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Published on: June 23, 2015
Rapamycin for treatment of type I autosomal dominant polycystic kidney disease (RAPYD-study): a randomized,
Giovanni Stallone1, Barbara Infante, Giuseppe Grandaliano
1Nephrology, Dialysis and Transplantation Unit, Department of Biomedical Sciences, University of Foggia, Foggia, Italy. g.stallone@unifg.it
Background:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of cystic kidney disease. An inappropriate stimulation of mammalian target of rapamycin may represent the converging point in the molecular pathways leading to renal cyst growth.
Methods:
The primary objectives of this prospective, open-label, randomized clinical trial were to assess whether rapamycin may reduce the progressive increase in single cyst and total kidney volume in type I ADPKD and the decline in renal function and to identify the optimal rapamycin dose. Fifty-five patients with type I ADPKD were enrolled and randomized to receive ramipril (Group A), ramipril + high-dose rapamycin (Group B, trough level 6-8 ng/mL) and ramipril + low-dose rapamycin (Group C, trough levels 2-4 ng/mL). Rapamycin efficacy was monitored measuring p70 phosphorylation in peripheral blood mononuclear cells.
Results:
Both rapamycin doses significantly reduced p70 phosphorylation. Nevertheless, total kidney volume increased in all groups after 24 months, although only in Groups A and B, was the final volume significantly higher compared with the baseline. Single cyst final volume was not significantly different in the three groups, although it was increased in Group A compared with the baseline, whereas in Groups B and C, it was significantly reduced. We did not observe any difference in renal function at 24 months among the three study groups. Group A presented a significant worsening of renal function that remained stable in both Groups B and C.
Conclusions:
Our study would suggest that rapamycin does not influence the progression of type I ADPKD, although the higher drug dose tested prevented both the increase in kidney volume and the worsening of renal function (RAPYD-study, EUDRACT No. 2007-006557-25).
Insights
Rapamycin did not halt autosomal dominant polycystic kidney disease (ADPKD) progression. However, a higher dose of rapamycin in type I ADPKD patients stabilized kidney volume and prevented renal function decline.
Area of Science:
- Nephrology
- Pharmacology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disorder.
- Aberrant mammalian target of rapamycin (mTOR) signaling is implicated in renal cystogenesis in ADPKD.
Purpose of the Study:
- To evaluate rapamycin's efficacy in reducing kidney and cyst volume in type I ADPKD.
- To assess rapamycin's impact on renal function decline.
- To determine the optimal rapamycin dosage for ADPKD treatment.
Main Methods:
- A prospective, open-label, randomized clinical trial involving 55 type I ADPKD patients.
- Patients received ramipril alone (Group A), ramipril plus high-dose rapamycin (Group B), or ramipril plus low-dose rapamycin (Group C).
- Rapamycin's effect was monitored via p70 phosphorylation in peripheral blood mononuclear cells.
Main Results:
- Both rapamycin doses reduced p70 phosphorylation; however, total kidney volume increased in all groups.
- Single cyst volume decreased significantly in rapamycin-treated groups (B and C) compared to baseline.
- No significant differences in overall renal function were observed at 24 months, but ramipril alone worsened function, while rapamycin groups maintained stability.
Conclusions:
- Rapamycin did not halt the progression of type I ADPKD.
- Higher-dose rapamycin demonstrated a potential to prevent kidney volume increase and preserve renal function in ADPKD patients.
