Combination Treatment of Difelikefalin and Tolvaptan for Late-Stage Polycystic Kidney Disease

Background: We have previously reported that, in the early stages of polycystic kidney disease (PKD), combination treatment of the kappa opioid agonist, difelikefalin, and the V2 vasopressin receptor antagonist, tolvaptan, maintained glomerular filtration rate and ameliorated polyuria and polydipsia associated with tolvaptan monotreatment. This current study tested the hypothesis that combination treatment of difelikefalin and tolvaptan can protect against worsening of PKD in the late stages. Methods: Six-month old PKD mice were divided into five groups and were treated daily (dose titrated to decrease urine osmolality) for 3-months with either difelikefalin, tolvaptan, a combination of difelikefalin and tolvaptan (D+T), a combination of difelikefalin and half does of tolvaptan (D+1/2T), or vehicle. Metabolic studies were performed monthly to measure 24-hour urine output and water intake during the study period. 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 determined in each group. Kidney tissue cAMP levels were also measured after mice were sacrificed. Results: Treatment of PKD mice with difelikefalin, tolvaptan, D+T, and D+1/2T all prevented a decline in GFR over time. D+1/2T reduced the ratio of kidney weight to body weight by 12% compared to PKD mice treated with vehicle. None of the treatments caused a statistically significant reduction in TKV. Compared to vehicle, treatment with D+1/2T produced increases in 24-hr urine volume and decreases in urine osmolality measured monthly in PKD mice that were greater in magnitude than responses produced by difelikefalin alone, but less than mice treated with tolvaptan or D+T. The combination treatments of D+T and D+1/2T both significantly decreased renal cAMP levels compared with vehicle. Conclusion: Together, these results suggest that combination treatment of difelikefalin and tolvaptan preserves kidney filtration function, reduces side effects, and decreases necessity of dose escalation of tolvaptan in late stages of PKD. (Funding DoD W81XWH-22-1-0046) Funding: Other U.S. Government Support