ADPKD Alterations in Hepatic Transporter Function

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Brief Title

ADPKD Alterations in Hepatic Transporter Function

Official Title

Endogenous Molecule Profiling in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Brief Summary

      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.
    

Detailed Description

      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.
    


Study Type

Observational


Primary Outcome

Difference in serum coproporphyrin I and III concentrations

Secondary Outcome

 Difference in serum and urine bile acid profiles

Condition

ADPKD


Study Arms / Comparison Groups

 Healthy subjects
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

24

Start Date

September 17, 2018

Completion Date

January 29, 2020

Primary Completion Date

January 29, 2020

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Vimal Derebail, MD, MPH, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03717883

Organization ID

16-2984

Secondary IDs

5R35GM122576-02

Responsible Party

Sponsor

Study Sponsor

University of North Carolina, Chapel Hill

Collaborators

 National Institute of General Medical Sciences (NIGMS)

Study Sponsor

Vimal Derebail, MD, MPH, Principal Investigator, University of North Carolina, Chapel Hill


Verification Date

March 2020