ADPKD Alterations in Hepatic Transporter Function

ADPKD is a relatively common genetic disease affecting about 1 out of every 1000 people
worldwide. Progression of ADPKD is characterized by the proliferation of fluid-filled kidney
cysts. Development of these cysts is progressive and can lead to end-stage renal disease and
ultimately, renal failure in many patients. The most common extra-renal complication of ADPKD
is the formation of liver cysts, which can vary from minor to extensive. Hepatic cysts can
develop from medium-sized bile ducts and complications (i.e., cyst rupture, infection,
obstruction of bile ducts, and compromised portal venous flow) can arise from increasing
cystic burden. Previous studies have shown that elevated levels of endogenous molecules such
as bile acids in ADPKD may indicate altered transporter function. Other endogenous molecules
such as coproporphyrin (CP) I and III may be used as probes to assess hepatic transporter
function.

The objective of this study is to investigate and quantify ADPKD-associated alterations in
endogenous molecule profiles (e.g., bile acids, CP) relative to subjects with non-ADPKD renal
disease and healthy individuals, and to investigate specific hepatic transporter
polymorphisms that may be related to the alterations. This is important because subjects with
ADPKD may be predisposed to adverse reactions associated with some medications that require
hepatic transporters for excretion.

Potential study participants will be pre-screened over the phone and then scheduled for a
2-hour study visit. All urine samples within the 2-hour interval will be collected from all
participants along with clinical, physical and questionnaire data. Fasting blood samples will
be collected at time 0 and 120 min.

Inclusion Criteria (all subjects):

- Provide signed and dated informed consent

- Willing to comply with all study procedures and be available for the duration of the
study

- Male or female, aged 18 to 65

- Negative quantitative human chorionic gonadotropin (hCG) blood test (for women of
child-bearing age only)

For healthy subjects:

- Normal liver functions tests (LFTs) as defined by the University of North Carolina
(UNC) hospital laboratory reference range [aspartate aminotransferase (AST)14-38 U/L,
alanine aminotransferase (ALT) 15-48 U/L, alkaline phosphatase 38-126 U/L]

- Normal clinical laboratory results including kidney function (serum creatinine) and
lipid panel as reviewed by the study physician

For subjects with ADPKD:

- Man or woman between the ages of 18 and 65 with documented ADPKD

For subjects with non-ADPKD renal disease:

- Man or woman between the ages of 18 and 65 with documented non-ADPKD renal disease as
determined by the study physician

Exclusion Criteria:

All Participants:

- Donation of blood within the last 30 days

- Diagnosis of human immunodeficiency virus (HIV) and/or untreated hepatitis C virus
(HCV)

- History of significant alcohol abuse and/or illicit drug use

- More than 1 glass of wine or 2 beers (or equivalent in % alcohol) per day during the
48 hours prior to study and/or screening visit

- Inability to fast for 8 hours prior to study and screening sample collection

- Women who are pregnant, trying to become pregnant, or breastfeeding

- Current or recent (within 30 days) use of bile acid sequestrants, bile acid
derivatives (i.e. ursodiol) or fibric acid derivatives

- History of diabetes or taking blood glucose lowering treatments

- Radiologic imaging consistent with cirrhosis and portal hypertension

- Evidence of decompensated liver disease defined as any of the following: serum albumin
<3.2 g/dL, total bilirubin > 1.5 mg/dL, or prothrombin time (PT)/international
normalized ratio (INR) > 1.3 times normal at screening, or history or presence of
ascites, encephalopathy, or bleeding from esophageal varices

- Estimated glomerular filtration rate (GFR)< 15 mL/min per 1.73 m2, or on dialysis, at
screening

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications (including
inhaled) within 14 days of study visit. Corticosteroids with minimal systemic
absorption (for example topical) and adrenal replacement steroid doses ≤ 10 mg daily
prednisone equivalent, are permitted in the absence of active autoimmune disease
provided the dose has been stable for ≥4 weeks and is not expected to change during
the course of the study.

- Primary, secondary or extra-hepatic malignancy

- BMI > 35 kg/m2 at screening

- Inability or unwillingness to give informed consent or abide by the study protocol

- History or other evidence of illness, any gastrointestinal surgery (e.g., gall bladder
removal), or any other conditions or drug therapies that would make the patient, in
the opinion of the investigator, unsuitable for the study (such as poorly controlled
psychiatric disease, coronary artery disease, gall bladder disease, active
gastrointestinal conditions or taking drugs known to interfere with bile acid
synthesis or metabolism or the metabolism/transport of other drugs)

Healthy Subjects:

- Taking concomitant medications, both prescription and non-prescription (including
herbal products and over-the-counter medications), other than oral contraceptives and
multivitamins (women stabilized on hormonal methods of birth control will be allowed
to participate)

- History or other evidence of liver, gall bladder, or intestinal disease in the opinion
of the study investigators

- BMI > 35 kg/m2 at screening.

Subjects with non-ADPKD renal disease:

- ADPKD

- Proteinuria of ≥3 grams per day of protein into the urine; or on a single spot urine
collection, the presence of ≥2 grams of protein per gram of urine creatinine (i.e.,
excluding patients with nephrotic-range proteinuria)

- Diabetic nephropathy patients