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 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: