Publications by authors named "Jérôme Harambat"

115 Publications

Preemptive Kidney Transplantation is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.

Transplantation 2021 Mar 18. Epub 2021 Mar 18.

1 University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR1219, Bordeaux, France. 2 Pediatric Nephrology Unit, Pellegrin-Enfants Hospital, Bordeaux University Hospital, Centre de Référence Maladies Rénales Rares Sorare, Bordeaux, France. 3 Pediatric Nephrology Unit, Robert Debré Hospital, Centre de Référence Maladies Rénales Rares Marhea, APHP, Paris, France. 4 Agence de la Biomédecine, REIN Registry, La Plaine-Saint Denis, France. 5 Pediatric Nephrology Unit, Necker Enfants-Malades Hospital, Centre de Référence Maladies Rénales Rares Marhea, APHP, Paris Descartes University, Paris, France. 6 Pediatric Nephrology Unit, Femme-Mère-Enfant Hospital, Lyon University Hospital, Centre de Référence Maladies Rénales Rares Nephrogones, Bron, France. 7 France Pediatric Nephrology Unit, Femme-Enfant-Adolescent Hospital, Nantes University Hospital, Nantes, France. 8 Pediatric Nephrology Unit, Jeanne de Flandre Hospital, Lille University Hospital, Lille, France. 9 Pediatric Nephrology Unit, Timone-Enfants Hospital, Marseille University Hospital, Marseille, France. 10 Pediatric Nephrology Unit, Children's Hospital, Toulouse University Hospital, Centre de Référence Maladies Rénales Rares Sorare, Toulouse, France. 11 Pediatric Nephrology Unit, Trousseau Hospital, Centre de Référence Maladies Rénales Rares Marhea, APHP, Paris, France. 12Pediatric Nephrology Unit, Arnaud de Villeneuve Hospital, Montpellier University Hospital, Centre de Référence Maladies Rénales Rares Sorare, Montpellier, France. 13 Pediatric Nephrology Unit, Felix Guyon Hospital, La Réunion University Hospital, Saint Denis, France. 14 Pediatric Nephrology Unit, Clocheville Hospital, Tours University Hospital, Tours, France. 15 Pediatric Nephrology Unit, Brabois Hospital, Nancy University Hospital, Vandoeuvre-les-Nancy, France. 15Pediatric Nephrology Unit, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France. 17 Pediatric Nephrology Unit, Archet Hospital, Nice University Hospital, Nice, France. 18 INSERM, Clinical Investigation Center-Clinical Epidemiology-CIC-1401, Bordeaux, France.

Background: Kidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease (ESKD). The aim of this study was to evaluate the impact of PKT and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.

Methods: We analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis or retransplant, whichever occurred first.

Results: 1911 patients were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 years. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared to patients transplanted after dialysis (HR 0.45; 95%CI 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when less than 6 months and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.

Conclusions: In France, PKT among pediatric patients is associated with a better graft survival when compared to KT after dialysis, even when less than 6 months. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with ESKD.
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http://dx.doi.org/10.1097/TP.0000000000003757DOI Listing
March 2021

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

Treatment strategy for Streptococcus pneumoniae-associated hemolytic uremic syndrome.

Pediatr Nephrol 2021 Mar 26. Epub 2021 Mar 26.

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

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http://dx.doi.org/10.1007/s00467-021-05053-4DOI Listing
March 2021

Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis.

Pediatr Nephrol 2021 Feb 26. Epub 2021 Feb 26.

Advicenne, Nîmes, France.

Background: A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months.

Methods: Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored.

Results: There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study.

Conclusions: Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable.

Trial Registration Number: Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.
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http://dx.doi.org/10.1007/s00467-020-04873-0DOI Listing
February 2021

A roadmap for optimizing chronic kidney disease patient care and patient-oriented research in the Eastern European nephrology community.

Clin Kidney J 2021 Jan 22;14(1):23-35. Epub 2020 Dec 22.

Division of Nephrology, Ambroise Paré University Hospital, APHP, University of Paris Ouest-Versailles-St-Quentin-en-Yvelines (UVSQ) av G De Gaulles Boulogne-Billancourt/Paris, x, FR 92100; Inserm U1018, CESP Team 5-Epidemiology of Renal and Cardiovascular Disease, Villejuif, France.

Chronic kidney disease (CKD) is a major health problem because of its high prevalence, associated complications and high treatment costs. Several aspects of CKD differ significantly in the Eastern European nephrology community compared with Western Europe because of different geographic, socio-economic, infrastructure, cultural and educational features. The two most frequent aetiologies of CKD, DM and hypertension, and many other predisposing factors, are more frequent in the Eastern region, resulting in more prevalent CKD Stages 3-5. Interventions may minimize the potential drawbacks of the high prevalence of CKD in Eastern Europe, which include several options at various stages of the disease, such as raising public, medical personnel and healthcare authorities awareness; early detection by screening high-risk populations; preventing progression and CKD-related complications by training health professionals and patients; promoting transplantation or home dialysis as the preferred modality; disseminating and implementing guidelines and guided therapy and encouraging/supporting country-specific observational research as well as international collaborative projects. Specific ways to significantly impact CKD-related problems in every region of Europe through education, science and networking are collaboration with non-nephrology European societies who have a common interest in CKD and its associated complications, representation through an advisory role within nephrology via national nephrology societies, contributing to the training of local nephrologists and stimulating patient-oriented research. The latter is mandatory to identify country-specific kidney disease-related priorities. Active involvement of patients in this research via collaboration with the European Kidney Patient Federation or national patient federations is imperative to ensure that projects reflect specific patient needs.
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http://dx.doi.org/10.1093/ckj/sfaa218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857792PMC
January 2021

Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies.

Pediatr Nephrol 2021 Jan 30. Epub 2021 Jan 30.

OxThera Intellectual Property AB, Stockholm, Sweden.

Background: In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01).

Methods: Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m were analyzed for a correlation between eGFR and Pox using Spearman's rank and Pearson's correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used.

Results: A total of 106 patients were analyzed. A statistically significant inverse Spearman's correlation between eGFR and Pox was observed across all analyses; correlation coefficients were - 0.44 in study OC3-DB-01, - 0.55 in study OC3-DB-02, - 0.51 in study OC5-DB-01, and - 0.49 in the pooled studies (p < 0.0064).

Conclusions: Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1-3b), demonstrating that a correlation is present before substantial loss in kidney function occurs.
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http://dx.doi.org/10.1007/s00467-020-04894-9DOI Listing
January 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

[Nephrocalcinosis in children].

Nephrol Ther 2021 Feb 15;17(1):58-66. Epub 2021 Jan 15.

Service de pédiatrie, unité de néphrologie pédiatrique, centre de références des maladies rénales rares, CHU de Bordeaux, place Amélie-Raba-Léon, 33000 Bordeaux, France. Electronic address:

Nephrocalcinosis is defined by calcium phosphate or calcium oxalate deposits in the kidney parenchyma, particularly in tubular epithelial cells and interstitial tissue. It should be differentiated from urolithiasis where calcium salts deposits are located in the kidney and urinary tract. The epidemiology of nephrocalcinosis in children is unknown but the condition is not so rare, with an increased incidence in preterm infants. Often detected as an incidental finding, nephrocalcinosis may be classified according to the radiological type: medullary, cortical or diffuse. Nephrocalcinosis in children can be caused by a variety of etiology. The most common causes concern medullary nephrocalcinosis and include hereditary tubular disorders, in particular distal renal tubular acidosis and Dent disease, metabolic disorders such as idiopathic hypercalciuria and hyperoxaluria, and iatrogenic causes such as vitamin D intoxication. In the newborn, the main cause is hypercalciuria of the premature baby, whose multifactorial origin is largely iatrogenic. Primary hyperoxaluria which can lead to early onset nephrocalcinosis and usually to chronic kidney disease should always be considered and further investigated. In order to provide a specific diagnosis, it is essential to take into account the family history, the clinical context and complete laboratory data. Early initiation of an appropriate etiological treatment is recommended and may prevent or delay the progression to chronic kidney disease in some cases.
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http://dx.doi.org/10.1016/j.nephro.2020.12.001DOI Listing
February 2021

Relapse rate of nephrotic syndrome in the time of COVID-19.

Pediatr Nephrol 2021 01 30;36(1):211-212. Epub 2020 Oct 30.

Pediatric Nephrology Unit, Centre de Référence Maladies Rénales Rares SoRare, Bordeaux University Hospital, Bordeaux, France.

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http://dx.doi.org/10.1007/s00467-020-04814-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595757PMC
January 2021

Dynamic prediction models for graft failure in paediatric kidney transplantation.

Nephrol Dial Transplant 2020 Sep 29. Epub 2020 Sep 29.

INSERM, Bordeaux Population Health Research Center, University of Bordeaux, UMR1219, Bordeaux, France.

Background: Several models have been proposed to predict kidney graft failure in adult recipients but none in younger recipients. Our objective was to propose a dynamic prediction model for graft failure in young kidney transplant recipients.

Methods: We included 793 kidney transplant recipients waitlisted before the age of 18 years who received a first kidney transplantation before the age of 21 years in France in 2002-13 and survived >90 days with a functioning graft. We used a Cox model including baseline predictors only (sex, age at transplant, primary kidney disease, dialysis duration, donor type and age, human leucocyte antigen matching, cytomegalovirus serostatus, cold ischaemia time and delayed graft function) and two joint models also accounting for post-transplant estimated glomerular filtration rate (eGFR) trajectory. Predictive performances were evaluated using a cross-validated area under the curve (AUC) and R2 curves.

Results: When predicting the risk of graft failure from any time within the first 7 years after paediatric kidney transplantation, the predictions for the following 3 or 5 years were accurate and much better with the joint models than with the Cox model (AUC ranged from 0.83 to 0.91 for the joint models versus 0.56 to 0.64 for the Cox model).

Conclusion: Accounting for post-transplant eGFR trajectory strongly increased the accuracy of graft failure prediction in young kidney transplant recipients.
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http://dx.doi.org/10.1093/ndt/gfaa180DOI Listing
September 2020

Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial.

BMJ Open 2020 09 23;10(9):e037306. Epub 2020 Sep 23.

Department of Pediatric Nephrology, Robert Debré Hospital, APHP, Paris, France.

Introduction: Guidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg's immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.

Methods And Analysis: We conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).

Ethics And Dissemination: The study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.

Trial Registration Number: NCT03560011.
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http://dx.doi.org/10.1136/bmjopen-2020-037306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513594PMC
September 2020

Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis.

Pediatr Nephrol 2021 Feb 27;36(2):341-347. Epub 2020 Aug 27.

Centre Hospitalier Universitaire de Bordeaux, Service de Pédiatrie, Centre de référence Maladies Rénales Rares du Sud-Ouest (SORARE), Bordeaux, France.

Background: Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce.

Methods: Retrospective study of 27 children with biopsy-proven lupus nephritis treated with MMF between 2008 and 2016. In 25 children, MPA-AUC was performed within 6 months after kidney biopsy and MMF initiation. Treatment response at 6 months was defined as normal or improved GFR by 25% compared with baseline, 50% reduction of proteinuria to < 0.5 g/day or 50 mg/mmol, and no hematuria.

Results: A total of 62 MPA-AUC were analyzed in 27 patients. Overall median was 44 mg h/L (interquartile range [IQR] 33-54). Individual dose adaptation was required in 32 cases (52%) to achieve target AUC of 30-60 mg h/L. At 6 months, 14/25 patients were defined as responders (56%, median MPA-AUC 49 mg h/L (40-59)) and 11/25 as non-responders (44%, 29 mg h/L (24-38)). Patients with MPA-AUC levels > 45, 30-45, and < 30 mg h/L had 6-month response rates of 89% (8/9), 60% (6/10), and 0% (0/6), respectively. In a logistic regression model adjusted for age, sex, lupus nephritis classification, and time since MMF initiation, an MPA-AUC > 45 mg h/L was significantly associated with therapeutic response (OR 3.6, 95% CI 2.4-9.5, p = 0.03).

Conclusions: Therapeutic drug monitoring leading to individualized dosing may improve efficacy of MMF. MPA-AUC > 45 mg h/L is associated with better response rate and may be considered as a target value in pediatric lupus nephritis.
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http://dx.doi.org/10.1007/s00467-020-04733-xDOI Listing
February 2021

Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

Pediatr Nephrol 2021 Jan 26;36(1):83-91. Epub 2020 Jul 26.

Advicenne, Nîmes, France.

Background: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme.

Methods: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety.

Results: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103.

Conclusions: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA.

Trial Registration: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04693-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701073PMC
January 2021

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.

ESPN/ERA-EDTA Registry, Amsterdam UMC, University of Amsterdam, Department of Medical Informatics, Amsterdam Public Health Research Institute, Meibergdreef 9, Amsterdam, The Netherlands.

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

Setting reasonable objectives for improving preemptive kidney transplantation rates in children.

Pediatr Nephrol 2020 12 25;35(12):2353-2360. Epub 2020 Jun 25.

Pediatric Nephrology Unit, Robert-Debré Hospital, APHP, Paris, France.

Background: This study aims to develop a method to estimate the potential of preemptive kidney transplantation (PKT) by identifying patients who were transplanted after a dialysis period (non-preemptive kidney transplantation (NPKT)) despite being medically suitable for PKT.

Methods: All children (< 18 years old) starting kidney replacement therapy (KRT) in France, between 2010 and 2016 and transplanted before December 31, 2017, were included. A propensity score (PS) of receiving PKT was estimated by multivariate logistic regression based on recipient medical characteristics. Healthcare use during the 24 months prior to KRT initiation was extracted from the French National Health Insurance database, and a pre-KRT follow-up of more than 18 months was considered sufficient to allow preemptive transplantation.

Results: Among 643 patients who started KRT, 149 (23.2%) were preemptively transplanted. Using PS stratification, among 391 NPKT patients, we identified 145 patients (37%) suitable for PKT, according to clinical characteristics. Mean age was 12.3 years, 67% were males, and 56% had urological abnormalities. Among those 145 patients, we identified 79 NPKT patients who started on dialysis despite early referral to a nephrologist (more than 18 months prior to KRT initiation).

Conclusions: This method estimates a potential of 228 (149 + 79) PKT (35%) among pediatric patients in France. A similar method could be used in adults or in other countries. Estimation of the rate of patients with CKD stage 5 medically suitable for PKT will be of interest for health policy makers when setting up objectives for improvement in preemptive kidney transplant access.
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http://dx.doi.org/10.1007/s00467-020-04653-wDOI Listing
December 2020

Ofatumumab treatment for nephrotic syndrome recurrence after pediatric renal transplantation.

Pediatr Nephrol 2020 08 18;35(8):1499-1506. Epub 2020 Apr 18.

Pediatric Department, University Hospital of Nantes, Nantes, France.

Background: Relapsing nephrotic syndrome (NS) after transplantation can be a challenge to treat. The result of the consequent long-lasting proteinuria is the loss of the graft. Disease recurrence after renal transplantation occurs in around half of cases, and the efficacy of therapeutic strategies is often limited. Recently, ofatumumab, a second-generation and fully human anti-CD20 monoclonal antibody, has been shown to be effective in severe situations.

Methods: We retrospectively collected data from the medical records of children with recurrence of NS after renal transplantation treated with ofatumumab in France, after failure of previous treatments.

Results: Six patients were included in this study in five centers with a median duration of follow-up of 10.5 months. Two different ofatumumab regimens were administered. The primary outcome was proteinuria at 6 months after the last dose of ofatumumab. No patient achieved a complete remission, 3/6 had a partial remission, and 3/6 had no response to ofatumumab. Four patients exhibited a minor allergic reaction with the first infusion. One patient died of infection, as a consequence of multiple factors. No malignancies were observed; however, the time of follow-up was not sufficient to see such disease.

Conclusions: Altogether, these results suggest ofatumumab has a poor efficacy in treating recurrence of NS after renal transplantation. However, it could be discussed in multidrug-resistant refractory NS, but infectious complications and overimmunosuppression have to be balanced. There is a need for further studies to confirm these findings and safety and to determine a standardized protocol in this indication.
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http://dx.doi.org/10.1007/s00467-020-04567-7DOI Listing
August 2020

Think Twice before Postponing Chronic Dialysis in Children.

J Am Soc Nephrol 2019 12 24;30(12):2473-2474. Epub 2019 Oct 24.

Department of Medical Informatics, Amsterdam Public Health Research Institute, European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.

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http://dx.doi.org/10.1681/ASN.2019090895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900805PMC
December 2019

Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease.

Pediatr Nephrol 2019 12 19;34(12):2571-2582. Epub 2019 Aug 19.

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

Background: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients.

Methods: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m.

Results: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 μmol/l (8.7) and 17.0 μmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors.

Conclusions: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.
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http://dx.doi.org/10.1007/s00467-019-04331-6DOI Listing
December 2019

Outcome of children with Shiga toxin-associated haemolytic uraemic syndrome treated with eculizumab: a matched cohort study.

Nephrol Dial Transplant 2020 12;35(12):2147-2153

Service de Pédiatrie, Unité de Néphrologie, Centre de référence Maladies Rénales Rares du Sud-ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Background: Treatment with eculizumab in Shiga toxin-associated haemolytic and uraemic syndrome (STEC-HUS) remains controversial despite its increasing utilization. The aim of our study was to evaluate the outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study.

Methods: Data were retrospectively collected from medical records of children diagnosed with STEC-HUS. The outcomes of patients treated with eculizumab for STEC-HUS were compared with those of a control group of untreated patients matched for age, sex and severity of acute kidney injury with a 1:2 matching scheme.

Results: Eighteen children (median age 40.6 months) with STEC-HUS treated with eculizumab were compared with 36 matched control patients (median age 36.4 months) who did not receive eculizumab. All patients survived in the two groups. Within 1 month of HUS onset, the evolution of haematological and renal parameters did not differ between the two groups. At 12 months of follow-up, renal outcome was not significantly different between the two groups. At the last follow-up, the prevalence of decreased glomerular filtration rate in the eculizumab group (27%) was not statistically different from that in controls (38%), as was the prevalence of proteinuria and high blood pressure. Children who received eculizumab more often had extrarenal sequelae during follow-up. Eculizumab treatment appeared to be safe in children with STEC-HUS.

Conclusion: The benefit of eculizumab on renal and extrarenal outcomes in STEC-HUS could not be established based on our findings. However, efficacy and safety are not best assessed by the observational design and small sample size of our study. Randomized controlled trials are thus required to determine the efficacy of eculizumab in this indication.
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http://dx.doi.org/10.1093/ndt/gfz158DOI Listing
December 2020

Targeted gene therapy in human-induced pluripotent stem cells from a patient with primary hyperoxaluria type 1 using CRISPR/Cas9 technology.

Biochem Biophys Res Commun 2019 10 8;517(4):677-683. Epub 2019 Aug 8.

Univ. Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076, Bordeaux, France. Electronic address:

Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disorder caused by a deficiency of the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which leads to overproduction of oxalate by the liver and results in urolithiasis, nephrocalcinosis and renal failure. The only curative treatment for PH1 is combined liver and kidney transplantation, which is limited by the lack of suitable organs, significant complications, and the life-long requirement for immunosuppressive agents to maintain organ tolerance. Hepatocyte-like cells (HLCs) generated from CRISPR/Cas9 genome-edited human-induced pluripotent stem cells would offer an attractive unlimited source of autologous gene-corrected liver cells as an alternative to orthotopic liver transplantation (OLT). Here we report the CRISPR/Cas9 nuclease-mediated gene targeting of a single-copy AGXT therapeutic minigene into the safe harbour AAVS1 locus in PH1-induced pluripotent stem cells (PH1-iPSCs) without off-target inserts. We obtained a robust expression of a codon-optimized AGT in HLCs derived from AAVS1 locus-edited PH1-iPSCs. Our study provides the proof of concept that CRISPR/Cas9-mediated integration of an AGXT minigene into the AAVS1 safe harbour locus in patient-specific iPSCs is an efficient strategy to generate functionally corrected hepatocytes, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of PH1.
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http://dx.doi.org/10.1016/j.bbrc.2019.07.109DOI Listing
October 2019

Impaired Systolic and Diastolic Left Ventricular Function in Children with Chronic Kidney Disease - Results from the 4C Study.

Sci Rep 2019 08 7;9(1):11462. Epub 2019 Aug 7.

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

Children with chronic kidney disease suffer from excessive cardiovascular mortality and early alterations of the cardiovascular system. Tissue doppler imaging is a validated echocardiographic tool to assess early systolic and diastolic cardiac dysfunction. We hypothesized that tissue Doppler velocities would reveal reduced cardiac function in children with chronic kidney disease compared to healthy children. A standardized echocardiographic exam was performed in 128 patients of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study aged 6-17 years with an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m. Tissue Doppler measurements included early (E') and late (A') diastolic and systolic (S') velocity at the mitral and septal annulus of the left ventricle. Measured values were normalized to z-scores using published reference data. Predictors of E'/A', E/E', S' and left ventricular mass index (LVMI) were assessed by multiple linear regression analyses. Tissue Doppler E' was reduced and tissue Doppler A' increased, resulting in a reduced tissue Doppler E'/A' ratio (z-score -0.14, p < 0.0001) indicating reduced diastolic function compared to healthy children. Reduced tissue Doppler E'/A' Z-Scores were independently associated with lower eGFR (p = 0.002) and increased systolic blood pressure (p = 0.02). While E/E' Z-Scores were increased (Z-score 0.57, p < 0.0001), patients treated with pharmacological RAS blockade but not with other antihypertensive treatments had significantly lower E/E' and higher E'/A' Z-Scores. Systolic tissue Doppler velocities were significantly decreased (Z-score -0.24, p = 0.001) and inversely correlated with E/E' Z-Scores (r = -0.41, p < 0.0001). LVMI was not associated with systolic or diastolic tissue Doppler velocities. Concentric left ventricular hypertrophy showed a tendency to lower S' in multivariate analysis (p = 0.13) but no association to diastolic function. Concentric left ventricular geometry was significantly associated with lower midwall fractional shortening. In summary, systolic and diastolic function assessed by tissue Doppler is impaired. eGFR, systolic blood pressure and the type of antihypertensive medications are significant predictors of diastolic function in children with CKD. Left ventricular morphology is largely independent of tissue Doppler velocities. Tissue Doppler velocities provide sensitive information about early left ventricular dysfunction in this population.
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http://dx.doi.org/10.1038/s41598-019-46653-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685994PMC
August 2019

Social deprivation is associated with poor kidney transplantation outcome in children.

Kidney Int 2019 09 28;96(3):769-776. Epub 2019 May 28.

University of Bordeaux, ISPED, Centre INSERM U1219-Bordeaux Population Health Research, Bordeaux, France; INSERM, Clinical Investigation Center-Clinical Epidemiology-CIC-1401, Bordeaux, France; Pediatric Nephrology Unit, Pellegrin-Enfants Hospital, Bordeaux University Hospital, Centre de Référence Maladies rénales rares Sorare, Bordeaux, France. Electronic address:

Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation.
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http://dx.doi.org/10.1016/j.kint.2019.05.011DOI Listing
September 2019

Determinants of Statural Growth in European Children With Chronic Kidney Disease: Findings From the Cardiovascular Comorbidity in Children With Chronic Kidney Disease (4C) Study.

Front Pediatr 2019 5;7:278. Epub 2019 Jul 5.

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

Failure of statural growth is one of the major long-term sequelae of chronic kidney disease (CKD) in children. In recent years effective therapeutic strategies have become available that lead to evidence based practice recommendations. To assess the current growth performance of European children and adolescents with CKD, we analyzed a cohort of 594 patients from 12 European countries who were followed prospectively for up to 6 years in the 4C Study. While all patients were on conservative treatment with a mean estimated glomerular filtration rate of 28 ml/min/1.73 m at study entry, 130 children commenced dialysis during the observation period. At time of enrolment the mean height standard deviation score (SDS) was -1.57; 36% of patients had a height below the third percentile. The prevalence of growth failure varied between countries from 7 to 44% Whereas patients on conservative treatment showed stable growth, height SDS gradually declined on those on dialysis. Parental height, pubertal status and treatment with recombinant growth hormone (GH) were positively, and the diagnosis of syndromic disease and CKD stage were negatively associated with height SDS during the observation period. Unexpectedly, higher body mass index (BMI) SDS was associated with lower height SDS both at enrolment and during follow up. Renal anemia, metabolic acidosis, and hyperparathyroidism were mostly mild and not predictive of growth rates by multivariable analysis. GH therapy was applied in only 15% of growth retarded patients with large variation between countries. When adjusting for all significant covariates listed above, the country of residence remained a highly significant predictor of overall growth performance. In conclusion, growth failure remains common in European children with CKD, despite improved general management of CKD complications. The widespread underutilization of GH, an approved efficacious therapy for CKD-associated growth failure, deserves further exploration.
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http://dx.doi.org/10.3389/fped.2019.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625460PMC
July 2019

Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study.

J Hypertens 2019 11;37(11):2247-2255

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

Introduction: Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD.

Methods: Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ± 3.2 years, estimated glomerular filtration rate 29 ± 12 ml/min per 1.73 m). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension.

Results: Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT.

Conclusion: INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function.
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http://dx.doi.org/10.1097/HJH.0000000000002160DOI Listing
November 2019

Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in Europe.

Nephrol Dial Transplant 2019 09;34(9):1469-1480

CNR-IFC, Ospedali Riuniti, Reggio Calabria, Italy.

The strengths and the limitations of research activities currently present in Europe are explored in order to outline how to proceed in the near future. Epidemiological and clinical research and public policy in Europe are generally considered to be comprehensive and successful, and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) is playing a key role in the field of nephrology research. The Nephrology and Public Policy Committee (NPPC) aims to improve the current situation and translation into public policy by planning eight research topics to be supported in the coming 5 years by ERA-EDTA.
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http://dx.doi.org/10.1093/ndt/gfz089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736134PMC
September 2019

Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease.

Nat Rev Nephrol 2019 09 13;15(9):577-589. Epub 2019 Jun 13.

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

Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD-Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3-5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045-0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making.
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http://dx.doi.org/10.1038/s41581-019-0161-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136166PMC
September 2019

Generation of induced pluripotent stem cells-derived hepatocyte-like cells for ex vivo gene therapy of primary hyperoxaluria type 1.

Stem Cell Res 2019 07 21;38:101467. Epub 2019 May 21.

Univ.Bordeaux, INSERM, BMGIC, U1035, CHU Bordeaux, 33076 Bordeaux, France. Electronic address:

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of the liver metabolism due to functional deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in overproduction of oxalate which complexes with calcium to form insoluble calcium-oxalate salts in urinary tracts, ultimately leading to end-stage renal disease. Currently, the only curative treatment for PH1 is combined liver-kidney transplantation, which is limited by donor organ shortage and lifelong requirement for immunosuppression. Transplantation of genetically modified autologous hepatocytes is an attractive therapeutic option for PH1. However, the use of fresh primary hepatocytes suffers from limitations such as organ availability, insufficient cell proliferation, loss of function, and the risk of immune rejection. We developed patient-specific induced pluripotent stem cells (PH1-iPSCs) free of reprogramming factors as a source of renewable and genetically defined autologous PH1-hepatocytes. We then investigated additive gene therapy using a lentiviral vector encoding wild-type AGT under the control of the liver-specific transthyretin promoter. Genetically modified PH1-iPSCs successfully provided hepatocyte-like cells (HLCs) that exhibited significant AGT expression at both RNA and protein levels after liver-specific differentiation process. These results pave the way for cell-based therapy of PH1 by transplantation of genetically modified autologous HLCs derived from patient-specific iPSCs.
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http://dx.doi.org/10.1016/j.scr.2019.101467DOI Listing
July 2019