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

Neus Roca; Alvaro Madrid; Mercedes Lopez; Gloria Fraga; Elias Jatem; Jorge Gonzalez; Cristina Martinez; Alfons Segarra

doi:10.1093/ckj/sfaa265

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

Clin Kidney J. 2020 Dec 14;14(7):1826-1834. doi: 10.1093/ckj/sfaa265. eCollection 2021 Jul.

Authors

Neus Roca¹, Alvaro Madrid², Mercedes Lopez³, Gloria Fraga^{3

4}, Elias Jatem^{5

6}, Jorge Gonzalez^{5

6}, Cristina Martinez⁵, Alfons Segarra^{5

6}

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.

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.

Keywords: cluster analysis; endotypes; focal segmental glomerulosclerosis; idiopathic nephrotic syndrome; inflammatory response; interleukins; lymphocyte populations.