Multidimensional inflammatory and immunological endotypes of idiopathic focal segmental glomerulosclerosis and their association with treatment outcomes

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Abstract

Objectives

Idiopathic focal segmental glomerulosclerosis (FSGS) has been linked to immunological and inflammatory response dysregulations. The aim of this study was to find endotypes of FSGS patients using a cluster (CL) analysis based on inflammatory and immunological variables, and to analyse whether a certain endotype is associated with response to treatment with corticosteroids.

Methods

This prospective observational study included patients with idiopathic FSGS diagnosed by kidney biopsy. Serum levels of soluble interleukin (IL)-1 receptor, tumoural necrosis factor alpha, Interferon gamma (IFNγ), IL-6, IL-17, IL-12, IL-23, IL-13, IL-4, IL-5, IL-6, haemopexin (Hx), haptoglobin (Hgl), soluble urokinase-type plasminogen activator receptor (suPAR) and urinary CD80 (uCD80) were measured with enzyme-linked immunosorbent assay or nephelometry. T-helper lymphocyte populations and T-regulatory lymphocytes were analysed by flow cytometry. A factorial analysis followed by a k-means CL analysis was performed.

Results

A total of 79 FSGS patients were included. Three CLs were identified. CL1 (27.8%) included IL-12, IL-17, IL-23 and a T helper 17 (Th17) pattern. CL2 (20.2%) included IL-4, IL-5, IL-13, immunoglobulin E and Th2 pattern. CL3 (51.8%) included IL-6, Hx, Hgl, suPAR and uCD80. There were no differences in age, gender, kidney function, albumin or proteinuria among CLs. About 42/79 patients (53.1%) showed cortico-resistance. The prevalence of cortico-resistance was significantly lower in CL2 (4/16, 25%) than in CL1 (16/26, 72.7%) and CL3 (22/41, 53.7%) (P = 0.018), with no significant differences between CLs 1 and 3 (P = 0.14).

Conclusions

Patients with FSGS and indistinguishable clinical presentation at diagnosis were classified in three distinct CLs according to predominant Th17, Th2 and acute inflammatory responses that display differences in clinical response to treatment with corticosteroids.

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Most cited references 32

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Focal Segmental Glomerulosclerosis.

Avi Z. Rosenberg, Jeffrey B. Kopp (2017)

Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Pathogenesis of lipoid nephrosis: a disorder of T-cell function.

J Shalhoub (1974)

Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane. The lack of evidence of a humoral antibody response, remission induced by measles which modifies cell-mediated immunity, the therapeutic benefits of steroids and cyclophosphamide which also abate cell-mediated responses, and the occurrence of this syndrome in Hodgkin's disease support this hypothesis. The susceptibility of untreated patients to pneumococcal infections may be of primary or secondary pathogenetic importance. Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease.

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Nephrotic syndrome in childhood.

Allison Eddy, Jordan Symons (2003)

Childhood nephrotic syndromes are most commonly caused by one of two idiopathic diseases: minimal-change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS). A third distinct type, membranous nephropathy, is rare in children. Other causes of isolated nephrotic syndrome can be subdivided into two major categories: rare genetic disorders, and secondary diseases associated with drugs, infections, or neoplasia. The cause of idiopathic nephrotic syndrome remains unknown, but evidence suggests it may be a primary T-cell disorder that leads to glomerular podocyte dysfunction. Genetic studies in children with familial nephrotic syndrome have identified mutations in genes that encode important podocyte proteins. Patients with idiopathic nephrotic syndrome are initially treated with corticosteroids. Steroid-responsiveness is of greater prognostic use than renal histology. Several second-line drugs, including alkylating agents, ciclosporin, and levamisole, may be effective for complicated and steroid-unresponsive MCNS and FSGS patients. Nephrotic syndrome is associated with several medical complications, the most severe and potentially fatal being bacterial infections and thromboembolism. Idiopathic nephrotic syndrome is a chronic relapsing disease for most steroid-responsive patients, whereas most children with refractory FSGS ultimately develop end-stage renal disease. Research is being done to further elucidate the disorder's molecular pathogenesis, identify new prognostic indicators, and to develop better approaches to treatment.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Kidney J

Journal ID (iso-abbrev): Clin Kidney J

Journal ID (publisher-id): ckj

Title: Clinical Kidney Journal

Publisher: Oxford University Press

ISSN (Print): 2048-8505

ISSN (Electronic): 2048-8513

Publication date Collection: July 2021

Publication date (Electronic): 14 December 2020

Publication date PMC-release: 14 December 2020

Volume: 14

Issue: 7

Pages: 1826-1834

Affiliations

[1 ] Servicio Nefrologia Pediátrica, Hospital Universitari de Vic, Universitat de Vic , Barcelona, Spain

[2 ] Servicio de Nefrología Pediátrica, Hospital de Sant Joan de Déu de Barcelona , Barcelona, Spain

[3 ] Servicio de Nefrología Pediátrica, Hospital Vall d’Hebrón , Barcelona, Spain

[4 ] Servicio de Nefrología Pediátrica, Hospital de la Santa Creu i Sant Pau , Barcelona, Spain

[5 ] Institut de Recerca Biomedica August Pi Sunyer , Lleida, Barcelona, Spain

[6 ] Servicio de Nefrologia, Hospital Universitario Arnau de Vilanova , Lleida, Spain

Author notes

Correspondence to: Alfons Segarra; E-mail: alsegarr@ 123456gmail.com

Article

Publisher ID: sfaa265

DOI: 10.1093/ckj/sfaa265

PMC ID: 8243272

PubMed ID: 34221390

SO-VID: f5a86cf3-046a-486d-b329-583b4a18fe09

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 30 July 2020

Date accepted : 07 December 2020

Date: 07 December 2020

Page count

Pages: 9

Multidimensional inflammatory and immunological endotypes of idiopathic focal segmental glomerulosclerosis and their association with treatment outcomes

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Abstract

Objectives

Methods

Results

Conclusions

Graphical Abstract

Related collections

Karger: Nephrology

Most cited references 32

Focal Segmental Glomerulosclerosis.

Pathogenesis of lipoid nephrosis: a disorder of T-cell function.

Nephrotic syndrome in childhood.

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