RESUMO
Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.
Assuntos
Estado Terminal/terapia , Medicina de Precisão , Sequenciamento Completo do Genoma , California , Estudos de Coortes , Efeitos Psicossociais da Doença , Cuidados Críticos , Feminino , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Masculino , Medicaid , Estudos Prospectivos , Resultado do Tratamento , Estados UnidosRESUMO
VACTERL association is defined as the nonrandom co-occurrence of a minimum of three of the following six key components: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Patients presenting with two components may also belong in the same spectrum. Additional components have been associated with VACTERL defects, including single umbilical artery, tethered spinal cord (TSC), and genital malformations. We observed a significant proportion of patients with bladder dysfunction (often called neurogenic bladder in the medical record) when reviewing a cohort of patients with VACTERL defects at our clinical center. Our finding calls attention to bladder dysfunction as an additional VACTERL phenotypic component. The prevalence of bladder dysfunction is greatest in those with genital anomalies, anorectal malformations, sacral dysplasia, renal anomalies, and TSC. We propose that patients with two or more VACTERL malformations be monitored for symptoms of bladder dysfunction if one or more of the identified risk factors are present until the achievement of urinary continence.
Assuntos
Cardiopatias Congênitas , Nefropatias , Deformidades Congênitas dos Membros , Humanos , Incidência , Bexiga Urinária , Esôfago/anormalidades , Traqueia/anormalidades , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/epidemiologia , Deformidades Congênitas dos Membros/complicações , Rim/anormalidades , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/diagnóstico , Coluna Vertebral/anormalidades , Canal Anal/anormalidades , Nefropatias/complicaçõesRESUMO
VACTERL association is typically defined as the presence of three components among these birth defects: vertebral anomalies, anal atresia, cardiac anomalies, esophageal atresia/tracheoesophageal fistula (EA/TEF), renal anomalies, and limb defects. There is increasing recognition that VACTERL and other recurrent constellations of embryonic development often overlap clinically and might share pathogenesis. We conducted a comprehensive chart review of a large patient population with VACTERL association from two tertiary care centers in California. We included patients with incomplete VACTERL expression, which we denoted as "partial VACTERL" (pVACTERL). We assessed the occurrence of craniofacial (CF) findings in these two groups and the combined cohort. We collected data on potential risk factors and demographic information such as sex, Hispanic ancestry, pregnancy complications, and maternal age. The study included 409 participants, of whom 263 had VACTERL and 146 pVACTERL. CF abnormalities were found in 17.3% of VACTERL patients and 9.4% of pVACTERL patients. In the VACTERL group, ear anomalies were found in 10.2%, microtia in 5.9%, hearing loss (HL) in 13.90%, and orofacial clefts in 3.1%. In the pVACTERL group, ear anomalies were found in 7.2%, microtia in 5.0%, HL in 9.3%, and orofacial cleft in 2.2%. Maternal diabetes significantly increased the risk for HL in VACTERL (odds ratio [OR]: 3.71, 95% confidence interval [CI]: 1.5-7.3) and pVACTERL patients (OR: 6.7, 95% CI: 1.70-23.4). Poorly controlled maternal diabetes significantly increased the risk for all the outcomes in VACTERL patients including CF anomalies (OR: 4.2, 95% CI: 1.9-9.6), ear anomalies (OR: 4.7, 95% CI: 1.8-11.8), microtia (OR: 5.4, 95% CI: 1.7-16.6), and HL (OR: 8.1, 95% CI: 3.4-19.4). Twin status was significantly associated with the occurrence of microtia (p = 0.038) in VACTERL patients. Occurrence of CF features, particularly ear anomalies, microtia, and HL, might be considered as part of phenotypic diversity of VACTERL association. Diabetes and twinning might appear to play a role in increasing the risk for this phenotype in VACTERL association.
RESUMO
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.
Assuntos
Síndrome de Zellweger , Humanos , Recém-Nascido , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genética , Síndrome de Zellweger/patologia , ATPases Associadas a Diversas Atividades Celulares/genética , Estudos de Associação Genética , Triagem Neonatal , LisofosfatidilcolinasRESUMO
A pair of siblings was ascertained due to multiple congenital anomalies, including strikingly similar facial, skeletal, and ocular abnormalities. Exome sequencing of both the children and their mother revealed two novel PIK3C2A variants in the siblings, c.4381delC (p.Arg1461Glufs*31) and c.1555C > T (p.Arg519Ter). PIK3C2A belongs to the Class IIa family of Phosphatidylinositol-3-kinases, which create second messenger lipids that regulate a wide range of downstream signaling pathways involved in cell growth, survival and migration. Tiosano et al. (2019) identified the first monogenic disorder associated with biallelic PIK3C2A loss-of-function variants (oculoskeletodental syndrome). The novel syndrome was characterized by short stature, coarse facial features, ocular and skeletal abnormalities. This report describes two additional siblings affected by the PIK3C2A-related syndrome, confirms core clinical features, establishes intrafamilial variability and expands the phenotype to include proteinuria.
Assuntos
Nanismo , Anormalidades Musculoesqueléticas , Nanismo/genética , Genótipo , Humanos , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/genética , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Irmãos , SíndromeRESUMO
PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Propionatos , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Biomarcadores , Testes Respiratórios , Humanos , Fígado , Ácido MetilmalônicoRESUMO
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is one of the most common gastrointestinal birth defects. It can occur in isolation or in association with other birth defects or genetic syndromes. We retrospectively reviewed the EA/TEF cases evaluated at Rady Children's Hospital San Diego (San Diego, CA) between 2007 and 2016. Data were collected for 157 patients. The majority of patients (105, 66.8%) had an associated major malformation present, and 52 patients (33.1%) had isolated EA/TEF. The patients with associated malformations were distributed as follows: 16 patients (10.2%) had a known genetic syndrome (the most common being Trisomy 21 in 11 patients); six patients (3.8%) had a suspected genetic syndrome; one patient had a suspected teratogenic syndrome (diabetic embryopathy); 30 patients had VACTERL association (19.1%); 32 patients had a "partial VACTERL" association (only two VACTERL-type defects without other malformation); nine patients (5.7%) had one additional non-VACTERL-type birth defect, two patients had VACTERL-type defects plus auricular malformations; and nine patients (5.7%) were classified as "unknown syndrome." A classification of the patterns of malformation of patients with congenital EA/TEF is proposed based on reviewing the data of this relatively large and phenotypically diverse patient group.
Assuntos
Anormalidades Múltiplas/epidemiologia , Canal Anal/anormalidades , Atresia Esofágica/epidemiologia , Esôfago/anormalidades , Cardiopatias Congênitas/epidemiologia , Rim/anormalidades , Deformidades Congênitas dos Membros/epidemiologia , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Fístula Traqueoesofágica/epidemiologia , Anormalidades Múltiplas/genética , Adulto , Síndrome de Down/complicações , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Atresia Esofágica/complicações , Atresia Esofágica/genética , Feminino , Doenças Fetais/epidemiologia , Doenças Fetais/genética , Doenças Fetais/patologia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/genética , Masculino , Idade Materna , Estudos Retrospectivos , Fístula Traqueoesofágica/complicações , Fístula Traqueoesofágica/genéticaRESUMO
Esophageal atresia (EA) is a congenital anomaly occurring in 2.3 per 10,000 live births. Due to advances in prenatal imaging, EA is more readily diagnosed, but data on the associated genetic diagnoses, other anomalies, and postnatal outcome for fetuses diagnosed prenatally with EA are scarce. We collected data from two academic medical centers (n = 61). Our data included fetuses with suspected EA on prenatal imaging that was confirmed postnatally and had at least one genetic test. In our cohort of 61 cases, 29 (49%) were born prematurely and 19% of those born alive died in the first 9 years of life. The most commonly associated birth defects were cardiac anomalies (67%) and spine anomalies (50%). A diagnosis was made in 61% of the cases; the most common diagnoses were vertebral defects, anal atresia, cardiac anomalies, tracheoesophageal fistula with esophageal atresia, radial or renal dysplasia, and limb anomalies association (43%, although 12% met only 2 of the criteria), trisomy 21 (5%), and CHARGE syndrome (5%). Our findings suggest that most fetuses with prenatally diagnosed EA have one or more additional major anomaly that warrants a more comprehensive clinical genetics evaluation. Fetuses diagnosed prenatally appear to represent a cohort with a worse outcome.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Congênitas/diagnóstico , Atresia Esofágica/diagnóstico , Cardiopatias Congênitas/diagnóstico , Diagnóstico Pré-Natal , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Síndrome de Down/diagnóstico , Síndrome de Down/diagnóstico por imagem , Síndrome de Down/fisiopatologia , Atresia Esofágica/complicações , Atresia Esofágica/diagnóstico por imagem , Atresia Esofágica/fisiopatologia , Esôfago/diagnóstico por imagem , Esôfago/fisiopatologia , Feminino , Feto/anormalidades , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Humanos , Recém-Nascido , Rim/diagnóstico por imagem , Rim/fisiopatologia , Masculino , Gravidez , Traqueia/diagnóstico por imagem , Traqueia/fisiopatologiaRESUMO
Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, causing progressive proximal tubular cell flattening, the so-called swan-neck lesion (SNL), and eventual renal failure. To determine the role of oxidative stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of the SNL lost mitochondria and superoxide production, and became surrounded by a thickened tubular basement membrane. Progression of the SNL as determined by staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was delayed by treatment with MitoQ (38 ± 4% vs. 28 ± 1%, P < 0.01). Through 9 mo, glomeruli had retained renin staining and intact macula densa, whereas SNL expressed transgelin, an actin-binding protein, but neither kidney injury molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal tubules exhibited localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis, leading to the formation of atubular glomeruli and accumulation of interstitial collagen. We conclude that nephron integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening of cells of the SNL through loss of mitochondria, upregulation of transgelin, and thickened basement membrane. This adaptation ultimately fails in adulthood, with proximal tubular disruption, formation of atubular glomeruli, and renal failure. Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and may provide therapeutic benefit in children with cystinosis.
Assuntos
Adaptação Fisiológica/fisiologia , Cistinose/patologia , Cistinose/fisiopatologia , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/fisiopatologia , Estresse Oxidativo/fisiologia , Sistemas de Transporte de Aminoácidos Neutros/deficiência , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cistinose/genética , Modelos Animais de Doenças , Feminino , Receptor Celular 1 do Vírus da Hepatite A , Túbulos Renais Proximais/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mutação/genética , Compostos Organofosforados/farmacologia , Superóxidos/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/farmacologiaRESUMO
In polycystic kidney disease (PKD), renal parenchyma is destroyed by cysts, hypothesized to obstruct nephrons. A signature of unilateral ureteral obstruction, proximal tubular atrophy leads to formation of atubular glomeruli. To determine whether this process occurs in PKD, kidneys from pcy mice (moderately progressive PKD), kidneys from cpk mice (rapidly progressive PKD), and human autosomal dominant PKD were examined in early and late stages. Integrity of the glomerulotubular junction and proximal tubular mass were determined in sections stained with Lotus tetragonolobus lectin. Development of proximal tubular atrophy and atubular glomeruli was determined in serial sections of individual glomeruli. In pcy mice, most glomerulotubular junctions were normal at 20 weeks, but by 30 weeks, 56% were atrophic and 25% of glomeruli were atubular; glomerulotubular junction integrity decreased with increasing cyst area (r = 0.83, P < 0.05). In cpk mice, all glomerulotubular junctions were normal at 10 days, but by 19 days, 26% had become abnormal. In early-stage autosomal dominant PKD kidneys, 50% of glomeruli were atubular or attached to atrophic tubules; in advanced disease, 100% were abnormal. Thus, proximal tubular injury in cystic kidneys closely parallels that observed with ureteral obstruction. These findings support the hypothesis that, in renal cystic disorders, cyst-dependent obstruction of medullary and cortical tubules initiates a process culminating in widespread destruction of proximal convoluted tubules at the glomerulotubular junction.
Assuntos
Glomérulos Renais/patologia , Túbulos Renais Proximais/patologia , Doenças Renais Policísticas/patologia , Obstrução Ureteral/complicações , Adulto , Animais , Cistos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Urinary tract obstruction and reduced nephron number often occur together as a result of maldevelopment of the kidneys and the urinary tract. We determined the role of nephron number on adaptation of the remaining nephrons of mice subjected to neonatal partial unilateral ureteral obstruction followed through adulthood. MATERIALS AND METHODS: Wild-type and Os/+ mice (the latter with 50% fewer nephrons) underwent sham operation or partial unilateral ureteral obstruction in the first 2 days of life. Additional mice underwent release of unilateral ureteral obstruction at 7 days. All kidneys were harvested at 3 weeks (weaning) or 6 weeks (adulthood). Glomerular number and area, glomerulotubular junction integrity, proximal tubular volume fraction and interstitial fibrosis were measured by histomorphometry. RESULTS: In the obstructed kidney unilateral ureteral obstruction caused additional nephron loss in Os/+ but not in wild-type mice. Glomerular growth from 3 to 6 weeks was impaired by ipsilateral obstruction and not preserved by release in wild-type or Os/+ mice. Proximal tubular growth was impaired and interstitial collagen was increased by ipsilateral obstruction in all mice. These conditions were attenuated by release of unilateral ureteral obstruction in wild-type mice but were not restored in Os/+ mice. Unilateral ureteral obstruction increased interstitial collagen in the contralateral kidney while release of obstruction enhanced tubular growth and reduced interstitial collagen. CONCLUSIONS: Unilateral ureteral obstruction in early postnatal development impairs adaptation to reduced nephron number and induces additional nephron loss despite release of obstruction. Premature and low birth weight infants with congenital obstructive nephropathy are likely at increased risk for progression of chronic kidney disease.
Assuntos
Glomérulos Renais/patologia , Néfrons/patologia , Insuficiência Renal/etiologia , Obstrução Ureteral/complicações , Animais , Animais Recém-Nascidos , Contagem de Células , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Feminino , Masculino , Camundongos , Insuficiência Renal/patologia , Obstrução Ureteral/congênito , Obstrução Ureteral/patologiaRESUMO
Most chronic kidney disease in children results from congenital or inherited disorders, which can be studied in mouse models. Following 2 weeks of unilateral ureteral obstruction (UUO) in the adult mouse, nephron loss is due to proximal tubular mitochondrial injury and cell death. In neonatal mice, proximal tubular cell death is delayed beyond 2 weeks of complete UUO, and release of partial UUO allows remodeling of remaining nephrons. Progressive cyst expansion develops in polycystic kidney disease (PKD), a common inherited renal disorder. The polycystic kidney and fibrosis (pcy)-mutant mouse (which develops late-onset PKD) develops thinning of the glomerulotubular junction in parallel with growth of cysts in adulthood. Renal insufficiency in nephropathic cystinosis, a rare inherited renal disorder, results from progressive tubular cystine accumulation. In the Ctns knockout mouse (a model of cystinosis), proximal tubular cells become flattened, with loss of mitochondria and thickening of tubular basement membrane. In each model, persistent obstructive or metabolic stress leads ultimately to the formation of atubular glomeruli. The initial "fight" response (proximal tubular survival) switches to a "flight" response (proximal tubular cell death) with ongoing oxidative injury and mitochondrial damage. Therapies should be directed at reducing proximal tubular mitochondrial oxidative injury to enhance repair and regeneration.
Assuntos
Nefropatias/congênito , Nefropatias/patologia , Túbulos Renais Proximais/lesões , Túbulos Renais Proximais/patologia , Animais , HumanosRESUMO
Unilateral ureteral obstruction (UUO), a widely used model of chronic kidney disease and congenital obstructive uropathy, causes proximal tubular injury and formation of atubular glomeruli. Because transforming growth factor-ß1 (TGF-ß1) is a central regulator of renal injury, neonatal and adult mice were subjected to complete UUO while under general anesthesia and treated with vehicle or ALK5 TGF-ß1 receptor inhibitor (IN-1130, 30 mg·kg(-1)·day(-1)). After 14 days, glomerulotubular integrity and proximal tubular mass were determined by morphometry of Lotus tetragonolobus lectin distribution, and the fraction of atubular glomeruli was determined by serial section analysis of randomly selected individual glomeruli. Glomerular area, macrophage infiltration, fibronectin distribution, and interstitial collagen were measured by morphometry. Compared with placebo, inhibition of TGF-ß1 by IN-1130 decreased apoptosis and formation of atubular glomeruli, prevented parenchymal loss, increased glomerular area and glomerulotubular integrity, and increased proximal tubule fraction of the adult obstructed kidney parenchyma from 17 to 30% (P < 0.05, respectively). IN-1130 decreased macrophage infiltration and fibronectin and collagen deposition in the adult obstructed kidney by â¼50% (P < 0.05, respectively). In contrast to these salutary effects in the adult, IN-1130 caused widespread necrosis in obstructed neonatal kidneys. We conclude that whereas IN-1130 reduces obstructive injury in adult kidneys through preservation of glomerulotubular integrity and proximal tubular mass, TGF-ß1 inhibition aggravates obstructive injury in neonates. These results indicate that while caution is necessary in treating congenital uropathies, ALK5 inhibitors may prevent nephron loss due to adult kidney disease.
Assuntos
Imidazóis/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Quinoxalinas/uso terapêutico , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Obstrução Ureteral/tratamento farmacológico , Fatores Etários , Animais , Animais Recém-Nascidos , Imidazóis/farmacologia , Glomérulos Renais/patologia , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinoxalinas/farmacologia , Obstrução Ureteral/patologiaRESUMO
Unilateral ureteral obstruction (UUO) in the adult mouse is the most widely used model of progressive renal disease: the proximal tubule is the nephron segment most severely affected and atubular glomeruli are formed after only 7 days of UUO. To determine the proximal nephron response to UUO in the maturing kidney, neonatal mice were examined 7 to 28 days following complete UUO under general anesthesia. Proximal tubular mass and maturation were determined by staining with Lotus tetragolonobus lectin. Superoxide was localized by nitroblue tetrazolium and collagen by Sirius red. Cell proliferation, cell death, PAX-2, megalin, α-smooth muscle actin (α-SMA), renin, and fibronectin were identified by immunohistochemistry. During the first 14 days of ipsilateral UUO, despite oxidative stress (4-hydroxynonenal staining), glomerulotubular continuity was maintained and mitochondrial superoxide production persisted. However, from 14 to 28 days, papillary growth was impaired and proximal tubules collapsed with increased apoptosis, autophagy, mitochondrial loss, and formation of atubular glomeruli. Fibronectin, α-SMA, and collagen increased in the obstructed kidney. Oxidative stress was present also in the contralateral kidney: renin was decreased, glomerulotubular maturation and papillary growth were delayed, followed by increased cortical and medullary growth. We conclude that neonatal UUO initially delays renal maturation and results in oxidative stress in both kidneys. In contrast to the adult, proximal tubular injury in the neonatal obstructed kidney is delayed at 14 days, followed only later by the formation of atubular glomeruli. Antioxidant therapies directed at proximal tubular mitochondria during early renal maturation may slow progression of congenital obstructive nephropathy.
Assuntos
Animais Recém-Nascidos/crescimento & desenvolvimento , Glomérulos Renais/crescimento & desenvolvimento , Rim/crescimento & desenvolvimento , Obstrução Ureteral/fisiopatologia , Actinas/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Doença Crônica , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibronectinas/metabolismo , Rim/metabolismo , Rim/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologiaRESUMO
Murine unilateral ureteral obstruction (UUO), a major model of progressive kidney disease, causes loss of proximal tubular mass and formation of atubular glomeruli. Adult C57BL/6 mice underwent a sham operation or reversible UUO under anesthesia. In group 1, kidneys were harvested after 7 days. In group 2, the obstruction was released after 7 days, and a physiological study of both kidneys was performed 30 days later. Renal blood flow (RBF), glomerular filtration rate (GFR), urine protein, and albumin excretion were measured after ligation of either the left or right ureter. Glomerular volume (periodic acid-Schiff), glomerulotubular integrity and proximal tubular mass (Lotus tetragonolobus lectin), and interstitial collagen (Sirius red) were measured by histomorphometry. Obstructed kidney weight was reduced by 15% at 7 days but was not different from sham after a 30-day recovery. Glomerular volume and proximal tubular area of the obstructed kidney were reduced by 55% at 7 days, but normalized after 30 days. Interstitial collagen deposition increased 2.4-fold after 7 days of UUO and normalized after release. However, GFR and RBF were reduced by 40% and urine albumin/protein ratio was increased 2.8-fold 30 days after release of UUO. This was associated with a 50% reduction in glomerulotubular integrity despite a 30-day recovery (P < 0.05 for all data). We conclude that release of 7-day UUO can arrest progression but does not restore normal function of the postobstructed kidney. Although the remaining intact nephrons have hypertrophied, glomerular injury is revealed by albuminuria. These results suggest that glomerulotubular injury should become the primary target of slowing progressive kidney disease.
Assuntos
Nefropatias/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Obstrução Ureteral/fisiopatologia , Animais , Colágeno/análise , Colágeno/metabolismo , Feminino , Taxa de Filtração Glomerular/fisiologia , Nefropatias/etiologia , Glomérulos Renais/patologia , Túbulos Renais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Proteinúria/etiologia , Proteinúria/patologia , Proteinúria/fisiopatologia , Obstrução Ureteral/complicações , Obstrução Ureteral/patologiaRESUMO
Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, α-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential "fight-or-flight" responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis.
Assuntos
Glomérulos Renais/patologia , Túbulos Renais Proximais/patologia , Obstrução Ureteral/patologia , Animais , Dilatação , Fibrose , Glomérulos Renais/metabolismo , Túbulos Renais Proximais/metabolismo , Camundongos , Necrose/metabolismo , Necrose/patologia , Superóxidos/metabolismo , Obstrução Ureteral/metabolismoRESUMO
Primary pancreatic lymphomas (PPL) are rare tumors, comprising 1% of extra-nodal lymphomas and 0.5% of all pancreatic masses. Fewer than 150 cases have been reported worldwide, which most commonly are large B cell lymphomas. T cell lymphomas comprise 4% of all PPL and present a 5-year survival rate of 0%. We report the case of a 28 year-old Peruvian woman who presented with a fatal acute cholangitis and a history of insidious weight loss and obstructive jaundice. The CT scan revaled a diffuse heterogeneus mass in the head of the pancreas along with a mildly dilated pancreatic duct and dilated intra and extra-hepatic bile ducts, no liver, splenic involvement, or retroperitoneal adenopathies were evident. An autopsy was performed and the histopathologic investigation confirmed a T cell non-Hodgkin lymphoma, CD3+ CD20-.
Assuntos
Linfoma de Células T/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adulto , Evolução Fatal , Feminino , HumanosRESUMO
Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.
Assuntos
Anormalidades do Olho/diagnóstico , Deficiência Intelectual/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Microcefalia/diagnóstico , Fenótipo , Pré-Escolar , Anormalidades do Olho/genética , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Masculino , Microcefalia/genética , Mutação , Irmãos , Ubiquitina-Proteína Ligases/genética , Sequenciamento Completo do GenomaRESUMO
Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.