Calcineurin Inhibitors in the Treatment of Primary Focal Segmental Glomerulosclerosis

Laurin, Louis Philippe; Nachman, Patrick H.; Foster, Bethany J.

doi:10.1177/2054358117692559

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…Standard treatment for FSGS used to include glucocorticoids and other immunosuppressive drugs. In particular, calcineurin inhibitors are used as first-line immunosuppressive agents; however, only a variable subset of patients undergoes complete proteinuria remission [47]. Individuals not undergoing complete remission frequently develop progressive CKD.…”

Section: P O D O C Y T O P a T H I E S W I T H F S G S L E S I O N Smentioning

confidence: 99%

SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

Anders

Peired

Romagnani

2020

Nephrology Dialysis Transplantation

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In 2020, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial first demonstrated that inhibition of the sodium–glucose transporter-2 (SGLT2) with dapagliflozin attenuates the progression of chronic kidney disease (CKD) with proteinuria in patients with or without diabetes at an unprecedented effect size. These results have far-reaching implications for a series of traditional concepts in Nephrology. It now became obvious that CKD with and without diabetes involves a predominant SGLT2-driven pathophysiology compared with the other pathogenic pathways currently under consideration. As SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, treating CKD rather than ‘diabetic nephropathy’ becomes the central paradigm. Indeed, in older adults with type 2 diabetes, CKD is rather of multifactorial origin. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard. The same applies for patients with podocytopathy-related focal segmental glomerulosclerosis lesions. From now on, IgAN and podocytopathy trials without SGLT2 inhibition as background therapy and without glomerular filtration rate decline as primary outcome criterion will be of limited value. These and other potential implications will trigger broad discussions and secondary research activities with conclusions difficult to predict today. However, one is for sure: Nephrology after the DAPA-CKD trial will be not the same as it was before. Finally!

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Section: P O D O C Y T O P a T H I E S W I T H F S G S L E S I O N Smentioning

confidence: 99%

SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

Anders

Peired

Romagnani

2020

Nephrology Dialysis Transplantation

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“…However, the small number of included studies and treatment protocols’ heterogeneity and potential publication bias limited their conclusion. [ 9 ] Thus, the effect of CNIs in the treatment of primary FSGS is still unclearly.…”

Section: Introductionmentioning

confidence: 99%

Calcineurin inhibitors in the treatment of primary focal segmental glomerulosclerosis

Xue¹,

Wang²,

Li³

et al. 2021

Medicine

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Background: Evidence suggesting a role for including calcineurin inhibitors(CNIs) in early therapy remains limited for low quality and mainly based on small observation cohort study. We will conduct a systematic reviews to explore the effect and adverse effect of calcineurin inhibitors compared with other interventions in the treatment of primary focal segmental glomerulosclerosis (FSGS). Methods: A comprehensive literature search of MEDLINE (through PubMed), EMBASE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL) will be conducted. Two investigators will independently select studies, extract data and assess the quality of the included study. Extracted information will include study characteristics, the contents of included randomized controlled trials, outcomes, the quality of randomized controlled trials and etc. A risk of bias tool will be used to assess the methodological quality. Any disagreement will be resolved by the third investigator. There is no requirement of ethical approval and informed consent. Results: This study will provide high-quality evidence for treatment of FSGS in terms of effectiveness and safety. Conclusion: This systematic review aims to provide evidence for treatment of FSGS in different CNIs. Registration: The systematic review and meta-analysis is registered in the OSF REGISTERS (10.17605/OSF.IO/3B7DE) international prospective register of systematic review.

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“…Focal and Segmental Glomerulosclerosis (FSGS) is a clinico-pathological syndrome referring to sclerotic lesions in some areas of some kidney glomeruli and nephrotic range proteinuria [1,2]. While corticosteroids or calcineurin inhibitors can ameliorate the disease, FSGS is frequently resistant to treatment and may progress to end stage renal disease (ESRD) [1,3]. The cell type mainly affected and causing FSGS is the podocyte (visceral glomerular epithelial cell).…”

Section: Introductionmentioning

confidence: 99%

Podocyte RNA sequencing reveals Wnt- and ECM-associated genes as central in FSGS

et al. 2020

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Loss of podocyte differentiation can cause nephrotic-range proteinuria and Focal and Segmental Glomerulosclerosis (FSGS). As specific therapy is still lacking, FSGS frequently progresses to end-stage renal disease. The exact molecular mechanisms of FSGS and gene expression changes in podocytes are complex and widely unknown as marker changes have mostly been assessed on the glomerular level. To gain a better insight, we isolated podocytes of miR-193a overexpressing mice, which suffer from FSGS due to suppression of the podocyte master regulator Wt1. We characterised the podocytic gene expression changes by RNAseq and identified many novel candidate genes not linked to FSGS so far. This included strong upregulation of the receptor tyrosine kinase EphA6 and a massive dysregulation of circadian genes including the loss of the transcriptional activator Arntl. By comparison with podocyte-specific changes in other FSGS models we found a shared dysregulation of genes associated with the Wnt signaling cascade, while classical podocyte-specific genes appeared widely unaltered. An overlap with gene expression screens from human FSGS patients revealed a strong enrichment in genes associated with extracellular matrix (ECM) and metabolism. Our data suggest that FSGS progression might frequently depend on pathways that are often overlooked when considering podocyte homeostasis.

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Calcineurin Inhibitors in the Treatment of Primary Focal Segmental Glomerulosclerosis

Cited by 7 publications

References 23 publications

SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

Calcineurin inhibitors in the treatment of primary focal segmental glomerulosclerosis

Podocyte RNA sequencing reveals Wnt- and ECM-associated genes as central in FSGS

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