Polycystic Kidney Clinical Trial
Official title:
Sirolimus Treatment in Patients With ADPKD
Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal
disease, characterized by the progressive development of fluid-filled cysts in the kidney
leading to progressive loss of renal function and eventually to renal failure. It is
responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western
countries. ADPKD progression is largely dependent on the development and growth of the cysts
and secondary disruption of the normal tissue. 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. Genetically in the ADPKD three different genes are implicated
(PKD1 85% of the cases, PKD2 15% and probably PDK3 not yet identified). PKD1 gene encodes a
protein named polycystin-1 (PC1). Defect in PC1 lead to aberrant activation of the enzyme
mTOR in the epithelial cells of the renal tubules which eventually leads to abnormal
proliferation of these cells and cysts generation.
Sirolimus (Rapamycin) 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 and could be extremely important for
the inhibition of cyst progression in ADPKD. Animal 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. It is a 6 month treatment with
sirolimus compared to conventional therapy in adult patients with ADPKD and normal renal
function or mild to moderate renal insufficiency.
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.
Study Design This will be a randomized, longitudinal, open, cross-over study with a baseline
evaluation and 6 month treatment period with sirolimus given in addition to conventional
anti-hypertensive therapy to appropriately control blood pressure, in ADPKD patients (n=16).
Sirolimus Patients will be given sirolimus starting at the oral daily dose of 3 mg, with
periodical whole blood level measurements. The daily dose will be adjusted to keep sirolimus
concentration within 10-15 ng/ml. Drug levels will be assessed at day 5 after starting
treatment and every two weeks for the first month; subsequently sirolimus concentrations
will be monitored at monthly intervals (or 5 days after drug dose adjustments) until the end
of the study.
Conventional Therapy There is no specific therapy for ADPKD patients. Conventional treatment
relates usually to the administration of antihypertensive drugs for patients with high blood
pressure. Thus, for the present study, no major change in antihypertensive treatment should
be introduced throughout the whole study period unless deemed clinically necessary (the
reason of the changes should be, however, clearly explained in the CRF). Only small changes
in the doses of the ongoing treatments are recommended in order to maintain the same level
of blood pressure control (target systolic/diastolic blood pressure <130/80 mnHg). This
approach is aimed to minimize the confounding effect of any change in concomitant treatments
on some efficacy variables (such as urinary protein excretion rate).
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
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