Research Viewpoints Deconvolution of a Lesion of FSGS

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Deleersnijder D, Van Craenenbroeck A.H,Sprangers B: Deconvolution of Focal Segmental Glomerulosclerosis Pathophysiology Using Transcriptomics Techniques. Glomerular Diseases Research DOI 10.1159/000518404

The lesion of FSGS can be due to many quite different pathogenic mechanisms. Sorting out the correct disease diagnosis can be a difficult challenge in individual cases and requires a careful systematic clinico-pathologic approach [1]. It has long been hoped that sophisticated molecular approaches using molecular analysis of kidney tissue, serum, or urine might ultimately lead to an accurate differentiation of the various causes of the FSGS, and also provide new insight into pathogenic pathways fostering the development of disease-specific treatment regimens, i.e., personalized medicine.

Deleersnijder and colleagues provide a very scholarly, well-written, comprehensive, and up-to-date review of the utility of cellular and tissue transcriptomics in devolving the lesion of FSGS into its discrete disease-specific fingerprints. Much has been accomplished and the future seems bright, but proof of the principle still needs much work before it can be considered clinically mainstream technology. Single cell or single nucleus transcriptomics seems to be the direction of future research. Reverse transcription-polymerase chain reaction and in situ hybridization seem to have limited applicability since only a few of the thousands of genes expressed can be studied. Microarray technology has the great advantage of high throughput, and fingerprints of many differentially expressed genes can be simultaneously analyzed. Microarray technology has already identified a number of target genes in FSGS lesions (such as those operating in the mTOR system), but this has not yet been translated into differential diagnosis or treatment regimens for the FSGA group of diseases. Nevertheless, tissue transcriptomics shows great promise in defining a treatment responsive compared to a treatment unresponsive subset of primary FSGS. Prognostic scoring systems based on transcriptomics have begun to evolve from such studies. Bulk RNA sequencing methods are less biased and show great utility in identifying small non-coding RNAs that regulate gene expression at the post-translational level (such as miR-21-5p that has been implicated in the generation of renal fibrosis). We have just scratched the surface of this complex but very important disease pathway.

Single cell and single nuclear RNA sequencing obviate some of the disadvantages of bulk RNA sequencing. The use of microfluidic technologies to separate single cells from mechanically or enzymatically disrupted whole tissue has been transformative. Many challenges exist in applying single cell or nucleus RNA sequencing to the deconvolution of a lesion of FSGS. Poor recovery of podocytes in single cell preparations is a weakness – one that might be overcome by using urine as a source of “viable but detached” podocytes in FSGS. Single cell technology is much more revealing in studies of kidney endothelial cell biology and tubule-interstitial changes in disease. Nevertheless, the field of “single-cell- omics” is moving rapidly and may yet be a “goldmine” of new information concerning patterns of pathogenesis in FSGS. A clean and unequivocal differentiation of primary, secondary, and genetic forms of the FSGS lesion is an ultimate goal, but final common pathways of pathogenesis that are shared among the diagnostic categories cannot be ignored. Progress in either arena will likely lead to new targets of treatment.

However, proper and careful clinico-pathologic analysis of FSGS cases studied by new omics approaches will still be a mandatory requirement of the analytic design.

References

1. De Vriese AS, Wetzels JF, Glassock RJ, Sethi S, Fervenza FC. Therapeutic trials in adult FSGS: lessons learned and the road forward. Nat Rev Nephrol. 2021 Sep;17(9):619–30.