To assess kidney oxygenation in obese, hyperfiltering adults with T2D before and after bariatric surgery for men and women separately determined by BOLD-MRI
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Appetite and general nutritional disorders
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in kidney oxygenation in obese, hyperfiltering adults with T2D after
bariatric surgery for men and women separately using BOLD-MRI
Secondary outcome
Main study parameters and endpoints: Kidney oxygenation: Oxygenation will be
assessed by BOLD-MRI. Cortical and Medullary oxygenation will be assessed.
Renal blood flow: Blood flow will be assessed by phase-contrast MRI. Kidney fat
percentage: Fat percentage will be assessed by a 3-point Dixon MRI. Renal
perfusion: Perfusion will be assessed by Arterial spin labeling (ASL). Kidney
Renal hemodynamics, (i.e., GFR, ERPF) will be measured by the gold standard
Iohexol and PAH clearance method based on timed urine sampling. In addition,
renal perfusion will be assessed by use of phase-contrast MRI. Insulin
sensitivity: will be measured by inducing a hyperinsulinemic-euglycemic clamp.
Metabolic parameters: plasma concentrations of glucose, FFAs and lipids will be
determined. Renal tubular function will be measured by 24-hour urine
electrolyte excretions; markers of renal damage will include 24-hour urinary
albumin excretion, albumin/creatinine ratio (UACR) and markers such as NGAL and
KIM-1; Blood pressure and heart rate will be measured by using an automatic
oscillometric device (Dinamap®); body anthropometrics; height, weight, BMI,
waist/hip circumference, body water and fat percentage (by bioimpedance
analysis); Additional urine and blood will be collected and appropriately
stored for conditional determination of metabolic, biochemical and exploratory
variables related to this project. VAT gene expression will be analyzed by RNA
sequencing.
Background summary
DKD (diabetic kidney disease) is the leading cause of chronic kidney disease
(CKD) and leading to significant morbidity and early mortality. Although
multiple mechanisms underlying DKD have been proposed, the exact underlying
mechanisms remain uncertain resulting in limited treatment options.
Accumulating evidence, derived from animal and human studies has indicated that
chronic kidney hypoxia is a key underlying determinant of DKD and recent
studies in T2D patients have related truncal obesity to glomerular
hyperfiltration and unfavorable kidney hemodynamic function that may drive
kidney hypoxia. Hyperfiltration is defined as increased whole-kidney GFR or as
single-nephron hyperfiltration in people with GFR in the normal range.
Hyperfiltration is an early recognized key factor driving kidney disease
progression in people with diabetes as it drives subsequent eGFR loss.
Increased and dysfunctional (i.e., altered adipose tissue biology) visceral
adipose tissue (VAT) present in central obesity is thought to disturb the
balance between kidney oxygen- consumption and delivery through secretion of
endocrine signals resulting in induction of insulin resistance, mitochondrial
dysfunction and impaired substrate metabolism amongst others. In line with this
theory, reduction of abdominal obesity following bariatric surgery has
demonstrated to improve kidney outcomes in some but not in all individuals. In
part this may be sex-specific. Since women have a lower risk for progression of
DKD, the role of kidney hypoxia in DKD need to be studied in this regard
individualized for sex. In this study, we will address the effects of bariatric
surgery on changes in kidney oxygenation using a sex-specific approach in
people with hyperfiltration.
Study objective
To assess kidney oxygenation in obese, hyperfiltering adults with T2D before
and after bariatric surgery for men and women separately determined by BOLD-MRI
Study design
A monocenter, prospective cohort study.
Study burden and risks
This study consists of three visits (one screening visit and two test day
visits) during which a total amount of 286 ml blood will be drawn. For healthy
controls this study consists of two visits (one screening visit and one test
day visit) during which a total amount of 151 ml blood will be drawn.
Participants will have to adhere to a *normal-salt* (9-12 grams or 150-200 mmol
per day) and -protein (1.0 g/kg per day) diet and will be asked to keep a food
journal in the three days prior to the testing day. Moreover, participants will
have to abstain from alcohol (24 hours), caffeine (12 hours) and nicotine (12
hours) and heavy exercise prior to and during the visits. Patient will undergo
an MRI during both visits which will last 30-45 min approximately. Iohexol,
PAH, insulin and glucose will be infused during both testing days. The infusion
of Iohexol can lead to a warm, sometimes painful sensation. Very rare adverse
effects (never experienced in > 800 test days in our center) include are
headache, stiffness, nerve pain, nausea, vomiting, fever, hives, stomach pain,
hallucinations and neurological symptoms. In patients with an allergy for
Iohexol it can elicit hypersensitive reactions, therefore we specifically check
a for this allergy at screening. The infusion of PAH can lead to a sensation of
warmth, or the desire to urinate or defecate during or shortly following the
infusion. Extremely large doses may cause osmotic diuresis. The side- and
adverse effects of insulin and glucose are negligible in the context of this
study.
During bariatric surgery visceral adipose tissue will be collected. The risk of
bleeding from the biopsy sites during surgery procedure is very low because the
biopsy sites are completely visible to the surgeon and local haemostasis will
be checked. In our
previous BARIA study (METC 2015.357), currently about 500 subjects included no
adverse events were seen during biopsies).
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
Group 1: Patients with obesity and hyperfiltration • ; man or women aged >=18
years and <70 years. • BMI >=35 • eGFR>90 ml/min calculated as by CKD-EPI •
Provision of signed and dated, written informed consent prior to any study
specific procedures • Hypertension should be controlled, i.e., <= 155/95 mmHg. •
Scheduled for gastric bypass or gastric sleeve Group 2: Non-diabetic lean
controls • male of female aged >=18 years and <40 years. • Provision of signed
and dated, written informed consent prior to any study specific procedures. •
Normal glucose tolerance confirmed by HbA1c • No hypertension • BMI >=18,5 and
<25 kg/m² Group 3: T2DM controls with overweight and eGFR 60-90 ml/min •
Caucasian; man or women aged >=18 years and <55 years. Females must be
pre-menopausal • Type 2 diabetes mellitus or pre-diabetes with HbA1c >=45mmol/
mol and <10% (<94mmol/mol) • BMI >=25 • eGFR 60-90 ml/min calculated as by
CKD-EPI • Hypertension should be controlled, i.e., <= 155/95 mmHg. Group 4:
Non-diabetic controls with overweight and eGFR 60-90 ml/min • Caucasian; male
of female aged >=18 years and <55 years. Females must be pre-menopausal • Normal
glucose tolerance confirmed by HbA1c • eGFR 60-90 ml/min calculated as by
CKD-EPI • Hypertension should be controlled, i.e., <= 155/95 mmHg. • BMI >=25
Exclusion criteria
Group 1 • Diagnosis of type 1 diabetes mellitus • Cardiovascular disease event
in the last 6 months prior to enrollment as assessed by the investigator,
including: myocardial infarction, cardiac surgery or revascularization
(CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or
significant cerebrovascular disease, unstable or previously undiagnosed
arrhythmia. • Chronic use of sodium-glucose transporter-2 inhibitors, oral
glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune
suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants
(TCAs), diuretics, or monoamine oxidase inhibitors. • Current urinary tract
infection or active nephritis • History of allergy/hypersensitivity to any of
the test agents • Contra-indication for MRI • Any other condition that prevents
participation as judged by investigator. Group 2: Non-diabetic lean controls
Exclusion criteria: • Macro-albuminuria (defined as UACR>30 mg/mmol) • . •
Cardiovascular disease event in the last 6 months prior to enrollment as
assessed by the investigator, including: myocardial infarction, cardiac surgery
or revascularization (CABG/PTCA), unstable angina, heart failure, transient
ischemic attack (TIA) or significant cerebrovascular disease, unstable or
previously undiagnosed arrhythmia. • Chronic use of renin-angiotensin-system
blockers, sodium-glucose transporter-2 inhibitors, DPP-4 inhibitors, oral
glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune
suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants
(TCAs), diuretics ormonoamine oxidase inhibitors. • Current urinary tract
infection or active nephritis • History of allergy/hypersensitivity to any of
the test agents • Contra-indication for MRI Group 3: T2DM controls with
overweight and eGFR 60-90 ml/min Exclusion criteria: • Diagnosis of type 1
diabetes mellitus • Post-menopausal females (defined as no menses >1 year and
follicle stimulating hormone (FSH) >31 U/L) • Cardiovascular disease event in
the last 6 months prior to enrollment as assessed by the investigator,
including: myocardial infarction, cardiac surgery or revascularization
(CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or
significant cerebrovascular disease, unstable or previously undiagnosed
arrhythmia. • Chronic use of sodium-glucose transporter-2 inhibitors, oral
glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune
suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants
(TCAs), diuretics, or monoamine oxidase inhibitors. • Current urinary tract
infection or active nephritis • History of allergy/hypersensitivity to any of
the test agents • Contra-indication for MRI • Any other condition that prevents
participation as judged by investigator. Group 4: Non-diabetic controls with
overweight and eGFR 60-90 ml/min • Post-menopausal females (defined as no
menses >1 year and follicle stimulating hormone (FSH) >31 U/L) • Cardiovascular
disease event in the last 6 months prior to enrollment as assessed by the
investigator, including: myocardial infarction, cardiac surgery or
revascularization (CABG/PTCA), unstable angina, heart failure, transient
ischemic attack (TIA) or significant cerebrovascular disease, unstable or
previously undiagnosed arrhythmia. • Chronic use of sodium-glucose
transporter-2 inhibitors, oral glucocorticoids, non-steroidal anti-inflammatory
drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics,
tricyclic antidepressants (TCAs), diuretics, or monoamine oxidase inhibitors. •
Current urinary tract infection or active nephritis • History of
allergy/hypersensitivity to any of the test agents • Contra-indication for MRI
• Any other condition that prevents participation as judged by investigator.
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| CCMO | NL83191.018.23 |