Patient case: 63-year-old female with aortic aneurysm; genetic feature: ACTA2

Clinical trial: Polycystic Liver Disease in Kidney Transplant

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.

Eligibility: 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

Relevance to patient case: not relevant