NAFLD Among Patients With Chronic Kidney Disease and the Effect of Kidney Transplantation
NCT ID: NCT03866421
Last Updated: 2022-05-02
Study Results
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Basic Information
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TERMINATED
3 participants
OBSERVATIONAL
2019-05-29
2022-03-31
Brief Summary
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The present protocol describes a study of the prevalence and etiology of NAFLD among patients scheduled for kidney transplantation and the possible effect of kidney transplantation on NAFLD.
The project is a prospective cohort study. The effect of kidney transplantation in patients with prediabetes or normal glucose tolerance compared to healthy controls will be examined regarding development and progression of fat accumulation in the liver.
Fat accumulation in the liver will be determined by magnetic resonance (MR) spectroscopy and the prevalence of NAFLD in the two groups 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.
An oral glucose tolerance test (OGTT) and an intra venous glucose infusion (IIGI) will be performed.
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Detailed Description
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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 the investigators 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 and transplantation. 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.
The role of bile acids and entero-endocrinology (including the incretin hormones glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) in the development of NAFLD in CKD patients remains unknown. There are also clear limitations of the current knowledge of NAFLD and its potential role in gluco-metabolic changes and new-onset diabetes often seen after kidney transplantation. Delineation of these issues may provide new treatment targets for the benefit of patients. 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 kidney transplanted patients.
New therapeutic strategies for the diagnosis and management of NAFLD in patients with CKD and kidney transplanted patients with prediabetes are needed and important challenges in the elucidation of the etiology, pathogenesis and prevalence of NAFLD in CKD and transplanted 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 investigate the effect of kidney transplantation compared to healthy control persons, on the development and progression of the fat accumulation by MR spectroscopy and the monitoring of the glucometabolic, enteroendocrine, lipidomic and metabolomic profiles.
Kidney transplanted patients with previous prediabetes or normal glucose tolerance will be examined. The fat accumulation in the liver will be measured by MR spectroscopy and the prevalence of NAFLD will be investigated.
Furthermore, secondary objectives are to investigate changes in lipodomic and metabolomic related profiles, insulin secretion and sensitivity, secretion and content of bile acids, GLP-1, GIP, glucagon and amino acids before transplantation compared to after transplantation.
Data and statistical analysis
The null hypothesis is that there is no difference in relative liver fat values before and after kidney transplantation. The alternative hypothesis is that there is an increase by 50% in relative liver fat values measured by MR spectroscopy after kidney transplantation compared to pre-transplant values. In the literature a prevalence of NAFLD of 60-70% in type 2- diabetic patients defined by a liver fat content above 6% is known. With an estimated standard deviation of 15% a two-sided t-test with α=0.05 and power of 80%, a sample size of 16 patients in a paired design is needed to demonstrate a difference between the time points of 50%.
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.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Kidney transplanted patients
Number of patients: 16
Patients on the waiting list for kidney transplantation with a living donor. The patients are screened with an OGTT before participation in the study, thereby excluding patients with diabetes mellitus.
Patients in this group are examined three times (baseline (before transplantation) and after three and twelve months after transplantation).
Same interventions as in the control Group.
Including/ Exclusion criteria are listed under the section "Eligibility"
MR spectroscopy of the liver
Magnetic resonance spectroscopy of the liver. Golden standard for non-invasive determination of NAFLD
Fibroscan of the liver
Transient Elastography for Measurement of liver fibrosis.
Continuous glucose monitoring (CGM) for four days.
CGM is attached to the abdominal skin for four days. Afterwards data is converted and analysed in a computer program.
Oral glucose tolerance test (OGTT)
OGTT with incretin hormones. Measured for three hours.
Intra venous glucose infusion (IIGI)
This test is combined with the OGTT to compare responses of parenteral vs enteral stimulation. The test is followed by a bolus of 5 g of L-arginin.
Dual Energy X-ray Absorptiometry (DEXA) scan
DEXA-scan of the body composition.
Blood samples
Immediately analyse of basic lab data. Later analyses for glucagon, amino acids, bile acids, lipidomics and metabolomics.
Clinical and demographic data
Measurements of blood pressure, pulse, height, weight.
Control group
Number of patients: 16
Participants in this group are matched on age and BMI according to the kidney transplanted patients.
Participants are screened with an OGTT before participation since only persons with normal glucose tolerance may be included in the study.
Furthermore, participants have to have normal kidney function.
Participants in this group are only examined once. Same interventions as in the kidney transplanted patient group
MR spectroscopy of the liver
Magnetic resonance spectroscopy of the liver. Golden standard for non-invasive determination of NAFLD
Fibroscan of the liver
Transient Elastography for Measurement of liver fibrosis.
Continuous glucose monitoring (CGM) for four days.
CGM is attached to the abdominal skin for four days. Afterwards data is converted and analysed in a computer program.
Oral glucose tolerance test (OGTT)
OGTT with incretin hormones. Measured for three hours.
Intra venous glucose infusion (IIGI)
This test is combined with the OGTT to compare responses of parenteral vs enteral stimulation. The test is followed by a bolus of 5 g of L-arginin.
Dual Energy X-ray Absorptiometry (DEXA) scan
DEXA-scan of the body composition.
Blood samples
Immediately analyse of basic lab data. Later analyses for glucagon, amino acids, bile acids, lipidomics and metabolomics.
Clinical and demographic data
Measurements of blood pressure, pulse, height, weight.
Interventions
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MR spectroscopy of the liver
Magnetic resonance spectroscopy of the liver. Golden standard for non-invasive determination of NAFLD
Fibroscan of the liver
Transient Elastography for Measurement of liver fibrosis.
Continuous glucose monitoring (CGM) for four days.
CGM is attached to the abdominal skin for four days. Afterwards data is converted and analysed in a computer program.
Oral glucose tolerance test (OGTT)
OGTT with incretin hormones. Measured for three hours.
Intra venous glucose infusion (IIGI)
This test is combined with the OGTT to compare responses of parenteral vs enteral stimulation. The test is followed by a bolus of 5 g of L-arginin.
Dual Energy X-ray Absorptiometry (DEXA) scan
DEXA-scan of the body composition.
Blood samples
Immediately analyse of basic lab data. Later analyses for glucagon, amino acids, bile acids, lipidomics and metabolomics.
Clinical and demographic data
Measurements of blood pressure, pulse, height, weight.
Eligibility Criteria
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Inclusion Criteria
* Impaired glucose tolerance: fasting glucose concentration \< 7,0 mmol/ l and a 2-hour glucose load ≥ 7,8 mmol/ l and \< 11,1 mmol/ l OR Impaired fasting glycaemia: Fasting blood glucose ≥ 6,1 mmol/ l and \< 7,0 mmol/ l and a 2-hour glucose load \< 7,8 mmol/ l OR Normal glucose tolerance: fasting glucose concentration \< 6,1 mmol/ l and a 2-hour glucose load \< 7,8 mmol/ l.
* Normal kidney function
* Normal glucose tolerance
Exclusion Criteria
* At the waiting list for liver transplantation OR
* Daily alcohol intake above 20 g and 30 g for women and men respectively OR
* Known hepatitis A, B or C or hepatocellular carcinoma or other known liver disease OR
* Pregnancy OR
* Weight \> 130 kg OR
* Implanted pacemaker
18 Years
90 Years
ALL
Yes
Sponsors
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Steno Diabetes Center Copenhagen
OTHER
Herlev and Gentofte Hospital
OTHER
The Novo Nordisk Foundation Center for Basic Metabolic Research
OTHER
Rigshospitalet, Denmark
OTHER
Responsible Party
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Bo Feldt-Rasmussen
Professor, Head of the Department of Nephrology
Principal Investigators
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Bo Feldt-Rasmussen, Professor
Role: PRINCIPAL_INVESTIGATOR
Rigshospitalet, Denmark
Locations
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Department of Nephrology
Copenhagen, , Denmark
Countries
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Other Identifiers
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NAFLD and CKD - Study 2
Identifier Type: -
Identifier Source: org_study_id
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