Single Center, Open-label Randomized Prospective Trial: Effect of Sirolimus on Polycystic Liver Disease
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
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Liver Volume at 2 Years After Kidney Transplantation
Liver volume at 2 years will be compared between the sirolimus and control (tacrolimus) groups using analysis of covariance (ANCOVA).
Patrick Dean, M.D.
United States: Institutional Review Board
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