Publications by authors named "Anna Bjerre"

68 Publications

Kidney Transplantation in Small Children: Association Between Body Weight and Outcome - A Report From the ESPN/ERA-EDTA Registry.

Transplantation 2021 Mar 26. Epub 2021 Mar 26.

Division of Pediatric Nephrology and Gastroenterology, Medical University Vienna, Austria ESPN/ERA-EDTA Registry, Amsterdam UMC, University of Amsterdam, Department of Medical Informatics, Amsterdam Public Health research institute, Meibergdreef 9, Amsterdam, the Netherlands; Department of Pediatric Nephrology, University Medical Center Ljubljana, Slovenia; Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Norway; Children's Medical Center, Landspitali-The National University Hospital of Iceland, and Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Karolinska Institutet- Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Pediatrics, Medical University Graz, Graz, Austria; Department of Pediatric Nephrology and Transplantation, New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Pediatric Nephrology, Erasmus MC- Sophia Children's Hospital, Rotterdam, the Netherlands; Nephrology Unit, University Children's Hospital, Zürich, Switzerland; S.C. Nefrologia e Dialisi, Azienda Ospefaliero-Universitaria di Perugia, Perugia, Italy; Department of Kidney Transplantation, Russian Children's Federal Clinical Hospital of Pirogov Russian National Research Medical University, Moscow, Russia; Department of Pediatric Nephrology, University Hospital Vall d'Hebron, Barcelona, Spain; Faculty of Medicine Seyhan, Adana Dr. Turgut Noyan Training and Research Center, Department of Pediatric Nephrology, Başkent University, Adana, Turkey; Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany; 1st Pediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece; 1st Department of Pediatrics, Semmelweis University Budapest, Budapest, Hungary; Pediatric Nephrology Unit, University Hospital of Nantes, Nantes, France; Department ofNephrology, Kidney Transplantation & Hypertension, The Children's Memorial Health Institute, Warsaw, Poland; Department of Nephrology, University Children's hospital, Belgrade, Serbia; Department of Pediatrics, University Hospital Motol, 2nd Medical Faculty and Faculty of Medicine in Plzen, Charles University Prague and Biomedical Centre, Prague, Czech Republic; Department of Pediatric Nephrology, Evelina London Children's Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom; Division of Pediatrics, Department of Medicine, University of Udine, Udine, Italy; Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France; Amsterdam UMC, University of Amsterdam, Department of Pediatric Nephrology, Emma Children's Hospital, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands.

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 ESPN/ERA-EDTA Registry on all children who started kidney replacement therapy (KRT) at <2.5 years of age and received a Tx between 2000 and 2016. Weight at Tx was categorized (<10 kg versus ≥10 kg) and Cox regression analysis was used to evaluate its association with graft survival.

Results: One hundred of the 601 children received a Tx below a weight of 10 kg during the study period. Primary renal disease groups were equal, but Tx <10 kg patients had lower pre-Tx weight gain per year (0.2 kg versus 2.1 kg; p<0.001) and had a higher preemptive Tx rate (23% versus 7%; p<0.001). No differences were found for posttransplant estimated glomerular filtration rates (eGFR) trajectories (p=0.23).The graft failure risk was higher in Tx <10 kg patients at 1 year (graft survival: 90% versus 95%; aHR: 3.84, 95% CI: 1.24-11.84), but not at 5 years (aHR: 1.71, 95% CI: 0.68-4.30).

Conclusions: Despite a lower 1-year graft survival rate, graft function and survival at 5 years were identical in Tx <10 kg patients when compared with Tx ≥10 kg patients. Our results suggest that early transplantation should be offered to a carefully selected group of patients weighing <10 kg.
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http://dx.doi.org/10.1097/TP.0000000000003771DOI Listing
March 2021

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients-A Cross-Validation Study.

Ther Drug Monit 2021 Jun;43(3):371-375

Department of Pharmacology, Oslo University Hospital; and.

Background: Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population.

Methods: Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography-tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing-Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference.

Results: A total of 39 SOT patients aged 4-18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6-13.6) mcg/L, with a difference between VAMS and venous blood samples of -0.2 ± 0.7 mcg/L. The relative mean difference was -1.3% [95% confidence interval (CI), -5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8-19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of -2.5% (95% confidence interval, -8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference.

Conclusions: Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population.
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http://dx.doi.org/10.1097/FTD.0000000000000873DOI Listing
June 2021

Ten-year trends in epidemiology and outcomes of pediatric kidney replacement therapy in Europe: data from the ESPN/ERA-EDTA Registry.

Pediatr Nephrol 2021 Jan 22. Epub 2021 Jan 22.

Department of Pediatrics, Bordeaux University Hospital, Bordeaux Population Health Research Center UMR 1219, University of Bordeaux, Bordeaux, France.

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 <15 years starting KRT 2007-2016 in 22 European countries participating in the ESPN/ERA-EDTA Registry since 2007. General population statistics were derived from Eurostat. Incidence and prevalence were expressed per million age-related population (pmarp) and time trends studied with JoinPoint regression. We analyzed survival trends using Cox regression.

Results: Incidence of children commencing KRT <15 years remained stable over the study period, varying between 5.5 and 6.6 pmarp. Incidence by treatment modality was unchanged over time: 2.0 for hemodialysis (HD) and peritoneal dialysis (PD) and 1.0 for transplantation. Prevalence increased in all age categories and overall rose 2% annually from 26.4 pmarp in 2007 to 32.1 pmarp in 2016. Kidney transplantation prevalence increased 5.1% annually 2007-2009, followed by 1.5% increase/year until 2016. Prevalence of PD steadily increased 1.4% per year over the entire period, and HD prevalence started increasing 6.1% per year from 2011 onwards. Five-year unadjusted patient survival on KRT was around 94% and similar for those initiating KRT 2007-2009 or 2010-2012 (adjusted HR: 0.98, 95% CI:0.71-1.35).

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.
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http://dx.doi.org/10.1007/s00467-021-04928-wDOI Listing
January 2021

Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

Ther Drug Monit 2021 04;43(2):247-255

Departments of Pharmacology and.

Background: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase.

Methods: This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry.

Results: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold.

Conclusions: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.
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http://dx.doi.org/10.1097/FTD.0000000000000835DOI Listing
April 2021

Cardiovascular Risk Factors are Inversely Associated With Omega-3 Polyunsaturated Fatty Acid Plasma Levels in Pediatric Kidney Transplant Recipients.

J Ren Nutr 2020 Aug 10. Epub 2020 Aug 10.

Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Objectives: High plasma levels of the omega-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid, and docosapentaenoic acid associates with positive outcomes in adult renal transplant recipients. However, data from pediatric populations are scarce. The aim of the study was to assess the fatty acid profile in a pediatric renal transplantation cohort and to examine the associations between plasma omega-3 fatty acids and cardiovascular disease (CVD) risk factors.

Methods: In this cross-sectional study comprising 53 children (median age, 12.2 years; 32 boys) with a renal transplant, we assessed the prevalence of CVD risk factors as well as markers of end organ damage: carotid intima-media thickness (cIMT) and left ventricular mass index. The associations between plasma omega-3 fatty acids and CVD risk factors were assessed.

Results: Twenty-five (47%) patients were preemptively transplanted. Seventy-six percent had dyslipidemia and 51% had hypertension. The mean left ventricular mass index was 40.4 ± 14.3 g/m, and 14% had left ventricular hypertrophy. The mean cIMT was 0.41 ± 0.04 mm. In a multivariate linear regression, EPA levels were inversely associated to blood pressure (β coeff. = -0.37, P = .007), triglycerides (β coeff. = -0.44, P = .01), and high-density lipoprotein cholesterol (β coeff. = -0.41, P = .01).

Conclusion: EPA levels are inversely associated with components of the metabolic syndrome, which may provide support for specific dietary advice or supplementation in this patient population. cIMT is less pronounced in our cohort than in comparable cohorts with lower rate of preemptive transplantations. Our results need replication in prospective cohorts.
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http://dx.doi.org/10.1053/j.jrn.2020.06.002DOI Listing
August 2020

Rare heterozygous GDF6 variants in patients with renal anomalies.

Eur J Hum Genet 2020 12 31;28(12):1681-1693. Epub 2020 Jul 31.

Department of Human Genetics, Hannover Medical School, 30625, Hannover, Germany.

Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.
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http://dx.doi.org/10.1038/s41431-020-0678-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784874PMC
December 2020

Results in the ESPN/ERA-EDTA Registry suggest disparities in access to kidney transplantation but little variation in graft survival of children across Europe.

Kidney Int 2020 08 26;98(2):464-475. Epub 2020 Apr 26.

Department of Paediatrics, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.

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 67% 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.
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http://dx.doi.org/10.1016/j.kint.2020.03.029DOI Listing
August 2020

GDF-15 - A matter of the heart or the kidney?

Int J Cardiol 2020 08;313:47

Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Norway; Department of Pediatric Research, Oslo University Hospital, Norway.

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http://dx.doi.org/10.1016/j.ijcard.2020.03.017DOI Listing
August 2020

Five decades with grandparent donors: The Norwegian strategy and experience.

Pediatr Transplant 2020 09 2;24(6):e13751. Epub 2020 Jun 2.

Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Living donors (LDs) are preferred over DDs for renal transplantation in children due to superior GS. Oslo University Hospital has never restricted living donation by upper age. The aim of this study was to investigate long-term outcomes using grandparents (GPLD) compared to PLD. Retrospective nationwide review in the period 1970-2017. First renal graft recipients using a GPLD were compared to PLD kidney recipients for long-term renal function and GS. 278 children (≤18 years) received a first renal transplant: 27/251 recipients with a GPLD/PLD. GPLD (median 59 (42-74) years) were significantly older than PLD (median 41 (23-65) years, (P < .001). Median DRAD was 52 (38-70) vs 28 (17-48) years, respectively. GS from GPLD and PLD had a 1-, 5-, and 10-year survival of 100%, 100%, and 90% vs 93%, 82%, and 72%, respectively (P = .6). In a multivariate Cox regression analysis adjusted for gender, donor age, recipient age, and year of transplant, this finding was similar (HR 0.98; 95% CI 0.34-2.84, P = .97). Five-year eGFR was 47.3 and 59.5 mL/min/1.73 m in the GPLD and PLD groups (P = .028), respectively. In this nationwide retrospective analysis, GS for pediatric renal recipients using GPLD was comparable to PLD. Renal function assessed as eGFR was lower in the GPLD group. The GPLD group was significantly older than the PLD group, but overall this did not impact transplant outcome. Based on these findings, older age alone should not exclude grandparent donations.
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http://dx.doi.org/10.1111/petr.13751DOI Listing
September 2020

Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal.

Am J Transplant 2021 01 27;21(1):123-137. Epub 2020 Jun 27.

Novartis Pharma AG, Basel, Switzerland.

CRADLE was a 36-month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced-exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6-month posttransplant or continue mycophenolate mofetil + standard-exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: -7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m ). Mean changes (z-score) in height (0.72 vs 0.39; P = .158) and weight (0.61 vs 0.82; P = .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P = .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE-related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491.
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http://dx.doi.org/10.1111/ajt.16005DOI Listing
January 2021

Surgical treatment for urinary incontinence in children.

Tidsskr Nor Laegeforen 2020 03 9;140(4). Epub 2020 Mar 9.

Only a small proportion of children with urinary tract malformations are incontinent, but it is important to identify those children for whom surgical treatment can eliminate or reduce urinary leakage.
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http://dx.doi.org/10.4045/tidsskr.18.0536DOI Listing
March 2020

Neurogenic bladder dysfunction in children.

Tidsskr Nor Laegeforen 2020 02 4;140(3). Epub 2020 Feb 4.

Neurogenic bladder dysfunction is the cause of a small proportion of urinary problems in children. Various neurological conditions can result in a change in neural control of the bladder, and also the colon. Some of these conditions are apparent at birth; others are discovered later, and it is important that the primary health service be aware of them, so that targeted treatment can be provided.
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http://dx.doi.org/10.4045/tidsskr.18.0347DOI Listing
February 2020

Growth Differentiation Factor 15 in Children with Chronic Kidney Disease and after Renal Transplantation.

Dis Markers 2020 6;2020:6162892. Epub 2020 Feb 6.

Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Norway.

Growth differentiation factor 15 (GDF-15) is strongly associated with cardiovascular disease (CVD). The aim of our study was to evaluate plasma and urinary levels of GDF-15 after pediatric renal transplantation (Rtx) and in children with chronic kidney disease (CKD) and its associations to cardiovascular risk factors. In this cross-sectional study, GDF-15 was measured in plasma and urine from 53 children with a renal transplant and 83 children with CKD and related to cardiovascular risk factors (hypertension, obesity, and cholesterol) and kidney function. Forty healthy children served as a control group. Plasma levels of GDF-15 (median and range) for a Tx (transplantation) cohort, CKD cohort, and healthy controls were, respectively, 865 ng/L (463-3039 ng/L), 508 ng/L (183-3279 ng/L), and 390 ng/L (306-657 ng/L). The CKD and Tx cohorts both had significantly higher GDF-15 levels than the control group ( < 0.001). Univariate associations between GDF-15 and hyperuricemia ( < 0.001), elevated triglycerides ( = 0.028), low HDL ( = 0.038), and obesity ( = 0.028) were found. However, mGFR ( < 0.001) and hemoglobin ( < 0.001) were the only significant predictors of GDF-15 in an adjusted analysis. Urinary GDF-15/creatinine ratios were 448 ng/mmol (74-5013 ng/mmol) and 540 ng/mmol (5-14960 ng/mmol) in the Tx cohort and CKD cohort, respectively. In the CKD cohort, it was weakly correlated to mGFR ( = -0.343, = 0.002). Plasma levels of GDF-15 are elevated in children with CKD and after Rtx. The levels were not associated with traditional cardiovascular risk factors but strongly associated with renal function.
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http://dx.doi.org/10.1155/2020/6162892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026715PMC
October 2020

Measured GFR by Utilizing Population Pharmacokinetic Methods to Determine Iohexol Clearance.

Kidney Int Rep 2020 Feb 6;5(2):189-198. Epub 2019 Dec 6.

Department of Pharmacy, University of Oslo, Oslo, Norway.

Introduction: There is an increasing demand for accurately measured glomerular filtration rate (GFR). Iohexol serum clearance has become a new gold standard, but it is challenging when GFR is low and 24-hour sampling is required for accurate results. The primary aim of this study was to develop an iohexol pharmacokinetic population model for accurate determination of individual GFR using limited sampling for up to 5 hours also when renal function is <40 ml/min.

Methods: A nonparametric iohexol population pharmacokinetic model was developed with rich data from 176 patients. In a validation cohort of 43 patients, a model-determined GFR (iohexol clearance) using different limited sampling strategies for up to 5 hours was compared with the strategy currently used in routine care, a log-linear 2-point method. In all, 1526 iohexol concentrations were used, from patients ranging in age from 1 to 82 years and GFR from 14 to 149 ml/min.

Results: The clinical 2-point method showed insufficient agreement compared with reference values; 15% of GFR values had an error of greater than ±10% even when sampling for 24 hours when estimating GFR <40 ml/min per 1.73 m (standard procedure). Restricted sampling the first 5 hours with the population model required 4 samples to determine GFR accurately. This strategy showed excellent agreement with the reference; <3% of GFR values had an error greater than ±10 %.

Conclusion: Using an iohexol population pharmacokinetic model allows for accurate determination of GFR within 5 hours when applying 4 optimally timed samples, even in patients with GFR <40 ml/min.
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http://dx.doi.org/10.1016/j.ekir.2019.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000849PMC
February 2020

Lower urinary tract dysfunction in children - a practical approach.

Tidsskr Nor Laegeforen 2020 02 29;140(2). Epub 2020 Jan 29.

More than 10 % of schoolchildren suffer from lower urinary tract dysfunction, often leading to contact with the healthcare system. The problem is socially limiting as well as mentally and physically demanding for children and their parents, and it is important to offer treatment. This article describes a structured approach that can form the basis for correct diagnosis and treatment.
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http://dx.doi.org/10.4045/tidsskr.18.0565DOI Listing
February 2020

Growth Patterns After Kidney Transplantation in European Children Over the Past 25 Years: An ESPN/ERA-EDTA Registry Study.

Transplantation 2020 01;104(1):137-144

Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France.

Background: Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry.

Methods: A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS.

Results: Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children <6 years were shortest at KT and showed the greatest increase in height, whereas there was no catch-up growth in children transplanted >12.

Conclusions: Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.
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http://dx.doi.org/10.1097/TP.0000000000002726DOI Listing
January 2020

Clinical and Complement Long-Term Follow-Up of a Pediatric Patient with C3 Mutation-Related Atypical Hemolytic Uremic Syndrome.

Case Rep Nephrol 2018 18;2018:3810249. Epub 2018 Dec 18.

Research Laboratory, Nordland Hospital, Bodø, Norway.

We report a pediatric patient with atypical hemolytic uremic syndrome due to a C3 gain-of-function mutation diagnosed in infancy. She was treated from the start with a constant dose of 300 mg eculizumab every second week from the onset and followed by routine complement analyses for six years. Her complement system was completely inhibited and the dose interval was prolonged from 2 to 3 weeks without alteration of the dose and the complement activity continued to be completely inhibited. Blood samples taken immediately before, immediately after, and between eculizumab doses were analyzed for eculizumab-C5 complexes and percentage of total complement activity, using the Wieslab® test, and compared to a pool of sera from 20 healthy controls. The patient exhibited complete complement inhibition at all three time-points and had no free circulating C5 suggesting there was complete binding to eculizumab. She has now been treated for six years with full complement blockade. We suggest therefore that analysis of complement activity using the Wieslab® test is useful for evaluating the effect of eculizumab when dose intervals are prolonged.
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http://dx.doi.org/10.1155/2018/3810249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312603PMC
December 2018

Estimating glomerular filtration rate in children: evaluation of creatinine- and cystatin C-based equations.

Pediatr Nephrol 2019 02 31;34(2):301-311. Epub 2018 Aug 31.

Department of Medical Biochemistry, Oslo University Hospital, PB 4950 Nydalen, 0424, Oslo, Norway.

Background: Glomerular filtration rate (GFR) estimated by creatinine- and/or cystatin C-based equations (eGFR) is widely used in daily practice. The purpose of our study was to compare new and old eGFR equations with measured GFR (mGFR) by iohexol clearance in a cohort of children with chronic kidney disease (CKD).

Methods: We examined 96 children (median age 9.2 years (range 0.25-17.5)) with CKD stages 1-5. A 7-point iohexol clearance (GFR7p) was defined as the reference method (median mGFR 66 mL/min/1.73 m, range 6-153). Ten different eGFR equations, with or without body height, were evaluated: Schwartz, Schwartz, Schwartz, CAPA, LM, (LM + CAPA) / 2, FAS, FAS, FAS, FAS. The accuracy was evaluated with percentage within 10 and 30% of GFR7p (P10 and P30).

Results: In the group with mGFR below 60 mL/min/1.73 m, the Schwartz equation had the lowest median bias (interquartile range; IQR) 3.27 (4.80) mL/min/1.73 m and the highest accuracy with P10 of 44% and P30 of 85%. In the group with mGFR above 60 mL/min/1.73 m, the Schwartz presented with the lowest bias 3.41 (13.1) mL/min/1.73 m and P10 of 62% and P30 of 98%. Overall, the Schwartz had the lowest bias - 1.49 (13.5) mL/min/1.73 m and both Schwartz and Schwartz showed P30 of 90%. P10 was 44 and 48%, respectively.

Conclusions: The Schwartz and the combined Schwartz present with lower bias and higher accuracy as compared to the other equations. The Schwartz equation is a good height-independent alternative to the Schwartz equation in children and can be reported directly by the laboratory information system.

Clinical Trial Registration: ClinicalTrials.gov , Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2.
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http://dx.doi.org/10.1007/s00467-018-4067-3DOI Listing
February 2019

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

Am J Transplant 2019 03 18;19(3):811-822. Epub 2018 Oct 18.

Novartis Pharma AG, Basel, Switzerland.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m with EVR/rTAC and 72.5 mL/min/1.73 m for sTAC/MMF (difference 3.8 mL/min/1.73m ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.
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http://dx.doi.org/10.1111/ajt.15081DOI Listing
March 2019

Small effort, high impact: Focus on physical activity improves oxygen uptake (VO ), quality of life, and mental health after pediatric renal transplantation.

Pediatr Transplant 2018 Jun 19:e13242. Epub 2018 Jun 19.

Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.

This study estimates the effects on peak oxygen uptake (VO ), QoL, and mental health after the introduction of an adjusted post-transplant follow-up program, that is, early physiotherapy and focus on the importance of physical activity. VO was measured by a treadmill exercise test in 20 renal-transplanted children on the adjusted post-transplant follow-up and compared with a group of 22 patients investigated in a previously, before the implementation of our new follow-up routines. PedsQL and The Strengths and Difficulties Questionnaire (SDQ) were used to assess QoL and mental health in 45 patients on the new as compared to 32 patients on the previous follow-up strategy. The patients exposed to early physiotherapy and a higher focus on physical activity had significantly higher VO (44.3 vs 33.5 mL kg  min , P = .031) in addition to improved QoL (P = .003) and mental health scores (P = .012). The cardiovascular risk profile was similar in both groups aside from significantly higher triglycerides in the present cohort. Small efforts as early physiotherapy and increased focus on physical activity after pediatric renal transplantation have significant impact on cardiorespiratory fitness, QoL, and mental health. The importance of physical activity should therefore be emphasized in follow-up programs.
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http://dx.doi.org/10.1111/petr.13242DOI Listing
June 2018

Standardization of pediatric uroradiological terms: A multidisciplinary European glossary.

J Pediatr Urol 2017 Dec 13;13(6):641-650. Epub 2017 Jul 13.

Pediatric Nephrology, Centro Hospitalar São João, Porto, Portugal.

To promote the standardization of nephro-uroradiological terms used in children, the European Society of Pediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication among different clinicians involved in pediatric urology and nephrology.
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http://dx.doi.org/10.1016/j.jpurol.2017.05.026DOI Listing
December 2017

Standardization of pediatric uroradiological terms: a multidisciplinary European glossary.

Pediatr Radiol 2018 02 15;48(2):291-303. Epub 2017 Nov 15.

Pediatric Nephrology, Centro Hospitalar São João, Porto, Portugal.

To promote the standardization of nephro-uroradiological terms used in children, the European Society of Paediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication between different clinicians involved in pediatric urology and nephrology.
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http://dx.doi.org/10.1007/s00247-017-4006-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790858PMC
February 2018

Iohexol plasma clearance in children: validation of multiple formulas and single-point sampling times.

Pediatr Nephrol 2018 04 13;33(4):683-696. Epub 2017 Nov 13.

Laboratory for Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.

Background: The non-ionic agent iohexol is increasingly used as the marker of choice for glomerular filtration rate (GFR) measurement. Estimates of GFR in children have low accuracy and limiting the number of blood-draws in this patient population is especially relevant. We have performed a study to evaluate different formulas for calculating measured GFR based on plasma iohexol clearance with blood sampling at only one time point (GFR1p) and to determine the optimal sampling time point.

Methods: Ninety-six children with chronic kidney disease (CKD) stage 1-5 (median age 9.2 years; range 3 months to 17.5 years) were examined in a cross-sectional study using iohexol clearance and blood sampling at seven time points within 5 h (GFR7p) as the reference method. Median GFR7p was 66 (range 6-153) mL/min/1.73 m. The performances of six different single time-point formulas (Fleming, Ham and Piepsz, Groth and Aasted, Stake, Jacobsson- and Jacobsson-modified) were validated against the reference. The two-point GFR (GFR2p) was calculated according to the Jødal and Brøchner-Mortensen formula.

Results: The GFR1p calculated according to Fleming with sampling at 3 h (GFR1p-Fleming) had the best overall performance, with 82% of measures within 10% of the reference value (P10). In children with a GFR ≥ 30 mL/min/1.73 m (n = 78), the GFR1p-Fleming had a P10 of 92.3%, which is not significantly different (p = 0.29) from that of GFR2p (P10 = 96.2%). Considerable differences within and between the different formulas were found for different CKD stages and different time points for blood sampling.

Conclusions: For determination of mGFR in children with CKD and an assumed GFR of ≥ 30 mL/min/1.73 m we recommend GFR1p-Fleming as the preferred single-point method as an alternative to GFR2p. For children with a GFR < 30 mL/min/1.73 m, we recommend the slope-GFR with at least two blood samples.

Clinical Trial Registration: ClinicalTrials.gov , Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2.
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http://dx.doi.org/10.1007/s00467-017-3841-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859061PMC
April 2018

Renal Function Influences Diagnostic Markers in Serum and Urine: A Study of Guanidinoacetate, Creatine, Human Epididymis Protein 4, and Neutrophil Gelatinase-Associated Lipocalin in Children.

J Appl Lab Med 2017 Nov;2(3):297-308

Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.

Background: Impaired renal function may affect the level of diagnostic disease markers. The aim of the study was to investigate the effect of measured glomerular filtration rate (GFR) on 4 diagnostic markers in blood and urine-guanidinoacetate (GAA), creatine (CRE), human epididymis protein 4 (HE4), and neutrophil gelatinase-associated lipocalin (NGAL)-and how this could affect the decision and reference limits.

Methods: We examined 96 children (median age 9.2 years, range 0.25-17.5) with different stages of chronic kidney disease (CKD). GFR [median 65.9 mL · min-1 · (1.73 m2)-1, range 6.3-153] was measured by iohexol clearance using 7 venous blood samples after iohexol injection. Fasting serum and urinary GAA, CRE, HE4, NGAL, and creatinine (crn) were analyzed. After appropriate transformation of the markers, a multiple linear regression analysis examined the influence of age, sex, and measured GFR.

Results: The level of GFR significantly affected S-GAA (P = 2 × 10-4) and U-GAA/crn (P = 5 ×10-11), leading to decreased values in renal impairment. GFR did not correlate significantly with the level of CRE and to a minor degree did the U-CRE/crn ratio (P = 0.54 and 0.01, respectively). The level of GFR significantly affected S-HE4 (P = 4 × 10-31) and U-HE4/S-HE4 ratio (P = 2 × 10-21) with increased serum values and decreased U-HE4/S-HE4 ratio in renal impairment. S-NGAL increased with decreasing kidney function (P = 2 × 10-19).

Conclusions: Diagnostic disease markers may be influenced by the renal function, and this must be taken into account when interpreting test results. Decreased renal function could change the level of the marker above or below decision limits, leading to diagnostic misinterpretation.

Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2.
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http://dx.doi.org/10.1373/jalm.2016.022145DOI Listing
November 2017

Renal involvement in paediatric systemic vasculitis.

Tidsskr Nor Laegeforen 2017 10 16;137(19). Epub 2017 Oct 16.

Background: Primary systemic vasculitis is a rare condition in children, which often has a slowly progressive course with diffuse symptoms and is therefore easily overlooked. Early initiation of treatment can prevent severe kidney disease. The aim of this study was to survey the extent of renal involvement in children with systemic vasculitis at Oslo University Hospital, Rikshospitalet.

Material And Method: This observational retrospective study was based on a review of medical records, laboratory results and renal biopsies from first admission to last check-up at Oslo University Hospital, Rikshospitalet, for the period 2000–14.

Results: A total of 66 children (35 boys) under 18 years of age were treated at the hospital for primary systemic vasculitis in the period in question. Objective signs of renal involvement were found in 39 (59 %) at the first consultation and in 42 (64 %) over the course of the disease. Twenty-nine patients (44 %) underwent renal biopsy. Of the 41 patients with proven renal involvement that were still alive at the time of the last check-up, 12 continued to require treatment for renal impairment. Three patients had undergone renal transplantation, 18 were in remission on immunosuppressive or antihypertensive treatment, while 11 patients had achieved medication-free renal remission.

Interpretation: There is a high prevalence of renal involvement in paediatric patients treated for systemic vasculitis at Oslo University Hospital, Rikshospitalet. At their final check-up, the majority of patients continue to require treatment and follow-up for kidney disease.
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http://dx.doi.org/10.4045/tidsskr.16.0592DOI Listing
October 2017

Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients-A Prospective Study.

Ther Drug Monit 2017 10;39(5):472-482

Departments of *Medical Biochemistry and †Pediatrics, Oslo University Hospital; ‡School of Pharmacy, University of Oslo; and §Department of Pharmacology, Oslo University Hospital, Oslo, Norway.

Background: Prednisolone is a standard component of immunosuppressive protocols in renal transplantation (Tx) and despite standardized treatment regimens, adverse side effects are still frequent. The aim of this study was to characterize the pharmacokinetics of prednisolone and prednisone in pediatric renal transplant recipients in the first 52 weeks post Tx, to describe the relationship between prednisolone and prednisone, and to investigate a possible relationship between the development of new-onset diabetes after Tx (NODAT) and glucocorticoid exposure.

Methods: Renal transplant recipients receiving prednisolone (n = 11, age 1-15 years) were included in this prospective open-label, descriptive, nonrandomized, and noninterventional study. Blood samples were drawn pre-Tx and during selected dose intervals (0, 1, 2, 4, 6, and 12 hours postdose; less frequent in children <10 kg) at 1, 2, 3, 4, 12, and 52 weeks post-Tx. Concentrations of prednisolone and cortisol, their inactive keto forms, plus methylprednisolone, were measured using a validated LC-MS/MS method. Genetic variants in the CYP3A4, CYP3A5, ABCB1, and HSD11B2 genes were analyzed using real-time polymerase chain reaction and Sanger sequencing. Correlation with NODAT was investigated.

Results: The patients displayed considerable intra- and inter-individual variability in prednisolone exposure, with up to 5-fold differences in the area under the concentration-time curve (AUC). There were up to 7-fold differences in prednisolone/prednisone AUC ratio between patients, and patients experiencing NODAT tended to have a higher ratio (>12) compared with patients without NODAT (<12). Genetic variants in CYP3A5 and ABCB1 were found, but due to the limited study population causality cannot be definitive.

Conclusions: The study suggests that a high prednisolone/prednisone AUC ratio may be a possible risk factor for NODAT. Further studies of individualization of glucocorticoid treatment in pediatric organ Tx are warranted.
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http://dx.doi.org/10.1097/FTD.0000000000000439DOI Listing
October 2017

Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis.

Lancet 2017 May 20;389(10084):2128-2137. Epub 2017 Mar 20.

ESPN/ERA-EDTA Registry, Amsterdam, Netherlands.

Background: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors.

Methods: In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy.

Findings: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15·8 deaths per 1000 patient-years (IQR 6·4-16·4). France had a mortality rate (9·2) of more than 3 SDs better, and Russia (35·2), Poland (39·9), Romania (47·4), and Bulgaria (68·6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0·69, 95% CI 0·52-0·91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1·31 [95% CI 1·13-1·53], p=0·0005, to 1·21 [0·97-1·51], p=0·10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%.

Interpretation: Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and quality of paediatric renal care. Differences between countries in their ability to accept and treat the youngest patients, who are the most complex and costly to treat, form an important source of disparity within this population. Our findings can be used by policy makers and health-care providers to explore potential strategies to help reduce these health disparities.

Funding: ERA-EDTA and ESPN.
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http://dx.doi.org/10.1016/S0140-6736(17)30063-6DOI Listing
May 2017