Fibrosis In Biopsies Research Articles

Fibroblast activation protein is a cellular marker of fibrotic activity in canine idiopathic pulmonary fibrosis.

Canine idiopathic pulmonary fibrosis (CIPF) is a progressive fibrotic interstitial lung disease of unknown etiology, afflicting aging West Highland white terriers (WHWTs) and leading to progressive respiratory failure. Fibroblast activation protein (FAP), a protease overexpressed in many cancers, is upregulated in idiopathic pulmonary fibrosis in humans. The aim of this study was to investigate FAP as a marker of active fibrosis in lung biopsies from WHWTs affected with CIPF, as well as the potential of plasmatic FAP as a biomarker. After establishing a scoring system to evaluate the severity and activity of fibrosis on histopathological lung sections, anti-FAP immunohistochemistry was performed on healthy and CIPF samples. FAP expression was characterized using both visual and digital quantitative pathology software analyses and then correlated to fibrosis severity and activity. Levels of plasmatic FAP in WHWTs affected with CIPF were measured by enzyme-linked immunosorbent assay and compared with healthy dogs. Lung samples from 22 WHWTs affected with CIPF were collected. According to the fibrosis scoring system, they were classified as cases of mild (5), moderate (9) and severe (8) fibrosis and were attributed scores of fibrosis activity. Fifteen healthy lung samples were classified as non-fibrotic. Healthy lung samples were FAP-negative, whereas fibroblasts were FAP-positive in 20 CIPF samples. FAP immunohistochemical expression correlated mildly with fibrosis severity (p < 0.05; R 2 = 0.22) but highly with fibrosis activity scores (p < 0.001; R 2 = 0.68). Digital image analysis detected a higher percentage of FAP-positive cells in areas of active fibrosis (p < 0.001) and FAP-positive cells were distributed outside mature fibrosis lesions, clustered in active fibrosis areas or scattered within alveolar septa. On the other hand, plasmatic FAP was significantly lower in dogs affected with CIPF compared with healthy dogs (p < 0.01). In conclusion, this study provides a valuable histological scoring system to assess the severity and activity of fibrosis in CIPF. It demonstrates that FAP is a good cellular marker of fibrotic activity in CIPF, and thus constitutes a promising target to be exploited for diagnostic and therapeutic applications. Additionally, it suggests that plasmatic FAP, although non-specific, could be altered in CIPF.

Impact of non-alcoholic fatty liver disease and fibrosis on mortality and kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A multi-cohort longitudinal study.

To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease. Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events. In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events. In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events.

Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: A two-sample mendelian randomization study.

The results of current studies on metabolic-dysfunction associated steatotic liver disease (MASLD)-related diseases, cognition and dementia are inconsistent. This study aimed to elucidate the effects of MASLD-related diseases on cognition and dementia. By using single-nucleotide polymorphisms (SNPs) associated with different traits of NAFLD (chronically elevated serum alanine aminotransferase levels [cALT], imaging-accessed and biopsy-proven NAFLD), metabolic dysfunction-associated steatohepatitis, and liver fibrosis and cirrhosis, we employed three methods of mendelian randomization (MR) analysis (inverse-variance weighted [IVW], weighted median, and MR-Egger) to determine the causal relationships between MASLD-related diseases and cognition and dementia. We used Cochran's Q test to examine the heterogeneity, and MR-PRESSO was used to identify outliers (NbDistribution = 10000). The horizontal pleiotropy was evaluated using the MR-Egger intercept test. A leave-one-out analysis was used to assess the impact of individual SNP on the overall MR results. We also repeated the MR analysis after excluding SNPs associated with confounding factors. The results of MR analysis suggested positive causal associations between MASLD confirmed by liver biopsy (p of IVW = 0.020, OR = 1.660, 95%CI = 1.082-2.546) and liver fibrosis and cirrhosis (p of IVW = 0.009, OR = 1.849, 95%CI = 1.169-2.922) with vascular dementia (VD). However, there was no evidence of a causal link between MASLD-related diseases and cognitive performance and other types of dementia (any dementia, Alzheimer's disease, dementia with lewy bodies, and frontotemporal dementia). Sensitivity tests supported the robustness of the results. This two-sample MR analysis suggests that genetically predicted MASLD and liver fibrosis and cirrhosis may increase the VD risk. Nonetheless, the causal effects of NAFLD-related diseases on VD need more in-depth research.

Biomarkers of fibrosis and portal hypertension in Fontan-associated liver disease in children and adults

BackgroundFontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD. AimInvestigate biomarkers correlating with severity of liver biopsy fibrosis in FALD. MethodsA retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores. ResultsSixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa. ConclusionsAPRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients.

Development of a Predictive Model for Assessing the Risk of Severe Renal Fibrosis in Kidney Biopsy

Development of a Predictive Model for Assessing the Risk of Severe Renal Fibrosis in Kidney Biopsy

Long-term Outcome of Asymptomatic Patients With Graft Fibrosis in Protocol Biopsies After Pediatric Liver Transplantation.

The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood. We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT. In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently ( P = 0.027). At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care.

WTP2.10 A retrospective study of effect of donor obesity on fibrosis and kidney outcome in live donor kidney transplantation

Abstract Aims Donor obesity has increased over the last decade. The aim of this study was to assess the effect of donor obesity on fibrosis in pre-implantation biopsy and kidney outcomes in live kidney transplants. Methods A series of 288 live kidney donors between 1998 and 2010 were studied. The series was divided into three groups according to the donor Body Mass Index (BMI); Normal BMI 17-24.9 (n=119), overweight BMI 25–29.9 (n=118) and obese BMI ≥30 (n=51). Donor and recipient demographics were gathered and recipient post-transplant renal function up to five years was retrieved. Fibrosis level in pre-implantation biopsies was analysed and graft and recipient survival were assessed. Results Hypertension and live kidney donor profile index LKDPI were statistically significantly higher in obese donors compared with non-obese donors (p=0.004 and p&amp;lt;0.001 respectively). Donor creatinine levels for obese group were comparable to the other two groups over three post-operative years (p=0.933). Fibrosis analysis showed no statistically significant difference among the three BMI groups (p=0.063). Donor obese group had statistically significant higher 5 year graft and patient loss rate compared with non-obese BMI groups (p=0.018 and p=0.015 respectively). Recipient post-operative creatinine levels showed no statistically significant differences among the three BMI groups (p=0.393). Similarly, fibrosis in pre-implantation biopsies had no statistically significant impact on recipient post-operative creatinine levels (p=0.243). Conclusions Donor obesity has no significant impact on fibrosis in the pre-implantation biopsy and on recipient post-operative kidney function. However, Donor obesity results in lower five-year graft and patient survival rate.

Importance of Follow-Up Biopsies in the Prediction of Renal Allograft Survival Following Polyomavirus-Associated Nephropathy.

Allograft biopsy is the gold standard for diagnosing polyomavirus-associated nephropathy. We aimed to establish the effects of histopathologic findings proposed by the Banff Polyomavirus Working Group on graft outcome. We also aimed to understand the clinical importance of follow-up biopsies for patients with polyomavirus-associated nephropathy. Our study included 22 patients with polyomavirus-associated nephropathy. All biopsies were classified according to the latest Banff Polyomavirus Working Group classification. Follow-up biopsies of all patients were evaluated in detail. The mean interval between polyomavirus-associated nephropathy and transplant was 10 ± 1.6 months. Of 22 patients, biopsy revealed stage 1 in 3 (13.6%), stage 2 in 17 (77.3%), and stage 3 in 2 patients (9.1%). Fourteen patients (63.6%) had polyomavirus viral load 3, 5 (22.7%) had polyomavirus viral load 2, and 3 had polyomavirus viral load 1. Among patients included in analyses, 18.2% had antibody-mediated rejection and 27.2% had T-cell-mediated rejection simultaneously with polyomavirus-associated nephropathy. Graft loss increased with increasing polyomavirus-associated nephropathy class and polyomavirus viral load (P = .015 and P = .002, respectively). The mean time of graft survival decreased with increasing degree of tubulitis, interstitial inflammation, plasma infiltration, and neutrophil infiltration. Patients with interstitial fibrosis, glomerular polyoma, and cortical plus medullar involvement showed earlier graft loss. Follow-up biopsies showed that diffuse interstitial fibrosis or persistent inflam-mation negatively influenced graft loss. The Banff Polyomavirus Working Group's schema significantly correlated with graft outcome. Early detection of polyomavirus-associated nephro-pathy and subsequent detection of persistent inflammation and interstitial fibrosis and tubular atrophy in follow-up biopsies and modification of immunosuppressive therapy can successfully prevent graft loss.

#5672 CORTICAL IRON DEPOSITION ASSESSED BY MAGNETIC RESONANCE IMAGE IS ASSOCIATED WITH KIDNEY FIBROSIS

Abstract Background and Aims Fibrosis is responsible for the loss of kidney function as a result of several insults, such as ischemia-reperfusion injury or hyperfiltration. This process can continue even after cessation of the primary insult, as documented in acute kidney injury to chronic kidney disease. Recently, we discovered that iron accumulation is a hallmark of fibrotic diseases [1]. We found that in mouse models, iron deposition in the kidney accompanies the progression of the disease. Based on these results, we propose that chronic-low grade hemolysis produced in situation like ischemia-reperfusion injury may be one of the drivers of fibrosis through the damage that the filtrated hemolytic iron cause to the kidneys. Early detection of this iron could help the detection of ongoing fibrogenesis and improve the outcomes by prompt intervention. The challenge of this approach is the lack of non-invasive markers of fibrosis. We evaluated if magnetic resonance image (MRI)-based detection of iron levels in the kidney are correlated to fibrosis in biopsies from kidney transplant recipients. Method After approval from the Institutional Revision Board, we carried out a transversal study in our center between 2020 and 2021. We evaluated iron deposits through MRI in patients who underwent a kidney biopsy (per protocol or by clinical indication) and its association with histological parameters. MRI was performed at the same period the biopsy was done. Iron deposits were estimated by using the R2* sequence considering the Grassedonio protocol [2]. Results We collected data from 15 kidney transplant recipients. Mean age was 58.3 years old. Mean time from kidney transplant to the biopsy was 4.3 years and mean eGFR was 44.4 ml/min/1.73 m2.We analyzed by MRI the R2* signal in the kidney cortex, and their level of fibrosis measured on the biopsies (IFTA score, interstitial fibrosis and tubular atrophy). We found that patients with high IFTA score (2 and 3) presented with significantly higher R2* signal (p = 0.005), than patients with low IFTA score (0 and 1). We also found positive and significant correlation between IFTA (0-3) and iron deposits (Spearman correlation index: r = 0.7537, p = 0.0012). Conclusion Iron deposits in the kidney are higher in patients with more fibrosis, and its detection through MRI could be considered a non-invasive marker.

Evaluation of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Renal Allograft Biopsies:- Comparison of Visual Analysis with Morphometric Quantification and its Correlation with Renal Function

ABSTRACT Introduction: With the increase in number of allografts being performed, the frequency of chronic allograft nephropathy (CAN) has also increased. It is characterized clinically by a progressive decline in glomerular filtration rate, and histologically, by a progressive interstitial fibrosis (IF) and tubular atrophy (TA) which can even be seen in recipients with good allograft function. Objectives: To compare visual analysis with morphometric quantification of interstitial fibrosis and tubular atrophy (IFTA) in renal allograft biopsies and its correlation with renal function. Materials and Methods: A total of 29 renal allograft biopsies were evaluated for fibrosis and tubular atrophy by light microscopy by visual method on Masson’s trichrome-stained and PAS-stained sections, respectively, as well as by computer-assisted morphometry. IFTA was graded as per Banff working classification of renal allograft pathology, which includes a four-point estimate of the prevalence of IF (ci score) and for tubular atrophy (ct score). The estimation of IF and TA by the two methods was correlated with the renal function state; the serum creatinine level. Result: The percentage of IFTA showed statistically significant correlation between manual and morphometric methods (P &lt; 0.001). Each of the method was correlated with serum creatinine level. IF showed a good correlation with serum creatinine by both the methods; however, no correlation could be established between TA and serum creatinine by either method. Conclusion: When calculating scoring IFTA as per Banff criteria, by either the visual method or the morphometric method, there was a significant correlation between the two methods. However when expressed only as a percentage of total area, the visual method was associated with slight overestimation of both the parameters.

Reproducibility and Generalizability of the Web-Based Tool to Predict Lamina Propria Fibrosis in Eosinophilic Esophagitis.

We investigated reproducibility and generalizability of the recently developed web-based model to predict lamina propria fibrosis (LPF) in esophageal biopsies with inadequate lamina propria (LP) from patients with eosinophilic esophagitis (EoE) using an independent dataset (N = 183). For grade and stage scores of LPF, the area under the curve for predictive model was 0.77 (0.69-0.84) and 0.75 (0.67-0.82), and its accuracy was 78% and 72%, respectively. These model performance metrics were similar to that of the original model. A significant positive correlation was noted between the models' predictive probability and the grade and stage of LPF assessed by a pathologist (grade: r2 = 0.48, P < 0.001; and stage: r2 = 0.39, P < 0.001). These results support the reproducibility and generalizability of the web-based model to predict the presence of LPF in esophageal biopsies with inadequate LP in EoE. Additional studies are warranted to refine the web-based predictive models to provide predictive probability for sub-scores of LPF severity.

Combination of everolimus and low-dose tacrolimus controls histological liver allograft injury as sufficiently as high-dose tacrolimus.

The combination of everolimus (EVR) and low-dose tacrolimus (lowTAC) prevents T cell-mediated rejection of liver grafts as sufficiently as high-dose tacrolimus (highTAC) and mycophenolate, but is associated with a preserved kidney function within the first years after orthotopic liver transplantation (OLT). However, none of the available studies assessed the histological pattern of graft injury or fibrosis in surveillance biopsies (svLbx). All svLbx taken under at least one month of stable immunosuppression with either EVR (aim 3-8 ng/ml) combined with lowTAC (aim 3-5 ng/ml) or highTAC (aim 5-8 ng/ml) combined with mycophenolate (500-1500 mg/day) within the first three to four years after OLT at our center were included. Patients who were switched to EVR because of insufficient control of alloreactivity were excluded. Reasons for switches to EVR were mainly malignancies before or after OLT, or chronic kidney injury. We were able to include 20 svLbx with EVR/lowTAC and 49 with highTAC/mycophenolate. Both groups had similar liver enzymes and similar kidney function. The EVR/lowTAC group exhibited lower TAC trough levels at svLbx (4.4 vs. 6.6 ng/ml; p<.001) in comparison to highTAC/mycophenolate. Histological graft injury quantified by the rejection activity index and hepatitis activity index (Ishak), as well as fibrosis were not significantly different between the EVR/lowTAC and highTAC/mycophenolate groups. Likewise, subclinical TCMR, histological criteria justifying immunosuppression minimization, and steatosis had equal prevalence in both regimens. Immunosuppression was adjusted according to the svLbx findings. Immunosuppression regimens had similarly low rates of rejection after immunosuppression reduction, when relevant graft injury was absent in the biopsy. In conclusion, EVR/lowTAC seems to control alloreactivity and histological graft injury as sufficiently as highTAC/mycophenolate within the first 3-4 years after OLT.

Challenges in Inter-rater Agreement on Lamina Propria Fibrosis in Esophageal Biopsies.

Mucosal biopsies in eosinophilic esophagitis (EoE) can exhibit lamina propria (LP) fibrosis, which may portend stenotic complications; however, the histologic diagnosis of LP fibrosis is subjective. We sought to assess and improve the consistency of LP fibrosis diagnosis among our pathologist group. At a large pediatric hospital, 25 esophageal biopsy slides from 19 patients (16 with EoE) exhibiting a wide spectrum of LP area, artifacts, and fibrosis severity were scanned into whole-slide images. Staff pediatric pathologists (n = 8) separate from the authors classified each biopsy by LP adequacy and fibrosis severity 1 month before and after completion of an educational tutorial. Consensus was defined as >70% agreement. At baseline, 16/25 (64%) cases reached consensus for no fibrosis (n = 3), fibrosis (n = 7), or inadequate LP (n = 6); agreement was fair (α = 0.34). Post-tutorial, 13/25 (52%) cases reached consensus for no fibrosis (n = 2), fibrosis (n = 7), or inadequate LP (n = 4); agreement was again fair (α = 0.33). There was moderate agreement in grading of fibrosis severity (α = 0.54). We document only fair-to-moderate agreement in the diagnosis of esophageal LP fibrosis and adequacy in a large pediatric pathologist group despite targeted education, highlighting a challenge in incorporating this feature into EoE research and clinical decision-making.

Shear-wave elastography for evaluation of hepatic stiffness in chronic viral hepatitis B and C.

To analyse the consistency between 2D shear-wave elastography (2D-SWE) stiffness and fibrosis in liver biopsy in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The secondary aim of the study was to analyse the consistency between liver stiffness in 2D-SWE and transient elastography (TE) measurements in patients with chronic hepatitis B and C. The study compared the results of hepatic stiffness assessment with 2D-SWE to available past liver biopsy reports in 153 patients with chronic HBV (n = 51) and HCV (n = 102) infection. In 43 patients with both hepatitides HBV (n = 8) and HCV (n = 35) we performed FibroScan on the same day as 2D-SWE. The appropriate statistical tests were applied for the analysis. Stiffness values analysed in the whole studied population showed a significant positive correlation with a stage of liver fibrosis in biopsy (r = 0.555, p < 0.001). If 2D-SWE was carried out within 24 months since liver biopsy the consistency of the results was 96%, and if the period between procedures exceeded 24 months the consistency was 81%. In 43 patients with both 2D-SWE and TE the coherence (r = 0.872, p < 0.001) and consistency (95%) between these two methods were high. Liver stiffness measured with 2D-SWE showed good consistency with stage of liver fibrosis in liver biopsies, particularly in HCV infected patients, and if the period between procedures did not exceed 24 months.

Increased fibrosis and microvessel disease in allograft endomyocardial biopsies of children with chronic graft failure due to cardiac allograft vasculopathy

IntroductionChronic graft failure (CGF) is the leading cause of mortality in pediatric heart transplant (PHT) patients and has multifactorial pathogenesis including cardiac allograft vasculopathy (CAV). CGF can present with microvessel disease (MVD) and myocardial fibrosis on endomyocardial biopsies (EMB). We investigated if CGF due to moderate- severe (M-S) CAV has histopathologic MVD and fibrosis prior to or at the time of CAV diagnosis. MethodThis retrospective case-control study included PHT with CGF secondary to M-S CAV. Control patients had no CAV or CGF. EMBs from CAV (3 sets: at 1-year post-transplant 1yrCAV, pre-CAV, and at the time of CAV diagnosis) and non-CAV cohorts were reviewed to grade the fibrosis and quantify MVD. Histopathologic changes were correlated and compared between CAV/non-CAV groups. ResultsEach group had 8 patients. The median age at transplantation and time since transplant were similar between the two groups (P=.71 and P=.91, respectively). Fibrosis grade was 3.0 for CAV cohort compared to 1.0 for control (P= .003) and MVD score was 2.1 in CAV and 0.5 in non-CAV patients (P=.003). Similar degrees of fibrosis and MVD were present even before any evidence of CAV (1yrCAV fibrosis grade 2.5, pre-CAV fibrosis grade 2; 1yrCAV vs CAV P=.75, pre-CAV vs CAV P=.63; 1yrCAV MVD score 2, pre-CAV MVD score 2; 1yrCAV vs CAV P=1, pre-CAV vs CAV P=.91). The degree of MVD correlated with fibrosis (r=0.63, P<.0001) for all EMBs. ConclusionSimultaneous myocardial fibrosis and MVD are noted in CGF secondary to M-S CAV, changes that occur before angiographic CAV. EMBs can reveal significant changes in patients with subsequent development of CAV and may be used to modify the follow-up and treatment for these high-risk patients.

Podocyte derived TNF-α mediates monocyte differentiation and contributes to glomerular injury.

Diabetes shortens the life expectancy by more than a decade, and the excess mortality in diabetes is correlated with the incidence of kidney disease. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Macrophage accumulation predicts the severity of kidney injury in human biopsies and experimental models of DKD. However, the mechanism underlying macrophage recruitment in diabetes glomeruli is unclear. Elevated plasma growth hormone (GH) levels in type I diabetes and acromegalic individuals impaired glomerular biology. In this study, we examined whether GH-stimulated podocytes contribute to macrophage accumulation. RNA-seq analysis revealed elevated TNF-α signaling in GH-treated human podocytes. Conditioned media from GH-treated podocytes (GH-CM) induced differentiation of monocytes to macrophages. On the other hand, neutralization of GH-CM with the TNF-α antibody diminished GH-CM's action on monocytes. The treatment of mice with GH resulted in increased macrophage recruitment, podocyte injury, and proteinuria. Furthermore, we noticed the activation of TNF-α signaling, macrophage accumulation, and fibrosis in DKD patients' kidney biopsies. Our findings suggest that podocytes could secrete TNF-α and contribute to macrophage migration, resulting in DKD-related renal inflammation. Inhibition of either GH action or TNF-α expression in podocytes could be a novel therapeutic approach for DKD treatment.

The gamma-glutamyl transferase to platelet ratio for noninvasive evaluation of liver fibrosis in patients with primary biliary cholangitis.

The gamma-glutamyl transferase to platelet ratio (GPR) has been reported to be as effective as the aspartate transaminase to platelet ratio index (APRI) and fibrosis index based on the 4 factors (FIB-4) in showing the fibrosis stage in patients with chronic hepatitis B. It has been demonstrated that APRI and FIB-4 are successful in the assessment of fibrosis in primary biliary cholangitis (PBC). We investigated the effectiveness of GPR in predicting advanced fibrosis and cirrhosis in patients with biopsy-proven untreated PBC. A total of 35 patients with biopsy-proven PBC were included in this study. The biopsy fibrosis stages of all patients at diagnosis were compared using the APRI, FIB-4, and GPR values. The diagnostic accuracy of GPR for detecting advanced fibrosis and cirrhosis was also investigated. The area under the receiver operating characteristic curve (AUROC) of GPR was 0.84, the cutoff point was 4.81, the sensitivity was 0.41, and the specificity was 0.96 for detecting advanced fibrosis. Our study showed that GPR was more sensitive than APRI and FIB-4 in detecting advanced fibrosis in patients with PBC. GPR could be used as an effective noninvasive marker in PBC to show advanced fibrosis at the time of diagnosis.

S1228 EUS-Guided Shear Wave Elastography Appears to Be More Accurate Than Transient Elastography in Predicting Liver Fibrosis Staging in Patients With Obesity

Introduction: Transient elastography (TE) is a non-invasive clinical tool used to assess liver stiffness measurement (LSM) and can be correlated to liver fibrosis staging. Obesity can make elastography challenging to perform due to increased abdominal wall thickness, with high failure rates for TE. Fibroscan XL probes have lower failure rates, though it is unclear if readings are reliable or correlate well with liver biopsies. EUS guided shear wave elastography (EUS-SWE) can potentially circumvent this limitation, as liver parenchyma via EUS can be visualized under a thin subcentimeter gastric or duodenal wall, which does not change appreciably with body habitus. We aim to determine whether TE or EUS-SWE correlate better with liver biopsy fibrosis staging for patients with obesity. Methods: A retrospective chart review was performed for patients with obesity at a single tertiary hospital from Dec 2021 to May 2022. Patients with obesity (BMI≥30) with LSM concerning for advanced fibrosis (F3 or F4) were referred for EUS-SWE and EUS guided liver biopsy, both of which performed in the left liver lobe. LSM (reported in kPa) were correlated with fibrosis staging on liver biopsy and were considered accurate if they fell within cutoff ranges: kPa ≤7 = F0-1, kPa 7-8 = F2, kPa 8-12 = F3, and kPa >12 = F4. No established cutoffs exist for EUS-SWE, so stiffness values were compared to that for TE on which were closer to TE cutoff ranges. Results: 12 consecutive patients with obesity underwent TE, EUS-SWE, and EUS guided liver biopsy. The mean age was 55.3 [range 18-69], 9 (75%) were females, and mean BMI was 44.9 [range 30.2-67.8]. LSM ranged from 9.1 to 41.9 kPa. Only 2 (17%) patients’ TE results correlated accurately with liver fibrosis staging on biopsy; see Table. Assuming similar fibrosis staging cutoff ranges for TE, EUS-SWE accurately downgraded 8 (67%) patients and demonstrated no change for 4 (33%) patients. EUS-SWE was closer to biopsy LSM cutoffs for 9 (75%) patients, while TE was more accurate in only 1 (8%) patient. Conclusion: In this small cohort of patients with obesity with possible advanced fibrosis, TE appeared to overdiagnose fibrosis stage, while EUS-SWE appeared to downgrade LSM appropriately for patients who were overdiagnosed. Larger cohort studies are ongoing to allow proper interpretation of EUS-SWE stiffness values and compare its utility and accuracy to TE. Table 1. - Individual patient data with basic demographics, transient elastography data, EUS shear wave elastography data, and data comparison and analysis Patient # Age Gender BMI TE LSM Value (kPa) Fibrosis Staging Based on TE Cutoff Fibrosis Stage on Biopsy (TE cutoffs) TE LSM as Compared to Fibrosis Staging on Biopsy EUS-SWE Stiffness (kPa) Closer to Biopsy Cutoffs? TE vs EUS-SWE How Did EUS-SWE Compare to TE via Fibrosis Staging ? 1 58 Female 62.4 9.1 F3 F0 (kPa≤7mmHg) Overstaged 5 EUS-SWE Downgraded 2 68 Female 39 9.9 F3 F0 (≤7) Overstaged 4.9 EUS-SWE Downgraded 3 59 Female 32.6 9.4 F3 F0 (≤7) Overstaged 6.3 EUS-SWE Downgraded 4 63 Female 32.8 15.7 F4 F0 (≤7) Overstaged 7.3 EUS-SWE Downgraded 5 48 Male 67.8 41.9 F4 F0 (≤7) Overstaged 7.3 EUS-SWE Downgraded 6 63 Female 38 9.4 F3 F0 (≤7) Overstaged 2 EUS-SWE Downgraded 7 56 Male 43.6 9.6 F3 F3 (8-12) Appropriate Stage 10.5 EUS-SWE No Change 8 18 Female 61.1 34.6 F4 F2 (7-8) Overstaged 19.6 EUS-SWE Downgraded 9 53 Female 32.6 20.5 F4 F4 (≥12) Appropriate Stage 21.7 Same No change 10 55 Male 34.9 12.2 F4 F2 (7-8) Overstaged 12.2 Same No Change 11 53 Female 30.2 14 F4 F3 (8-12) Overstaged 15.2 TE No Change 12 69 Female 64.1 14.7 F4 F2 (7-8) Overstaged 10.2 EUS-SWE Downgraded

Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis.

Uromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice. We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair. We found urine uromodulin to be correlated with serum creatinine (rho=-0.43; P<0.001), bicarbonate (0.20; P<0.001), and hemoglobin (0.11; P=0.03) at the time of biopsy but not with urine albumin (-0.07; P=0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: -3.5% [95% confidence intervals, -5.7% to -1.2%] and glomerulosclerosis: -3.3% [95% confidence intervals, -5.9% to -0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: -2.5% [95% confidence intervals, -4.6% to -0.4%] and glomerulosclerosis: -0.9% [95% confidence intervals, -3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models. Higher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.

IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β-catenin pathway.

AKI (acute kidney injury) with maladaptive repair plays exacerbated role in renal fibrosis characterized by tubulointerstitial fibrosis. Previously, we reported that IKKα contributed to kidney regeneration and inhibited inflammation. Here, we first identified the role and mechanism of IKKα on TGF-β1-induced fibrosis in human tubular epithelial cells and fibrotic kidneys. IKKα was up-regulated in kidney tubular epithelium in unilateral ureteral obstruction (UUO) and unilateral ischemic reperfusion injury (UIRI) mice. Immunohistochemical staining showed that IKKα was positively correlated with the extent of kidney fibrosis in tissue biopsies from chronic kidney disease (CKD) patients. Compared with wild-type controls, Ksp-IKKα-/- mice exhibited inactivated Wnt/β-catenin pathway, decreased serum creatinine and interstitial fibrosis in the kidney after IRI. In TGF-β1-stimulated human tubular epithelial cells, IKKα overexpression enhanced β-catenin nuclear translocation. Blocking IKKα by siRNA specifically suppressed β-catenin activation and downstream profibrotic genes such as fibronectin and α-smooth muscle actin (α-SMA). Taken together, our study demonstrated that IKKα aggravated renal fibrogenesis by activating Wnt/β-catenin signalling pathway, providing a new target for the treatment of kidney fibrosis.