Kidney Week 2025 Annual Meeting-Sex and Kidney Metabolism: A New Frontier to Better Understand and Treat Kidney Diseases

Video Transcription

Video Summary

This session on sex differences in kidney metabolism highlighted how biological sex shapes kidney disease risk, progression, and response to injury, with implications for new therapies.<br /><br />Dr. Sergi Clotet-Frias described work showing males have faster diabetic kidney disease (DKD) progression and that androgens worsen early DKD features in mice. In human proximal tubule cells, androgen (DHT) exposure strongly upregulated metabolic enzymes. Comparing male vs female donor tubular cells (even without hormones), male cells were larger, had more mitochondrial area, higher glycolysis and oxygen consumption, more lactate secretion, and greater oxidative stress and susceptibility to high glucose injury. Metabolomics showed higher TCA-cycle intermediates in male cells, while female cells had higher pyruvate, a potential antioxidant. Clinically, higher pyruvate in cohorts associated with better kidney function and lower mortality, especially in women. He also presented a therapeutic angle: inhibiting the X-linked histone demethylase KDM6A reduced high-glucose–induced glycolysis/lactate secretion and inflammatory cytokines, and transcriptomics pointed to KDM6A-driven lipogenesis (via SREBP2) and possible regulation of SGLT2 expression.<br /><br />Dr. Pascal Schlosser presented CKDGen analyses of chromosome X across ~900,000 participants, identifying 23 genome-wide significant X-linked loci for eGFR and urate, including sex-specific signals. Several loci showed sex interactions and enrichment for nearby androgen response elements, supporting an androgen-regulated mechanism for some X-linked effects.<br /><br />Dr. Katalin Susztak/Komalinka (Toronto) focused on ischemia-reperfusion injury (IRI) and transplantation. Males are more susceptible to IRI; normothermic ex vivo kidney perfusion preserved mitochondrial proteins and respiration in pigs and reduced circulating mitochondrial DNA in humans. She linked sex differences to greater male proximal tubule mitochondrial flux and suggested female antioxidant advantages (metallothioneins, glutathione balance, pyruvate). HNF4α emerged as a regulator of perfusion-preserved mitochondrial programs and a potential therapeutic target.<br /><br />Dr. Art Arnold reviewed sex chromosome biology and models (four core genotypes, XY*), emphasizing that sex differences can arise from both hormones and intrinsic XX vs XY gene effects, including X-escape genes, and announced new sex-chromosome–modified rat resources for broader disease studies.

Asset Subtitle

Moderator(s): Sofia Ahmed, Joel Neugarten

Presentation(s):

Sex-Specific Manipulation of Kidney Metabolism: A Novel Therapeutic Opportunity in DKD? - Sergi Clotet Freixas
What Do Multi-Trait Genetic Analyses Tell Us About Sex Chromosomes and the Kidneys? - Pascal Schlosser
How Does Sex Influence Metabolism and Kidney Repair in Ischemia Reperfusion Injury? - Ana Konvalinka
What Do Animal Models Tell Us About the Role of Sex Chromosomes and Sex Hormones in Kidney Diseases? - Arthur Arnold

Meta Tag

Date 11/8/2025

Pathway 1 CKD Non-Dialysis

Session ID 507764

Keywords

sex differences

kidney metabolism

diabetic kidney disease (DKD)

androgens

dihydrotestosterone (DHT)

proximal tubule cells

mitochondrial function

glycolysis

oxidative stress

pyruvate

KDM6A

SGLT2

CKDGen

X chromosome loci

ischemia-reperfusion injury (IRI)