<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03826381</url>
  </required_header>
  <id_info>
    <org_study_id>NAFLD and CKD - Study 1</org_study_id>
    <nct_id>NCT03826381</nct_id>
  </id_info>
  <brief_title>NAFLD Among Patients With Type 2 Diabetes and CKD</brief_title>
  <official_title>Prevalence and Metabolic Impact of Non-alcoholic Fatty Liver Disease in Patients With Type 2 Diabetes With Normal Renal Function or Chronic Kidney Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in&#xD;
      developed countries affecting approximately 30 % of the general adult population. It&#xD;
      represents an important pathogenic factor in the development of type 2-diabetes and is&#xD;
      associated with a high risk of cardiovascular disease. Previous studies of patients with&#xD;
      chronic kidney disease (CKD) have demonstrated an increased risk for NAFLD and the presence&#xD;
      of both CKD and NAFLD is likely to increase the risk for cardiovascular disease.&#xD;
&#xD;
      The present protocol describes a study of the prevalence and etiology of NAFLD among patients&#xD;
      with type 2-diabetes with CKD.&#xD;
&#xD;
      The study is a cross-sectional study. Fat accumulation in the liver will be determined by&#xD;
      Magnetic resonance (MR) spectroscopy and the prevalence of NAFLD among patients with type&#xD;
      2-diabetes with normal kidney function or CKD stage 3-5 will be investigated. A continuous&#xD;
      glucose monitoring (CGM) for four days, Dual Energy X-ray Absorptiometry (DEXA) scanning,&#xD;
      fibro scanning of the liver, bile acid analysis, metabolomic and lipidomic analysis will also&#xD;
      be performed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION&#xD;
&#xD;
      Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in&#xD;
      developed countries affecting approximately 30 % of the general adult population. The disease&#xD;
      is defined by an increased fat accumulation in the liver cells (&gt;5 %), not caused by&#xD;
      excessive alcohol intake (a threshold of 20 g per day for women and 30 g per day for men),&#xD;
      autoimmunity, drugs or viral hepatitis. The histological spectrum of NAFLD ranges from simple&#xD;
      steatosis to non-alcoholic steatohepatitis (NASH). Simple steatosis defined as steatosis&#xD;
      without injury of the hepatocytes in form of ballooning and NASH defined as the presence of&#xD;
      hepatic steatosis and inflammation with ballooned hepatocytes with or without fibrosis. The&#xD;
      degree of fibrosis is an important prognostic factor and is related to liver related&#xD;
      complications and mortality.&#xD;
&#xD;
      Diabetes is the single most important cause of end-stage renal disease (ESRD). Furthermore,&#xD;
      more than 25 % of patients with moderate to severe chronic kidney disease (CKD) have&#xD;
      pre-diabetic characteristics such as impaired glucose tolerance or impaired fasting glucose.&#xD;
      NAFLD represents an important pathogenic factor in the development of type 2-diabetes and is&#xD;
      associated with an increased risk of cardiovascular disease, insulin resistance and&#xD;
      overweight.&#xD;
&#xD;
      Previous studies of patients with CKD with/without diabetes demonstrated, with less sensitive&#xD;
      ultrasonic methods than what we plan to use in the present project, a high prevalence of&#xD;
      NAFLD. Furthermore, the presence of both NAFLD and CKD is likely to increase the risk for&#xD;
      cardiovascular diseases and mortality, particular among overweight patients. NAFLD is present&#xD;
      in both diabetic and nondiabetic patients with ESRD. The co-existence of CKD, NAFLD and&#xD;
      gluco-metabolic disturbances, including diabetes, is a research topic with increasing focus&#xD;
      on. Co-morbidities in CKD such as impaired insulin sensitivity, diabetes, impaired&#xD;
      calcium-phosphate metabolism, hypertension and hypertriglyceridemia constitute risk factors&#xD;
      for NAFLD. Unfortunately, several treatments of CKD, including kidney transplantation, have&#xD;
      been shown to impair lipid metabolism and increase insulin resistance especially in the&#xD;
      liver. Importantly, lifestyle changes and medical treatment modalities have been shown to&#xD;
      have only minor impact on reducing the prevalence of these disturbances in patients with CKD.&#xD;
&#xD;
      In patients with NAFLD, either due to metabolic stress (obesity) or toxic substances&#xD;
      (immunosuppressive treatment), liver damage and the impact on insulin resistance is reflected&#xD;
      in characteristic modifications of metabolites and lipids in liver tissue, as well as in&#xD;
      circulating blood, which may help to identify and interpret the pathogenesis of liver damage&#xD;
      in the setting of CKD. One recent hypothesis for linking liver damage and CKD involves a&#xD;
      change in gut microbiota due to impaired renal function, leading to a leaky gut with damage&#xD;
      of the gut-blood barrier. This transfers gut microbiota metabolites to the blood, leading to&#xD;
      a pathogen-associated molecular pattern, reflected in changes in lipidomic and metabolomic&#xD;
      profile in the blood. Such changes have in other conditions been associated with insulin&#xD;
      resistance and have been linked to liver damage leading to NAFLD and later potentially&#xD;
      fibrosis.&#xD;
&#xD;
      Very little information about bile acid metabolism in the development of NAFLD in CKD&#xD;
      patients with type 2-diabetes is available. Risk factors for NAFLD among patients with CKD&#xD;
      have only been investigated in small-scale studies with often inadequate methods. No studies&#xD;
      have investigated the impact of fat lipid content measured by MR spectroscopy in patients&#xD;
      with type 2-diabetes and CKD stage 3-5. New therapeutic strategies for the diagnosis and&#xD;
      management of NAFLD in patients with CKD with diabetes are needed and important challenges in&#xD;
      the elucidation of the ethology, pathogenesis and prevalence of NAFLD in CKD patients&#xD;
      exist.Thus, this project will bring new knowledge among a group of patients with high&#xD;
      morbidity and an increased risk of mortality - a knowledge that may provide new guidelines&#xD;
      for prevention and treatment of NAFLD.&#xD;
&#xD;
      Objectives&#xD;
&#xD;
      The primary objective of this project is to study the association between the kidney function&#xD;
      and the prevalence of NAFLD and the association with type 2-diabetes.&#xD;
&#xD;
      Furthermore, secondary objectives are to investigate potential associations between NAFLD in&#xD;
      type 2-diabetes CKD patients and glucose profiles, metabolomics- and lipidomics profiles,&#xD;
      intestinal peptides and the bile acid metabolism.&#xD;
&#xD;
      METHODS&#xD;
&#xD;
      Study design and population&#xD;
&#xD;
      This is a cross-sectional cohort study involving 54 patients with type 2-diabetes with normal&#xD;
      kidney function and 54 patients with type 2-diabetes and CKD stage 3-5 (not on dialysis).&#xD;
&#xD;
      The patients will be recruited from the outdoor clinic of either endocrinology or nephrology&#xD;
      at Rigshospitalet, Herlev Hospital, Steno Diabetes Center Copenhagen and Gentofte Hospital.&#xD;
&#xD;
      Examinations&#xD;
&#xD;
      The project involves following methods.&#xD;
&#xD;
      Magnetic resonance (MR) spectroscopy Fibroscan and clinical index Blood samples Dual Energy&#xD;
      X-ray Absorptiometry scan Continuous Glucose Monitoring Clinical examination&#xD;
&#xD;
      Data and statistical analysis&#xD;
&#xD;
      The null hypothesis is that there is no difference in relative liver lipid signal measured by&#xD;
      MR spectroscopy between type 2-diabetic patients with CKD stage 3-5 and patients with type&#xD;
      2-diabetes and normal renal function.&#xD;
&#xD;
      The alternative hypothesis is that there is a difference of 30% in liver lipid signal between&#xD;
      type 2-diabetic patients with CKD stage 3-5 and patients with type 2-diabetes and normal&#xD;
      renal function. In the literature content in relative liver fat signal in patients with type&#xD;
      2-diabetes and CKD 3-5 is about 60% and in type 2-diabetes patients with normal function it&#xD;
      is about 30%. In a two-sided t-test with α=0.05 and power of 80%, a sample size of 98&#xD;
      patients in a parallel design is needed to demonstrate a difference in relative liver fat&#xD;
      signal between type 2-diabetes patients with CKD 3 and 5 and type 2 diabetes patients with&#xD;
      normal renal function of 30%. A total of 108 patients, including 10 extra patients, are&#xD;
      planned to be examined.&#xD;
&#xD;
      After completion of the study and data completion the results are analysed according to&#xD;
      primary and secondary endpoints. Results are reported as mean values with confidence interval&#xD;
      or median and range. Data are analysed with parametric (normally distributed data) or&#xD;
      non-parametric statistics (non-normal distributed data). A 95 % confidence interval is&#xD;
      accepted as statistically significant (p &lt; 0.05).&#xD;
&#xD;
      All data will be pseudo anonymised.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 6, 2019</start_date>
  <completion_date type="Actual">June 23, 2021</completion_date>
  <primary_completion_date type="Actual">June 23, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Prevalence of NAFLD and actual estimate of liver signal measured by MR spectroscopy</measure>
    <time_frame>1 day</time_frame>
    <description>Liver signal is measured by MR spectroscopy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Prevalence and actual estimate of liver lipid signal measured by MR spectroscopy in relation to bile acids measured in the blood</measure>
    <time_frame>2 visits - MR spectroscopy one day, blood samples another day.</time_frame>
    <description>Liver lipid signal measured by MR spectroscopy. Bile acids are measured and analysed from blood samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NAFLD, as measured by MR spectroscopy, and its association with metabolomics and lipidomic profiles measured in the blood in relation to impaired renal function</measure>
    <time_frame>1 day</time_frame>
    <description>Measured by blood samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of fibrosis</measure>
    <time_frame>1 day</time_frame>
    <description>As determined by fibroscan of the liver.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NAFLD, as measured by MR spectroscopy, and its association with glucose profiles in relation to impaired renal function</measure>
    <time_frame>4 days</time_frame>
    <description>Continuous Glucose Monitoring is used.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">100</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <condition>Chronic Kidney Diseases</condition>
  <condition>Type2 Diabetes</condition>
  <arm_group>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
    <description>Number of patients: 54&#xD;
Patients in this group are diagnosed with Diabetes type 2. Kidney function: eGFR is &gt; 60, absence of clinical proteinuria.&#xD;
Inclusion- and exclusion criteria are listed under section &quot;Eligibility&quot;. Examinations performed in this group are listed under the section &quot;Groups and Interventions&quot; and the same as in the other group.&#xD;
The patients are examined once.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <description>Number of patients: 54&#xD;
Patients in this group are all diagnosed with diabetes type 2. Furthermore, the patients have chronic kidney disease stage 3-5 (eGFR &lt;60).&#xD;
Inclusion- and exclusion criteria are listed under section &quot;Eligibility&quot;. Examinations performed in this group are listed under the section &quot;Groups and Interventions&quot; are the same as in the other group.&#xD;
The patients are examined once.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Magnetic resonance (MR) spectroscopy of the liver</intervention_name>
    <description>Magnetic resonance (MR) spectroscopy of the liver. Golden standard for non-invasive determination of NAFLD</description>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Fibroscan</intervention_name>
    <description>Transient Elastography for Measurement of liver fibrosis.</description>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Continuous glucose monitoring (CGM) for four days.</intervention_name>
    <description>CGM is attached to the abdominal skin for four days. Afterwards data is converted and analysed in a computer program.</description>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Dual Energy X-ray Absorptiometry (DEXA) scan</intervention_name>
    <description>DEXA-scan of the body composition.</description>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Blood samples</intervention_name>
    <description>Immediately analyse of basic lab data. Later analyses for glucagon, amino acids, bile acids, lipidomics and metabolomics.</description>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Clinical and demographic data</intervention_name>
    <description>Measurements of blood pressure, pulse, height, weight.</description>
    <arm_group_label>Study 1: DM2 + CKD stage 3-5</arm_group_label>
    <arm_group_label>Study 1: DM2 + normal kidney function</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples will be collected for both immediately analyses (basic lab data) and later&#xD;
      analyses (bile acids,lipidomics and metabolomics) and stored for 10 years whereafter they&#xD;
      will be destroyed.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Total number of participants: 108 divided in two Groups:&#xD;
&#xD;
          -  54 patients with diabetes type 2 and normal kidney function (eGFR &gt;60 and absense of&#xD;
             clinical proteinuria)&#xD;
&#xD;
          -  54 patients with diabetes type 2 and chronic kidney disease stage 3-5&#xD;
&#xD;
        The patients are recruited from the department of Endocrinology or Nephrology at&#xD;
        Rigshospitalet (if necessary, from Herlev Hospital, Gentofte Hospital or Steno Diabetes&#xD;
        Center Copenhagen also).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          -  Diagnosed type 2-diabetes&#xD;
&#xD;
          -  eGFR &gt; 60 ml/ min/ 1,73 m2 with absence of proteinuria (N=54) OR eGFR &lt; 60 ml/ min/&#xD;
             1,73 m2 (N=54)&#xD;
&#xD;
          -  Outpatient at the department of endocrinology at either Rigshospitalet, Herlev&#xD;
             Hospital, Gentofte Hospital or Steno Diabetes Center Copenhagen OR Outpatient at the&#xD;
             department of nephrology at either Rigshospitalet or Herlev Hospital&#xD;
&#xD;
        EXCLUSION CRITERIA&#xD;
&#xD;
          -  End stage liver disease as diagnosed by MELD (model for end stage liver disease)&#xD;
             criteria OR&#xD;
&#xD;
          -  At the waiting list for liver transplantation OR&#xD;
&#xD;
          -  Daily alcohol intake above 20 g and 30 g for women and men respectively OR&#xD;
&#xD;
          -  Known hepatitis A, B or C or hepatocellular carcinoma or other known liver disease OR&#xD;
&#xD;
          -  Dialysis therapy OR&#xD;
&#xD;
          -  Pregnancy OR&#xD;
&#xD;
          -  Weight &gt; 130 kg OR&#xD;
&#xD;
          -  Implanted pacemaker&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bo Feldt-Rasmussen, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Nephrology, Rishospitalet, University of Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Nephrology</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>March 18, 2018</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>August 31, 2021</last_update_submitted>
  <last_update_submitted_qc>August 31, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Bo Feldt-Rasmussen</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03826381
org study id: NAFLD and CKD - Study 1
nct id: NCT03826381
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in
      developed countries affecting approximately 30 % of the general adult population. It
      represents an important pathogenic factor in the development of type 2-diabetes and is
      associated with a high risk of cardiovascular disease. Previous studies of patients with
      chronic kidney disease (CKD) have demonstrated an increased risk for NAFLD and the presence
      of both CKD and NAFLD is likely to increase the risk for cardiovascular disease.

      The present protocol describes a study of the prevalence and etiology of NAFLD among patients
      with type 2-diabetes with CKD.

      The study is a cross-sectional study. Fat accumulation in the liver will be determined by
      Magnetic resonance (MR) spectroscopy and the prevalence of NAFLD among patients with type
      2-diabetes with normal kidney function or CKD stage 3-5 will be investigated. A continuous
      glucose monitoring (CGM) for four days, Dual Energy X-ray Absorptiometry (DEXA) scanning,
      fibro scanning of the liver, bile acid analysis, metabolomic and lipidomic analysis will also
      be performed.
INTRODUCTION

      Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in
      developed countries affecting approximately 30 % of the general adult population. The disease
      is defined by an increased fat accumulation in the liver cells (>5 %), not caused by
      excessive alcohol intake (a threshold of 20 g per day for women and 30 g per day for men),
      autoimmunity, drugs or viral hepatitis. The histological spectrum of NAFLD ranges from simple
      steatosis to non-alcoholic steatohepatitis (NASH). Simple steatosis defined as steatosis
      without injury of the hepatocytes in form of ballooning and NASH defined as the presence of
      hepatic steatosis and inflammation with ballooned hepatocytes with or without fibrosis. The
      degree of fibrosis is an important prognostic factor and is related to liver related
      complications and mortality.

      Diabetes is the single most important cause of end-stage renal disease (ESRD). Furthermore,
      more than 25 % of patients with moderate to severe chronic kidney disease (CKD) have
      pre-diabetic characteristics such as impaired glucose tolerance or impaired fasting glucose.
      NAFLD represents an important pathogenic factor in the development of type 2-diabetes and is
      associated with an increased risk of cardiovascular disease, insulin resistance and
      overweight.

      Previous studies of patients with CKD with/without diabetes demonstrated, with less sensitive
      ultrasonic methods than what we plan to use in the present project, a high prevalence of
      NAFLD. Furthermore, the presence of both NAFLD and CKD is likely to increase the risk for
      cardiovascular diseases and mortality, particular among overweight patients. NAFLD is present
      in both diabetic and nondiabetic patients with ESRD. The co-existence of CKD, NAFLD and
      gluco-metabolic disturbances, including diabetes, is a research topic with increasing focus
      on. Co-morbidities in CKD such as impaired insulin sensitivity, diabetes, impaired
      calcium-phosphate metabolism, hypertension and hypertriglyceridemia constitute risk factors
      for NAFLD. Unfortunately, several treatments of CKD, including kidney transplantation, have
      been shown to impair lipid metabolism and increase insulin resistance especially in the
      liver. Importantly, lifestyle changes and medical treatment modalities have been shown to
      have only minor impact on reducing the prevalence of these disturbances in patients with CKD.

      In patients with NAFLD, either due to metabolic stress (obesity) or toxic substances
      (immunosuppressive treatment), liver damage and the impact on insulin resistance is reflected
      in characteristic modifications of metabolites and lipids in liver tissue, as well as in
      circulating blood, which may help to identify and interpret the pathogenesis of liver damage
      in the setting of CKD. One recent hypothesis for linking liver damage and CKD involves a
      change in gut microbiota due to impaired renal function, leading to a leaky gut with damage
      of the gut-blood barrier. This transfers gut microbiota metabolites to the blood, leading to
      a pathogen-associated molecular pattern, reflected in changes in lipidomic and metabolomic
      profile in the blood. Such changes have in other conditions been associated with insulin
      resistance and have been linked to liver damage leading to NAFLD and later potentially
      fibrosis.

      Very little information about bile acid metabolism in the development of NAFLD in CKD
      patients with type 2-diabetes is available. Risk factors for NAFLD among patients with CKD
      have only been investigated in small-scale studies with often inadequate methods. No studies
      have investigated the impact of fat lipid content measured by MR spectroscopy in patients
      with type 2-diabetes and CKD stage 3-5. New therapeutic strategies for the diagnosis and
      management of NAFLD in patients with CKD with diabetes are needed and important challenges in
      the elucidation of the ethology, pathogenesis and prevalence of NAFLD in CKD patients
      exist.Thus, this project will bring new knowledge among a group of patients with high
      morbidity and an increased risk of mortality - a knowledge that may provide new guidelines
      for prevention and treatment of NAFLD.

      Objectives

      The primary objective of this project is to study the association between the kidney function
      and the prevalence of NAFLD and the association with type 2-diabetes.

      Furthermore, secondary objectives are to investigate potential associations between NAFLD in
      type 2-diabetes CKD patients and glucose profiles, metabolomics- and lipidomics profiles,
      intestinal peptides and the bile acid metabolism.

      METHODS

      Study design and population

      This is a cross-sectional cohort study involving 54 patients with type 2-diabetes with normal
      kidney function and 54 patients with type 2-diabetes and CKD stage 3-5 (not on dialysis).

      The patients will be recruited from the outdoor clinic of either endocrinology or nephrology
      at Rigshospitalet, Herlev Hospital, Steno Diabetes Center Copenhagen and Gentofte Hospital.

      Examinations

      The project involves following methods.

      Magnetic resonance (MR) spectroscopy Fibroscan and clinical index Blood samples Dual Energy
      X-ray Absorptiometry scan Continuous Glucose Monitoring Clinical examination

      Data and statistical analysis

      The null hypothesis is that there is no difference in relative liver lipid signal measured by
      MR spectroscopy between type 2-diabetic patients with CKD stage 3-5 and patients with type
      2-diabetes and normal renal function.

      The alternative hypothesis is that there is a difference of 30% in liver lipid signal between
      type 2-diabetic patients with CKD stage 3-5 and patients with type 2-diabetes and normal
      renal function. In the literature content in relative liver fat signal in patients with type
      2-diabetes and CKD 3-5 is about 60% and in type 2-diabetes patients with normal function it
      is about 30%. In a two-sided t-test with α=0.05 and power of 80%, a sample size of 98
      patients in a parallel design is needed to demonstrate a difference in relative liver fat
      signal between type 2-diabetes patients with CKD 3 and 5 and type 2 diabetes patients with
      normal renal function of 30%. A total of 108 patients, including 10 extra patients, are
      planned to be examined.

      After completion of the study and data completion the results are analysed according to
      primary and secondary endpoints. Results are reported as mean values with confidence interval
      or median and range. Data are analysed with parametric (normally distributed data) or
      non-parametric statistics (non-normal distributed data). A 95 % confidence interval is
      accepted as statistically significant (p < 0.05).

      All data will be pseudo anonymised.
observational model: Cohort
time perspective: Cross-Sectional
measure: Prevalence of NAFLD and actual estimate of liver signal measured by MR spectroscopy
time frame: 1 day
description: Liver signal is measured by MR spectroscopy
measure: Prevalence and actual estimate of liver lipid signal measured by MR spectroscopy in relation to bile acids measured in the blood
time frame: 2 visits - MR spectroscopy one day, blood samples another day.
description: Liver lipid signal measured by MR spectroscopy. Bile acids are measured and analysed from blood samples.
measure: NAFLD, as measured by MR spectroscopy, and its association with metabolomics and lipidomic profiles measured in the blood in relation to impaired renal function
time frame: 1 day
description: Measured by blood samples.
measure: The prevalence of fibrosis
time frame: 1 day
description: As determined by fibroscan of the liver.
measure: NAFLD, as measured by MR spectroscopy, and its association with glucose profiles in relation to impaired renal function
time frame: 4 days
description: Continuous Glucose Monitoring is used.
arm group label: Study 1: DM2 + normal kidney function
description: Number of patients: 54
Patients in this group are diagnosed with Diabetes type 2. Kidney function: eGFR is > 60, absence of clinical proteinuria.
Inclusion- and exclusion criteria are listed under section "Eligibility". Examinations performed in this group are listed under the section "Groups and Interventions" and the same as in the other group.
The patients are examined once.
arm group label: Study 1: DM2 + CKD stage 3-5
description: Number of patients: 54
Patients in this group are all diagnosed with diabetes type 2. Furthermore, the patients have chronic kidney disease stage 3-5 (eGFR <60).
Inclusion- and exclusion criteria are listed under section "Eligibility". Examinations performed in this group are listed under the section "Groups and Interventions" are the same as in the other group.
The patients are examined once.
intervention type: Diagnostic Test
intervention name: Magnetic resonance (MR) spectroscopy of the liver
description: Magnetic resonance (MR) spectroscopy of the liver. Golden standard for non-invasive determination of NAFLD
arm group label: Study 1: DM2 + CKD stage 3-5
arm group label: Study 1: DM2 + normal kidney function
intervention type: Diagnostic Test
intervention name: Fibroscan
description: Transient Elastography for Measurement of liver fibrosis.
arm group label: Study 1: DM2 + CKD stage 3-5
arm group label: Study 1: DM2 + normal kidney function
intervention type: Device
intervention name: Continuous glucose monitoring (CGM) for four days.
description: CGM is attached to the abdominal skin for four days. Afterwards data is converted and analysed in a computer program.
arm group label: Study 1: DM2 + CKD stage 3-5
arm group label: Study 1: DM2 + normal kidney function
intervention type: Radiation
intervention name: Dual Energy X-ray Absorptiometry (DEXA) scan
description: DEXA-scan of the body composition.
arm group label: Study 1: DM2 + CKD stage 3-5
arm group label: Study 1: DM2 + normal kidney function
intervention type: Biological
intervention name: Blood samples
description: Immediately analyse of basic lab data. Later analyses for glucagon, amino acids, bile acids, lipidomics and metabolomics.
arm group label: Study 1: DM2 + CKD stage 3-5
arm group label: Study 1: DM2 + normal kidney function
intervention type: Other
intervention name: Clinical and demographic data
description: Measurements of blood pressure, pulse, height, weight.
arm group label: Study 1: DM2 + CKD stage 3-5
arm group label: Study 1: DM2 + normal kidney function
Blood samples will be collected for both immediately analyses (basic lab data) and later
      analyses (bile acids,lipidomics and metabolomics) and stored for 10 years whereafter they
      will be destroyed.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Bo Feldt-Rasmussen, Professor
role: Principal Investigator
affiliation: Department of Nephrology, Rishospitalet, University of Copenhagen
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Bo Feldt-Rasmussen
investigator title: Professor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
sharing ipd: No