ADPKD Alterations in Hepatic Transporter Function
ADPKD Alterations in Hepatic Transporter Function
This is a single center, comparative cohort study to investigate alterations in hepatic
 transporter function in subjects with autosomal dominant polycystic kidney disease (ADPKD)
 compared to healthy subjects and subjects with non-ADPKD renal disease. Eligible subjects
 will be 18-65 years of age and of any race/ethnicity and gender.
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