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Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized
William E Braun1, Jesse D Schold, Brian R Stephany
1Glickman Urological and Kidney Institute,, †Quantitative Health Sciences, and, ‡Imaging Institute, Cleveland Clinic, Cleveland, Ohio.
Background And Objectives:
The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily.
Design, Setting, Participants, & Measurements:
In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography.
Results:
Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m(2); n=9) than in the SC group (-11.2 ± 9.1 ml/min per 1.73 m(2); n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6 ± 12.1 ml/min per 1.73 m(2); n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range ± SD, 2.40 ± 0.64 to 2.90 ± 1.20 ng/ml) compared with those in the STD group (3.93 ± 2.27 to 5.77 ± 1.06 ng/ml) (P<0.01).
Conclusion:
Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.
Insights
Low-dose rapamycin significantly increased kidney function in autosomal dominant polycystic kidney disease (ADPKD) patients over 12 months. This treatment showed a notable improvement in iGFR compared to standard care, without affecting total kidney volume.
Area of Science:
- Nephrology
- Pharmacology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation.
- Previous studies on mammalian target of rapamycin (mTOR) inhibitors for ADPKD showed no significant benefit on total kidney volume (TKV) or estimated glomerular filtration rate (eGFR).
Purpose of the Study:
- To evaluate the effect of two different doses of rapamycin on kidney function in ADPKD patients.
- To assess the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV as a secondary endpoint.
Main Methods:
- A 12-month open-label pilot study involving 30 adult ADPKD patients.
- Patients were randomized into three groups: low-dose (LD) rapamycin, standard-dose (STD) rapamycin, or standard care (SC).
- Kidney function was assessed using iGFR and TKV via noncontrast computed tomography.
Main Results:
- The LD rapamycin group showed a significant increase in iGFR at 12 months compared to the SC group (P<0.01).
- The STD rapamycin group did not show a significant increase in iGFR compared to SC (P=0.07), but combined LD+STD groups did (P<0.01).
- Neither eGFR nor TKV showed significant changes from baseline in any group after 12 months. LD group maintained significantly lower rapamycin trough levels than STD group.
Conclusions:
- Low-dose rapamycin treatment led to a significant improvement in iGFR in ADPKD patients over 12 months.
- The observed increase in iGFR with LD rapamycin was not associated with changes in TKV.
- These findings suggest a potential therapeutic benefit of carefully dosed rapamycin in managing ADPKD kidney function.
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