well as novel phenotypes for known heart disease genes. Some genetic diagnoses have immediate implications for treatment: CALM1 with life-threatening arrhythmias, and TAZ with good cardiac prognosis. The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2, HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2), development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP). Conclusions Childhood cardiomyopathies are typically caused by rare, family-specific mutations, most commonly de novo, indicating that next-generation sequencing of trios is the approach of choice in their diagnosis. Genetic diagnoses may suggest intervention strategies and predict prognosis, offering valuable tools for prioritization of patients for transplantation versus conservative treatment.