The boundaries of normal kidney tissue for biomedical research.

Purpose Of Review: In this review, we highlight the importance of understanding the inherent biological variability in normal kidney, or healthy reference tissue, to establish an accurate reference point for biomedical research. We explore this and the advantages and limitations of various sources of healthy reference tissue suitable for structural and omics-level studies.

Recent Findings: Several large consortia are employing omic technologies for diseased and normal kidney tissue, underscoring the importance of utilizing healthy reference tissue in these studies.

Framework for precision medicine in focal segmental glomerulosclerosis: Translation of sparsentan-responsive genes in a rat model to kidney disease associated proteins in biofluids.

Unlabelled: Sparsentan, a dual endothelin receptor A inhibitor and angiotensin blocker, reduced proteinuria in patients with focal segmental glomerulosclerosis (FSGS) in Phase II and Phase III studies. However, the estimated glomerular filtration rate (eGFR) endpoint was not achieved, partially attributed to disease heterogeneity among participants. Sparsentan reversed the molecular fingerprint in kidneys of an adriamycin-challenged rat model of chronic kidney disease, consistent with the phenotypic data.

A transcription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease.

The maintenance of a healthy epithelial-endothelial juxtaposition requires cross-talk within glomerular cellular niches. We sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. From 74 human kidney samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular capillary endothelial (EC-GC) and mesangial cells.

Clinical Relevance of Computational Pathology Analysis of Interplay Between Kidney Microvasculature and Interstitial Microenvironment.

Background: Interstitial fibrosis and tubular atrophy (IFTA), and density and shape of peritubular capillaries (PTCs), are independently prognostic of disease progression. This study aimed to identify novel digital biomarkers of disease progression and assess the clinical relevance of the interplay between a variety of PTC characteristics and their microenvironment in glomerular diseases.

Methods: A total of 344 NEPTUNE/CureGN participants were included: 112 minimal change disease, 134 focal segmental glomerulosclerosis, 61 membranous nephropathy, and 37 IgA nephropathy.

Inflammation in Areas of Fibrosis Precedes Loss of Kidney Function in Lupus Nephritis.

Background: Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as nonspecific "scar reaction." This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN.

Methods: Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies.

Computational staining of CD3/CD20 positive lymphocytes in human tissues with experimental confirmation in a genetically engineered mouse model.

Introduction: Immune dysregulation plays a major role in cancer progression. The quantification of lymphocytic spatial inflammation may enable spatial system biology, improve understanding of therapeutic resistance, and contribute to prognostic imaging biomarkers.

Methods: In this paper, we propose a knowledge-guided deep learning framework to measure the lymphocytic spatial architecture on human H&E tissue, where the fidelity of training labels is maximized through single-cell resolution image registration of H&E to IHC.

Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans.

Background: Apolipoprotein L1 gene () variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of variants with CKD in West Africans, a major group in the Black population.

Methods: We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease.

Attenuated kidney oxidative metabolism in young adults with type 1 diabetes.

BACKGROUNDIn type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.METHODSYoung adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship.RESULTSParticipants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs.

Characterization of arteriosclerosis based on computer-aided measurements of intra-arterial thickness.

Purpose: Our purpose is to develop a computer vision approach to quantify intra-arterial thickness on digital pathology images of kidney biopsies as a computational biomarker of arteriosclerosis.

Approach: The severity of the arteriosclerosis was scored (0 to 3) in 753 arteries from 33 trichrome-stained whole slide images (WSIs) of kidney biopsies, and the outer contours of the media, intima, and lumen were manually delineated by a renal pathologist. We then developed a multi-class deep learning (DL) framework for segmenting the different intra-arterial compartments (training dataset: 648 arteries from 24 WSIs; testing dataset: 105 arteries from 9 WSIs).

miRNA and mRNA Signatures in Human Acute Kidney Injury Tissue.

Acute kidney injury (AKI) is an important contributor to the development of chronic kidney disease (CKD). There is a need to understand molecular mediators that drive recovery and progression to CKD. In particular, the regulatory role of miRNAs in AKI is poorly understood.

Investigating quantitative histological characteristics in renal pathology using HistoLens.

HistoLens is an open-source graphical user interface developed using MATLAB AppDesigner for visual and quantitative analysis of histological datasets. HistoLens enables users to interrogate sets of digitally annotated whole slide images to efficiently characterize histological differences between disease and experimental groups. Users can dynamically visualize the distribution of 448 hand-engineered features quantifying color, texture, morphology, and distribution across microanatomic sub-compartments.

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

Background: 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.

Methods: 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).

: A web-based application for in-depth exploration of multi-omics data with brightfield histology.

Spatial -OMICS technologies facilitate the interrogation of molecular profiles in the context of the underlying histopathology and tissue microenvironment. Paired analysis of histopathology and molecular data can provide pathologists with otherwise unobtainable insights into biological mechanisms. To connect the disparate molecular and histopathologic features into a single workspace, we developed (unctional nit tate dentificati in WSIs [Whole Slide Images]), a web-based tool that provides users with a broad array of visualization and analytical tools including deep learning-based algorithms for in-depth interrogation of spatial -OMICS datasets and their associated high-resolution histology images.

ComPRePS: An Automated Cloud-based Image Analysis tool to democratize AI in Digital Pathology.

Artificial intelligence (AI) has extensive applications in a wide range of disciplines including healthcare and clinical practice. Advances in high-resolution whole-slide brightfield microscopy allow for the digitization of histologically stained tissue sections, producing gigapixel-scale whole-slide images (WSI). The significant improvement in computing and revolution of deep neural network (DNN)-based AI technologies over the last decade allow us to integrate massively parallelized computational power, cutting-edge AI algorithms, and big data storage, management, and processing.

Protein N-glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease.

Background: Diabetes is expected to directly impact renal glycosylation, yet to date, there has not been a comprehensive evaluation of alterations in N-glycan composition in the glomeruli of patients with diabetic kidney disease (DKD).

Methods: We used untargeted mass spectrometry imaging to identify N-glycan structures in healthy and sclerotic glomeruli in FFPE sections from needle biopsies of five patients with DKD and three healthy kidney samples. Regional proteomics was performed on glomeruli from additional biopsies from the same patients to compare the abundances of enzymes involved in glycosylation.

Plasma Proteins Associated with Chronic Histopathologic Lesions on Kidney Biopsy.

Key Points: Proteomic profiling identified 35 blood proteins associated with chronic histopathologic lesions in the kidney. Testican-2 was expressed in the glomerulus, released by the kidney into circulation, and inversely associated with glomerulosclerosis severity. NELL1 was expressed in tubular epithelial cells, released by the kidney into circulation, and inversely associated with interstitial fibrosis and tubular atrophy severity.

ComPRePS: An Automated Cloud-based Image Analysis tool to democratize AI in Digital Pathology.

Artificial intelligence (AI) has extensive applications in a wide range of disciplines including healthcare and clinical practice. Advances in high-resolution whole-slide brightfield microscopy allow for the digitization of histologically stained tissue sections, producing gigapixel-scale whole-slide images (WSI). The significant improvement in computing and revolution of deep neural network (DNN)-based AI technologies over the last decade allow us to integrate massively parallelized computational power, cutting-edge AI algorithms, and big data storage, management, and processing.

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response.

Unbiased kidney-centric molecular categorization of chronic kidney disease as a step towards precision medicine.

Current classification of chronic kidney disease (CKD) into stages using indirect systemic measures (estimated glomerular filtration rate (eGFR) and albuminuria) is agnostic to the heterogeneity of underlying molecular processes in the kidney thereby limiting precision medicine approaches. To generate a novel CKD categorization that directly reflects within kidney disease drivers we analyzed publicly available transcriptomic data from kidney biopsy tissue. A Self-Organizing Maps unsupervised artificial neural network machine-learning algorithm was used to stratify a total of 369 patients with CKD and 46 living kidney donors as healthy controls.

Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis.

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches.

Multi-omics data integration shines a light on the renal medulla.

The renal medulla maintains salt and water balance and is prone to dysregulation because of high oxygen demand. Challenges in obtaining high-quality tissue have limited characterization of molecular programs regulating the medulla. Haug et al.

The chromatin landscape of healthy and injured cell types in the human kidney.

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states.

Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome.

Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS.

AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an inborn error of metabolism caused by inactivating mutations in , the gene encoding sphingosine-1-phosphate lyase (SPL), an essential enzyme needed to degrade sphingolipids. SPLIS features include glomerulosclerosis, adrenal insufficiency, neurological defects, ichthyosis, and immune deficiency. Currently, there is no cure for SPLIS, and severely affected patients often die in the first years of life.

Genetic Analysis of Obesity-Induced Diabetic Nephropathy in BTBR Mice.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the U.S. and has a significant impact on human suffering.