Journal of Kidney

Outpacing Current Nephrotic Syndrome Classification Systems

Vaibhav Israni^{* *}Correspondence: Vaibhav Israni, Editorial Office, Journal of Kidney, Belgium, Email:

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Introduction

The majority of nephrotic syndrome diagnoses in adults and children in the United States are due to Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD), respectively. FSGS and MCD are not illnesses, but rather histologic injury patterns marked by glomerular epithelial cell destruction and filtration barrier abnormalities. Both FSGS and MCD might present clinically as a nephrotic syndrome with diverse glomerular disease and varying responsiveness to treatment. Our existing categorization systems, which focus on a handful of morphologic criteria, do not properly account for the variety of clinic pathologic presentations due to the significant degree of variability associated with these disorders.

These constraints jeopardize the accuracy of diagnosis and prognosis, as well as the creation of sensible therapies. Novel techniques to improve our diagnostic capabilities for the nephrotic syndrome are desperately needed. The use of integrated structural and molecular histopathologic analyses to refine the current FSGS and MCD classification scheme may improve our diagnostic and prognostic capabilities in glomerular disease, as well as our understanding of the mechanisms of podocyte dysfunction and glomerular injury in nephrotic syndrome.

Hodgin et al. introduce a novel glomerular disease score system in this issue of AJKD to classify FSGS and MCD patients, combining histologic markers with clinical outcomes and molecular phenotypes not covered in our existing disease categorization methods. The authors believe that quantifying disease-related structural and molecular alterations will offer clinically and physiologically different information for these patient groupings. Current immunosuppressive medications may not yield long-term remission of proteinuria and maintenance of kidney function in all FSGS and MCD patients, indicating that some subsets of patients may have different molecular pathways underlying their disease pathogenesis.

In other words, one size does not fit all when it comes to treating FSGS and MCD. Thus, patient subgrouping supported by genetic profiling and a more precise scored evaluation of glomerular structural alterations may better guide precision medicine efforts in future mechanistic investigations and therapeutic trials.

The author of this study looked at 37 possible descriptors of structural and cellular abnormalities in the glomeruli of kidney biopsies from 221 adults and children with FSGS or MCD in the Nephrotic Syndrome Study Network (NEPTUNE), a prospective cohort. These glomeruli were documented and scored using these characteristics on an electronic scoring sheet for the NEPTUNE Digital Pathology Scoring System (NDPSS).

In addition to the traditional classification system, which described broader histopathologic patterns of FSGS variants, each NDPSS descriptor was quantified separately for detailed characteristics such as degree and location of sclerosis, hyaline deposits in epithelial cells, location of hyalinosis, degree of epithelial cell hypertrophy and hyperplasia, presence of marginating leukocytes, and presence of spikes.

NEPTUNE participants were classified into subgroups X, Y, and Z based on electronic scores, and these subgroups were subjected to molecular and clinical profiling. The scientists also identified the characteristics driving cluster membership using multinomial regression, including global sclerosis without hyalinosis, obsolescence, and segmental epithelial cell hypertrophy.

The researchers discovered that cluster X had the largest amount of adults, African Americans, and FSGS patients, whereas cluster Z had the highest proportion of pediatric patients and MCD patients. Furthermore, even after correcting for illness diagnosis, cluster X had the lowest likelihood of proteinuria remission, the highest risk of disease progression, and the steepest estimated glomerular filtration rate reduction. Post-hoc analysis revealed that the use of immune suppressants following biopsy did not explain variations in subgroup outcomes.

Bulk RNA sequencing of microdissected glomeruli from a selection of these patients' biopsies was done to investigate the molecular causes of these variations among clusters, and gene expression patterns were compared between cluster X and clusters Y and Z combined (X versus Y+Z). The authors revealed that podocyte-related genes were downregulated in cluster X while monocyte and macrophage genes were increased, which was consistent with the larger number of foam cells (lipid-laden macrophages) identified in cluster X. Cluster X also enriched for pathways related to inflammation, innate immunity, and fibrosis.

Although it is uncertain whether this work yielded unique insights or new avenues of research, it does give proof of concept that thorough histopathologic characterization and genetic profiling of pathology specimens may provide a viable approach for researching FSGS and MCD. The authors recognize that not all characteristics were adequately represented among the available biopsies, potentially underestimating certain descriptors' prognostic ability. Furthermore, while the presented RNA sequencing data was DE convolved to identify cell type abundance, a higher degree of resolution can be achieved using other cutting-edge omics technologies such as single-cell RNA sequencing, and single-cell ATAC-seq (assay for transposase-accessible chromatin using sequencing), and high-resolution spatial transcriptomics.