Kidney Week 2025 Annual Meeting-Small Molecules to Modulate CKD-MBD

Video Transcription

Video Summary

The session opens with three talks on bone–kidney mineral metabolism in CKD, focusing on new molecular targets.

<strong>Talk 1 (Mark V. Vine): Salt-inducible kinase (SIK) inhibitors in bone and kidney.</strong> PTH maintains calcium via bone resorption (RANKL) but can also promote bone formation (via suppressing sclerostin), with outcomes depending on continuous vs intermittent exposure. Vine’s group identifies SIK2/3 as key downstream mediators of PTH/PKA signaling: PTH inhibits SIKs, allowing CRTC and class II HDAC regulators to enter the nucleus and change gene expression. Bone-specific SIK2/3 deletion mimics constitutively active PTH receptor phenotypes (high trabecular bone, cortical loss). In kidney, SIK inhibition or renal SIK2/3 deletion increases CYP27B1 and circulating 1,25(OH)₂D, causing hypercalcemia and suppressed PTH, without strong phosphate effects. Human kidney organoids confirm PTH/SIK-inhibitor induction of CYP27B1 and 1,25(OH)₂D, blocked by FGF23 and dependent on CRTC factors. A selective oral SIK2/3 inhibitor (SK124) increases bone formation and rescues cortical bone/strength in adenine CKD models, and unexpectedly shows renal-protective signals in injury models. Potential applications include osteoporosis, CKD-MBD, kidney protection, and hypoparathyroidism.

<strong>Talk 2 (Talia Nabi): mTOR in parathyroid hyperplasia.</strong> In adenine/high-phosphate CKD rats, parathyroid proteomics show increased phosphorylation and mTORC1 activation (pS6), with proliferation. Rapamycin prevents and reverses parathyroid proliferation and lowers PTH, including in organ culture, suggesting direct gland effects. Parathyroid-specific mTOR deletion disrupts gland structure and blunts PTH rise after acute kidney injury; parathyroid-specific TSC1 deletion hyperactivates mTOR, causing enlarged cystic glands, high PTH/hypercalcemia, bone loss, and reduced survival—partially reversible with rapamycin/everolimus. Preliminary human/transplant database data suggest mTOR inhibitors associate with lower PTH and secondary HPT incidence.

<strong>Talk 3 (Timur R.): Targeting phosphate transport.</strong> Reviews intestinal and renal phosphate transport (NPT2B, PITs, paracellular; renal NPT2A/NPT2C). Intestinal approaches include tenapanor (reduces paracellular uptake). A selective NPT2A inhibitor increases phosphaturia and lowers serum phosphate even in 5/6 nephrectomy models, but also increases natriuresis and appears to reduce ENaC open probability. Safety questions remain: NPT2A loss plus vitamin D can worsen nephrocalcinosis and impair kidney function in mice, raising concern about calcification risk and human genetic variability.

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 Pharmacology

Session ID 507255

Keywords

chronic kidney disease

CKD-mineral and bone disorder

bone-kidney mineral metabolism

salt-inducible kinase inhibitors

SIK2/3

parathyroid hormone signaling

CYP27B1 induction

1,25-dihydroxyvitamin D

FGF23 regulation

mTORC1 activation

secondary hyperparathyroidism

phosphate transport inhibition

NPT2A inhibitor