Kidney Week

Abstract: FR-PO1166

Propensity Score Matching in CKD: Evaluating Guca2b as a Biomarker for Diagnosis and Treatment Monitoring

Session Information

• CKD: Kidney Function and Extrarenal Complications
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

• Carrithers, Aaron L., PrognostX Health, LaGrange, Kentucky, United States

Aaron L. Carrithers, MD

• Morrison, Luke E., PrognostX Health, LaGrange, Kentucky, United States

Luke E. Morrison

• Ott, Ryan, Ethos Biosciences, Newtown Square, Pennsylvania, United States

Ryan Ott, MBA

• Carrithers, Stephen L., PrognostX Health, LaGrange, Kentucky, United States

Stephen L. Carrithers, PhD

Background

Limitations of early diagnosis of CKD with standard of care have been well documented. Guanylate cyclase activator 2B (Guca2b), a prohormone that delivers the bioactive hormone moiety uroguanylin to its receptors lining the nephron, has recently been shown to significantly increase in the circulation during increased severity of renal impairment and early chronic kidney damage. Guca2b exhibits a dual paracrine-endocrine secretion mechanism, being released into the tubular lumen and arterioles, where protease activation in the glomerulus enables immediate nephroprotective effects on the proximal tubule (PT) by maintaining salt and fluid homeostasis and conserving energetic expenditure. Guca2b mediates natriuresis and kaliuretic actions through cGMP-dependent and -independent pathways. These include downregulation of the PT Na⁺-pump, inhibition of Na⁺/H⁺ exchanger (akin to SGLT2i’s) and Na⁺/K⁺/2Cl^- in the mTAL (site of action for loop diuretics), and distal ClC-K2 chloride channels (mitigating activation by AII and emulating renoprotective properties of ACEI/ARBs).

Methods

To account for potential differential treatment effects on circulating Guca2b levels as an early biomarker for CKD and balance covariates between CKD stages and controls, nearest neighbor propensity score matching with caliper width 0.2x±SD of the logit was conducted on age, race, gender, and eGFR in a 426-patient case-control observational study. Median treatment effect on circulating Guca2b levels (ng/ml) was calculated for cases and controls treated with therapeutic agents that act on tubular salt transport channels.

Results

Mild reductions in Guca2b levels were observed across all treatment groups within the nested G3a/G3b subgroups, yet none were statistically significant: loop diuretics (3.57 vs 3.81; MTE, -0.54; n=18), thiazide diuretics (3.10 vs 3.16; MTE, -0.06; n=18), all diuretics (3.41 vs 4.02; MTE, -0.61; n=28), and ACEI/ARBs (3.06 vs 3.51; MTE, -0.45; n=32). Baseline characteristics and eGFR’s were matched in stage A1/A2 CKD patients to healthy controls, demonstrating significantly higher mean Guca2b levels (2.70 vs 1.20, n=43, p<0.05) yet lower than matched G3a/G3b (2.55 vs 3.94, n=37, p<0.05).

Conclusion

This study suggests a multifactorial mechanism of early renal pathogenesis independent of GFR and potential biomarker for early CKD detection.

Funding

• NIDDK Support