Clinical trial NCT03866421: NAFLD Among Patients With Chronic Kidney Disease and the Effect of Kidney Transplantation
Official title: Prevalence and Metabolic Impact of Non-alcoholic Fatty Liver Disease in Patients With Chronic Kidney Disease and the Effect of Kidney Transplantation on These Parameters
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Non-Alcoholic Fatty Liver Disease
Chronic Kidney Diseases
PreDiabetes
Kidney Transplant
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Steno Diabetes Center Copenhagen
name: Herlev and Gentofte Hospital
name: The Novo Nordisk Foundation Center for Basic Metabolic Research
First posted: 2019-03-07
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Total number of participants: 32 divided in two Groups:

* 16 kidney transplanted patients
* 16 healthy control persons

The 16 kidney transplanted patients are scheduled for kidney transplantation with a living donor at Rigshospitalet. They will be recruited from the donor- and recipient register for kidney transplantation at Rigshospitalet and Herlev Hospital.

The 16 healthy persons in the control group will be recruited through advertisement.

All participants are screened by an OGTT before inclusion in the study.

Brief 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 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.

Detailed 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 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.

Eligibility criteria: Inclusion Criteria (kidney transplanted patients):

* Outpatient at the department of nephrology at either Rigshospitalet or Herlev Hospital scheduled for a kidney transplantation with a living donor
* 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.

Inclusion criteria (control group):

* Normal kidney function
* Normal glucose tolerance

Exclusion Criteria:

* End stage liver disease as diagnosed by MELD (model for end stage liver disease) criteria OR
* 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

Primary outcomes:
measure: Changes in relative lipid signal measured by MR spectroscopy in the liver before kidney transplantation compared with three and twelve months after kidney transplantation
timeFrame: Kidney transplanted patients: 3 visits á 1 hour (baseline (before transplantation), three months and twelve months after transplantation), Control group: One hour
Secondary outcomes:
measure: Prevalence of fibrosis in the liver before and after kidney transplantation measured by fibroscan.
timeFrame: Kidney transplanted patients: 3 visits x 15 minutes (baseline (before transplantation), three months and twelve months after transplantation), Control group: 15 minutes
measure: Prevalence of fibrosis in the liver before and after kidney transplantation measured in clinical index (NAFLD fibrosis score).
timeFrame: Kidney transplanted patients: 3 visits á one day (baseline (before transplantation), three months and twelve months after transplantation), Control group: One day
measure: Prevalence of fibrosis in the liver before and after kidney transplantation measured by clinical index (FIB-4 score).
timeFrame: Kidney transplanted patients: 3 visits á one day (baseline (before transplantation), three months and twelve months after transplantation), Control group: One day
measure: Glycemic variability associated with NAFLD, as measured by MR spectroscopy, before and after kidney transplantation
timeFrame: Kidney transplanted patients: 4 days x3 visits (baseline (before transplantation), three months and twelve months after transplantation), Control group: 4 days
measure: Mean glucose associated with NAFLD, as measured by MR spectroscopy, before and after kidney transplantation
timeFrame: Kidney transplanted patients: 4 days x3 visits (baseline (before transplantation), three months and twelve months after transplantation), Control group: 4 days
measure: Change in insulin secretion during an OGTT compared with an IIGI before and at three and twelve months after transplantation and the association to NAFLD.
timeFrame: Kidney transplanted patients: 2 days x3 (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 2 days
measure: Change in insulin sensitivity during an OGTT compared with an IIGI before and at three and twelve months after transplantation and the association to NAFLD.
timeFrame: Kidney transplanted patients: 2 days x3 (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 2 days
measure: The secretion and content of GLP-1 and GIP during an OGTT before and after kidney transplantation analysed from blood samples
timeFrame: Kidney transplanted patients: 3 hours x3 visits - through study completion (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 3 hours
measure: The secretion and content of GLP-1, GIP and glucagon during an IIGI before and after kidney transplantation analysed from blood samples
timeFrame: Kidney transplanted patients: 4 hours x3 visits - through study completion (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 4 hours
measure: The effect of GLP-1 and GIP on insulin and glucagon response to arginine
timeFrame: Kidney transplanted patients: 4 hours x3 visits - through study completion (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 4 hours
measure: The secretion and content of bile acids analysed from blood samples before and after kidney transplantation and the association to NAFLD
timeFrame: Kidney transplanted patients: 1 day x 3 visits - through study completion (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 1 day
measure: Change in metabolomics before kidney transplantation compared with three and twelve months after kidney transplantation, analysed from blood samples and the association with the difference in liver fat measured by MRS.
timeFrame: Kidney transplanted patients: 3 visits (baseline (before transplantation), three months and twelve months after transplantation), Control group: One day
measure: Acute illness of non-renal or hepatic origin
timeFrame: Only kidney transplanted patients: Ongoing for up to 15 months - baseline until last visit (twelve months after transplantation)
measure: Death rate during follow up in the Group of kidney transplanted patients
timeFrame: Only kidney transplanted patients: Ongoing for up to 15 months - baseline until last visit (twelve months after transplantation)
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Nephrology
Study officials:
affiliation: Rigshospitalet, Denmark
name: Bo Feldt-Rasmussen, Professor
role: PRINCIPAL_INVESTIGATOR
References: