1,720,985 research outputs found
Intrarenal arteriosclerosis and telomere attrition associate with dysregulation of the cholesterol pathway
No full textBACKGROUND: Recently, we demonstrated that arteriosclerosis in the smaller intrarenal arteries is associated with shorter telomere length, independently of history of cardiovascular events and calendar age. This suggests that intrarenal arteriosclerosis reflects replicative senescence, although the underlying molecular alterations remain unclear. RESULTS: Shorter intrarenal telomere length associated significantly with the presence of renal arteriosclerosis (T/S ratio 0.91±0.15 vs. 1.20±0.23 with vs. without arteriosclerosis, p=0.007, test cohort; T/S ratio 0.98 ±0.26 vs. 1.03 ±0.18 with vs. without arteriosclerosis, p=0.02, validation cohort). The presence versus absence of intrarenal arteriosclerosis was associated with differential expression of 1472 transcripts. Pathway analysis revealed enrichment of molecules involved in the superpathway of cholesterol biosynthesis as the most significant. The differential expression of these genes was confirmed in the independent validation cohort. Furthermore, the specific mRNA expression of the molecules in the superpathway of cholesterol biosynthesis associated significantly with intrarenal telomere length, and with history of cardiovascular events. INTERPRETATION: Our study illustrates that the superpathway of cholesterol biosynthesis interacts with the previously published association between shorter telomere length and arteriosclerosis. METHODS: This study included a test cohort of 40 consecutive kidney donors (calendar age 48.0 ± 15), with biopsies obtained prior to transplantation. Intrarenal leucocyte telomere length content was assessed using quantitative RT-PCR. Whole genome microarray mRNA expression analysis was performed using Affymetrix Gene 2.0 ST arrays. We investigated the associations between mRNA gene expression, telomere length as marker of replicative senescence, and intrarenal arteriosclerosis (Banff "cv" score = vascular fibrous intimal thickening = intimal hyperplasia) using adjusted multiple regression models. For biological interpretation and pathway overrepresentation analysis, we used Ingenuity Pathway Analysis. The significant pathways and genes were validated in an independent validation cohort of 173 kidney biopsies obtained prior to transplantation.status: Publishe
Replicative senescence and arteriosclerosis after kidney transplantation
No full textBackground
Replicative senescence is associated with telomere shortening. In native kidneys, obtained prior to transplantation, we recently described and validated a significant association between shorter intrarenal telomere length and renal arteriosclerosis. After renal transplantation, animal experiments suggested that ischaemia–reperfusion injury, acute rejection episodes and cytomegalovirus disease associate with accelerated renal allograft senescence. The association between post-transplant events and replicative senescence has not yet been evaluated in a human setting.
Methods
In a cohort of 134 kidney allograft recipients, we performed protocol-specified renal allograft biopsies at 3 months, 1 year, 2 years and 5 years after transplantation (n = 579 biopsies). We used quantitative real-time polymerase chain reaction to measure intrarenal relative average telomere length (T/S ratio). The association between donor and recipient demographic factors, post-transplant clinical/histological events, renal allograft histological evolution by 5 years post-transplant and intrarenal telomere length at 5 years after transplantation was studied using multiple regression models.
Results
At 5 years after transplantation, shorter intrarenal telomere length was associated with male donor gender, older donor age, donor history of hypertension and donor cardiovascular risk, which confirms the associations observed in native kidneys. Recipient characteristics and post-transplant events like delayed graft function, acute rejection episodes, presence of donor-specific antibodies, cytomegalovirus disease and immunosuppressive regimen did not associate with alterations of intrarenal telomere length at 5 years. Independent of donor age and donor cardiovascular risk, intrarenal arteriosclerosis in protocol biopsies obtained at 5 years after transplantation and progressive arteriosclerosis over time after transplantation associated with shorter telomere length, while this was not the case for other histological lesions. Moreover, telomere attrition augments the association between older donor age and the presence of severe arteriosclerosis. In the group with the oldest donor age and shortest telomere length, there was significantly more severe arteriosclerosis (43%) in protocol biopsies at 5 years after transplantation, compared with other combinations (13–28%) (P = 0.001). Intrarenal arteriosclerosis at 5 years after transplantation did not associate with post-transplant clinical events.
Conclusions
We demonstrate that intrarenal telomere length at 5 years after transplantation, as a marker for replicative senescence, associates with renal arteriosclerosis and reflects kidney donor characteristics, but not post-transplant events.sponsorship: This research was funded by the Clinical Research Foundation of the University Hospitals Leuven; Novartis Research Grant BE1301071489 (87184); European Research Council (ERC2012-StG 310898); and Research Foundation Flanders (FWO G.0.873.11.N.10). (Clinical Research Foundation of the University Hospitals Leuven, Novartis|BE1301071489 (87184), European Research Council|ERC2012-StG 310898, Research Foundation Flanders (FWO)|G.0.873.11.N.10)status: Publishe
Newborn glomerular function and gestational particulate air pollution
No full textBackground Nephron number variability may hold significance in the Developmental Origins of Health and Disease hypothesis. We explore the impact of gestational particulate pollution exposure on cord blood cystatin C, a marker for glomerular function, as an indicator for glomerular health at birth. Methods From February 2010 onwards, the ENVIRONAGE cohort includes over 2200 mothers giving birth at the East-Limburg hospital in Genk, Belgium. Mothers without planned caesarean section who are able to fill out a Dutch questionnaire are eligible. Here, we evaluated cord blood cystatin C levels from 1484 mother-child pairs participating in the ENVIRONAGE cohort. We employed multiple linear regression models and distributed lag models to assess the association between cord blood cystatin C and gestational particulate air pollution exposure. Findings Average +/- SD levels of cord blood cystatin C levels amounted to 2.16 +/- 0.35 mg/L. Adjusting for covariates, every 0.5 mu g/m(3) and 5 mu g/m(3) increment in gestational exposure to black carbon (BC) and fine particulate matter (PM2.5) corresponded to increases of 0.04 mg/L (95% CI 0.01-0.07) and 0.07 mg/L (95% CI 0.03-0.11) in cord blood cystatin C levels (p < 0.01), respectively. Third-trimester exposure showed similar associations, with a 0.04 mg/L (95% CI 0.00-0.08) and 0.06 mg/L (95% CI 0.04-0.09) increase for BC and PM2.5 (p < 0.02). No significant associations were observed when considering only the first and second trimester exposure. Interpretation Our findings indicate that particulate air pollution during the entire pregnancy, with the strongest effect sizes from week 27 onwards, may affect newborn kidney function, with potential long-term implications for later health.Funding
Special Research Fund (Bijzonder Onderzoeksfonds, BOF), Flemish Scientific Research Fund (Fonds Wetenschappelijk Onderzoek, FWO), and Methusalem
Acknowledgements
This ENVIRONAGE birth cohort study is supported Methusalum grant and the Flemish Scientific Research Fund (FWO, N1516112/ G087311N10). LR acknowledges funding from the Special Research Fund (Bijzonder Onderzoeksfonds, BOF) for a doctoral fellowship (BOF20DOC15). The authors want to express their greatest gratitude to the participating parents and children, as well as the staff of the maternity ward, the midwives, and the staff of the clinical laboratory of the East-Limburg Hospital in Genk
Renal transcriptome-wide analyses in association with kidney black carbon load
No full textRationale and objectiveInhaled black carbon (BC) has been previously shown to reach and accumulate in the kidneys. As kidneys filter toxicants, they may be susceptible to adverse effects caused by BC accumulation. We studied gene expressions and pathways related to BC particle load in kidney biopsy tissue.Study designGene expression was measured in 29 kidney biopsies performed at one or two years post-transplantation using Affymetrix microarray. We performed a transcriptome-wide association analysis using linear regression analyses, adjusting for individual characteristics to investigate alterations in gene expression in association with kidney BC. Finally, we performed overrepresentation analyses (ConsensusPathDB) to identify enriched pathways and gene ontology sets.ResultsThe geometric mean (5th, 95th percentile) of BC particle levels was 5.4 x 103 (1.5 x 103, 4.1 x 104) number of BC particles per mm(3) kidney tissue. The BC particle load associated with gene expression in overrepresenting pathways related to ciliopathies, macrophage-derived proteins involved in anti-inflammatory response, DNA damage response, TP53 regulation, and necrosis. We identified BC associated genes involved in GO terms ciliogenesis and ciliary structure, including genes involved in the ciliary plasm and axoneme. Furthermore, we found significantly BC-associated genes involved in RNA-related processes, including e.g., genes in the integrator complex.ConclusionsHere, we identified genes and pathways associated with real-life kidney BC particle load, indicating alterations in gene expression involved in assembly and maintenance of primary cilia, the anti-inflammatory properties of the innate immune system, and DNA damage-related pathways. These findings highlight the need for public health measures to reduce exposure and protect kidney health in at-risk populations.Funding
LR acknowledges funding from the Special Research Fund (Special Research Fund, BOF) for a doctoral fellowship: BOF20DOC15. The BC work is supported by a Methusalem grant from TSN. The Research Foundation Flanders (FWO) funds JC (1196119 N) and MN (1844019 N). Additionally, MN is supported by an ERAcoSysMed H2020 grant (JTC2_29), and a C3 internal grant from the KU Leuven (C32/17/049). None of the funding agencies had a role in the design and conduct of the study, in the collection, analysis and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Acknowledgements
The authors want to express their greatest gratitude to the kidney transplant patients, as well as the staff of the department of Nephrology at the University Hospitals Leuven
Lupus, DNA Methylation, and Air Pollution: A Malicious Triad
No full textThe pathogenesis of systemic lupus erythematosus (SLE) remains elusive to this day; however, genetic, epigenetic, and environmental factors have been implicated to be involved in disease pathogenesis. Recently, it was demonstrated that in systemic lupus erythematosus (SLE) patients, interferon-regulated genes are hypomethylated in naïve CD4+ T cells, CD19+ B lymphocytes, and CD14+ monocytes. This suggests that interferon-regulated genes may have been epigenetically poised in SLE patients for rapid expression upon stimulation by different environmental factors. Additionally, environmental studies have identified DNA (hypo)methylation changes as a potential mechanism of environmentally induced health effects in utero, during childhood and in adults. Finally, epidemiologic studies have firmly established air pollution as a crucial SLE risk factor, as studies showed an association between fine particulate matter (PM2.5) and traditional SLE biomarkers related to disease flare, hospital admissions, and an increased SLEDAI score. In this review, the relationship between aberrant epigenetic regulation, the environment, and the development of SLE will be discussed
Primary FSGS is not associated with worse kidney outcome compared with other FSGS subtypes
No full textBackground Studies that compare kidney outcomes across patients with different forms of focal segmental glomerulosclerosis (FSGS) are lacking. Methods This retrospective study compared annual estimated glomerular filtration rate (eGFR) slope and kidney failure rate (eGFR <15 mL/min/1.73 m(2) or initiation of kidney replacement therapy) across patients with biopsy-proven primary, maladaptive, genetic and undetermined FSGS. Patients were included from two Belgian tertiary referral hospitals, from 2010 until 2022. Associations between covariates and kidney failure were estimated using Cox and Fine and Gray models. eGFR slopes were estimated using linear mixed-effects models. Results Eighty-two patients were subdivided into primary (28.1%), maladaptive (40.2%), genetic (14.6%) and undetermined FSGS (17.1%) groups. Kidney failure occurred in 22 patients (26.8%). Primary FSGS patients exhibited higher baseline eGFR and less chronic changes on biopsy. The annual eGFR slope was -2.5 mL/min in primary, -2.5 mL/min in maladaptive, -4.6 mL/min in genetic and -4.4 mL/min in undetermined FSGS. Female sex was associated with a lower kidney failure rate and higher eGFR slope. Higher proteinuria at biopsy was associated with a higher kidney failure rate, lower eGFR slope and a higher mortality rate. Global sclerosis on kidney biopsy was associated with lower baseline eGFR, while a higher percentage of segmental sclerosis rather associated with more rapid eGFR decline [-1.5 mL/min/year per 10% increase, 95% confidence interval (-2.2, -0.7)]. Conclusions Patients with primary FSGS were biopsied earlier in their disease course and exhibited surprisingly good kidney outcome. Overall, sex, baseline eGFR, proteinuria and the degree of focal and global glomerulosclerosis play a more important role in estimating the prognosis of patients with FSGS than merely the FSGS etiology.FUNDING
D.D. is supported by a PhD Fellowship grant fundamental research from the Research Foundation Flanders (F.W.O.) (grant number 11L5622N). M.C. is supported by the Research Foundation Flanders (F.W.O.) (grant 12D6423N). A.H.V.C. is supported by a postdoctoral grant from the University Hospitals Leuven (KOOR) and a Research Foundation Flanders (FWO) SBO project (S006722N). B.K.M. is a senior clinical investigator of F.W.O. (1 800 820 N) and received grant support from KU Leuven (3M190551 and C14/21/103).
ACKNOWLEDGEMENTS
This study was approved by the ethical committees of the academic hospitals of UZ Leuven and UZ Ghent (study reference S66295). All study participants were informed on the use of their data for this retrospective analysis
Adverse Effects of fine particulate matter on human kidney functioning: a systematic review
No full textBACKGROUND: Ambient fine particulate matter (PM < 2.5 μm, PM2.5) is gaining increasing attention as an environmental risk factor for health. The kidneys are considered a particularly vulnerable target to the toxic effects that PM2.5 exerts. Alteration of kidney function may lead to a disrupted homeostasis, affecting disparate tissues in the body. This review intends to summarize all relevant knowledge published between January 2000 and December 2021 on the effects of ambient PM2.5 and the adverse effects on kidney function in adults (≥ 18 years). RESULTS AND DISCUSSION: Studies published in peer-reviewed journals, written in English, regarding the effects of PM2.5 on kidney function and the development and/or exacerbation of kidney disease(s) were included. Of the 587 nonduplicate studies evaluated, 40 were included, comprising of studies on healthy or diagnosed with pre-existing disease (sub)populations. Most of the studies were cohort studies (n = 27), followed by 10 cross-sectional, 1 ecological and 2 time-series studies. One longitudinal study was considered intermediate risk of bias, the other included studies were considered low risk of bias. A large portion of the studies (n = 36) showed that PM2.5 exposure worsened kidney outcome(s) investigated; however, some studies show contradictory results. Measurement of the estimated glomerular filtration rate, for instance, was found to be positively associated (n = 8) as well as negatively associated (n = 4) with PM2.5. LIMITATIONS AND CONCLUSION: The main limitations of the included studies include residual confounding (e.g., smoking) and lack of individual exposure levels. The majority of included studies focused on specific subpopulations, which may limit generalizability. Evidence of the detrimental effects that ambient PM2.5 may exert on kidney function is emerging. However, further investigations are required to determine how and to what extent air pollution, specifically PM2.5, exerts adverse effects on the kidney and alters its function. REGISTRATION: The systematic review protocol was submitted and published by the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020175615 ).sponsorship: The authors acknowledge funding from the Special Research Fund (BOF) from Hasselt University granted to LR (BOF20DOC15) and the Flemish Scientific Research Foundation (FWO) funding granted to KVB (G059219N). BOF and FWO had no role in the design, conduct, and preparation of the manuscript. (Special Research Fund (BOF) from Hasselt University|BOF20DOC15, Flemish Scientific Research Foundation (FWO)|G059219N)status: Publishe
Relative biodistribution and accumulation of carbonaceous nanoparticles inside the murine and human kidney
No full textBackground
Epidemiological and toxicological studies underscore the adverse health effects of combustion-derived particles, such as carbonaceous nanoparticles (CNPs), which translocate to various organs, including the kidneys. Given the kidneys play a crucial role in filtering toxins, CNP accumulation may pose a risk to renal function. We investigated CNP biodistribution in murine and human kidney tissue to assess potential impacts on kidney health.
Methods
In the controlled murine model, wild-type C57BL/6J mice were exposed to CNPs through whole-body exposure. Human kidney tissue was analyzed without prior knowledge of exposure history. CNPs in kidney tissue were detected using femtosecond-pulsed illumination and quantified via a peak-finding algorithm. Renal components – the glomerulus, proximal and distal tubules, and blood vessels – were visualized through immunofluorescence. Colocalization of CNPs with renal structures was quantified using the Just Another Colocalization Plugin. Structural differences were evaluated using Kruskal-Wallis tests.
Results
CNPs were detected in all investigated renal structures of both mouse and human kidneys, providing direct evidence of their translocation. The relative distribution was comparable between species, with no statistically significant differences in colocalization (q > 0.05). The percentages of CNPs in mice vs. humans colocalized with glomeruli (1.46 % vs. 1.91 %), proximal tubules (13.43 % vs. 16.10 %), distal tubules (2.72 % vs. 3.25 %), and blood vessels and capillaries (4.16 % vs. 5.21 %).
Conclusions
Proximal tubules exhibited the highest relative CNP accumulation in both species. This aligns with research linking environmental pollutants, such as black carbon, to decreased tubular kidney function, suggesting proximal tubule involvement in particle processing.the Special Research Fund (BOF) from Hasselt University
the Research Foundation Flanders (FWO)
the European Union’s Horizon 2020
The authors acknowledge funding from the Special Research Fund (BOF) from Hasselt University granted to L.R. (BOF20DOC15) and funding from the Research Foundation Flanders (FWO) granted to K.V. (G059219). Additionally, the animal study was supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 814978 (TUBE). BOF nor FWO nor TUBE had no role in the design, conduct, and preparation of the manuscript.
Acknowledgements
The authors wish to thank and acknowledge Mr. J. Boere, Mr. E. Duistermaat, and Mr. P. Fokkens with the assistance and the execution of the exposure experiments. Furthermore, the authors wish to thank Roel P.F. Schins and his colleagues with the assistance in setting up the exposure and feedback. Additionally, the authors wish to acknowledge and thank Mr. R. Braeken for the fixation and paraffin embedding of mouse kidney tissue samples and the AOMC for the microscopy support. The authors wish to thank Ms. J. De Loor for her aid with collection and transportation of kidney biopsy tissue. The authors also thank the centers of the Leuven Collaborative Group for Renal Transplantation, as well as the clinicians, lab technicians, surgeons, nursing staff, and patients in the study
Ambient black carbon reaches the kidneys
No full textBackground: Ultrafine particles, including black carbon (BC), can reach the systemic circulation and therefore may distribute to distant organs upon inhalation. The kidneys may be particularly vulnerable to the adverse effects of BC exposure due to their filtration function. Objectives: We hypothesized that BC particles reach the kidneys via the systemic circulation, where the particles may reside in structural components of kidney tissue and impair kidney function. Methods: In kidney biopsies from 25 transplant patients, we visualized BC particles using white light generation under femtosecond-pulsed illumination. The presence of urinary kidney injury molecule-1 (KIM-1) and cystatin c (CysC) were evaluated with ELISA. We assessed the association between internal and external exposure matrices and urinary biomarkers using Pearson correlation and linear regression models. Results: BC particles could be identified in all biopsy samples with a geometric mean (5th, 95th percentile) of 1.80 × 103 (3.65 × 102, 7.50 × 103) particles/mm3 kidney tissue, predominantly observed in the interstitium (100 %) and tubules (80 %), followed by the blood vessels and capillaries (40 %), and the glomerulus (24 %). Independent from covariates and potential confounders, we found that each 10 % higher tissue BC load resulted in 8.24 % (p = 0.03) higher urinary KIM-1. In addition, residential proximity to a major road was inversely associated with urinary CysC (+10 % distance: −4.68 %; p = 0.01) and KIM-1 (+10 % distance: −3.99 %; p < 0.01). Other urinary biomarkers, e.g., the estimated glomerular filtration rate or creatinine clearance showed no significant associations. Discussion and conclusion: Our findings that BC particles accumulate near different structural components of the kidney represent a potential mechanism explaining the detrimental effects of particle air pollution exposure on kidney function. Furthermore, urinary KIM-1 and CysC show potential as air pollution-induced kidney injury biomarkers for taking a first step in addressing the adverse effects BC might exert on kidney function
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