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
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Changes in relative lipid signal measured by MR spectroscopy in the liver before kidney transplantation compared with three and twelve months after kidney transplantation
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- •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
结局指标
主要结局
Changes in relative lipid signal measured by MR spectroscopy in the liver before kidney transplantation compared with three and twelve months after kidney transplantation
时间窗: Kidney transplanted patients: 3 visits á 1 hour (baseline (before transplantation), three months and twelve months after transplantation), Control group: One hour
Liver signal is measured by MR spectroscopy (the non-invasive method for determination of NAFLD)
次要结局
- Prevalence of fibrosis in the liver before and after kidney transplantation measured by fibroscan.(Kidney transplanted patients: 3 visits x 15 minutes (baseline (before transplantation), three months and twelve months after transplantation), Control group: 15 minutes)
- Prevalence of fibrosis in the liver before and after kidney transplantation measured in clinical index (NAFLD fibrosis score).(Kidney transplanted patients: 3 visits á one day (baseline (before transplantation), three months and twelve months after transplantation), Control group: One day)
- Glycemic variability associated with NAFLD, as measured by MR spectroscopy, before and after kidney transplantation(Kidney transplanted patients: 4 days x3 visits (baseline (before transplantation), three months and twelve months after transplantation), Control group: 4 days)
- The effect of GLP-1 and GIP on insulin and glucagon response to arginine(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)
- The secretion and content of bile acids analysed from blood samples before and after kidney transplantation and the association to NAFLD(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)
- 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.(Kidney transplanted patients: 3 visits (baseline (before transplantation), three months and twelve months after transplantation), Control group: One day)
- Prevalence of fibrosis in the liver before and after kidney transplantation measured by clinical index (FIB-4 score).(Kidney transplanted patients: 3 visits á one day (baseline (before transplantation), three months and twelve months after transplantation), Control group: One day)
- Mean glucose associated with NAFLD, as measured by MR spectroscopy, before and after kidney transplantation(Kidney transplanted patients: 4 days x3 visits (baseline (before transplantation), three months and twelve months after transplantation), Control group: 4 days)
- 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.(Kidney transplanted patients: 2 days x3 (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 2 days)
- Acute illness of non-renal or hepatic origin(Only kidney transplanted patients: Ongoing for up to 15 months - baseline until last visit (twelve months after transplantation))
- 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.(Kidney transplanted patients: 2 days x3 (baseline (before transplantation) and after three and twelve months after transplantation, Control group: 2 days)
- The secretion and content of GLP-1 and GIP during an OGTT before and after kidney transplantation analysed from blood samples(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)
- The secretion and content of GLP-1, GIP and glucagon during an IIGI before and after kidney transplantation analysed from blood samples(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)
- Death rate during follow up in the Group of kidney transplanted patients(Only kidney transplanted patients: Ongoing for up to 15 months - baseline until last visit (twelve months after transplantation))
研究者
Bo Feldt-Rasmussen
Professor, Head of the Department of Nephrology
Rigshospitalet, Denmark