Publications by authors named "Franz Schaefer"

383 Publications

Publisher Correction: Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group.

Nat Rev Nephrol 2021 Apr 30. Epub 2021 Apr 30.

Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

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http://dx.doi.org/10.1038/s41581-021-00431-5DOI Listing
April 2021

Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.

Kidney Int 2021 Apr 30. Epub 2021 Apr 30.

Department of Pediatrics, University Hospital Cologne and University of Cologne, Faculty of Medicine, Cologne, Germany.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.
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http://dx.doi.org/10.1016/j.kint.2021.04.019DOI Listing
April 2021

Fiji plugins for qualitative image annotations: routine analysis and application to image classification.

F1000Res 2020 15;9:1248. Epub 2020 Oct 15.

Acquifer Imaging GmbH, Heidelberg, Germany.

Quantitative measurements and qualitative description of scientific images are both important to describe the complexity of digital image data. While various software solutions for quantitative measurements in images exist, there is a lack of simple tools for the qualitative description of images in common user-oriented image analysis software. To address this issue, we developed a set of Fiji plugins that facilitate the systematic manual annotation of images or image-regions. From a list of user-defined keywords, these plugins generate an easy-to-use graphical interface with buttons or checkboxes for the assignment of single or multiple pre-defined categories to full images or individual regions of interest. In addition to qualitative annotations, any quantitative measurement from the standard Fiji options can also be automatically reported. Besides the interactive user interface, keyboard shortcuts are available to speed-up the annotation process for larger datasets. The annotations are reported in a Fiji result table that can be exported as a pre-formatted csv file, for further analysis with common spreadsheet software or custom automated pipelines. To illustrate possible use case of the annotations, and facilitate the analysis of the generated annotations, we provide examples of such pipelines, including data-visualization solutions in Fiji and KNIME, as well as a complete workflow for training and application of a deep learning model for image classification in KNIME. Ultimately, the plugins enable standardized routine sample evaluation, classification, or ground-truth category annotation of any digital image data compatible with Fiji.
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http://dx.doi.org/10.12688/f1000research.26872.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014705PMC
April 2021

European Reference Networks: challenges and opportunities.

J Community Genet 2021 Mar 17. Epub 2021 Mar 17.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

European Reference Networks (ERNs) were founded on the principle that many rare disease (RD) issues are pan-European and any single Member State cannot solve them alone. In 2021, ERNs are already in the deployment stage; however, their day-to-day functioning and realization of their potential are still severely hampered by many challenges, including issues in governance and regulation, lack of legal status, insufficient and unsustainable funding, lack of ERN integration into national systems, endangered collaboration with UK RD experts due to Brexit, insufficient exploitation of ERN potential in RD research, underappreciation of highly qualified human resources, problems with the involvement of patient representatives, and still unclear place of ERNs in the overall European RD and digital ecosystem. Bold and innovative solutions that must be taken to solve these challenges inevitably involve pan-European collaboration across several sectors and among multistakeholder RD communities and in many cases crucially rely on the constructive dialogue and coherent, united decisions of national and European authorities that are based on common EU values. Importantly, unresolved challenges may have a strong impact on the further sustainability of ERNs and their ability to realize full potential in addressing huge unmet needs of RD patients and their families.
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http://dx.doi.org/10.1007/s12687-021-00521-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968406PMC
March 2021

Hemodiafiltration maintains a sustained improvement in blood pressure compared to conventional hemodialysis in children-the HDF, heart and height (3H) study.

Pediatr Nephrol 2021 Feb 24. Epub 2021 Feb 24.

Division of Pediatrics, Department of Medicine, University of Udine, Udine, Italy.

Background: Hypertension is prevalent in children on dialysis and associated with cardiovascular disease. We studied the blood pressure (BP) trends and the evolution of BP over 1 year in children on conventional hemodialysis (HD) vs. hemodiafiltration (HDF).

Methods: This is a post hoc analysis of the "3H - HDF-Hearts-Height" dataset, a multicenter, parallel-arm observational study. Seventy-eight children on HD and 55 on HDF who had three 24-h ambulatory BP monitoring (ABPM) measures over 1 year were included. Mean arterial pressure (MAP) was calculated and hypertension defined as 24-h MAP standard deviation score (SDS) ≥95th percentile.

Results: Poor agreement between pre-dialysis systolic BP-SDS and 24-h MAP was found (mean difference - 0.6; 95% limits of agreement -4.9-3.8). At baseline, 82% on HD and 44% on HDF were hypertensive, with uncontrolled hypertension in 88% vs. 25% respectively; p < 0.001. At 12 months, children on HDF had consistently lower MAP-SDS compared to those on HD (p < 0.001). Over 1-year follow-up, the HD group had mean MAP-SDS increase of +0.98 (95%CI 0.77-1.20; p < 0.0001), whereas the HDF group had a non-significant increase of +0.15 (95%CI -0.10-0.40; p = 0.23). Significant predictors of MAP-SDS were dialysis modality (β = +0.83 [95%CI +0.51 - +1.15] HD vs. HDF, p < 0.0001) and higher inter-dialytic-weight-gain (IDWG)% (β = 0.13 [95%CI 0.06-0.19]; p = 0.0003).

Conclusions: Children on HD had a significant and sustained increase in BP over 1 year compared to a stable BP in those on HDF, despite an equivalent dialysis dose. Higher IDWG% was associated with higher 24-h MAP-SDS in both groups.
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http://dx.doi.org/10.1007/s00467-021-04930-2DOI Listing
February 2021

U-IMD: the first Unified European registry for inherited metabolic diseases.

Orphanet J Rare Dis 2021 02 18;16(1):95. Epub 2021 Feb 18.

Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, Centre for Child and Adolescent Medicine, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI).

Results: In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered.

Conclusion: The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies.
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http://dx.doi.org/10.1186/s13023-021-01726-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893973PMC
February 2021

Differential assessment of fluid compartments by bioimpedance in pediatric patients with kidney diseases.

Pediatr Nephrol 2021 Feb 12. Epub 2021 Feb 12.

Pediatric Nephrology Division, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Background: The kidney is central for maintaining water balance. As a corollary, patients with impaired kidney function are prone to pathological fluid volumes. Total body water (TBW) is distributed between the extracellular (ECW) and intracellular fluid compartments (ICW). In clinical practice, the judgment of hydration status does not allow to distinguish between ECW and ICW. Here, we evaluate the hydration status in children with chronic kidney disease by analyzing TBW, ECW, and ICW.

Methods: Hydration was quantified using whole-body bioimpedance spectroscopy (BCM) in 128 outpatients (1-25 years, 52 girls). Forty-two were transplanted (TPL), 43 suffered from chronic kidney disease without kidney replacement therapy (CKD), 21 were on peritoneal dialysis (PD), and 22 on hemodialysis (HD). HD patients were investigated before, after, and sequentially during dialysis.

Results: The ECW and ICW values obtained by BCM were of the same magnitude as those from the literature using isotope dilution. When compared with a healthy control group, TBW was increased in 9 TPL, 9 CKD, 1 PD, and 11 HD patients before but in none after dialysis. The decline of overhydration during dialysis (p < 0.001, n = 22) correlated with the change in body weight (R = 0.62). The kinetics of fluid compartment changes assessed twice in six HD patients revealed a reproducible linear decay of the ECW/ICW ratio due to an increase of ICW and a decrease of ECW.

Conclusion: BCM quantifies TBW and acute changes of ECW and ICW in children with chronic kidney failure. The clinical utility of measuring TBW, ECW, and ICW should be defined in the future.
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http://dx.doi.org/10.1007/s00467-020-04912-wDOI Listing
February 2021

Mortality in Children Treated With Maintenance Peritoneal Dialysis: Findings From the International Pediatric Peritoneal Dialysis Network Registry.

Am J Kidney Dis 2021 Feb 5. Epub 2021 Feb 5.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University, Heidelberg, Germany.

Rationale & Objective: Research on pediatric kidney replacement therapy (KRT) has primarily focused on Europe and North America. In this study, we describe the mortality risk of children treated with maintenance peritoneal dialysis (MPD) in different parts of the world and characterize the associated demographic and macroeconomic factors.

Study Design: Prospective cohort study.

Setting & Participants: Patients younger than 19 years at inclusion into the International Pediatric Peritoneal Dialysis Network registry, who initiated MPD between 1996 and 2017.

Exposure: Region as primary exposure (Asia, Western Europe, Eastern Europe, Latin America, North America, and Oceania). Other demographic, clinical, and macroeconomic (4 income groups based on gross national income) factors also were studied.

Outcome: All-cause MPD mortality.

Analytical Approach: Patients were observed for 3 years, and the mortality rates in different regions and income groups were calculated. Cause-specific hazards models with random effects were fit to calculate the proportional change in variance for factors that could explain variation in mortality rates.

Results: A total of 2,956 patients with a median age of 7.8 years at the start of KRT were included. After 3 years, the overall probability of death was 5%, ranging from 2% in North America to 9% in Eastern Europe. Mortality rates were higher in low-income countries than in high-income countries. Income category explained 50.1% of the variance in mortality risk between regions. Other explanatory factors included peritoneal dialysis modality at start (22.5%) and body mass index (11.1%).

Limitations: The interpretation of interregional survival differences as found in this study may be hampered by selection bias.

Conclusions: This study shows that the overall 3-year patient survival on pediatric MPD is high, and that country income is associated with patient survival.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.031DOI Listing
February 2021

Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group.

Nat Rev Nephrol 2021 04 29;17(4):277-289. Epub 2021 Jan 29.

Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin-angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant.
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http://dx.doi.org/10.1038/s41581-020-00384-1DOI Listing
April 2021

Treatment and long-term outcome in primary nephrogenic diabetes insipidus.

Nephrol Dial Transplant 2020 Dec 26. Epub 2020 Dec 26.

Department of Paediatrics, Division of Nephrology, Erciyes University Faculty of Medicine, Kayseri,Turkey.

Background: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome.

Methods: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form.

Results: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0-60) years and at last follow-up 14.0 (0.1-70) years. In adults, height was normal with a mean (standard deviation) score of -0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients.

Conclusion: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems.
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http://dx.doi.org/10.1093/ndt/gfaa243DOI Listing
December 2020

COVID-19 in children treated with immunosuppressive medication for kidney diseases.

Arch Dis Child 2020 Dec 21. Epub 2020 Dec 21.

Division of Pediatric Nephrology, Heidelberg University Hospital, Heidelberg, Germany.

Background: Children are recognised as at lower risk of severe COVID-19 compared with adults, but the impact of immunosuppression is yet to be determined. This study aims to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess disease severity.

Methods: Cross-sectional study hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. Anonymised data were submitted online for any child (age <20 years) with COVID-19 taking immunosuppressive medication for a kidney condition. Study recruited for 16 weeks from 15 March 2020 to 05 July 2020. The primary outcome was severity of COVID-19.

Results: 113 children were reported in this study from 30 different countries. Median age: 13 years (49% male). Main underlying reasons for immunosuppressive therapy: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Immunosuppressive medications used include: glucocorticoids (76%), mycophenolate mofetil (MMF) (54%), tacrolimus/ciclosporine A (58%), rituximab/ofatumumab (11%). 78% required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications.

Conclusions: This global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection. We therefore suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy.
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http://dx.doi.org/10.1136/archdischild-2020-320616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754669PMC
December 2020

Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome.

BMC Nephrol 2020 11 30;21(1):520. Epub 2020 Nov 30.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Approximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant.

Methods: This is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed.

Discussion: The study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols.

Trial Registration: This trial was prospectively registered to the Clinicaltrial.gov ( NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/ ) and Clinical Trials Registry of India ( CTRI/2019/04/018517 dated 09/04/2019).
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http://dx.doi.org/10.1186/s12882-020-02153-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706288PMC
November 2020

Active vitamin D is cardioprotective in experimental uraemia but not in children with CKD Stages 3-5.

Nephrol Dial Transplant 2021 02;36(3):442-451

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: Uraemic cardiac remodelling is associated with vitamin D and Klotho deficiency, elevated fibroblast growth factor 23 (FGF23) and activation of the renin-angiotensin system (RAS). The cardioprotective properties of active vitamin D analogues in this setting are unclear.

Methods: In rats with 5/6 nephrectomy (5/6Nx) treated with calcitriol, the cardiac phenotype and local RAS activation were investigated compared with controls. A nested case-control study was performed within the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study, including children with chronic kidney disease (CKD) Stages 3-5 [estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m2] treated with and without active vitamin D. Echocardiograms, plasma FGF23 and soluble Klotho (sKlotho) were assessed at baseline and after 9 months.

Results: In rats with 5/6Nx, left ventricular (LV) hypertrophy, LV fibrosis and upregulated cardiac RAS were dose-dependently attenuated by calcitriol. Calcitriol further stimulated FGF23 synthesis in bone but not in the heart, and normalized suppressed renal Klotho expression. In the 4C study cohort, treatment over a mean period of 9 months with active vitamin D was associated with increased FGF23 and phosphate and decreased sKlotho and eGFR compared with vitamin D naïve controls, whereas LV mass index did not differ between groups.

Conclusions: Active vitamin D ameliorates cardiac remodelling and normalizes renal Klotho expression in 5/6Nx rats but does not improve the cardiac phenotype in children with CKD Stages 3-5. This discrepancy may be due to further enhancement of circulating FGF23 and faster progression of CKD associated with reduced sKlotho and higher serum phosphate in vitamin D-treated patients.
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http://dx.doi.org/10.1093/ndt/gfaa227DOI Listing
February 2021

Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice.

Sci Rep 2020 11 9;10(1):19302. Epub 2020 Nov 9.

Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Lindwurmstr.4, 80337, Munich, Germany.

Congenital obstructive nephropathy hinders normal kidney development. The severity and the duration of obstruction determine the compensatory growth of the contralateral, intact opposite kidney. We investigated the regulation of renal developmental genes, that are relevant in congenital anomalies of the kidney and urinary tract (CAKUT) in obstructed and contralateral (intact opposite) kidneys after unilateral ureteral obstruction (UUO) in neonatal and adult mice. Newborn and adult mice were subjected to complete UUO or sham-operation, and were sacrificed 1, 5, 12 and 19 days later. Quantitative RT-PCR was performed in obstructed, intact opposite kidneys and sham controls for Gdnf, Pax2, Six4, Six2, Dach1, Eya1, Bmp4, and Hnf-1β. Neonatal UUO induced an early and strong upregulation of all genes. In contrast, adult UUO kidneys showed a delayed and less pronounced upregulation. Intact opposite kidneys of neonatal mice revealed a strong upregulation of all developmental genes, whereas intact opposite kidneys of adult mice demonstrated only a weak response. Only neonatal mice exhibited an increase in BMP4 protein expression whereas adult kidneys strongly upregulated phosphatidylinositol 3 kinase class III, essential for compensatory hypertrophy. In conclusion, gene regulation differs in neonatal and adult mice with UUO. Repair and compensatory hypertrophy involve different genetic programs in developing and adult obstructed kidneys.
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http://dx.doi.org/10.1038/s41598-020-76328-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653944PMC
November 2020

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children.

PLoS One 2020 27;15(10):e0240446. Epub 2020 Oct 27.

Division of Pediatric Nephrology, Center of Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591021PMC
December 2020

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD).

Sci Rep 2020 09 29;10(1):16025. Epub 2020 Sep 29.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4-15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.
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http://dx.doi.org/10.1038/s41598-020-71956-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525474PMC
September 2020

Pediatric kidney transplantation in China: an analysis from the IPNA Global Kidney Replacement Therapy Registry.

Pediatr Nephrol 2021 Mar 15;36(3):685-692. Epub 2020 Sep 15.

Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.

Background: The International Pediatric Nephrology Association (IPNA) Global Kidney Replacement Therapy (KRT) Registry was established to evaluate the incidence and outcomes of kidney replacement therapy (dialysis and transplantation) provided to children worldwide. Analysis of registry data for separate regions is feasible.

Methods: Three centers located in Shanghai, Guangzhou, and Zhengzhou, which have the greatest number of pediatric kidney transplantation cases in China, participated in this analysis of transplant data. Data were registered by each center for patients under the age of 19 years who received a single-organ kidney transplant for the first time between 2011 and 2018.

Results: In total, 415 patients (59.8% male) aged 1.4-18.7 (median 12.1) years were followed for 0.3-97.1 (median 27.7) months. The number of kidney transplants increased from a total of 129 during 2011-2014 to 286 cases during 2015-2018. 85.8% of patients received the transplanted kidney from a pediatric (age < 19 years) donor, and deceased donors accounted for 94% of all donors. 8.0% of grafts were lost. One and 5-year patient survival rates were 97.6% and 95.5%, respectively. The major cause of death was infection (7/14). Similar graft and patient survival rates were observed for organs from pediatric and adult donors in 6-11 and 12-18 year recipient age groups, whereas recipients < 6 years showed inferior patient and graft survival.

Conclusions: Pediatric kidney transplantation shows favorable short-term and medium-term outcomes in China. Our experience supports use of pediatric donors in pediatric kidney transplantation, but attention directed to the outcome of recipients aged under 6 is necessary. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04745-7DOI Listing
March 2021

Pathophysiology and consequences of arterial stiffness in children with chronic kidney disease.

Pediatr Nephrol 2020 Sep 7. Epub 2020 Sep 7.

Great Ormond Street Hospital for Children NHS Foundation Trust, University College London, Institute of Child Health, London, UK.

Changes in arterial structure and function are seen early in the course of chronic kidney disease (CKD) and have been causally associated with cardiovascular (CV) morbidity. Numerous potential injuries encompassing both traditional and uremia-specific CV risk factors can induce structural arterial changes and accelerate arterial stiffening. When the buffering capacity of the normally elastic arteries is reduced, damage to vulnerable microcirculatory beds can occur. Moreover, the resultant increase to cardiac afterload contributes to the development of left ventricular hypertrophy and cardiac dysfunction. Adult studies have linked arterial stiffness with increased risk of mortality, CV events, cognitive decline, and CKD progression. Pulse wave velocity (PWV) is currently the gold standard of arterial stiffness assessment but its measurement in children is challenging due to technical difficulties and physiologic aspects related to growth and poor standardization between algorithms for calculating PWV. Nevertheless, studies in pediatric CKD have reported increased arterial stiffness in children with advanced CKD, on dialysis, and after kidney transplantation. Development of arterial stiffness in children with CKD is closely related to mineral-bone disease and hypertension, but other factors may also play a significant role. The clinical relevance of accelerated arterial stiffness in childhood on cardiovascular outcomes in adult life remains unclear, and prospective studies are needed. In this review we discuss mechanisms leading to arterial stiffness in CKD and its clinical implications, along with issues surrounding the technical aspects of arterial stiffness assessment in children.
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http://dx.doi.org/10.1007/s00467-020-04732-yDOI Listing
September 2020

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease.

Kidney Int 2021 03 1;99(3):737-749. Epub 2020 Aug 1.

Department of Pediatrics, Hôpital Nord, CHU de Saint Etienne, Saint Etienne, France.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.
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http://dx.doi.org/10.1016/j.kint.2020.06.043DOI Listing
March 2021

Patient- and parent proxy-reported outcome measures for life participation in children with chronic kidney disease: a systematic review.

Nephrol Dial Transplant 2020 11;35(11):1924-1937

Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia.

Background: The burden of chronic kidney disease (CKD) and its treatment may severely limit the ability of children with CKD to do daily tasks and participate in family, school, sporting and recreational activities. Life participation is critically important to affected children and their families; however, the appropriateness and validity of available measures used to assess this outcome are uncertain. The aim of this study was to identify the characteristics, content and psychometric properties of existing measures for life participation used in children with CKD.

Methods: We searched MEDLINE, Embase, PsychINFO, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Kidney and Transplant register to August 2019 for all studies that used a measure to report life participation in children with CKD. For each measure, we extracted and analyzed the characteristics, dimensions of life participation and psychometric properties.

Results: From 128 studies, we identified 63 different measures used to assess life participation in children with CKD. Twenty-five (40%) of the measures were patient reported, 7 (11%) were parent proxy reported and 31 (49%) had both self and parent proxy reports available. Twenty-two were used in one study only. The Pediatric Quality of Life Inventory version 4.0 generic module was used most frequently in 62 (48%) studies. Seven (11%) were designed to assess ability to participate in life, with 56 (89%) designed to assess other constructs (e.g. quality of life) with a subscale or selected questions on life participation. Across all measures, the three most frequent activities specified were social activities with friends and/or family, leisure activities and self-care activities. Validation data in the pediatric CKD population were available for only 19 (30%) measures.

Conclusions: Life participation is inconsistently measured in children with CKD and the measures used vary in their characteristics, content and validity. Validation data supporting these measures in this population are often incomplete and are sparse. A meaningful and validated measure for life participation in children with CKD is needed.
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http://dx.doi.org/10.1093/ndt/gfaa132DOI Listing
November 2020

A phenomenographic study: Exploring the variations of registered nurses' perceived roles and experiences as HIV counselors.

Enferm Clin 2020 06;30 Suppl 5:216-220

MSU-Iligan Institute of Technology, Andres Bonifacio Ave., Tibanga, Iligan City, 9200 Lanao del Norte, Philippines.

Objectives: The study explored the variations of registered nurses' perceived roles and experiences before, during and after HIV counseling.

Methods: The study is anchored on Parse's Human Becoming Theory structured around three abiding themes: meaning, rhythmicity, and transcendence. A qualitative phenomenographical approach was used and the data were collected through semi structured, face-to-face, in-depth interview sessions with ten registered nurses who were eligible under the set criterion: HIV counselors employed in both government and private health facilities with HIV Testing and Counseling facilities and services in Iligan City and Cagayan de Oro City. Verbatim transcriptions were analyzed in iterative process using Jan Larssons and Inger Holmstrom's (2007) seven simple steps of phenomenographic analysis. Triangulation and validation established rigor and trustworthiness of the data.

Results: Emergent themes of differences in participants' perceived roles and experiences conveyed in a metaphor: The Employee vs. The Educator; The Professional vs. The Shepherd.

Conclusion: The variations ascertained the association of perceived roles and experiences of HIV Counselors and posited equally vast challenges as nursing takes the core in collaboration for the care of persons living with HIV toward a dignified death.
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http://dx.doi.org/10.1016/j.enfcli.2019.11.058DOI Listing
June 2020

[Kidney Cysts and Cystic Nephropathies in Children - A Consensus Guideline by 10 German Medical Societies].

Klin Padiatr 2020 Sep 13;232(5):228-248. Epub 2020 Jul 13.

Center for Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology, University Hospital Heidelberg, Heidelberg.

This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.
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http://dx.doi.org/10.1055/a-1179-0728DOI Listing
September 2020

Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet-ESPN inherited glomerulopathy working group.

Eur J Hum Genet 2020 10 28;28(10):1368-1378. Epub 2020 May 28.

Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases (MARHEA), Necker Hospital, APHP, 75015, Paris, France.

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype-phenotype correlations.
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http://dx.doi.org/10.1038/s41431-020-0642-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608398PMC
October 2020

Targeting optimal PD management in children: what have we learned from the IPPN registry?

Pediatr Nephrol 2021 May 27;36(5):1053-1063. Epub 2020 May 27.

Children's Mercy Hospital, Kansas City, KS, USA.

National and international registries have great potential for providing data that describe disease burden, treatments, and outcomes especially in rare diseases. In the setting of pediatric end-stage renal disease (ESRD), the available data are limited to highly developed countries, whereas the lack of data from emerging economies blurs the global perspective. In order to improve the pediatric dialysis care worldwide, provide global benchmarking of pediatric dialysis outcome, and assign useful tools and management algorithms based on evidence-based medicine, the International Pediatric Peritoneal Dialysis Network (IPPN) was established in 2007. In recent years, the Registry has provided comprehensive data on relevant clinical issues in pediatric peritoneal dialysis patients including nutritional status, growth, cardiovascular disease, anemia management, mineral and bone disorders, preservation of residual kidney function, access-related complications, and impact of associated comorbidities. A unique feature of the registry is the ability to compare practices and outcomes between countries and world regions. In the current review, we describe study design and collection methods, summarize the core IPPN findings based on its 12-year experience and 13 publications, and discuss the future perspective.
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http://dx.doi.org/10.1007/s00467-020-04598-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009785PMC
May 2021

The severity of COVID-19 in children on immunosuppressive medication.

Lancet Child Adolesc Health 2020 07 13;4(7):e17-e18. Epub 2020 May 13.

Department of Nephrology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.

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http://dx.doi.org/10.1016/S2352-4642(20)30145-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220160PMC
July 2020

Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

Kidney Int 2020 06 9;97(6):1117-1129. Epub 2020 Mar 9.

Executive Managing Editor, Kidney International.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.
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http://dx.doi.org/10.1016/j.kint.2020.02.010DOI Listing
June 2020

IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome.

Pediatr Nephrol 2020 08 7;35(8):1529-1561. Epub 2020 May 7.

Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
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http://dx.doi.org/10.1007/s00467-020-04519-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316686PMC
August 2020

Cinacalcet studies in pediatric subjects with secondary hyperparathyroidism receiving dialysis.

Pediatr Nephrol 2020 09 4;35(9):1679-1697. Epub 2020 May 4.

Department of Pediatric Nephrology, Rheumatology and Dermatology, Femme Mère Enfant Hospital, Bron, France.

Background: Secondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe.

Methods: This review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies.

Results: The Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies.

Conclusions: To help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.
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http://dx.doi.org/10.1007/s00467-020-04516-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385021PMC
September 2020

Targeting Tubulointerstitium to Predict Kidney Outcomes in Childhood Nephrotic Syndrome.

Kidney Int Rep 2020 Apr 21;5(4):383-385. Epub 2020 Jan 21.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.ekir.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136428PMC
April 2020

Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy.

Nat Rev Nephrol 2020 08 8;16(8):471-482. Epub 2020 Apr 8.

Division of Nephrology, University of Missouri-Kansas City School of Medicine, Children's Mercy, Kansas City, MO, USA.

Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.
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http://dx.doi.org/10.1038/s41581-020-0267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366888PMC
August 2020