Sirolimus Treatment in Patients With ADPKD

Introduction Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disease, responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western countries. The disease is characterized by the progressive development of fluid-filled cysts in the kidney. The renal cysts originate from the epithelia of the nephrons and are lined by a single layer of cells that have a higher rate of cellular growth and proliferation. At comparable levels of blood pressure control and proteinuria, patients with ADPKD have faster decline in glomerular filtration rate (GFR) than those with other renal diseases and do not seem to benefit to the same extent of ACE inhibitor therapy. Thus, renoprotective interventions in ADPKD - in addition to achieve maximal reduction of arterial blood pressure and proteinuria and to limit the effects of additional potential promoters of disease progression such as dyslipidemia, chronic hyperglycemia or smoking - should also be specifically aimed to correct the dysregulation of epithelial cell growth, secretion, and matrix interactions characteristic of the disease.

ADPKD shows genetic heterogeneity, with at least three different genes implicated: the PKD1 gene (85% of the cases), the PKD2 (15% of the cases), and probably a PDK3 gene (not yet identified). PKD1 gene was identified more than a decade ago, the development of treatment strategies has been hampered by a lack of understanding of the function of polycystin-1 (PC1), the protein encoded by the PKD1 gene. However, a new function of PC1 has been recently identified, which suggests a possibility for future treatment options. Indeed, it has been reported that PC1 tail interacts with tuberin, the product of the TSC2 gene. The main function of tuberin is to inactivate the Ser/Thr kinase mTOR which, in turn, promotes phosphorylation of two proteins, S6-kinase and 4E-BP1. mTOR activity has been linked to increased cell growth, proliferation, apoptosis and changes in differentiation. Researchers have subsequently shown that in ADPKD experimental animal models cyst lining epithelial cells exhibited very high mTOR activity, and hypothesized that PC1 normally suppresses mTOR activity and that defects in PC1 (and in other proteins) lead to aberrant mTOR activation. Of interest, all these proteins are localized to primary cilia or renal epithelial cells or to the basal bodies from which cilia emanate. This finding has led to the view that loss of cilia function leads to cysts formation in the kidney. The finding that mTOR is inappropriately activated in polycystic kidney disease mouse models suggests that mTOR activation may be a consequence of the loss of cilia function. If mTOR is such a converging point, it would be worthwhile as possible drug target for treatment of renal cystic disorders.

Sirolimus is an immunosuppressant mostly used for the management of kidney transplant recipients. This drug by very specifically and effectively inhibiting mTOR, exerts antiproliferative and growth inhibiting effects that might serve preventing uncontrolled tubular cell proliferation and could be extremely important for the inhibition of cyst progression in APKD. Interestingly, studies in rat models of ADPKD have shown that short-term treatment with sirolimus resulted in dramatic reduction of kidney size, prevented the loss of kidney function, and lowered cyst volume density. Similarly, retrospective observations from kidney transplant recipients have documented that sirolimus treatment reduced kidney volumes by 25%, whereas there was no effect in patients not given the drug.

Overall, these findings provide the basis for designing a prospective study in ADPKD patients aimed to document the efficacy of sirolimus treatment in preventing further increase or even reducing the total kidney volume and the renal volume taken up by small cysts, eventually halting kidney disease progression. As an additional aim of the present study, we will assess the safety profile of sirolimus, when given to ADPKD patients.

Aim The general aim of this study is to assess the efficacy and safety of 6 month treatment with sirolimus (on the top of the best available therapy) as compared to conventional therapy in adult patients with ADPKD and normal renal function or mild to moderate renal insufficiency. In particular we will compare the change over baseline of the total kidney volume volume in sirolimus and conventional treatment ADPKD groups during 6 month follow-up.