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Jørgensen HS, Vervloet M, Cavalier E, Bacchetta J, de Borst MH, Bover J, Cozzolino M, Ferreira AC, Hansen D, Herrmann M, de Jongh R, Mazzaferro S, Wan M, Shroff R, Evenepoel P. The role of nutritional vitamin D in chronic kidney disease-mineral and bone disorder in children and adults with chronic kidney disease, on dialysis, and after kidney transplantation-a European consensus statement. Nephrol Dial Transplant 2025; 40:797-822. [PMID: 39875204 PMCID: PMC11960744 DOI: 10.1093/ndt/gfae293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Indexed: 01/30/2025] Open
Abstract
Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations. In a collaboration between the European Renal Osteodystrophy initiative of the European Renal Association (ERA) and the European Society for Paediatric Nephrology (ESPN), an expert panel performed an extensive literature review and formulated clinical practice points on vitamin D supplementation in children and adults with CKD and after kidney transplantation. These were reviewed by a Delphi panel of members from relevant working groups of the ERA and ESPN. Key clinical practice points include recommendations to monitor for, and correct, vitamin D deficiency in children and adults with CKD and after kidney transplantation, targeting 25-hydroxyvitamin D levels >75 nmol/l (>30 ng/ml). Although vitamin D supplementation appears well-tolerated and safe, it is recommended to avoid mega-doses (≥100 000 IU) and very high levels of 25 hydroxyvitamin D (>150-200 nmol/l, or 60-80 ng/ml) to reduce the risk of toxicity. Future clinical trials should investigate the benefit of vitamin D supplementation on patient-relevant outcomes in the setting of vitamin D deficiency across different stages of CKD.
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Affiliation(s)
- Hanne Skou Jørgensen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Nephrology, Aalborg University Hospital, Aalborg, Denmark
| | - Marc Vervloet
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Etienne Cavalier
- Department of Clinical Chemistry, CIRM, University of Liege, CHU de Liège, Liège, Belgium
| | - Justine Bacchetta
- Department of Pediatric Nephrology, Reference Center for Rare Diseases of Calcium and Phosphate, INSERM1033 Research Unit, Hospices Civils de Lyon, Université Lyon 1, Lyon, France
| | - Martin H de Borst
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jordi Bover
- Department of Nephrology, University Hospital Germans Trias i Pujol, Badalona (Barcelona), Catalonià, Spain
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - Ana Carina Ferreira
- Nephrology Department, Hospital Curry Cabral | ULS São José, Lisbon, Portugal and Nova Medical School, Lisbon, Portugal
| | - Ditte Hansen
- Department of Nephrology, Copenhagen University Hospital-Herlev, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Markus Herrmann
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Renate de Jongh
- Department of Endocrinology and Metabolism, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Sandro Mazzaferro
- Department of Translation and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Mandy Wan
- Institute of Pharmaceutical Science, King's College London, London, UK and Department of Evelina Pharmacy, Guys' & St Thomas' NHS Foundation Trust, London, UK
| | - Rukshana Shroff
- Renal Unit, UCL Great Ormond Street Hospital for Children; University College London, London, UK
| | - Pieter Evenepoel
- Department of Microbiology, Immunology and Transplantation; Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
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Magagnoli L, Cassia M, Galassi A, Ciceri P, Massó E, Gelpi R, Bover J, Cozzolino M. Vitamin D: are all compounds equal? Clin Kidney J 2025; 18:i61-i96. [PMID: 40083955 PMCID: PMC11903094 DOI: 10.1093/ckj/sfae417] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Indexed: 03/16/2025] Open
Abstract
Vitamin D is a pre-hormone essential for maintaining mineral homeostasis and also plays significant roles in bone, cardiovascular and renal health. Vitamin D deficiency is prevalent in the general population, and even more so in chronic kidney disease (CKD) patients, in which it contributes to the development and progression of mineral and bone disorder. The landscape of vitamin D treatment has evolved, with several analogues now available, each possessing distinct pharmacokinetic and pharmacodynamic properties, efficacies and safety profiles. This diversity allows for tailored, personalized approaches to treatment in CKD patients. This review aims to provide a comprehensive overview of vitamin D, including its natural sources and metabolism, and examines the main available pharmacological vitamin D products. Particular emphasis is placed on their application in CKD management, highlighting how these compounds can be strategically used to address both vitamin D deficiency and secondary hyperparathyroidism, while also acknowledging the ongoing debate about their impact on bone health and other clinical outcomes.
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Affiliation(s)
| | - Matthias Cassia
- Nephrology Unit, Spedali Civili di Brescia Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Andrea Galassi
- Renal and Dialysis Unit, ASST Rhodense, Garbagnate, Milan, Italy
| | - Paola Ciceri
- Laboratory of Experimental Nephrology, Department of Health Sciences, University of Milan, Milan, Italy
| | - Elisabet Massó
- Nephrology Department, University Hospital Germans Trias I Pujol, REMAR-IGTP Group, RICORS 2040 Network, Barcelona, Spain
| | - Rosana Gelpi
- Nephrology Department, University Hospital Germans Trias I Pujol, REMAR-IGTP Group, RICORS 2040 Network, Barcelona, Spain
| | - Jordi Bover
- Nephrology Department, University Hospital Germans Trias I Pujol, REMAR-IGTP Group, RICORS 2040 Network, Barcelona, Spain
| | - Mario Cozzolino
- Department of Health Sciences, University of Milan, Milan, Italy
- Renal Division, ASST Santi Paolo e Carlo, Milan, Italy
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Jørgensen HS, de Loor H, Billen J, Peersman N, Vermeersch P, Heijboer AC, Ivison F, Vanderschueren D, Bouillon R, Naesens M, Kuypers D, Evenepoel P. Vitamin D Metabolites Before and After Kidney Transplantation in Patients Who Are Anephric. Am J Kidney Dis 2024:S0272-6386(24)00782-0. [PMID: 38796137 DOI: 10.1053/j.ajkd.2024.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/14/2024] [Accepted: 03/26/2024] [Indexed: 05/28/2024]
Abstract
RATIONALE & OBJECTIVE Kidneys are vital for vitamin D metabolism, and disruptions in both production and catabolism occur in chronic kidney disease. Although vitamin D activation occurs in numerous tissues, the kidneys are the most relevant source of circulating active vitamin D. This study investigates extrarenal vitamin D activation and the impact of kidney transplantation on vitamin D metabolism in patients who are anephric. STUDY DESIGN Case series. SETTING & PARTICIPANTS Adult patients with previous bilateral nephrectomy (anephric) not receiving active vitamin D therapy evaluated at the time of (N=38) and 1 year after (n=25) kidney transplantation. ANALYTICAL APPROACH Chromatography with tandem mass spectrometry was used to measure vitamin D metabolites. Activity of CYP24A1 [24,25(OH)2D/25(OH)D] and CYP27B1 [1α,25(OH)2D/25(OH)D] is expressed as metabolic ratios. Differences between time points were evaluated by paired t-test or Wilcoxon matched-pairs signed-rank test. RESULTS At time of transplantation, 1α,25(OH)2D was detectable in all patients (4-36pg/mL). There was a linear relationship between 25(OH)D and 1α,25(OH)2D levels (r=0.58, P<0.001), with 25(OH)D explaining 34% of the variation in 1α,25(OH)2D levels. There were no associations between 1α,25(OH)2D and biointact parathyroid hormone (PTH) or fibroblast growth factor 23 (FGF-23). One year after transplantation, 1α,25(OH)2D levels recovered (+205%), and CYP27B1 activity increased (+352%). Measures of vitamin D catabolism, 24,25(OH)2D and CYP24A1 activity increased 3- to 5-fold. Also, at 12 months after transplantation, 1α,25(OH)2D was positively correlated with PTH (ρ=0.603, P=0.04) but not with levels of 25(OH)D or FGF-23. LIMITATIONS Retrospective, observational study design with a small cohort size. CONCLUSIONS Low-normal levels of 1α,25(OH)2D was demonstrated in anephric patients, indicating production outside the kidneys. This extrarenal CYP27B1 activity may be more substrate driven than hormonally regulated. Kidney transplantation seems to restore kidney CYP27B1 and CYP24A1 activity, as evaluated by vitamin D metabolic ratios, resulting in both increased vitamin D production and catabolism. These findings may have implications for vitamin D supplementation strategies in the setting of kidney failure and transplantation. PLAIN-LANGUAGE SUMMARY Vitamin D activation occurs in multiple tissues, but the kidneys are considered the only relevant source of circulating levels. This study investigates vitamin D activation outside the kidneys by measuring vitamin D metabolites in 38 patients without kidneys. Active vitamin D was detectable in all patients, indicating production outside of the kidneys. There was a strong relationship between active and precursor vitamin D levels, but no association with mineral metabolism hormones, indicating that vitamin D production was more substrate dependent than hormonally regulated. One year after kidney transplantation, active vitamin D levels increased 2-fold and breakdown products increased 3-fold, indicating that production and degradation of the hormone recovers after kidney transplantation. These findings are relevant for future research into vitamin D supplementation in kidney failure.
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Affiliation(s)
- Hanne Skou Jørgensen
- Institute of Clinical Medicine, Aarhus University, Aarhus, and Department of Nephrology, Aalborg University Hospital, Aalborg, Denmark
| | - Henriette de Loor
- Department of Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven University Hospitals, Leuven, Belgium
| | - Jaak Billen
- Clinical Department of Laboratory Medicine, Leuven University Hospitals, Leuven, Belgium
| | - Nele Peersman
- Department of Cardiovascular Sciences, Leuven University Hospitals, Leuven, Belgium; Clinical Department of Laboratory Medicine, Leuven University Hospitals, Leuven, Belgium
| | - Pieter Vermeersch
- Department of Cardiovascular Sciences, Leuven University Hospitals, Leuven, Belgium; Clinical Department of Laboratory Medicine, Leuven University Hospitals, Leuven, Belgium
| | - Annemieke C Heijboer
- Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam and University of Amsterdam, Amsterdam, the Netherlands
| | - Fiona Ivison
- Department of Clinical Biochemistry, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Dirk Vanderschueren
- Laboratory of Clinical and Experimental Endocrinology, Leuven University Hospitals, Leuven, Belgium; KU Leuven, and Clinical Department of Endocrinology, Leuven University Hospitals, Leuven, Belgium
| | - Roger Bouillon
- Department of Cardiovascular Sciences, Leuven University Hospitals, Leuven, Belgium
| | - Maarten Naesens
- Department of Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven University Hospitals, Leuven, Belgium; Department of Medicine, Division of Nephrology, Leuven University Hospitals, Leuven, Belgium
| | - Dirk Kuypers
- Department of Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven University Hospitals, Leuven, Belgium; Department of Medicine, Division of Nephrology, Leuven University Hospitals, Leuven, Belgium
| | - Pieter Evenepoel
- Department of Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven University Hospitals, Leuven, Belgium; Department of Medicine, Division of Nephrology, Leuven University Hospitals, Leuven, Belgium.
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Paliu IA, Olinca MV, Ianosi SL, Georgescu CV, Turcu-Stiolica A, Diaconu M, Dumitrescu CI, Tica AA. CYP27B1 Enzyme in Psoriasis: A Preliminary Study of Immunohistochemical Observations. Life (Basel) 2023; 14:15. [PMID: 38276264 PMCID: PMC10817706 DOI: 10.3390/life14010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/11/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Connections between vitamin D and psoriasis have been a matter of interest for the past decades, with its active metabolite, 1,25(OH)2 vitamin D, being valued for antiproliferative and immunomodulatory effects. However, none of vitamin D's actions could be possible without the CYP27B1 enzyme that bio-activates this metabolite of interest. In order to see if there is any link between the enzyme expression and the disease's particularities, we conducted a preliminary study that involved 11 skin biopsies of patients with mild (n = 4) or moderate to severe psoriasis (n = 7). The cell proliferation antigen Ki67 and the CD45RO+ marker were also assessed. Compared with healthy skin, in psoriasis, it is reported that the enzyme's expression seems to be more ubiquitous, but a clear correlation between the disease's severity and the CYP27B1 expression was, to our knowledge, lacking. We found that, in patients with very mild psoriasis, the enzyme expression was observed in the epidermal stratum basale in a similar manner as in healthy skin specimens. Contrary, for higher severity scores, a divergent result was observed, with the enzyme being either variably spread in the epidermal stratum spinosum or completely absent. Unlike malignant diseases, a significant connection between CYP27B1 and Ki67 (p = 0.313) or CYP27B1 and CD45RO+ (p = 0.657) does not seem to be relevant in psoriasis.
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Affiliation(s)
- Iulia-Alexandra Paliu
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (I.-A.P.); (M.D.); (C.-I.D.); (A.-A.T.)
| | - Maria-Victoria Olinca
- Department of Pathology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Simona-Laura Ianosi
- Department of Dermatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - Adina Turcu-Stiolica
- Department of Pharmacoeconomics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Magdalena Diaconu
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (I.-A.P.); (M.D.); (C.-I.D.); (A.-A.T.)
| | - Cristiana-Iulia Dumitrescu
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (I.-A.P.); (M.D.); (C.-I.D.); (A.-A.T.)
| | - Andrei-Adrian Tica
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (I.-A.P.); (M.D.); (C.-I.D.); (A.-A.T.)
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Sunderraj A, Wong M, Gutiérrez OM, Wolf M, Akhabue E, Carnethon MR, Yancy CW, Isakova T. Associations of FGF23 with 10-Year Change in eGFR and UACR and with Incident CKD in the CARDIA Cohort. KIDNEY360 2023; 4:e1236-e1244. [PMID: 37265357 PMCID: PMC10547221 DOI: 10.34067/kid.0000000000000172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 05/12/2023] [Indexed: 06/03/2023]
Abstract
Key Points FGF23 has a nonlinear positive association with incident CKD among healthy, middle-aged adults. The relationship between FGF23 and incident CKD was only significant among participants with cFGF23 levels in the highest quartile. FGF23 is not associated with 10-year change in eGFR or 10-year change in UACR among healthy, middle-aged adults. Background The relationship of fibroblast growth factor 23 (FGF23) with incident CKD has been examined in older but not younger populations. Methods Linear regression models were used to examine the associations of c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) with 10-year change (1995–96 to 2005–06) in eGFR and urine albumin-to-creatinine ratio (UACR) in the Coronary Artery Risk Development in Young Adults cohort. Cox proportional hazard models were used to assess the association of cFGF23 with incident CKD, defined as eGFR <60 ml/min per 1.73 m2 or UACR ≥30 mg/g. Multivariable models were adjusted for age, sex, race, education, field center, physical activity, body mass index, diabetes, smoking, and systolic BP. Results Among 2511 participants, the mean age was 45±3.6 years; mean eGFR was 96.5±14.0 ml/min per 1.73 m2; and median UACR was 4.3 (interquartile range, 3.0–6.7) mg/g. Most (62.6%) participants were nonsmokers; the prevalence of diabetes was low (6.6%); and median values for 10-year changes in eGFR and UACR were modest (−5.50 ml/min per 1.73 m2 and 0.70 mg/g, respectively). No consistent associations between cFGF23 and 10-year change in eGFR and UACR were observed. During a median follow-up of 9.98 years, incident CKD developed in 258 participants. There was a nonlinear association of cFGF23 with incident CKD, and relative to the lowest quartile of cFGF23, a significant relationship was detected only among participants in the highest quartile (hazard ratio, 1.58; 95% confidence interval, 1.09 to 2.27). Similar findings were observed for iFGF23. Conclusion Among middle-aged adults in the Coronary Artery Risk Development in Young Adults cohort, median eGFR and UACR changes were modest and cFGF23 and iFGF23 were not consistently associated with 10-year change in eGFR or UACR. A nonlinear relationship was observed between cFGF23 and incident CKD, with individuals with highest cFGF23 levels being at risk of developing CKD.
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Affiliation(s)
- Ashwin Sunderraj
- Department of Medicine and Clinical and Translational Immunocardiology Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Mandy Wong
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Orlando M. Gutiérrez
- Department of Medicine and Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Myles Wolf
- Department of Medicine and Duke Clinical Research Institute, Duke University, Durham, North Carolina
| | - Ehimare Akhabue
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Mercedes R. Carnethon
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Clyde W. Yancy
- Department of Medicine and Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Tamara Isakova
- Department of Medicine and Center for Translational Metabolism and Health, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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John JV, McCarthy A, Karan A, Xie J. Electrospun Nanofibers for Wound Management. CHEMNANOMAT : CHEMISTRY OF NANOMATERIALS FOR ENERGY, BIOLOGY AND MORE 2022; 8:e202100349. [PMID: 35990019 PMCID: PMC9384963 DOI: 10.1002/cnma.202100349] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Indexed: 06/15/2023]
Abstract
Electrospun nanofibers show great potential in biomedical applications. This mini review article traces the recent advances in electrospun nanofibers for wound management via various approaches. Initially, we provide a short note on the four phases of wound healing, including hemostasis, inflammation, proliferation, and remodeling. Then, we state how the nanofiber dressings can stop bleeding and reduce the pain. Following that, we discuss the delivery of therapeutics and cells using different types of nanofibers for enhancing cell migration, angiogenesis, and re-epithelialization, resulting in the promotion of wound healing. Finally, we present the conclusions and future perspectives regarding the use of electrospun nanofibers for wound management.
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Affiliation(s)
- Johnson V John
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198 (USA)
| | - Alec McCarthy
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198 (USA)
| | - Anik Karan
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198 (USA)
| | - Jingwei Xie
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198 (USA)
- Department of Mechanical and Materials Engineering, College of Engineering, University of Nebraska Lincoln, Lincoln, NE 68588 (USA)
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Expression of renal vitamin D receptors and metabolizing enzymes in IgA nephropathy. Acta Histochem 2021; 123:151740. [PMID: 34111685 DOI: 10.1016/j.acthis.2021.151740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/29/2021] [Accepted: 06/03/2021] [Indexed: 11/22/2022]
Abstract
AIM One of the main causes of end-stage renal disease (ESRD) in the world is IgA nephropathy (IgAN). Since kidney is a key player in vitamin D metabolism, we investigated the expression of renal vitamin D receptors (VDR) and metabolizing enzymes in IgA nephropathy patients (IgAN-P). METHODS The sample included twelve IgAN-P who underwent ultrasound-guided renal biopsies and five controls who underwent nephrectomy due to clear renal carcinoma. Immunofluorescent staining was used to determine the expression of VDR, 25-hydroxyvitamin D3 -alpha-hydroxylase (1alpha-OHase) and vitamin D3 24-hydroxylase (CYP24A1). RESULTS Significant increase in expression of VDR, which was prominent in distal tubular cells (DTCs) in tissues from IgAN-P, was found in comparison to the controls (p = 0.0368). The expression of 1alpha-OHase, calcitriol synthesizing enzyme, was significantly lower in IgAN-P, in comparison with controls (p < 0.0001). The opposite, expression of CYP24A1 (vitamin D degrading enzyme), was significantly higher in IgAN-P in comparison with controls (p = 0.0003). Additionally, we found significant negative correlation between percentage of CYP24A1 immunoreactive nuclei in proximal tubular cells (PTCs) and estimated glomerular filtration rate (eGFR) in IgAN-P (r = -0.6139; p = 0.0337). CONCLUSIONS Our research indicates substantially decreased renal calcitriol production and increased vitamin D degradation in kidneys of IgAN-P, but larger studies are needed to confirm our results.
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Bonavia A, Stiles N. Renohepatic crosstalk: a review of the effects of acute kidney injury on the liver. Nephrol Dial Transplant 2021; 37:1218-1228. [PMID: 33527986 DOI: 10.1093/ndt/gfaa297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Indexed: 12/13/2022] Open
Abstract
Several theories regarding acute kidney injury (AKI)-related mortality have been entertained, although mounting evidence supports the paradigm that impaired kidney function directly and adversely affects the function of several remote organs. The kidneys and liver are fundamental to human metabolism and detoxification, and it is therefore hardly surprising that critical illness complicated by hepatorenal dysfunction portends a poor prognosis. Several diseases can simultaneously impact the proper functioning of the liver and kidneys, although this review will address the impact of AKI on liver function. While evidence for this relationship in humans remains sparse, we present supportive studies and then discuss the most likely mechanisms by which AKI can cause liver dysfunction. These include 'traditional' complications of AKI (uremia, volume overload and acute metabolic acidosis, among others) as well as systemic inflammation, hepatic leukocyte infiltration, cytokine-mediated liver injury and hepatic oxidative stress. We conclude by addressing the therapeutic implications of these findings to clinical medicine.
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Affiliation(s)
- Anthony Bonavia
- Department of Anesthesiology and Perioperative Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.,Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Nicholas Stiles
- Department of Anesthesiology and Perioperative Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
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Abstract
Protein-bound uremic toxins (PBUTs) are bioactive microbiota metabolites originated exclusively from protein fermentation of the bacterial community resident within the gut microbiota, whose composition and function is profoundly different in the chronic kidney disease (CKD) population. PBUTs accumulate in the later stages of CKD because they cannot be efficiently removed by conventional hemodialysis due to their high binding affinity for albumin, worsening their toxic effects, especially at the cardiovascular level. The accumulation of uremic toxins, along with oxidative stress products and pro-inflammatory cytokines, characterizes the uremic status of CKD patients which is increasingly associated to a state of immune dysfunction including both immune activation and immunodepression. Furthermore, the links between immune activation and cardiovascular disease (CVD), and between immunodepression and infection diseases, which are the two major complications of CKD, are becoming more and more evident. This review summarizes and discusses the current state of knowledge on the role of the main PBUTs, namely indoxyl sulfate and p-cresyl sulfate, as regulators of immune response in CKD, in order to understand whether a microbiota modulation may be useful in the management of its main complications, CVD, and infections. Summarizing the direct effects of PBUT on immune system we may conclude that PCS seemed to be associated to an immune deficiency status of CKD mainly related to the adaptative immune response, while IS seemed to reflect the activation of both innate and adaptative immune systems likely responsible of the CKD-associated inflammation. However, the exact role of IS and PCS on immunity modulation in physiological and pathological state still needs in-depth investigation, particularly in vivo studies.
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Affiliation(s)
| | - Carmela Cosola
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Elena Ranieri
- Molecular Medicine Center, Clinical Pathology, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
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Evenepoel P, Dejongh S, Verbeke K, Meijers B. The Role of Gut Dysbiosis in the Bone-Vascular Axis in Chronic Kidney Disease. Toxins (Basel) 2020; 12:toxins12050285. [PMID: 32365480 PMCID: PMC7290823 DOI: 10.3390/toxins12050285] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 12/12/2022] Open
Abstract
Patients with chronic kidney disease (CKD) are at increased risk of bone mineral density loss and vascular calcification. Bone demineralization and vascular mineralization often concur in CKD, similar to what observed in the general population. This contradictory association is commonly referred to as the 'calcification paradox' or the bone-vascular axis. Mounting evidence indicates that CKD-associated gut dysbiosis may be involved in the pathogenesis of the bone-vascular axis. A disrupted intestinal barrier function, a metabolic shift from a predominant saccharolytic to a proteolytic fermentation pattern, and a decreased generation of vitamin K may, alone or in concert, drive a vascular and skeletal pathobiology in CKD patients. A better understanding of the role of gut dysbiosis in the bone-vascular axis may open avenues for novel therapeutics, including nutriceuticals.
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Affiliation(s)
- Pieter Evenepoel
- Laboratory of Nephrology, Department of Immunology and Microbiology, KU Leuven—University of Leuven, B-3000 Leuven, Belgium
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, B-3000 Leuven, Belgium
- Correspondence: ; Tel.: +32-16-344591; Fax: +32-16-344599
| | - Sander Dejongh
- Laboratory of Nephrology, Department of Immunology and Microbiology, KU Leuven—University of Leuven, B-3000 Leuven, Belgium
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, B-3000 Leuven, Belgium
| | - Kristin Verbeke
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven—University of Leuven, B-3000 Leuven, Belgium
| | - Bjorn Meijers
- Laboratory of Nephrology, Department of Immunology and Microbiology, KU Leuven—University of Leuven, B-3000 Leuven, Belgium
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, B-3000 Leuven, Belgium
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11
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Glorieux G, Gryp T, Perna A. Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease. Toxins (Basel) 2020; 12:toxins12040245. [PMID: 32290429 PMCID: PMC7232434 DOI: 10.3390/toxins12040245] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/08/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023] Open
Abstract
Several of the uremic toxins, which are difficult to remove by dialysis, originate from the gut bacterial metabolism. This opens opportunities for novel targets trying to decrease circulating levels of these toxins and their pathophysiological effects. The current review focuses on immunomodulatory effects of these toxins both at their side of origin and in the circulation. In the gut end products of the bacterial metabolism such as p-cresol, trimethylamine and H2S affect the intestinal barrier structure and function while in the circulation the related uremic toxins stimulate cells of the immune system. Both conditions contribute to the pro-inflammatory status of patients with chronic kidney disease (CKD). Generation and/or absorption of these toxin precursors could be targeted to decrease plasma levels of their respective uremic toxins and to reduce micro-inflammation in CKD.
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Affiliation(s)
- Griet Glorieux
- Nephrology Division, Ghent University Hospital and Ghent University, 9000 Ghent, Belgium;
- Correspondence: ; Tel.: +32-9-3324511
| | - Tessa Gryp
- Nephrology Division, Ghent University Hospital and Ghent University, 9000 Ghent, Belgium;
| | - Alessandra Perna
- First Division of Nephrology, Department of Translational Medical Sciences, School of Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy;
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12
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13
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Liu WC, Tomino Y, Lu KC. Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120. Toxins (Basel) 2018; 10:toxins10090367. [PMID: 30208594 PMCID: PMC6162782 DOI: 10.3390/toxins10090367] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/07/2018] [Accepted: 09/08/2018] [Indexed: 02/07/2023] Open
Abstract
Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients. These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function. Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions. Furthermore, they destroy the quantity and quality of bone. Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine. Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress. This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients. Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use. This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients.
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Affiliation(s)
- Wen-Chih Liu
- Division of Nephrology, Department of Internal Medicine, Tungs' Taichung Metro Harbor Hospital, Taichung City 435, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 106, Taiwan.
| | - Yasuhiko Tomino
- Asian Pacific Renal Research Promotion Office, Medical Corporation SHOWAKAI, Tokyo 160-0023, Japan.
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 243, Taiwan.
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14
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Meijers B, Jouret F, Evenepoel P. Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease. Pharmacol Res 2018; 133:101-107. [DOI: 10.1016/j.phrs.2018.04.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 04/02/2018] [Accepted: 04/27/2018] [Indexed: 12/12/2022]
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15
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Rossaint J, Unruh M, Zarbock A. Fibroblast growth factor 23 actions in inflammation: a key factor in CKD outcomes. Nephrol Dial Transplant 2018; 32:1448-1453. [PMID: 27659127 DOI: 10.1093/ndt/gfw331] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 08/01/2016] [Indexed: 02/07/2023] Open
Abstract
During chronic kidney disease (CKD), bone mineral metabolism is disturbed owing in part to the endogenous hormone fibroblast growth factor 23 (FGF23). Elevated FGF23 levels are seen in CKD patients. Current research has demonstrated that FGF23 directly modulates the immune response and host defense to bacterial infections. FGF23 also impairs the activation and recruitment of neutrophils, which are the main immune effector cells required for host defense against bacterial infections. In addition, while FGF23 levels reduce leukocyte recruitment and functions, inflammatory conditions may also-in a reverse fashion-contribute to elevated FGF23 levels in the circulation. In this context, altered hypoxia inducible factor 1α signaling and iron metabolism may contribute to intact FGF23 (iFGF23) production. This review examines evidence on the role of FGF23 in inflammation, immune cell function and recruitment as well as the regulation of FGF23 during inflammation and the clinical implications of this process for the immune system in individuals with CKD. Clinical observations and laboratory investigations indicate an important role of FGF23 in directly modulating leukocyte activation and recruitment behavior with consequences on host defense against bacterial infections. This novel observation may in part explain the increased infectious risk among patients with CKD. However, studies of FGF23 neutralization also revealed increased mortality after sustained administration over several weeks in rats. Thus, therapeutic interventions targeting FGF23 must be carefully evaluated.
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Affiliation(s)
- Jan Rossaint
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Mark Unruh
- Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.,Section of Neprology, New Mexico Veteran Affairs Hospital, Albuquerque, NM, USA
| | - Alexander Zarbock
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
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16
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Arababadi MK, Nosratabadi R, Asadikaram G. Vitamin D and toll like receptors. Life Sci 2018; 203:105-111. [PMID: 29596922 DOI: 10.1016/j.lfs.2018.03.040] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 03/10/2018] [Accepted: 03/20/2018] [Indexed: 12/17/2022]
Abstract
It has been demonstrated that vitamin D (VD) significantly modulates immune responses. Toll like receptors (TLRs) are the main innate immunity receptors which are expressed on the cell membrane and intracellular vesicles and recognize several pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to induce immune responses. Based on the important roles played by TLRs in physiologic and pathologic functions of immune responses and due to the immunomodulatory functions of VD, it has been hypothesized that VD may present its immunomodulatory functions via modulation of TLRs. This review article collates recent studies regarding the interactions between VD and TLRs and discussed the controversial investigations.
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Affiliation(s)
- Mohammad Kazemi Arababadi
- Department of Immunology, Faculty of Medicine, Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Reza Nosratabadi
- Department of Immunology, Faculty of Medicine, Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Asadikaram
- Neuroscience Research Center, Institute of Neuropharmacology and Department of Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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17
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Richter B, Faul C. FGF23 Actions on Target Tissues-With and Without Klotho. Front Endocrinol (Lausanne) 2018; 9:189. [PMID: 29770125 PMCID: PMC5940753 DOI: 10.3389/fendo.2018.00189] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/06/2018] [Indexed: 12/11/2022] Open
Abstract
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in "classic" klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23's potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might-at least partially-underlie the pleiotropic tissue-protective functions of klotho.
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18
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Keane KN, Cruzat VF, Calton EK, Hart PH, Soares MJ, Newsholme P, Yovich JL. Molecular actions of vitamin D in reproductive cell biology. Reproduction 2017; 153:R29-R42. [PMID: 30390417 DOI: 10.1530/rep-16-0386] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vitamin D (VitD) is an important secosteroid and has attracted attention in several areas of research due to common VitD deficiency in the population, and its potential to regulate molecular pathways related to chronic and inflammatory diseases. VitD metabolites and the VitD receptor (VDR) influence many tissues including those of the reproductive system. VDR expression has been demonstrated in various cell types of the male reproductive tract, including spermatozoa and germ cells, and in female reproductive tissues including the ovaries, placenta and endometrium. However, the molecular role of VitD signalling and metabolism in reproductive function have not been fully established. Consequently, the aim of this work is to review current metabolic and molecular aspects of the VitD–VDR axis in reproductive medicine and to propose the direction of future research. Specifically, the influence of VitD on sperm motility, calcium handling, capacitation, acrosin reaction and lipid metabolism is examined. In addition, we will also discuss the effect of VitD on sex hormone secretion and receptor expression in primary granulosa cells, along with the impact on cytokine production in trophoblast cells. The review concludes with a discussion of the recent developments in VitD–VDR signalling specifically related to altered cellular bioenergetics, which is an emerging concept in the field of reproductive medicine.
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Affiliation(s)
- Kevin N Keane
- School of Biomedical SciencesCurtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.,PIVET Medical CentrePerth, Western Australia, Australia
| | - Vinicius F Cruzat
- School of Biomedical SciencesCurtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Emily K Calton
- Health Promotion & Disease PreventionSchool of Public Health, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Prue H Hart
- Telethon Kids InstituteUniversity of Western Australia, Perth, Western Australia, Australia
| | - Mario J Soares
- Health Promotion & Disease PreventionSchool of Public Health, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Philip Newsholme
- School of Biomedical SciencesCurtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - John L Yovich
- School of Biomedical SciencesCurtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.,PIVET Medical CentrePerth, Western Australia, Australia
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19
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David V, Francis C, Babitt JL. Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol 2017; 312:F1-F8. [PMID: 27582104 PMCID: PMC5283889 DOI: 10.1152/ajprenal.00359.2016] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 08/20/2016] [Indexed: 01/10/2023] Open
Abstract
The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotransporters as well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients.
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Affiliation(s)
- Valentin David
- Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Connor Francis
- Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Jodie L Babitt
- Nephrology Division, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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20
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Meireles MS, Kamimura MA, Dalboni MA, Giffoni de Carvalho JT, Aoike DT, Cuppari L. Effect of cholecalciferol on vitamin D-regulatory proteins in monocytes and on inflammatory markers in dialysis patients: A randomized controlled trial. Clin Nutr 2016; 35:1251-1258. [DOI: 10.1016/j.clnu.2016.04.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 03/31/2016] [Accepted: 04/05/2016] [Indexed: 01/08/2023]
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21
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Tanaka S, Ninomiya T, Taniguchi M, Fujisaki K, Tokumoto M, Hirakata H, Ooboshi H, Kitazono T, Tsuruya K. Comparison of oral versus intravenous vitamin D receptor activator in reducing infection-related mortality in hemodialysis patients: the Q-Cohort Study. Nephrol Dial Transplant 2016; 31:1152-1160. [DOI: 10.1093/ndt/gfw205] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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22
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Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstädt HJ, Meersch M, Unruh M, Zarbock A. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest 2016; 126:962-74. [PMID: 26878171 DOI: 10.1172/jci83470] [Citation(s) in RCA: 221] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 12/18/2015] [Indexed: 12/28/2022] Open
Abstract
Chronic kidney disease (CKD) has been associated with impaired host response and increased susceptibility to infections. Leukocyte recruitment during inflammation must be tightly regulated to protect the host against pathogens. FGF23 levels are increased in blood during CKD, and levels of this hormone have been associated with a variety of adverse effects in CKD patients. Here, we have shown that CKD impairs leukocyte recruitment into inflamed tissue and host defense in mice and humans. FGF23 neutralization during CKD in murine models restored leukocyte recruitment and host defense. Intravital microscopy of animals with chronic kidney failure showed that FGF23 inhibits chemokine-activated leukocyte arrest on the endothelium, and downregulation of FGF receptor 2 (FGFR2) on PMNs rescued host defense in these mice. In vitro, FGF23 inhibited PMN adhesion, arrest under flow, and transendothelial migration. Mechanistically, FGF23 binding to FGFR2 counteracted selectin- and chemokine-triggered β2 integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rap1. Moreover, knockdown of PKA abolished the inhibitory effect of FGF23 on integrin activation. Together, our data reveal that FGF23 acts directly on PMNs and dampens host defense by direct interference with chemokine signaling and integrin activation.
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23
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Shiba T, Makino I, Kawakami K, Kato I, Kobayashi T, Kaneko K. p-Cresyl sulfate suppresses lipopolysaccharide-induced anti-bacterial immune responses in murine macrophages in vitro. Toxicol Lett 2016; 245:24-30. [PMID: 26784855 DOI: 10.1016/j.toxlet.2016.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 12/11/2015] [Accepted: 01/13/2016] [Indexed: 11/18/2022]
Abstract
p-Cresyl sulfate (pCS) is a known uremic toxin that is metabolized from p-cresol produced by intestinal bacteria. Abnormal accumulation of pCS in the blood is a characteristic of chronic kidney disease (CKD). pCS is suggested to cause immune dysfunction and increase the risk of infectious diseases in CKD patients. In this study, we focused on the effects of pCS on macrophage functions related to host defense. We evaluated the effects of pCS on cytokine production, nitric oxide (NO) production, arginase activity, expression of cell-surface molecules, and phagocytosis in the macrophage-like cell line, RAW264.7. pCS significantly decreased interleukin (IL)-12 p40 production and increased IL-10 production. pCS also decreased NO production, but did not influence arginase activity. pCS suppressed lipopolysaccharide-induced CD40 expression on the cell surface, but did not influence phagocytosis. We further assessed whether the effects of pCS observed in the macrophage-like cell line were consistent in primary macrophages. Similar to RAW264.7 cells, pCS decreased IL-12 p40 and p70 production and increased IL-10 production in primary peritoneal macrophages. These data indicate that pCS suppresses certain macrophage functions that contribute to host defense, and may play a role in CKD-related immune dysfunction.
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Affiliation(s)
- Takahiro Shiba
- Yakult Central Institute, 5-11 Izumi, Kunitachi-Shi, Tokyo 186-8650, Japan.
| | - Ikuyo Makino
- Yakult Central Institute, 5-11 Izumi, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Koji Kawakami
- Yakult Central Institute, 5-11 Izumi, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Ikuo Kato
- Yakult Central Institute, 5-11 Izumi, Kunitachi-Shi, Tokyo 186-8650, Japan
| | | | - Kimiyuki Kaneko
- Yakult Central Institute, 5-11 Izumi, Kunitachi-Shi, Tokyo 186-8650, Japan
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24
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Jiang J, Chen G, Shuler FD, Wang CH, Xie J. Local Sustained Delivery of 25-Hydroxyvitamin D3 for Production of Antimicrobial Peptides. Pharm Res 2015; 32:2851-62. [PMID: 25773720 PMCID: PMC4529368 DOI: 10.1007/s11095-015-1667-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/04/2015] [Indexed: 01/22/2023]
Abstract
PURPOSE This study seeks to develop fiber membranes for local sustained delivery of 25-hydroxyvitamin D3 to induce the expression and secretion of LL-37 at or near the surgical site, which provides a novel therapeutic approach to minimize the risk of infections. METHODS 25-hydroxyvitamin D3 loaded poly(L-lactide) (PLA) and poly(ε-caprolactone) (PCL) fibers were produced by electrospinning. The morphology of obtained fibers was characterized using atomic force microscope (AFM) and scanning electron microscope (SEM). 25-hydroxyvitamin D3 releasing kinetics were quantified by enzyme-linked immunosorbent assay (ELISA) kit. The expression of cathelicidin (hCAP 18) and LL-37 was analyzed by immunofluorescence staining and ELISA kit. The antibacterial activity test was conducted by incubating pseudomonas aeruginosa in a monocytes' lysis solution. RESULTS AFM images suggest that the surface of PCL fibers is smooth, however, the surface of PLA fibers is relatively rough, in particular, after encapsulation of 25-hydroxyvitamin D3. The duration of 25-hydroxyvitamin D3 release can last more than 4 weeks for all the tested samples. Plasma treatment can promote the release rate of 25-hydroxyvitamin D3. Human keratinocytes and monocytes express significantly higher levels of hCAP18/LL-37 after incubation with plasma treated and 25-hydroxyvitamin D3 loaded PCL fibers than the cells incubated with around ten times amount of free drug. After incubation with this fiber formulation for 5 days LL-37 in the lysis solutions of U937 cells can effectively kill the bacteria. CONCLUSIONS Plasma treated and 25-hydroxyvitamin D3 loaded PCL fibers induce significantly higher levels of antimicrobial peptide production in human keratinocytes and monocytes without producing cytotoxicity.
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Affiliation(s)
- Jiang Jiang
- Department of Surgery and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Guojun Chen
- Bruker Nano Surface Division, Santa Barbara, CA 93117, United States
| | - Franklin D. Shuler
- Department of Orthopaedic Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25755 United States
| | - Chi-Hwa Wang
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, 117585
| | - Jingwei Xie
- Department of Surgery and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States,
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25
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Carbone F, Mach F, Vuilleumier N, Montecucco F. Potential pathophysiological role for the vitamin D deficiency in essential hypertension. World J Cardiol 2014; 6:260-276. [PMID: 24944756 PMCID: PMC4062123 DOI: 10.4330/wjc.v6.i5.260] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 03/24/2014] [Accepted: 04/11/2014] [Indexed: 02/06/2023] Open
Abstract
Vitamin D deficiency has been indicated as a pandemic emerging public health problem. In addition to the well-known role on calcium-phosphorus homeostasis in the bone, vitamin D-mediated processes have been recently investigated on other diseases, such as infections, cancer and cardiovascular diseases. Recently, both the discovery of paracrine actions of vitamin D (recognized as “local vitamin D system”) and the link of vitamin D with renin-angiotensin-aldosterone system and the fibroblast growth factor 23/klotho pathways highlighted its active cardiovascular activity. Focusing on hypertension, this review summarizes the more recent experimental evidence involving the vitamin D system and deficiency in the cardiovascular pathophysiology. In particular, we updated the vascular synthesis/catabolism of vitamin D and its complex interactions between the various endocrine networks involved in the regulation of blood pressure in humans. On the other hand, the conflicting results emerged from the comparison between observational and interventional studies emphasize the fragmentary nature of our knowledge in the field of vitamin D and hypertension, strongly suggesting the need of further researches in this field.
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26
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Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol 2014; 25:1897-907. [PMID: 24812165 DOI: 10.1681/asn.2013101062] [Citation(s) in RCA: 521] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.
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Affiliation(s)
| | - Eva Schepers
- Nephrology Section, Ghent University Hospital, Ghent, Belgium
| | | | - Evi V Nagler
- Nephrology Section, Ghent University Hospital, Ghent, Belgium
| | - Griet Glorieux
- Nephrology Section, Ghent University Hospital, Ghent, Belgium
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27
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Abstract
Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and an array of laboratory abnormalities. The latter classically include disturbances in the parathyroid hormone/vitamin D axis. More recently, fibroblast growth factor 23 (FGF23) and klotho also have been identified as important regulators of mineral metabolism. Klotho deficiency and high circulating FGF23 levels precede secondary hyperparathyroidism in CKD patients. Levels of FGF23 and parathyroid hormone increase along the progression of CKD to maintain mineral homeostasis and to overcome end-organ resistance. It is hard to define when the increase of both hormones becomes maladaptive. CKD-MBD is associated with adverse outcomes including cardiovascular disease and mortality. This review summarizes the complex pathophysiology of CKD-MBD and outlines which laboratory abnormalities represent biomarkers of disease severity, which laboratory abnormalities are predictors of cardiovascular disease, and which laboratory abnormalities should be considered (direct) uremic toxins exerting organ damage. This information may help to streamline current and future therapeutic efforts.
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28
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Vitamin D and the Immune System from the Nephrologist's Viewpoint. ISRN ENDOCRINOLOGY 2014; 2014:105456. [PMID: 24587915 PMCID: PMC3920624 DOI: 10.1155/2014/105456] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Accepted: 12/04/2013] [Indexed: 02/07/2023]
Abstract
Vitamin D and its analogues are widely used as treatments by clinical nephrologists, especially when treating chronic kidney disease (CKD) patients with secondary hyperparathyroidism. As CKD progresses, the ability to compensate for elevations in parathyroid hormone (PTH) and fibroblast growth factor-23 and for decreases in 1,25(OH)2D3 becomes inadequate, which results in hyperphosphatemia, abnormal bone disorders, and extra-skeletal calcification. In addition to its calciotropic effect on the regulation of calcium, phosphate, and parathyroid hormone, vitamin D has many other noncalciotropic effects, including controlling cell differentiation/proliferation and having immunomodulatory effects. There are several immune dysregulations that can be noted when renal function declines. Physicians need to know well both the classical and nonclassical functions of vitamin D. This review is an analysis from the nephrologist's viewpoint and focuses on the relationship between the vitamin D and the immune system, together with vitamin's clinical use to treat kidney diseases.
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Shiba T, Kawakami K, Sasaki T, Makino I, Kato I, Kobayashi T, Uchida K, Kaneko K. Effects of intestinal bacteria-derived p-cresyl sulfate on Th1-type immune response in vivo and in vitro. Toxicol Appl Pharmacol 2013; 274:191-9. [PMID: 24161588 DOI: 10.1016/j.taap.2013.10.016] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Revised: 09/23/2013] [Accepted: 10/14/2013] [Indexed: 10/26/2022]
Abstract
Protein fermentation by intestinal bacteria generates various compounds that are not synthesized by their hosts. An example is p-cresol, which is produced from tyrosine. Patients with chronic kidney disease (CKD) accumulate high concentrations of intestinal bacteria-derived p-cresyl sulfate (pCS), which is the major metabolite of p-cresol, in their blood, and this accumulation contributes to certain CKD-associated disorders. Immune dysfunction is a CKD-associated disorder that frequently contributes to infectious diseases among CKD patients. Although some studies imply pCS as an etiological factor, the relation between pCS and immune systems is poorly understood. In the present study, we investigated the immunological effects of pCS derived from intestinal bacteria in mice. For this purpose, we fed mice a tyrosine-rich diet that causes the accumulation of pCS in their blood. The mice were shown to exhibit decreased Th1-driven 2, 4-dinitrofluorobenzene-induced contact hypersensitivity response. The concentration of pCS in blood was negatively correlated with the degree of the contact hypersensitivity response. In contrast, the T cell-dependent antibody response was not influenced by the accumulated pCS. We also examined the in vitro cytokine responses by T cells in the presence of pCS. The production of IFN-γ was suppressed by pCS. Further, pCS decreased the percentage of IFN-γ-producing Th1 cells. Our results suggest that intestinal bacteria-derived pCS suppressesTh1-type cellular immune responses.
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Affiliation(s)
- Takahiro Shiba
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan.
| | - Koji Kawakami
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Takashi Sasaki
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Ikuyo Makino
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Ikuo Kato
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Toshihide Kobayashi
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Kazumi Uchida
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
| | - Kimiyuki Kaneko
- Safety Research Department, Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-Shi, Tokyo 186-8650, Japan
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