Publications by authors named "Djalila Mekahli"

70 Publications

Cytopenia in autosomal dominant polycystic kidney disease (ADPKD): merely an association or a disease-related feature with prognostic implications?

Pediatr Nephrol 2021 Jan 27. Epub 2021 Jan 27.

Department of Development and Regeneration, GPURE, PKD Research Group, Laboratory of Pediatrics, KU Leuven, Leuven, Belgium.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with distinct cytopenias in observational studies; the most consistent and strongest association is seen with alternations in the lymphocytic lineages. Although the underlying mechanism of these associations is unclear, it has been hypothesized to be secondary to sequestration of white blood cells in cystic organs, or related to the uremic environment in chronic kidney disease (CKD). However, since mutations in PKD1 or -2 affect several immunomodulating pathways, cytopenia may well be an unrecognized extrarenal manifestation of ADPKD. Furthermore, many important questions on the clinical implications of this finding and the effect on the disease course in these patients are unanswered. In this review article, we provide an overview of the current evidence on cytopenia in ADPKD and explore the underlying mechanisms of this association and its potential prognostic implications. Based on the current literature, we hypothesize that polycystin deficiency can disturb immune cell homeostasis and that cytopenia is thus an intrinsic feature of ADPKD, related to genetic factors. Taken together, these findings warrant further investigation to establish the exact etiology and role of cytopenia in patients with ADPKD.
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http://dx.doi.org/10.1007/s00467-021-04937-9DOI Listing
January 2021

Recent progress in the LC-MS/MS analysis of oxidative stress biomarkers.

Electrophoresis 2021 Feb 28;42(4):402-428. Epub 2020 Dec 28.

Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, Leuven, Belgium.

The presence of a dynamic and balanced equilibrium between the production of reactive oxygen (ROS) and nitrogen (RNS) species and the in-house antioxidant defense mechanisms is characteristic for a healthy body. During oxidative stress (OS), this balance is switched to increased production of ROS and RNS, exceeding the capacity of physiological antioxidant systems. This can cause damage to biological molecules, leading to loss of function and even cell death. Nowadays, there is increasing scientific and clinical interest in OS and the associated parameters to measure the degree of OS in biofluids. An increasing number of reports using LC-MS/MS methods for the analysis of OS biomarkers can be found. Since bioanalysis is usually complicated by matrix effects, various types of cleanup procedures are used to effectively separate the biomarkers from the matrix. This is an essential part of the analysis to prepare a reproducible and homogenous solution suitable for injection onto the column. The present review gives a summary of the chromatographic methods used for the determination of OS biomarkers in both urine and plasma, serum, and whole blood samples. The first part mainly describes the biological background of the different OS biomarkers, while the second part reports examples of chromatographic methods for the analysis of different metabolites connected with OS in biofluids, covering a period from 2015 till early 2020. The selected examples mainly include LC-MS/MS methods for isoprostanes, oxidized proteins, oxidized lipoproteins, and DNA/RNA biomarkers. The last part explains the clinical relevance of this review.
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http://dx.doi.org/10.1002/elps.202000208DOI Listing
February 2021

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.

Department of Pediatrics, Faculty of Medicine, University Hospital Cologne and University of Cologne, Kerpener Str. 62, 50937, Cologne, 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

Creatinine at Birth Correlates with Gestational Age and Birth Weight: Another Factor of the Imbroglio in Early Neonatal Life.

Neonatology 2020 22;117(5):637-640. Epub 2020 Sep 22.

Division of Clinical Pharmacology, Children's National Health Hospital, Washington, District of Columbia, USA.

Background: Serum creatinine (Scr) in early neonatal life (first week of life) displays extensive variability; hence, a better understanding is needed to use Scr as a diagnostic biomarker for acute kidney injury (AKI).

Objective: The objective of this study was to explore Scr trends and its covariates in early neonatal life.

Methods: Analysis of a rich, pooled Scr dataset (enzymatic assay) of 4,509 Scr observations in 1,181 neonates in the first week of life with birth weight, gestational age (GA), and postnatal age as covariates was conducted. Descriptive data were summarized as median and range. The Spearman rank correlation test was used to examine Scr, while the Mann-Whitney U test was used to determine the differences between the different GA (≤32, 33-36, or ≥37 weeks) categories.

Results: The median Scr at delivery was 55.7 (range 28.3-194.5) µmol/L, correlating with birth weight (r = 0.088) or GA (r = 0.183) for the full dataset. At birth, the median Scr was highest in term (≥37-week) neonates. In early neonatal life (median Scr values), there was a gradual increase to attain a peak Scr by day 2-3, highest and most delayed in neonates ≤32 weeks GA. This is followed by a blunted decrease when ≤32-week neonates were compared to those of 33-36 or ≥37 weeks GA.

Conclusions: The Scr pattern in early neonatal life is complex, with the highest Scr at birth in full-term neonates, while those ≤32 weeks GA displayed the highest and delayed peak Scr with a subsequent blunted decrease. Knowledge of these patterns is crucial to explore the utility of Scr as an AKI biomarker.
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http://dx.doi.org/10.1159/000510658DOI Listing
September 2020

Characterizing dynamics of serum creatinine and creatinine clearance in extremely low birth weight neonates during the first 6 weeks of life.

Pediatr Nephrol 2021 Mar 17;36(3):649-659. Epub 2020 Sep 17.

Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.

Background: Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight (≤ 1000 g; ELBW) neonates remains challenging.

Methods: We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated.

Results: A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤ 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth.

Conclusions: We report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population.
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http://dx.doi.org/10.1007/s00467-020-04749-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851041PMC
March 2021

Renal Precision Medicine in Neonates and Acute Kidney Injury: How to Convert a Cloud of Creatinine Observations to Support Clinical Decisions.

Front Pediatr 2020 28;8:366. Epub 2020 Jul 28.

Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Renal precision medicine in neonates is useful to support decision making on pharmacotherapy, signal detection of adverse (drug) events, and individual prediction of short- and long-term prognosis. To estimate kidney function or glomerular filtration rate (GFR), the most commonly measured and readily accessible biomarker is serum creatinine (S). However, there is extensive variability in S observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for S, but also exist for Cystatin C. Observations in extreme low birth weight (ELBW) and term asphyxiated neonates will illustrate how renal precision medicine contributes to neonatal precision medicine. When the Kidney Disease Improving Global Outcome (KDIGO) definition of acute kidney injury (AKI) is used, this results in an incidence up to 50% in ELBW neonates, associated with increased mortality and morbidity. However, urine output criteria needed adaptations to broader time intervals or weight trends, while S and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile S values to better describe postnatal trends and have illustrated its relevance by quantifying an adverse drug event (ibuprofen) and by explaining individual amikacin clearance. Term asphyxiated neonates also commonly display AKI. While oliguria is a specific AKI indicator, the majority of term asphyxiated cases are non-oliguric. Asphyxia results in a clinical significant-commonly transient-mean GFR decrease (-50%) with a lower renal drug elimination. But there is still major (unexplained) inter-individual variability in GFR and subsequent renal drug elimination between these asphyxiated neonates. Recently, the Baby-NINJA (nephrotoxic injury negated by just-in-time action) study provided evidence on the concept that a focus on nephrotoxic injury negation has a significant impact on AKI incidence and severity. It is hereby important to realize that follow-up should not be discontinued at discharge, as there are concerns about long-term renal outcome. These illustrations suggest that integration of renal (patho)physiology into neonatal precision medicine are an important tool to improve contemporary neonatal care, not only for the short-term but also with a positive health impact throughout life.
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http://dx.doi.org/10.3389/fped.2020.00366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399072PMC
July 2020

Glomerular Filtration Rate in Former Extreme Low Birth Weight Infants over the Full Pediatric Age Range: A Pooled Analysis.

Int J Environ Res Public Health 2020 03 24;17(6). Epub 2020 Mar 24.

Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Various cohort studies document a lower glomerular filtration rate (GFR) in former extremely low birth weight (ELBW, <1000 g) neonates throughout childhood when compared to term controls. The current aim is to pool these studies to describe the GFR pattern over the pediatric age range. To do so, we conducted a systematic review on studies reporting on GFR measurements in former ELBW cases while GFR data of healthy age-matched controls included in these studies were co-collected. Based on 248 hits, 6 case-control and 3 cohort studies were identified, with 444 GFR measurements in 380 former ELBW cases (median age 5.3-20.7 years). The majority were small (17-78 cases) single center studies, with heterogeneity in GFR measurement (inulin, cystatin C or creatinine estimated GFR formulae) tools. Despite this, the median GFR (mL/min/1.73 m) within case-control studies was consistently lower (-13%, range -8% to -25%) in cases, so that a relevant minority (15-30%) has a eGFR<90 mL/min/1.73 m). Consequently, this pooled analysis describes a consistent pattern of reduced eGFR in former ELBW cases throughout childhood. Research should focus on perinatal risk factors for impaired GFR and long-term outcome, but is hampered by single center cohorts, study size and heterogeneity of GFR assessment tools.
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http://dx.doi.org/10.3390/ijerph17062144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142917PMC
March 2020

Bortezomib for autoimmune hemolytic anemia after intestinal transplantation.

Pediatr Transplant 2020 06 12;24(4):e13700. Epub 2020 Mar 12.

Hematology, University Hospitals Leuven, Leuven, Belgium.

AIHA is rare in the general population and associated with a mortality of 8%. In contrast, AIHA occurs in up to 12.2% of cases after intestinal transplantation and is associated with mortality up to 50%. Treatment entails a "step-up" approach including corticosteroids, IvIg, plasmapheresis, and rituximab. However, AIHA after transplantation often is refractory to this strategy, contributing to a poor outcome. We describe a child with microvillous inclusion disease who developed AIHA 1 year after multivisceral transplantation that was refractory to standard therapy and was subsequently treated with bortezomib.We observed remission of AIHA within 1 week after the start of bortezomib. Bortezomib was associated with transient diarrhea, leucopenia, and elevated liver enzymes. Three years later, he remains in remission without important complications. Published data on bortezomib for autoimmune cytopenias outside SOT are discussed. This is the first report to support bortezomib as an important therapeutic alternative for AIHA after SOT. The occurrence and treatment of AIHA after SOT, and specifically intestinal transplantation, should be the subject of future registry studies to collect additional experience and explore the optimal therapeutic approach.
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http://dx.doi.org/10.1111/petr.13700DOI Listing
June 2020

Implications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial.

Sci Rep 2020 03 9;10(1):4294. Epub 2020 Mar 9.

PKD Research Group, Laboratory of Pediatrics, University Hospitals Leuven, Leuven, Belgium.

It is unknown whether early diagnosis of autosomal dominant polycystic kidney disease (ADPKD) can enable earlier management and improve outcomes. We conducted a post hoc analysis of data from the TEMPO 3:4 trial. Subjects were stratified by ADPKD diagnosis at age ≤18 (childhood diagnosis [CD]) or>18 (adulthood diagnosis [AD]). Groups were compared for baseline characteristics and total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline over 3 years. 294 CD and 1148 AD subjects were analyzed. At inclusion, CD subjects were younger (mean age 34.2 versus 39.8 years; p < 0.0001) and had better eGFR (mean ± SD 87.4 ± 23.9 versus 80.1 ± 20.7 mL/min/1.73 m; p < 0.0001), while CD had more severe Mayo risk classification (p < 0.0001) and more PKD1 mutations (p = 0.003). No statistical differences were found in TKV or eGFR change. At study end, placebo-treated CD subjects had better eGFR than projected by a prediction equation (mean difference ±SD for observed versus predicted eGFR: 2.18 ± 10.7 mL/min/1.73 m; p = 0.0475). However, these results are not confirmed when excluding stage 1 CKD. Whether CD subjects, despite their risk profile, have a slower disease course than predicted remains inconclusive. Future studies are needed to confirm that early diagnosis and management can alter the disease course of ADPKD.
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http://dx.doi.org/10.1038/s41598-020-61303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062834PMC
March 2020

ADPedKD: A Global Online Platform on the Management of Children With ADPKD.

Kidney Int Rep 2019 Sep 29;4(9):1271-1284. Epub 2019 May 29.

Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of renal failure. For several decades, ADPKD was regarded as an adult-onset disease. In the past decade, it has become more widely appreciated that the disease course begins in childhood. However, evidence-based guidelines on how to manage and approach children diagnosed with or at risk of ADPKD are lacking. Also, scoring systems to stratify patients into risk categories have been established only for adults. Overall, there are insufficient data on the clinical course during childhood. We therefore initiated the global ADPedKD project to establish a large international pediatric ADPKD cohort for deep characterization.

Methods: Global ADPedKD is an international multicenter observational study focusing on childhood-diagnosed ADPKD. This collaborative project is based on interoperable Web-based databases, comprising 7 regional and independent but uniformly organized chapters, namely Africa, Asia, Australia, Europe, North America, South America, and the United Kingdom. In the database, a detailed basic data questionnaire, including genetics, is used in combination with data entry from follow-up visits, to provide both retrospective and prospective longitudinal data on clinical, radiologic, and laboratory findings, as well as therapeutic interventions.

Discussion: The global ADPedKD initiative aims to characterize in detail the most extensive international pediatric ADPKD cohort reported to date, providing evidence for the development of unified diagnostic, follow-up, and treatment recommendations regarding modifiable disease factors. Moreover, this registry will serve as a platform for the development of clinical and/or biochemical markers predicting the risk of early and progressive disease.
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http://dx.doi.org/10.1016/j.ekir.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732756PMC
September 2019

Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD).

Sci Rep 2019 05 28;9(1):7919. Epub 2019 May 28.

Department of Pediatrics, University Hospital of Cologne, Cologne, Germany.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.
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http://dx.doi.org/10.1038/s41598-019-43488-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538621PMC
May 2019

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people.

Nat Rev Nephrol 2019 11;15(11):713-726

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

These recommendations were systematically developed on behalf of the Network for Early Onset Cystic Kidney Disease (NEOCYST) by an international group of experts in autosomal dominant polycystic kidney disease (ADPKD) from paediatric and adult nephrology, human genetics, paediatric radiology and ethics specialties together with patient representatives. They have been endorsed by the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN). For asymptomatic minors at risk of ADPKD, ongoing surveillance (repeated screening for treatable disease manifestations without diagnostic testing) or immediate diagnostic screening are equally valid clinical approaches. Ultrasonography is the current radiological method of choice for screening. Sonographic detection of one or more cysts in an at-risk child is highly suggestive of ADPKD, but a negative scan cannot rule out ADPKD in childhood. Genetic testing is recommended for infants with very-early-onset symptomatic disease and for children with a negative family history and progressive disease. Children with a positive family history and either confirmed or unknown disease status should be monitored for hypertension (preferably by ambulatory blood pressure monitoring) and albuminuria. Currently, vasopressin antagonists should not be offered routinely but off-label use can be considered in selected children. No consensus was reached on the use of statins, but mTOR inhibitors and somatostatin analogues are not recommended. Children with ADPKD should be strongly encouraged to achieve the low dietary salt intake that is recommended for all children.
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http://dx.doi.org/10.1038/s41581-019-0155-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136168PMC
November 2019

Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial.

Eur J Pediatr 2019 Jul 3;178(7):1013-1021. Epub 2019 May 3.

Otsuka Pharmaceutical Development & Commercialization, 2440 Research Boulevard, Rockville, MD, 20850, USA.

This report describes the rationale and design of a study assessing tolvaptan in children with autosomal dominant polycystic kidney disease (ADPKD). Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial. Phase B is a 2-year, open-label extension. The target population is at least 60 children aged 12-17 years, diagnosed by family history and/or genetic criteria and the presence of ≥ 10 renal cysts, each ≥ 0.5 cm on magnetic resonance imaging. Subjects will be allocated into 4 groups: females 15-17 years; females 12-14 years; males 15-17 years; and males 12-14 years. Up to 40 subjects aged 4-11 years may also enroll, provided they meet the entry criteria. Weight-adjusted tolvaptan doses, titrated once to achieve a tolerated maintenance dose, and matching placebo will be administered twice-daily. Assessments include spot urine osmolality and specific gravity (co-primary endpoints), height-adjusted total kidney volume, estimated glomerular filtration rate, pharmacodynamic parameters (urine volume, fluid intake and fluid balance, serum sodium, serum creatinine, free water clearance), pharmacokinetic parameters, safety (aquaretic adverse events, changes from baseline in creatinine, vital signs, laboratory values including liver function tests), and generic pediatric quality of life assessments.Conclusion: This will be the first clinical study to evaluate tolvaptan in pediatric ADPKD. What is Known: • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing the development of cysts that impede kidney function over time and eventually induce renal failure • There are few data on the effects of tolvaptan, the only treatment approved for adults to slow disease progression, in pediatric ADPKD patients with early-stage disease What is New: • A phase 3, placebo-controlled study is evaluating tolvaptan over 3 years in children and adolescents with ADPKD • This study is designed to account for challenges of tolvaptan dosing and outcome assessment specific to the pediatric population.
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http://dx.doi.org/10.1007/s00431-019-03384-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565642PMC
July 2019

Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction.

J Clin Immunol 2019 04 5;39(3):298-308. Epub 2019 Mar 5.

Laboratory for Inborn Errors of Immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, EU, Belgium.

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.
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http://dx.doi.org/10.1007/s10875-019-00603-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647034PMC
April 2019

Imaging of Kidney Cysts and Cystic Kidney Diseases in Children: An International Working Group Consensus Statement.

Radiology 2019 03 1;290(3):769-782. Epub 2019 Jan 1.

From the Department of General Pediatrics, Adolescent Medicine and Neonatology, Center for Pediatrics, Medical Center-University of Freiburg, Mathildenstr 1, 79106 Freiburg, Germany (C.G.); Department of Pediatric Radiology, Jeanne de Flandre Mother and Child Hospital, University of Lille, Lille, France (E.F.A.); Department of Pediatric Radiology, University Hospital of Leuven, Leuven, Belgium (L.B.); Department of Pediatrics, University Hospital of Cologne, Cologne, Germany (K.B.); Department of Bioengineering, IRCCS Mario Negri Institute for Pharmacological Research, Bergamo, Italy (A.C.); Department of Pediatrics II, University Hospital Essen, Essen, Germany (M.C.); Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany (D.H., D.F., L.P.); Division of Nephrology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pa (E.A.H.); Department of General Pediatrics, University Children's Hospital, Münster, Germany (J.K., A.T.); Department of Pediatrics and Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany (M.C.L.); Department of Pediatric Nephrology, University Hospital of Leuven, Leuven, Belgium (D.M.); PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, GPURE, KU Leuven, Leuven, Belgium (D.M.); PKD Research Group, Department of Development and Regeneration, Catholic University Leuven (KU Leuven), Leuven, Belgium (D.M.); Academic Nephrology Unit, Department of Infection Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, England (A.C.M.O.); Department of Nephrology, Fundació Puigvert, Autonomous University of Barcelona, IIB Sant Pau, REDINREN, Barcelona, Spain (R.T.); University College London Great Ormond Street, Institute of Child Health, London, England (P.J.D.W.); and Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany (F.S.).

Kidney cysts can manifest as focal disease (simple and complex kidney cysts), affect a whole kidney (eg, multicystic dysplastic kidney or cystic dysplasia), or manifest as bilateral cystic disease (eg, autosomal recessive polycystic kidney disease [ARPKD] or autosomal dominant polycystic kidney disease [ADPKD]). In children, as opposed to adults, a larger proportion of kidney cysts are due to genetic diseases (eg, HNF1B nephropathy, various ciliopathies, and tuberous sclerosis complex), and fewer patients have simple cysts or acquired cystic kidney disease. The purpose of this consensus statement is to provide clinical guidance on standardization of imaging tests to evaluate kidney cysts in children. A committee of international experts in pediatric nephrology, pediatric radiology, pediatric US, and adult nephrology prepared systematic literature reviews and formulated recommendations at a consensus meeting. The final statement was endorsed by the European Society of Pediatric Radiology, the European Federation of Societies for Ultrasound in Medicine and Biology, the European Society of Pediatric Nephrology, and reviewed by the European Reference Network for Rare Kidney Diseases. Main recommendations are as follows: US is the method of choice when assessing pediatric kidney cysts, with selected indications for MRI and contrast-enhanced US. CT should be avoided whenever possible because of ionizing radiation. Renal US yields essential diagnostic information in many cases. In patients with ARPKD or other ciliopathies, abdominal US is needed for diagnosis and screening of portal hypertension. US is usually sufficient for follow-up kidney imaging, but MRI can be valuable for clinical trials in patients with ADPKD or in older children with tuberous sclerosis complex to evaluate both kidney cysts and angiomyolipomas.
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http://dx.doi.org/10.1148/radiol.2018181243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394734PMC
March 2019

Unmet needs and challenges for follow-up and treatment of autosomal dominant polycystic kidney disease: the paediatric perspective.

Clin Kidney J 2018 Dec 17;11(Suppl 1):i14-i26. Epub 2018 Dec 17.

Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.

Awareness is growing that the clinical course of autosomal dominant polycystic kidney disease (ADPKD) already begins in childhood, with a broad range of both symptomatic and asymptomatic features. Knowing that parenchymal destruction with cyst formation and growth starts early in life, it seems reasonable to assume that early intervention may yield the best chances for preserving renal outcome. Interventions may involve lifestyle modifications, hypertension control and the use of disease-modifying treatments once these become available for the paediatric population with an acceptable risk and side-effect profile. Until then, screening of at-risk children is controversial and not generally recommended since this might cause psychosocial and financial harm. Also, the clinical and research communities are facing important questions as to the nature of potential interventions and their optimal indications and timing. Indeed, challenges include the identification and validation of indicators, both measuring and predicting disease progression from childhood, and the discrimination of slow from rapid progressors in the paediatric population. This discrimination will improve both the cost-effectiveness and benefit-to-risk ratio of therapies. Furthermore, we will need to define outcome measures, and to evaluate the possibility of a potential therapeutic window of opportunity in childhood. The recently established international register ADPedKD will help in elucidating these questions. In this review, we provide an overview of the current knowledge on paediatric ADPKD as a future therapeutic target population and its unmet challenges.
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http://dx.doi.org/10.1093/ckj/sfy088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295604PMC
December 2018

Correction to: Chronic Aichi Virus Infection in a Patient with X-Linked Agammaglobulinemia.

J Clin Immunol 2018 Nov;38(8):938-939

Laboratory of inborn errors of immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, Belgium.

The original version of this article unfortunately did not display the appropriate captions in the figure. The correct version is displayed below.
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http://dx.doi.org/10.1007/s10875-018-0570-3DOI Listing
November 2018

Copeptin in the Diagnosis of Diabetes Insipidus.

N Engl J Med 2018 11;379(18):1784-5

University of Liège Hospital, Liège, Belgium

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http://dx.doi.org/10.1056/NEJMc1811694DOI Listing
November 2018

Chronic Aichi Virus Infection in a Patient with X-Linked Agammaglobulinemia.

J Clin Immunol 2018 10 11;38(7):748-752. Epub 2018 Oct 11.

Department of Immunology and Microbiology, Laboratory of inborn errors of immunity, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1007/s10875-018-0558-zDOI Listing
October 2018

Fundamental insights into autosomal dominant polycystic kidney disease from human-based cell models.

Pediatr Nephrol 2019 10 13;34(10):1697-1715. Epub 2018 Sep 13.

PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, GPURE, KU Leuven, Leuven, Belgium.

Several animal- and human-derived models are used in autosomal dominant polycystic kidney disease (ADPKD) research to gain insight in the disease mechanism. However, a consistent correlation between animal and human ADPKD models is lacking. Therefore, established human-derived models are relevant to affirm research results and translate findings into a clinical set-up. In this review, we give an extensive overview of the existing human-based cell models. We discuss their source (urine, nephrectomy and stem cell), immortalisation procedures, genetic engineering, kidney segmental origin and characterisation with nephron segment markers. We summarise the most studied pathways and lessons learned from these different ADPKD models. Finally, we issue recommendations for the derivation of human-derived cell lines and for experimental set-ups with these cell lines.
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http://dx.doi.org/10.1007/s00467-018-4057-5DOI Listing
October 2019

Renal Replacement Therapy in children with severe developmental disability: guiding questions for decision-making.

Eur J Pediatr 2018 Dec 7;177(12):1735-1743. Epub 2018 Sep 7.

Department of Pediatric Nephrology and Organ Transplantation, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

Whether to initiate or to withhold Renal Replacement Therapy (RRT) in children with severe developmental disability (DD) remains a topic of intense debate. The present study investigated the opinion of professionals on this difficult issue and proposed a checklist with guiding questions for decision-making. Clinicians affiliated to different organizations involved in pediatric nephrology worldwide were invited to respond to a web-based survey. This survey focused on the collection of demographic data of the respondents together with their opinion concerning the decision-making regarding RRT in a particular case and for children with severe DD in general. A total of 286 professionals responded to the survey. Sixty-six percent supported initiating RRT in the child of the case report, with pre-emptive transplantation being the preferred modality. Important arguments pro RRT initiation in children with severe DD in general were parental preference, decrease of suffering, and improvement of survival and quality of life. Important contraindications included low IQ, severe comorbidities, and inability of the patient to take medication or for the family to provide sufficient care.Conclusion: The present study presents an inventory on the opinions of health care professionals involved in RRT in children regarding the treatment of children with DD and assists in the decision-making process by identifying important medical and psychosocial arguments for initiating or withholding RRT in severe DD patients. What is Known: •Renal Replacement Therapy (RRT) in children with severe developmental disability (DD) is a topic of intense debate. •Previous studies on the opinion of professionals mainly focused on the use of IQ as an argument in the decision-making whether or not starting RRT. What is New: •The present study investigated the opinion of professionals with regard to considering initiation or withholding RRT in children with severe DD and identified medical and psychosocial arguments playing a role in the decision-making process. •Based on these arguments, a checklist with guiding questions for decision-making is proposed.
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http://dx.doi.org/10.1007/s00431-018-3238-3DOI Listing
December 2018

Simultaneous determination of allantoin and adenosine in human urine using liquid chromatography - UV detection.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Oct 27;1096:201-207. Epub 2018 Aug 27.

KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, B-3000 Leuven, Belgium.

We report a HPLC-UV method for the quantitative determination of allantoin and adenosine in human urine, validated according to the acceptance criteria of both the USA Food and Drug Administration (FDA) guideline for bioanalytical method validation and the European Medicines Agency (EMA) validation guidelines. Both allantoins and adenosine are compounds of the purine catabolic pathway. Adenosine is situated at the top as a uric acid (UA) precursor, while allantoin is the best-known degradation product of UA. These two compounds are endogenously present in human urine. Chromatographic separation was achieved with a gradient elution at 0.6 mL/min using a Zorbax SB-Aq column coupled to a Zorbax SB-Aq guard column. Three different mobile phases were used: mobile phase A consisted of 10 mM KHPO (pH 4.7) in milli-Q water, mobile phase B was 12.5 mM KHPO (pH 4.7) - ACN (80:20) and mobile phase C consisted of ACN - HO (50:50). The linear response range in human urine was 14-800 μM for allantoin and 1.25-50 μM for adenosine. The recoveries of allantoin, adenosine and the internal standard were greater than 93.8%. The intra-day accuracy ranged between 99.5 and 104.9% for allantoin and between 96.6 and 107.3% for adenosine, while the inter-day accuracy ranged respectively from 91.2 to 103.0% and from 94.5 to 107.8%. The intra-day precision range was from 0.8 to 6.2% RSD for allantoin and from 0.6 to 15.0% for adenosine. The inter-day precision ranged from 2.1-17.5% for allantoin and from 2.9-17.9% for adenosine. This method was successfully applied to analyze both compounds in urine samples of healthy volunteers. In conclusion, an accurate, precise and stable HPLC-UV method was developed and validated to quantify the endogenously present compounds allantoin and adenosine in human urine samples.
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http://dx.doi.org/10.1016/j.jchromb.2018.08.026DOI Listing
October 2018

Oxidative stress in chronic kidney disease.

Pediatr Nephrol 2019 06 13;34(6):975-991. Epub 2018 Aug 13.

Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven - University of Leuven, 3000, Leuven, Belgium.

Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the balance is not disturbed, OS has a role in physiological adaptations and signal transduction. However, an excessive amount of ROS and RNS results in the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease (CKD), increased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients.
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http://dx.doi.org/10.1007/s00467-018-4005-4DOI Listing
June 2019

Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression?

Pediatr Nephrol 2019 06 13;34(6):993-1008. Epub 2018 Aug 13.

Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, 3000, Leuven, Belgium.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2 genes, is the most common hereditary renal disease. Renal manifestations of ADPKD are gradual cyst development and kidney enlargement ultimately leading to end-stage renal disease. ADPKD also causes extrarenal manifestations, including endothelial dysfunction and hypertension. Both of these complications are linked with reduced nitric oxide levels related to excessive oxidative stress (OS). OS, defined as disturbances in the prooxidant/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen and nitrogen free radicals. Next to endothelial dysfunction and hypertension, there is cumulative evidence that OS occurs in the early stages of ADPKD. In the current review, we aim to summarize the cardiovascular complications and the relevance of OS in ADPKD and, more specifically, in the early stages of the disease. First, we will briefly introduce the link between ADPKD and the early cardiovascular complications including hypertension. Secondly, we will describe the potential role of OS in the early stages of ADPKD and its possible importance beyond the chronic kidney disease (CKD) effect. Finally, we will discuss some pharmacological agents capable of reducing reactive oxygen species and OS, which might represent potential treatment targets for ADPKD.
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http://dx.doi.org/10.1007/s00467-018-4004-5DOI Listing
June 2019

Renal progression factors in young patients with tuberous sclerosis complex: a retrospective cohort study.

Pediatr Nephrol 2018 11 9;33(11):2085-2093. Epub 2018 Jul 9.

Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Background: Renal pathology in tuberous sclerosis complex (TSC) is characterized by the growth of angiomyolipoma and renal cysts, and in rare cases renal cell carcinoma. Other consequences of renal involvement in TSC, including hypertension, proteinuria, and hyperfiltration, are not well studied. We aimed to analyze the early manifestations of the renal TSC phenotype in a young TSC cohort and to explore common, modifiable risk factors.

Methods: In this retrospective cohort study, TSC patients attending the TSC clinics of two tertiary hospitals were included. Data on demographics, history, genotype, kidney function, hematuria, proteinuria, blood pressure, and renal imaging were collected.

Results: Eighty patients were included, with a median age of 0.8 years (0.0-63.0) at first presentation, and a median follow-up time of 10.2 (0.4-41.0) years. Mutation analysis was available in 64 patients (80%). Renal lesions (cysts or angiomyolipoma) were observed in 55/73 (75%). Thirty-two percent (19/60) were hypertensive, 8/51 (16%) had proteinuria, and 18/71 (25%) had hyperfiltration (median eGFR 154 ml/min/m). Six (7.5%) patients had developed end stage renal disease at the last follow-up. No association was found between hyperfiltration, hypertension, or proteinuria and CKD ≥ 3. Cox regression showed a significant positive association between the presence of a renal intervention and CKD ≥ 3 (Hazard-Ratio 3.91, P < 0.05).

Conclusions: Besides renal cysts and angiomyolipoma, the modifiable progression factors hypertension, proteinuria, and hyperfiltration occur frequently and early in TSC patients. This represents a preventive treatment target.
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http://dx.doi.org/10.1007/s00467-018-4003-6DOI Listing
November 2018

Gastrostomy Tube Insertion in Pediatric Patients With Autosomal Recessive Polycystic Kidney Disease (ARPKD): Current Practice.

Front Pediatr 2018 4;6:164. Epub 2018 Jun 4.

Department of Pediatrics, University Hospital of Cologne, Cologne, Germany.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe hepatorenal disorder of childhood. Early renal disease in ARPKD may require renal replacement therapy and is associated with failure to thrive resulting in a need for nasogastric tube feeding or gastrostomy. In ARPKD patients, the benefit of a gastrostomy in nutrition and growth needs to be weighed against the potential risk of complications of congenital hepatic fibrosis (CHF) and portal hypertension like variceal bleeding. CHF in ARPKD has thus been considered as a relative contraindication for gastrostomy insertion. Yet, data on gastrostomies in pediatric patients with ARPKD is lacking. We conducted a web-based survey study among pediatric nephrologists, pediatric hepatologists and pediatric gastroenterologists on their opinions on and experiences with gastrostomy insertion in ARPKD patients. 196 participants from 39 countries shared their opinion. 45% of participants support gastrostomy insertion in all ARPKD patients, but portal hypertension is considered to be a contraindication by a subgroup of participants. Patient-specific data was provided for 38 patients indicating complications of gastrostomy that were in principal comparable to non-ARPKD patients. Bleeding episodes were reported in 3/38 patients (7.9%). Two patients developed additional severe complications. Gastrostomy was retrospectively considered as the right decision for the patient in 35/38 (92.1%) of the cases. This report on the results of an online survey gives first insights into the clinical practice of gastrostomy insertion in ARPKD patients. For the majority of participating physicians benefits of gastrostomy insertion retrospectively outweigh complications and risks. More data will be required to lay the foundation for clinical recommendations.
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http://dx.doi.org/10.3389/fped.2018.00164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994991PMC
June 2018

Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease.

J Pediatr 2018 08 9;199:22-28.e6. Epub 2018 May 9.

Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.

Objective: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis.

Study Design: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life.

Results: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys.

Conclusions: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.
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http://dx.doi.org/10.1016/j.jpeds.2018.03.052DOI Listing
August 2018

Liver transplantation for very severe hepatopulmonary syndrome due to vitamin A-induced chronic liver disease in a patient with Shwachman-Diamond syndrome.

Orphanet J Rare Dis 2018 05 2;13(1):69. Epub 2018 May 2.

Laboratory of Inborn Errors of Immunity, Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Vitamin A intoxication is a rare cause of liver disease, but the risk increases in patients with underlying liver dysfunction. We present a patient with Shwachman-Diamond Syndrome who developed liver fibrosis, portal hypertension and very severe hepatopulmonary syndrome as a consequence of chronic vitamin A intoxication. She underwent successful liver transplantation with complete resolution of the pulmonary shunting.
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http://dx.doi.org/10.1186/s13023-018-0818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930429PMC
May 2018

Prevalence of Hypertension in Children with Early-Stage ADPKD.

Clin J Am Soc Nephrol 2018 06 19;13(6):874-883. Epub 2018 Apr 19.

Division of Nephrology, Department of Pediatric Subspecialties, and

Background And Objectives: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited.

Design, Setting, Participants, & Measurements: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected.

Results: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; =0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; =0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; =0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; =0.10).

Conclusions: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.
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http://dx.doi.org/10.2215/CJN.11401017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989684PMC
June 2018

Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells.

Sci Rep 2018 04 9;8(1):5704. Epub 2018 Apr 9.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, 70125, Italy.

Clinical and fundamental research suggest that altered calcium and cAMP signaling might be the most proximal events in ADPKD pathogenesis. Cells from ADPKD cysts have a reduced resting cytosolic calcium [Ca] and increased cAMP levels. CaSR plays an essential role in regulating calcium homeostasis. Its activation is associated with [Ca] increase and cAMP decrease, making CaSR a possible therapeutic target. Human conditionally immortalized Proximal Tubular Epithelial cells (ciPTEC) with stable knockdown of PKD1 (ciPTEC-PC1KD) and ciPTEC generated from an ADPKD1 patient (ciPTEC-PC1Pt) were used as experimental tools. CaSR functional expression was confirmed by studies showing that the calcimimetic NPS-R568 induced a significant increase in [Ca] in ciPTEC-PC1KD and ciPTEC-PC1Pt. Resting [Ca] were significantly lower in ciPTEC-PC1KD with respect to ciPTECwt, confirming calcium dysregulation. As in native cyst cells, significantly higher cAMP levels and mTOR activity were found in ciPTEC-PC1KD compared to ciPTECwt. Of note, NPS-R568 treatment significantly reduced intracellular cAMP and mTOR activity in ciPTEC-PC1KD and ciPTEC-PC1Pt. To conclude, we demonstrated that selective CaSR activation in human ciPTEC carrying PKD1 mutation increases [Ca], reduces intracellular cAMP and mTOR activity, reversing the principal dysregulations considered the most proximal events in ADPKD pathogenesis, making CaSR a possible candidate as therapeutic target.
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http://dx.doi.org/10.1038/s41598-018-23732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890283PMC
April 2018