Publications by authors named "Martin Konrad"

110 Publications

Differential diagnosis of vitamin D-related hypercalcemia using serum vitamin D metabolite profiling.

J Bone Miner Res 2021 Apr 15. Epub 2021 Apr 15.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada, K7L3N6.

Genetic causes of vitamin D-related hypercalcemia are known to involve mutation of 25-hydroxyvitamin D-24-hydroxylase CYP24A1 or the sodium phosphate co-transporter SLC34A1; which result in excessive 1,25-(OH) D hormonal action. However, at least 20% of idiopathic hypercalcemia (IH) cases remain unresolved. In this case-control study, we used precision vitamin D metabolite profiling based on LC-MS/MS of an expanded range of vitamin D metabolites - to screen German and French cohorts of hypercalcemia patients, to identify patients with altered vitamin D metabolism where involvement of CYP24A1 or SLC34A1 mutation had been ruled out, and possessed normal 25-OH-D :24,25-(OH) D ratios. Profiles were compared to those of hypercalcemia patients with hypervitaminosis D, Williams-Beuren syndrome (WBS), CYP24A1 mutation, and normal subjects with a range of 25-OH-D levels. We observed that certain IH and WBS patients exhibited a unique profile comprising 8-10-fold higher serum 23,25,26-(OH) D and 25-OH-D -26,23-lactone than normals; as well as very low serum 1,25-(OH) D (2-5 pg/mL) and elevated 1,24,25-(OH) D , which we interpret implies hypersensitive expression of vitamin D-dependent genes, including CYP24A1, as a general underlying mechanism of hypercalcemia in these patients. As serum 25-OH-D and 24,25-(OH) D remained normal, we excluded the possibility that the aberrant profile was caused by hypervitaminosis D, but instead points to an underlying genetic cause that parallels the effect of Williams Syndrome Transcription Factor deficiency in WBS. Furthermore, we observed normalization of serum calcium and vitamin D metabolite profiles at follow up of an IH patient where 25-OH-D was reduced to 9 ng/mL, suggesting that symptomatic IH may depend on vitamin D nutritional status. Other hypercalcemic patients with complex conditions exhibited distinct vitamin D metabolite profiles. Our work points to the importance of serum vitamin D metabolite profiling in the differential diagnosis of vitamin D-related hypercalcemia that can rationalize expensive genetic testing, and assist healthcare providers in selecting appropriate treatment.
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http://dx.doi.org/10.1002/jbmr.4306DOI Listing
April 2021

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness.

J Am Soc Nephrol 2021 Apr 2. Epub 2021 Apr 2.

Department of General Pediatrics, Pediatric Nephrology, University Children's Hospital, Munster, Germany.

Background: The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na,K-ATPase function but are also involved in potassium and pH sensing. Genetic defects in cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.

Methods: A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.

Results: We identified mutations in the gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in oocytes significantly reduced currents.

Conclusions: Biallelic variants in were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.
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http://dx.doi.org/10.1681/ASN.2020111587DOI Listing
April 2021

The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2).

Hum Mutat 2021 Apr 1;42(4):473-486. Epub 2021 Mar 1.

Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. Mg uptake assays demonstrated loss-of-function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44-0.72 mmol/L), which could not be fully corrected by Mg supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR.
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http://dx.doi.org/10.1002/humu.24182DOI Listing
April 2021

Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders.

Kidney Int 2021 02;99(2):324-335

Department of Renal Medicine, University College London, London, United Kingdom; Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.
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http://dx.doi.org/10.1016/j.kint.2020.10.035DOI Listing
February 2021

First Reported Nosocomial Outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 in a Pediatric Dialysis Unit.

Clin Infect Dis 2021 01;72(2):265-270

Institute of Hygiene, University Hospital Münster, Münster, Germany.

Background: Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory condition caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was initially detected in China in December 2019. Currently, in Germany >140 000 cases of COVID-19 are confirmed. Here we report a nosocomial outbreak of SARS-CoV-2 infections in the pediatric dialysis unit of the University Hospital Münster (UHM).

Methods: Single-step real-time reverse-transcription polymerase chain reaction (rRT-PCR) from nasopharyngeal swabs was used to diagnose the index patient and identify infected contacts. Epidemiological links were analyzed by patient interviews and medical record reviews. In addition, each contact was assessed for exposure to the index case and monitored for clinical symptoms. Cycle threshold (Ct) values of all positive test results were compared between symptomatic and asymptomatic cases.

Results: Forty-eight cases were involved in this nosocomial outbreak. Nine contact cases developed laboratory-confirmed COVID-19 infections. Two SARS-CoV-2-positive cases remained clinically asymptomatic. Eleven cases reported flulike symptoms without positive results. Ct values were significantly lower in cases presenting typical COVID-19 symptoms, suggesting high viral shedding (P = .007).

Conclusions: Person-to-person transmission was at the heart of a hospital outbreak of SARS-CoV-2 between healthcare workers (HCWs) and patients in the pediatric dialysis unit at UHM. Semiquantitative rRT-PCR results suggest that individuals with high viral load pose a risk to spread SARS-CoV-2 in the hospital setting. Our epidemiological observation highlights the need to develop strategies to trace and monitor SARS-CoV-2-infected HCWs to prevent COVID-19 outbreaks in the hospital setting.
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http://dx.doi.org/10.1093/cid/ciaa491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197625PMC
January 2021

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

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

Department of Renal Medicine, University College London, London,UK.

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

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

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

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

Autosomal Recessive Renal Tubular Dysgenesis Caused by a Founder Mutation of Angiotensinogen.

Kidney Int Rep 2020 Nov 20;5(11):2042-2051. Epub 2020 Aug 20.

Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, National Defense Medical Center, Taiwan.

Introduction: Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in , , , and is a very rare but fatal disorder with an unknown prevalence.

Methods: We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined.

Results: All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in , which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels.

Conclusion: This mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT.
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http://dx.doi.org/10.1016/j.ekir.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609895PMC
November 2020

Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Clin Genet 2021 Jan 25;99(1):143-156. Epub 2020 Oct 25.

Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
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http://dx.doi.org/10.1111/cge.13861DOI Listing
January 2021

Systematic evaluation of olfaction in patients with hereditary cystic kidney diseases/renal ciliopathies.

J Med Genet 2020 Sep 11. Epub 2020 Sep 11.

University Children's Hospital, Department of General Pediatrics, Universitätsklinikum Münster, Münster, Germany

Background: Hereditary cystic kidney diseases such as nephronophthisis, polycystic kidney disease and Bardet-Biedl syndrome (BBS) are caused by a dysfunction of primary cilia. Cilia are involved in a variety of cellular functions and perceptions, with one of them being the sense of smell. Hyposmia is a typical feature found in patients with BBS. However, reports of olfactory dysfunction in other cystic kidney diseases are sparse. Here we provide a systematic survey on olfaction in a large cohort of patients displaying genetically determined renal ciliopathies.

Methods: We performed a match-controlled systematic olfactory evaluation in a group of 75 patients with a defined genetic background using age adapted and validated odour identification tests.

Results: Test results revealed a significant olfactory deficit in patients carrying variants (n=4), while all other genetic disorders causing nephronophthisis (n=25) or polycystic kidney disease (n=18) were not associated with an impaired sense of smell. Also in patients with BBS, olfactory performance was depending on the underlying molecular defect. While defects in the gene (n=9) had no impact on the sense of smell, all other gene disorders (n=19) were associated with significant hyposmia. Noteworthy, there was no correlation of the olfactory deficit with the level of renal impairment.

Conclusion: Hyposmia is a part of the clinical spectrum of BBS and of other renal ciliopathies. Depending on the genetic background, clinicians should be aware of this subtle and so far underappreciated symptom when clinically assessing patients with or gene variants.
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http://dx.doi.org/10.1136/jmedgenet-2020-107192DOI Listing
September 2020

Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers.

J Pediatr Endocrinol Metab 2020 Aug 31;33(10):1353-1358. Epub 2020 Aug 31.

Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany.

Objectives Both CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today. Case presentation Hypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis. Conclusions A biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.
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http://dx.doi.org/10.1515/jpem-2020-0169DOI Listing
August 2020

variants are associated with multiple congenital anomalies including ciliopathy phenotypes.

J Med Genet 2020 Jul 6. Epub 2020 Jul 6.

Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

Background: Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.

Methods: Among individuals from four unrelated families, we identified variants in ( that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted in frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of patient variants through rescue experiments in the frog model.

Results: Patients with variants of were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of in embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype in frog embryos depleted of introduction of patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.

Conclusion: These findings in both patient tissues and shed light on how mutations in may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.
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http://dx.doi.org/10.1136/jmedgenet-2019-106805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785698PMC
July 2020

Twelve-month outcome in juvenile proliferative lupus nephritis: results of the German registry study.

Pediatr Nephrol 2020 07 19;35(7):1235-1246. Epub 2020 Mar 19.

Department of Paediatric Kidney, Liver and Metabolic Diseases, Paediatric Research Center, Hannover Medical School Children's Hospital, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare.

Methods: Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015.

Results: At the time of diagnosis, median age was 13.7 (interquartile range 11.8-15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75 ml/min/1.73 m. At 12 months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26-22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients.

Conclusions: In this cohort of juvenile proliferative LN, renal outcome at 12 months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04501-xDOI Listing
July 2020

Why Are There so Many Plant Species That Transiently Flush Young Leaves Red in the Tropics?

Front Plant Sci 2020 18;11:83. Epub 2020 Feb 18.

College of Life Science & Technology, Honghe University, Mengzi, China.

Delayed greening of young leaves is a ubiquitous and visually striking phenomenon in the tropics. Here, we investigated the potential ecological functions of red coloration patterns in young leaves. To detect any protective function of the red coloration on the young leaves, leaf damage by insect herbivores was recorded in the field. To determine capacity for chemical defense, the concentrations of tannins and anthocyanins were measured in both young and mature leaves. To test the hypothesis that anthocyanins function as photo-protective molecules, chlorophyll content, maximum photochemical efficiency of ( / ), non-photochemical quenching (), and effective quantum yield of ( ) were measured in the field. Phylogenetic relationships were analyzed to test the relationary significance of the occurrence of redness in young leaves. Compared to the coloration in non-red leaves, young red leaves had significant higher anthocyanins and tannins content and lower herbivore damages. Young, red leaves had the lowest / values, which were significantly lower than those of non-red leaves. values in young red leaves were comparable to those of other groups. Although young red leaves had high , these values were significantly lower than those of the other three groups. The results suggest that the red coloration of young leaves protects them from insect herbivory primary by chemical defense through high concentrations of tannins and anthocyanins. Additionally, low / values in young red leaves indicate that anthocyanins might not be functioning as light attenuators to compensate for insufficient photo-protection mediated by . And finally, red coloration in young leaves is predominantly a result of adaptation to heavy herbivory stress but without significant intrinsic phylogenetic relationship of plant species.
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http://dx.doi.org/10.3389/fpls.2020.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041174PMC
February 2020

Distribution and management of the pediatric refugee population with renal replacement: A German pediatric cohort.

Pediatr Nephrol 2021 Feb 2;36(2):271-277. Epub 2020 Jan 2.

Division of Pediatric Nephrology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

With migration rising, the pediatric nephrology community is faced with challenges concerning the management of end-stage kidney disease (ESKD) in the pediatric refugee population. Data on the care of the pediatric refugee cohort on renal replacement therapy (RRT) is not available. A survey conducted by us in 2018 showed that the group of refugee children arriving to Germany during the years 2015-2017 accounts for approximately 20% of the total pediatric dialysis population in Germany. Provision of (medical) care for these children and their families is often hampered by psychosocial problems, cultural differences, language barriers, and administrative issues. Treating centers need to provide additional human as well as financial and logistic resources. In this educational review, we raise awareness and discuss possible challenges occurring in the treatment of refugee children with ESKD.
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http://dx.doi.org/10.1007/s00467-019-04374-9DOI Listing
February 2021

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

Treatment and long-term outcome in primary distal renal tubular acidosis.

Nephrol Dial Transplant 2019 06;34(6):981-991

Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

Background: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome.

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 (±1.16). 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.
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http://dx.doi.org/10.1093/ndt/gfy409DOI Listing
June 2019

HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry.

Pediatr Nephrol 2019 06 21;34(6):1065-1075. Epub 2019 Jan 21.

Pediatric Nephrology, University Children's Hospital Marburg, Baldingerstrasse 1, 35033, Marburg, Germany.

Background: HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult.

Methods: Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases.

Results: Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of - 0.33 ml/min/1.73m per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was - 2.8 ml/min/1.73m (± 13.2), in the total cohort - 1.0 ml/min/1.73m (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases.

Conclusions: In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.
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http://dx.doi.org/10.1007/s00467-018-4188-8DOI Listing
June 2019

Juvenile onset IIH and mutations.

Bone Rep 2018 Dec 21;9:42-46. Epub 2018 Jun 21.

Department of General Pediatrics, University Children's Hospital, Münster, Germany.

The term Idiopathic infantile hypercalcemia (IIH) was first introduced almost 70 years ago when symptomatic hypercalcemia developed in children after receiving high doses of vitamin D for the prevention of rickets. The underlying pathophysiology remained unknown until recessive mutations in encoding Vitamin D-24-hydroxylase were discovered. The defect in vitamin D degradation leads to an accumulation of active 1,25(OH)D with subsequent hypercalcemia. Enhanced renal calcium excretions lead to hypercalciuria and nephrocalcinosis. Meanwhile, the phenotypic spectrum associated with mutations has significantly broadened. Patients may present at all age groups with symptoms originating from increased serum calcium levels as well as from increased urinary calcium excretions, i.e. kidney stones. Possible long term sequelae comprise chronic renal failure as well as cardiovascular disease. Here, we present a family with two affected siblings with differing clinical presentation as an example for the phenotypic variability of CYP24A1 defects.
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http://dx.doi.org/10.1016/j.bonr.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303532PMC
December 2018

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability.

Am J Hum Genet 2018 11;103(5):808-816

Department of General Pediatrics, University Children's Hospital, Münster 48149, Germany.

Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. Whole-exome sequencing and conventional Sanger sequencing identified heterozygous de novo mutations in the catalytic Na, K-ATPase α1 subunit (ATP1A1). Functional characterization of mutant Na, K-ATPase α1 subunits in heterologous expression systems revealed not only a loss of Na, K-ATPase function but also abnormal cation permeabilities, which led to membrane depolarization and possibly aggravated the effect of the loss of physiological pump activity. These findings underline the indispensable role of the α1 isoform of the Na, K-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218849PMC
November 2018

Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study).

BMJ Open 2018 10 10;8(10):e024882. Epub 2018 Oct 10.

Department of Pediatrics, University Children's Hospital Köln, University Hospital Köln, Köln, Germany.

Introduction: Idiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only.

Methods And Design: The study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment.

Ethics And Dissemination: Ethics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal.

Trial Registration Number: DRKS0006547; EudraCT2014-001991-76; Pre-result.

Date Of Registration: 30 October 2014; 24 February 2017.
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http://dx.doi.org/10.1136/bmjopen-2018-024882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252704PMC
October 2018

A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings.

Turk J Pediatr 2018 ;60(1):76-80

Departments of Pediatric Nephrology, İzmir Tepecik Training and Research Hospital, , Izmir.

Alparslan C, Öncel EP, Akbay S, Alaygut D, Mutlubaş F, Tatlı M, Konrad M, Yavaşcan Ö, Kasap-Demir B. A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings. Turk J Pediatr 2018; 60: 76-80. Familial hypomagnesemic hypercalciuric nephrocalcinosis (FHHNC) (OMIM: 248250) is characterized by hypomagnesemia, hypercalciuria and nephrocalcinosis. FHHNC inevitably progresses to end-stage renal disease in decades. Mutations in CLDN-16 and CLDN-19 genes are associated with disrupted magnesium handling in the thick ascending limp of Henle`s loop. Patients with mutations in these genes share similar clinical features, and those with CLDN-19 gene mutations have ocular findings in addition. A 2-month-old boy, was admitted to our clinic with the complaints of upper respiratory tract infection. He was the first-born child of consanguineous parents. Laboratory findings revealed hypocalcemia and hypomagnesemia. Bilateral medullary nephrocalcinosis was detected on abdominal ultrasound. His ophthalmologic examination was unremarkable. With hypomagnesemia, hypercalciuria and nephrocalcinosis, the patient was considered to have FHHNC. Oral magnessium supplementation was initiated. Four years of follow-up has been completed uneventfully. When 6-days-old the brother of the case above was admitted with seizure. The patient was resistant to calcium and anticonvulsant drugs and the seizure activity could only be controlled after magnesium infusion. Biochemistry profile revealed hypocalcemia and hypomagnesemia. Urinary calcium extraction was 11 mg/kg/day. Medullary nephrocalcinosis was reported on renal ultrasound. His eye examination, echocardiography, transfontanel ultrasound and electroencephalography were normal. Due to the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis, and the medical history of his elder brother, he was diagnosed with FHHNC. After correction of the electrolyte abnormalities, he was discharged from hospital and is currently being followed-up without any problem. In this manuscript, we shared our experience about a novel homozygous mutation (W99C) in CLDN-16 gene causing FHHNC in a couple of Turkish siblings.
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http://dx.doi.org/10.24953/turkjped.2018.01.011DOI Listing
January 2019

A de novo KCNA1 Mutation in a Patient with Tetany and Hypomagnesemia.

Nephron 2018 23;139(4):359-366. Epub 2018 May 23.

Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

Mutations in the KCNA1 gene encoding the voltage-gated potassium (K+) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg2+) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg2+ levels, renal Mg2+ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K+ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.
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http://dx.doi.org/10.1159/000488954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492638PMC
September 2019

Network for Early Onset Cystic Kidney Diseases-A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood.

Front Pediatr 2018 13;6:24. Epub 2018 Feb 13.

Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany.

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing "revolution" in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress.
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http://dx.doi.org/10.3389/fped.2018.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819567PMC
February 2018

Perinatal Diagnosis, Management, and Follow-up of Cystic Renal Diseases: A Clinical Practice Recommendation With Systematic Literature Reviews.

JAMA Pediatr 2018 01;172(1):74-86

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

Importance: Prenatal and neonatal cystic kidney diseases are a group of rare disorders manifesting as single, multiple unilateral, or bilateral cysts or with increased echogenicity of the renal cortex without macroscopic cysts. They may be accompanied by grossly enlarged kidneys, renal oligohydramnios, pulmonary hypoplasia, extrarenal abnormalities, and neonatal kidney failure. The prognosis is extremely variable from trivial to very severe or even uniformly fatal, which poses significant challenges to prenatal counseling and management.

Objective: To provide a clinical practice recommendation for fetal medicine specialists, obstetricians, neonatologists, pediatric nephrologists, pediatricians, and human geneticists by aggregating current evidence and consensus expert opinion on current management of cystic nephropathies before and after birth.

Methods: After 8 systematic literature reviews on clinically relevant questions were prepared (including 90 studies up to mid-2016), recommendations were formulated and formally graded at a consensus meeting that included experts from all relevant specialties. After further discussion, the final version was voted on by all members using the Delphi method. The recommendations were reviewed and endorsed by the working groups on inherited renal disorders of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and European Society for Paediatric Nephrology (ESPN); the German Society of Obstetrics and Gynecology (DGGG), German Society of Perinatal Medicine (DGPM), and German Society of Ultrasound in Medicine (DEGUM); and the alliance of patient organizations, PKD International.

Recommendations: The group makes a number of recommendations on prenatal and postnatal imaging by ultrasound and magnetic resonance imaging, genetic testing, prenatal counseling, in utero therapeutic interventions, and postnatal management of prenatal and neonatal cystic kidney diseases, including provision of renal replacement therapy in neonates. In addition to detailed knowledge about possible etiologies and their prognosis, physicians need to be aware of recent improvements and remaining challenges of childhood chronic kidney disease, neonatal renal replacement therapy, and intensive pulmonary care to manage these cases and to empower parents for informed decision making.
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http://dx.doi.org/10.1001/jamapediatrics.2017.3938DOI Listing
January 2018

Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.

Clin J Am Soc Nephrol 2017 Dec 16;12(12):1974-1983. Epub 2017 Nov 16.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes ( to ) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD.

Design, Setting, Participants, & Measurements: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years.

Results: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous deletion was, by far, the most frequent genetic defect (=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the group and 66% [61 of 92] for children without ). A homozygous deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non- group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood.

Conclusions: Mutations in genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.
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http://dx.doi.org/10.2215/CJN.01280217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718263PMC
December 2017

Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes.

J Am Soc Nephrol 2018 01 1;29(1):335-348. Epub 2017 Nov 1.

Institute of Physiology, University of Zürich, Zurich, Switzerland;

Magnesium (Mg) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg, which is crucial for Mg homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (4.4×10) near , which encodes an epithelial Mg channel, and rs35929 (2.1×10), a variant of , which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg regulated the expression of the highly conserved ortholog , and knockdown resulted in renal Mg wasting and metabolic disturbances. Finally, rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg deficiency to insulin resistance and obesity.
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http://dx.doi.org/10.1681/ASN.2017030267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748908PMC
January 2018

Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases.

J Appl Genet 2017 Aug 3;58(3):349-353. Epub 2017 May 3.

Department of Nephrology, The Children's Memorial Health Institute, Warsaw, Poland.

Idiopathic infantile hypercalcemia (IIH) is a mineral metabolism disorder characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. The periodical increase in incidence of IIH, which occurred in the twentieth century in the United Kingdom, Poland, and West Germany, turned out to be a side effect of rickets over-prophylaxis. It was recently discovered that the condition is linked to two genes, CYP24A1 and SLC34A1. The aim of the study was to search for pathogenic variants of the genes in adult persons who were shortlisted in infancy as IIH caused by "hypersensitivity to vit. D". All persons were found to carry mutations in CYP24A1 or SLC34A1, nine and two persons respectively. The changes were biallelic, with one exception. Incidence of IIH in Polish population estimated on the basis of allele frequency of recurrent p.R396W CYP24A1 variant, is 1:32,465 births. It indicates that at least a thousand homozygotes and compound heterozygotes with risk of IIH live in the country. Differences in mechanism of developing hypercalcemia indicate that its prevention may vary in both IIH defects. Theoretically, vit. D restriction is a first indication for CYP24A1 defect (which disturbs 1,25(OH)D degradation) and phosphate supplementation for SLC34A1 defect (which impairs renal phosphate transport). In conclusion, we suggest that molecular testing for CYP24A1 and SLC34A1 mutations should be performed in each case of idiopathic hypercalcemia/hypercalciuria, both in children and adults, to determine the proper way for acute treatment and complications prevention.
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http://dx.doi.org/10.1007/s13353-017-0397-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509812PMC
August 2017

Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4.

Clin Infect Dis 2017 Jun;64(12):1637-1643

University Children's Hospital, University Medical Center Hamburg-Eppendorf.

Background.: In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking.

Methods.: Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak.

Results.: Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes.

Conclusions.: The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.
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http://dx.doi.org/10.1093/cid/cix218DOI Listing
June 2017

Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2017 01;91(1):24-33

Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique, Paris, France; Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.
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http://dx.doi.org/10.1016/j.kint.2016.09.046DOI Listing
January 2017

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

Nephrol Dial Transplant 2018 01;33(1):85-94

University College London, Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service Trust, London, UK.

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 m2, 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.
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http://dx.doi.org/10.1093/ndt/gfw350DOI Listing
January 2018