Sirolimus Therapy to Halt the Progression of ADPKD

Abstract

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR Ն40 ml/min per 1.73 m 2 . In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46 Ϯ 81 ml; P ϭ 0.047) than on conventional therapy (70 Ϯ 72 ml; P ϭ 0.002), but we did not detect a difference between the two treatments (P ϭ 0.45). Cyst volume was stable on sirolimus and increased by 55 Ϯ 75 ml (P ϭ 0.013) on conventional therapy, whereas parenchymal volume increased by 26 Ϯ 30 ml (P ϭ 0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease

“…The association between baseline TKV and baseline iothalamate clearance (GFR) was modestly significant in 241 participants (r=2 0.39, P,0.001), However, only 29 participants reached stage 3 CKD (GFR of 60 ml/min per 1.73 m 2 ), and only those with the largest kidneys (.1500 cc) demonstrated a significant decline in GFR (24.33 ml/min per yr) in the first 3 years of follow-up (4). Results from three recent prospective clinical trials of relatively short duration have not demonstrated an association between changes in TKV and GFR (23)(24)(25), questioning the value of TKV as a disease marker in ADPKD (26). We present the results of 8 years of follow-up in study participants to determine the extent to which baseline TKV predicts the future development of renal insufficiency.…”

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

“…After observational findings that, in patients with ADPKD receiving a kidney transplant, cyst growth was slowed by sirolimus-based immunosuppressive therapy (4), a pilot, prospective, randomized, crossover trial found that 6-month sirolimus therapy, unlike conventional therapy, halted the growth of total cyst volume in 15 patients with normal renal function or mild to moderate renal dysfunction (9). However, two subsequent large clinical trials (10,11) failed to show a clear beneficial effect of either sirolimus or everolimus in patients with CKD stages 2-3b renal function.…”

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…Clinical trials testing the efficacy of mTOR inhibitors were recently evaluated. [13][14][15][16][17][18][19] mTOR plays a central role in regulating cell growth by integrating signals from growth factors, nutrients, and cellular energy levels. mTOR is a serine/threonine kinase that forms two distinct physical and functional complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2).…”