scholarly journals P0218SHEAR WAVE ELASTOGRAPHY AS A NON-INVASIVE MARKER OF RENAL FIBROSIS IN NATIVE DIABETIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Charmaine Sia ◽  
Emmett Wong Tsz Yeung Wong ◽  
Christopher Cheang Han Leo ◽  
Weng Kin Wong ◽  
Boon Wee Teo ◽  
...  

Abstract Background and Aims Current assessment of diabetic kidney disease (DKD) is limited to estimated glomerular filtration rate (eGFR) and albuminuria. These are inadequate as DKD often has heterogenous clinical phenotypes. There is need for a marker of intra-renal fibrosis. Native kidney biopsy remains the only reference method in clinical practice for this purpose, but is invasive and impractical for repeated evaluations. Recently, two-dimensional ultrasound shear wave elastography (SWE) has emerged as a non-invasive technique to assess renal parenchymal stiffness with renal fibrosis. We aim to investigate SWE-derived estimates of tissue stiffness with different DKD stages in an Asian population. Method In this cross-sectional pilot study, 58 patients with DKD were recruited from a single centre ambulatory Nephrology clinic. Laboratory values were taken within 1 week of undergoing SWE, with DKD staging by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines and eGFR calculated using the CKD-EPI equation. 13 patients had histological diagnoses of DKD; 2 (15.3%) Stage G1-2; 5 (38.5%) Stage G3; 5 (38.5%) Stage G4 and 1 (7.7%) Stage G5 subjects, with native kidney biopsies performed within 4 months of study recruitment. 2D SWE was performed with a 2-5 MHz transducer on an Axiplorer© ultrasound system (Supersonic Imagine, Paris) by a single Nephrologist blinded to laboratory results. Using a previously described protocol, 6 SWE measurements were taken from the cortical mid-pole of bilateral kidneys, and renal elasticity estimated as Young’s Modulus (YM) in kilopascals (kPa), (Figure 1). Results Study population were 62.1% male (36/58) and 62.1% ethnic Chinese (36/58), with diabetes duration of 11.7 ± 9.2 years. Median eGFR was 35.0 (40-101) mL/min per 1.73 m2, with 6 (10.3%) DKD Stage G1-2; 34 (58.6%) Stage G3; 13 (22.4%) Stage G4 and 5 (8.6%) Stage G5 patients. There were moderate correlations between YM values in bilateral kidneys. Left kidney maximal YM generally increased in accordance with DKD stage (Stage G1-2: 20.6 kPa, Stage G3A: 13.5 kPa, Stage G3B: 22.4 kPa, Stage G4-5: 30.9 kPa, p <0.01). Kidney depth correlated moderately with body mass index (BMI). After controlling kidney depth and BMI, there was a moderately positive correlation between right kidney YM and DKD stage (Maximal YM; r = 0.4, p < 0.01, Mean YM; r = 0.31, p = 0.02). eGFR negatively correlated with bilateral kidney maximal YM (right r = -0.2, p = 0.04, and left r = -0.3, p = 0.03, respectively). Importantly, there was a strong correlation between right kidney mean YM and histological grading of interstitial fibrosis and tubular atrophy (r = 0.9, p = 0.01). There is no correlation between kidney elasticity and percentage of sclerosed glomeruli. Using a cut-off of 13.5 kPa for mean estimated tissue YM, the area under the receiver operator curve was 0.8 to distinguish DKD Stage G1 and G2 from G3A (sensitivity 83.3%, specificity 80.0%). Conclusion SWE-derived estimates of renal stiffness appear to increase with DKD stage. The strong correlation with histological markers of fibrosis indicate that observed differences are due to renal parenchymal stiffness. SWE shows promise as a non-invasive marker of renal fibrosis, although large multi-centre studies are required to validate these findings.

2021 ◽  
Vol 1 (1) ◽  
pp. 15-26
Author(s):  
Devang M. Patel ◽  
Yuxin Yang ◽  
Kexin Shi ◽  
Tieqiao Wu ◽  
Mark E. Cooper ◽  
...  

Abstract Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.


2019 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Kianoush Makvandi ◽  
Gert Jensen ◽  
Paul Hockings ◽  
Tim Unnerstall ◽  
Henrik Leonhardt ◽  
...  

Author(s):  
Vicki Thallas-Bonke ◽  
Sih Min Tan ◽  
Runa S Lindblom ◽  
Matthew Snelson ◽  
Cesare Granata ◽  
...  

Abstract Background The NADPH oxidase isoform, Nox4, mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in diabetic kidney disease within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. Methods We generated a proximal tubular specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the Sglt2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. Results Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of diabetic kidney disease including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKOSTZ mice compared to Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. Conclusion Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence diabetic kidney disease development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes.


2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jing Sun ◽  
Yangwei Wang ◽  
Wenpeng Cui ◽  
Yan Lou ◽  
Guangdong Sun ◽  
...  

One of the commonest causes of end-stage renal disease is diabetic kidney disease (DKD). Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM) proteins in glomerular basement membranes and the tubulointerstitium, is the final manifestation of DKD. The TGF-βpathway triggers epithelial-to-mesenchymal transition (EMT), which plays a key role in the accumulation of ECM proteins in DKD. DCCT/EDIC studies have shown that DKD often persists and progresses despite glycemic control in diabetes once DKD sets in due to prior exposure to hyperglycemia called “metabolic memory.” These imply that epigenetic factors modulate kidney gene expression. There is evidence to suggest that in diabetes and hyperglycemia, epigenetic histone modifications have a significant effect in modulating renal fibrotic and ECM gene expression induced by TGF-β1, as well as its downstream profibrotic genes. Histone modifications are also implicated in renal fibrosis through its ability to regulate the EMT process triggered by TGF-βsignaling. In view of this, efforts are being made to develop HAT, HDAC, and HMT inhibitors to delay, stop, or even reverse DKD. In this review, we outline the latest advances that are being made to regulate histone modifications involved in DKD.


2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Cuiping Liu ◽  
Ludan Qin ◽  
Jingya Ding ◽  
Luping Zhou ◽  
Chenlin Gao ◽  
...  

Aim. To explore the role of group 2 innate lymphoid cells (ILC2s) in the pathogenesis of renal fibrosis in diabetic kidney disease (DKD). Methods. The proportion of ILC2s and the levels of Th2 cytokines (IL-4, IL-5, and IL-13) in the peripheral blood of normal control subjects (NC) or patients with type 2 diabetes mellitus (DM), early diabetic kidney disease (DKD1), or late diabetic kidney disease (DKD2) were analyzed by flow cytometry and ELISA. The expression of transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen1, IL-4Rα, and IL-13Rα1 in renal tubular epithelial cells (HK-2) induced by IL-4, IL-13, or high glucose was analyzed by ELISA or qPCR. Results. The proportion of ILC2s and the levels of IL-4, IL-5, and IL-13 were significantly increased in DKD patients and were positively correlated with the severity of DKD (P<0.05). The expression of TGF-β1, FN, and collagen1 was significantly upregulated in HK-2 cells induced by IL-4 or IL-13 (P<0.05). Moreover, the IL-4Rα and IL-13Rα1 mRNA in HK2 cells were increased followed by high glucose alone or combined with IL-4 or IL-13, but the differences were not statistically significant (P>0.05). However, compared with high-glucose stimulation alone, the expression of TGF-β1, FN, and collagen1 was significantly increased in HK-2 cells induced by high glucose combined with IL-4 or IL-13 (P<0.05). Conclusions. ILC2s may participate in renal fibrosis in DKD partly via TGF-β1 signal pathway.


2020 ◽  
Vol 11 ◽  
Author(s):  
Hiroko Sakuma ◽  
Shinji Hagiwara ◽  
Phillip Kantharidis ◽  
Tomohito Gohda ◽  
Yusuke Suzuki

Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18–22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.


Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 514-P
Author(s):  
LU DAN QIN ◽  
CUIPING LIU ◽  
LUPING ZHOU ◽  
CHENLIN GAO ◽  
TING ZHANG ◽  
...  

2021 ◽  
Author(s):  
Om Prakash Dwivedi ◽  
Karina Barreiro ◽  
Annemari Käräjämäki ◽  
Erkka Valo ◽  
Rashmi B Prasad ◽  
...  

Diabetic kidney disease (DKD) is a severe complication of type 1 diabetes (T1D), which lacks non-invasive early biomarkers. Although less explored, mRNAs in urinary extracellular vesicles (uEV) could reflect changes in the kidney transcriptome during DKD development. We performed genome-wide mRNA sequencing of >100 uEV samples from two T1D cohorts with 24-hour and overnight urine collections. Our uEV pipeline allowed reproducible detection of >10,000 mRNAs bearing overall similarity to kidney transcriptome. uEV from T1D DKD groups showed significant upregulation of 13 genes, prevalently expressed by proximal tubular cells within the kidney. Strikingly, six genes involved in cellular stress responses including protection against oxidative stress (GPX3, NOX4, MSRB, MSRA, HRSP12 and CRYAB) correlated with hyperglycemia and long-term changes in kidney function independent of albuminuria status. The study identified genes associated with glycemic stress in T1D DKD and confirmed the utility of uEV in capturing pathological gene expression signatures from kidney.


2022 ◽  
Author(s):  
Jin-Lin Chu ◽  
Shu-Hong Bi ◽  
Yao He ◽  
Rui-Yao Ma ◽  
Xing-Yu Wan ◽  
...  

Abstract Background: Complications of diabetes mellitus (DM) are the leading cause of DM-related disability and mortality. Notably, diabetic kidney disease (DKD), one of the main complications of DM, has become a frequent cause of end-stage renal disease. A clinically convenient, non-invasive approach for monitoring the development of DKD would benefit the overall life quality of patients with DM and contribute to lower medical burdens through promoting preventive interventions.Methods: We utilized 5hmC-Seal to profile genome-wide 5-hydroxymethylcytosines in plasma cell-free DNA (cfDNA). Candidate genes were identified by intersecting the differentially modified 5hmC marker genes (DMGs) and differentially expressed genes (DEGs) from the GEO datasets GSE30528 and GSE30529. Cytoscape software was used to construct the protein-protein interaction (PPI) network and identify the hub genes.Results: The final gene panel of 9 hub genes, including (CTNNB1, PTEN, MYD88, ITGAM, CD28, ITGB2, VCAM1, CXCR4, CD44) were confirmed. Further analysis indicated that this 9-gene signature showed a good capacity to distinguish between DKD and DM. Conclusions: The 5hmC-Seal assay was successfully applied to the cfDNA samples from a cohort of DM patients with or without DKD. Altered 5hmC signatures in plasma cfDNA indicate that 5hmC-Seal has the potential to be a non-invasive epigenetic tool for monitoring the development of DKD and be a part of diabetic care.


Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1126-P
Author(s):  
HIDDO LAMBERS. HEERSPINK ◽  
PAUL PERCO ◽  
JOHANNES LEIERER ◽  
MICHAEL K. HANSEN ◽  
ANDREAS HEINZEL ◽  
...  

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