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Exploring the Molecular Mechanisms of Chronic Kidney Disease
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Exploring the Molecular Mechanisms of Chronic Kidney Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 1533

Special Issue Editor

Dr. Juan Miguel Diaz-Tocados

E-Mail Website
Guest Editor
Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida (IRBLleida), Arnau de Vilanova University Hospital, 25198 Lleida, Spain
Interests: bone disease; mineral metabolism; renal disease; vascular calcification; calcium-sensing receptor; fibroblast growth factor 23; sclerostin; vitamin D; parathyroid hormone
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is a global challenge, currently affecting approximately 1 in 10 individuals, accounting for over 800 million people with CKD worldwide. Unfortunately, the prevalence of CKD is increasing, estimated to become the fifth leading cause of death by 2040, which underscores the significant social and economic impact of this devastating disease. Research efforts focus on the prevention of CKD progression and associated complications that usually lead to increased hospitalization and higher mortality risk. Understanding the distinct molecular mechanisms underlying CKD development is key for identifying new therapeutic approaches and achieving the optimization of patient care.

This Special Issue aims to compile cutting-edge research on the molecular features of renal diseases and CKD-associated disorders, including metabolic bone disease, anemia, cardiovascular disease, diabetes and hypertension. In addition, novel molecular actions of current treatments and emerging drugs, as well as future strategies for preventing complications associated with dialysis or renal transplantation are also included.

Dr. Juan Miguel Diaz-Tocados
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • chronic kidney disease
  • hereditary renal disease
  • renal hypertension
  • diabetic nephropathy
  • secondary hyperparathyroidism
  • cardiovascular disease
  • renal osteodystrophy
  • peritoneal dialysis
  • hemodialysis
  • anemia
  • metabolic acidosis

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Published Papers (2 papers)

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Research

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12 pages, 2365 KiB  
Article
Citrate Dialysate with and without Magnesium Supplementation in Hemodiafiltration: A Comparative Study Versus Acetate
by Diana Rodríguez-Espinosa, Elena Cuadrado-Payán, Naira Rico, Mercè Torra, Rosa María Fernández, Gregori Casals, María Rodríguez-García, Francisco Maduell and José Jesús Broseta
Int. J. Mol. Sci. 2024, 25(15), 8491; https://doi.org/10.3390/ijms25158491 - 3 Aug 2024
Viewed by 672
Abstract
The choice of dialysate buffer in hemodialysis is crucial, with acetate being widely used despite complications. Citrate has emerged as an alternative because of its favorable effects, yet concerns persist about its impact on calcium and magnesium levels. This study investigates the influence [...] Read more.
The choice of dialysate buffer in hemodialysis is crucial, with acetate being widely used despite complications. Citrate has emerged as an alternative because of its favorable effects, yet concerns persist about its impact on calcium and magnesium levels. This study investigates the influence of citrate dialysates (CDs) with and without additional magnesium supplementation on CKD-MBD biomarkers and assesses their ability to chelate divalent metals compared to acetate dialysates (ADs). A prospective crossover study was conducted in a single center, involving patients on thrice-weekly online hemodiafiltration (HDF). The following four dialysates were compared: two acetate-based and two citrate-based. Calcium, magnesium, iPTH, iron, selenium, cadmium, copper, zinc, BUN, albumin, creatinine, bicarbonate, and pH were monitored before and after each dialysis session. Seventy-two HDF sessions were performed on eighteen patients. The CDs showed stability in iPTH levels and reduced post-dialysis total calcium, with no significant increase in adverse events. Magnesium supplementation with CDs prevented hypomagnesemia. However, no significant differences among dialysates were observed in the chelation of other divalent metals. CDs, particularly with higher magnesium concentrations, offer promising benefits, including prevention of hypomagnesemia and stabilization of CKD-MBD parameters, suggesting citrate as a viable alternative to acetate. Further studies are warranted to elucidate long-term outcomes and optimize dialysate formulations. Until then, given our results, we recommend that when a CD is used, it should be used with a 0.75 mmol/L Mg concentration rather than a 0.5 mmol/L one. Full article
(This article belongs to the Special Issue Exploring the Molecular Mechanisms of Chronic Kidney Disease)
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Figure 1

Figure 1
<p>Violin plots of pre- and post-dialysis concentrations with each dialysate for (<b>A</b>). magnesium, (<b>B</b>). ionized calcium, (<b>C</b>). total calcium, (<b>D</b>). PTH, (<b>E</b>). iron, (<b>F</b>). copper, (<b>G</b>). zinc, (<b>H</b>). selenium, and (<b>I</b>). cadmium. iPTH: intact parathyroid hormone. SmartBag<sup>®</sup> 211.25: acetate dialysate with a calcium concentration of 1.25 mmol/L and magnesium concentration of 0.5 mmol/L, SmartBag<sup>®</sup> 211.5: acetate dialysate with a calcium concentration of 1.5 mmol/L and magnesium concentration of 0.5 mmol/L, SmartBag<sup>®</sup> CA 211.5: citrate dialysate with a calcium concentration of 1.5 mmol/L and magnesium concentration of 0.5 mmol/L, and SmartBag<sup>®</sup> CA 211.5-0.75: citrate dialysate with a calcium concentration of 1.5 mmol/L and magnesium concentration of 0.75 mmol/L.</p> Full article ">Figure 2
<p>Correlation of the delta between the pre- and post-dialysis intact PTH blood concentration with iCa (<b>A</b>), total calcium (<b>B</b>), and magnesium (<b>C</b>) blood values. iCa, ionized calcium; iPTH, intact parathyroid hormone.</p> Full article ">

Review

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21 pages, 4656 KiB  
Review
Clinical Properties and Non-Clinical Testing of Mineralocorticoid Receptor Antagonists in In Vitro Cell Models
by Luka Varda, Robert Ekart, Mitja Lainscak, Uroš Maver and Sebastjan Bevc
Int. J. Mol. Sci. 2024, 25(16), 9088; https://doi.org/10.3390/ijms25169088 - 22 Aug 2024
Viewed by 627
Abstract
Mineralocorticoid receptor antagonists (MRAs) are one of the renin–angiotensin–aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid [...] Read more.
Mineralocorticoid receptor antagonists (MRAs) are one of the renin–angiotensin–aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs. Full article
(This article belongs to the Special Issue Exploring the Molecular Mechanisms of Chronic Kidney Disease)
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Figure 1

Figure 1
<p>The renin–angiotensin–aldosterone system (RAAS) and effector sites of RAAS inhibitors—direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and MRAs (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p> Full article ">Figure 2
<p>Number of results per year in ScienceDirect database search with keywords “in-vitro” and “mineralocorticoid receptor antagonist” conducted in March 2024.</p> Full article ">Figure 3
<p>Clinical properties of most widely used mineralocorticoid receptor antagonists (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p> Full article ">Figure 4
<p>Summary of in vitro cellular models used for the testing of spironolactone, eplerenone, and finerenone (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>). PTEC—proximal tubular epithelial cell.</p> Full article ">Figure 5
<p>Human conditionally immortalized podocytes were put under mechanical stress. (<b>A</b>) Immunostaining for LC3 puncta and 4′,6-diamidino-2-phenylindole (DAPI)—binding to DNA and presenting nucleus was performed at 0 h, 12 h, 24 h, and 48 h and visualised under confocal microscope (magnification ×1200). LC3 dots are most prominent in the perinuclear and cytoplasmic regions (white arrows in merged images). LC3 puncta staining is lower at 12 h, 24 h, and 48 h, suggesting lower autophagy under mechanical stress. (<b>B</b>) Quantification of LC3 puncta staining showing statistically significant reduction at 24 h and 48 h (b) and statistically non-significant reduction at 12 h (a) [<a href="#B96-ijms-25-09088" class="html-bibr">96</a>]. »Reproduced with permission from Li et al., <span class="html-italic">Spironolactone promotes autophagy</span> via <span class="html-italic">inhibiting PI3K/AKT/mTOR signalling pathway and reduce adhesive capacity damage in podocytes under mechanical stress.</span> Published by Bioscience Reports—Portland Press, 2016«. The article is licensed under an open access Creative Commons CC BY 4.0 license [<a href="#B96-ijms-25-09088" class="html-bibr">96</a>].</p> Full article ">Figure 6
<p>Kidney biopsies of IgA nephropathy patients were obtained, and human mesangial cells (HMC) and human PTEC of IgA nephropathy patients were cultured, and the expression of MRs, 11β hydroxysteroid dehydrogenase (11β-HSD2), and CYP11B2 were determined using qPCR and immunofluorescence. (<b>A</b>) Both cell types expressed MR mRNA, whereas HMC also expressed 11β-HSD2 and CYP11B2. (<b>B</b>) Immunofluorescence of MR expression on PTEC (arrows) under magnification ×200. (<b>C</b>) Detection of all three markers in kidney biopsies of IgA nephropathy patients and controls under magnification ×200—MRs was expressed in glomeruli and tubules, whereas the other two markers were only in glomeruli. (<b>D</b>) A five-point scale was used to show increased glomerular CYP11B2 staining in IgA nephropathy patients compared to controls. (<b>E</b>) A five-point scale was used to show increased tubular MR staining in IgA nephropathy patients compared to controls. [<a href="#B110-ijms-25-09088" class="html-bibr">110</a>]. »Reproduced with permission from Leung et al., <span class="html-italic">Oxidative damages in tubular epithelial cells in IgA nephropathy: role of crosstalk between angiotensin II and aldosterone</span>; published by Journal of Translational Medicine—Springer Link, 2011«. The article is licensed under an open access Creative Commons CC BY 4.0 license [<a href="#B110-ijms-25-09088" class="html-bibr">110</a>].</p> Full article ">Figure 7
<p>Both tested MRAs can delay MR nuclear translocation. (<b>A</b>) After culturing human kidney GFP-MR cells for 48 h, incubation with aldosterone, spironolactone, and finerenone followed. Anti-GFP antibodies were used for immunocytochemistry with automated ArrayScan VTI fluorescent microscope (left side). DAPI was used for marking the nucleus (right side)—magnification ×20. With aldosterone treatment, complete accumulation of GFP-hMR in the nucleus was seen, but not with finerenone and spironolacotne, where it was partially located in the nucleus (<b>B</b>) Translocation index (average nuclear intensity/average cytoplasmic intensity) was calculated. (<b>C</b>) Average nuclear fluorescence intensity values calculated. V—vehicle; A—aldosterone; S—spironolactone; F—finerenone; Aldo—aldosterone; Spiro—spironolactone; Fine—finerenone [<a href="#B124-ijms-25-09088" class="html-bibr">124</a>]. »Reproduced with permission from Amazit et al., <span class="html-italic">Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1</span>; published by Journal of Biological Chemistry—currently published by Elsevier; originally published by American Society for Biochemistry and Molecular Biology., 2015«. The article is licensed under an open access Creative Commons CC BY 4.0 license [<a href="#B124-ijms-25-09088" class="html-bibr">124</a>].</p> Full article ">
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