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Background: Urate through NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent caspase-1 activation stimulates macrophages to secrete inteleukin-1β (IL-1β). Urate also enhances adaptive immunity indirectly through its effect on antigen presenting cells. In this study, the direct effect of urate on isolated primary human T-cells was evaluated. Methods: Isolated T-cells were cultured with or without monosodium urate crystals in the presence or not of the NLRP3 inflammasome inhibitor glyburide. Activated cleaved caspase-1 was assessed by means of western blotting, whereas caspase- 1 activity was measured colorimetrically in the cell lysates. IL-1β was measured in the supernatants by means of enzyme-linked immunosorbent assay. T-cell proliferation was assessed by means of bromodeoxyuridine labelling and immunoenzymatic detection. Results: Urate induced caspase-1 activation and IL-1β release by T-cells. It also induced proliferation of T-cells. Glyburide inhibited urate-induced caspase-1 activation, IL-1β secretion and proliferation. Conclusions: Urate, a well defined danger signal, stimulates directly human T-cells in a NLRP3 infmmasomela-dependent way. The subsequent IL-1β secretion could enhance inflammation, whereas expansion of T-cell clones could facilitate a subsequent adaptive immune response. [ABSTRACT FROM AUTHOR]

Background: Urate through Nacht Domain, Leucine-Rich Repeat, and pyrin domain-containing protein 3 (NALP3) dependent caspase-1 activation stimulates macrophages to secrete inteleukin-1β (IL-1β). Purinergic receptor P2X7 plays a role in the urate induced NALP3 activation. Urate also enhances adaptive immunity indirectly through its effect on antigen presenting cells. In this study, the direct effect of urate on primary human lymphocytes was evaluated. Methods: Lymphocytes were cultured with or without monosodium urate crystals in the presence or not of a P2X7 inhibitor. Caspase-1 activity was assessed colorimetrically in cell lysates and IL-1β was measured in supernatants with ELISA. Whole lymphocyte viability and proliferation, as well as T-cell proliferation were assessed by means of 2,3-bis- (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay and of flow cytometry respectively. Results: Urate induced caspase-1 activation and IL-1β release by lymphocytes. It also induced proliferation of whole lymphocytes and T-cells as well. P2X7 inhibitor abrogated lymphocyte proliferation. Conclusions: Urate, a well defined danger signal, stimulates directly human lymphocytes in a P2X7 dependent way. The subsequent IL-1β secretion could enhance inflammation, whereas expansion of lymphocyte clones could facilitate a subsequent adaptive immune response. [ABSTRACT FROM AUTHOR]

Introduction. Serotonin receptors are present in osteoblasts and osteoclasts, and serotonin affects bone metabolism. The association of plasma serotonin with markers of bone formation and bone resorption in hemodialysis patients was evaluated. Materials and Methods. Twenty-four hemodialysis patients (11 diabetics) and 22 healthy volunteers were enrolled into the study. Serotonin was assessed in platelet-free plasma, whereas the markers of osteoblastic activity N-terminal midfragment osteocalcin and total procollagen type-1 aminoterminal propeptide as well as the marker of osteoclastic activity beta-isomerized C-terminal cross-linked peptide of collagen type I were measured in serum. Serum intact parathyroid hormone was also assessed. Results. Serotonin did not significantly differ between hemodialysis patients and healthy volunteers. All evaluated markers of bone metabolism and intact parathyroid hormone were much higher in hemodialysis patients. Serotonin was significantly correlated with all evaluated markers of bone metabolism in hemodialysis patients. Serotonin was reversely related to the patients' age. Serotonin, osteocalcin, procollagen type-1 aminoterminal propeptide, and beta-isomerized C-terminal cross-linked peptide of collagen type I were much lower in diabetic hemodialysis patients. Conclusions. Serotonin may increase both bone formation and bone resorption in hemodialysis patients. The reverse relation of serotonin to patients' age as well as its lower levels in diabetic hemodialysis patients indicate that low plasma serotonin may contribute to the higher incidence of low-turnover bone disease that characterizes old and diabetic hemodialysis patients. [ABSTRACT FROM AUTHOR]

Hyperkalemia is a relative common and sometimes life threatening electorlyte disorder. Although its symptomatic treatment is relatively easy, since precise therapeutic algorithms are available, its differential diagnosis is more complicated. The present review aims to unfold the differential diagnosis of hypekalemia using a pathophysiological, albeit clinically useful, approach. The basic elements of potassium homeostasis are provided, the causes of hyperkalemia are categorized and analysed and finally the required for the diferrential diagnosis laboratory tests are mentioned. Hippokratia 2012, 16, 4: 294-302 [ABSTRACT FROM AUTHOR]

Introduction. Angiogenesis plays a role in the pathogenesis of coronary heart disease (CHD) and diabetes mellitus (DM) pathology, and certain angiogenic factors are increased by inflammation. The aim of this study was to evaluate plasma angiogenin and vascular endothelial factor A (VEGFA) levels in hemodialysis patients, as well as the effect of CHD, DM, and inflammation on these markers. Materials and Methods. Sixty-six hemodialysis patients were enrolled in the study, of whom 22 (33.3%) suffered from CHD , 22 (33.3%) from DM, and 28 (42.4%) from inflammation. They were compared with 24 healthy volunteers. Plasma angiogenin and VEGFA were assessed by means of enzyme-linked immunosorbent assay, and serum C-reactive protein was measured with an immunoturbidimetric method. These markers were compared between hemodialysis patients with and without CHD, DM, and inflammation. Results. Compared to healthy volunteers, plasma angiogenin was significantly higher in hemodialysis patients (263.57 ± 65.95 ng/mL versus 499.15 ± 175.68 ng/mL; P < .001). Similarly, plasma VEGFA was markedly increased in hemodialysis patients (median, 60.50 pg/mL; range, 280 pg/mL), compared to healthy volunteers (median, 28.84 pg/mL; range, 59.40 pg/mL; P < .001). Neither angiogenin nor VEGFA levels differed significantly between hemodialysis patients with and without CHD, DM, or inflammation. Conclusions. Plasma angiogenin and VEGFA levels are markedly increased in hemodialysis patients, but not associated with CHD, DM, or inflammation among hemodialysis patients. [ABSTRACT FROM AUTHOR]

Besides extracellular matrix production, fibroblasts are able to produce various cytokines. Their ubiquitous position makes fibroblasts appropriate cells for sensing various noxious stimuli and for attracting immune cells in the affected area. In the present study the effect of lipopolysaccharide (LPS) and cobalt chloride (CoCl2) on the above fibroblasts functions were evaluated in primary human skin fibroblasts cultures. Collagen, matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1, transforming growth factor-β1, interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) were measured in fibroblasts culture supernatants. Fibroblasts proliferation and viability were assessed as well. Hypoxia inducible factor-1α and the phosphorylated p65 portion of NF-κB were assessed in fibroblasts protein extracts. LPS and CoCl2 had a minor effect on fibrosis related factors in human primary fibroblasts, possibly due to the absence of interplay with other cell types in the used experimental system. On the contrary both LPS and CoCl2 increased significantly IL-8. LPS also increased considerably MCP-1, but CoCl2 decreased it. Thus LPS and CoCl2 induce a sentinel, nevertheless not identical, phenotype in primary human fibroblasts. The last disparity could result in different body response to infectious or hypoxic noxious stimuli. [ABSTRACT FROM AUTHOR]

Hemodialysis (HD) patients are particularly predisposed to infections. It seems that the HD procedure per se as well as disturbances in both innate and adaptive immunity significantly contribute to this susceptibility. Infections are the major cause of morbidity and the second cause of death following cardiovascular events in HD patients. Episodes of bacteremia and pneumonia account for the majority of severe infections in this population. In addition to these bacterial infections another common problem in HD units is the blood transmitted viral infections, particularly infections caused by hepatitis B virus, hepatitis C virus and Human immunodeficiency virus. A number of safety concerns exist for limiting the spread of these viral infections among HD patients and the staff of the unit. The aim of the present review is to present in a concise albeit practical form the difficult aspect of infections in HD. For practical reasons the review is separated in two parts. The present first part covers bacteremia and respiratory infections, while the second part will cover blood transmitted viral infections. [ABSTRACT FROM AUTHOR]

Abstract Background Although renal involvement in advanced haematological malignancies is common, glomerulonephritis associated with lymphoproliferative disorders is rare, and the related pathogenetic mechanisms are still poorly understood. We present a rare case of chronic lymphocytic leukaemia(CLL)-associated focal segmental glomerulosclerosis with nephrotic-range proteinuria. Case presentation A 53-year-old Caucasian man, previously healthy, with no history of hypertension, alcohol use or smoking presented with rapid weight gain, massive peripheral oedema, and hypertension. Laboratory findings included a white blood cell count of 49,800 cells/mm3 with an absolute lymphocyte count of 47,000 cells/mm3, serum albumin of 2.3 g/dL, urea 65 mg/dL, and creatinine 1.5 mg/dL. A 24-hour urine collection contained 7.1 g protein and significant haematuria. A peripheral blood smear showed mature lymphocytosis and smudge cells. Diagnostic imaging showed mild paraaortic lymphadenopathy with no renal abnormalities. Bone marrow aspiration and trephine biopsy showed diffuse and focal infiltration with B-CLL lymphocytes. Percutaneous renal biopsy revealed total sclerosis in 3/21(14%) of the glomeruli and focal and segmental solidification and sclerosis in 4/21 (19%) glomeruli. A regimen of fludarabine, cyclophosphamide and rituximab was successful in inducing remission of the CLL and clinical resolution of the nephritic-range proteinuria. Conclusions A multidisciplinary approach to monitor both the malignancy and the glomerular lesions is crucial for the optimal management of paraneoplastic glomerulonephritis. Although chemotherapy with fludarabine, cyclophosphamide and rituximab successfully treated CLL-associated nephrotic syndrome in our patient, further studies are required to confirm efficacy in this setting.

Background: In males with end stage renal disease biochemical hypogonadism is a frequent finding. Testosterone and sex hormone binding globulin (SHBG) have been associated with insulin resistance, a well-known condition in uremia. The aim of the present study was to investigate in males on chronic hemodialysis the relationship of testosterone and SHBG serum levels with insulin resistance., Methods: In a cross-sectional study we enrolled men treated with chronic hemodialysis who did not suffer from an acute illness or other endocrinopathy, as well as primary hypogonadism, and were not hospitalised. Diabetes mellitus, diabetic nephropathy or previous transplantation were not exclusion criteria. As controls we used a community-based group of healthy males matched for age and Body Mass Index (BMI). We assessed the BMI (kg/m 2 ) from body weight and height, the body fat content (%) by bioelectrical impedance and serum testosterone (ng/ml), SHBG (nmol/L) and estradiol (pg/ml) by standard methods. Testosterone < 3.25 ng/ml defined biochemical hypogonadism. In non-diabetic males, we calculated the homeostasis model assessment index (HOMA-R), an estimate of insulin resistance, from serum fasting insulin and glucose., Results: 27 men (age 54.4 ± 19 years) on chronic hemodialysis (treatment duration 29.1 ± 14.4 months) and 51 healthy men (age 47.1 ± 9.6 years) were included. In men on hemodialysis vs. healthy men there were increased serum levels of SHBG (40.9 ± 26.9 vs. 27.6 ± 11.9 nmol/L; p = 0.031) and a significantly enhanced frequency of biochemical hypogonadism (22.2 vs. 3.9%; p = 0.011). In cases without diabetes (n = 22) a significant correlation was observed between the HOMA-R (r = -0.586, p = 0.004) and the fasting insulin levels (r = -0.650, p = 0.001) on the one hand and the serum SHBG levels on the other., Conclusions: Our findings confirm enhanced prevalence of biochemical hypogonadism in males on chronic hemodialysis. In non-diabetic cases the serum levels of SHBG correlated with serum insulin and insulin resistance., (© 2024. The Author(s).)

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.

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 (OR G ) 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 OR G 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; OR G = 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.

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 (OR G ) 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.

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.

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.

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-1β and TGF-β1. 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.

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.

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-1β, IL-8, and TGF-β1. 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.

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.

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., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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.

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-1β 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.

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.

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)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Leon J. Schurgers received institutional grants from Bayer, Boehringer Ingelheim, NattoPharma, and Immuno Diagnostic Systems (IDS, but this does not alter our adherence to PLOS ONE policies on sharing data and materials.