RESUMEN
Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.
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Envejecimiento Prematuro , Insuficiencia Renal Crónica , Femenino , Ratones , Animales , Embarazo , Humanos , Envejecimiento Prematuro/metabolismo , Obesidad/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Dieta Alta en Grasa/efectos adversos , Envejecimiento/genéticaRESUMEN
Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated dietary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular protein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intrauterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncompromised pregnancy. On postnatal (P) days P2-P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and proteomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus mitigating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proinflammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.
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Ácidos Grasos Omega-3 , Embarazo , Humanos , Animales , Ratas , Femenino , Ácidos Grasos Omega-3/farmacología , Dieta , Fosfolípidos , Ácido Araquidónico , Retardo del Crecimiento Fetal/metabolismo , Riñón/metabolismoRESUMEN
PURPOSE OF REVIEW: The purpose of this update is to summarize current knowledge on the pathophysiology of immunglobulin A (IgA) vasculitis nephritis (IgAVN) as well as to critically review evidence for established therapeutic regimes and available biomarkers. An additional purpose is to raise the discussion what could be done to further improve our understanding of IgAVN, identify patients at risk for adverse outcome and increase the evidence for therapy recommendations. RECENT FINDINGS: Clinical and experimental studies have established the concept of a multilevel pathogenesis. Toll-like-receptor activation, B cell proliferation, micro-RNAs and complement activation have been identified or confirmed as potential therapeutic targets which can modify the course of the disease. Currently, kidney injury molecule-1, monocyte chemotactic protein-1, N-acetyl-ß-glucosaminidase, and angiotensinogen are the most promising urinary biomarkers for early diagnosis of renal involvement in IgA vasculitis. SUMMARY: Close surveillance of all IgAV patients for renal involvement is recommended. Given the multilevel pathogenesis, early treatment of even mild cases should be initiated. Further therapeutic options should be considered in case first-line therapy (mostly corticosteroids) has no effect. The evidence supporting current therapeutic regimes is predominantly based on expert opinion. Prospective studies are needed and should involve substances inhibiting B cell proliferation and complement activation.
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Vasculitis por IgA , Enfermedades Renales , Nefritis , Biomarcadores , Femenino , Humanos , Vasculitis por IgA/diagnóstico , Vasculitis por IgA/tratamiento farmacológico , Inmunoglobulina A , Masculino , Nefritis/etiologíaRESUMEN
Intrauterine growth restriction (IUGR) due to an adverse intrauterine environment predisposes to arterial hypertension and loss of kidney function. Here, we investigated whether vascular dysregulation in renal interlobar arteries (RIAs) may contribute to hypertensive glomerular damage after IUGR. In rats, IUGR was induced by bilateral uterine vessel ligation. Offspring of nonoperated rats served as controls. From postnatal day 49, blood pressure was telemetrically recorded. On postnatal day 70, we evaluated contractile function in RIAs and mesenteric arteries. In addition, blood, urine, and glomerular parameters as well as renal collagen deposition were analyzed. IUGR RIAs not only showed loss of stretch activation in 9 of 11 arteries and reduced stretch-induced myogenic tone but also showed a shift of the concentration-response relation of acetylcholine-induced relaxation toward lower concentrations. However, IUGR RIAs also exhibited augmented contractions through phenylephrine. Systemic mean arterial pressure [mean difference: 4.8 mmHg (daytime) and 5.7 mmHg (night)], mean glomerular area (IUGR: 9,754 ± 338 µm2 and control: 8,395 ± 227 µm2), and urinary protein-to-creatinine ratio (IUGR: 1.67 ± 0.13 g/g and control: 1.26 ± 0.10 g/g) were elevated after IUGR. We conclude that male IUGR rat offspring may have increased vulnerability toward hypertensive glomerular damage due to loss of myogenic tone and augmented endothelium-dependent relaxation in RIAs.NEW & NOTEWORTHY For the first time, our study presents wire myography data from renal interlobar arteries (RIAs) and mesenteric arteries of young adult rat offspring after intrauterine growth restriction (IUGR). Our data indicate that myogenic tone in RIAs is dysfunctional after IUGR. Furthermore, IUGR offspring suffer from mild arterial hypertension, glomerular hypertrophy, and increased urinary protein-to-creatinine ratio. Dysregulation of vascular tone in RIAs could be an important variable that impacts upon vulnerability toward glomerular injury after IUGR.
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Retardo del Crecimiento Fetal/metabolismo , Hipertensión/fisiopatología , Riñón/metabolismo , Arteria Renal/fisiopatología , Animales , Presión Sanguínea/fisiología , Retardo del Crecimiento Fetal/fisiopatología , Riñón/efectos de los fármacos , Masculino , Arterias Mesentéricas/efectos de los fármacos , Fenilefrina/farmacología , RatasRESUMEN
BACKGROUND: For 10 consecutive years, the ESPN/ERA-EDTA Registry has included data on children with stage 5 chronic kidney disease (CKD 5) receiving kidney replacement therapy (KRT) in Europe. We examined trends in incidence and prevalence of KRT and patient survival. METHODS: We included all children aged <15 years starting KRT 2007-2016 in 22 European countries participating in the ESPN/ERA-EDTA Registry since 2007. General population statistics were derived from Eurostat. Incidence and prevalence were expressed per million age-related population (pmarp) and time trends studied with JoinPoint regression. We analyzed survival trends using Cox regression. RESULTS: Incidence of children commencing KRT <15 years remained stable over the study period, varying between 5.5 and 6.6 pmarp. Incidence by treatment modality was unchanged over time: 2.0 for hemodialysis (HD) and peritoneal dialysis (PD) and 1.0 for transplantation. Prevalence increased in all age categories and overall rose 2% annually from 26.4 pmarp in 2007 to 32.1 pmarp in 2016. Kidney transplantation prevalence increased 5.1% annually 2007-2009, followed by 1.5% increase/year until 2016. Prevalence of PD steadily increased 1.4% per year over the entire period, and HD prevalence started increasing 6.1% per year from 2011 onwards. Five-year unadjusted patient survival on KRT was around 94% and similar for those initiating KRT 2007-2009 or 2010-2012 (adjusted HR: 0.98, 95% CI:0.71-1.35). CONCLUSIONS: We found a stable incidence and increasing prevalence of European children on KRT 2007-2016. Five-year patient survival was good and was unchanged over time. These data can inform patients and healthcare providers and aid health policy makers on future resource planning of pediatric KRT in Europe.
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Terapia de Reemplazo Renal , Niño , Ácido Edético , Europa (Continente)/epidemiología , Humanos , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/terapia , Sistema de RegistrosRESUMEN
BACKGROUND: Paediatric dialysis patients still suffer from high morbidity rates. To improve this, quality assurance programs like the German QiNKid (Quality in Nephrology for Children)-Registry have been developed. In our study, the significance of underlying renal disease on a range of clinical and laboratory parameters impacting morbidity and mortality was analysed. Our aim was to evaluate whether or not disease-specific dialysis strategies should be considered in planning dialysis for a patient. METHODS: Inclusion criteria were defined as follows: (1) CAKUT (congenital anomalies of the kidney and urinary tract) or glomerular disease patient, (2) < 18 years of age, (3) haemodialysis or peritoneal dialysis patient. Only measurements obtained from day 90 to 365 after the date of the first dialysis in the registry were analysed. Laboratory (serum albumin, haemoglobin, ferritin, calcium, phosphate, parathyroid hormone) and clinical parameters (height, blood pressure) were analysed using mixed effects models accounting for the correlation of repeated measures in individual patients. RESULTS: The study cohort comprised n = 167 CAKUT and n = 55 glomerular disease patients. Glomerular disease patients had significantly higher odds of hypoalbuminemia (OR 13.90, 95% CI 1.35-159.99; p = 0.0274), anaemia (OR 3.31, 95% CI 1.22-9.13; p = 0.0197), hyperphosphatemia (OR 9.69, 95% CI 2.65-37.26; p = 0.0006) and diastolic hypertension (OR 3.38, 95% CI 1.20-9.79; p = 0.0212). CONCLUSIONS: Glomerular disease patients might require more intensive dialysis regimens. The evaluation of hydration status should be given more attention, since conditions differing between the cohorts can be linked to overhydration. The QiNKid-Registry allows monitoring of the quality of paediatric dialysis in a nationwide cohort.
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Glomerulonefritis/complicaciones , Fallo Renal Crónico/terapia , Garantía de la Calidad de Atención de Salud , Sistema de Registros , Diálisis Renal/normas , Anomalías Urogenitales/complicaciones , Reflujo Vesicoureteral/complicaciones , Adolescente , Anemia/etiología , Calcio/sangre , Niño , Preescolar , Femenino , Ferritinas/sangre , Alemania , Tasa de Filtración Glomerular , Hemoglobinas/metabolismo , Humanos , Hiperfosfatemia/etiología , Hipertensión/etiología , Hipoalbuminemia/etiología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/fisiopatología , Glomérulos Renales , Masculino , Hormona Paratiroidea/sangre , Fosfatos/sangre , Diálisis Renal/efectos adversos , Diálisis Renal/métodos , Estudios Retrospectivos , Albúmina Sérica/metabolismoRESUMEN
BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial. METHODS: This retrospective, single-center study involved 18 patients presenting with HSPN and nephrotic-range proteinuria. We aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) and identify a cut-off level for estimated mycophenolic acid area under the curve (eMPA-AUC0-12h) values, which can predict complete remission with high sensitivity. RESULTS: Despite prior insufficient therapeutic response to corticosteroids, 89% of patients showed a significant decrease in proteinuria after 1 month of MMF treatment. None of them relapsed during treatment; however, two children relapsed after discontinuation. Based on results of a receiver operating characteristic (ROC) analysis, an eMPA-AUC0-12h >56.4 mg*h/l was a predictor for complete remission within 3 months (80% sensitivity, 83.3% specificity, p = 0.035). During MMF administration, we encountered no adverse event requiring discontinuation of treatment. CONCLUSION: Our study demonstrates that MMF is a safe and potentially effective secondary treatment option for children with HSPN to achieve and maintain long-term remission without serious side effects. To achieve complete remission within 3 months, resolve severe inflammatory glomerular lesions, and avoid progression to chronic kidney disease, we propose timely diagnosis and early initiation of MMF with an eMPA-AUC0-12h value of 56.4 mg*h/l.
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Monitoreo de Drogas/métodos , Inhibidores Enzimáticos/administración & dosificación , Glucocorticoides/administración & dosificación , Vasculitis por IgA/tratamiento farmacológico , Ácido Micofenólico/administración & dosificación , Nefritis/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Alemania , Glucocorticoides/efectos adversos , Humanos , Vasculitis por IgA/complicaciones , Riñón/patología , Masculino , Ácido Micofenólico/efectos adversos , Nefritis/etiología , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Curva ROC , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Regulation of placental nutrient transport significantly affects fetal development and may modify intrauterine growth restriction (IUGR) and fetal programming. We hypothesized that placental nutrient transporters are differentially affected both by utero-placental insufficiency and prenatal surgical stress. Pregnant rats underwent bilateral uterine artery and vein ligation (LIG), sham operation (SOP) or no operation (controls, C) on gestational day E19. Placentas were obtained by caesarean section 4 h (LIG, n=20 placentas; SOP, n=24; C, n=12), 24 h (LIG, n=28; SOP, n=20; C, n=12) and 72 h (LIG, n=20; SOP, n=20; C, n=24) after surgery. Gene and protein expression of placental nutrient transporters for fatty acids (h-FABP, CD36), amino acids (SNAT1, SNAT2) and glucose (GLUT-1, Connexin 26) were examined by qRT-PCR, western blot and immunohistochemistry. Interestingly, the mean protein expression of h-FABP was doubled in placentas of LIG and SOP animals 4, 24 (SOP significant) and 72 h (SOP significant) after surgery. CD36 protein was significantly increased in LIG after 72 h. SNAT1 and SNAT2 protein and gene expressions were significantly reduced in LIG and SOP after 24 h. Further significantly reduced proteins were GLUT-1 in LIG (4 h, 72 h) and SOP (24 h), and Connexin 26 in LIG (72 h). In conclusion, placental nutrient transporters are differentially affected both by reduced blood flow and stress, probably modifying the already disturbed intrauterine milieu and contributing to IUGR and fetal programming. Increased fatty acid transport capacity may affect energy metabolism and could be a compensatory reaction with positive effects on brain development. J. Cell. Biochem. 117: 1594-1603, 2016. © 2015 Wiley Periodicals, Inc.
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Sistema de Transporte de Aminoácidos A/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Antígenos CD36/metabolismo , Conexinas/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Placenta/metabolismo , Animales , Conexina 26 , Proteína 3 de Unión a Ácidos Grasos , Femenino , Embarazo , Ratas , Ratas WistarRESUMEN
PURPOSE OF REVIEW: Perinatal programming of renal function reflects the epigenetic alteration of genetically determined development by environmental factors. These include intrauterine malnutrition, pre and postnatal overnutrition, glucocorticoids, and certain toxins such as smoking. This review aims to summarize the most important findings. RECENT FINDINGS: Human studies may show an increased susceptibility toward the general prevalence of renal failure in already small for gestational age children and adolescents. In particular, glomerular diseases present with a more severe clinical course. Partially related, partially independently, arterial hypertension is found in this at-risk group. The findings can mostly be confirmed in animal models. Both intrauterine nutrient deprived and overfed rodents show a tendency toward developing glomerulosclerosis and other renal disorders. Animal studies attempt to imitate clinical conditions, however, there are difficulties in transferring the findings to the human setting. The reduction of nephron number, especially in intrauterine growth-restricted humans and animals, is one mechanism of perinatal programming in the kidneys. In addition, vascular and endocrine alterations are prevalent. The molecular changes behind these mechanisms include epigenetic changes such as DNA-methylation, microRNAs, and histone modifications. SUMMARY: Future research will have to establish clinical studies with clear and well defined inclusion criteria which also reflect prenatal life. The use of transgenic animal models might help to obtain a deeper insight into the underlying mechanisms.
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Enfermedades Renales/embriología , Riñón/embriología , Investigación Biomédica/tendencias , Desarrollo Embrionario/genética , Desarrollo Embrionario/fisiología , Epigénesis Genética , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/fisiopatología , Humanos , Riñón/fisiología , Enfermedades Renales/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/genéticaRESUMEN
BACKGROUND: Growth restriction and retarded bone age are common findings in children with chronic kidney disease (CKD). We compared the automated BoneXpert™ method with the manual assessment of an X-ray of the non-dominant hand. METHODS: In this retrospective multicenter study, 359 patients with CKD stages 2-5, aged 2-14.5 (girls) or 2.5-17 years (boys) were included. Bone age was determined manually by three experts (according to Greulich and Pyle). Automated determination of bone age was performed using the image analysis software BoneXpert™. RESULTS: There was a strong correlation between the automatic and the manual method (r = 0.983, p < 0.001). The automatic method tended to generate higher bone age values (0.64 ± 0.73 years) in the younger patients (4-5 years) and to underestimate retardation or acceleration of bone age. The so-called "bone health index" (BHI) was reduced in comparison to the reference population. Bone health index standard deviation score (BHI-SDS) was not related to the stage of CKD, but weakly negatively correlated with plasma PTH concentrations (r = 0.12, p = 0.019). CONCLUSIONS: BoneXpert™ allows an objective, time-saving, and in general valid bone age assessment in children with CKD. Possible underestimation of retarded or accelerated bone age should be taken into account. Validation of the BHI needs further study.
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Determinación de la Edad por el Esqueleto/métodos , Enfermedades Óseas/diagnóstico , Enfermedades Óseas/etiología , Insuficiencia Renal Crónica/complicaciones , Adolescente , Automatización , Enfermedades Óseas/diagnóstico por imagen , Niño , Preescolar , Femenino , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/patología , Mano/diagnóstico por imagen , Estado de Salud , Humanos , Procesamiento de Imagen Asistido por Computador , Pruebas de Función Renal , Masculino , Hormona Paratiroidea/sangre , Insuficiencia Renal Crónica/diagnóstico por imagen , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Intrauterine growth restriction (IUGR) and being small for gestational age (SGA) are two distinct conditions with different implications for short- and long-term child development. SGA is present if the estimated fetal or birth weight is below the tenth percentile. IUGR can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnion, lack of growth in the interval, estimated weight below the third percentile) and can also be present in fetuses and neonates with weights above the tenth percentile. There is a need to differentiate between IUGR and SGA whenever possible, as IUGR in particular is associated with greater perinatal morbidity, prematurity and mortality, as well as an increased risk for diseases in later life. Recognizing fetuses and newborns being "at risk" in order to monitor them accordingly and deliver them in good time, as well as to provide adequate follow up care to ameliorate adverse sequelae is still challenging. This review article discusses approaches to differentiate IUGR from SGA and further increase diagnostic accuracy. Since adverse prenatal influences increase but individually optimized further child development decreases the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood. Moreover, we present current concepts of pathophysiology, with a focus on oxidative stress and consecutive inflammatory and metabolic changes as key molecular mechanisms of adverse sequelae, and look at future scientific opportunities and challenges. Most importantly, awareness needs to be raised that pre- and postnatal care of IUGR neonates should be regarded as a continuum.
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Retardo del Crecimiento Fetal , Enfermedades del Recién Nacido , Femenino , Humanos , Recién Nacido , Embarazo , Feto , Recien Nacido Prematuro , Recién Nacido Pequeño para la Edad Gestacional/fisiología , Estrés OxidativoRESUMEN
Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF's active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.
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Ácido Micofenólico , Podocitos , Animales , Ratones , Citoesqueleto de Actina/metabolismo , Supervivencia Celular , Cicloheximida , Ácido Micofenólico/farmacología , Podocitos/metabolismoRESUMEN
Adverse perinatal circumstances can cause acute kidney injury (AKI) and contribute to chronic kidney disease (CKD). Accumulating evidence indicate that a wide spectrum of perinatal conditions interferes with normal kidney development and ultimately leads to aberrant kidney structure and function later in life. The present review addresses the lack of mechanistic knowledge with regard to perinatal origins of CKD and provides a comprehensive overview of pre- and peri-natal insults, including genetic predisposition, suboptimal nutritional supply, obesity and maternal metabolic disorders as well as placental insufficiency leading to intrauterine growth restriction (IUGR), prematurity, infections, inflammatory processes, and the need for life-saving treatments (e.g. oxygen supplementation, mechanical ventilation, medications) in neonates. Finally, we discuss future preventive, therapeutic, and regenerative directions. In summary, this review highlights the perinatal vulnerability of the kidney and the early origins of increased susceptibility toward AKI and CKD during postnatal life. Promotion of kidney health and prevention of disease require the understanding of perinatal injury in order to optimize perinatal micro- and macro-environments and enable normal kidney development.
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Lesión Renal Aguda , Enfermedades del Recién Nacido , Enfermedades del Prematuro , Insuficiencia Renal Crónica , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Femenino , Humanos , Recién Nacido , Enfermedades del Prematuro/terapia , Riñón , Placenta , Embarazo , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/prevención & controlRESUMEN
Maternal malnutrition is associated with decreased nutrient transfer to the foetus, which may lead to foetal growth restriction, predisposing children to a variety of diseases. However, regulation of placental nutrient transfer during decreased nutrient availability is not fully understood. In the present study, the aim was to investigate changes in levels of placental nutrient transporters accompanying maternal hypoglycaemia following different durations and stages of gestation in rats. Maternal hypoglycaemia was induced by insulin-infusion throughout gestation until gestation day (GD)20 or until end of organogenesis (GD17), with sacrifice on GD17 or GD20. Protein levels of placental glucose transporters GLUT1 (45/55 kDa isotypes) and GLUT3, amino acid transporters SNAT1 and SNAT2, and insulin receptor (InsR) were assessed. On GD17, GLUT1-45, GLUT3, and SNAT1 levels were increased and InsR levels decreased versus controls. On GD20, following hypoglycaemia throughout gestation, GLUT3 levels were increased, GLUT1-55 showed the same trend. After cessation of hypoglycaemia at end of organogenesis, GLUT1-55, GLUT3, and InsR levels were increased versus controls, whereas SNAT1 levels were decreased. The increases in levels of placental nutrient transporters seen during maternal hypoglycaemia and hyperinsulinemia likely reflect an adaptive response to optimise foetal nutrient supply and development during limited availability of glucose.
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Hipoglucemia , Placenta , Sistemas de Transporte de Aminoácidos/metabolismo , Animales , Femenino , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 3/metabolismo , Hipoglucemia/metabolismo , Intercambio Materno-Fetal , Nutrientes , Placenta/metabolismo , Embarazo , RatasRESUMEN
Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by "sham" operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.
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Retardo del Crecimiento Fetal , Insuficiencia Placentaria , Animales , Femenino , Retardo del Crecimiento Fetal/etiología , Hipocampo/metabolismo , Masculino , Placenta/metabolismo , Embarazo , Ratas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Lung development is not completed at birth, but expands beyond infancy, rendering the lung highly susceptible to injury. Exposure to various influences during a critical window of organ growth can interfere with the finely-tuned process of development and induce pathological processes with aberrant alveolarization and long-term structural and functional sequelae. This concept of developmental origins of chronic disease has been coined as perinatal programming. Some adverse perinatal factors, including prematurity along with respiratory support, are well-recognized to induce bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease that is characterized by arrest of alveolar and microvascular formation as well as lung matrix remodeling. While the pathogenesis of various experimental models focus on oxygen toxicity, mechanical ventilation and inflammation, the role of nutrition before and after birth remain poorly investigated. There is accumulating clinical and experimental evidence that intrauterine growth restriction (IUGR) as a consequence of limited nutritive supply due to placental insufficiency or maternal malnutrition is a major risk factor for BPD and impaired lung function later in life. In contrast, a surplus of nutrition with perinatal maternal obesity, accelerated postnatal weight gain and early childhood obesity is associated with wheezing and adverse clinical course of chronic lung diseases, such as asthma. While the link between perinatal nutrition and lung health has been described, the underlying mechanisms remain poorly understood. There are initial data showing that inflammatory and nutrient sensing processes are involved in programming of alveolarization, pulmonary angiogenesis, and composition of extracellular matrix. Here, we provide a comprehensive overview of the current knowledge regarding the impact of perinatal metabolism and nutrition on the lung and beyond the cardiopulmonary system as well as possible mechanisms determining the individual susceptibility to CLD early in life. We aim to emphasize the importance of unraveling the mechanisms of perinatal metabolic programming to develop novel preventive and therapeutic avenues.
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Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p < 0.01) and restored in CLM fed animals (p < 0.05). LysoPC(18:2) levels at PN42 correlated inversely with adult blood glucose levels. These data indicate that early-life LysoPC(18:2) blood levels may predict adult blood glucose levels and are affected by a postnatal diet with an adapted lipid droplet structure in IUGR offspring.
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In the last years, great advances have been made in the effort to understand how nutritional influences can affect long-term renal health. Evidence has accumulated that maternal nutrition before and during pregnancy and lactation as well as early postnatal nutrition is of special significance. In this review, we summarize epidemiologic and experimental data on the renal effects of perinatal exposure to energy restriction, low-protein diet, high-fat diet, high-fructose diet, and high- and low-salt diet as well as micronutrient deficiencies. Interestingly, different modifications during early-life diet may end up with similar sequelae for the offspring. On the other hand, molecular pathways can be influenced in opposite directions by different dietary interventions during early life. Importantly, postnatal nutrition significantly modifies the phenotype induced by maternal diet. Sequelae of altered macro- or micronutrient intakes include altered nephron count, blood pressure dysregulation, altered sodium handling, endothelial dysfunction, inflammation, mitochondrial dysfunction, and oxidative stress. In addition, renal prostaglandin metabolism as well as renal AMPK, mTOR, and PPAR signaling can be affected and the renin-angiotensin-aldosterone system may be dysregulated. Lately, the influence of early-life diet on gut microbiota leading to altered short chain fatty acid profiles has been discussed in the etiology of arterial hypertension. Against this background, the preventive and therapeutic potential of perinatal nutritional interventions regarding kidney disease is an emerging field of research. Especially individuals at risk (e.g., newborns from mothers who suffered from malnutrition during gestation) could disproportionately benefit from well-targeted dietary interventions.
RESUMEN
This study was performed to identify transcriptional alterations in male intrauterine growth restricted (IUGR) rats during and at the end of nephrogenesis in order to generate hypotheses which molecular mechanisms contribute to adverse kidney programming. IUGR was induced by low protein (LP) diet throughout pregnancy, bilateral uterine vessel ligation (LIG), or intrauterine stress (IUS) by sham operation. Offspring of unimpaired dams served as controls. Significant acute kidney damage was ruled out by negative results for proteins indicative of ER-stress, autophagy, apoptosis, or infiltration with macrophages. Renal gene expression was examined by transcriptome microarrays, demonstrating 53 (LP, n = 12; LIG, n = 32; IUS, n = 9) and 134 (LP, n = 10; LIG, n = 41; IUS, n = 83) differentially expressed transcripts on postnatal days (PND) 1 and 7, respectively. Reduced Pilra (all IUGR groups, PND 7), Nupr1 (LP and LIG, PND 7), and Kap (LIG, PND 1) as well as increased Ccl20, S100a8/a9 (LIG, PND 1), Ifna4, and Ltb4r2 (IUS, PND 7) indicated that inflammation-related molecular dysregulation could be a "common" feature after IUGR of different origins. Network analyses of transcripts and predicted upstream regulators hinted at proinflammatory adaptions mainly in LIG (arachidonic acid-binding, neutrophil aggregation, toll-like-receptor, NF-kappa B, and TNF signaling) and dysregulation of AMPK and PPAR signaling in LP pups. The latter may increase susceptibility towards obesity-associated kidney damage. Western blots of the most prominent predicted upstream regulators confirmed significant dysregulation of RICTOR in LP (PND 7) and LIG pups (PND 1), suggesting that mTOR-related processes could further modulate kidney programming in these groups of IUGR pups. KEY MESSAGES: Inflammation-related transcripts are dysregulated in neonatal IUGR rat kidneys. Upstream analyses indicate renal metabolic dysregulation after low protein diet. RICTOR is dysregulated after low protein diet and uterine vessel ligation.
Asunto(s)
Retardo del Crecimiento Fetal/genética , Riñón/metabolismo , Animales , Animales Recién Nacidos , Riñón/crecimiento & desarrollo , Masculino , Tamaño de los Órganos , Ratas Wistar , TranscriptomaRESUMEN
BACKGROUND: Increased circulating visfatin may be associated both with endothelial damage and with increased mortality in end-stage renal disease (ESRD). HDL cholesterol is an independent, strong inverse predictor of cardiovascular events. However, associations between visfatin and parameters of lipid metabolism are unclear. Moreover, serum concentrations of visfatin measured by an enzyme immuno assay (EIA) are conflicting and do not correlate with ELISA (enzyme-linked immunosorbent assay) data, which predominantly detect enzymatically active visfatin. METHODS: A total of 74 haemodialysis (HD) patients and 35 control individuals (C) were studied. All subjects (mean age 62.9 years) provided fasted blood samples (HD patients after 66-69 h without dialysis). Circulating visfatin was measured by the ELISA. Body composition was evaluated using waist circumference, skinfold thickness and body impedance analysis. Results obtained by the ELISA were compared with EIA data. RESULTS: Active serum visfatin was increased in HD (5.58 +/- 6.50 ng/ml) versus C [0.97 +/- 1.79 ng/ml, mean +/- SD; P < 0.0001 by multiple regression analysis (MRA)] independently of plasma glucose, serum insulin, diabetes, HDL cholesterol and body composition. Within the HD group, only plasma HDL cholesterol (4% lower per additional mg/dl HDL; P = 0.001) and insulin-treated diabetes mellitus [subgroup of n = 18; 119% higher compared with patients without diabetes (n = 40); P = 0.011] were independently (by MRA) associated with active serum visfatin. Visfatin measured by an EIA showed no correlation with ELISA data. CONCLUSIONS: Our study provides reliable data on active visfatin in HD patients using a well-characterized ELISA. Loss of renal function is accompanied by increased circulating active visfatin concentrations in our patients. Furthermore, decreased HDL cholesterol may hint at an increased probability of cardiovascular events in HD patients with elevated serum visfatin.