Interstitial Fibrosis And Tubular Atrophy Research Articles

Towards clinical translation of urinary vitronectin for non-invasive detection and monitoring of renal fibrosis in kidney transplant patients.

Interstitial fibrosis and tubular atrophy (IFTA) is a critical factor in the prognosis of kidney health. Currently, IFTA quantitation in kidney biopsy samples is crucial for diagnosis and assessing disease severity, but the available non-invasive biomarkers are not satisfactory. Proteomic studies identified urinary vitronectin (VTN) as a potential biomarker for kidney fibrosis. As mass spectrometry techniques are not practical for use in clinical settings, we tested whether evaluation of urinary VTN levels through enzyme-linked immunosorbent assay (ELISA) can help monitor fibrotic changes in kidney transplant recipients and prove the clinical viability of the assay. A total of 58 kidney transplant (KTx) patients who underwent renal biopsy were included in the study. Patients were categorized into two groups referred as no fibrosis (0%) or with fibrosis (≥ 5%) based on their histological findings. In a subsequent/follow-up analysis, the time elapsed from transplantation was also considered. The urinary levels of VTN were measured using ELISA. VTN (p = 0.0180) and VTN normalized by urinary creatinine levels (p = 0.0037), were significantly increased in patients with fibrotic grafts. When focusing on patients with long-term grafts (> 3 years from transplantation, n = 36), VTN exhibited superior potential in identifying fibrotic grafts compared to albuminuria (VTN p = 0.0040 vs. albuminuria p = 0.0132). Importantly, in this group, while albuminuria correctly identified 71% of fibrotic patients, the combination of VTN plus albuminuria correctly classified 89% of fibrotic grafts detected by renal biopsy. VTN has emerged as a valid indicator of renal fibrosis. Of interest, urinary levels of VTN in combination with conventional clinical parameters (such as albuminuria) significantly improved the non-invasive detection of renal fibrosis in kidney transplant patients.

Non-invasive assessment of IgA nephropathy severity with [18F] AlF-NOTA-FAPI-04 PET/CT imaging

Abstract Background Renal biopsy plays a crucial role in diagnosing and assessing the severity of IgA nephropathy (IgAN), despite being an invasive procedure with potential risk of failure. Our study focused on evaluating the capability of [18F] AlF-NOTA-FAPI-04 PET/CT in identifying the extent of pathological alterations in IgAN. Methods Twenty patients (13 males and 7 females; mean age, 44 ± 16 years) with newly diagnosed primary IgAN and 10 patients (7 males and 3 females; mean age, 51 ± 4 years) without known renal disease underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues from biopsies were stained with various techniques and examined using immunofluorescence. The Oxford classification was used to evaluate pathological indicators. Immunohistochemical staining was conducted to assess α-smooth muscle actin (αSMA) and FAP expression. Renal FAPI uptake measured by PET/CT (SUVmax and SUVmean) was correlated with histological findings. Results The renal parenchymal FAPI uptake was significantly higher in IgAN patients compared to control patients (SUVmax = 3.9 ± 1.3 vs 1.9 ± 0.4, SUVmean = 3.6 ± 1.2 vs 1.5 ± 0.4; all P < 0.001). We identified a significant difference in renal parenchymal FAPI uptake among the various categories of the Oxford classification. Correlation analysis revealed a positive association between SUVmax and interstitial fibrosis and tubular atrophy (IF/TA), as well as tubulointerstitial inflammation (TII) scores in scarred cortex and non-scarred cortex (r = 0.637, 0.593, and 0.491, all P < 0.05), Similar associations were observed between SUVmean and these scores (r = 0.641, 0.592, and 0.479, all P < 0.05). Furthermore, significant positive correlations were observed between SUVmax or SUVmean and the staining scores for glomerular αSMA and FAP, as well as for tubulointerstitial αSMA and FAP (all P < 0.01). Conclusion [18F] AlF-NOTA-FAPI-04 PET/CT imaging offers IgAN patients a non-invasive and reproducible auxiliary modality to monitor disease progression.

Diagnostic value of TRIM22 in diabetic kidney disease and its mechanism.

Diabetic kidney disease (DKD) is the primary reason of chronic kidney disease. Our objective was to discover potential autophagy-related biomarkers of tubulointerstitial injury in DKD and assess their clinical value. We retrieved four datasets (GSE104954, GSE30122, GSE30529, and GSE99340) of renal tubule samples from Gene Expression Omnibus (GEO) and used two algorithms (LASSO and SVM-RFE) to screen for autophagy-related differentially expressed genes (ARDEGs) in DKD. Tripartite motif containing 22 (TRIM22) was identified for subsequent validation. Validation of TRIM22 and autophagic indicators expression in clinical samples and HK-2 cells stimulated by high glucose using immunohistochemistry, immunofluorescence, and western blot. We identified four ARDEGs (TRIM22, PLK2, HTR2B, and FAS) using a diagnostic gene model. ROC curves further confirmed that TRIM22 had the best diagnostic efficacy for DKD. Both clinical samples and HK-2 cells stimulated by high glucose showed high protein expression of TRIM22. The correlation analysis revealed that TRIM22 correlates with SQSTM1, NGAL, and some clinical and pathological indicators in patients with DKD. We identified TRIM22 as a potential diagnostic biomarker for DKD, revealing its high diagnostic value in patients with DKD with moderate-to-severe interstitial fibrosis and tubular atrophy (IFTA). TRIM22 is involved in tubulointerstitial injury and autophagy dysregulation in DKD.

Evaluation of urinary volatile organic compounds as a novel metabolomic biomarker to assess chronic kidney disease progression

BackgroundThere is a need to develop accurate and reliable non-invasive methods to evaluate chronic kidney disease (CKD) status and assess disease progression. Given it is recognized that dysregulation in metabolic pathways occur from early CKD, there is a basis in utilizing metabolomic biomarkers to monitor CKD progression. Volatile Organic Compounds (VOCs), a form of metabolomic biomarker, are gaseous products of metabolic processes in organisms which are typically released with greater abundance in disease conditions when there is dysregulation in metabolism. How urinary VOCs reflect the abnormal metabolic profile of patients with CKD status is unknown. Our study aimed to explore this.MethodsIndividuals aged 18–75 years undergoing kidney biopsy were included. Pre-biopsy urine samples were collected. All biopsy samples had an interstitial fibrosis and tubular atrophy (IFTA) grade scored by standardized assessment. Urine supernatant was extracted from residue and sampled for stir bar sorptive extraction followed by Gas chromatography–mass spectrometry (GC-MS) analysis. Post-processing of GC-MS data separated complex mixtures of VOCs based on their volatility and polarity. Mass-to-charge ratios and fragment patterns were measured for individual VOCs identification and quantification. Linear discriminant analysis (LDA) was performed to assess the ability of urinary VOCs in discriminating between IFTA 0 (‘no or minimal IFTA’ i.e. <10%, IFTA), IFTA 1 (‘mild IFTA’ i.e. 10–25% IFTA) and IFTA ≥ 2 (‘moderate or severe IFTA’ i.e. >25% IFTA). Linear regression analysis adjusting for age, sex, estimated glomerular filtration rate, diabetes mellitus (DM) status, and albuminuria was conducted to determine significantly regulated urinary VOCs amongst the groups.Results64 study participants (22 individuals IFTA 0, 15 individuals IFTA 1, 27 individuals IFTA ≥ 2) were included. There were 34 VOCs identified from GC-MS which were statistically associated with correct classification between the IFTA groups, and LDA demonstrated individuals with IFTA 0, IFTA 1 and IFTA ≥ 2 could be significantly separated by their urinary VOCs profile (p < 0.001). Multivariate linear regression analysis reported 4 VOCs significantly upregulated in the IFTA 1 compared to the IFTA 0 group, and 2 VOCs significantly upregulated in the IFTA ≥ 2 compared to the IFTA 1 group (p < 0.05). Significantly upregulated urinary VOCs belonged to one of four functional groups - aldehydes, ketones, hydrocarbons, or alcohols.ConclusionsWe report novel links between urinary VOCs and tubulointerstitial histopathology. Our findings suggest the application of urinary VOCs as a metabolomic biomarker may have a useful clinical role to non-invasively assess CKD status during disease progression.

Clinicopathological Characteristics and Kidney Outcomes in Biopsy-Confirmed Acute Interstitial Nephritis

IntroductionAcute interstitial nephritis (AIN) is a significant cause of acute kidney injury, with varying etiologies and outcomes. This study aimed to examine the causes, clinical characteristics, management, and kidney outcomes in patients with biopsy-confirmed AIN. MethodsA retrospective review was conducted on 166 patients diagnosed with AIN via kidney biopsy at Mayo Clinic between 2012 and 2023. Demographic, clinical, laboratory, and pathological data were collected. The primary outcome was kidney function recovery within the first six months. Statistical analyses included univariable and multivariable logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards modeling. ResultsMedications were the primary cause of AIN (67%), followed by autoimmune diseases (20%) and infections (6%). Within six months, 76% of patients achieved kidney recovery. Multivariable analysis indicated that moderate to severe interstitial fibrosis and tubular atrophy (IFTA) and dialysis requirement were associated with non-recovery, whereas a prebiopsy diagnosis of AIN was positively associated with kidney recovery. Drug-related AIN had higher recovery rates compared to all other causes (81% versus 66%, P = 0.04), and moderate to severe IFTA and dialysis need remained significant predictors for decreased recovery. Steroid therapy, used in 81% of patients, did not significantly influence kidney recovery in the overall cohort or in drug-induced AIN. ConclusionThis study provides insights into the characteristics and outcomes of biopsy-confirmed AIN. IFTA and dialysis requirement were significant factors associated with worse kidney outcomes. These findings may help inform clinical management and prognostication in AIN patients.

Development and validation of a nomogram for predicting the interstitial fibrosis and tubular atrophy in patients with lupus nephritis.

Interstitial fibrosis and tubular atrophy (IFTA) were frequent histologic features of lupus nephritis (LN), and LN patients with IFTA have poor renal outcomes. In this study, we aimed to construct prediction models for the IFTA in LN patients. This retrospective study included 303 patients with biopsy proven LN at the Affiliated Hospital of Qingdao University and Union Hospital of Fujian Medical University. The participants were randomly divided into development and validation cohorts. They were further divided into IFTA and non-IFTA groups. The least absolute shrinkage and selection operator (LASSO) regression model with laboratory test results collected at the time of kidney biopsy was used to optimize feature selection for the risk model. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the LASSO regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and ROC curve analysis. Internal validation was assessed using the bootstrapping validation. A nomogram for individual assessment was constructed based on the preferable model. Predictors contained in the prediction nomogram included age, body mass index (BMI), mean arterial pressure (MAP), logANA, C3, eGFR and serum uric acid. The model displayed good discrimination with a C-index of 0.794 (95% CI 0.734-0.854) and good calibration. High C-index value of 0.857 (95% CI 0.776-0.938) could still be reached in the interval validation. A nomogram model based on the LASSO model was created for producing a probability score of IFTA in LN patients. With excellent predictive abilities, the nomogram may provide a simple and reliable tool to distinguish LN patients with IFTA and helps physicians make clinical decisions in their comprehensive assessment.

Multicenter, prospective, observational study for urinary exosomal biomarkers of kidney allograft fibrosis

Severity of deceased donor kidney fibrosis impacts graft survival in deceased-donor kidney transplantation. Our aim was to identify potential miRNA biomarkers in urinary exosomes that mirror interstitial fibrosis and tubular atrophy (IFTA) severity. Among 109 urine samples from deceased donors, 34 displayed no IFTA in the zero-day biopsy (No IFTA group), while the remaining 75 deceased donor kidneys exhibited an IFTA score ≥ 1 (IFTA group). After analyzing previous reports and electronic databases, six miRNAs (miR-19, miR-21, miR-29c, miR-150, miR-200b, and miR-205) were selected as potential IFTA biomarker candidates. MiR-21, miR-29c, miR-150, and miR-205 levels were significantly higher, while miR-19 expression was significantly lower in the IFTA group. MiR-21 (AUC = 0.762; P < 0.001) and miR-29c (AUC = 0.795; P < 0.001) showed good predictive accuracy for IFTA. In the No IFTA group, the eGFR level at 1 week after transplantation was significantly higher compared to the IFTA group (41.34 mL/min/1.73m2 vs. 28.65 mL/min/1.73m2, P = 0.012). These findings signify the potential of urinary exosomal miRNAs as valuable biomarker candidates for evaluating the severity of IFTA in deceased donor kidneys before they undergo recovery.

Clinical Relevance of Computationally Derived Tubular Features: Spatial Relationships and the Development of Tubulointerstitial Scarring in MCD/FSGS.

Visual scoring of tubular damage has limitations in capturing the full spectrum of structural changes and prognostic potential. We investigate if computationally quantified tubular features can enhance prognostication and reveal spatial relationships with interstitial fibrosis. Deep-learning and image-processing-based segmentations were employed in N=254/266 PAS-WSIs from the NEPTUNE/CureGN datasets (135/153 focal segmental glomerulosclerosis and 119/113 minimal change disease) for: cortex, tubular lumen (TL), epithelium (TE), nuclei (TN), and basement membrane (TBM). N=104 pathomic features were extracted from these segmented tubular substructures and summarized at the patient level using summary statistics. The tubular features were quantified across the biopsy and in manually segmented regions of mature interstitial fibrosis and tubular atrophy (IFTA), pre-IFTA and non-IFTA in the NEPTUNE dataset. Minimum Redundancy Maximum Relevance was used in the NEPTUNE dataset to select features most associated with disease progression and proteinuria remission. Ridge-penalized Cox models evaluated their predictive discrimination compared to clinical/demographic data and visual-assessment. Models were evaluated in the CureGN dataset. N=9 features were predictive of disease progression and/or proteinuria remission. Models with tubular features had high prognostic accuracy in both NEPTUNE and CureGN datasets and increased prognostic accuracy for both outcomes (5.6%-7.7% and 1.6%-4.6% increase for disease progression and proteinuria remission, respectively) compared to conventional parameters alone in the NEPTUNE dataset. TBM thickness/area and TE simplification progressively increased from non- to pre- and mature IFTA. Previously under-recognized, quantifiable, and clinically relevant tubular features in the kidney parenchyma can enhance understanding of mechanisms of disease progression and risk stratification.

Clinicopathological characteristics of pediatric ANCA-associated glomerulonephritis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and glomerulonephritis is uncommon in children. We sought to characterize the histological and clinical features of the disease and report on risk factors for adverse outcomes in a pediatric cohort. Retrospective single-center cohort of all pediatric (< 20years) patients diagnosed with ANCA-associated glomerulonephritis (AAGN) by kidney biopsy between 2002 and 2022 at Johns Hopkins University. Histological and clinical features were extracted from the medical record. Clinical, laboratory, and histological findings were analyzed to determine the association with kidney failure (KF) and/or death. A total of 17 patients were identified (GPA n = 7, MPA = 10) with a median age of 15years (IQR 12-17) at presentation, a slight female predominance (59%), with seven patients reaching the composite outcome of death (n = 1) or kidney failure (n = 6). There was no difference in presenting clinical symptoms or extra-renal manifestations between the two groups. Univariable Cox regression identified several factors associated with an increased hazard of endpoint including the degree of global or segmental sclerosis, interstitial fibrosis and tubular atrophy (IFTA), C3 and C1q staining, presence of subendothelial deposits, and proteinuria. Multivariable regression was not performed due to the small sample size. We saw a trend towards increased utilization of plasma exchange and a decrease in cyclophosphamide utilization in the more recent era. There was no association between treatment modality and outcome. Pediatric AAGN is a rare disease associated with significant morbidity. We identified glomerulosclerosis and IFTA on histology, and proteinuria on initial presentation as risk factors for KF/death.

Exploring kidney allograft rejection: A proof-of-concept study using spatial transcriptomics

In this proof-of-concept study, spatial transcriptomics combined with public single-cell ribonucleic acid-sequencing data were used to explore the potential of this technology to study kidney allograft rejection. We aimed to map gene expression patterns within diverse pathologic states by examining biopsies classified across nonrejection, T cell–mediated acute rejection, interstitial fibrosis, and tubular atrophy. Our results revealed distinct immune cell signatures, including those of T and B lymphocytes, monocytes, mast cells, and plasma cells, and their spatial organization within the renal interstitium. We also mapped chemokine receptors and ligands to study immune cell migration and recruitment. Finally, our analysis demonstrated differential spatial enrichment of transcription signatures associated with kidney allograft rejection across various biopsy regions. Interstitium regions displayed higher enrichment scores for rejection-associated gene expression patterns than tubular areas, which had negative scores. This implies that these signatures are primarily driven by processes unfolding in the renal interstitium. Overall, this study highlights the value of spatial transcriptomics for revealing cellular heterogeneity and immune signatures in renal transplant biopsies and demonstrates its potential for studying the molecular and cellular mechanisms associated with rejection. However, certain limitations must be borne in mind regarding the development and future applications of this technology.

Impact of hyperparathyroidism on allograft histology and function after kidney transplantation: Rethinking its causal role in graft dysfunction.

The causal relationship between hyperparathyroidism and kidney graft dysfunction remains inconclusive. Applying Bradford-Hill's temporality and consistency causation principles, we assessed the effect of parathyroid hormone (iPTH) on graft histology and eGFR trajectory on kidney transplant recipients (KTRs) with normal time-zero graft biopsies. Retrospective cohort study evaluating the effect of hyperparathyroidism on interstitial fibrosis and tubular atrophy (IF/TA) development in 1232 graft biopsies. Pre-transplant hyperparathyroidism was categorized by KDIGO or KDOQI criteria, and post-transplant hyperparathyroidism by iPTH>1× and>2× the URL 1 year after transplantation. We included 325 KTRs (56% female, age 38±13 years, follow-up 4.2 years [IQR: 2.7-5.8]). Based on pre-transplant iPTH levels, 26% and 66% exceeded the KDIGO and KDOQI targets, respectively. There were no significant differences in the development of>25% IF/TA between KTRs with pre-transplant iPTH levels above and within target range according to KDIGO (53%vs. 62%, P=.16, HR.94 [95% CI:.67-1.32]) and KDOQI (60%vs. 60%, P=1.0, HR 1.19 [95% CI:.88-1.60]) criteria. Similarly, there were no differences when using 1 year post-transplant iPTH cut-offs>88 pg/mL (58%vs. 64%, P=.33) and>176 pg/mL (55%vs. 62%, P=.19). After adjusting for confounders, no significant differences were observed in eGFR trajectories among the iPTH strata. In young KTRs who received a healthy graft, no association was found between increased pre- and post-transplant iPTH levels and graft dysfunction, as assessed histologically and through eGFR trajectory. The concept of hyperparathyroidism as a risk factor for graft dysfunction in recipients at low risk requires reevaluation.

A new index for the outcome of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a common pathological form of nephrotic syndrome. This study analyzed the value of pathological lesions and clinical prognosis of different segmental glomerulosclerosis ratios in FSGS. Two hundred and six FSGS patients were collected from Dec 2013 to Apr 2016. The patients were divided into two groups according to the proportion of glomerular segmental sclerosis: F1 (SSR ≤ 15%, n = 133) and F2 (SSR > 15%, n = 73). The clinical and pathological data were recorded and analyzed, and statistical differences were observed between the serum uric acid level and the percentage of chronic renal failure. The pathological results showed significant differences in interstitial fibrosis and tubular atrophy (IFTA), degree of mesangial hyperplasia, vascular lesions, synaptopodin intensity, and foot process effacement between the two groups. Multivariate logistic regression analysis showed significant differences in creatinine (OR: 1.008) and F2 group (OR: 1.19). In all patients, the prognoses of urine protein and serum creatinine levels were statistically different. Multivariate Cox regression analysis revealed that F2 (hazard ratio: 2.306, 95% CI 1.022–5.207) was associated with a risk of ESRD (end stage renal disease). The proportion of segmental glomerulosclerosis provides a guiding value in the pathological diagnosis and clinical prognosis of FSGS.

18F] AlF-NOTA-FAPI-04 PET/CT for non-invasive assessment of tubular injury in kidney diseases.

[18F] AlF-NOTA-FAPI-04 is a novel positron emission tomography (PET) ligand, which specifically targets fibroblast activation protein (FAP) expression as a FAP inhibitor (FAPI). We analysed the diagnostic value of [18F] AlF-NOTA-FAPI-04 PET/CT for the non-invasive assessment of kidney interstitial inflammation and fibrosis in different renal pathologies. Twenty-six patients (14 males and 12 females; mean age, 50.5±16.5 years) with a wide range of kidney diseases and 10 patients (six males and four females; mean age, 55.4±8.6 years) without known evidence of renal disease as disease controls underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues obtained from kidney biopsies were stained with haematoxylin and eosin, periodic acid-Schiff, Masson's trichome, and periodic acid-silver methenamine. Immunohistochemical staining was also performed to assess the expression of α-smooth muscle actin (αSMA) and FAP. Renal parenchymal FAPI uptake reflected by maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) measurements on PET/CT was analysed against pathohistological findings. We found that renal parenchymal FAPI uptake was significantly higher in patients with various kidney diseases than in control patients in this study (SUVmax=4.3±1.8vs 1.9±0.4, SUVmean=3.9±1.7vs 1.5±0.4, respectively; all P<0.001). All kidney diseases, both in acute and chronic kidney disease, had increased renal parenchymal uptake to varying degrees. The correlation analysis indicated a positive association between the SUVmax and the tubulointerstitial inflammation (TII), interstitial fibrosis and tubular atrophy (IF/TA), and TII+IF/TA scores (r=0.612, 0.681, and 0.754, all P<0.05), and between the SUVmean and the TII, IF/TA, and TII+IF/TA scores (r=0.603, 0.700, and 0.748, all P<0.05). Furthermore, we found significant positive correlations between both SUVmax and the SUVmean with SMA and FAP staining scores (r=0.686 and 0.732, r=0.667 and 0.739, respectively; both P<0.001). [18F] AlF-NOTA-FAPI-04 PET/CT is clinically available for the comprehensive and non-invasive assessment of tubular injury in various kidney diseases.

Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease

ObjectiveObesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. MethodsWe evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). ResultsRSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = −0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = −0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = −0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). ConclusionRSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

ExKidneyBERT: a language model for kidney transplant pathology reports and the crucial role of extended vocabularies.

Pathology reports contain key information about the patient's diagnosis as well as important gross and microscopic findings. These information-rich clinical reports offer an invaluable resource for clinical studies, but data extraction and analysis from such unstructured texts is often manual and tedious. While neural information retrieval systems (typically implemented as deep learning methods for natural language processing) are automatic and flexible, they typically require a large domain-specific text corpus for training, making them infeasible for many medical subdomains. Thus, an automated data extraction method for pathology reports that does not require a large training corpus would be of significant value and utility. To develop a language model-based neural information retrieval system that can be trained on small datasets and validate it by training it on renal transplant-pathology reports to extract relevant information for two predefined questions: (1) "What kind of rejection does the patient show?"; (2) "What is the grade of interstitial fibrosis and tubular atrophy (IFTA)?" Kidney BERT was developed by pre-training Clinical BERT on 3.4K renal transplant pathology reports and 1.5M words. Then, exKidneyBERT was developed by extending Clinical BERT's tokenizer with six technical keywords and repeating the pre-training procedure. This extended the model's vocabulary. All three models were fine-tuned with information retrieval heads. The model with extended vocabulary, exKidneyBERT, outperformed Clinical BERT and Kidney BERT in both questions. For rejection, exKidneyBERT achieved an 83.3% overlap ratio for antibody-mediated rejection (ABMR) and 79.2% for T-cell mediated rejection (TCMR). For IFTA, exKidneyBERT had a 95.8% exact match rate. ExKidneyBERT is a high-performing model for extracting information from renal pathology reports. Additional pre-training of BERT language models on specialized small domains does not necessarily improve performance. Extending the BERT tokenizer's vocabulary library is essential for specialized domains to improve performance, especially when pre-training on small corpora.

Predictive Ability of Interstitial Fibrosis and Tubular Atrophy Scoring in Determining the Severity of Diabetic Kidney Disease: A Cross-sectional Study

Introduction: Diabetic Kidney Disease (DKD) is a major complication of Diabetes Mellitus (DM). Renal biopsy is the gold standard for the diagnosis and management of many renal diseases. Renal Interstitial Fibrosis and Tubular Atrophy (IFTA), as well as the number of obsolescent glomeruli, are prognostic factors associated with Diabetic Nephropathy (DN). Aim: To describe the renal biopsy profile of patients with DM presenting with renal disease and to determine the significance of IFTA scoring and the number of obsolescent glomeruli in predicting DKD and its severity. Materials and Methods: This cross-sectional study was conducted over a period of three years, from 2019 to 2022, involving a total of 189 patients selected through purposive sampling. Patients with DM who presented with renal disease and required renal biopsy to confirm the diagnosis were admitted to the Department of General Medicine and Nephrology at Kempegowda Institute of Medical Sciences Hospital and Research Centre, Bengaluru, Karnataka, India. The biopsy reports were obtained and analysed. Data were analysed using Statistical Package for the Social Sciences (SPSS) version 20.0 and results were expressed using descriptive and inferential statistics. A p-value of &lt;0.05 was considered statistically significant. Results: The mean age of the participants was 53.02±11.00 years, with an age range from 21 to 81 years. Among the subjects, 78.3% were males and 21.7 were females. Based on the renal biopsy findings, DN was the most common condition, found in 127 subjects (67.6%). Nearly 50.0% of those with DN had Class IV chronic DN, followed by Class III (42.5%). Chronic interstitial nephritis was the most common Non Diabetic Kidney Disease (NDKD), accounting for 24.6% of cases. IFTA scoring was significantly associated with DKD and there was a significant positive correlation between the severity of IFTA scores and the number of obsolescent glomeruli with the class of DKD. A unit rise in the IFTA score and the number of obsolescent glomeruli increased the risk of having severe DKD (Class III and Class IV) by 4.32 times and 1.24 times, respectively, compared to those with less severe forms (Class I and II) (p&lt;0.05). Conclusion: The IFTA scoring and the number of obsolescent glomeruli were found to be significant independent predictors of the severity of DKD.

Immune landscape of the kidney allograft in response to rejection.

Preventing kidney graft dysfunction and rejection is a critical step in addressing the nationwide organ shortage and improving patient outcomes. While kidney transplants (KT) are performed more frequently, the overall number of patients on the waitlist consistently exceeds organ availability. Despite improved short-term outcomes in KT, comparable progress in long-term allograft survival has not been achieved. Major cause of graft loss at 5 years post-KT is chronic allograft dysfunction (CAD) characterized by interstitial fibrosis and tubular atrophy (IFTA). Accordingly, proactive prevention of CAD requires a comprehensive understanding of the immune mechanisms associated with either further dysfunction or impaired repair. Allograft rejection is primed by innate immune cells and carried out by adaptive immune cells. The rejection process is primarily facilitated by antibody-mediated rejection (ABMR) and T cell-mediated rejection (TCMR). It is essential to better elucidate the actions of individual immune cell subclasses (e.g. B memory, Tregs, Macrophage type 1 and 2) throughout the rejection process, rather than limiting our understanding to broad classes of immune cells. Embracing multi-omic approaches may be the solution in acknowledging these intricacies and decoding these enigmatic pathways. A transition alongside advancing technology will better allow organ biology to find its place in this era of precision and personalized medicine.

Differential impact of glomerular and tubule-interstitial histological changes on kidney outcome between non-proteinuric and proteinuric diabetic nephropathy.

Studies on kidney function and histological findings in diabetic nephropathy (DN) with low urinary protein (UP) are few. We examined the differential impact of histological changes on kidney outcomes between non-proteinuric and proteinuric DN. Patients diagnosed with DN by renal biopsy during 1981-2014 were divided into non-proteinuric (UP ≤ 0.5g/day) and proteinuric (UP > 0.5g/day) DN. The Cox proportional hazard model was used to examine the association of glomerular lesions (GLs) and interstitial fibrosis and tubular atrophy (IFTA) with end-stage kidney disease (ESKD) development after adjusting for relevant confounders. The non-proteinuric and proteinuric DN groups included 197 and 199 patients, respectively. During the 10.7-year median follow-up period, 16 and 83 patients developed ESKD in the non-proteinuric and proteinuric DN groups, respectively. In the multivariable Cox hazard model, hazard ratios (HRs) [95% confidence intervals (CIs)] of GL and IFTA for ESKD in proteinuric DN were 2.94 [1.67-5.36] and 3.82 [2.06-7.53], respectively. Meanwhile, HRs [95% CIs] of GL and IFTA in non-proteinuric DN were < 0.01 [0-2.48] and 4.98 [1.33-18.0], respectively. IFTA was consistently associated with higher incidences of ESKD regardless of proteinuria levels (P for interaction = 0.49). The prognostic impact of GLs on ESKD was significantly decreased as proteinuria levels decreased (P for interaction < 0.01). IFTA is consistently a useful predictor of kidney prognosis in both non-proteinuric and proteinuric DN, while GLs are a significant predictor of kidney prognosis only in proteinuric DN.

Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis

Rationale & ObjectiveFew data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics, and correlates of histological disease severity, in adults with FSGS who underwent a clinical kidney biopsy. Study DesignReal-world cohort study with data derived from health records. Setting& Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories during 1 January 2016 to 31 May 2020. ExposuresRace, CKD stage, nephrotic proteinuria, age, sex, and hypertension. OutcomesSevere histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical ApproachDemographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed by multiple logistic regression. ResultsAmong 2,011 patients with FSGS, 40.6% were White and 23.6% Black. White patients were older (52.8 versus 45.5 years, P < 0.001) with higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 versus 43.1 ml/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% versus 14.6%, P < 0.001) or IFTA >50% (34.6% versus 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (odds ratio 2.46; 95% confidence interval 1.59, 3.79; P < 0.001). A higher proportion of patients with nephrotic than non-nephrotic proteinuria exhibited diffuse foot process effacement. LimitationsUnequal representation across United States (US) regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. ConclusionsBlack patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications.

Plasma D-dimer levels are associated with disease progression in diabetic nephropathy: a two-center cohort study

Background This study aimed to investigate the relationship between plasma D-dimer levels, clinicopathological features, and clinical outcomes in patients with biopsy-proven diabetic nephropathy (DN). Methods A total of 137 patients with biopsy-proven DN were enrolled in this two-center cohort study. Patients were stratified into tertiles based on plasma D-dimer levels. We investigated the relationship between plasma D-dimer levels and clinical outcomes, including a composite of death, a 40% decline in estimated glomerular filtration rate (e-GFR) from baseline, or end-stage renal disease (ESRD) (defined as e-GFR < 15 mL/min/1.73 m2 or need for renal replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), assessed using Cox regression models with adjustment for confounders. Results At baseline, the mean age was 52.61 ± 11.63 years, and the mean e-GFR was 58.02 ± 28.77 mL/min/1.73 m2. During a median 26-month follow-up period, 65 (47% of patients) achieved clinical outcomes. Compared with the low plasma D-dimer level group, those with higher plasma D-dimer levels were more likely to have higher 24-h proteinuria (p = .002), lower e-GFR (p = .001), lower hemoglobin (p = .001), a higher glomerular lesion class (p = .03), and higher interstitial fibrosis and tubular atrophy (IFTA) scores (p = .002). After adjustment for demographic, DN-specific covariates, and treatments, it was observed that a higher tertile of plasma D-dimer was nonlinearly associated with an increased risk of the clinical outcomes (Hazard Ratio (HR) for tertile 2 vs. 1, 1.7; 95% Confidence Interval (CI), 0.80–3.75; HR for tertile 3 vs. 1, 2.2; 95% CI, 0.93–5.27; p for trend = .001) in the Cox proportional hazards models. Conclusion In this study, DN patients with higher levels of plasma D-dimer had higher 24-h proteinuria, lower e-GFR, a higher glomerular lesion class, and higher IFTA scores. Furthermore, a high level of plasma D-dimer was nonlinearly associated with DN progression.