Biomedicines

Research

11 pages, 458 KiB

Open AccessArticle

Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease

by Francesco Baratta, Laura D’Erasmo, Alessia Di Costanzo, Ilaria Umbro, Daniele Pastori, Francesco Angelico and Maria Del Ben

Biomedicines 2022, 10(3), 720; https://doi.org/10.3390/biomedicines10030720 - 19 Mar 2022

Cited by 7 | Viewed by 2784

Abstract

The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in [...] Read more.

The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients. The present study is a post hoc analysis of the Plinio Study (ClinicalTrials.gov: NCT04036357). PNPLA3, TM6SF2, MBOAT7 and GCKR genes were analyzed by using real-time PCR with TaqMan probes. Glomerular filtration rate (GFR) was estimated with CKD-EPI. We analyzed 538 NAFLD; 47.2% had GFR < 90 mL/min/1.73 m² while 5.9% had GFR < 60 mL/min/1.73 m². The distribution of genotypes was superimposable according to GFR cut-offs. Results from the multivariable regression model did not show any correlation between genotypes and renal function. Conversely, metabolic syndrome was highly associated with GFR < 90 mL/min/1.73 m² (odds ratio (OR): 1.58 [1.10–2.28]) and arterial hypertension with GFR < 60 mL/min/1.73 m² (OR: 1.50 [1.05–2.14]). In conclusion, the association between NAFLD and CKD might be related to the shared metabolic risk factors rather than the genetic NAFLD background. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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21 pages, 5857 KiB

Open AccessArticle

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

by Adrian Cordido, Marta Vizoso-Gonzalez, Laura Nuñez-Gonzalez, Alberto Molares-Vila, Maria del Pilar Chantada-Vazquez, Susana B. Bravo and Miguel A. Garcia-Gonzalez

Biomedicines 2022, 10(2), 290; https://doi.org/10.3390/biomedicines10020290 - 27 Jan 2022

Cited by 1 | Viewed by 3527

Abstract

(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient [...] Read more.

(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient therapeutic approaches are th6us needed. In this context, the present work has a principal aim to find novel molecular pathways, as well as new therapeutic targets, involved in the hepatic cystogenesis process. (2) Methods: Quantitative proteomics based on SWATH–MS technology were performed comparing hepatic proteomes of Wild Type and mutant/polycystic livers in a polycystic kidney disease (PKD) murine model (Pkd1^cond/cond;Tam-Cre^−/+). (3) Results: We identified several proteins altered in abundance, with two-fold cut-off up-regulation or down-regulation and an adjusted p-value significantly related to hepatic cystogenesis. Then, we performed enrichment and a protein–protein analysis identifying a cluster focused on hepatic fibrinogens. Finally, we validated a selection of targets by RT-qPCR, Western blotting and immunohistochemistry, finding a high correlation with quantitative proteomics data and validating the fibrinogen complex. (4) Conclusions: This work identified a novel molecular pathway in cystic liver disease, highlighting the fibrinogen complex as a possible new therapeutic target for PLD. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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9 pages, 623 KiB

Open AccessArticle

Early Chronic Kidney Disease (G1-G3a) in Combination with Steatosis as a Predictor of Incident Ischemic Heart Disease: A Longitudinal Study in Non-Diabetic Koreans

by Sung-Bum Lee, Byoung-Jin Park, Yong-Jae Lee and Dong-Hyuk Jung

Biomedicines 2021, 9(10), 1358; https://doi.org/10.3390/biomedicines9101358 - 29 Sep 2021

Cited by 3 | Viewed by 1959

Abstract

Hepatic steatosis and chronic kidney disease (CKD) in the advanced stages are closely related to cardiovascular diseases. Despite the potential connection between early CKD (G1-G3a) and hepatic steatosis on cardiometabolic risks, few studies have revealed their causal link to ischemic heart disease (IHD). [...] Read more.

Hepatic steatosis and chronic kidney disease (CKD) in the advanced stages are closely related to cardiovascular diseases. Despite the potential connection between early CKD (G1-G3a) and hepatic steatosis on cardiometabolic risks, few studies have revealed their causal link to ischemic heart disease (IHD). We prospectively investigated the combined effect of CKD in earlier stages and hepatic steatosis on incident IHD risk in large-scale, non-diabetic Koreans. Data were assessed from 16,531 participants without diabetes from the Health Risk Assessment Study (HERAS) and Korea Health Insurance Review and Assessment (HIRA) data. We divided the study population into four groups according to the existence of early CKD and hepatic steatosis: controls, early CKD only, hepatic steatosis only, and both early CKD and hepatic steatosis. We prospectively assessed hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD using multivariate Cox proportional-hazard regression models over a 50-month period. During the follow-up period, 326 (2.0%) patients developed IHD. HRs of IHD in the four groups were 1.00 (controls), 1.26 (95% CI 0.72–2.19), 1.19 (95% CI 0.90–1.57) and 1.76 (95% CI 1.04–2.97), respectively, after adjusting for potential confounding variables. Even less than stage 3A, CKD could precede and predict IHD in patients with hepatic steatosis. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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24 pages, 3104 KiB

Open AccessArticle

Protein-Bound Uremic Toxins Induce Reactive Oxygen Species-Dependent and Inflammasome-Mediated IL-1β Production in Kidney Proximal Tubule Cells

by Milos Mihajlovic, Merle M. Krebber, Yi Yang, Sabbir Ahmed, Valeria Lozovanu, Daria Andreeva, Marianne C. Verhaar and Rosalinde Masereeuw

Biomedicines 2021, 9(10), 1326; https://doi.org/10.3390/biomedicines9101326 - 26 Sep 2021

Cited by 18 | Viewed by 3543

Abstract

Protein bound-uremic toxins (PBUTs) are not efficiently removed by hemodialysis in chronic kidney disease (CKD) patients and their accumulation leads to various co-morbidities via cellular dysfunction, inflammation and oxidative stress. Moreover, it has been shown that increased intrarenal expression of the NLRP3 receptor [...] Read more.

Protein bound-uremic toxins (PBUTs) are not efficiently removed by hemodialysis in chronic kidney disease (CKD) patients and their accumulation leads to various co-morbidities via cellular dysfunction, inflammation and oxidative stress. Moreover, it has been shown that increased intrarenal expression of the NLRP3 receptor and IL-1β are associated with reduced kidney function, suggesting a critical role for the NLRP3 inflammasome in CKD progression. Here, we evaluated the effect of PBUTs on inflammasome-mediated IL-1β production in vitro and in vivo. Exposure of human conditionally immortalized proximal tubule epithelial cells to indoxyl sulfate (IS) and a mixture of anionic PBUTs (UT mix) increased expression levels of NLRP3, caspase-1 and IL-1β, accompanied by a significant increase in IL-1β secretion and caspase-1 activity. Furthermore, IS and UT mix induced the production of intracellular reactive oxygen species, and caspase-1 activity and IL-1β secretion were reduced in the presence of antioxidant N-acetylcysteine. IS and UT mix also induced NF-κB activation as evidenced by p65 nuclear translocation and IL-1β production, which was counteracted by an IKK inhibitor. In vivo, using subtotal nephrectomy CKD rats, a significant increase in total plasma levels of IS and the PBUTs, kynurenic acid and hippuric acid, was found, as well as enhanced urinary malondialdehyde levels. CKD kidney tissue showed an increasing trend in expression of NLRP3 inflammasome components, and a decreasing trend in superoxide dismutase-1 levels. In conclusion, we showed that PBUTs induce inflammasome-mediated IL-1β production in proximal tubule cells via oxidative stress and NF-κB signaling, suggesting their involvement in disease-associated inflammatory processes. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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14 pages, 1677 KiB

Open AccessArticle

Bile Duct Ligation Upregulates Expression and Function of L-Amino Acid Transporter 1 at Blood–Brain Barrier of Rats via Activation of Aryl Hydrocarbon Receptor by Bilirubin

by Xiaoke Zheng, Hanyu Yang, Lan Qin, Siqian Wang, Lei Xie, Lu Yang, Weimin Kong, Liang Zhu, Li Liu and Xiaodong Liu

Biomedicines 2021, 9(10), 1320; https://doi.org/10.3390/biomedicines9101320 - 26 Sep 2021

Cited by 2 | Viewed by 2534

Abstract

Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1). We aimed to investigate whether liver failure induced by bile duct ligation (BDL) increases [...] Read more.

Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1). We aimed to investigate whether liver failure induced by bile duct ligation (BDL) increases levels of brain AAAs by affecting the expression and function of LAT1. The LAT1 function was assessed using the brain distribution of gabapentin. It was found that BDL significantly increased levels of gabapentin, phenylalanine, and tryptophan in the cortex, hippocampus, and striatum of rats, and upregulated the expression of total LAT1 protein in hippocampus and striatum as well as cortex membrane LAT1 protein. HCMEC/D3 served as in vitro BBB model, and the data showed that both the serum of BDL rats and bilirubin induced LAT1 expression and function, while bilirubin oxidase almost abolished the upregulation of LAT1 protein by bilirubin and the serum of BDL rats. The enhanced function and expression of LAT1 were also observed in the hippocampus and striatum of hyperbilirubinemia rats. Both aryl hydrocarbon receptor (AhR) antagonist α-naphthoflavone and AhR silencing obviously attenuated the upregulation of LAT1 protein by bilirubin or omeprazole. This study provides the first evidence that BDL upregulates LAT1 at the rat BBB, attributed to the activation of AhR by the increased plasma bilirubin. The results highlight the mechanisms causing BDL-increased levels of brain AAAs and their physiological significance. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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24 pages, 3778 KiB

Open AccessArticle

Caveolin-1 in Kidney Chronic Antibody-Mediated Rejection: An Integrated Immunohistochemical and Transcriptomic Analysis Based on the Banff Human Organ Transplant (B-HOT) Gene Panel

by Alessandro Gambella, Antonella Barreca, Simona Osella-Abate, Emanuel Bottasso, Manuela Maria Giarin, Mauro Papotti, Luigi Biancone, Jasna Metovic, Giammarco Collemi, Paola Cassoni and Luca Bertero

Biomedicines 2021, 9(10), 1318; https://doi.org/10.3390/biomedicines9101318 - 26 Sep 2021

Cited by 9 | Viewed by 3045

Abstract

Caveolin-1 overexpression has previously been reported as a marker of endothelial injury in kidney chronic antibody-mediated rejection (c-ABMR), but conclusive evidence supporting its use for daily diagnostic practice is missing. This study aims to evaluate if Caveolin-1 can be considered an immunohistochemical surrogate [...] Read more.

Caveolin-1 overexpression has previously been reported as a marker of endothelial injury in kidney chronic antibody-mediated rejection (c-ABMR), but conclusive evidence supporting its use for daily diagnostic practice is missing. This study aims to evaluate if Caveolin-1 can be considered an immunohistochemical surrogate marker of c-ABMR. Caveolin-1 expression was analyzed in a selected series of 22 c-ABMR samples and 11 controls. Caveolin-1 immunohistochemistry proved positive in peritubular and glomerular capillaries of c-ABMR specimens, irrespective of C4d status whereas all controls were negative. Multiplex gene expression profiling in c-ABMR cases confirmed Caveolin-1 overexpression and identified additional genes (n = 220) and pathways, including MHC Class II antigen presentation and Type II interferon signaling. No differences in terms of gene expression (including Caveolin-1 gene) were observed according to C4d status. Conversely, immune cell signatures showed a NK-cell prevalence in C4d-negative samples compared with a B-cell predominance in C4d-positive cases, a finding confirmed by immunohistochemical assessment. Finally, differentially expressed genes were observed between c-ABMR and controls in pathways associated with Caveolin-1 functions (angiogenesis, cell metabolism and cell–ECM interaction). Based on our findings, Caveolin-1 resulted as a key player in c-ABMR, supporting its role as a marker of this condition irrespective of C4d status. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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Graphical abstract

12 pages, 3511 KiB

Open AccessArticle

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

by Camilla Grønkjær Jensen, Michael Schou Jensen, Stine Julie Tingskov, Peter Olinga, Rikke Nørregaard and Henricus A. M. Mutsaers

Biomedicines 2021, 9(8), 856; https://doi.org/10.3390/biomedicines9080856 - 22 Jul 2021

Cited by 7 | Viewed by 2775

Abstract

Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute [...] Read more.

Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to the wide variety of comorbidities observed in these patients. To illustrate, catabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) gives rise to numerous biologically active metabolites implicated in CKD progression. Here, we evaluated the effect of antagonizing IDO on renal fibrogenesis. To this end, we antagonized IDO using 1-methyl-D-tryptophan (1-MT) and BMS-98620 in TGF-β-treated murine precision-cut kidney slices (mPCKS) and in mice subjected to unilateral ureteral obstruction (UUO). The fibrotic response was evaluated on both the gene and protein level using qPCR and western blotting. Our results demonstrated that treatment with 1-MT or BMS-985205 markedly reduced TGF-β-mediated fibrosis in mPCKS, as seen by a decreased expression of collagen type 1, fibronectin, and α-smooth muscle actin. Moreover, IDO protein expression clearly increased following UUO, however, treatment of UUO mice with either 1-MT or BMS-986205 did not significantly affect the gene and protein expression of the tested fibrosis markers. However, both inhibitors significantly reduced the renal deposition of collagen in UUO mice as shown by Sirius red and trichrome staining. In conclusion, this study demonstrates that IDO antagonism effectively mitigates fibrogenesis in mPCKS and reduces renal collagen accumulation in UUO mice. These findings warrant further research into the clinical application of IDO inhibitors for the treatment of renal fibrosis. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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14 pages, 3613 KiB

Open AccessArticle

TGF-β1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-β1 Signaling Pathway

by Jung-Yoon Heo, Jun-Young Do, Yunmee Lho, A-Young Kim, Sang-Woon Kim and Seok-Hui Kang

Biomedicines 2021, 9(7), 839; https://doi.org/10.3390/biomedicines9070839 - 19 Jul 2021

Cited by 15 | Viewed by 3074

Abstract

We investigated the effect of SB525334 (TGF-β receptor type 1 (TβRI) inhibitor) on the epithelial to mesenchymal transition (EMT) signaling pathway in human peritoneal mesothelial cells (HPMCs) and a peritoneal fibrosis mouse model. In vitro experiments were performed using HPMCs. HPMCs [...] Read more.

We investigated the effect of SB525334 (TGF-β receptor type 1 (TβRI) inhibitor) on the epithelial to mesenchymal transition (EMT) signaling pathway in human peritoneal mesothelial cells (HPMCs) and a peritoneal fibrosis mouse model. In vitro experiments were performed using HPMCs. HPMCs were treated with TGF-β1 and/or SB525334. In vivo experiments were conducted with male C57/BL6 mice. The 0.1% chlorhexidine gluconate (CG) was intraperitoneally injected with or without SB52534 administration by oral gavage. Mice were euthanized after 28 days. EMT using TGF-β1-treated HPMCs included morphological changes, cell migration and invasion, EMT markers and collagen synthesis. These pathological changes were reversed by co-treatment with SB525334. CG injection was associated with an increase in peritoneal fibrosis and thickness, which functionally resulted in an increase in the glucose absorption via peritoneum. Co-treatment with SB525334 attenuated these changes. The levels of EMT protein markers and immunohistochemical staining for fibrosis showed similar trends. Immunofluorescence staining for EMT markers showed induction of transformed cells with both epithelial and mesenchymal cell markers, which decreased upon co-treatment with SB525334. SB525334 effectively attenuated the TGF-β1-induced EMT in HPMCs. Cotreatment with SB525334 improved peritoneal thickness and fibrosis and recovered peritoneal membrane function in a peritoneal fibrosis mouse model. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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12 pages, 4904 KiB

Open AccessArticle

Chronic Kidney Disease Induced by Cisplatin, Folic Acid and Renal Ischemia Reperfusion Induces Anemia and Promotes GATA-2 Activation in Mice

by Gabriel Rufino Estrela, Leandro Ceotto Freitas-Lima, Alexandre Budu, Adriano Cleis de Arruda, Mauro Sergio Perilhão, Ricardo Ambrósio Fock, Jonatan Barrera-Chimal and Ronaldo Carvalho Araújo

Biomedicines 2021, 9(7), 769; https://doi.org/10.3390/biomedicines9070769 - 2 Jul 2021

Cited by 11 | Viewed by 3899

Abstract

Anemia is a common feature of chronic kidney disease (CKD). It is a process related to erythropoietin deficiency, shortened erythrocyte survival, uremic erythropoiesis inhibitors, and disordered iron homeostasis. Animal models of CKD-induced anemia are missing and would be desirable in order to study [...] Read more.

Anemia is a common feature of chronic kidney disease (CKD). It is a process related to erythropoietin deficiency, shortened erythrocyte survival, uremic erythropoiesis inhibitors, and disordered iron homeostasis. Animal models of CKD-induced anemia are missing and would be desirable in order to study anemia mechanisms and facilitate the development of novel therapeutic tools. We induced three different models of CKD in mice and evaluated the development of anemia characteristics. Mice were subjected to unilateral ischemia-reperfusion or received repeated low doses of cisplatin or folic acid to induce nephropathy. Renal function, kidney injury and fibrotic markers were measured to confirm CKD. Moreover, serum hemoglobin, ferritin and erythropoietin were analyzed. Renal mRNA levels of HIF-2α, erythropoietin, hepcidin, GATA-2, and GATA-2 target genes were also determined. All three CKD models presented increased levels of creatinine, urea, and proteinuria. Renal up-regulation of NGAL, KIM-1, and TNF-α mRNA levels was observed. Moreover, the three CKD models developed fibrosis and presented increased fibrotic markers and α-SMA protein levels. CKD induced decreased hemoglobin and ferritin levels and increased erythropoietin levels in the serum. Renal tissue showed decreased erythropoietin and HIF-2α mRNA levels, while an increase in the iron metabolism regulator hepcidin was observed. GATA-2 transcription factor (erythropoietin repressor) mRNA levels were increased in all CKD models, as well as its target genes. We established three models of CKD-induced anemia, regardless of the mechanism and severity of kidney injury. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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Review

Jump to: Research, Other

34 pages, 905 KiB

Open AccessReview

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

by Veronika A. Prikhodko, Natalia N. Bezborodkina and Sergey V. Okovityi

Biomedicines 2022, 10(2), 274; https://doi.org/10.3390/biomedicines10020274 - 26 Jan 2022

Cited by 31 | Viewed by 8232

Abstract

Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic [...] Read more.

Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 1678 KiB

Open AccessReview

Kidney Cancer and Chronic Kidney Disease: Too Close for Comfort

by Pedro Caetano Pinto, Cindy Rönnau, Martin Burchardt and Ingmar Wolff

Biomedicines 2021, 9(12), 1761; https://doi.org/10.3390/biomedicines9121761 - 24 Nov 2021

Cited by 10 | Viewed by 3030

Abstract

Kidney cancer and chronic kidney disease are two renal pathologies with very different clinical management strategies and therapeutical options. Nonetheless, the cellular and molecular mechanisms underlying both conditions are closely related. Renal physiology is adapted to operate with a limited oxygen supply, making [...] Read more.

Kidney cancer and chronic kidney disease are two renal pathologies with very different clinical management strategies and therapeutical options. Nonetheless, the cellular and molecular mechanisms underlying both conditions are closely related. Renal physiology is adapted to operate with a limited oxygen supply, making the kidney remarkably equipped to respond to hypoxia. This tightly regulated response mechanism is at the heart of kidney cancer, leading to the onset of malignant cellular phenotypes. Although elusive, the role of hypoxia in chronic kidney diseases is emerging as related to fibrosis, a pivotal factor in decaying renal function. The present review offers a perspective on the common biological traits shared between kidney cancer and chronic kidney disease and the available and prospective therapies for both conditions. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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19 pages, 1441 KiB

Open AccessReview

Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis

by Chanbin Lee, Minju Kim, Jinsol Han, Myunghee Yoon and Youngmi Jung

Biomedicines 2021, 9(11), 1598; https://doi.org/10.3390/biomedicines9111598 - 2 Nov 2021

Cited by 29 | Viewed by 3881

Abstract

Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) [...] Read more.

Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 1197 KiB

Open AccessReview

Lipid Disorders in NAFLD and Chronic Kidney Disease

by Meng Yang, Chang-An Geng, Xinguang Liu and Min Guan

Biomedicines 2021, 9(10), 1405; https://doi.org/10.3390/biomedicines9101405 - 6 Oct 2021

Cited by 16 | Viewed by 4302

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and is characterized by exaggerated lipid accumulation, inflammation and even fibrosis. It has been shown that NAFLD increases the risk of other chronic diseases, particularly chronic kidney disease (CKD). [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and is characterized by exaggerated lipid accumulation, inflammation and even fibrosis. It has been shown that NAFLD increases the risk of other chronic diseases, particularly chronic kidney disease (CKD). Lipid in excess could lead to liver and kidney lesions and even end-stage disease through diverse pathways. Dysregulation of lipid uptake, oxidation or de novo lipogenesis contributes to the toxic effects of ectopic lipids which promotes the development and progression of NAFLD and CKD via triggering oxidative stress, apoptosis, pro-inflammatory and profibrotic responses. Importantly, dyslipidemia and release of pro-inflammatory cytokines caused by NAFLD (specifically, nonalcoholic steatohepatitis) are considered to play important roles in the pathological progression of CKD. Growing evidence of similarities between the pathogenic mechanisms of NAFLD and those of CKD has attracted attention and urged researchers to discover their common therapeutic targets. Here, we summarize the current understanding of molecular aberrations underlying the lipid metabolism of NAFLD and CKD and clinical evidence that suggests the relevance of these pathways in humans. This review also highlights the orchestrated inter-organ cross-talk in lipid disorders, as well as therapeutic options and opportunities to counteract NAFLD and CKD. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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11 pages, 719 KiB

Open AccessReview

Nonalcoholic Fatty Liver Disease and the Kidney: A Review

by Ilaria Umbro, Francesco Baratta, Francesco Angelico and Maria Del Ben

Biomedicines 2021, 9(10), 1370; https://doi.org/10.3390/biomedicines9101370 - 1 Oct 2021

Cited by 11 | Viewed by 2868

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with several extrahepatic manifestations such as cardiovascular disease and sleep apnea. Furthermore, NAFLD is reported to be associated with an increased risk of incident chronic kidney disease (CKD). Inflammation and oxidative stress are suggested to be [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is associated with several extrahepatic manifestations such as cardiovascular disease and sleep apnea. Furthermore, NAFLD is reported to be associated with an increased risk of incident chronic kidney disease (CKD). Inflammation and oxidative stress are suggested to be the key factors involved in the inflammatory mechanisms and pathways linking NAFLD to CKD and are responsible for both the pathogenesis and the progression of CKD in NAFLD patients. This review aims to provide a more comprehensive overview of the association between CKD and NAFLD, also considering the effect of increasing severity of NAFLD. A PubMed search was conducted using the terms “non-alcoholic fatty liver disease AND kidney”. In total, 537 articles were retrieved in the last five years and 12 articles were included in the qualitative analysis. Our results showed that CKD developed more frequently in NAFLD patients compared to those without NAFLD. This association persisted after adjustment for traditional risk factors and according to the severity of NAFLD. Therefore, patients with NAFLD should be considered at high risk of CKD. Intensive multidisciplinary surveillance over time is needed, where hepatologists and nephrologists must act together for better and earlier treatment of NAFLD patients. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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Other

Jump to: Research, Review

9 pages, 969 KiB

Open AccessCase Report

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19

by Désirée Tampe, Peter Korsten, Sebastian C. B. Bremer, Martin S. Winkler and Björn Tampe

Biomedicines 2021, 9(12), 1841; https://doi.org/10.3390/biomedicines9121841 - 5 Dec 2021

Cited by 9 | Viewed by 3487

Abstract

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of [...] Read more.

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver’s excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches)

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