Clinical Proof-Of-Concept Trial To Assess The Therapeutic Effect Of Sirolimus In Patients With Autosomal Dominant Polycystic Kidney Disease: SUISSE ADPKD Study

Andreas L Serra; Andreas D Kistler; Diane Poster; Marian Struker; Rudolf P Wüthrich; Dominik Weishaupt; Frank Tschirch


BMC Nephrology 

In This Article

Abstract and Background


Background: Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD). Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cyst growth and renal volume expansion, and that the inhibition of mTOR with rapamycin (sirolimus) markedly slows cyst development and renal functional deterioration. Based on these promising results in animals we have designed and initiated the first randomized controlled trial (RCT) to examine the effectiveness, safety and tolerability of sirolimus to retard disease progression in ADPKD.
Method/Design: This single center, randomised controlled, open label trial assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus (Rapamune®) in patients with autosomal dominant polycystic kidney disease and preserved renal function. The primary outcome will be the inhibition of kidney volume growth measured by magnetic resonance imaging (MRI) volumetry. Secondary outcome parameters will be preservation of renal function, safety and tolerability of sirolimus.
Discussion: The results from this proof-of-concept RCT will for the first time show whether treatment with sirolimus effectively retards cyst growth in patients with ADPKD.


Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage renal disease (ESRD), affecting all ethnic groups worldwide, with an incidence of 1 in 500 to 1 in 1000.[1] ADPKD is characterized by the progressive development of innumerable cysts in both kidneys, which distort the normal kidney architecture and leads to a loss of renal function. The development of renal failure is highly variable, but typically patients develop ESRD by the age of 40 to 50 years, necessitating renal replacement therapy (RRT) and/or kidney transplantation.[2] Apart from blood pressure control and symptomatic treatment of cyst bleedings and infections there is no curative therapy for this disease.[3] PKD1 and PKD2 encode the proteins polycystin-1 and polycystin-2 which are expressed in the kidney and function together to regulate growth and morphologic configuration of renal epithelial cells.[4] Mutation in PKD1 leads to a more severe phenotype of ADPKD than mutations in PKD2, with ESRD occurring on average 20 years earlier (53.4 versus 72.7 years).[5]

In ADPKD progressive cyst growth generally precedes the development of renal insufficiency. Compensatory mechanisms (hyperfiltration) maintain renal function virtually normal for decades despite continuous cyst growth. By the time renal function starts to decline, the kidneys are usually grossly enlarged with little normal renal parenchyma recognisable on imaging studies. Data from the consortium for radiologic imaging studies of polycystic kidney disease (CRISP) and others have shown that the rate of kidney volume growth is a predictor of renal functional decline and therefore kidney volume is used as surrogate marker of disease progression especially in clinical intervention trials for ADPKD.[6,7]

Non-invasive radiologic methods are available to monitor the growth rate of kidney volume. Renal ultrasound measurements are operator-dependent and not precisely reproducible. Unenhanced and contrast enhanced Computer tomography (CT) scanning is reported to be an accurate method to determine kidney volume, but it involves ionizing radiation and potentially nephrotoxic contrast medium and is therefore not an ideal method in patients with reduced kidney function needing repetitive measurements.[8,9] Due to its high soft tissue contrast and the lack of ionizing irradiation Magnetic resonance imaging (MRI) is also considered useful to monitor kidney volume changes in ADPKD. The analysis of sequential MRI scans was shown to be accurate to monitor rates of kidney volume enlargement in ADPKD.[7]

Sirolimus is an immunosuppressant that binds to FK Binding Protein-12 (FKBP-12) and inhibits the activation of the mTOR, a key regulatory kinase of growth and proliferation. Sirolimus is approved for the prevention of graft rejection following renal transplantation. Due to its antiproliferative properties it is also used in coated stents to prevent coronary artery restenosis after angioplasty.[10] Furthermore it has shown clinical effectiveness in kidney transplant recipients with Kaposi's sarcoma.[11]

We have shown previously that the mTOR inhibitors rapamycin and everolimus effectively reduce cyst growth and loss of renal function in an experimental animal model for PKD.[12,13] Additional studies have shown that rapamycin is also effective in various mouse models of polycystic kidney disease, including dominant and recessive forms.[14] Of interest, an analysis of ADPKD patients which received a renal transplant, revealed that cystic kidney volumes regressed under immunosuppression with sirolimus.[15] Based on these promising results we have designed and initiated the first clinical trial to examine the effectiveness and safety of sirolimus in young patients with early manifestations of ADPKD and intact renal function.


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