Interstitial Fibrosis And Tubular Atrophy Research Articles

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.

Plasma Proteins associated with Chronic Histopathologic Lesions on Kidney Biopsy.

The severity of chronic histopathologic lesions on kidney biopsy is independently associated with higher risk of progressive chronic kidney disease (CKD). Because kidney biopsies are invasive, identification of blood markers that report on underlying kidney histopathology has the potential to enhance CKD care. We examined the association between 6592 plasma protein levels measured by aptamers and the severity of interstitial fibrosis and tubular atrophy (IFTA), glomerulosclerosis, arteriolar sclerosis, and arterial sclerosis among 434 participants of the Boston Kidney Biopsy Cohort. For proteins significantly associated with at least one histologic lesion, we assessed renal arteriovenous protein gradients among 21 individuals who had undergone invasive catheterization and assessed the expression of the cognate gene among 47 individuals with single cell RNA sequencing data in the Kidney Precision Medicine Project. In models adjusted for estimated glomerular filtration rate (eGFR), proteinuria, and demographic factors, we identified 35 proteins associated with one or more chronic histologic lesions, including 20 specific for IFTA, 8 specific for glomerulosclerosis, and 1 specific for arteriolar sclerosis. In general, higher levels of these proteins were associated with more severe histologic score and lower eGFR. Exceptions included testican-2 and NELL1, which were associated with less glomerulosclerosis and IFTA, respectively, and higher eGFR; notably, both of these proteins demonstrated significantly higher levels from artery to renal vein, demonstrating net kidney release. In the Kidney Precision Medicine Project, 13 of the 35 protein hits had cognate gene expression enriched in one or more cell types in the kidney, including podocyte expression of select glomerulosclerosis markers (including testican-2) and tubular expression of several IFTA markers (including NELL1). Proteomic analysis identified circulating proteins associated with chronic histopathologic lesions, some of which have concordant site-specific expression within the kidney.

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.

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.

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.

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.

Reconfiguration and loss of peritubular capillaries in chronic kidney disease

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

Construction of predictive model of interstitial fibrosis and tubular atrophy after kidney transplantation with machine learning algorithms.

Background: Interstitial fibrosis and tubular atrophy (IFTA) are the histopathological manifestations of chronic kidney disease (CKD) and one of the causes of long-term renal loss in transplanted kidneys. Necroptosis as a type of programmed death plays an important role in the development of IFTA, and in the late functional decline and even loss of grafts. In this study, 13 machine learning algorithms were used to construct IFTA diagnostic models based on necroptosis-related genes. Methods: We screened all 162 "kidney transplant"-related cohorts in the GEO database and obtained five data sets (training sets: GSE98320 and GSE76882, validation sets: GSE22459 and GSE53605, and survival set: GSE21374). The training set was constructed after removing batch effects of GSE98320 and GSE76882 by using the SVA package. The differentially expressed gene (DEG) analysis was used to identify necroptosis-related DEGs. A total of 13 machine learning algorithms-LASSO, Ridge, Enet, Stepglm, SVM, glmboost, LDA, plsRglm, random forest, GBM, XGBoost, Naive Bayes, and ANNs-were used to construct 114 IFTA diagnostic models, and the optimal models were screened by the AUC values. Post-transplantation patients were then grouped using consensus clustering, and the different subgroups were further explored using PCA, Kaplan-Meier (KM) survival analysis, functional enrichment analysis, CIBERSOFT, and single-sample Gene Set Enrichment Analysis. Results: A total of 55 necroptosis-related DEGs were identified by taking the intersection of the DEGs and necroptosis-related gene sets. Stepglm[both]+RF is the optimal model with an average AUC of 0.822. A total of four molecular subgroups of renal transplantation patients were obtained by clustering, and significant upregulation of fibrosis-related pathways and upregulation of immune response-related pathways were found in the C4 group, which had poor prognosis. Conclusion: Based on the combination of the 13 machine learning algorithms, we developed 114 IFTA classification models. Furthermore, we tested the top model using two independent data sets from GEO.

Clinical Relevance of Computationally Derived Spatial Relationships Between Interstitial Fibrosis and Tubular Atrophy (IFTA) and Peritubular Capillary Features

Clinical Relevance of Computationally Derived Spatial Relationships Between Interstitial Fibrosis and Tubular Atrophy (IFTA) and Peritubular Capillary Features

The Importance of 1-Year Protocol Biopsy in the Long-Term Prognosis of Kidney Transplants—5-Years Follow-Up

Protocol biopsies are performed to detect subclinical pathologies that may lead to future graft dysfunction. However, they are not routinely performed interventions in every transplant center. There is no established regimen for performing them. The study aimed to evaluate if protocol biopsies can improve long-term patient outcomes after detecting early disorders and modifying treatment. Our observational study included 61 patients who underwent protocol biopsy 12 months after the transplantation. Based on the biopsy results, patients with abnormal histologic material (n=37) were divided into 3 study groups as follows: patients with mild inflammatory lesions (n=21), patients with interstitial fibrosis and tubular atrophy (IFTA) grade II to III (n=12), and patients with BK virus nephropathy (n=4). The control group (n=24) included kidney recipients with IFTA 0 to I grade. Outcomes after 5-year follow-up were evaluated. Five years after the biopsy, patients in the control group had stable graft function (5-year change in serum creatinine was -0.09 mg/dL). An increase in serum creatinine levels was observed in patients with IFTA II to III compared with the control group (0.14 mg/dL, P=.04). Immunosuppressive treatment was modified in the group with mild inflammatory changes and in the BKV group after the biopsy result. In the group with mild inflammatory lesions, renal function was stable (change of serum creatinine was -0.01 mg/dL, P=.51). In the BKV nephropathy group, there was a significant reduction in serum creatine levels (-0.48 mg/dL, P=.016). The analysis showed no diagnostic value for serum creatinine concentration (95% CI 0.49-0.78, P=.08). Protocol biopsies are useful for detecting early pathologies and preventing allograft failure. They greatly benefit patients with detectable pathology that can be treated or in whom therapy modification is possible.

Urine Proteomics Link Complement Activation with Interstitial Fibrosis/Tubular Atrophy in Lupus Nephritis Patients

BackgroundIntrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRβ), platelet-derived growth factor beta (PDGFβ) and platelet-derived growth factor receptor beta (PDGFRβ). MethodsWe included urine samples from 46 adults and pediatric biopsy-proven lupus nephritis patients who underwent clinically indicated kidney biopsies between 2010 and 2019. We compared individual urinary complement components and the urinary C9-to-CD59 ratio between LN patients with moderate/severe IFTA and none/mild IFTA. IFTA was defined as none/mild (<25% of interstitium affected) versus moderate/severe (≥ 25% of interstitium affected). Proteomics analysis was performed using mass spectrometry (Orbitrap Fusion Lumos, Thermo Scientific) and processed by the Proteome Discoverer. Urinary complement proteins enriched in LN patients with moderate/severe IFTA were correlated with serum creatinine, TGFβR1, TGFβR2, PDGFβ, and PDGFRβ. ResultsOf the 46 LN patients included in the study, 41 (89.1%) were women, 20 (43.5%) self-identified as Hispanic or Latino, and 26 (56.5%) self-identified as Black or African American. Ten of the 46 (21.7%) LN patients had moderate/severe IFTA on kidney biopsy. LN patients with moderate/severe IFTA had an increased urinary C9-to-CD59 ratio [median 0.91 (0.83-1.05) vs 0.81 (0.76-0.91), p=0.01]. Urinary C3 and CFI levels in LN patients with moderate/severe IFTA were higher compared to those with none/mild IFTA [C3 median (IQR) 24.4(23.5-25.5) vs. 20.2 (18.5–22.2), p= 0.02], [CFI medium (IQR) 28.8 (21.8-30.6) vs. 20.4 (18.5-22.9), p=0.01]. Complement C9, CD59, C3 and CFI correlated with TGFβR1, PDGFβ, and PDGFRβ, while C9, CD59 and C3 correlated with TGFβR2. ConclusionThis study is one of the first to compare the urinary complement profile in LN patients with moderate/severe IFTA and none/mild IFTA in human tissues. This study identified C3, CFI, and C9-to-CD59 ratio as potential markers of tubulointerstitial fibrosis in LN.

Discovery of Biomarkers Related to Interstitial Fibrosis and Tubular Atrophy among Kidney Transplant Recipients by mRNA-Sequencing.

Interstitial fibrosis and tubular atrophy (IF/TA) after kidney transplantation causes a chronic deterioration of graft function. IF/TA can be diagnosed by means of a graft biopsy, which is a necessity as non-invasive diagnostic methods are unavailable. In this study, we identified IF/TA-related differentially expressed genes (DEGs) through next-generation sequencing using peripheral blood mononuclear cells. Blood samples from kidney transplant recipients undergoing standard immunosuppressive therapy (tacrolimus/mycophenolate mofetil or mycophenolate sodium/steroid) and diagnosed as IF/TA (n = 41) or normal (controls; n = 41) at their one-year protocol biopsy were recruited between January of 2020 and August of 2020. DEGs were derived through mRNA sequencing and validated by means of a quantitative real-time polymerase chain reaction. We identified 34 DEGs related to IF/TA. ADAMTS2, PLIN5, CLDN9, and KCNJ15 demonstrated a log2(fold change) of >1.5 and an area under the receiver operating characteristic curve (AUC) value of >0.6, with ADAMTS2 showing the largest AUC value and expression levels, which were 3.5-fold higher in the IF/TA group relative to that observed in the control group. We identified and validated DEGs related to IF/TA progression at one-year post-transplantation. Specifically, we identified ADAMTS2 as a potential IF/TA biomarker.

A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases.

With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).

Polar vasculosis is associated with better kidney outcome in type 2 diabetes with biopsy-proven diabetic kidney disease: A multicenter cohort study.

This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. We enrolled 811 patients with type 2 diabetes, biopsy-proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow-up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person-years) and 79 of 134 (11.4 events/100 person-years) cases with and without polar vasculosis, respectively. Kaplan-Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all-cause mortality before DKD progression as a competing event. This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria.

Cumulative smoking dose is associated with subclinical renal injury: a pathological study in individuals without chronic kidney disease.

Epidemiological studies have identified smoking as an independent risk factor for development of chronic kidney disease. However, the early renal pathological lesions have not been clearly elucidated. We investigated time-zero biopsy specimens from 547 living kidney donors and evaluated the relationships between smoking and renal histological changes, including arteriolar hyalinization, intimal thickening of small-medium arteries, global glomerulosclerosis, and interstitial fibrosis and tubular atrophy (IF/TA). A total of 199 subjects (36.4%) had smoking history; 92 (16.8%) and 107 (19.6%) subjects had <20 pack-years and ≥20 pack-years of smoking, respectively. Cumulative smoking dose was significantly associated with prevalence of arteriolar hyalinization: the multivariable-adjusted odds ratio (OR) per 20 pack-year increase was 1.50 (95% confidence interval 1.15-1.97). The ORs for smokers with <20 pack-years and ≥20 pack-years versus never-smokers were 1.76 (1.01-3.09) and 2.56 (1.48-4.44), respectively. Smoking was also associated with prevalence of >10% global glomerulosclerosis: the OR per 20 pack-year increase was 1.24 (0.96-1.59). The ORs for smokers with <20 pack-years and ≥20 pack-years versus never-smokers were 1.50 (0.98-2.78) and 2.11 (1.18-3.79), respectively. The ORs for these pathological changes increased significantly depending on cumulative smoking dose. Intimal thickening of small-medium arteries and IF/TA were not associated with smoking status. The prevalence of arteriolar hyalinization remained higher in patients with ≥10 years since smoking cessation than in never-smokers [OR 2.23 (1.03-4.83)]. Subclinical pathological injury caused by smoking is potentially associated with renal arteriolar hyalinization and glomerular ischaemia.

The role of tubulointerstitial markers in differential diagnosis and prognosis in patients with type 2 diabetes and biopsy proven diabetic kidney disease

ObjectiveTo evaluate the potential application of tubularinterstitial biomarkers in the differential diagnosis of diabetic kidney disease (DKD) from non-diabetic kidney disease (NDKD), as well as investigate key clinical and pathological parameters to help improve the stratification of patients according to end-stage renal disease risk. Methods132 type 2 diabetic patients with chronic kidney disease were enrolled. Patients were categorized into 2 groups according to the renal biopsy results: DKD (n = 61) and NDKD (n = 71).The independent factors of the occurrence of DKD and the diagnostic implications of tubular biomarkers were explored by logistic regression and receiver-operating characteristic curve analysis. Furthermore, predictors were analyzed by least absolute shrinkage and selection operator regression, and constructed a new model for predicting the unfavorable renal outcomes through Cox proportional hazard regression analysis. ResultsSerum neutrophil gelatinase-associated lipocalin (sNGAL) (OR = 1.007; 95%CI = [1.003, 1.012], p = 0.001) was identified as an independent risk factor for the occurrence of DKD in diabetic patients with CKD. Tubular biomarkers including sNGAL, N-acetyl-β-D-glucosaminidase and β2 microglobulin (β2-MG) could complement albuminuria for DKD detection (AUC = 0.926, specificity = 90.14%, sensitivity = 80.33%).Moreover, among of the 47 variables, 4 predictors such as sNGAL, interstitial fibrosis and tubular atrophy (IFTA)score, β2-MG and estimated glomerular filtration rate were selected to construct a new model for predicting the unfavorable renal outcomes through regression analysis. sNGAL (HR = 1.004; 95%CI = [1.001, 1.007], p = 0.013), IFTA score of 2 (HR = 4.283; 95%CI = [1.086, 16.881], p = 0.038), and IFTA score of 3 (HR = 6.855; 95%CI = [1.766, 26.610], p = 0.005) were considered to be independent risk factors for unfavorable renal outcomes. ConclusionsTubulointerstitial injury in DKD is independently associated with renal function decline and routinely detected tubular biomarkers are able to enhance the level of non-invasive diagnosis of DKD beyond traditional factors.