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15 pages, 2546 KiB

Open AccessArticle

Upregulation in Inflammation and Collagen Expression in Perirenal but Not in Mesenteric Adipose Tissue from Diabetic Munich Wistar Frömter Rats

by Elena Vega-Martín, Daniel González-Moreno, Marta Sanz-Gómez, Ana Karen Guzmán-Aguayo, Francisco Javier Manzano-Lista, Angela Schulz, Isabel Aránguez, Reinhold Kreutz and María S. Fernández-Alfonso

Int. J. Mol. Sci. 2023, 24(23), 17008; https://doi.org/10.3390/ijms242317008 - 30 Nov 2023

Cited by 1 | Viewed by 746

Abstract

Perirenal adipose tissue (PRAT) surrounding the kidney is emerging as a player and novel independent risk factor in diabetic kidney disease (DKD); DKD is a complication of diabetes and is a major cause of increased cardiovascular (CV) risk and CV mortality in affected [...] Read more.

Perirenal adipose tissue (PRAT) surrounding the kidney is emerging as a player and novel independent risk factor in diabetic kidney disease (DKD); DKD is a complication of diabetes and is a major cause of increased cardiovascular (CV) risk and CV mortality in affected patients. We determined the effect of diabetes induction on (i) kidney and CV damage and (ii) on the expression of proinflammatory and profibrotic factors in both the PRAT and the mesenteric adipose tissue (MAT) of Munich Wistar Frömter (MWF) rats. The 16-week-old male MWF rats (n = 10 rats/group) were fed standard chow (MWF-C) or a high-fat/high-sucrose diet for 6 weeks together with low-dose streptozotocin (15 mg/kg i.p.) at the start of dietary exposure (MWF-D). Phenotyping was performed at the end of treatment through determining water intake, urine excretion, and oral glucose tolerance; use of the homeostatic model assessment–insulin resistance index (HOMA-IR) evidenced the development of overt diabetes manifestation in MWF-D rats. The kidney damage markers Kim-1 and Ngal were significantly higher in MWF-D rats, as were the amounts of PRAT and MAT. A diabetes-induced upregulation in IL-1, IL-6, Tnf-α, and Tgf-β was observed in both the PRAT and the MAT. Col1A1 was increased in the PRAT but not in the MAT of MWF-D, whereas IL-10 was lower and higher in the PRAT and the MAT, respectively. Urinary albumin excretion and blood pressure were not further increased by diabetes induction, while heart weight was higher in the MWF-D. In conclusion, our results show a proinflammatory and profibrotic in vivo environment in PRAT induced by diabetes which might be associated with kidney damage progression in the MWF strain. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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20 pages, 5611 KiB

Open AccessArticle

Engineered Bone Marrow Stem Cell-Sheets Alleviate Renal Damage in a Rat Chronic Glomerulonephritis Model

by Bin Wang, Kyungsook Kim, Mi Tian, Sumako Kameishi, Lili Zhuang, Teruo Okano and Yufeng Huang

Int. J. Mol. Sci. 2023, 24(4), 3711; https://doi.org/10.3390/ijms24043711 - 13 Feb 2023

Cited by 1 | Viewed by 2298

Abstract

Although mesenchymal stem cell (MSC)-based regenerative therapy is being developed for the treatment of kidney diseases, cell delivery and engraftment still need to be improved. Cell sheet technology has been developed as a new cell delivery method, to recover cells as a sheet [...] Read more.

Although mesenchymal stem cell (MSC)-based regenerative therapy is being developed for the treatment of kidney diseases, cell delivery and engraftment still need to be improved. Cell sheet technology has been developed as a new cell delivery method, to recover cells as a sheet form retaining intrinsic cell adhesion proteins, which promotes its transplantation efficiency to the target tissue. We thus hypothesized that MSC sheets would therapeutically reduce kidney disease with high transplantation efficiency. When the chronic glomerulonephritis was induced by two injections of the anti-Thy 1.1 antibody (OX-7) in rats, the therapeutic efficacy of rat bone marrow stem cell (rBMSC) sheet transplantation was evaluated. The rBMSC-sheets were prepared using the temperature-responsive cell-culture surfaces and transplanted as patches onto the surface of two kidneys of each rat at 24 h after the first injection of OX-7. At 4 weeks, retention of the transplanted MSC-sheets was confirmed, and the animals with MSC-sheets showed significant reductions in proteinuria, glomerular staining for extracellular matrix protein, and renal production of TGFß1, PAI-1, collagen I, and fibronectin. The treatment also ameliorated podocyte and renal tubular injury, as evidenced by a reversal in the reductions of WT-1, podocin, and nephrin and by renal overexpression of KIM-1 and NGAL. Furthermore, the treatment enhanced gene expression of regenerative factors, and IL-10, Bcl-2, and HO-1 mRNA levels, but reduced TSP-1 levels, NF-kB, and NAPDH oxidase production in the kidney. These results strongly support our hypothesis that MSC-sheets facilitated MSC transplantation and function, and effectively retarded progressive renal fibrosis via paracrine actions on anti-cellular inflammation, oxidative stress, and apoptosis and promoted regeneration. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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11 pages, 3984 KiB

Open AccessArticle

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis

by Peter Korsten, Eva Baier, Samy Hakroush and Björn Tampe

Int. J. Mol. Sci. 2023, 24(4), 3072; https://doi.org/10.3390/ijms24043072 - 04 Feb 2023

Cited by 4 | Viewed by 1828

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis [...] Read more.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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11 pages, 1458 KiB

Open AccessArticle

Serum and Urine Biomarkers Related to Kidney Fibrosis Predict Kidney Outcome in Czech Patients with IgA Nephropathy

by Michaela Neprasova, Dita Maixnerova, Nadja Sparding, Federica Genovese, Morten Asser Karsdal, Helena Koprivova, Marek Kollar, Miloslav Suchanek, Zdenka Hruskova and Vladimir Tesar

Int. J. Mol. Sci. 2023, 24(3), 2064; https://doi.org/10.3390/ijms24032064 - 20 Jan 2023

Cited by 4 | Viewed by 1465

Abstract

We evaluated biomarkers related to kidney fibrosis for the outcome of patients with IgA nephropathy (IgAN). Clinical parameters (estimated glomerular filtration rate, hypertension, proteinuria) and histological findings were assessed in 134 patients with IgAN at the time of diagnosis and followed up prospectively [...] Read more.

We evaluated biomarkers related to kidney fibrosis for the outcome of patients with IgA nephropathy (IgAN). Clinical parameters (estimated glomerular filtration rate, hypertension, proteinuria) and histological findings were assessed in 134 patients with IgAN at the time of diagnosis and followed up prospectively (mean follow-up time, 56.5 months). We measured biomarkers of collagen and laminin turnover in serum and urine collected at the time of kidney biopsy using a novel enzyme-linked immunosorbent assay. Linear discriminant analysis and logistic regression models were used to predict the patient’s kidney outcome. Five serum and urine biomarkers of laminin and collagen turnover (sLG1M, sPRO-C3, sPRO-C6, uPRO-C6/Cr, uC3M/Cr) could significantly differentiae IgAN patients with a worse prognosis. Clinical parameters (glomerular filtration rate (GFR), proteinuria) distinguished patients at risk of IgAN progression with a specificity of 87.3% and a sensitivity of 45.2% (area under the curve-AUC 0.751). The addition of the biomarkers significantly increased the prognostic ability with a specificity of 85.1% and a sensitivity of 73.3% (AUC 0.905). We have identified three serum (sLG1M, sPRO-C3, sPRO-C6) and two urinary markers (uPRO-C6/Cr, u-C3M /Cr) that significantly improve the prognostic ability of markers of kidney function to identify an IgAN patient’s risk of progressing to ESKD. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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14 pages, 3250 KiB

Open AccessArticle

PLVAP as an Early Marker of Glomerular Endothelial Damage in Mice with Diabetic Kidney Disease

by Elena E. Wolf, Anne Steglich, Friederike Kessel, Hannah Kröger, Jan Sradnick, Simone Reichelt-Wurm, Kathrin Eidenschink, Miriam C. Banas, Eckhard Wolf, Rüdiger Wanke, Florian Gembardt and Vladimir T. Todorov

Int. J. Mol. Sci. 2023, 24(2), 1094; https://doi.org/10.3390/ijms24021094 - 06 Jan 2023

Cited by 2 | Viewed by 2121

Abstract

Plasmalemma vesicle-associated protein (PLVAP) is the main component of endothelial diaphragms in fenestrae, caveolae, and transendothelial channels. PLVAP is expressed in the adult kidney glomerulus upon injury. Glomerular endothelial injury is associated with progressive loss of kidney function in diabetic kidney disease (DKD). [...] Read more.

Plasmalemma vesicle-associated protein (PLVAP) is the main component of endothelial diaphragms in fenestrae, caveolae, and transendothelial channels. PLVAP is expressed in the adult kidney glomerulus upon injury. Glomerular endothelial injury is associated with progressive loss of kidney function in diabetic kidney disease (DKD). This study aimed to investigate whether PLVAP could serve as a marker for glomerular endothelial damage in DKD. Glomerular PLVAP expression was analyzed in different mouse models of DKD and their respective healthy control animals using automatic digital quantification of histological whole kidney sections. Transgenic mice expressing a dominant-negative GIP receptor (GIPR^dn) in pancreatic beta-cells as a model for diabetes mellitus (DM) type 1 and black and tan brachyuric (BTBR) ob/ob mice, as a model for DM type 2, were used. Distinct PLVAP induction was observed in all diabetic models studied. Traces of glomerular PLVAP expression could be identified in the healthy control kidneys using automated quantification. Stainings for other endothelial injury markers such as CD31 or the erythroblast transformation-specific related gene (ERG) displayed no differences between diabetic and healthy groups at the time points when PLVAP was induced. The same was also true for the mesangial cells marker α8Integrin, while the podocyte marker nephrin appeared to be diminished only in BTBR ob/ob mice. Glomerular hypertrophy, which is one of the initial morphological signs of diabetic kidney damage, was observed in both diabetic models. These findings suggest that PLVAP is an early marker of glomerular endothelial injury in diabetes-induced kidney damage in mice. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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16 pages, 2126 KiB

Open AccessArticle

Imbalance in Bone Morphogenic Proteins 2 and 7 Is Associated with Renal and Cardiovascular Damage in Chronic Kidney Disease

by Francisco Javier Manzano-Lista, Marta Sanz-Gómez, Daniel González-Moreno, Elena Vega-Martín, Marta Gil-Ortega, Angela Schulz, Miguel Ángel Rubio, Gema Ruiz-Hurtado, Luis Miguel Ruilope, Isabel Aránguez, Reinhold Kreutz and María S. Fernández-Alfonso

Int. J. Mol. Sci. 2023, 24(1), 40; https://doi.org/10.3390/ijms24010040 - 20 Dec 2022

Cited by 3 | Viewed by 1764

Abstract

Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 [...] Read more.

Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 were determined by ELISA in CKD patients (stages I–III; n = 95) and Munich Wistar Frömter (MWF) rats. Age-matched Wistar rats were used as a control. The expression of BMP-2, BMP-7, and profibrotic and calcification factors was determined in kidney and perivascular adipose tissues (PVAT). BMP-2 was higher in stage III CKD patients compared to control subjects. BMP-7 was lower at any CKD stage compared to controls, with a significant further reduction in stage III patients. A similar imbalance was observed in MWF rats together with the increase in systolic (SBP) and diastolic blood pressure (DBP), or pulse wave velocity (PWV). MWF exhibited elevated urinary albumin excretion (UAE) and renal expression of BMP-2 or kidney damage markers, Kim-1 and Ngal, whereas renal BMP-7 was significantly lower than in Wistar rats. SBP, DBP, PWV, UAE, and plasma creatinine positively correlated with the plasma BMP-2/BMP-7 ratio. Periaortic and mesenteric PVAT from MWF rats showed an increased expression of BMP-2 and profibrotic and calcification markers compared to Wistar rats, together with a reduced BMP-7 expression. BMP-2 and BMP-7 imbalance in plasma, kidney, and PVATs is associated with vascular damage, suggesting a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, their combined analysis stratified by CKD stages might be of clinical interest to provide information about the degree of renal and vascular damage in CKD. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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16 pages, 1976 KiB

Open AccessArticle

The Importance of Toll-like Receptor 9 Expression on Monocytes and Dendritic Cells in the Context of Epstein–Barr Virus Infection in the Immunopathogenesis of Primary Glomerulonephritis

by Iwona Smarz-Widelska, Sebastian Mertowski, Paulina Mertowska, Izabela Korona-Głowniak, Anna Hymos, Ewelina Grywalska and Wojciech Załuska

Int. J. Mol. Sci. 2022, 23(19), 11796; https://doi.org/10.3390/ijms231911796 - 05 Oct 2022

Cited by 1 | Viewed by 1512

Abstract

Toll-like receptor 9 (TLR9) is activated by unmethylated cytosine-phosphate-guanosine (CpG) dinucleotides found in the genomes of pathogens such as Epstein–Barr virus (EBV). The aim of this study was to determine the role of TLR9 in the immunopathogenesis of IgA nephropathy (IgAN) and membranoproliferative [...] Read more.

Toll-like receptor 9 (TLR9) is activated by unmethylated cytosine-phosphate-guanosine (CpG) dinucleotides found in the genomes of pathogens such as Epstein–Barr virus (EBV). The aim of this study was to determine the role of TLR9 in the immunopathogenesis of IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) in the context of Epstein–Barr virus (EBV) infection. For this purpose, the frequency of TLR9-positive monocytes and dendritic cells (DCs, i.e., BDCA-1; myeloid dendritic cells, and BDCA-2; plasmocytoid dendritic cells) was studied, and a quantitative analysis of the concentration of TLR9 in the serum of patients diagnosed with IgAN and MPGN was undertaken. Higher frequencies of TLR9-positive DCs and monocytes in IgAN and MPGN patients were observed as compared with the control group. Patients diagnosed with GN exhibited a higher percentage of BDCA-1+CD19− and BDCA-2+CD123+ DCs than patients in the control group. Moreover, serum TLR9 concentration was shown to be significantly correlated with EBV DNA copy number/µg DNA, IgG, IgM, serum albumin, total protein in 24-h urine collection test and the frequency of BDCA-2+CD123+ DCs in peripheral blood. Our findings confirm that TLR9 may be involved in the development of IgAN and MPGN. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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21 pages, 4555 KiB

Open AccessArticle

Unravelling the Inflammatory Processes in the Early Stages of Diabetic Nephropathy and the Potential Effect of (S_s)-DS-ONJ

by Laura Gómez-Jaramillo, Fátima Cano-Cano, Elena M. Sánchez-Fernández, Carmen Ortiz Mellet, José M. García-Fernández, Martín Alcalá, Fabiola Álvarez-Gallego, Marta Iturregui, María del Carmen González-Montelongo, Antonio Campos-Caro, Ana I. Arroba and Manuel Aguilar-Diosdado

Int. J. Mol. Sci. 2022, 23(15), 8450; https://doi.org/10.3390/ijms23158450 - 30 Jul 2022

Cited by 3 | Viewed by 1658

Abstract

Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. The authors demonstrate that the glycolipid mimetic (S_s)-DS-ONJ is able to abolish inflammation via the induction of autophagy flux and [...] Read more.

Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. The authors demonstrate that the glycolipid mimetic (S_s)-DS-ONJ is able to abolish inflammation via the induction of autophagy flux and provokes the inhibition of inflammasome complex in ex vivo and in vitro models, using adult kidney explants from BB rats. The contribution of (S_s)-DS-ONJ to reducing inflammatory events is mediated by the inhibition of classical stress kinase pathways and the blocking of inflammasome complex activation. The (S_s)-DS-ONJ treatment is able to inhibit the epithelial-to-mesenchymal transition (EMT) progression, but only when the IL18 levels are reduced by the treatment. These findings suggest that (S_s)-DS-ONJ could be a novel, and multifactorial treatment for DN. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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15 pages, 3182 KiB

Open AccessArticle

Dosing Limitation for Intra-Renal Arterial Infusion of Mesenchymal Stromal Cells

by Anders Munk, Christina Søndergaard Duvald, Michael Pedersen, Stine Lohmann, Anna Krarup Keller, Bjarne Kuno Møller, Steffen Ringgaard, Niels Henrik Buus, Bente Jespersen and Marco Eijken

Int. J. Mol. Sci. 2022, 23(15), 8268; https://doi.org/10.3390/ijms23158268 - 27 Jul 2022

Cited by 5 | Viewed by 1734

Abstract

The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates [...] Read more.

The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates safety issues with MSCs in systemic circulation, it introduces new safety concerns in the kidneys. In a porcine model, we employed intra-renal arterial infusion of ten million allogenic adipose tissue-derived MSCs. In order to trigger any potential adverse events, a higher dose (hundred million MSCs) was also included. The kidney function was studied by magnetic resonance imaging after the MSC infusion and again at two weeks post-treatment. The kidneys were assessed by single kidney glomerular filtration rate (skGFR) measurements, histology and inflammation, and fibrosis-related gene expression. None of the measured parameters were affected immediately after the administration of ten million MSCs, but the administration of one hundred million MSCs induced severe adverse events. Renal perfusion was reduced immediately after MSC administration which coincided with the presence of microthrombi in the glomeruli and signs of an instant blood-mediated inflammatory reaction. At two weeks post-treatment, the kidneys that were treated with one hundred million MSCs showed reduced skGFR, signs of tissue inflammation, and glomerular and tubular damage. In conclusions, the intra-renal administration of ten million MSCs is well-tolerated by the porcine kidney. However, higher concentrations (one hundred million MSCs) caused severe kidney damage, implying that very high doses of intra-renally administered MSCs should be undertaken with caution. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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16 pages, 3860 KiB

Open AccessArticle

Urine-Derived Stem Cell-Secreted Klotho Plays a Crucial Role in the HK-2 Fibrosis Model by Inhibiting the TGF-β Signaling Pathway

by Sang-Heon Kim, Jeong-Ah Jin, Hyung Joon So, Sung Hoon Lee, Tae-Wook Kang, Jae-Ung Lee, Dae Eun Choi, Jin Young Jeong, Yoon-Kyung Chang, Hyunsu Choi, Youngjun Lee, Young-Kwon Seo and Hong-Ki Lee

Int. J. Mol. Sci. 2022, 23(9), 5012; https://doi.org/10.3390/ijms23095012 - 30 Apr 2022

Cited by 6 | Viewed by 2686

Abstract

Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor [...] Read more.

Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor against CKD. Urine-derived stem cells (UDSCs) have been identified as a novel stem cell source for kidney regeneration and CKD treatment because of their kidney tissue-specific origin. However, the relationship between UDSCs and Klotho in the kidneys is not yet known. In this study, we discovered that UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-inhibiting ability of UDSCs. Here, we suggest an alternative cell source that can overcome the limitations of MSCs through the synergetic effect of the origin specificity of UDSCs and the anti-fibrotic effect of Klotho. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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11 pages, 617 KiB

Open AccessReview

Current and Future Therapeutical Options in Alport Syndrome

by Jana Reiterová and Vladimír Tesař

Int. J. Mol. Sci. 2023, 24(6), 5522; https://doi.org/10.3390/ijms24065522 - 14 Mar 2023

Cited by 2 | Viewed by 3602

Abstract

Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in COL4A3 and COL4A4 genes with autosomal recessive or autosomal dominant transmission or in the COL4A5 gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic [...] Read more.

Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in COL4A3 and COL4A4 genes with autosomal recessive or autosomal dominant transmission or in the COL4A5 gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic hematuria, followed by proteinuria and chronic renal insufficiency with end-stage renal disease in young adults. Nowadays, there is no curative treatment available. The inhibitors of RAS (renin-angiotensin system) since childhood slow the progression of the disease. Sodium-glucose cotransporter-2 inhibitors seem to be promising drugs from DAPA-CKD (dapagliflozin–chronic kidney disease) study, but only a limited number of patients with Alport syndrome was included. Endothelin type A receptor and angiotensin II type 1 receptor combined inhibitors, and lipid-lowering agents are used in ongoing studies in patients with AS and focal segmental glomerulosclerosis (FSGS). Hydroxychloroquine in AS is studied in a clinical trial in China. Molecular genetic diagnosis of AS is crucial not only for prognosis prediction but also for future therapeutic options. Different types of mutations will require various types of gene, RNA, or protein therapy to improve the function, the of final protein product. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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18 pages, 337 KiB

Open AccessReview

Biomarker-Development Proteomics in Kidney Transplantation: An Updated Review

by Vittorio Sirolli, Luca Piscitani and Mario Bonomini

Int. J. Mol. Sci. 2023, 24(6), 5287; https://doi.org/10.3390/ijms24065287 - 09 Mar 2023

Cited by 1 | Viewed by 1752

Abstract

Kidney transplantation (KT) is the optimal therapeutic strategy for patients with end-stage renal disease. The key to post-transplantation management is careful surveillance of allograft function. Kidney injury may occur from several different causes that require different patient management approaches. However, routine clinical monitoring [...] Read more.

Kidney transplantation (KT) is the optimal therapeutic strategy for patients with end-stage renal disease. The key to post-transplantation management is careful surveillance of allograft function. Kidney injury may occur from several different causes that require different patient management approaches. However, routine clinical monitoring has several limitations and detects alterations only at a later stage of graft damage. Accurate new noninvasive biomarker molecules are clearly needed for continuous monitoring after KT in the hope that early diagnosis of allograft dysfunction will lead to an improvement in the clinical outcome. The advent of “omics sciences”, and in particular of proteomic technologies, has revolutionized medical research. Proteomic technologies allow us to achieve the identification, quantification, and functional characterization of proteins/peptides in biological samples such as urine or blood through supervised or targeted analysis. Many studies have investigated proteomic techniques as potential molecular markers discriminating among or predicting allograft outcomes. Proteomic studies in KT have explored the whole transplant process: donor, organ procurement, preservation, and posttransplant surgery. The current article reviews the most recent findings on proteomic studies in the setting of renal transplantation in order to better understand the effective potential of this new diagnostic approach. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

13 pages, 603 KiB

Open AccessReview

Serum Biomarkers of Renal Fibrosis: A Systematic Review

by Alice Barinotti, Massimo Radin, Irene Cecchi, Silvia Grazietta Foddai, Elena Rubini, Dario Roccatello and Savino Sciascia

Int. J. Mol. Sci. 2022, 23(22), 14139; https://doi.org/10.3390/ijms232214139 - 16 Nov 2022

Cited by 8 | Viewed by 1702

Abstract

Chronic kidney disease (CKD) is a widely diffuse pathological condition which deeply impacts upon an affected patient’s quality of life and its worldwide rate is predicted to further rise. The main biological mechanism underlying CKD is renal fibrosis, a non-reversible process representing, for [...] Read more.

Chronic kidney disease (CKD) is a widely diffuse pathological condition which deeply impacts upon an affected patient’s quality of life and its worldwide rate is predicted to further rise. The main biological mechanism underlying CKD is renal fibrosis, a non-reversible process representing, for the affected system, a point of no return of tissue damage and dysfunction, deeply reducing the possible therapeutic strategies at the disposal of physicians. The best tool clinicians can use to address the extent of renal fibrosis at any level (glomeruli, tubule-interstitium, vasculature) is kidney biopsy that, despite its overall safety, remains an invasive procedure showing some shortcomings. Thus, the identification of novel non-invasive renal fibrosis biomarkers would be of fundamental importance. Here, when systematically reviewing the available evidence on serological biomarkers associated with renal fibrosis evaluated in patients suffering from CKD in the last five years, we found that despite the presence of several promising biomarkers, the level of observed evidence is still very scattered. Probably, the use of multiple measures capable of addressing different aspects involved in this condition would be the most suitable way to capture the high complexity characterizing the renal fibrotic process, having consequently a great impact on clinical practice by maximizing prevention, diagnosis, and management. Full article

(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy 2.0)

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