Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease

Abstract

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 (7.7612.5 ml/min per 1.73 m 2 ; n=9) than in the SC group (211.269.1 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 (1.6612.1 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 range6SD, 2.4060.64 to 2.9061.20 ng/ml) compared with those in the STD group (3.9362.27 to 5.7761.06 ng/ml) (P,0.01). ConclusionPatients 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.

m-TOR Inhibitors in the Current Practice

“…This discovery represents a potential novel therapeutic approach for glycogen storage diseases (for GSD III) [78][79].…”

“…Different case reports demonstrated sirolimus as a key role in reducing kidney volume in patients with early-stage ADPKD and delaying decline in kidney function compared with those receiving standard care. However, the current clinical trials are limited with confounding results [79][80][81].…”

“…Mutations in PRKAG2 are responsible for familial cardiac hypertrophy and Wolff-Parkinson-White syndrome. The knowledge that an important hallmark of cardiac hypertrophy (a major risk for cardiac morbidity and mortality) is hyperactivation of the PI3K-mTOR cascade, initiated a discussion whether inhibition of the mTOR pathway could be beneficial in treating such disorders [79,82,83].…”

“…Phosphorylation of IRS1, which is known to antagonize IRS signaling, is elevated in animal models of obesity and in muscle from type 2 diabetic patients. Insulin resistance is the hallmark for both, obesity and type 2 diabetes [79,84,85].…”

Novel Treatments of Autosomal Dominant Polycystic Kidney Disease

“…It was in this context that Braun et al proposed and executed a new pilot trial with 30 patients of low-dose versus standard-dose sirolimus with tracking of GFR by radiolabeled iothalamate clearance (being more precise) in addition to TKV (assessed by noncontrast computed tomography imaging) and blood levels of sirolimus (36). The investigators reasoned that radiolabeled iothalamate clearance measurements may reveal a treatment effect that might be missed by either traditional creatinine clearance or eGFR calculations from a serum creatinine measurement.…”