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Kidney Week

Abstract: TH-PO411

New Therapy for Early-Stage Polycystic Kidney Disease: Combination of Difelikefalin and Tolvaptan

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Gao, Juan, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Johnson, Kara, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Haggard, Madison Grace, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Denys, Ian Bart, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Naljayan, Mihran V., LSU Health New Orleans, New Orleans, Louisiana, United States
  • Kapusta, Daniel R., LSU Health New Orleans, New Orleans, Louisiana, United States
Background

We have reported that difelikefalin, a partial agonist of kappa opioid receptors, produces a centrally mediated water diuresis presumably by inhibiting the central release of vasopressin (AVP). Since plasma AVP is elevated and participates in mediating polycystic kidney disease (PKD), we tested the hypothesis that difelikefalin would be superior to the V2 AVP antagonist, tolvaptan, in slowing progression of early-stage PKD.

Methods

Three-month old PKD mice were divided into 4 groups and were treated daily (dose titrated to decrease urine osmolality) for 3-months with either difelikefalin, tolvaptan, combination of difelikefalin and tolvaptan (D+T), or vehicle. Glomeruli filtration rate (GFR; beginning, midterm, endpoint) and total kidney volume (TKV, calculated as length, width, and depth of kidneys after mice were sacrificed) were measured in each group. Metabolic studies were also performed to measure 24-hour urine output and water intake.

Results

The results demonstrated that in contrast to vehicle treatment, difelikefalin, tolvaptan, and D+T each prevented a significant decline in GFR during the 3-month PKD disease progression. However, at the termination of study only D+T markedly reduced TKV compared with vehicle treated PKD mice (188 ± 12 vs 228 ±10 mm3, resp.). In other studies, it was shown that the same age PKD mice treated for 3-months with difelikefalin combined with a half dose of tolvaptan (D+1/2T) was as efficacious in preventing a decline in GFR and suppressing an increase in TKV as D+T. Compared to baseline levels, water intake and urine output were significantly elevated in PKD mice treated with tolvaptan and D+T. Importantly, PKD mice treated with D+1/2T had significantly reduced urine output and water intake than PKD mice treated with tolvaptan alone or D+T.

Conclusion

Together, these findings suggest that difelikefalin not only potentiates the effect of tolvaptan but also allows a reduced dose of tolvaptan to achieve the same protection of renal function and kidney size, but with less polyuria and polydipsia. Thus, the combination of half-dose tolvaptan and difelikefalin is superior to tolvaptan alone in maintaining GFR and TKV and causes fewer side effects. (Funding DoD W81XWH-22-1-0046)

Funding

  • Other U.S. Government Support