Kidney Week

Abstract: PO1457

Dysregulated T Cell Metabolomic Profile in Patients with Steroid-Resistant Nephrotic Syndrome

Session Information

• Glomerular Diseases: Immunology and Inflammation in IgANP, C3GP, TMA, and Nephrotic Diseases
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Chan, Chang-Yien, National University Singapore Yong Loo Lin School of Medicine, Singapore, Singapore

Chang-Yien Chan, PhD

• Lu, Liangjian, Khoo Teck Puat - National University Children's Medical Institute, Singapore, Singapore

Liangjian Lu,

• Teo, Sharon, Khoo Teck Puat - National University Children's Medical Institute, Singapore, Singapore

Sharon Teo,

• Zhang, Yaochun, National University Singapore Yong Loo Lin School of Medicine, Singapore, Singapore

Yaochun Zhang,

• Lam, Kong Peng, Agency for Science Technology and Research, Singapore, Singapore

Kong Peng Lam,

• Ng, Kar Hui, National University Singapore Yong Loo Lin School of Medicine, Singapore, Singapore

Kar Hui Ng,

• Yap, Hui Kim, National University Singapore Yong Loo Lin School of Medicine, Singapore, Singapore

Hui Kim Yap,

Background

We have recently reported early relapse following rituximab in patients with minimal change disease was associated with baseline reduction in regulatory T-cells and T-cell hyporesponsiveness to activation, suggesting chronic T-cell activation. This study aimed to compare T-cell activation and characterise the metabolic alterations associated with T-cell hyporesponsiveness in patients with steroid-dependent (SDNS) and steroid-resistant nephrotic syndrome (SRNS) in relapse.

Methods

A total of 48 patients with childhood-onset SDNS (n=31) and SRNS (n=17) were recruited during relapse. T-cell activation assay was performed on whole blood while metabolomic profiling was performed on purified stimulated CD4 T-cell culture supernatants (n=23) using GC-MS/MS and analysed using Shimadzu Smart Metabolites Database. Differences in the metabolomic profile between SDNS and SRNS were identified using PLS-DA (SIMCA), and pathway analysis was performed using MetaboAnalyst 4.0. Metabolomic validation assay was performed using Glucose 6 Phosphate Dehydrogenase (G6DP) assay kit.

Results

SRNS patients had significant lower T-cell expression of CD69 (88±2.3% vs 91±3.1%, P=0.024) and IFNγ (1.9±0.73% vs 6.6±1.35%, P=0.016) compared to SDNS patients. PLS-DA modeling of the 93 metabolites identified in CD4 culture supernatants yielded one fitted component, in which 24% of the variability in metabolites measured (R²X) could explain 58% of the variation in steroid-response (R²Y). Of note, 85% of the metabolites tended to be lower in SRNS compared to SDNS patients. Pathway analysis of the 38 metabolites with VIP>1 implicated the biosynthetic pathways glyoxylate and dicarboxylate metabolism, ascorbate and aldarate metabolism as well as galactose metabolism (Benjamini-Hochberg P<0.05). Interestingly, the 2 metabolites with the highest VIP score have been implicated as downstream products in the pentose phosphate pathway and were reduced in SRNS compared to SDNS patients (P<0.001). G6DP activities in SDNS patients in relapse negatively correlated with T-cell expression of CD69 (r=-0.58, P<0.047).

Conclusion

We demonstrated that muted T-cells response to in vitro stimulation in SRNS patients was associated with metabolic quiescence, with dysregulated biosynthetic pathways including the pentose phosphate shunt.

Funding

• Government Support – Non-U.S.