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  • Oxford University Press (OUP)  (8)
  • 1
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    MO044HIGH DIETARY PHOSPHATE INTAKE ENHANCES INTACT FGF23 AND CAUSES ACUTE TUBULAR INJURY WITH SEVERE INFLAMMATION AND FIBROSIS IN UNTREATED MICE
    Oxford University Press (OUP) ; 2020
    In:  Nephrology Dialysis Transplantation Vol. 35, No. Supplement_3 ( 2020-06-01)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 35, No. Supplement_3 ( 2020-06-01)
    Abstract: In early stages of chronic kidney disease (CKD) rising levels of the phosphaturic hormone fibroblast growth factor (FGF) 23 maintain the phosphate homeostasis, whereas in end-stage kidney disease hyperphosphatemia manifests. Both elevated FGF23 and phosphate levels contribute to CKD progression and are associated with an increased mortality in CKD patients. So far, it is unknown whether high inorganic phosphate uptake causes renal injury as well in the absence of CKD. Therefore, we analyzed the effects of a long-term high phosphate diet (HPD) on the renal function in healthy mice. Method We studied the effects of a 2% HPD compared to a 0.8% normal phosphate diet (NPD) fed to healthy male C57BL/6 mice. After six month, blood pressure and metabolic serum and urine parameters were measured. The renal function was characterized by histology, flow cytometry and gene expression analysis. Additionally, we investigate the effects of elevated FGF23 and phosphate on mouse proximal tubular cells (mPT) in vitro. Results Feeding of a HPD for 6 months significantly increased systolic blood pressure (95 vs 79 mmHg; p=0.003), plasma creatinine (0.33±0.01 vs 0.29±0.02 mg/dL; p=0.004), C-term FGF23 (1991±394 vs 309±56 pg/mL; p & lt;0.0001), intact FGF23 (1701±429 vs 191±30 pg/mL; p & lt;0.0001) and urinary phosphate excretion (1732±968 vs 520±123 mg/dL; p=0.0005) compared to NPD controls, whereas serum phosphate (14.3±5.3 vs 13.4±2.9 mg/dL; p=0.68) and parathyroid hormone levels (417±104 vs 544±187 pg/mL; p=0.51) remained unchanged. The HPD caused acute tubular injury in the renal cortex with loss of polarity of proximal tubular epithelial cells and enhanced renal fibrosis and inflammation demonstrated by PAS and Picrosirius red staining. These histological pathologies were associated with a 100-fold increase of KIM-1 and a 7-fold increase of NGAL mRNA expression in the kidneys of HPD mice compared to the NPD group. In HPD mice, flow cytometry analysis showed a reduced storage of Ly6Chi monocytes in the spleen, whereas Ly6Chi monocytes, granulocytes, macrophages, B-cells, and CD4+ T-cells (each p & lt;0.05) were significantly induced in the kidney compared to NPD-fed mice. Histological staining’s displayed an accumulation of B- and T-cells in regions of tubular injury in HPD mice. Furthermore, the HPD significantly enhanced the mRNA expression of the chemotactic markers for monocytes Il34 and Ccl2 and inflammatory cytokines Tnfα and Il1β. Whether enhanced phosphaturia directly or HPD-mediated increase of intact FGF23 cause the renal toxicity is currently investigated in mPTs. Conclusion Chronic high phosphate load induces kidney injury in the proximal tubules with severe inflammation and fibrosis in healthy mice. Our results suggest that a controlled dietary intake of inorganic phosphate is not only important for CKD patients but also for the general population.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfaa140.MO044
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 2
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    Effect of nusinersen on motor, respiratory and bulbar function in early-onset spinal muscular atrophy
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 2 ( 2023-02-13), p. 668-677
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 2 ( 2023-02-13), p. 668-677
    Abstract: 5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children & gt;2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac252
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
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  • 3
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    Reducing meat and/or dairy consumption in adults: a systematic review and meta-analysis of effects on protein intake, anthropometric values, and body composition
    Oxford University Press (OUP) ; 2023
    In:  Nutrition Reviews ( 2023-05-26)
    Details
    In: Nutrition Reviews, Oxford University Press (OUP), ( 2023-05-26)
    Abstract: Consumers are increasingly encouraged to reduce meat and dairy consumption. However, few meta-analyses of randomized controlled trials (RCTs) on the effect of reducing meat and/or dairy on (absolute) protein intake, anthropometric values, and body composition are available. Objective The aim of this systematic review and meta-analysis was to evaluate the effect of reducing meat and/or dairy consumption on (absolute) protein intake, anthropometric values, and body composition in adults aged ≥ 45 years. Data Sources The MEDLINE, Cochrane CENTRAL, Embase, ClinicalTrials.gov, and International Clinical Trials Registry Platform databases were searched up to November 24, 2021. Data Extraction Randomized controlled trials reporting protein intake, anthropometric values, and body composition were included. Data Analysis Data were pooled using random-effects models and expressed as the mean difference (MD) with 95%CI. Heterogeneity was assessed and quantified using Cochran’s Q and I2 statistics. In total, 19 RCTs with a median duration of 12 weeks (range, 4–24 weeks) and a total enrollment of 1475 participants were included. Participants who consumed meat- and/or dairy-reduced diets had a significantly lower protein intake than those who consumed control diets (9 RCTs; MD, −14 g/d; 95%CI, −20 to −8; I2 = 81%). Reducing meat and/or dairy consumption had no significant effect on body weight (14 RCTs; MD, −1.2 kg; 95%CI, −3 to 0.7; I2 = 12%), body mass index (13 RCTs; MD, −0.3 kg/m2; 95%CI, −1 to 0.4; I2 = 34%), waist circumference (9 RCTs; MD, −0.5 cm; 95%CI, −2.1 to 1.1; I2 = 26%), amount of body fat (8 RCTs; MD, −1.0 kg; 95%CI, −3.0 to 1.0; I2 = 48%), or lean body mass (9 RCTs; MD, −0.4 kg; 95%CI, −1.5 to 0.7; I2 = 0%). Conclusion Reduction of meat and/or dairy appears to reduce protein intake. There is no evidence of a significant impact on anthropometric values or body composition. More long-term intervention studies with defined amounts of meat and dairy are needed to investigate the long-term effects on nutrient intakes and health outcomes. Systematic Review Registration PROSPERO registration no. CRD42020207325.
    Type of Medium: Online Resource
    ISSN: 1753-4887
    URL: Article
    DOI: 10.1093/nutrit/nuad055
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2066844-2
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  • 4
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    Ventromedial Prefrontal Volume in Adolescence Predicts Hyperactive/Inattentive Symptoms in Adulthood
    Oxford University Press (OUP) ; 2019
    In:  Cerebral Cortex Vol. 29, No. 5 ( 2019-05-01), p. 1866-1874
    Details
    In: Cerebral Cortex, Oxford University Press (OUP), Vol. 29, No. 5 ( 2019-05-01), p. 1866-1874
    Type of Medium: Online Resource
    ISSN: 1047-3211 , 1460-2199
    URL: Article
    DOI: 10.1093/cercor/bhy066
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1483485-6
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  • 5
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    Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 Global Rheumatology Alliance registry
    Oxford University Press (OUP) ; 2022
    In:  Rheumatology Vol. 61, No. SI2 ( 2022-06-28), p. SI151-SI156
    Details
    In: Rheumatology, Oxford University Press (OUP), Vol. 61, No. SI2 ( 2022-06-28), p. SI151-SI156
    Abstract: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. Methods Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher’s exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. Results Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13–96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. Conclusion No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keac142
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474143-X
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  • 6
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    MO448: Progressive Tubular Injury Caused by High Phosphate Intake is Associated With Activation of STAT3/KIM-1 Signalling and Macrophage Recruitment in Mice
    Oxford University Press (OUP) ; 2022
    In:  Nephrology Dialysis Transplantation Vol. 37, No. Supplement_3 ( 2022-05-03)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 37, No. Supplement_3 ( 2022-05-03)
    Abstract: Dietary phosphate intake greatly exceeds the recommended daily allowance in the Western population. Elevated phosphate levels are linked to increased cardiovascular and all-cause mortality, impaired bone health and premature ageing. The renal effects of chronic high dietary phosphate intake for healthy individuals are still not clear. METHOD Male C57BL/6 mice received a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD) for 1 to 6 months. We collected blood, urine and kidneys to investigate phosphate metabolism and progression of kidney injury. In vitro analysis for the toxic effects of phosphate or the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor (FGF) 23 was done in HK-2 humane proximal tubule (PT) cells. RESULTS HPD in mice caused hyperphosphataemia despite increased phosphaturia. Both intact FGF23 and PTH plasma levels were significantly increased in mice on HPD at 1 month onward. Mice on HPD showed significantly increased creatinine levels and albuminuria. Histopathological analysis of the kidneys revealed increased PT injury in mice receiving HPD compared to NPD controls from 2 months onward followed by a rapid progression of organ damage from month 5 to 6. Picrosirius red staining of kidney sections showed a progressively increased accumulation of collagen fibers in renal cortex of mice on HPD, which was significant from 4 months onward and accompanied by enhanced expression of transforming growth factor-β1, collagen 1 and fibronectin. The significant induction of the tubular injury marker Havcr1, encodes for Kim-1, started already after 1 month of feeding HPD, progressed over time and was strongest after 6 months. Immunofluorescence staining revealed Kim-1 localization to damaged PT, which was most prominent after 3 and 6 months of HPD. Renal Kim-1 protein levels were positively associated with tubular injury score and tubulointerstitial fibrosis. Histological staining and quantification revealed significantly increased number of pStat3+ cells in PTs of HPD-fed mice at months 1, 2, 5 and 6, indicating activated Stat3 signaling. The number of pStat3+ cells was positively associated with Kim-1 synthesis. Inflammation cytokine array with kidney tissue lysates showed, among others, enhanced expression of monocyte chemoattractant protein (MCP)-1 and macrophage colony-stimulating factor (MCSF) in HPD-fed mice. The mRNA expression of Csf1 (encodes for MCSF) was upregulated in HPD-fed mice and most pronounced after 6 months. Ccl2 mRNA expression (encodes for MCP-1) was significantly enhanced after 3, 5 and 6 months of HPD compared to NPD. Immunofluorescence staining showed a strong and specific induction of MCP-1 in PT epithelial cells due to HPD. The HPD-induced Ccl2 expression was positively associated with Kim-1 expression indicating an interaction between pStat3/Kim-1 signalling pathway and MCP-1. Immunohistochemical staining and flow cytometry analysis revealed a significantly increased recruitment of F4/80+ macrophages in renal tissue of HPD-fed mice after 3 and 6 months. The enhanced renal macrophage recruitment in the entire HPD cohort was associated with increased MCP-1 protein synthesis and increased tubular injury score. In vitro experiments using HK-2 cells showed that stimulation with FGF23 or high phosphate, but not PTH, induced the phosphorylation of STAT3. Interestingly, only treatment with high phosphate significantly upregulated HAVCR1 and CCL2 expression. CONCLUSION Chronic oral phosphate load in mice induced progressive inflammatory kidney injury dominated by macrophages. The direct toxic effects of phosphate are mediated by Stat3/Kim-1 signalling activation in PT cells. Our data support the hypothesis that kidney injury induced by widespread high dietary phosphate intake may cause a global health problem and underline the urgent need for clinical studies on this issue.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfac070.062
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    The Impact of COVID-19 on Patients with IBD in a Prospective European Cohort Study
    Oxford University Press (OUP) ; 2023
    In:  Journal of Crohn's and Colitis Vol. 17, No. 1 ( 2023-01-26), p. 37-48
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 17, No. 1 ( 2023-01-26), p. 37-48
    Abstract: There are concerns regarding the potential impact of the COVID-19 outbreak on patients with inflammatory bowel disease [IBD]. We report on the impact of the COVID-19 outbreak in a European prospective cohort study of patients with IBD Patients and Methods We prospectively collected data from 5457 patients with IBD nested in the ongoing I-CARE project and still followed up in April 2020, with monthly online monitoring of clinical activity, treatment, imaging and endoscopy. Investigators were also contacted to report incidental cases. Results In total, 233 [4.3%] reported COVID-19 and 12 [0.2%] severe COVID-19, with no COVID-19 deaths. The risk of COVID-19 in patients with IBD was not increased compared to the general population (standardized incidence ratio [SIR]: 1.18, 95% confidence interval [CI] [1.03–1.34], p = 0.009), as well as the risk of severe COVID-19 (SIR: 0.69, 95% CI [0.35–1.20] , p = 0.93). We did not observe any negative impact of the different IBD-related medication on the risk of either COVID-19 or severe COVID-19. In 2020, the COVID-19 outbreak resulted in a drastic decrease in endoscopic and imaging procedures from March to May 2020 compared to 2018 and 2019. No impacts on clinical IBD disease activity as well as ongoing treatment were noted. Conclusion No increases in either COVID-19 or severe COVID-19 incidences were observed in patients with IBD. There was no impact of COVID-19 on IBD-related medication and clinical activity. Access to endoscopy and imaging was restricted during the first months of the first COVID-19 outbreak.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjac091
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2389631-0
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  • 8
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    FC 004PHOSPHATE FACILITATES PHOSPHATURIA BY PIT-2-MEDIATED ACTIVATION OF ERK1/2 SIGNALLING INTERNALIZING NAPI-2A FROM THE APICAL BRUSH BORDER MEMBRANE INDEPENDENT OF FGF23
    Oxford University Press (OUP) ; 2021
    In:  Nephrology Dialysis Transplantation Vol. 36, No. Supplement_1 ( 2021-05-29)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 36, No. Supplement_1 ( 2021-05-29)
    Abstract: Increased phosphate load stimulates the secretion of fibroblast growth factor (FGF) 23 in the bone leading to decreased phosphate reabsorption in the kidney. FGF23 activates FGFR1/Klotho/ERK1/2 signalling in proximal tubule cells to suppress type II sodium phosphate transporters NaPi-2a and NaPi-2c in the apical brush border membrane (BBM) resulting in lower serum phosphate levels. The type III sodium-dependent phosphate transporters PiT-1 and PiT-2 are expressed in key organs of phosphate regulation and were shown to activate ERK1/2 in osseous cells in the presence of high extracellular phosphate. Furthermore, PiT-2 was shown to be responsible for the phosphate-dependent FGF23 secretion in bone cells. Whether phosphate itself can be sensed by kidney cells and stimulate its own excretion remains unknown. The aim of our study was to examine the molecular mechanism regulating renal phosphate transport in the setting of chronic oral phosphate loading in mice and to analyse phosphate sensing as well as phosphaturic actions of phosphate itself independent of FGF23. Method First, eight-week-old male C57BL/6 wildtype mice were fed a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD). Mice were sacrificed after six months and blood and urine were collected to determine parameters of phosphate homeostasis. Kidneys were isolated to evaluate the HPD-induced regulation of phosphate transporters by qPCR, immunoblot and histological analyses. Second, murine proximal tubule (mPT) cells were stimulated with either phosphate or FGF23 in the presence or absence of Foscarnet, as an inhibitor of phosphate transporters, to verify the molecular mechanism of phosphate sensing. Results Although, HPD caused significantly elevated circulating levels of intact FGF23 which resulted in hyperphosphaturia, serum phosphate levels were still enhanced compared to NPD-fed mice. Renal Klotho protein expression was significantly reduced in HPD mice and histological staining demonstrated lower Klotho accumulation in proximal and distal tubule cells, while FGFR1 was not altered. The FGF23/Klotho/FGFR1 downstream pathway revealed neither a clear activation of the ERK1/2 signalling pathway nor induction of the transcription factor Egr-1 due to HPD. Nevertheless, NaPi-2a mRNA expression was significantly reduced in HPD-fed mice compared to NPD group and NaPi-2c was unchanged. The amount of NaPi-2a protein in isolated BBM vesicles of HPD-fed mice was lower compared to NPD and immunofluorescent staining confirmed the internalisation of NaPi-2a from the apical BBM. Among the type III sodium-dependent phosphate cotransporters, renal PiT-1 mRNA expression was not altered in HPD-fed mice, but PiT-2 was significantly increased compared to NPD group and immunofluorescent staining revealed an enhanced localization of PiT-2 on the basolateral membrane of proximal tubule cells. Stimulation of mPTs with phosphate or FGF23 increased the expression of PiT-2, induced the phosphorylation of ERK1/2 and decreased NaPi-2a in vitro. The pre-treatment with Foscarnet blunted the phosphate-mediated activation of ERK1/2 signalling pathway, but not the FGF23-induced effects, suggesting a direct phosphate transporter-regulating mechanism of high phosphate in renal proximal tubule cells. Conclusion A chronic high dietary intake of phosphate results in downregulation of renal Klotho causing hyperphosphatemia, suggesting in part a renal resistance of FGF23/Klotho signalling pathway. However, HPD-induced internalization NaPi-2a from the apical BBM pointing to an FGF23-independent mechanism regulating phosphate reabsorption. Our data indicate that in the settings of high phosphate-mediated renal resistance of FGF23, phosphate itself may stimulate its urinary secretion via PiT-2-mediated activation of ERK1/2 signalling pathway which results in NaPi-2a downregulation and hyperphosphaturia independent of FGF23.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfab124.001
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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