Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03826381 |
| Other study ID # |
NAFLD and CKD - Study 1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 6, 2019 |
| Est. completion date |
June 23, 2021 |
Study information
| Verified date |
August 2021 |
| Source |
Rigshospitalet, Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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.
Description:
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.
