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Molecular Insights and Novel Therapeutics in Chronic Kidney Disease

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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: 31 October 2026 | Viewed by 5650

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Editor

Prof. Dr. Marijn Speeckaert

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Guest Editor

Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium
Interests: biochemistry; biomarkers; hypertension; cardiovascular disease; kidney disease, diabetes
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Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) remains a major global health challenge, characterized by progressive loss of renal function, high morbidity, and limited treatment options beyond supportive care and renal replacement therapy. Despite advances in clinical management, the molecular mechanisms underlying CKD initiation and progression are still incompletely understood, hampering the development of targeted and personalized therapies. This Special Issue, “Molecular Insights and Novel Therapeutics in Chronic Kidney Disease”, aims to bring together cutting-edge research and reviews that explore the molecular basis of CKD, identify novel biomarkers, and highlight innovative therapeutic approaches. We particularly welcome contributions that leverage high-throughput omics technologies (transcriptomics, genomics, proteomics, metabolomics, and epigenomics) to unravel disease mechanisms, discover biomarkers for risk prediction, and guide precision medicine strategies. Topics of interest include but are not limited to molecular pathways driving inflammation, fibrosis, and immune dysregulation in CKD; omics-based discovery of biomarkers for early diagnosis, prognosis, and therapeutic monitoring; integration of multi-omics datasets with bioinformatics and machine learning to define CKD subtypes; translational studies linking molecular insights to clinical outcomes; emerging therapeutic strategies, including novel drugs, biologics, gene- and cell-based therapies, and repurposed agents targeting key molecular pathways; experimental models that provide mechanistic insight and support therapeutic innovation. By collecting state-of-the-art findings at the interface of molecular nephrology, systems biology, and therapeutic development, this Special Issue seeks to advance our understanding of CKD and pave the way toward precision nephrology.

Prof. Dr. Marijn Speeckaert
Guest Editor

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Keywords

chronic kidney disease (CKD)
molecular mechanisms
precision medicine

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Published Papers (5 papers)

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Research

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18 pages, 729 KB

Open AccessArticle

Endothelin-2 and Its Association with Uric Acid Levels and Systemic Inflammation: Relevance to Chronic Kidney Disease Progression

by Alexander Bozhidarov Blazhev, Krasimir Kostov, Borislav Ivanov Ignatov, Tsvetelina Eftimova, Tatyana Nedkova Simeonova and Svetla Ognyanova Blazheva

Int. J. Mol. Sci. 2026, 27(1), 540; https://doi.org/10.3390/ijms27010540 - 5 Jan 2026

Cited by 1 | Viewed by 1092

Abstract

Chronic kidney disease (CKD) is associated with chronic inflammation and metabolic dysregulation. While endothelin-1 (ET-1) has been extensively studied, the role of endothelin-2 (ET-2) in CKD remains poorly understood. This cross-sectional study included 76 participants, 12 healthy controls and 64 CKD patients, stratified into three groups based on estimated glomerular filtration rate (eGFR): Group 1 (eGFR ≥ 90 mL/min/1.73 m²), Group 2 (eGFR 45–89 mL/min/1.73 m²), and Group 3 (eGFR 15–44 mL/min/1.73 m²). Serum concentrations of ET-1, ET-2, ET-3, uric acid (UA), and inflammatory markers (hsCRP and IL-6) were measured. ET-2 levels were significantly higher in the advanced CKD group (median 24.49 pg/mL) compared to controls (median 19.32 pg/mL; p = 0.030). No significant differences were observed for ET-1 or ET-3 across groups. ET-2 levels positively correlated with UA (rho = 0.243, p = 0.036), hsCRP (rho = 0.241, p = 0.039), and IL-6 (rho = 0.244, p = 0.038). These findings suggest that ET-2 may represent a potential biomarker reflecting metabolic and inflammatory dysregulation in CKD and highlight its possible relevance in disease severity assessment. Full article

(This article belongs to the Special Issue Molecular Insights and Novel Therapeutics in Chronic Kidney Disease)

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17 pages, 4001 KB

Open AccessArticle

Plumericin Modulates the AhR–NFκB–Nrf2 Signaling Network to Counteract Indoxyl Sulfate-Induced Intestinal Epithelial Cells Impairment

by Rosaria Margherita Rispoli, Stefan Schwaiger, Ada Popolo, Giuseppina Autore, Marco Gargaro, Hermann Stuppner and Stefania Marzocco

Int. J. Mol. Sci. 2026, 27(1), 293; https://doi.org/10.3390/ijms27010293 - 27 Dec 2025

Cited by 2 | Viewed by 1143

Abstract

Intestinal impairment plays a pivotal role in many chronic conditions, including chronic kidney disease (CKD), a progressive disorder affecting over 800 million people worldwide. CKD does not only affect the kidney, but it is recognized as a systemic condition characterized by chronic low-grade inflammation, that contributes to disease progression and associated complications. The intestine is one of the major sources of CKD-associated inflammation, also due to the production and accumulation of some uremic toxins, normally excreted by healthy kidneys, such as indoxyl sulfate (IS). IS is a pro-inflammatory and pro-oxidant protein-bound uremic toxin that increases intestinal epithelial permeability, promotes microbial translocation, and enhances inflammatory and oxidative responses. Although IS-induced intestinal damage has been documented, the underlying molecular mechanisms and effective therapeutic strategies to counteract its effects remain to be elucidated. Against this backdrop in the present study, we investigated the impact of plumericin, an iridoid spironolactone, on IS-induced intestinal impairment using IEC-6, an intestinal epithelial cells model. In IS-treated IEC-6, plumericin reduces apoptosis, inhibits inflammation and oxidative stress, and restores epithelial wound repair. In these conditions plumericin also promotes Nrf-2 and inhibits NF-kB and AhR activation induced by IS. Moreover, the same inhibitory effect of plumericin on inflammation and oxidative stress and in promoting wound repair is also observed in the presence of IS and pro-inflammatory stimuli, as occurs in CKD considering the associated systemic low-grade inflammation. These findings suggest that plumericin may represent a promising therapeutic candidate for intestinal impairment in CKD acting with an integrated mechanism. Full article

(This article belongs to the Special Issue Molecular Insights and Novel Therapeutics in Chronic Kidney Disease)

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35 pages, 10424 KB

Open AccessReview

Molecular and Genetic Determinants of Nephrocalcinosis: Mechanisms, Genotype–Phenotype Correlations, and Precision Medicine

by Setalia Popa, Andrei Cristian Grădinaru, Elena Emanuela Braha, Mihaela Grămescu, Ramona Babici, Cristina Ailenei and Lăcrămioara Ionela Butnariu

Int. J. Mol. Sci. 2026, 27(8), 3616; https://doi.org/10.3390/ijms27083616 - 18 Apr 2026

Viewed by 754

Abstract

Nephrocalcinosis, defined as the deposition of calcium salts within the renal parenchyma, represents a radiologic and pathologic endpoint shared by a broad spectrum of metabolic and monogenic disorders. Advances in genomic medicine have identified more than 30 genes involved in tubular transport, mineral and acid–base homeostasis, oxalate metabolism, mitochondrial function, ciliary signaling, and nephron development, reframing nephrocalcinosis as a heterogeneous manifestation of discrete molecular defects rather than a single disease entity. Despite this diversity, these conditions converge on common physicochemical pathways of tubular supersaturation, crystal nucleation, growth, and intrarenal retention. These processes are amplified by the intrinsic vulnerability of the renal medulla—characterized by hyperosmolality, hypoxia, and slow tubular flow—and by epithelial injury, loss of crystallization inhibitors, and impaired ciliary signaling. Distinct genotype–phenotype signatures, including age at onset, biochemical profiles, and extrarenal manifestations, provide important diagnostic clues and help differentiate major monogenic entities. The increasing availability of targeted gene panels, whole-exome sequencing, and whole-genome sequencing has substantially improved diagnostic yield, particularly in pediatric populations. Molecular diagnosis now directly informs therapeutic decision-making and long-term management, enabling a shift toward precision nephrology. This narrative review integrates genetic, mechanistic, and clinical perspectives to illustrate how molecular diagnosis reshapes the evaluation, prognosis, and treatment of nephrocalcinosis. Full article

(This article belongs to the Special Issue Molecular Insights and Novel Therapeutics in Chronic Kidney Disease)

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18 pages, 1133 KB

Open AccessReview

Therapeutic Strategies Targeting the Kidney–Liver–Immune–Heart Network: Circadian and Mechanosensory Pathways in CKD-Associated Cardiac Injury

by Yuya Yoshida, Kohei Fukuoka, Tomohito Tanihara, Kengo Hamamura, Akito Tsuruta, Satoru Koyanagi, Shigehiro Ohdo and Naoya Matsunaga

Int. J. Mol. Sci. 2026, 27(8), 3436; https://doi.org/10.3390/ijms27083436 - 11 Apr 2026

Cited by 1 | Viewed by 921

Abstract

The present review discusses vitamin A/retinoid metabolism as a cross-organ axis in which hepatic clock-dependent retinoid handling may affect immune clock gene expression through the stimulation of retinoic acid 6–Janus kinase 2–signal transducer and activator of transcription 5 signaling, potentially promoting pro-inflammatory monocyte states. We further highlight mechanosensory signaling as a second convergent layer that integrates hemodynamic forces with tissue microenvironmental cues. Among these pathways, G protein-coupled receptor 68, a proton- and flow-sensitive G protein-coupled receptor, is discussed as a representative druggable node linking mechanical and inflammatory signaling in chronic kidney disease-associated cardiac injury. Finally, we outline potential therapeutic directions, including (i) circadian alignment/chronopharmacology, (ii) modulation of retinoid metabolism and signaling, and (iii) targeted inhibition of primary immune and mechanosensory effectors. Full article

(This article belongs to the Special Issue Molecular Insights and Novel Therapeutics in Chronic Kidney Disease)

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23 pages, 743 KB

Open AccessReview

Molecular Mechanisms of APOL1-Associated Kidney Disease

by Charlotte Delrue, Reinhart Speeckaert and Marijn M. Speeckaert

Int. J. Mol. Sci. 2026, 27(6), 2863; https://doi.org/10.3390/ijms27062863 - 21 Mar 2026

Viewed by 1057

Abstract

The discovery of apolipoprotein L1 (APOL1) risk polymorphisms has significantly changed our knowledge of kidney disease susceptibility and development in African American populations. Several non-diabetic kidney disorders, such as focal segmental glomerulosclerosis (FSGS), collapsing glomerulopathy, HIV-associated nephropathy (HIVAN), and accelerated chronic kidney disease (CKD) development, are significantly more likely to occur in people with two coding variations, G1 and G2. The significance of context-dependent pathogenic processes is highlighted by the poor penetrance and remarkable phenotypic variety of APOL1-associated kidney disease, despite its substantial impact. This review synthesizes current knowledge of APOL1 biology through a molecular framework, emphasizing gain-of-toxic-function effects of risk variants in podocytes, dysregulated ion fluxes, mitochondrial dysfunction, impaired proteostasis, and activation of innate immune and inflammatory signaling pathways. We describe how the well-recognized “second-hit” paradigm has a biological basis, driven by strong inducibility by interferons and immunological activation, as well as strict basal regulation of APOL1 expression. Lastly, we explore future approaches to precision nephrology and highlight translational advancements, such as APOL1 gene-silencing techniques. This review provides a mechanistic roadmap for translating APOL1 biology into targeted therapeutic strategies by integrating genetics, cell biology, immunology, and systems-level approaches. Full article

(This article belongs to the Special Issue Molecular Insights and Novel Therapeutics in Chronic Kidney Disease)

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