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Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-ß signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases.
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Cardiomiopatia Hipertrófica , Cílios , Adulto , Animais , Cardiomiopatia Hipertrófica/metabolismo , Criança , Cílios/genética , Cílios/metabolismo , Fibrose , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim , Fígado , Mutação/genética , Peixe-Zebra/genéticaRESUMO
BACKGROUND: Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH. METHODS: Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results. RESULTS: NPHP1 and NPHP4 were both absent in all individuals with disease-causing NPHP1 variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a "variant of unknown significance." In individuals with an NPHP4 genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants in NPHP1 and NPHP4, respectively. CONCLUSIONS: IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis-both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.
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BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3 , which encodes the Na + -Cl - cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield. METHODS: Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants. RESULTS: A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns. CONCLUSION: Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.
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Síndrome de Gitelman , Humanos , Síndrome de Gitelman/genética , Síndrome de Gitelman/patologia , Íntrons/genética , Mutação , Membro 3 da Família 12 de Carreador de Soluto/genética , ÉxonsRESUMO
BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
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DNA Mitocondrial/genética , Síndrome de Gitelman/genética , Mutação , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Pré-Escolar , Feminino , Genótipo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patologia , Células HEK293 , Humanos , Lactente , Rim/metabolismo , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Modelos Biológicos , Conformação de Ácido Nucleico , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA de Transferência de Isoleucina/química , RNA de Transferência de Isoleucina/genética , RNA de Transferência de Fenilalanina/química , RNA de Transferência de Fenilalanina/genética , Membro 3 da Família 12 de Carreador de Soluto/genética , Adulto JovemRESUMO
BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.
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Síndrome de Bartter , Síndrome de Gitelman , Hiperparatireoidismo , Criança , Humanos , Síndrome de Gitelman/complicações , Hormônio Paratireóideo , Síndrome de Bartter/complicações , Estudos Transversais , Fosfatos , Homeostase , CálcioRESUMO
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 TMEM67 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 BBS1 gene (n=9) had no impact on the sense of smell, all other BBS 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 BBS or TMEM67 gene variants.
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Ciliopatias/diagnóstico , Ciliopatias/genética , Predisposição Genética para Doença , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Fenótipo , Olfato , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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 discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model. RESULTS: Patients with variants of DLG5 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 dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 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 Xenopus shed light on how mutations in DLG5 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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Ciliopatias/genética , Anormalidades Congênitas/genética , Proteínas de Membrana/genética , Mutação , Proteínas Supressoras de Tumor/genética , Animais , Encéfalo/patologia , Criança , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Feto/anormalidades , Técnicas de Silenciamento de Genes , Proteínas Hedgehog/metabolismo , Humanos , Rim/patologia , Masculino , Linhagem , Transdução de Sinais , Sequenciamento do Exoma , XenopusRESUMO
BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
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Cardiomiopatia Dilatada/genética , Hipercalciúria/genética , Nefropatias/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação de Sentido Incorreto , Nefrocalcinose/genética , Erros Inatos do Transporte Tubular Renal/genética , Serina-Treonina Quinases TOR/metabolismo , Cardiomiopatia Dilatada/metabolismo , Feminino , Células HEK293 , Humanos , Hipercalciúria/metabolismo , Nefropatias/metabolismo , Túbulos Renais Distais/metabolismo , Masculino , Modelos Moleculares , Natriurese/genética , Nefrocalcinose/metabolismo , Linhagem , Conformação Proteica , Erros Inatos do Transporte Tubular Renal/metabolismo , Convulsões/genética , Convulsões/metabolismo , Transdução de Sinais , Sequenciamento do Exoma , Sequenciamento Completo do GenomaRESUMO
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 KCNJ10 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 KCNJ16 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 Xenopus oocytes significantly reduced currents. CONCLUSIONS: Biallelic variants in KCNJ16 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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Desequilíbrio Ácido-Base/genética , Perda Auditiva Neurossensorial/genética , Hipopotassemia/genética , Nefropatias/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adolescente , Adulto , Alelos , Animais , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Túbulos Renais , Mutação com Perda de Função , Masculino , Camundongos , Néfrons/metabolismo , Oócitos , Linhagem , Fenótipo , RNA Mensageiro/metabolismo , Reabsorção Renal/genética , Sais/metabolismo , Sequenciamento do Exoma , Xenopus laevis , Adulto JovemRESUMO
Although animal models show a clear link between noise exposure and damage to afferent cochlear synapses, the relationship between noise exposure and efferent function appears to be more complex. Animal studies indicate that high intensity noise exposure reduces efferent medial olivocochlear (MOC) reflex strength, whereas chronic moderate noise exposure is associated with a conditioning effect that enhances the MOC reflex. The MOC reflex is predicted to improve speech-in-noise perception and protects against noise-induced auditory damage by reducing cochlear gain. In humans, MOC reflex strength can be estimated by measuring contralateral inhibition of distortion product otoacoustic emissions (DPOAEs). The objective of this study was to determine the impact of military noise exposure on efferent auditory function by measuring DPOAE contralateral inhibition in young Veterans and non-Veterans with normal audiograms. Compared with non-Veteran controls, Veterans with high levels of reported noise exposure demonstrated a trend of reduced contralateral inhibition across a broad frequency range, suggesting efferent damage. Veterans with moderate noise exposure showed trends of reduced inhibition from 3 to 4 kHz but greater inhibition from 1 to 1.5 kHz, consistent with conditioning. These findings suggest that, in humans, the impact of noise exposure on the MOC reflex differs depending on the noise intensity and duration.
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Audição , Emissões Otoacústicas Espontâneas , Animais , Humanos , Emissões Otoacústicas Espontâneas/fisiologia , Estimulação Acústica , Audição/fisiologia , Ruído/efeitos adversos , Cóclea/fisiologia , Núcleo Olivar/fisiologiaRESUMO
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. 25 Mg2+ 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 Mg2+ 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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Proteínas de Transporte de Cátions , Deficiência Intelectual , Proteínas de Transporte de Cátions/genética , Ciclinas/genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , FenótipoRESUMO
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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COVID-19 , Infecção Hospitalar , Criança , China/epidemiologia , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Alemanha , Humanos , Diálise Renal , SARS-CoV-2RESUMO
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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Alcalose , Síndrome de Bartter , Hipopotassemia , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Síndrome de Bartter/terapia , Consenso , Humanos , Doenças RarasRESUMO
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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Deficiência Intelectual/genética , Mutação/genética , Erros Inatos do Transporte Tubular Renal/genética , Convulsões/genética , ATPase Trocadora de Sódio-Potássio/genética , Criança , Pré-Escolar , Feminino , Células Germinativas , Heterozigoto , Homeostase/genética , Humanos , Lactente , Recém-Nascido , Rim/patologia , Magnésio/metabolismo , Masculino , Fenótipo , Isoformas de Proteínas/genéticaRESUMO
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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Colágeno Tipo IV/genética , Estudos de Associação Genética , Nefrite Hereditária/genética , Insuficiência Renal/genética , Adolescente , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Genes Ligados ao Cromossomo X/genética , Testes Genéticos , Humanos , Lactente , Rim/patologia , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/patologia , Nefrite Hereditária/terapia , Insuficiência Renal/diagnóstico , Insuficiência Renal/patologia , Insuficiência Renal/terapiaRESUMO
Distal renal tubular acidosis (dRTA) is characterized by an impaired ability of the distal tubule to excrete acid, leading to metabolic acidosis. Associated complications include bone disease, growth failure, urolithiasis and hypokalaemia. Due to its rarity, there is limited evidence to guide diagnosis and management; however, available data strongly suggest that metabolic control of the acidosis by alkali supplementation can halt or revert almost all complications. Despite this, cohort studies show that adequate metabolic control is present in only about half of patients, highlighting problems with treatment provision or adherence. With these clinical practice points the authors, part of the working groups tubulopathies in the European Rare Kidney Disease Reference network and inherited kidney diseases of the European Society for Paediatric Nephrology, aim to provide guidance for the management of patients with dRTA to facilitate adequate treatment and establish an initial best practice standard against which treatment of patients can be audited.
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Acidose Tubular Renal , Acidose , Hipopotassemia , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/etiologia , Acidose Tubular Renal/terapia , Criança , Estudos de Coortes , Humanos , Hipopotassemia/diagnóstico , Hipopotassemia/etiologia , RimRESUMO
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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Falência Renal Crônica , Nefrologia , Refugiados , Criança , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Diálise Renal , Terapia de Substituição RenalRESUMO
OBJECTIVE: Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT). METHODS: Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter. RESULTS: We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14-13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 [0.33] vs. 1.79 [0.55]) at V0 and (1.70 [0.36] vs. 1.71 [0.51]) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions. CONCLUSIONS: Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.Gov ( Clinicaltrials.gov identifier: NCT01561118) on March 22, 2012.
Assuntos
Treino Aeróbico , Diálise Renal , Adolescente , Criança , Terapia por Exercício , Feminino , Humanos , Masculino , Qualidade de VidaRESUMO
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.
RESUMO
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 m2. 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.