Sirolimus Treatment in Patients With Autosomal Dominant Polycystic Kidney Disease: Renal Efficacy and Safety
Condition: Polycystic Kidney
MeSH terms: Polycystic Kidney Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Sirolimus; conventional therapy
Intervention type(s): Drug; Drug
Intervention description(s): Patients will be given Sirolimus starting at the oral daily dose of 3 mg with periodically whole blood level measurements. The daily dose will be adjusted to keep sirolimus concentration within 10-15 ng/ml.; Antihypertensive drugs for patients with high blood pressure.
Intervention MeSH terms: Sirolimus
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment