Clinicopathological characteristics and disease chronicity in native kidney biopsies in Flanders.

Background: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry provides complete population data on kidney disease epidemiology in the region of Flanders (Belgium), as it captures all native kidney biopsies performed in its population of 6.5 million inhabitants. Methods: From 2017 until 2019, 2054 adult kidney biopsies were included from 26 nephrology centers (one biopsy per patient). Data on nephrotic and nephritic syndrome were available in 1992 and 2026 biopsies, respectively. In a subgroup of 898 biopsies containing ≥10 glomeruli from 2018 to 2019, disease chronicity was graded using the Mayo Clinic Chronicity Score (MCCS). The association between clinical variables and MCCS was determined using simple and multiple linear regression models. Results: Nephrotic syndrome (present in 378 patients, 19.0%) was most frequently caused by minimal change disease in younger patients (18-44 years), membranous nephropathy in older patients (45-74 years) and amyloidosis in the elderly (>75 years). Nephritic syndrome (present in 421 patients, 20.8%) was most frequently caused by immunoglobulin A nephropathy (IgAN) in younger patients (18-64 years) and ANCA-associated vasculitis (AAV) in older patients (>64 years). AAV and IgAN were the most frequent underlying diagnoses in biopsies in which crescents were identified. In multivariable analysis, acute and chronic kidney disease and diagnoses of diabetic kidney disease, nephrosclerosis and hyperoxaluria/hypercalcemic nephropathy were associated with the highest MCCS increases. Conclusions: The FCGG registry validates data from previous Western European registries and provides a snapshot of disease chronicity in the whole biopsied Flemish population.

Epidemiology and clinicopathological characteristics of native kidney disease in children in Flanders, Belgium.

BACKGROUND: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is a population-based kidney biopsy registry that has been including all native kidney biopsies performed in children in Flanders (Belgium), since 2017. METHODS: From 2017 to 2020, 148 pediatric (< 18 years) native kidney biopsies were included. Each biopsy received a histopathological and final nephrological diagnosis, and concordance between both was assessed. Disease chronicity, summarized by the Mayo Clinic Chronicity Score, was determined on 122 biopsies with > 5 glomeruli. RESULTS: Kidney biopsy rate was high (29.0 biopsies per million children per year), median age was 10.0 years (IQR 5.8-14.7), and boys predominated (56.1% males). A total of 140 biopsies (94.6%) showed a representative pathology result. Glomerular disease was most prevalent, with IgA nephropathy/IgA vasculitis (43 biopsies, 29.1%) and minimal change disease (MCD) (29 biopsies, 19.6%) being the overall most frequent diagnoses. In general, diagnostic concordance was high (80.7%). In Alport syndrome and focal segmental glomerulosclerosis (FSGS), concordance was lower, as the nephrological diagnosis was often determined by results of genetic analysis. Nephrotic syndrome was the most frequent indication for kidney biopsy (31.8%) and was mainly caused by MCD and FSGS. The degree of disease chronicity on kidney biopsies was generally low, although 27.3% of biopsies with a diagnosis of FSGS showed moderate-to-severe chronic damage. CONCLUSIONS: The presented epidemiological findings validate data from previous European registry studies and may inspire kidney biopsy registries worldwide to implement novel features such as clinicopathological concordance and chronicity grading. A higher resolution version of the Graphical abstract is available as Supplementary information.

Epidemiology of native kidney disease in Flanders: results from the FCGG kidney biopsy registry.

Background: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is the first population-based native kidney biopsy registry in Flanders, Belgium. In this first analysis, we report on patient demographics, frequency distribution and incidence rate of biopsied kidney disease in adults in Flanders. Methods: From January 2017 to December 2019, a total of 2054 adult first native kidney biopsies were included. A 'double diagnostic coding' strategy was used, in which every biopsy sample received a histopathological and final clinical diagnosis. Frequency distribution and incidence rate of both diagnoses were reported and compared with other European registries. Results: The median age at biopsy was 61.1 years (interquartile range, 46.1-71.7); male patients were more prevalent (62.1%) and biopsy incidence rate was 129.3 per million persons per year. Immunoglobulin A nephropathy was the most frequently diagnosed kidney disease (355 biopsies, 17.3% of total) with a similar frequency as in previously published European registries. The frequency of tubulointerstitial nephritis (220 biopsies, 10.7%) and diabetic kidney disease (154 biopsies, 7.5%) was remarkably higher, which may be attributed to changes in disease incidence as well as biopsy practices. Discordances between histopathological and final clinical diagnoses were noted and indicate areas for improvement in diagnostic coding systems. Conclusions: The FCGG registry, with its 'double diagnostic coding' strategy, provides useful population-based epidemiological data on a large Western European population and allows subgroup selection for future research.

Current Methodological Challenges of Single-Cell and Single-Nucleus RNA-Sequencing in Glomerular Diseases.

Single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) allow transcriptomic profiling of thousands of cells from a renal biopsy specimen at a single-cell resolution. Both methods are promising tools to unravel the underlying pathophysiology of glomerular diseases. This review provides an overview of the technical challenges that should be addressed when designing single-cell transcriptomics experiments that focus on glomerulopathies. The isolation of glomerular cells from core needle biopsy specimens for single-cell transcriptomics remains difficult and depends upon five major factors. First, core needle biopsies generate little tissue material, and several samples are required to identify glomerular cells. Second, both fresh and frozen tissue samples may yield glomerular cells, although every experimental pipeline has different (dis)advantages. Third, enrichment for glomerular cells in human tissue before single-cell analysis is challenging because no effective standardized pipelines are available. Fourth, the current warm cell-dissociation protocols may damage glomerular cells and induce transcriptional artifacts, which can be minimized by using cold dissociation techniques at the cost of less efficient cell dissociation. Finally, snRNA-seq methods may be superior to scRNA-seq in isolating glomerular cells; however, the efficacy of snRNA-seq on core needle biopsy specimens remains to be proven. The field of single-cell omics is rapidly evolving, and the integration of these techniques in multiomics assays will undoubtedly create new insights in the complex pathophysiology of glomerular diseases.

Deconvolution of Focal Segmental Glomerulosclerosis Pathophysiology Using Transcriptomics Techniques.

Background: Focal segmental glomerulosclerosis is a histopathological pattern of renal injury and comprises a heterogeneous group of clinical conditions with different pathophysiology, clinical course, prognosis, and treatment. Nevertheless, subtype differentiation in clinical practice often remains challenging, and we currently lack reliable diagnostic, prognostic, and therapeutic biomarkers. The advent of new transcriptomics techniques in kidney research poses great potential in the identification of gene expression biomarkers that can be applied in clinical practice. Summary: Transcriptomics techniques have been completely revolutionized in the last 2 decades, with the evolution from low-throughput reverse-transcription polymerase chain reaction and in situ hybridization techniques to microarrays and next-generation sequencing techniques, including RNA-sequencing and single-cell transcriptomics. The integration of human gene expression profiles with functional in vitro and in vivo experiments provides a deeper mechanistic insight into the candidate genes, which enable the development of novel-targeted therapies. The correlation of gene expression profiles with clinical outcomes of large patient cohorts allows for the development of clinically applicable biomarkers that can aid in diagnosis and predict prognosis and therapy response. Finally, the integration of transcriptomics with other "omics" modalities creates a holistic view on disease pathophysiology. Key Messages: New transcriptomics techniques allow high-throughput gene expression profiling of patients with focal segmental glomerulosclerosis (FSGS). The integration with clinical outcomes and fundamental mechanistic studies enables the discovery of new clinically useful biomarkers that will finally improve the clinical outcome of patients with FSGS.