Interstitial Fibrosis In Patients Research Articles

Abstract 4135080: Relation of focal and diffuse myocardial fibrosis to left bundle branch block in patients with dilated cardiomyopathy and structurally normal heart

The role of fibrosis in etiology of left bundle branch block (LBBB) in still not defined. The aim of this study was to assess the relation of focal and diffuse LV fibrosis to LBBB in patients with dilated cardiomyopathy (DCM) and in patients with structurally normal heart. Materials and methods: 60 DCM with LBBB (DCM-LBBB group, 46.7% male, mean age 57[50;63] years), 50 non-LBBB DCM (78% male, mean age 43[32.3;54] years), 15 patients (53.3% male, mean age 39[28;50] years) with LBBB and no signs of structural heart disease and 10 healthy volunteers (HV) were included in the study. Endomyocardial biopsy (EMB) was performed in 15(24,6%) LBBB-DCM and 16(32%) non-LBBB DCM patients and allowed the quantification of collagen volume fraction (CVF, Fig.1A-D). All patients and HV underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) analysis. Obtained LGE LV images were post-proceed for core scar (CS) and gray zone (GZ) calculation and 3D reconstruction. Diffuse LV interstitial fibrosis was estimated on all LGE-CMR images with the novel introduced marker - diffuse intensity ratio (DIR). Results: DIR was validated on EMB samples: the percentage of CVF (8.2[4.6;10.8]%) correlated with the DIR value (0.71 ± 0.13) in the same segment (r=0.66, p<0.001, Fig.1E-F). The value of CVF (Fig1A-D) and LGE presence in the septum in both DCM groups (Fig2) was comparable (8.2[4.6; 10.3] versus 7.6[6.1;15.3]%, p=0.82 and 19 (31.7%) versus 17 (34%) patients in non-LBBB DCM group respectively, p=0.8) Moreover, the presence of LGE and midwall fibrosis in septum was not related to the QRS duration (p=0.93 and 0.59). In non-LBBB DCM patients the percentage of CS was significantly higher (4.0[1.55; 11.68]% versus 1.4[0.05;8.5]% in LBBB-DCM patients, p=0.047), whereas percentage of GZ and total fibrosis in both DCM groups was comparable (Fig.3A,B). DIR value was higher in patients with idiopathic LBBB than in HV (0.54±0.09 versus 0.34±0.1, p<0.001) while the percentage of GZ and CS was extremely low and did not differ from its amount in HV (Fig.3C,D). Conclusion: Neither focal (including midwall striae) nor interstitial fibrosis is associated with LBBB in patients with DCM. Diffuse inflammation in LBBB-DCM patients may contribute to the progression of systolic dysfunction but is not the reason for LBBB. The increased value of interstitial fibrosis in patients with LBBB may reflect latent diffuse process in myocardium inexorably leading to DCM development.

Serial quantitative stress perfusion cardiac magnetic resonance in patients undergoing coronary artery bypass grafting; prediction of symptomatic benefit

Abstract Background Serial multiparametric cardiovascular magnetic resonance (CMR) in patients undergoing coronary artery bypass grafting (CABG) may provide mechanistic insight into dynamic and persistent abnormalities of the myocardium in patients with stable coronary artery disease (CAD). Objectives To assess for dynamic CMR markers of myocardial hypoperfusion and cardiac remodelling in patients undergoing CABG. Methods Patients with CAD awaiting elective CABG were recruited into an observational cohort study. Baseline evaluation included bloods, Seattle Angina Questionnaire-7, and adenosine stress perfusion CMR. Automated fully quantitative stress and rest myocardial blood flow was calculated, alongside assessment of the visual ischaemic burden. Native and post-contrast septal T1 indices were also measured. Repeat evaluation at 6-12 months post CABG was performed. Results Of 43 patients who underwent serial evaluation with CMR (mean age 62.1±9.3, median LVEF 68% [IQR: 62-73%]), there was improvement in the median visual ischaemic burden (18% [IQR: 11-21] vs 42% [IQR: 27-51], P<0.001), mean global stress myocardial blood flow (1.5±0.5 ml/min/g vs 1.3±0.5 ml/min/g, P=0.002) and median global myocardial perfusion reserve (2.4 [IQR: 1.7-2.8] vs 1.7 [IQR: 1.4-2.2], P=0.002) following CABG. Greater improvement in the SAQ-7 summary score was associated with a larger visual ischaemic burden at baseline (ρ=0.44, P=0.004) and a greater decrease in the visual ischaemic burden following CABG (ρ=-0.38, P=0.02). Quantitative MBF metrics did not associate with baseline or change in SAQ-7 summary score. Mean LV extracellular matrix volume decreased following CABG (16.6±3.6ml/m2 vs 18.2±4.6ml/m2, P=0.009). Conclusion Multiparametric CMR identifies dynamic changes in markers of myocardial perfusion and interstitial fibrosis in patients following CABG. Visual assessment of inducible myocardial hypoperfusion may identify patients who will derive the most symptomatic benefit from CABG. The results, however, suggest an important degree of residual inducible ischaemia and an unclear clinical role for CMR-derived MBF calculations.Serial CMR perfusion dataAssociation of SAQ with perfusion

Left ventricular reverse remodeling and reduction of interstitial fibrosis in patients with severe aortic stenosis who underwent transcatheter aortic valve implantation

BackgroundLeft ventricular (LV) structural and functional changes have been reported in patients with aortic stenosis (AS) who have undergone transcatheter aortic valve implantation (TAVI); however, the relationship between change in LV structure and systolic function and tissue characteristics assessed via cardiovascular magnetic resonance imaging (CMRI) post-TAVI has been not fully elucidated. This study aimed to investigate this relationship in patients with severe AS who underwent TAVI and CMRI. MethodsIn this retrospective study, 65 patients who underwent TAVI and CMRI at the 6-month follow-up were analyzed. The relationship between percent changes in LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), and LV mass (LVM) (⊿LVEDV, ⊿LVESV, ⊿LVEF, and ⊿LVM) and those in the native T1 value (⊿native T1) was analyzed using a correlation analysis. Moreover, extracellular volume fraction (ECV) value changes were analyzed. ResultsThe ⊿native T1 significantly decreased from 1292.8 (1269.9–1318.4) ms at pre-TAVI to 1282.3 (1262.6–1310.2) ms at the 6-month follow-up (P = 0.022). A significant positive correlation between ⊿LVEDV, ⊿LVESV, and ⊿LVM and ⊿native T1 (r = 0.351, P = 0.004; r = 0.339, P = 0.006; r = 0.261, P = 0.035, respectively) and a tendency toward a negative correlation between ⊿LVEF and ⊿native T1 (r = −0.237, P = 0.058) were observed. The ECV value increased significantly from 26.7 % (25.3–28.3) to 28.2 % (25.7–30.5) (P = 0.002). ConclusionsThe decrease in native T1 might be associated with LV reverse remodeling. Evaluating structural and functional changes using CMRI may be useful for patient management.

Development and validation of a diagnostic nomogram to evaluate tubular atrophy/interstitial fibrosis of IgA nephropathy.

Background: IgA nephropathy (IgAN) is a cause of chronic kidney disease (CKD). Tubular atrophy/interstitial fibrosis is associated with IgAN prognosis. However, simple tools for predicting pathological lesions of IgAN remain limited. Our objective was to develop a tool for evaluating tubular atrophy/interstitial fibrosis in patients with IgAN. Methods: In this cross-sectional study, 410 biopsy-verified IgAN patients were included. The factors associated with the incident interstitial fibrosis or tubular atrophy in IgAN were confirmed by using logistic regression analysis. A nomogram was developed using logistic regression coefficients to evaluate tubular atrophy or interstitial fibrosis. Receiver operating characteristic curves (ROC) and calibration curves were used to determine the discriminative ability and predictive accuracy of the nomogram. Results: In this study, the IgAN patients with tubular atrophy or interstitial fibrosis were older and had a higher percentage of males, hypertension and urinary protein excretion (UPE), with high levels of serum cystatin C, serum creatinine, high-sensitivity C-reactive protein and serum C4. The eGFRcr-cys equation calculated using serum creatinine, cystatin C and UPE were considered independent influencing factors of tubular atrophy or interstitial fibrosis in patients with IgAN. Furthermore, the nomogram demonstrated good discrimination (AUC: 0.87, 95% CI 0.81 to 0.93) and calibration in the validation cohort. Conclusion: The eGFRcr-cys and UPE are associated with tubular atrophy or interstitial fibrosis in patients with IgAN. Diagnostic nomogram can predict tubular atrophy or interstitial fibrosis in IgAN.

Myocardial Interstitial Fibrosis in Hypertensive Heart Disease: From Mechanisms to Clinical Management.

Hypertensive heart disease (HHD) can no longer be considered as the beneficial adaptive result of the hypertrophy of cardiomyocytes in response to pressure overload leading to the development of left ventricular hypertrophy. The current evidence indicates that in patients with HHD, pathological lesions in the myocardium lead to maladaptive structural remodeling and subsequent alterations in cardiac function, electrical activity, and perfusion, all contributing to poor outcomes. Diffuse myocardial interstitial fibrosis is probably the most critically involved lesion in these disorders. Therefore, in this review, we will focus on the histological characteristics, the mechanisms, and the clinical consequences of myocardial interstitial fibrosis in patients with HHD. In addition, we will consider the most useful tools for the noninvasive diagnosis of myocardial interstitial fibrosis in patients with HHD, as well as the most effective available therapeutic strategies to prevent its development or facilitate its regression in this patient population. Finally, we will issue a call to action for the need for more fundamental and clinical research on myocardial interstitial fibrosis in HHD.

Evaluation of interstitial fibrosis in chronic kidney disease by multiparametric functional MRI and histopathologic analysis.

To investigate the diagnostic value of functional MRI to assess renal interstitial fibrosis in patients with chronic kidney disease (CKD). We prospectively recruited 80 CKD patients who underwent renal biopsies and 16 healthy volunteers to undergo multiparametric functional MRI examinations. The Oxford MEST-C classification was used to score the interstitial fibrosis. The diagnostic performance of functional MRI to discriminate interstitial fibrosis was evaluated by calculating the area under the receiver operating characteristic (ROC) curves. IgA nephropathy (60%) accounted for the majority of pathologic type in the CKD patients. Apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) was correlated with interstitial fibrosis (rho = -0.73). Decreased renal blood flow (RBF) derived from arterial spin labeling (rho = -0.78) and decreased perfusion fraction (f) derived from DWI (rho = -0.70) were accompanied by increased interstitial fibrosis. The T1 value from T1 mapping correlated with interstitial fibrosis (rho = 0.67) (all p < 0.01). The areas under the ROC curve for the discrimination of ≤ 25% vs. > 25% and ≤ 50% vs. > 50% interstitial fibrosis were 0.87 (95% confidence interval, 0.78 to 0.94) and 0.93 (0.86 to 0.98) by ADC, 0.84 (0.74 to 0.91) and 0.94 (0.86 to 0.98) by f, 0.93 (0.85 to 0.98) and 0.90 (0.82 to 0.96) by RBF, and 0.91 (0.83 to 0.96) and 0.77 (0.66 to 0.85) by T1, respectively. Functional MRI parameters were strongly correlated with the interstitial fibrosis of CKD. Therefore, it might a powerful tool to assess interstitial fibrosis of CKD noninvasively. • In CKD patients, the renal cortical ADC value decreased and T1 value increased significantly compared with healthy volunteers. • Functional MRI revealed significantly decreased renal perfusion in CKD patients compared with healthy volunteers. • The renal cortical ADC, f, RBF, and T1 values were strongly correlated with the interstitial fibrosis of CKD.

A meta-analysis of the effects of endothelial nitric oxide synthase 4ba polymorphism on renal interstitial fibrosis in diabetic nephropathy.

This study aimed to investigate the relationship between endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphism and renal interstitial fibrosis in patients with diabetic nephropathy (DN) via a meta-analysis, in the hope of providing guidance for the genotypic detection of DN. The Boolean logic search method was adopted. A literature search of PubMed, Medline, CNKI, and other databases from inception to June 2020 was performed using the search terms "eNOS 4b/a", "diabetes", "renal interstitial fibrosis", and "kidney disease". Literatures with a DN group, a non-nephropathy diabetic group, and a normal control group were screened. Review Manager software was employed to perform the meta-analysis. A total of 13 articles were included in the meta-analysis, the majority of which had a low risk of bias (i.e., medium and high quality). The results of the meta-analysis indicated that the genotypic distribution frequency of eNOS4bb in patients with DN was significantly lower than that in the non-nephropathy diabetic group (Z=3.19, P=0.001). The genotypic distribution frequency of eNOS4aa was significantly higher in non-nephropathy diabetic patients than in the normal control group (Z=2.57, P=0.01). The genotypic distribution frequency of eNOS4ba was not statistically different between patients with DN and non-nephropathy diabetic patients (Z=1.45, P=0.15). The genotypic distribution frequency of eNOS4bb in DN patients was significantly lower than that in the normal control group (Z=3.03, P=0.002); however, the genotypic distribution frequency of eNOS4ba was significantly greater than that of the normal controls (Z=2.36, P=0.02), as was that of eNOS4aa (Z=2.34, P=0.02). Genotypic polymorphism of eNOS 4b/a was closely related to DN. Moreover, the genotypic distribution frequency of eNOS4bb in DN renal interstitial patients was lower than that in non-nephropathy diabetic patients and normal controls.

La fibrosis intersticial miocárdica en la era de la medicina de precisión. El fenotipado basado en biomarcadores para un tratamiento personalizado

Myocardial interstitial fibrosis is a constant pathological finding in structural heart diseases of various etiologies that evolve with heart failure. Although fibrosis facilitates heart failure progression, until now no therapeutic strategy has been developed that ensures its reversal. A possible explanation for this may lie in the vision of myocardial interstitial fibrosis as a homogeneous lesion instead of a heterogeneous lesion in which different phenotypes can be distinguished using appropriate criteria. In addition, the notion that the heterogeneity of myocardial interstitial fibrosis may be cardiac disease-specific must be also considered when approaching this entity. Therefore, we propose that myocardial interstitial fibrosis represents a true challenge for transitioning from usual care to biomarker-based personalized treatment and precision medicine in heart failure. As a proof-of-concept, in this review we discuss the phenotyping of myocardial interstitial fibrosis in patients with heart failure attributable to hypertensive heart disease based on its histomolecular alterations and provide evidence of the prognostic relevance of the resulting stratification. Furthermore, we discuss the available information on some circulating biomarkers and certain pharmacological agents useful for noninvasive identification and personalized treatment, respectively, of those phenotypes.

1047 Increased interstitial fibrosis in patients with mitral valve prolapse and mitro-annular dysjunction

Abstract Background in patients with myxomatous mitral valve prolapse (MVP), mitral annular disjunction (MAD) has been associated with the presence of late gadolinium enhancement (LGE) at papillary muscle level and the risk of sudden cardiac death. However, patients with MAD but no detectable LGE still may have arrhythmia. We investigated the relation between MAD and the presence of interstitial fibrosis in the basal inferior left ventricular myocardium. Methods 28 patient with MVP and associated MAD underwent Cardiovascular Magnetic Resonance imaging (CMR) at 1.5 T scanner (Aera, Siemens Medical Solutions, Erlangen, Germany). Exclusion criteria were ischemic heart disease, infiltrative cardiomyopathy and contraindication to CMR. 12 patients with mitral valve regurgitation but no MAD and 10 patients without mitral disease served as the control group. MAD severity was measured from LA wall-posterior MV leaflet junction to the top of the LV infero-basal wall during end systole. Insterstitial fibrosis was assessed by calculating the extracellular volume (ECV) from T1 mapping of the left ventricular basal slice acquired before and after Gadolinium injection. Results Mean age was 47,5+\-23,3 years and 60% were male. ECV was higher in patients with MVP compared with controls (basal septum: 0.27 ± 0.04 vs 0.23 ± 0.03 p = 0.006; basal inferoposterior wall 0.28 ± 0.03 vs 0.23 ± 0.02 p = 0.003) and there was a significant correlation between MAD severity and ECV of the basal inferior wall (spearman rho 0.68, p &amp;lt; 0.0001) (Figure 1). Among MVP patients, ECV of the basal inferoposterior wall was higher in patients positive for LGE in the papillary muscles (ECV 0.31 ± 0.03 vs 0.27 ± 0.03 p 0,004). Conclusion In MVP patients, MAD severity was associated with a higher amount of interstitial fibrosis even in the absence of detectable macroscopic fibrosis in the papillary muscle region. Abstract 1047 Figure 1

Myocardial interstitial fibrosis in the era of precision medicine. Biomarker-based phenotyping for a personalized treatment.

Myocardial interstitial fibrosis is a constant pathological finding in structural heart diseases of various etiologies that evolve with heart failure. Although fibrosis facilitates heart failure progression, until now no therapeutic strategy has been developed that ensures its reversal. A possible explanation for this may lie in the vision of myocardial interstitial fibrosis as a homogeneous lesion instead of a heterogeneous lesion in which different phenotypes can be distinguished using appropriate criteria. In addition, the notion that the heterogeneity of myocardial interstitial fibrosis may be cardiac disease-specific must be also considered when approaching this entity. Therefore, we propose that myocardial interstitial fibrosis represents a true challenge for transitioning from usual care to biomarker-based personalized treatment and precision medicine in heart failure. As a proof-of-concept, in this review we discuss the phenotyping of myocardial interstitial fibrosis in patients with heart failure attributable to hypertensive heart disease based on its histomolecular alterations and provide evidence of the prognostic relevance of the resulting stratification. Furthermore, we discuss the available information on some circulating biomarkers and certain pharmacological agents useful for noninvasive identification and personalized treatment, respectively, of those phenotypes.

Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload-associated maladaptation.

Cardiac pressure overload (for example due to aortic stenosis) induces irreversible myocardial dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis in patients. In contrast to adult, neonatal mice can efficiently regenerate the heart after injury in the first week after birth. To decipher whether insufficient cardiac regeneration contributes to the progression of pressure overload dependent disease, we established a transverse aortic constriction protocol in neonatal mice (nTAC). nTAC in the non-regenerative stage (at postnatal day P7) induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, nTAC in the regenerative stage (at P1) largely prevented these maladaptive responses and was in particular associated with enhanced myocardial angiogenesis and increased cardiomyocyte proliferation, which both supported adaptation during nTAC. A comparative transcriptomic analysis between hearts after regenerative versus non-regenerative nTAC suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response. Our new nTAC model can be used to identify mediators of adaptation during pressure overload and to discover novel potential therapeutic strategies.

Combination of Functional Magnetic Resonance Imaging and Histopathologic Analysis to Evaluate Interstitial Fibrosis in Kidney Allografts.

Recent developments indicated that functional magnetic resonance imaging (MRI) could potentially provide noninvasive assessment of kidney interstitial fibrosis in patients with kidney diseases, but direct evidence from histopathology is scarce. We aimed to explore the diagnostic utilities of functional MRI for the evaluation of kidney allograft interstitial fibrosis. We prospectively examined 103 kidney transplant recipients who underwent for-cause biopsies and 20 biopsy-proven normal subjects with functional MRI. Histomorphometric analyses of interstitial fibrosis and peritubular capillary densities were performed on digitally scanned Masson's trichrome- and CD34-stained slides, respectively. The performances of functional MRI to discriminate interstitial fibrosis were assessed by calculating the area under the curve using receiver-operating characteristic curve. Main pathologic findings in this single-center cohort were representative of common diagnostic entities in the kidney allografts, with rejection (32%) and glomerulonephritides (31%) accounting for the majority of diagnoses. Apparent diffusion coefficient from diffusion-weighted imaging correlated with interstitial fibrosis (ρ=-0.77; P<0.001). Additionally, decreased arterial spin labelings were accompanied by peritubular capillary density reductions (r=0.77; P<0.001). Blood oxygen level-dependent (BOLD) imaging demonstrated cortical hypoxia with increasing interstitial fibrosis (ρ=0.61; P<0.001). The area under the curve for the discrimination of ≤25% versus >25% interstitial fibrosis and ≤50% versus >50% interstitial fibrosis were 0.87 (95% confidence interval [95% CI], 0.79 to 0.93) and 0.88 (95% CI, 0.80 to 0.93) by apparent diffusion coefficient, 0.92 (95% CI, 0.85 to 0.97) and 0.94 (95% CI, 0.87 to 0.98) by arterial spin labeling, 0.81 (95% CI, 0.72 to 0.88) and 0.86 (95% CI, 0.78 to 0.92) by perfusion fraction, 0.79 (95% CI, 0.69 to 0.87) and 0.85 (95% CI, 0.76 to 0.92) by BOLD imaging, respectively. Functional MRI measurements were strongly correlated with kidney allograft interstitial fibrosis. The performances of functional MRI for discriminating ≤50% versus >50% interstitial fibrosis were good to excellent.

Hepatocyte Growth Factor-Secreting Mesothelial Cell Sheets Suppress Progressive Fibrosis in a Rat Model of CKD.

Although hepatocyte growth factor (HGF) has antifibrotic effects and is involved in angiogenesis and vasodilation, systemic administration of HGF to prevent kidney fibrosis is not a feasible strategy for suppressing interstitial fibrosis in patients with CKD. We investigated a novel therapy involving HGF transgenic cell sheets grown in culture from human mesothelial cells and administered to rats with unilateral ureteral obstruction (UUO). We compared progression of fibrosis in rats with UUO that received one of five interventions: HGF-transgenic mesothelial cell sheets transplanted to the kidney surface, HGF-transgenic mesothelial cell sheets transplanted to thigh, mesotherial cell sheets transplanted to kidney, no sheets, or HGF injections. HGF transgenic cell sheets transplanted to the kidney strongly suppressed the induction of myofibroblasts and collagen in the kidney for 28 days; other interventions did not. Additionally, the HGF-secreting cell sheets ameliorated loss of peritubular capillaries and maintained renal blood flow. These findings suggest that cell sheet therapy is a novel and promising strategy for inhibiting progressive fibrosis in CKD.

Accuracy of Urinary Epidermal Growth Factor to Creatinine Ratio to Predict 24-Hour Urine Epidermal Growth Factor and Interstitial Kidney Fibrosis in Patients with IgA Nephropathy.

Urinary levels of EGF may be a noninvasive biomarker of the degree of interstitial fibrosis. However, all the available data are based on studies that examined the EGF/creatinine ratio in spot urine samples. The agreement between EGF/creatinine ratio and 24-hours EGF excretion has not been analyzed, neither has it been established which of these two measurements is a better predictor of the degree of interstitial fibrosis. To investigate whether the EGF/creatinine ratio can predict 24-hours EGF, and which of these two measures is a better predictor of interstitial fibrosis in patients with IgA nephropathy (IgAN). This is a cross-sectional study including 80 patients with IgAN. EGF levels were measured by ELISA in spot second-morning and 24-hours urine samples. We analyzed the concordance between these two measures and their respective ability to predict interstitial kidney fibrosis. The intraclass correlation coefficient between 24-hours and spot EGF/creatinine was 0.63 (95% CI: 0.54 - 0.70), bias was 2.7 µg/mL (95% CI: 2.1 - 7.5). Passing-Bablok regression did not show a significant deviation from linearity (p = 0.72). Bland-Altman showed a systematic and proportional error between both EGF measures. Spot EGF/creatinine ratios overestimated the 24-hours EGF at low excretion values and underestimated it at high excretion values. In univariate analyses, 24-hours excretion of EGF was a better predictor of interstitial fibrosis than spot EGF/creatinine ratio (R2: 0.43 vs. 0.30, p = 0.000). In multivariate analyses, the 24-hours excretion of EGF plus GFR, significantly improved the prediction of interstitial fibrosis when compared with GFR alone (R2: 0.52 vs. 0.39, p = 0.000). When spot-urine EGF was introduced instead of the 24-hours excretion, the model was statistically significant but had a lower predictive capacity (R2: 0.46 spot EGF/creatinine vs. R2: 0.52 24-hours EGF excretion, p = 0.000). The 24-hours excretion of EGF should be considered as the first-choice measure to estimate the interstitial fibrosis. The EGF/creatinine ratio cannot accurately estimate the total EGF excretion of but it also improves the estimation of the fibrosis surface, and, consequently, could be an alternative whenever 24-hours urine samples cannot be obtained.

Association of high body mass index with development of interstitial fibrosis in patients with IgA nephropathy

BackgroundThe worldwide prevalence of obesity is increasing. Obesity is associated with a variety of chronic diseases, including chronic kidney disease. Several studies suggested that body mass index (BMI) could be an independent risk factor for progression of IgA nephropathy (IgAN). However, whether high BMI is associated with progression of IgAN remains uncertain.MethodsThis retrospective study included patients with biopsy proven IgAN from 2006 to 2017 in Sichuan Provincial People’s Hospital. BMI was categorized according to the WHO Asian guideline: underweight (< 18.5 kg/m2), normal weight (18.5-25 kg/m2), overweight (25-28 kg/m2) and obese (≥28 kg/m2). The main outcome was development of end-stage renal disease (ESRD) or a decline in eGFR by at least 30%. The association of BMI and IgAN progression was determined by propensity-score-matched cohort analysis.ResultsFour hundred eighty one patients with IgAN were finally enrolled in this study. The mean age was 37 ± 11 years and 40.3% were men. There was no significant difference in clinical and pathological characteristics among the four-group patients categorized by BMI. After matching with propensity scores, no significant correlation between BMI and renal outcomes was seen. However, compared with the reference group (18.5≦BMI≦25 kg/m2), being overweight (odd ratio [OR], 2.28; 95%CI: 1.06–4.88; P = 0.034) and obese (OR, 3.43; 95%CI: 1.06–11.04; P = 0.039) was associated with a high risk of interstitial fibrosis. In the cross figure demonstrating the association of BMI subgroup and interstitial fibrosis on renal outcomes, ORs of interstitial fibrosis groups were higher than those of no interstitial fibrosis. Compared with other BMI subgroups, patients with 18.5-25 kg/m2 had lowest ORs.ConclusionsHigh BMI and interstitial fibrosis were associated with progression of IgAN. Interstitial fibrosis appears to be common in IgAN patients with elevated BMI.

Serum uromodulin as an early biomarker of tubular atrophy and interstitial fibrosis in patients with glomerulopathies

To assess the significance of the serum uromodulin (Tamm-Horsfall protein - THP) concentration (Sumo) as an early biomarker of tubular atrophy (TA) and interstitial renal fibrosis (IF) in patients with glomerulopathies. 84 patients with glomerulopathy and 11 practically healthy persons (control) were examined. Uromodulin concentrations in serum and urine (Uumo) were measured, renal excretion of this protein and the estimated glomerular filtration rate (eGFR) were established. A semi-quantitative assessment of nephrobioptates was performed. Sumo decreases with a minimum expression of tubular atrophy (TA) or interstitial fibrosis (IF), when the values of eGFR still remain normal. Variations of such excretory parameters of THP as Uumo, daily excretion, and ratio: urinary uromodulin / urinary creatinine, did not manifest a similar trend. Sumo is promising as an early biomarker of fibrotic and atrophic renal damage. The parameters of renal excretion of THP do not seem to have this property. The reason for the delay in the decline of Uumo in the progression of CKD as compared to the decrease in Sumo seems to be the need to maintain a sufficient Uumo to counteract urinary tract infection and stone formation.

Virtual Touch Tissue Quantification for Assessing Renal Pathology in Idiopathic Nephrotic Syndrome

The aim of this study was to evaluate Virtual Touch tissue quantification in assessing renal interstitial fibrosis in patients with idiopathic nephrotic syndrome. Ninety patients with idiopathic nephrotic syndrome were assigned to mild, moderate and severe groups depending on the degree of renal interstitial fibrosis on histopathologic examination of renal biopsy specimens. Thirty healthy patients were also selected as the control group. Virtual Touch tissue quantification was performed to measure the shear wave velocity of the renal parenchyma. There was no statistically significant difference in shear wave velocity between the mild and control groups (p > 0.05); however, the moderate and severe groups did significantly differ compared with the control (p < 0.001). The area under the receiver operating characteristic curve value for the shear wave velocity of renal interstitial fibrosis in the moderate group versus the control and mild groups together was 0.869 (95% confidence interval: 0.791–0.947) and that in the severe group versus the control, mild and moderate groups together was 0.954 (95% confidence interval: 0.917–0.998). The corresponding best cutoff points were 2.41 and 2.77 m/s, with sensitivities of 91.7% and 86.8%, specificities of 78.0% and 92.0%, negative predictive values 0.907 and 0.907, positive predictive values 0.800 and 0.971 and Youden index values of 0.697 and 0.788, respectively. Virtual Touch tissue quantification may non-invasively and quantitatively estimate the degree of renal interstitial fibrosis in patients with idiopathic nephrotic syndrome as a baseline for monitoring progression and treatment response.

Value of urinary levels of interleukin-6, epidermal growth factor, monocyte chemoattractant protein type 1 and transforming growth factor β1 in predicting the extent of fibrosis lesions in kidney biopsies of patients with IgA nephropathy

ObjectiveTo analyse the associations between urinary levels of IL-6 EGF, MCP-1 and TGFβ1 and clinical, biochemical and histopathological characteristics in patients with primary IgA nephropathy and their ability to predict the extent of lesions of glomerular and/or interstitial sclerosis. Patients and methodsA total of 58 patients with IgA nephropathy were studied. We determined the urine levels of IL-6, EGF, MCP-1, and TGFβ1 at the time of diagnosis. The extent of glomerular and interstitial fibrosis was analysed by quantitative morphometry and kidney biopsies were classified according to the Oxford criteria. We analysed the ability of these molecules to predict the extent of glomerular and interstitial fibrosis lesions. ResultsIL-6, TGFβ1 and MCP-1 were associated with focal glomerulosclerosis and interstitial fibrosis extension but not with the presence of mesangial, extracapillary or endocapillary proliferation. EGF showed a negative association with interstitial fibrosis. By categorising patients according to the Oxford classification, patients with T1 and T2 scores had significantly higher levels of IL-6, MCP-1, TGF-β1 and significantly lower levels of EGF than patients with T0 scores. By multiple regression and logistic regression analyses, the levels of MCP-1, IL-6 and EGF were independent predictors of the fibrosis surface, after adjusting for age and eGFR. ConclusionThe urinary concentration of IL-6, EGF and MCP-1 provides additional information that significantly improves the estimation of the surface of interstitial fibrosis in patients with IgA nephropathy.

Valor de los niveles urinarios de interleucina 6, factor de crecimiento epidérmico, proteína quimioatractante de monocitos de tipo 1 y factor de crecimiento transformante β1 para la predicción de la extensión de las lesiones de fibrosis en biopsias de enfermos con nefropatía IgA

ObjectiveTo analyse the associations between urinary levels of IL-6 EGF, MCP-1 and TGFβ1 and clinical, biochemical and histopathological characteristics in patients with primary IgA nephropathy and their ability to predict the extent of lesions of glomerular and/or interstitial sclerosis. Patients and methodsA total of 58 patients with IgA nephropathy were studied. We determined the urine levels of IL-6, EGF, MCP-1, and TGFβ1 at the time of diagnosis. The extent of glomerular and interstitial fibrosis was analyzed by quantitative morphometry and kidney biopsies were classified according to the Oxford criteria. We analysed the ability of these molecules to predict the extent of glomerular and interstitial fibrosis lesions. ResultsIL-6, TGFβ1 and MCP-1 were associated with focal glomerulosclerosis and interstitial fibrosis extension but not with the presence of mesangial, extracapillary or endocapillary proliferation. EGF showed a negative association with interstitial fibrosis. By categorising patients according to the Oxford classification, patients with T1 and T2 scores had significantly higher levels of IL-6, MCP-1, TGF-β1 and significantly lower levels of EGF than patients with T0 scores. By multiple regression and logistic regression analyses, the levels of MCP-1, IL-6 and EGF were independent predictors of the fibrosis surface, after adjusting for age and eGFR. ConclusionThe urinary concentration of IL-6, EGF and MCP-1 provides additional information that significantly improves the estimation of the surface of interstitial fibrosis in patients with IgA nephropathy.

Lysine 63 ubiquitination is involved in the progression of tubular damage in diabetic nephropathy

The purpose of our study was to evaluate how hyperglycemia (HG) influences Lys63 protein ubiquitination and its involvement in tubular damage and fibrosis in diabetic nephropathy (DN). Gene and protein expression of UBE2v1, a ubiquitin-conjugating E2-enzyme variant that mediates Lys63-linked ubiquitination, and Lys63-ubiquitinated proteins increased in HK2 tubular cells under HG. Matrix-assisted laser desorption/ionization-time of flight/tandem mass spectrometry identified 30 Lys63-ubiquitinated proteins, mainly involved in cellular organization, such as β-actin, whose Lys63 ubiquitination increased under HG, leading to cytoskeleton disorganization. This effect was reversed by the inhibitor of the Ubc13/UBE2v1 complex NSC697923. Western blot analysis confirmed that UBE2v1 silencing in HK2 under HG, restored Lys63-β-actin ubiquitination levels to the basal condition. Immunohistochemistry on patients with type 2 diabetic (T2D) revealed an increase in UBE2v1- and Lys63-ubiquitinated proteins, particularly in kidneys of patients with DN compared with control kidneys and other nondiabetic renal diseases, such as membranous nephropathy. Increased Lys63 ubiquitination both in vivo in patients with DN and in vitro, correlated with α-SMA expression, whereas UBE2v1 silencing reduced HG-induced α-SMA protein levels, returning them to basal expression. In conclusion, UBE2v1- and Lys63-ubiquitinated proteins increase in vitro under HG, as well as in vivo in T2D, is augmented in patients with DN, and may affect cytoskeleton organization and influence epithelial-to-mesenchymal transition. This process may drive the progression of tubular damage and interstitial fibrosis in patients with DN.-Pontrelli, P., Conserva, F., Papale, M., Oranger, A., Barozzino, M., Vocino, G., Rochetti, M. T., Gigante, M., Castellano, G., Rossini, M., Simone, S., Laviola, L., Giorgino, F., Grandaliano, G., Di Paolo, S., Gesualdo, L. Lysine 63 ubiquitination is involved in the progression of tubular damage in diabetic nephropathy.