2-Deoxy-glucose ameliorates the peritoneal mesothelial and endothelial barrier function perturbation occurring due to Peritoneal Dialysis fluids exposure.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

Sodium-Glucose Transporter 2 (SGLT2) Inhibitors and Iron Deficiency in Heart Failure and Chronic Kidney Disease: A Literature Review.

Heart failure (HF) and chronic kidney disease (CKD) are associated with high mortality. In both disorders, impaired iron homeostasis, mostly in the form of a functional iron deficiency, is a frequent co-morbidity. In HF, functional iron deficiency and management by i.v. iron supplementation have been proven to affect both prognosis and functional capacity. In the same context, iron supplementation is routine for the adequate management of renal anemia in CKD. In numerous recent studies in HF and in CKD, sodium-glucose transporter 2 (SGLT2) inhibitor treatment has been proven to significantly reduce mortality. Furthermore, the same trials showed that these drugs alleviate iron deficiency and anemia. These effects of SGLT2 inhibitors may be due to an amelioration of inflammation with reduced interleukin-6 (IL-6) and to an enhancement of autophagy with increased sirtuin 1 (SIRT1), both associated with modified production of hepcidin and enhanced ferritinophagy. However, the exact pathogenic basis of the beneficial SGLT2 inhibitor action is not fully elucidated. Nevertheless, effects on iron homeostasis might be a potential explanatory mechanism for the powerful SGLT2 inhibitors' cardiovascular and renal outcome benefits. In addition, the interaction between iron supplementation and SGLT2 inhibitors and its potential impact on prognosis remains to be clarified by future studies. This review represents a significant effort to explore the complex relationships involved, seeking to elucidate the intricate mechanisms by which SGLT2 inhibitors influence iron homeostasis.

Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis.

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.

Remedies for Kidney Ailments in Physica by Hildegard von Bingen (1098-1179).

OBJECTIVES: Hildegard von Bingen (Hildegardis Bingensis; Saint Hildegard), the Sibyl of the Rhine (AD 1098-1179), was a Benedictine abbess, musician, poet, writer, counselor, and healer. As an influential personality of the 12th century, she was advisor of kings, princes, and bishops. Her medical work is collected in 2 books (AD 1152-1163): Physica and Causae et Curae. We aimed to investigate the characteristics of the nephrology-oriented remedies in Physica and compare these with the respective remedies in De Materia Medica (AD 1st century) by Dioscorides Pedanios Anazarbeus. MATERIALS AND METHODS: Physica is a collection of 9 volumes with an inventory of plants, trees, elements, stones, animals, and metals and describes the associated natural therapeutic properties. We studied all 293 plants (230 herbaceous plants, and 63 trees) in this treatise and recorded all nephrology-related remedies. In addition, we recorded the treatment indications of the same remedies in De Materia Medica. Nephrology-oriented material was defined as any item with nephrology-related pharmacological action (diuretic) or indication (eg, dysuria, nephritis, stones, sand, dropsy). Our findings are presented as simple descriptive statistics. RESULTS: Among all plants, there were 15 (5.1%) of nephrological interest (11 herbaceous plants and 4 trees). Only some of the natural ingredients mentioned in Physica were found with the same indication in the ancient text, De Materia Medica (9 of 15). The nephrological treatment indications described in Physica included dysuria, nephritic pain, and lithiasis in 87% and dropsy (edema) in 13.0%, which is comparable with 10% in De Materia Medica. CONCLUSIONS: Physica provides a reliable account of medicine in the 12th century as it was practiced by the clergy for generations. It also incorporates Hildegard's personal observations and contemporary folk remedies. This fact is supported by the limited similarity of nephrological remedies in Hildegard's Physica with the respective remedies in De Materia Medica.

Publications With Nephrological Themes Appearing Diachronically in the PubMed Bibliographical Database.

OBJECTIVES: Nephrology in the last 50 years has undergone important scientific developments, which have formally revolutionized clinical practice, including renal biopsy, renal replacement therapy, and transplantation. The understanding of the pathogenesis and the clinical course of renal disease has also steadily improved, resulting in renewal of definitions, classifications, and therapeutics in nephrology. In this context, publications with nephrological content are also expanding. The aim of this bibliographic study was to analyze publications related to nephrology-specific key words in the PubMed database. MATERIALS AND METHODS: We included the key words "nephrology," "acute renal failure," "renal biopsy," "hemodialysis," "peritoneal dialysis," and "renal transplantation" as search terms in PubMed in May 2022. We also used the term "kidney" as an alternative to "renal." RESULTS: "Nephrology" appeared 185 545 times in searches, with its appearance expanding in the past 3 decades since 1948. The term "acute renal failure" was found in 1932 in 1 publication and in a total number of 92 278 publications. Renal biopsy appeared since 1943 in 18 048 publications. "Hemodialysis" appeared in 182 730 citations, with the first in 1915. "Peritoneal dialysis" appeared in 32 266 citations for the first time in 1901 and in 1946 in human application. One publication on "renal transplantation" appeared in 1946, with 106 075 total publications related to renal transplantation. CONCLUSIONS: We viewed a clear expansion of nephro-logical publications in the past decades. Hemodialysis remains the most frequently used term in nephrology-related publications. Historical analysis of the PubMed database is useful as a tool to understand the research and publication trends in nephrology, as we approach the new era of precision medicine.

Successful Shrinkage of a Giant Cutaneous Squamous Cell Carcinoma with Immunotherapy in a Kidney Transplant Recipient.

A 56-year-old male living donor kidney transplant recipient presented with a giant cutaneous squamous cell carcinoma in his right parotid region. Programmed radiotherapy had been previously terminated due to lesion ulceration and bleeding. He was characterized as a terminal case. We applied cemiplimab, which is an immune checkpoint inhibitor against the pro-grammed cell death receptor PD-1. After 6 months, the cutaneous squamous cell carcinoma had shrunk and had stopped bleeding. The patient was treated with methylprednisolone, cyclosporine, and mycophenolate mofetil during this period. He had 2 rejection episodes defined as doubling baseline serum creatinine with no other explanation. Both episodes were successfully treated with intravenous methylprednisolone, while immunotherapy was postponed for 10 days. In both cases, serum creatinine returned to baseline within 1 week. Immune checkpoint inhibitors are indicated for invasive cutaneous squamous cell carcinoma therapy, and the risk of acute rejection should not prevent the use of these agents in kidney transplant recipients, because immune checkpoint inhibitors may enhance the quantity and quality of life of such patients.

Tumor Necrosis Factor-α G-308A Polymorphism and Sporadic IgA Nephropathy: A Meta-Analysis Using a Genetic Model-Free Approach.

Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine, involved in the pathogenesis and progression of immunoglobulin A nephropathy (IgAN). A bi-allelic polymorphism in the promoter region, at position -308 (G/A) of the TNF-α gene (rs1800629) is associated with an increased TNF-a production. However, several previous association studies of TNF-α G-308A polymorphism and IgAN rendered contradictory findings. The objective of the present study is to shed light on these inconclusive results and clarify the role of TNF-α and any possible contribution of this factor in the development and progression of sporadic IgAN. Therefore, a meta-analysis of all available genetic association studies relating the TNF-α G-308A polymorphism to the risk for development and/or progression of IgAN was conducted. Seven studies were included in the meta-analysis. Three of them included populations of European descent (Caucasians) and four involved Asians. The generalized odds ratio (ORG) was used to estimate the risk for the development and/or progression of the disease. Overall, the meta-analysis did not detect any significant association between the G-308A variant and both the risk of developing IgAN and the risk for progression of IgAN. In conclusion, these results suggest that TNF-α does not constitute a key component in the genetic architecture of sporadic IgAN. However, further evidence deciphering the influence of TNF-α on IgAN is still needed.

Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells.

Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1ß and TGF-ß1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.

Therapeutic Advances in Diabetic Kidney Disease.

Although sodium glucose co-transporter type 2 (SGLT-2) inhibitors were initially introduced as glucose-lowering medications, it was later discovered that cardiorenal protection is the most important treatment effect of these agents. A triad of landmark trials consistently showed the benefits of SGLT-2 inhibitors on kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD), irrespective of the presence or absence of Type 2 diabetes (T2D). Furthermore, finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that safely and effectively improved cardiorenal outcomes in a large Phase 3 clinical trial program that included >13,000 patients with T2D and a wide spectrum of CKD. These two drug categories have shared and distinct mechanisms of action, generating the hypothesis that an overadditive cardiorenal benefit with their combined use may be biologically plausible. In this article, we describe the mechanism of action, and we provide an overview of the evidence for cardiorenal protection with SGLT-2 inhibitors and the nonsteroidal MRA finerenone in patients with CKD associated with T2D.

Indoleamine 2,3-dioxygenase controls purinergic receptor-mediated ischemia-reperfusion injury in renal tubular epithelial cells.

OBJECTIVES: Ischemia-reperfusion (I-R) injury is the most common cause of acute kidney injury (AKI). Experimental studies have shown that indoleamine 2,3-dioxygenase 1 (IDO) and the purinergic receptor P2X7 contribute to kidney I-R injury. We evaluated whether there is an interplay between IDO and P2X7 in the pathogenesis of I-R injury. METHODS: Primary renal proximal tubular epithelial cells (RPTECs) were subjected to anoxia or reoxygenation with or without specific inhibitors. Cell imaging, colorimetric assays, and Western blotting were used. RESULTS: Cell imaging revealed that inhibition of IDO, or all the purinergic receptors with an ATPase, or specific inhibition of P2X7 rescued the cells from anoxia or reoxygenation-induced cell death. This was confirmed with LDH release assay, which also detected the ferroptotic nature of cell death due to reoxygenation. On the contrary, activated cleaved caspase 3 increased during anoxia, showing that apoptosis prevails. All the aforementioned treatments prevented caspase increase. Both anoxia and reoxygenation increased extracellular ATP, IDO, and P2X7 expression. IDO remained unaffected by the above-mentioned treatments. On the contrary, treatment with apyrase or inhibition of P2X7decreased extracellular ATP and P2X7 expression, which are also decreased by inhibition of IDO. The first indicates a positive feedback loop regarding P2X7 activation, expression and function, while the latter implies that IDO controls P2X7 expression. CONCLUSIONS: In RPRECs subjected to anoxia or reoxygenation, IDO is upregulated, increasing P2X7 and contributing to anoxia or reoxygenation-induced cell death. Clarifying the molecular mechanisms implicated in kidney I-R injury is of particular interest since it may lead to new therapeutic strategies against AKI.

Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells.

Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium-glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1ß, IL-8, and TGF-ß1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches.

Hypertension in Dialysis Patients: Diagnostic Approaches and Evaluation of Epidemiology.

Whereas hypertension is an established cardiovascular risk factor in the general population, the contribution of increased blood pressure (BP) to the huge burden of cardiovascular morbidity and mortality in patients receiving dialysis continues to be debated. In a large part, this controversy is attributable to particular difficulties in the accurate diagnosis of hypertension. The reverse epidemiology of hypertension in dialysis patients is based on evidence from large cohort studies showing that routine predialysis or postdialysis BP measurements exhibit a U-shaped or J-shaped association with cardiovascular or all-cause mortality. However, substantial evidence supports the notion that home or ambulatory BP measurements are superior to dialysis-unit BP recordings in diagnosing hypertension, in detecting evidence of target-organ damage and in prognosticating the all-cause death risk. In the first part of this article, we explore the accuracy of different methods of BP measurement in diagnosing hypertension among patients on dialysis. In the second part, we describe how the epidemiology of hypertension is modified when the assessment of BP is based on dialysis-unit versus home or ambulatory recordings.

Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis.

Renal fibrosis (RF) constitutes the common end-point of all kinds of chronic kidney disease (CKD), regardless of the initial cause of disease. The aim of the present study was to identify the key players of fibrosis in the context of diabetic nephropathy (DN). A systematic review and meta-analysis of all available genetic association studies regarding the genes that are included in signaling pathways related to RF were performed. The evaluated studies were published in English and they were included in PubMed and the GWAS Catalog. After an extensive literature review and search of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, eight signaling pathways related to RF were selected and all available genetic association studies of these genes were meta-analyzed. ACE, AGT, EDN1, EPO, FLT4, GREM1, IL1B, IL6, IL10, IL12RB1, NOS3, TGFB1, IGF2/INS/TH cluster, and VEGFA were highlighted as the key genetic components driving the fibrosis process in DN. The present systematic review and meta-analysis indicate, as key players of fibrosis in DN, sixteen genes. However, the results should be interpreted with caution because the number of studies was relatively small.

Inhibition of Malate Dehydrogenase-2 Protects Renal Tubular Epithelial Cells from Anoxia-Reoxygenation-Induced Death or Senescence.

Ischemia-reperfusion injury is the leading cause of acute kidney injury. Reactive oxygen species (ROS) production causes cell death or senescence. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate dehydrogenase-2 (MDH-2) decreases hypoxia-inducible factor-1α and oxidative stress and protects from apoptotic or ferroptotic cell death. Inhibition of MDH-2 decreased reoxygenation-induced upregulation of p53 and p21, restored the levels of the proliferation marker Ki-67, and prevented the upregulation of the senescence marker beta-galactosidase and interleukin-1ß production. MDH-2 inhibition reduced the reoxygenation-induced upregulation of ATP, but the alterations of critical cell metabolism enzymes allowed enough ATP production to prevent cell energy collapse. Thus, inhibition of the Krebs cycle at the level of MDH-2 protects RPTECs from anoxia-reoxygenation-induced death or senescence. MDH-2 may be a promising pharmaceutical target against ischemia-reperfusion injury.

Fatigue and Quality of Life in Children with Chronic Kidney Disease.

Background: This study investigates the effect of chronic kidney disease (CKD) stage on fatigue and health-related quality of life (HRQoL) in the pediatric population. Material and Methods: The PedsQL (Pediatric Quality of Life Inventory) Multidimensional Fatigue Scale (subcategories: general, sleep/rest, and cognitive fatigue) and HRQoL Generic Core Scales (subcategories: physical, emotional, social, and school functioning) questionnaires were completed by 30 patients aged from 7 to 18 years old with CKD stage 2−4, CKD stage 5 on dialysis (CKD 5D), and kidney transplantation (KTx), as well as their parents. Results: Both low "Total Fatigue" and "Total HRQoL" scores were reported in 16.7% of patients. "Sleep/Rest Fatigue", "Emotional Functioning", and "School functioning" were the lowest scored subcategories. CKD 5D/KTx patients presented lower "Sleep/Rest Fatigue" (p = 0.022) and, more frequently, low "School Functioning" scores (p = 0.029). The "Total HRQoL" score was correlated to the "Total Fatigue" score (rs = 0.625, p < 0.001). A low "Sleep/Rest Fatigue" score was associated with low "Physical Functioning", "School Functioning", and "Total HRQoL" scores (p = 0.016, p = 0.001, and p = 0.047 respectively). Parents' HRQoL score was lower than patients' score on "Physical Functioning" (p = 0.040) and "School Functioning" subcategories (p = 0.045). Conclusions: Fatigue and disturbed HRQoL are mostly observed in CKD 5D and KTx pediatric patients, and are associated with sleep disorders and school dysfunction. Fatigue affects HRQoL, which is perceived as more deteriorated by the patients' parents.

Rituximab Administered for Recurrent Membranous Nephropathy in a Kidney Transplant Recipient Did Not Eliminate Donor-Specific Antibodies.

Chronic active antibody-mediated rejection is the leading cause of kidney transplant failure. Although various immunosuppressive agents have been tested, rituximab included, presently there is no effective treatment. There are reports about the beneficial role of certain immunosuppressive protocols that include rituximab to reduce donor-specific antibodies, the cause of chronic active antibody-mediated rejection. If an immunosuppressive agent reduces donor-specific antibodies, its administration before the occurrence of chronic active antibody-mediated rejection may be beneficial. We describe a case of a renaltransplantrecipient with recurrent membranous nephropathy and recent development of donor-specific antibodies but without histological evidence of active antibody-mediated rejection. The patient received 3 weekly doses of rituximab for recurrent membranous nephropathy, and complete remission was achieved. One year after, he has preserved an excellentrenal function without proteinuria. However, repeated measurements of donor-specific antibodies revealed that rituximab only modestly reduced donor-specific antibodies. Donor-specific antibody levels remained considerably higher than the laboratory reference value. Thus,rituximab alone may not have a role to prevent chronic active antibody- mediated rejection in patients with donor-specific antibodies.

Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury.

Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence-associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild-type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence-associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation-associated post-IRI chronic kidney dysfunction.

VItamin K In PEritonial DIAlysis (VIKIPEDIA): Rationale and study protocol for a randomized controlled trial.

Vascular calcification (VC) is an active process, resulting from the disturbance of balance between inhibitors and promoters of calcification, in favor of the latter. Matrix Gla Protein, a powerful inhibitor of VC, needs vitamin K to become active. In vitamin K depletion, plasma levels of the inactive form of MGP, dephosphorylated, uncarboxylated MGP (dp-ucMGP) are increased and associated with VC and cardiovascular (CV) outcomes. End Stage Renal Disease (ESRD) patients have increased circulating dp-ucMGP levels and accelerated VC. VItamin K In PEritoneal DIAlysis (VIKIPEDIA) is a prospective, randomized, open label, placebo-controlled trial, evaluating the effect of vitamin K2 supplementation on arterial stiffness and CV events in ESRD patients undergoing peritoneal dialysis (PD). Forty-four PD patients will be included in the study. At baseline, dp-ucMGP and pulse-wave velocity (PWV) will be assessed and then patients will be randomized (1:1 ratio) to vitamin K (1000 µg MK-7/day) or placebo for 1.5 years. The primary endpoint of this trial is the change in PWV in the placebo group as compared to the treatment group. Secondary endpoints are the occurrence of CV events, mortality, changes in PD adequacy, change in 24-hour ambulatory blood pressure indexes and aortic systolic blood pressure and changes in calcium/phosphorus/parathormone metabolism. VIKIPEDIA is a new superiority randomized, open label, placebo-controlled trial aiming to determine the effect of vitamin K2 supplementation on VC, CV disease and calcium/phosphorus metabolism, in PD patients. Trial registration: The protocol of this study is registered at ClinicalTrials.gov with identification number NCT04900610 (25 May 2021).