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Autosomal-dominant polycystic kidney disease (ADPKD) is the most common heritable kidney disorder with a prevalence of 1 in 400 to 1 in 1000 and accounting for ∼5% of the patient population requiring maintenance dialysis [1, 2]. Polycystins are required for the maintenance of differentiated epithelium, are expressed in kidney, liver and pancreas tubular cells, vascular smooth muscle cells and endothelium and play a role in multiple signalling pathways [3]. Disturbance of function results in increased tubular cell proliferation and apoptosis, fluid secretion resulting in progressive renal cyst formation and proliferation [1]. Mutations of the PKD1 gene, encoding polycystin-1, a membrane receptor, account for 85% of cases. A further 15% of cases are due to mutations of the PKD2 gene, encoding polycystin-2, a calcium-permeable channel binding polycystin-1. In general, PKD1 disease is associated with a more severe clinical phenotype than PKD2, with earlier onset of end-stage kidney disease (mean age 54 years compared with 74 years) and greater numbers of renal cysts [1, 4, 5]. The mTOR pathway is regulated by polycystin and plays a role in multiple pathways, including the regulation of cell growth and proliferation. mTOR signalling is increased in murine models and human ADPKD, while mTOR inhibitors reverse disease progression in the former [6–8]. These findings together with the regression of hepatic disease seen in sirolimus-treated transplant recipients [9] have stimulated interest in mTOR inhibitors as a potential therapeutic agent for human ADPKD. The challenge for triallists is the slow progression of clinical disease. Unlike the murine models of polycystic disease, human disease is characterized by progression over decades [1, 2]. The development of reliable surrogates for meaningful clinical outcomes has been a requirement for clinical research. In this context, the observational Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) has been a key influence [10]. Guidance published in 2006, it has provided a framework for subsequent clinical trials, establishing MRI-determined total kidney volume as a surrogate for disease progression. CRISP characterized a cohort of 232 adults with ADPKD from four US centres with a mean total kidney volume of 1060 mL at baseline and followed them for 3 years. The total kidney volume increased by an annual mean 204 ± 246 mL or 5.27 ± 3.92%. Kidney function declined in those with a total kidney volume >1500 mL at baseline with estimated glomerular filtration rate (eGFR) falling by 4.33 ± 8.07 mL/min/year. Based on these findings, trials have been designed using the total kidney volume as a surrogate for disease progression, and have recruited participants with total kidney volumes of 1500 mL or more. In 2010, two key randomized, placebo-controlled trials were published testing the hypothesis that mTOR inhibition would prevent or retard ADPKD disease progression. Walz et al. [11] examined the effect of treatment with 5 mg/day of the mTOR inhibitor, everolimus, for 2 years in 433 participants with ADPKD and CKD stage II or III. The mean eGFR at baseline was 55 mL/min and the total kidney volume was nearly 2000 mL. The study showed that despite retarding kidney size increase, mTOR inhibition with everolimus had no overall impact on kidney function. The total kidney volume increase was 301 mL over 2 years in the placebo group compared with 230 mL in the everolimus group (P = 0.06). However, there was no impact on eGFR, which declined by 8.9 mL/ min in the everolimus group compared with 7.7 mL/min in the placebo group over 2 years. Proteinuria also increased in the everolimus group. In the same issue, Serra et al. [12] reported the impact of sirolimus 2 mg daily compared with placebo over 18 months in 100 young adults with ADPKD, enlarging kidney size and near normal kidney function (eGFR 70 mL/min or higher). Sirolimus dosages were targeted to achieve levels of 4–10 μmol/L. Treatment had no impact on the total kidney volume or eGFR. Albuminuria increased in the sirolimus group but not the placebo group. Together, the publication of these studies checked enthusiasm for pursuing studies of mTOR inhibitors in ADPKD. One explanation advanced for the results was that the degree of mTOR inhibition was inadequate [13, 14]. The regression of hepatic volume seen in sirolimus-treated kidney graft recipients with ADPKD [9] in the transplant setting occurred where sirolimus trough levels were typically 10–15 ng/mL. The dosing in ADPKD murine models is also substantially higher than

mTOR inhibition in autosomal-dominant polycystic kidney disease (ADPKD): the question remains open