Polycystic Liver Disease in Kidney Transplant

Brief Title

Polycystic Liver Disease in Kidney Transplant

Official Title

Single Center, Open-label Randomized Prospective Trial: Effect of Sirolimus on Polycystic Liver Disease

Brief Summary

      The purpose of this study is to see if one kind of immunosuppressive drug has better effects
      for the patient's polycystic liver disease than another type. Tacrolimus and Sirolimus are
      the two immunosuppressive drugs that will be compared for this study. Both drugs have been
      commonly prescribed to prevent rejection.
    

Detailed Description

      Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease
      with a prevalence of 1 in 400-1000 livebirths. ADPKD is caused by mutations to polycystic
      kidney disease 1 gene (PKD1) (approximately 85% of cases) or polycystic kidney disease 2 gene
      (PKD2) (the remaining 15%) gene, encoding polycystin-1 (PC1) and polycystin-2 (PC2),
      respectively. PC1 is a putative cell-surface, receptor-like protein with yet to-be-identified
      ligand(s), and PC2 a channel protein with a high conductance to Ca2+.

      Polycystic liver disease (PLD) is the most common extra-renal manifestation in ADPKD, present
      in > 90% of ADPKD patients by age 30. Liver cysts in ADPKD originate from biliary
      micro-hamartoma or focal proliferations of biliary ductules and from peribiliary glands.
      Excessive proliferation of biliary epithelial cells, combined with neovascularization,
      altered cell-extracellular matrix (ECM) interaction/ECM remodeling and cAMP-mediated fluid
      secretion, is required for the development and expansion of PLD liver cysts.

      PLD may become symptomatic with acute complications such as cyst hemorrhage, rupture and
      infection. Chronic symptoms are frequently associated with massively enlarged PLD, including
      abdominal distension and pain; dyspnea; gastroesophageal reflux and early satiety which may
      lead to malnutrition; mechanical lower back pain; obstruction of the inferior vena cava,
      hepatic and portal veins (leading to dialysis-associated hypotension, hepatic venous outflow
      obstruction, and portal hypertension) and biliary obstruction. Currently, apart from invasive
      interventions such as cyst aspiration with sclerosis, cyst fenestration combined hepatic
      resection and cyst fenestration, liver transplantation and, rarely, selective hepatic artery
      embolization, no medical therapy is available.

      The objective of this study is to conduct a prospective, open-label, randomized trial to
      examine the effect of sirolimus on total liver volume in kidney transplant recipients with
      ADPKD.

      Four weeks following kidney transplant, subjects will undergo iothalamate clearance
      measurement, 24-hour urine collection and protein measurement and physical examination by a
      transplant surgeon. Patients will be randomized to receive either sirolimus-based
      immunosuppression or to continue tacrolimus-based immunosuppression unless one of the
      following conditions are noted:

        1. Complications of the kidney transplant incision, including, but not limited to:
           superficial wound infection, deep wound infection, and fascial dehiscence

        2. Iothalamate clearance measurement less than 40 mL/min/1.72m^2

        3. Urinary protein excretion greater than 800 mg/24 hours. Subjects with the above
           conditions will continue to receive tacrolimus-based immunosuppression at the discretion
           of the treating physician/surgeon.

      Enrolled subjects will undergo abdominal and pelvic CT scans within 3 months before or after
      kidney transplantation and at one, two, and three years after kidney transplantation.
    


Study Type

Interventional


Primary Outcome

Liver Volume at 2 Years After Kidney Transplantation


Condition

Polycystic Liver Disease

Intervention

Tacrolimus

Study Arms / Comparison Groups

 Control Group
Description:  Tacrolimus, mycophenolate mofetil, and prednisone

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

2

Start Date

February 2009

Completion Date

December 2012

Primary Completion Date

December 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Adults (> 18 years old) with stage IV or V chronic kidney due to ADPKD

          -  Primary kidney transplant

          -  Living or deceased donor kidney transplant

          -  Estimate total liver volume of 2.5 to 7.5 L

          -  In addition, at the discretion of the principal investigator(s), certain subjects with
             numerous liver cysts but with liver volume < 2.5 liters may be enrolled.

        Exclusion Criteria:

          -  Pediatric patients (< 18 years of age)

          -  Patients with Body Mass Index (BMI) greater than or equal to 40 kg/m^2

          -  Multi-organ transplant (kidney-liver, etc.)

          -  When people who have one blood type receive blood from someone with a different blood
             type, it may cause their immune system to react. This is called (ABO) incompatibility.
             ABO-incompatible or positive cross-match recipients

          -  Patients with severe hyperlipidemia (serum cholesterol > 350 mg/dl or serum
             triglycerides > 500 mg/dl)

          -  Patients with leukopenia (WBC < 3000 10/ml)

          -  Patients unwilling to return to the transplant center for late follow-up visits

          -  Patients who are currently pregnant or breast-feeding or who expect to be pregnant
             during the study period

          -  Female patients of child bearing potential and men with sexual partners of child
             bearing potential who do not agree to use a medically accepted method of contraception
             during the study period

          -  Patients who are not eligible for Thymoglobulin induction
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Patrick Dean, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00934791

Organization ID

08-004315


Responsible Party

Principal Investigator

Study Sponsor

Mayo Clinic

Collaborators

 Wyeth is now a wholly owned subsidiary of Pfizer

Study Sponsor

Patrick Dean, M.D., Principal Investigator, Mayo Clinic


Verification Date

February 2013