The Effects of Bariatric Surgery on Kidney Oxygenation in Obese Adults With Type 2 Diabetes and Hyperfiltration

In this study the investigators will examine the effects of VAT reduction by bariatric surgery on kidney hypoxia and compare kidney oxygenation before- and after surgery in both sexes using BOLD-MRI and measures of kidney hemodynamic function. Furthermore, the investigators will assess whether kidney oxygenation is reduced in obese T2D men and women versus various controls as described below. This will determine whether kidney hypoxia can be appointed as a modifiable pathogenic factor in early DKD and non-surgical interventions targeting kidney hypoxia can be designed to slow DKD progression.

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, the investigators will address the effects of bariatric surgery on changes in kidney oxygenation using a sex-specific approach in people with hyperfiltration.

Eligibility Criteria:
Group 1: T2DM patients with obesity and hyperfiltration

Inclusion criteria:

* 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 ≥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

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 2: Non-diabetic lean controls

Inclusion criteria:

* Caucasian; male of female aged ≥18 years and \<40 years. Females must be pre-menopausal
* 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

Exclusion criteria:

* Macro-albuminuria (defined as UACR\>30 mg/mmol)
* 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 renin-angiotensin-system blockers, sodium-glucose transporter-2 inhibitors, GLP-1 receptor agonists, 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