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BACKGROUND: Accurate interpretation of everyday laboratory work is crucial for the early detection of impaired kidney function. Bedside estimation of glomerular filtration rate (eGFR) in children is based on serum creatinine standardized for body mass, most commonly using the revised Schwartz equation using height. This study evaluates how data presentation affects the correct assessment of children's kidney function. METHODS: In this survey-based study, 121 physicians treating children routinely in a tertiary hospital answered 11 clinical questions requiring assessment of kidney function based on serum creatinine with general (adult) or pediatric normal serum creatinine ranges, or by presented eGFR. The demographic data of the participants were collected. RESULTS: Presenting eGFR values rather than the customary presentation of serum creatinine and anthropometric parameters more than quadrupled the number of physicians who accurately estimated pediatric kidney function; 38.8% of physicians correctly assessed kidney function when presented with eGFR values but misinterpreted it when equivalent creatinine values were presented (p < 0.001). Seniority, specialty, and self-reported frequency of pediatric kidney function assessment did not affect the interpretation. CONCLUSIONS: Presenting physicians with calculated eGFR can dramatically improve the ability of the medical team to assess kidney function correctly in children. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Insuficiencia Renal , Adulto , Niño , Humanos , Tasa de Filtración Glomerular , Creatinina , RiñónRESUMEN
BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Pruebas Genéticas , Enfermedades Renales , Niño , Humanos , Enfermedades Renales/genética , Fenotipo , Derivación y Consulta , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Low nephron number at birth is associated with a high risk of CKD in adulthood because nephrogenesis is completed in utero. Poor intrauterine environment impairs nephron endowment via an undefined molecular mechanism. A calorie-restricted diet (CRD) mouse model examined the effect of malnutrition during pregnancy on nephron progenitor cells (NPCs). METHODS: Daily caloric intake was reduced by 30% during pregnancy. mRNA expression, the cell cycle, and metabolic activity were evaluated in sorted Six2 NPCs. The results were validated using transgenic mice, oral nutrient supplementation, and organ cultures. RESULTS: Maternal CRD is associated with low nephron number in offspring, compromising kidney function at an older age. RNA-seq identified cell cycle regulators and the mTORC1 pathway, among other pathways, that maternal malnutrition in NPCs modifies. Metabolomics analysis of NPCs singled out the methionine pathway as crucial for NPC proliferation and maintenance. Methionine deprivation reduced NPC proliferation and lowered NPC number per tip in embryonic kidney cultures, with rescue from methionine metabolite supplementation. Importantly, in vivo, the negative effect of caloric restriction on nephrogenesis was prevented by adding methionine to the otherwise restricted diet during pregnancy or by removing one Tsc1 allele in NPCs. CONCLUSIONS: These findings show that mTORC1 signaling and methionine metabolism are central to the cellular and metabolic effects of malnutrition during pregnancy on NPCs, contributing to nephrogenesis and later, to kidney health in adulthood.
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Desnutrición/fisiopatología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Metionina/metabolismo , Nefronas/embriología , Células Madre/metabolismo , Animales , Restricción Calórica , Ciclo Celular , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Proteínas de Homeodominio/genética , Desnutrición/metabolismo , Metabolómica , Metionina/administración & dosificación , Metionina/deficiencia , Metionina/farmacología , Ratones , Ratones Transgénicos , Nefronas/metabolismo , Nefronas/patología , Técnicas de Cultivo de Órganos , Embarazo , ARN Mensajero , RNA-Seq , Transducción de Señal , Células Madre/fisiología , Factores de Transcripción/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/genéticaRESUMEN
PURPOSE: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome. METHODS: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (WES), and Sanger sequencing. RESULTS: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4, and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1-p.R461* mutation has been identified in 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia, whereas mutations in NPHP4 were associated with high myopia. CONCLUSION: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Unión a Calmodulina/genética , Ciliopatías/genética , Proteínas del Citoesqueleto/genética , Enfermedades Renales Quísticas/genética , Amaurosis Congénita de Leber/genética , Mutación , Atrofias Ópticas Hereditarias/genética , Proteínas/genética , Adolescente , Niño , Preescolar , Ciliopatías/diagnóstico , Ciliopatías/fisiopatología , Pruebas de Percepción de Colores , Análisis Mutacional de ADN , Electrorretinografía , Femenino , Humanos , Lactante , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/fisiopatología , Amaurosis Congénita de Leber/diagnóstico , Amaurosis Congénita de Leber/fisiopatología , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Atrofias Ópticas Hereditarias/diagnóstico , Atrofias Ópticas Hereditarias/fisiopatología , Linaje , Fenotipo , Retina/fisiopatología , Estudios Retrospectivos , Agudeza Visual/fisiología , Pruebas del Campo Visual , Secuenciación del Exoma , Adulto JovenRESUMEN
Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one Tsc1 allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both Tsc1 alleles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor.
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Nefronas , Organogénesis/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Transgénicos , Nefronas/química , Nefronas/citología , Nefronas/crecimiento & desarrollo , Nefronas/fisiología , Serina-Treonina Quinasas TOR/genética , Proteína 1 del Complejo de la Esclerosis TuberosaRESUMEN
Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.
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Hiperparatiroidismo Secundario/metabolismo , Glándulas Paratiroides/patología , Insuficiencia Renal Crónica/complicaciones , Proliferación Celular , Regulación hacia Abajo , Factor-23 de Crecimiento de Fibroblastos , Humanos , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/patología , Glándulas Paratiroides/metabolismo , Receptores de Calcitriol/metabolismo , Receptores Sensibles al Calcio/metabolismo , Insuficiencia Renal Crónica/metabolismoRESUMEN
BACKGROUND: Renal damage is a progressive complication of sickle cell disease (SCD). Microalbuminuria is common in children with SCD, while a smaller number of children have more severe renal manifestations necessitating kidney biopsy. There is limited information on renal biopsy findings in children with SCD and subsequent management and outcome. METHODS: This is a multicenter retrospective analysis of renal biopsy findings and clinical outcomes in children and adolescents with SCD. We included children and adolescents (age ≤ 20 years) with SCD who had a kidney biopsy performed at a pediatric nephrology unit. The clinical indication for biopsy, biopsy findings, subsequent treatments, and outcomes were analyzed. RESULTS: Thirty-six SCD patients (ages 4-19 years) were identified from 14 centers with a median follow-up of 2.6 years (0.4-10.4 years). The indications for biopsy were proteinuria (92%) and elevated creatinine (30%). All biopsies had abnormal findings, including mesangial hypercellularity (75%), focal segmental glomerulosclerosis (30%), membranoproliferative glomerulonephritis (16%), and thrombotic microangiopathy (2%). There was increased use of hydroxyurea, angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers following renal biopsy. At last follow-up, 3 patients were deceased, 2 developed insulin-dependent diabetes mellitus, 6 initiated chronic hemodialysis, 1 received a bone marrow transplant, and 1 received a kidney transplant. CONCLUSIONS: Renal biopsies, while not commonly performed in children with SCD, were universally abnormal. Outcomes were poor in this cohort of patients despite a variety of post-biopsy interventions. Effective early intervention to prevent chronic kidney disease (CKD) is needed to reduce morbidity and mortality in children with SCD.
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Albuminuria/etiología , Anemia de Células Falciformes/complicaciones , Riñón/patología , Insuficiencia Renal Crónica/etiología , Adolescente , Albuminuria/sangre , Albuminuria/patología , Albuminuria/orina , Anemia de Células Falciformes/sangre , Biopsia , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Masculino , Medio Oeste de Estados Unidos , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/prevención & control , Insuficiencia Renal Crónica/orina , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Early detection of acute kidney injury (AKI) after cardiac surgery has improved recently with the discovery and validation of novel urinary biomarkers. However, objective tools to predict the risk of AKI before the insult are still missing. We tested the hypothesis that pre-operative serum fibroblast growth factor 23 (FGF23) concentrations would be elevated in children who develop AKI after heart surgery with cardiopulmonary bypass (CPB). We also compared post-operative FGF23 concentrations to other biomarkers for early detection of AKI. METHODS: Blood and urine samples were collected in a prospective observational study from 83 children with congenital heart disease. Severe AKI (sAKI) development (KDIGO stages II-III) in the first seven days after surgery was the primary outcome. RESULTS: Thirty of 76 (39.5%) and 11/76 (14.5%) of patients developed AKI and sAKI, respectively. Pre-operative serum creatinine, cystatin C, and urine biomarker concentrations did not differ between sAKI patients and controls. Pre-operative serum FGF23 levels were higher in patients who developed sAKI (median [IQR] value of 819 RU/ml [397.7, 1196.8] vs. 324.3 RU/ml [124.6, 679.8] (p = 0.02). FGF23 12-24 h after the termination of CPB was also associated with sAKI in the first week after surgery (498 RU/ml [226, 928] vs. 1435 RU/ml [831, 12,996]). CONCLUSIONS: Pre- and post-operative FGF23 levels are higher in children who develop sAKI after cardiac surgery. We suggest FGF23 may be able to detect sub-clinical kidney injury and can be used with demographic AKI risk factors to enhance post-operative sAKI risk prediction.
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Lesión Renal Aguda/diagnóstico , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Factores de Crecimiento de Fibroblastos/sangre , Cardiopatías Congénitas/cirugía , Complicaciones Posoperatorias/diagnóstico , Lesión Renal Aguda/sangre , Lesión Renal Aguda/etiología , Lesión Renal Aguda/orina , Factores de Edad , Biomarcadores/sangre , Biomarcadores/orina , Puente Cardiopulmonar/efectos adversos , Preescolar , Creatinina/sangre , Cistatina C/sangre , Diagnóstico Precoz , Femenino , Factor-23 de Crecimiento de Fibroblastos , Cardiopatías Congénitas/sangre , Humanos , Lactante , Recién Nacido , Masculino , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/orina , Periodo Preoperatorio , Pronóstico , Estudios Prospectivos , Curva ROC , Medición de Riesgo/métodos , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
AIMS: Acute kidney injury (AKI) occurs in 30 - 40% of children after cardiac surgery (CS) and is associated with poor prognosis. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with a pivotal role in phosphorus and vitamin D metabolism. We assessed FGF23 as an early marker for severe AKI (sAKI) in infants after CS. MATERIALS AND METHODS: Samples were previously collected in a multicenter observational study from children after CS. Serum FGF23 (n = 41) and urine AKI biomarker levels (n = 35) were assessed 4 - 8 hours after bypass. sAKI was defined as ≥ 100% rise in serum creatinine over baseline. Non-parametric and ROC analyses were used to evaluate the association between FGF23, urine AKI markers, and sAKI in the week after CS. RESULTS: Serum FGF23, urine NGAL, and urine KIM1 were higher in sAKI patients. The AUC-ROC for urine NGAL (0.74, [0.49 - 0.99]), urine KIM1 (0.79, [0.68 - 0.98]), and serum FGF23 (0.74, [0.5 - 0.9]) showed fair prediction of sAKI. CONCLUSION: Early measurement of FGF23 has predictive ability in infants who develop sAKI after CS with cardiopulmonary bypass.â©.
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Lesión Renal Aguda/diagnóstico , Procedimientos Quirúrgicos Cardíacos , Factores de Crecimiento de Fibroblastos/sangre , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Proteínas de Fase Aguda/orina , Biomarcadores/sangre , Biomarcadores/orina , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Lactante , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Curva ROCRESUMEN
Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6(p-/-) mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid-induced AKI. Uremic rpS6(p-/-) mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6.
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Hiperparatiroidismo Secundario/metabolismo , Hiperparatiroidismo Secundario/patología , Complejos Multiproteicos/fisiología , Glándulas Paratiroides/patología , Proteína S6 Ribosómica/metabolismo , Serina-Treonina Quinasas TOR/fisiología , Animales , Proliferación Celular , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE OF REVIEW: Allogenic kidney transplantation use is limited because of a shortage of kidney organ donors and the risks associated with a long-term immunosuppression. An emerging treatment prospect is autologous transplants of ex vivo produced human kidneys. Here we will review the research advances in this area. RECENT FINDINGS: The creation of human induced pluripotent cells (iPSCs) from somatic cells and the emergence of several differentiation protocols that are able to convert iPSCs cells into self-organizing kidney organoids are two large steps toward assembling a human kidney in vitro. Several groups have successfully generated urine-producing kidney organoids upon transplantation in a mouse host. Additional advances in culturing nephron progenitors in vitro may provide another source for kidney engineering, and the emergence of genome editing technology will facilitate correction of congenital mutations. SUMMARY: Basic research into the development of metanephric kidneys and iPSC differentiation protocols, the therapeutic use of iPSCs, along with emergence of new technologies such as CRISPR/Cas9 genome editing have accelerated a trend that may prove transformative in the treatment of ESRD and congenital kidney disorders.
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Trasplante de Riñón , Riñón , Ingeniería de Tejidos , Trasplante Autólogo , Animales , Diferenciación Celular , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/fisiología , Riñón/citología , Riñón/fisiología , Ratones , Organoides/citología , Organoides/fisiologíaRESUMEN
1,25(OH)2D3, the active form of vitamin D, has an antiproliferative and antifibrotic effect on hepatic stellate cells. Our aim was to investigate the potential of 1,25(OH)2D3 to inhibit the development of liver fibrosis and to ameliorate established fibrosis in vivo. The antifibrotic effect of 1,25(OH)2D3 was investigated in a thioacetamide (TAA) model (as a preventive treatment and as a remedial treatment) and in a bile duct ligation model. In the preventive model, rats received simultaneously intraperitoneum injection of TAA and/or 1,25(OH)2D3 for 10 wk. In the remedial model, rats were treated with TAA for 10 wk and then received 1,25(OH)2D3 or saline for 8 wk. Fibrotic score was determined by Masson staining. Collagen I, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP1), platelet-derived growth factor (PDGF), and transforming growth factor-ß (TGF-ß) expression were measured by Western blot analysis and real-time PCR. Hypercalemia was detected by chemistry measurements. Preventive treatment of 1,25(OH)2D3 significantly suppressed liver fibrosis both macroscopically and microscopically and significantly lowered the fibrotic score of the TAA + 1,25(OH)2D3 group compared with the TAA group. 1,25(OH)2D3 significantly inhibited expression of PDGF and TGF-ß by â¼50% and suppressed the expression of collagen Iα1, TIMP1, and α-SMA by approximately three-, two-, and threefold, respectively. In contrast, 1,25(OH)2D3 was inefficient in amelioration of established liver fibrosis. Administration of 1,25(OH)2D3 to bile duct ligation rats led to a high mortality rate probably caused by hypercalcemia. We conclude that 1,25(OH)2D3 may be considered as a potential preventive treatment in an in vivo model but failed to ameliorate established cirrhosis.
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Fibrosis/metabolismo , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patología , Tioacetamida/farmacología , Vitamina D/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Fibrosis/inducido químicamente , Fibrosis/patología , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/metabolismo , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/metabolismo , Masculino , Ratas WistarRESUMEN
Helicobacter cinaedi is known to cause invasive infections in immunocompromised adults. Here we report the first case of H. cinaedi bacteremia in a child with nephrotic syndrome. The patient presented with a mild transient febrile illness that resolved spontaneously. We discuss the diagnostic challenges associated with this case and the microbiologic approach, including genomic analysis. Furthermore, we review the current case together with all previous pediatric cases (n = 6). Notably, all cases involved neonates or otherwise immunocompromised individuals and were characterized by severe disease with complicated infections (eg, meningitis, cholangitis and arthritis). H. cinaedi bacteremia in children is associated with a wide spectrum of clinical presentations ranging from mild to life-threatening conditions. This bacterium may be difficult to diagnose and require specialized methods.
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Artritis , Bacteriemia , Infecciones por Helicobacter , Helicobacter , Humanos , Recién Nacido , Artritis/complicaciones , Bacteriemia/microbiología , Helicobacter/genética , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVES: Very low birth weight (VLBW) infants are at high risk of developing acute kidney injury (AKI), presumably secondary to low kidney reserves, stressful postnatal events, and drug exposures. Our study aimed to identify the prevalence, risk factors, and outcomes associated with AKI in VLBW infants. STUDY DESIGN: Records of all VLBW infants admitted to two medical campuses between January 2019 and June 2020 were retrospectively reviewed. AKI was classified using the modified KDIGO definition to include only serum creatinine. Risk factors and composite outcomes were compared between infants with and without AKI. We evaluated the main predictors of AKI and death with forward stepwise regression analysis. RESULTS: 152 VLBW infants were enrolled. 21% of them developed AKI. Based on the multivariable analysis, the most significant predictors of AKI were the use of vasopressors, patent ductus arteriosus, and bloodstream infection. AKI had a strong and independent association with neonatal mortality. CONCLUSIONS: AKI is common in VLBW infants and is a significant risk factor for mortality. Efforts to prevent AKI are necessary to prevent its harmful effects.
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Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in mice, indicating the potential therapeutic effects of arginine deprivation for the treatment of TSC-associated kidney disease.
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Esclerosis Tuberosa , Humanos , Ratones , Animales , Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/metabolismo , Arginina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Riñón/metabolismoRESUMEN
Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD. Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield. Results: Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%). Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.
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Lesión Renal Aguda/inducido químicamente , Analgésicos/efectos adversos , Metahemoglobinemia/inducido químicamente , Nefritis Intersticial/inducido químicamente , Fenazopiridina/efectos adversos , Trastornos de la Pigmentación/inducido químicamente , Enfermedad Aguda , Lesión Renal Aguda/diagnóstico , Adolescente , Femenino , Humanos , Metahemoglobinemia/diagnóstico , Nefritis Intersticial/diagnóstico , Trastornos de la Pigmentación/diagnósticoRESUMEN
Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased PTH gene expression is post-transcriptional and mediated by PTH mRNA-protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP.
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Neonatal thrombotic microangiopathy (TMA) is a rare and severe disease characterized by a triad of non-immune hemolytic anemia, thrombocytopenia, and organ dysfunction in neonates. We describe herein an early-term infant who underwent hemicolectomy at 4 days of age due to intestinal perforation. Following surgery, the patient had recurrent bouts of vomiting and abdominal distention, together with acute kidney injury, non-immune hemolytic anemia, and severe thrombocytopenia. Low complement levels raised the possibility of complement-mediated neonatal TMA. Finally, genetic tests identified a heterozygous mutation in the complement factor I gene. Anti-C5 monoclonal antibody therapy led to complete cessation of the hematological and renal manifestations, but symptoms of intestinal obstruction recurred. Intestinal biopsy demonstrated aganglionosis, compatible with Hirschsprung disease. This presentation is the first known case of neonatal complement-mediated TMA associated with Hirschsprung disease. Moreover, it highlights the importance of considering a diagnosis of TMA in cases of atypical neonatal infectious presentation.