Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort

BACKGROUND: Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. METHODS: Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. RESULTS: Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m(2), P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. CONCLUSIONS: CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria

Genetic drivers of kidney defects in the digeorge syndrome

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P = 4.5×1014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-Altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

Rare variants in BNC2 are implicated in autosomal-dominant congenital lower urinary-tract obstruction

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853(∗)]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage

Ramipril and Risk of Hyperkalemia in Chronic Hemodialysis Patients

Angiotensin converting enzyme (ACE) inhibitors provide well known cardiorenal-protective benefits added to antihypertensive effects in chronic renal disease. These agents are underused in management of patients receiving hemodialysis (HD) because of common concern of hyperkalemia. However, few studies have investigated effect of renin angiotensin aldosterone system (RAAS) blockade on serum potassium in hemodialysis patients. We assessed the safety of ramipril in patients on maintenance HD. We enrolled 28 adult end stage renal disease (ESRD) patients treated by maintenance HD and prescribed them ramipril in doses of 1.25 to 5 mg per day. They underwent serum potassium concentration measurements before ramipril introduction and in 1 to 3 months afterwards. No significant increase in kalemia was found. Results of our study encourage the use of ACE inhibitors in chronically hemodialyzed patients, but close potassium monitoring is mandatory

Treatment and long-Term outcome in primary distal renal tubular acidosis

PubMedID: 30773598Background. Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-Termoutcome. Methods. We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. Results. Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (61.16). There was an increased prevalence of chronic kidney disease (CKD) Stage -2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. Conclusion. Long-Term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients. © The Author(s) 2018.Erciyes Üniversitesi Iran University of Medical Sciences Università degli Studi di Padova Chung Hua University American Ornithologists' Union University of Queensland 7Centre University College London Aristotle University of Thessaloniki Lunds Universitet Cairo University National Rosacea Society Heart of England NHS Foundation Trust Centre hospitalier universitaire Sainte-Justine Erasmus Universiteit Rotterdam Aristotle University of Thessaloniki1Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK, 2Centre for Nephrology, University College London, London, UK, 3Division of Nephrology, Bambino Gesù Children’s Hospital—IRCCS, Rome, Italy, 4Pediatric Nephrology—CHU Arnaud de Villeneuve, Montpellier University Hospital, Montpellier, France, 5Ali-Asghar Clinical Research Development Center, Iran University of Medical Sciences, Tehran, Iran, 6Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland, 7Centre de référence Maladies rénales rares, Bron, France, 8ASST Niguarda, Milan, Italy, 9Department of Pediatrics, University Hospital of Cologne, Cologne, Germany, 10University Hospital Leuven, Leuven, Belgium, 11King Edward Memorial Hospital, Pune, India, 12Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt, 13Hospital Universitario Vall d’Hebron, Barcelona, Spain, 14Division of Pediatric Nephrology, NRS Medical College, Kolkata, India, 15Pediatric Nephrology, Dialysis and Transplant Unit, Azienda Ospedaliera & University of Padova, Padova, Italy, 16University Children’s Hospital, Medical School, Skopje, Macedonia, 17National Medical and Research Centre for Children’s Health, Moscow, Russia, 18Centre Hospitalier Universitaire de Toulouse, Service de Nephrologie Pediatrique, Hopital des Enfants, Centre De Reference des Maladies Rénales Rares du Sud Ouest, Toulouse, France, 19Hospital Universitario Central de Asturias, Oviedo, Spain, 20Radboud University Medical Centre, Nijmegen, The Netherlands, 21Nephrology and Dialysis Unit, Department of Woman, Child and Urological Diseases, Azienda Ospedaliero—Universitaria Sant’Orsola-Malpighi, Bologna, Italy, 22Charité Universitätsmedizin Berlin, Berlin, Germany, 23University Children’s Hospital, Münster, Germany, 24Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands, 25Centro Hospitalar de Lisboa Central, Lisbon, Portugal, 26Fourth Pediatric Department, Aristotle University, Thessaloniki, Greece, 27Lady Cilento Children’s Hospital, Brisbane, Australia, 28School of Medicine, the University of Queensland, Brisbane, Australia, 29Department of Pediatric Nephrology, Pamukkale University School of Medicine, Denizli, Turkey, 30Nephrology Unit Azienda Ospedaliera, Papa Giovani XXIII, Bergamo, Italy, 31Karolinska Institutet, Lund University,Sweden,GroupFlorenceNightingaleHospitals,Ist32· anbul, Turkey,Fondazione Policlinico A. Gemelli, Universita` Cattolica del33 Sacro Cuore, Rome, Italy, 34Pediatric Nephrology Center of Excellence and Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, 35Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy, 36Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, Naples, Italy, 37Pediatric Department, Lillebaelt Hospital Kolding, Kolding, Denmark, 38Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital of Heidelberg, Heidelberg, Germany, 39Haseki Education and Research Hospital, Istanbul, Turkey, 40Belarusian State Medical University, Minsk, Belarus, 41Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France, 42Pediatric Nephrology Unit, AOU Policlinic G Martino, Messina, Italy, 43Necker Hospital, Paris, France, 44Faculty of Medicine, Department of Pediatric Nephrology, Erciyes University, Kayseri, Turkey, 45Cukurova University, Adana, Turkey, 46Nephrology Centre, Santaros Klinikos, Vilnius University, Vilnius, Lithuania, 47University Hospital of Lille, France, 48Department of Renal Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia, 49University Hospital Centre Zagreb, Zagreb, Croatia, 50Department of Pediatrics, SMDZ in Zabrze, SUM in Katowice, Poland, 51Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany,The European dRTA Consortium consists of the authors, as well as: Amira Peco-Antic(Department of Nephrology, University Children’s Hospital, Belgrade, Serbia), Amrit Kaur (Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, UK), Antonino Paglialunga (ASP de Ragusa, Modica, Italy), Aude Servais (Department of Nephrology, Centre Hospitalier Universitaire Necker, APHP, Paris, France), Branko Lutovac (Clinical Centre of Montenegro, Institute for Children’s Disease, Podgorica, Montenegro), Ewout J. Hoorn (Erasmus Medical Center, Rotterdam, The Netherlands), Hadas Shasha-Lavsky (Galilee Medical Center, Nahariya, Israel), Jerome Harambat (Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France), Astrid Godron-Dubrasquet (Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France), Kathrin Buder (Pediatric Department, University Hospital, Carl Gustav Carus Dresden, Dresden, Germany), Lise Allard (Department of Pediatrics, Angers University Hospital, Angers, France), Ludwig Patzer (Children’s Hospital St Elisabeth and St Barbara, Halle, Germany), Marina Shumikhina (Filatov Children’s Clinical Hospital No. 13, Moscow, Russia), Matthias Hansen (KfH Centre of Paediatric Nephrology, Clementine Children’s Hospital, Frankfurt, Germany), Nikoleta Printza (First Pediatric Department, Aristotle University, Thessaloniki, Greece), Nuran Küc¸ük (Kartal Dr. Lütfi Kırdar Training and Research Hospital, İstanbul, Turkey), Ortraud Beringer (University Children’s Hospital, Ulm, Germany), Rajendra Bhimma (Inkosi Albert Luthuli, Central Hospital, Durban, South Africa), Rimante Cerkauskiene (Faculty of Medicine, Children’s Hospital, Vilnius University, Vilnius, Lithuania; Santaros Klinikos, Vilnius University Hospital, Vilnius, Lithuania), Thomas J. Neuhaus (Children’s Hospital of Lucerne, Cantonal Hospital of Lucerne, Lucerne, Switzerland), Valbona Stavileci (Pediatric Clinic, Prishtina, Kosovo), Tim Ulinski (Pediatric Nephrology Department, Armand Trousseau University Hospital, APHP, Paris, France), Nida Temizkan Dincel (Health Sciences University, Izmir Dr Behcet Uz Children’s Hospital, İzmir, Turkey) and Nilufar Mohebbi (Division of Nephrology, University Hospital Zurich, Zurich, Switzerland