Degree Of Interstitial Fibrosis Research Articles

Canagliflozin can improve cardiac function in HFpEF rats partly by regulating ferroptosis

Objective: To explore the effects of canagliflozin on cardiac function and its regulation of ferroptosis in rats with heart failure with preserved ejection fraction (HFpEF). Methods: Thirty-two 7-week-old Dahl salt-sensitive rats were selected and randomly divided into four groups: the control group (fed with low-salt diet), the HFpEF group (fed with high-salt diet), the canagliflozin 20 group (fed with high-salt diet and 20 mg·kg-1·d-1 canagliflozin), and the canagliflozin 30 group (fed with high-salt diet and 30 mg·kg-1·day-1 canagliflozin). Body weight and blood pressure of the rats in each group were monitored. Metabolic cage tests were conducted at the10th week of the experiment, and echocardiography was performed at the 12th week, after which the rats were killed. Blood and left ventricular samples were collected. HE staining, Masson staining, Prussian blue iron staining, and reactive oxygen species staining were performed to observe the cardiomyocyte size and shape, degree of interstitial fibrosis, iron staining, reactive oxygen species production under optical microscope. The ultrastructure of cardiomyocytes was observed under electron microscope. Western blotting and real-time fluorescent quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression levels of proteins and mRNA related to ferroptosis in left ventricular myocardial tissue of rats in each group. Results: After 1 week of adaptive feeding, all rats survived. Metabolic cage results showed that compared with control group, rats in the HFpEF group, canagliflozin 20 group and canagliflozin 30 group had more food intake, water intake and urine output, and lower body weight (all P<0.05). These changes were more pronounced in canagliflozin 20 group and canagliflozin 30 group than in HFPEF group, and only the body weight at the 12th week showed a statistically significant difference between canagliflozin 20 group and canagliflozin 30 group (P<0.05). The blood pressure of 6th week and 12th week, heart weight and left ventricular corrected mass of 12th week of rats in HFpEF group were higher than those in control group, canagliflozin 20 group and canagliflozin 30 group, while the ratio of early mitral valve peak velocity to late mitral valve peak velocity of 12th week was lower (all P<0.05). HE and Masson staining showed that compared to control group, the myocardial fibers in the left ventricular myocardial tissue of rats in HFpEF group were disordered, with larger cell diameter ((0.032±0.004) mm vs. (0.023±0.003) mm, P<0.05), irregular shape, obvious proliferation of interstitial collagen fibers, and higher collagen volume fraction (0.168±0.028 vs. 0.118±0.013, P<0.05). Compared with HFpEF group, rats in the canagliflozin 20 group and canagliflozin 30 had more orderly arranged myocardial fibers, more regular cardiomyocyte shape, smaller cell diameter, and lower collagen volume fraction (P<0.05). It was observed under electron microscopy that, compared to control group, most of the striated muscles in myocardial tissue of HFpEF group were broken, and the Z line and M line could not be clearly distinguished, some changes such as mitochondrial swelling, membrane thickening, cristae reduction or even disappearance occurred. In the canagliflozin 20 group and canagliflozin 30 group, the arrangement of striated muscles in the myocardial tissue of rats tended to be more regular, and the morphological changes of mitochondria were milder. Prussian blue iron staining results showed that the iron content in myocardial tissue of rats in HFpEF group was higher than that in control group, canagliflozin 20 group and canagliflozin 30 group. Reactive oxygen species staining results showed that the reactive oxygen species content in the myocardial tissue of rats in HFpEF group was higher than that of control group, canagliflozin 20 group and canagliflozin 30 group. Biochemical analysis of myocardial tissue showed that Fe2+ and malondialdehyde content in myocardial tissue of rats in HFpEF group were higher than those in control group, canagliflozin 20 group and canagliflozin 30 group, while glutathione content was lower (all P<0.05). Western blot and RT-qPCR detection results showed that compared to control group, rats in HFpEF group had higher expression levels of transferrin receptor 1 (protein relative expression level: 1.37±0.16 vs. 0.31±0.12), acyl-CoA synthetase long-chain family member 4 (protein relative expression level: 1.31±0.15 vs. 0.63±0.09) protein and mRNA, and lower expression levels of ferritin heavy chain 1 (protein relative expression level: 0.45±0.08 vs. 1.41±0.15) protein and mRNA (all P<0.05). There was no statistically significant difference in these indicators between canagliflozin 20 group and the canagliflozin 30 group (all P>0.05). There was no significant difference in levels of glutathione peroxidase 4 protein and mRNA expression in myocardial tissue of rats in four groups(P>0.05). Conclusion: Canagliflozin improves cardiac function in HFpEF rats by regulating the ferroptosis mechanism.

Tubular biomarkers and histology in lupus nephritis.

The relevance of tubulo-interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. A single-center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2-microglobulin, alpha 1-microglobulin, NGAL, uKIM-1, MCP-1, uDKK-3, and uUMOD. The serum markers sKIM-1 and sUMOD were also analyzed. A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p = .001) and tubular atrophy (rho = 0.781, p = .001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = -0.562, p = .037) and tubular atrophy (rho = -0.694, p = .006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM-1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p = .001], MCP-1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p = .001], sKIM-1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p = .001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p = .028]. The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients.

#1347 Development and validation of a nomogram for predicting complete kidney function recovery after drug-induced acute interstitial nephritis

Abstract Background and Aims Drug-induced acute interstitial nephritis (DI-AIN) represents a common cause of acute kidney injury. Early withdrawal of the culprit drug along with corticosteroid therapy (CS) remains the mainstay of treatment. Despite this, up to 50% of patients may not fully recover kidney function after DI-AIN. The aims of this study were to develop and externally validate a predictive nomogram to assess the probability of complete recovery (CR) of kidney function at 6 months after treatment. Method Multicenter, retrospective, observational study in 13 nephrology departments belonging to the GLOSEN group. Patients with biopsy proven DI-AIN treated with CS between 1996-2023 were included. Other potential causes of AIN such as infections or systemic diseases were carefully ruled out. Dataset was randomly divided into training group (n = 164) and validation group (n = 60). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of CR (serum creatinine value &amp;lt;25% of the last value before DI-AIN), and used to build the nomogram. Accuracy of the nomogram was assessed by discrimination and risk calibration, in the training and validation sets. Results The study group comprised 224 patients with DI-AIN, of whom: 51 (31%) in the training group and 19 (32%) in the validation set, achieved CR at 6 months after treatment with CS. Median age was 70 (IQR 57–76), and 115 (51%) were males. The clinical characteristics were well balanced between the training and validation data sets. The selected variables by LASSO were age (under/above 65 years), gender, degree of interstitial fibrosis and time to CS initiation (under/above 7 days). Based on multivariable logistic regression model, a nomogram was developed for assessing the probability of CR (Fig. 1). The area under the curve (AUC) of the nomogram was 0.809 (95% CI 0.721–0.880) indicating a good discriminative power. Bootstrap self- sampling was performed 1000 times for validation of the nomogram model. The AUC was 0.837 (95 % CI: 0.705–0.931), indicating good predictive stability. Calibration plot revealed that the predicted outcomes aligned well with the observations. Decision curve analysis (DCA), and clinical impact curve analysis (CICA) suggested that the model had clinical benefit. Conclusion We constructed and validated a practical nomogram with good discrimination and calibration, to predict the probability of CR of kidney function at 6 months in DI-AIN treated with corticosteroids. This clinical tool can provide clinicians with an estimate of kidney prognosis and can potentially assist them in titrating the intensity and duration of corticosteroid therapy.

Clinicopathologic Characteristics, Etiologies, and Outcome of Secondary Oxalate Nephropathy

ObjectiveTo report the clinicopathologic characteristics, prognostic indicators, prognosis, and transplant outcome of secondary oxalate nephropathy (ON). Patients and MethodsWe performed a retrospective analysis of 113 consecutive patients with secondary ON diagnosed at Mayo Clinic in Rochester, Minnesota, between January 1, 2001, and March 1, 2023. ResultsThe incidence of secondary ON among all native biopsies from Mayo Clinic patients over the study period (n=11,617) was 0.97%. ON was attributed to enteric hyperoxaluria in 60% of the 113 patients (68; most commonly Roux-en-Y gastric bypass), excessive ingestion of foods high in oxalate or oxalate precursors in 23% (26) (most commonly vitamin C), and idiopathic in 17% (19). Most patients presented with acute kidney injury (AKI) (particularly in the ingestion group) or AKI on chronic kidney disease, and 53% (60 of 113) were diabetic. Calcium oxalate crystals were accompanied by acute tubular injury, inflammation, and interstitial fibrosis and tubular atrophy. Concurrent pathologic conditions were present in 53% of the patients (60 of 113), most commonly diabetic nephropathy. After a median follow-up of 36 months, 27% of the patients (30 of 112) had kidney recovery, 19% (21 of 112) had persistent kidney dysfunction, 54% (61 of 112) had development of kidney failure, and 29% (32 of 112) died. The mean kidney survival was worse for patients with a concurrent pathologic lesion (30 months vs 96 months for those without a concurrent pathologic lesion; P<.001). Independent predictors of kidney failure were the degree of interstitial fibrosis and tubular atrophy and nadir estimated glomerular filtration rate but not the degree of crystal deposition. After a median follow-up of 58 months in 23 patients who received kidney transplant, 4 had graft loss (due to ON in 3). The 2-, 5-, and 10-year graft survivals were 90% (18 of 20), 79% (11 of 14), and 50% (6 of 12). ConclusionON is a rare cause of AKI or AKI on chronic kidney disease. Most patients have comorbid pathologic conditions, particularly diabetic nephropathy, which worsen the prognosis. Recurrence in the renal allograft and graft loss may occur if hyperoxaluria is not controlled.

Reconfiguration and loss of peritubular capillaries in chronic kidney disease

Functional and structural alterations of peritubular capillaries (PTCs) are a major determinant of chronic kidney disease (CKD). Using a software-based algorithm for semiautomatic segmentation and morphometric quantification, this study analyzes alterations of PTC shape associated with chronic tubulointerstitial injury in three mouse models and in human biopsies. In normal kidney tissue PTC shape was predominantly elongated, whereas the majority of PTCs associated with chronic tubulointerstitial injury had a rounder shape. This was reflected by significantly reduced PTC luminal area, perimeter and diameters as well as by significantly increased circularity and roundness. These morphological alterations were consistent in all mouse models and human kidney biopsies. The mean circularity of PTCs correlated significantly with categorized glomerular filtration rates and the degree of interstitial fibrosis and tubular atrophy (IFTA) and classified the presence of CKD or IFTA. 3D reconstruction of renal capillaries revealed not only a significant reduction, but more importantly a substantial simplification and reconfiguration of the renal microvasculature in mice with chronic tubulointerstitial injury. Computational modelling predicted that round PTCs can deliver oxygen more homogeneously to the surrounding tissue. Our findings indicate that alterations of PTC shape represent a common and uniform reaction to chronic tubulointerstitial injury independent of the underlying kidney disease.

Abstract 15057: miR-132 Inhibitor CDR 132L Attenuates Cardiac Remodeling by Exhibiting Anti-Fibrotic Effects

Introduction: Increased cardiac expression levels of miRNA miR-132 have been associated with pathological cardiac remodeling including cardiac fibrosis. As a selective inhibitor for miR-132, the synthetic antisense oligonucleotide CDR132L, is capable to reverse cellular pathology and restore normal heart function. Pharmacological inhibition of miR-132 as well as genetic knockout has been shown to protect mice from transverse aortic constriction induced cardiac remodeling including interstitial fibrosis. Methods and Results: Treatment effects of CDR132L were investigated in several different pig models of ischemic and non-ischemic heart failure (HF) with the aim to further elucidate CDR132L’s mode of action and confirm species-independent effects on fibrotic remodeling. In a pig model of subacute post myocardial infarction (MI) induced HF, CDR132L was administered on day 3 and day 28 by intravenous (IV) or intracoronary (IC) infusion at doses of 1, 5 and 10 mg/kg and followed until day 56. In a chronic post-MI HF large animal model, beneficial effects were confirmed in a 6-month study comparing 5 monthly and 3 monthly repeated IV administrations of 5 mg/kg CDR132L starting one month post-MI. Further, CDR132L was tested in a porcine model of percutaneous aortic constriction by implantation of a reduction stent in the thoracic aorta and two IC injections of CDR132L on day 0 and day 28 followed for 56 days. As part of the pharmacodynamic analyses in these models, paraffin sections of cardiac tissue from the left ventricular remote region were stained with picrosirius red (PSR) and fibrosis was assessed based on collagen quantity. Analysis of fibrosis in PSR-staining revealed that the degree of interstitial fibrosis was significantly reduced in CDR132L treatment groups compared to placebo between 22% and 61%. Moreover, results of the first-in-human safety and tolerability study of CDR132L in patients with stable HF of ischemic origin (NCT04045405) showed encouraging positive trends for relevant cardiac fibrosis biomarkers. Conclusion: By blocking aberrant miR-132 expression, CDR132L is capable to halt and reverse pathological cardiac remodeling partly due to its anti-fibrotic effects.

Neuropilin 1 promotes unilateral ureteral obstruction-induced renal fibrosis via RACK1 in renal tubular epithelial cells.

Neuropilin 1 (NRP1) is a single-channel transmembrane glycoprotein whose role and mechanism in renal fibrosis remain incompletely elucidated. Therefore, we investigated the effect of NRP1 on renal fibrosis and its potential mechanism. NRP1 expression in the renal sections from patients with chronic kidney disease (CKD) and a unilateral ureteral obstruction (UUO) mouse model was detected. Nrp1 overexpression or knockdown plasmid was transfected into mice, TKPTS mouse kidney proximal tubular epithelial cells (TECs), and rat kidney fibroblasts, after which pathological injury evaluation and fibrosis marker detection were conducted. The direct interaction of the receptor of activated protein C kinase 1 (RACK1) with NRP1 was validated by immunoprecipitation and Western blot analysis. We found that the upregulated renal NRP1 expression in patients with CKD was located in proximal TECs, consistent with the degree of interstitial fibrosis. In the UUO mouse model, NRP1 expression was upregulated in the kidney, and overexpression of Nrp1 increased the mRNA and protein expression of fibronectin (Fn) and α-smooth muscle actin (α-SMA), whereas Nrp1 knockdown significantly reduced Fn and α-SMA expression and downregulated the inflammatory response. NRP1 promoted transforming growth factor β1 (TGF-β1)-induced profibrotic responses in the TKPTS cells and fibroblasts, and Nrp1 knockdown partially reversed these responses. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry verified that NRP1 can directly bind to RACK1, and Rack1 knockdown reversed the NRP1-induced fibrotic response. In summary, NRP1 may enhance the TGF-β1 pathway by binding to RACK1, thus promoting renal fibrosis.NEW & NOTEWORTHY Although a few studies have confirmed the correlation between neuropilin 1 (NRP1) and renal diseases, the mechanism of NRP1 in renal fibrosis remains unclear. Here, we investigated the effects of NRP1 on renal fibrosis through in vitro and in vivo experiments and explored the possible downstream mechanisms. We found that NRP1 can stimulate the TGF-β1 signaling pathway, possibly by binding to RACK1, thereby promoting renal fibrosis.

Using Ultrahigh b -Value Diffusion-Weighted Imaging to Noninvasively Assess Renal Fibrosis in a Rabbit Model of Renal Artery Stenosis.

This study aimed to investigate the feasibility of diffusion-weighted imaging with ultrahigh b values ( ub DWI) for the evaluation of renal fibrosis (RF) induced by renal artery stenosis (RAS) in a rabbit model. Thirty-two rabbits underwent left RAS operation, whereas 8 rabbits received sham surgery. All rabbits underwent ub DWI ( b = 0-4500 s/mm 2 ). The standard apparent diffusion coefficient (ADC st ), molecular diffusion coefficient ( D ), perfusion fraction ( f ), perfusion-related diffusion coefficient ( D *) and ultrahigh apparent diffusion coefficient (ADC uh ) were longitudinally assessed before operation and at weeks 2, 4, and 6 after operation. The degree of interstitial fibrosis and the expression of aquaporin (AQP) 1 and AQP2 were determined through pathological examination. In the stenotic kidney, the ADC st , D , f , and ADC uh values of the renal parenchyma significantly decreased compared with those at baseline (all P < 0.05), whereas the D * values significantly increased after RAS induction ( P < 0.05). The ADC st , D , D *, and f were weakly to moderately correlated with interstitial fibrosis as well as with the expression of AQP1 and AQP2. Furthermore, the ADC uh negatively correlated with interstitial fibrosis ( ρ = -0.782, P < 0.001) and positively correlated with AQP1 and AQP2 expression ( ρ = 0.794, P < 0.001, and ρ = 0.789, P < 0.001, respectively). Diffusion-weighted imaging with ultrahigh b values shows the potential for noninvasive assessment of the progression of RF in rabbits with unilateral RAS. The ADC uh derived from ub DWI could reflect the expression of AQPs in RF.

Endurance training induced cellular electrophysiological remodeling in a small and a large animal athlete’s heart model

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funding: It was supported by NKFIH grants (K-19992, K- 135464, GINOP-2.3.2-15-2016-00047). Background The positive impact of regular exercise on a healthy and fulfilling lifestyle. Therefore, active athletes are considered the healthiest members of our society. However, there is an increasing amount of evidence that long-term high-intensity sporting activity could also have adverse effects on the heart, such as impaired electrophysiological properties. Heavy long-term training can lead to structural and functional remodelling of the heart, which in turn, can evoke malignant cardiac arrhythmias. Purpose To develop animal models with a significant translational value of the human athlete’s heart and to investigate underlying malignant drivers of cardiac arrhythmias due to the long-term endurance training in in vitro studies. Methods 24 dogs from both sexes and 26 male guinea pigs were randomly assigned to sedentary (’Sed’) and trained (’Tr’) groups (n = 12-12; n=13-13). The latter group underwent a long-term endurance interval-training program on the treadmill 5 days a week for 4 months. ECG recordings and echocardiography validated the characteristic of athlete’s heart. After heart removal, the degree of interstitial fibrosis was quantified and ventricular myocytes were enzymatically dissociated via retrograde perfusion. The transmembrane ionic currents were recorded using the whole-cell configuration of the patch-clamp technique. The action potentials were measured by the perforated patch-clamp technique. Immunocytochemistry measurements were performed to determine the density of transmembrane ion channels. Results Based on the ECG and ECHO results, the vigorous training program resulted in significant cardiac adaptation in both species. In addition, it caused mild ventricular fibrosis. The repolarization is reflected as the 90 percent of action potential duration (APD90). It was significantly lengthened in the left ventricular myocytes of ‘Tr’ dogs. (‘Tr’ vs. ‘Sed’ 472.8±29.6 ms; =29 vs. 369.3±31.4 ms; n=24, p=0.023) and there was no difference in the case of guinea pigs. The amplitude of the transient outward current (Ito), which is not expressed in the guinea pig heart, was significantly smaller in the ‘Tr’ dogs (‘Tr’ vs. ‘Sed’ 7.6±0.6 pA/pF, n=54 vs. 10.2±1.0 pA/pF, n=42, p&amp;lt;0.05). Under the currently used protocols, no differences were detected in the magnitude of other ionic currents. The HCN4 gene expression was significantly higher in isolated myocytes in ’Tr’ dogs. Conclusion Increased ectopic activity is not rare among top athletes. Our results suggest an association between increased arrhythmia susceptibility and impaired repolarisation reserve related to down-regulation of Ito and prolonged APD90 and enhanced fibrotic changes. The overexpression of HCN4 gene in hypertrophic hearts, similar to heart failure, may evoke malignant ventricular arrhythmias. Further studies are warranted to clarify this hypothesis in more detail.

Significance of interstitial fibrosis and p16 in papillary thyroid carcinoma.

We enrolled 264 patients with papillary thyroid carcinoma (PTC). We performed immunohistochemical detection of p16 and determined the degree of interstitial fibrosis (IF). The expression of p16 was associated with pathological tumor-node-metastasis (pTNM) stage and age (p < 0.05). The cancer-specific survival (CSS) was longer in p16-negative patients (195.73 vs. 181.78 months, p = 0.007). p16 was significantly related to the degree of IF (r = 0.130, p = 0.035). PTC patients with no or mild fibrosis tended to have a larger tumor (p = 0.045). The degree of fibrosis was related to the proportion of papillary structure components (p = 0.025). Univariate and multivariate survival analyses showed that relapse-free survival (RFS) was longer in patients with moderate/severe IF (p < 0.05). In summary, p16 was correlated with prognosis and IF of PTC. Patients with moderate/severe IF tend to have better prognosis in RFS.

СORONAVIRUS INFECTION WITH AN OBESITY

Summary. Relevance of the topic: most of the world is obese and there are enough cases of the impact of this pathology on the development of a complicated and severe course of novel coronavirus (COVID-19) infection. Purpose of the study: to study literature data on the effect of obesity on the course of novel coronavirus infection. Objectives : 1. To consider obesity as a factor contributing to the intensification of inflammatory reactions. 2. To study the etiology and pathogenesis of COVID-19 infection. 3. To establish the relationship between obesity and complications arising from coronavirus infection. Results. The most common feature of COVID-19 is severe acute respiratory syndrome caused by progressive lung consolidation. There is a positive correlation between the duration of COVID-19 infection and the degree of interstitial fibrosis. Extensive pulmonary fibrosis is one of the main causes of pulmonary consolidation due to the excessive extracellular matrix component produced by activated myofibroblasts [7]. Pulmonary lipofibroblasts are a special type of adipocytes that contain typical lipid droplets and are close to the second type of alveolar epithelial cells of the pulmonary interstitium. Lipofibroblasts may result from ectopic fat deposition, which plays a vital role in the progression of COVID-19 in these patients. When exposed to various stimulants, such as hyperoxia and infection of lung lipofibroblasts, a transdifferentiated myogenic phenotype called myofibroblasts occurs, which causes pulmonary fibrosis [10]. A significant number of obese patients have impaired glucose metabolism, which is considered a risk factor and leads to death. SARS infection has been found to cause hyperglycemia in some patients due to dysfunction of the islets of the pancreas as a result of a viral attack. A similar effect occurs after infection with SARS-COV-2. This explains why 52% of those infected with SARS-COV-2 had hyperglycemia. The level of glucose increase in metabolic disorders in obese patients can be much higher. Hyperglycemia leads to a number of complications, including osmotic imbalance of fluid and electrolytes, hyperosmolar non-ketonemic coma, worsening skeletal muscle catabolism, impaired wound healing, altered coagulation, and increased susceptibility to infections [4]. In addition, hyperglycemia impairs the body's immune function. All of this worsens the clinical outcome of COVID-19. Notably, proper blood glucose control reduces mortality in critically ill patients, highlighting the importance of blood glucose control. Conclusion. The relationship between obesity as a factor complicating the course of SARS-COV-2 infection has been shown. This mainly concerns the development of a cytokine storm due to the release of IL-1, IL-6, IL-10 by adipose tissue, as well as TNF- α . It should be noted that obesity affects the occurrence of concomitant metabolic diseases in patients, such as type 2 diabetes mellitus, coronary heart disease, atherosclerosis, etc., leading to acute myocardial infarction, increased thrombus formation and many other serious conditions. In addition, it is difficult for obese patients to provide specialized medical care when connecting to a ventilator, preventing pressure ulcers and attaching a secondary infection.

СORONAVIRUS INFECTION WITH AN OBESITY

Summary. Relevance of the topic: most of the world is obese and there are enough cases of the impact of this pathology on the development of a complicated and severe course of novel coronavirus (COVID-19) infection. Purpose of the study: to study literature data on the effect of obesity on the course of novel coronavirus infection. Objectives : 1. To consider obesity as a factor contributing to the intensification of inflammatory reactions. 2. To study the etiology and pathogenesis of COVID-19 infection. 3. To establish the relationship between obesity and complications arising from coronavirus infection. Results. The most common feature of COVID-19 is severe acute respiratory syndrome caused by progressive lung consolidation. There is a positive correlation between the duration of COVID-19 infection and the degree of interstitial fibrosis. Extensive pulmonary fibrosis is one of the main causes of pulmonary consolidation due to the excessive extracellular matrix component produced by activated myofibroblasts [7]. Pulmonary lipofibroblasts are a special type of adipocytes that contain typical lipid droplets and are close to the second type of alveolar epithelial cells of the pulmonary interstitium. Lipofibroblasts may result from ectopic fat deposition, which plays a vital role in the progression of COVID-19 in these patients. When exposed to various stimulants, such as hyperoxia and infection of lung lipofibroblasts, a transdifferentiated myogenic phenotype called myofibroblasts occurs, which causes pulmonary fibrosis [10]. A significant number of obese patients have impaired glucose metabolism, which is considered a risk factor and leads to death. SARS infection has been found to cause hyperglycemia in some patients due to dysfunction of the islets of the pancreas as a result of a viral attack. A similar effect occurs after infection with SARS-COV-2. This explains why 52% of those infected with SARS-COV-2 had hyperglycemia. The level of glucose increase in metabolic disorders in obese patients can be much higher. Hyperglycemia leads to a number of complications, including osmotic imbalance of fluid and electrolytes, hyperosmolar non-ketonemic coma, worsening skeletal muscle catabolism, impaired wound healing, altered coagulation, and increased susceptibility to infections [4]. In addition, hyperglycemia impairs the body's immune function. All of this worsens the clinical outcome of COVID-19. Notably, proper blood glucose control reduces mortality in critically ill patients, highlighting the importance of blood glucose control. Conclusion. The relationship between obesity as a factor complicating the course of SARS-COV-2 infection has been shown. This mainly concerns the development of a cytokine storm due to the release of IL-1, IL-6, IL-10 by adipose tissue, as well as TNF- α . It should be noted that obesity affects the occurrence of concomitant metabolic diseases in patients, such as type 2 diabetes mellitus, coronary heart disease, atherosclerosis, etc., leading to acute myocardial infarction, increased thrombus formation and many other serious conditions. In addition, it is difficult for obese patients to provide specialized medical care when connecting to a ventilator, preventing pressure ulcers and attaching a secondary infection.

Application of the ANCA Renal Risk Score in the United States: A Single-Center Experience

Application of the ANCA Renal Risk Score in the United States: A Single-Center Experience

MO073HISTOLOGICAL PREDICTORS OF PROTEINURIA AND RENAL OUTCOMES IN PRIMARY MEMBRANOUS NEPHROPATHY: IS INTERSTITIAL FIBROSIS THE MAIN CHARACTER?

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in older white adults, with an incidence of 12 cases per millions of people per year. Primary MN (PMN, 75%-80% of MNs) is an organ-specific autoimmune disease caused by antibodies anti-PLA2R and anti-THSD7A. Regardless of treatment one third of patients progresses to end-stage renal disease and two third develop non-progressive chronic kidney disease. Renal biopsy is the gold standard for MN diagnosis. Several clinical and biochemical markers have been associated with the risk of progressive loss of kidney function while contrasting results have been obtained by the few studies which have examined the prognostic value of histologic findings. In this study the clinical outcome of patients with PMN has been considered based on the prognostic value of histological findings. Method Forty-nine patients with PMN of our Nephrology Unit at Padova University Hospital from 2003 to 2018 were considered. 16 patients were excluded from the study due to missing data. Age, comorbidities, proteinuria (g/day) and renal function (eGFR, CKD-EPI) were collected. eGFR decline and decrease of proteinuria were used as clinical outcomes. The follow-up was considered from renal biopsy to the last visit (in absence of GFR decline or decrease in proteinuria). Histological grading (0-3) was assigned to parameters (glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis (IF), vascular hyalinosis (VH)) and were evaluated separately or in combination (as GSTIV score). Morphometric analysis was used to quantify IF and expressed in percentage as the mean of area covered by pixel. Statistical analysis was performed using Fisher’s exact test and Mann-Whitney U-test where appropriate. Cox regression analyses (univariate and multivariate) were performed to identify variables associated with both renal outcomes and p&amp;lt;0.05 was considered as significant. ROC curves were used to determine interstitial fibrosis cut-off values predictive for both outcomes. Area under the curve (AUC) between 0.8 and 1.0 was considered as significant. Diagnostic accuracy was assessed by Specificity (Sp), Sensibility (Se), positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios. Results Patients with no decrease of proteinuria had a greater degree of IF vs those with a full response (p=0.006). Univariate Cox analyses identified age ≥65 years (HR 4.92), pre-existing CKD (HR 12.98) and IF (HR3.05) as significant predictors of renal function decline in all patients. Multivariate Cox analysis confirmed these variables (age ≥65 years HR 3.05, CKD HR 6.35, IF HR 3.03). In patients without CKD only IF was significantly associated with eGFR decline in both Cox univariate and multivariate analysis (HR 4.34 and 5.05 respectively). ROC analysis showed that IF threshold of 17.80% identified patients with eGFR reduction (AUC 0.65, Se 0.50, Sp 0.79, PPV 0.75, NPV 0.45, LR+ 2.38, LR-0.63) and IF threshold of 18.04% the lack of proteinuria reduction (AUC 0.78, Se 0.70, Sp 0.83, PPV 0.67, NPV 0.80, LR+ 4.12, LR- 0.36). Conclusion Our study shows that IF could be used as a histologic predictor of renal and proteinuria outcomes. Biopsy report should therefore also include quantitative IF data that could be helpful for the choice of a more appropriate therapeutic approach.

Unmet needs in the treatment of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a complex heterogeneous cardiovascular disorder characterized by hypertrophied and disorganized myocytes with varying degrees of interstitial fibrosis. The current management strategies include genetic and familial screening, symptom control and prevention of sudden cardiac death in those at high risk. Until recently, septal reduction therapy and heart transplantation were the only disease modifying treatments available to manage HCM, but emerging pharmacotherapies show promising results in controlled clinical trials. In this article, we will review the unmet needs in the treatment of HCM incorporating novel therapies.

36. ASSOCIATION OF ELECTROCARDIOGRAM PARAMETERS OF ATRIAL AND VENTRICULAR REMODELING WITH INTERSTITIAL FIBROSIS IN HYPERTENSIVE PATIENTS

Background: Cardiac remodeling is frequently seen in hypertensive patients and one of the causes of its process is interstitial fibrosis. Electrocardiogram (ECG) is a practical tool to detect impulse heterogeneity, reflecting fibrosis. Objective: To prove association of ECG parameters with interstitial fibrosis in hypertension which might be used to monitor effectiveness of therapies and prognosis. Methods: This is a cross-sectional study whose subjects were diagnosed with hypertension recruited from public healthcare from December 2018 until January 2019. Exclusion criteria were elderly (&gt;65 years old), known coronary artery disease, heart failure, and valvular heart diseases. Association between ECG parameters which reflects atrial remodeling, represented by P-wave Dispersion (PWD), and ventricular remodeling, represented by QT dispersion (QTd), with degree of interstitial fibrosis, represented by soluble ST2 (SST2) from blood serum, which has been proven for detecting myocardial fibrosis, were analyzed using Spearman's correlation. Multivariate analysis was performed to adjust the outcome with age and sex. Results: From 36 subjects recruited, 24 (66.7%) subjects were female. The median age was 57 (45-65) years old. There were significant moderate correlations between SST2 with PWD (p 0.001; r 0.498), and QTd (p 0.002; r 0.462). After multivariate analysis, the correlation remains significant for PWD (p 0.001) and QTd (p 0.018). The moderate correlation between ECG parameters and SST2 maybe due to the fibrosis caused by myocardial damage in hypertension is subtler than heart failure. Conclusion: There are moderate correlations between ECG parameters of atrial and ventricular remodeling with interstitial fibrosis in hypertensive patients.

ARHGDIB and AT1R autoantibodies are differentially related to the development and presence of chronic antibody-mediated rejection and fibrosis in kidney allografts

The role of non-HLA autoantibodies in chronic-active antibody-mediated rejection (c-aABMR) of kidney transplants is largely unknown. In this study, the presence and clinical relevance of non-HLA autoantibodies using a recently developed multiplex Luminex-based assay were investigated. Patients with a kidney allograft biopsy at least 6 months after transplantation with a diagnosis of c-aABMR (n = 36) or no rejection (n = 21) were included. Pre-transplantation sera and sera at time of biopsy were tested for the presence of 14 relevant autoantibodies.A significantly higher signal for autoantibodies against Rho GDP‐dissociation inhibitor 2 (ARHGDIB) was detected in recipients with c-aABMR as compared to recipients with no rejection. However, ARHGDIB autoantibodies did not associate with graft survival. Levels of autoantibodies against angiotensin II type 1-receptor (AT1R) and peroxisomal trans‐2‐enoyl‐CoA reductase (PECR) were increased in recipients with interstitial fibrosis in their kidney biopsy. Only the signal for AT1R autoantibody showed a linear relationship with the degree of interstitial fibrosis and was associated with graft survival.In conclusion, anti-ARHGDIB autoantibodies are increased when c-aABMR is diagnosed but are not associated with graft survival, while higher levels of AT1R autoantibody are specifically associated with the presence of interstitial fibrosis and graft survival.

Modulation of NADPH oxidase and Nrf2/HO-1 pathway by vanillin in cisplatin-induced nephrotoxicity in rats.

To investigate the protective effect of vanillin in cisplatin (CP)-induced nephrotoxicity in rats and elucidate the role of nrf-2 and its downstream antioxidant molecules. Rats received vanillin (100mg/kg orally) for 10 constitutive days and CP (7.5mg/kg, once, ip) on day 6 of vanillin administration. Cisplatin suppressed body weight gain, increased serum urea and creatinine and renal malondialdehyde and nitric oxide while decreased renal total antioxidant capacity. Up-regulation of NADPH oxidase-4 (NOX-4) was marked in renal tissue of CP-treated rats along with down-regulation of the antioxidant genes (nuclear factor erythroid 2-related factor2 (NRF2) and haem oxygenase-1(HO-1)). Increased tumour necrosis factor-α and decreased interleukin-10 with increased myeloperoxidase activity were apparent in renal tissue of CP-treated rats along with marked tubular injury, neutrophil infiltration and increased apoptosis (caspase-3) and some degree of interstitial fibrosis. Vanillin prophylactic administration prevented the deterioration of kidney function, oxidative and nitrosative stress. It also suppressed NOX-4 and up-regulated NRF2 and HO-1 expression in renal tissue. Inflammation, apoptosis and tubular injury were also inhibited by vanillin. The antioxidant mechanism by which vanillin protected against CP-induced nephrotoxicity involved the inhibition of NOX-4 along with the stimulation of Nrf2/HO-1 signalling pathway. These in turn inhibited inflammation and apoptosis.

Incidence of glomerulonephritis in the western part of Switzerland over the last decade

Glomerulonephritis is a rare yet serious group of diseases with a high risk of progression to end-stage renal disease. For optimal healthcare planning, detailed epidemiological and demographic data are essential. Despite their clinical relevance, these data are largely lacking in Switzerland. The objective of this study was to assess the incidence of the different forms of glomerulonephritis in the western part of Switzerland and its changes over the last 10 years, compared with international data. We listed all renal biopsy reports analysed between 2007 and 2016 at the University hospital of Lausanne, the renal pathology reference centre of all hospitals in the cantons of Vaud, Fribourg, Valais and Neuch&acirc;tel. Biopsies with a first diagnosis of primary glomerulonephritis were included in the analysis. The incidence was calculated as the number of patients newly diagnosed with glomerulonephritis divided by the number of inhabitants of all the above-mentioned cantons during the year under review, as retrieved from the federal statistical office of Switzerland. We collected biopsy reports from 864 patients between 2007 and 2016; 168 biopsies met the inclusion criteria. The most common primary glomerulonephritis was IgA nephropathy at 32.7% of cases, followed by lupus nephritis (29.8%) and pauci-immune glomerulonephritis (11.9%). Overall, the mean incidence of glomerulonephritis was 1.3/100,000/year. Between 2007 and 2016, the incidence of all glomerulonephritis taken together remained stable. The same was true for the incidence of IgA nephropathy, lupus nephritis and pauci-immune glomerulonephritis. In contrast, we observed a trend towards higher creatinine levels, proteinuria and degree of interstitial fibrosis at diagnosis. The incidence of glomerulonephritis in the western part of Switzerland was low and remained stable over time, in line with European data.

Magnetic Resonance Imaging for Evaluation of Interstitial Fibrosis in Kidney Allografts.

This prospective trial was primarily designed to investigate whether the results of T1-weighted MRI associate with the degree of IF. Thirty-two kidney transplant recipients were subjected to 1.5-Tesla MRI scans shortly before or after routine allograft biopsies. MRI parameters [T1 and T2 relaxation times; apparent diffusion coefficient (ADC)] were assessed for cortical and medullary sections. Advanced IF (Banff ci score >1) was associated with higher cortical T1 (but not T2) values [1451 (median; interquartile range: 1331-1506) versus 1306 (1197-1321) ms in subjects with ci scores ≤1; P = 0.011; receiver operating characteristic area under the curve for prediction of ci > 1: 0.76]. In parallel, T1 values were associated with kidney function and proteinuria. There was also a relationship between IF and corticomedullary differences on ADC maps (receiver operating characteristic area under the curve for prediction of ci ≤ 1: 0.79). Our results support the use of MRI for noninvasive assessment of allograft scarring. Future studies will have to clarify the role of T1 (and ADC) mapping as a surrogate endpoint reflecting the progression of chronic graft damage.