Glucose Metabolism During Hemodialysis

ESRD Clinical Trial

Official title:

Glucose Metabolism During Hemodialysis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01800188
• Other study ID #: H-2-2012-171
• Status: Completed
• Phase: N/A
• First received: February 25, 2013
• Last updated: November 18, 2013
• Start date: February 2013

Study information

• Verified date: November 2013
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Ethics CommitteeDenmark: Danish Dataprotection Agency
• Study type: Observational

Clinical Trial Summary

Disturbed glucose metabolism is a common feature of patients with end-stage renal disease (ESRD). Several hormones responsible of a stable blood glucose including insulin, glucagon, and the gastrointestinal insulinotropic hormones Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Peptide (GIP) are elevated in patients with ESRD. These hormones are all medium sized peptides which theoretically makes them removable during high efficient hemodialysis. A significant removal could have consequences for the treatment of patients with diabetes and ESRD.

The purpose of this study is to determine whether insulin, glucagon, GLP-1 and GIP are cleared during high efficient hemodialysis and hemodiafiltration. The investigators hypothesize that a significant amount of these hormones is removed during hemodialysis and to a larger extend during hemodiafiltration.

Description:

BACKGROUND

Disturbed glucose metabolism is a common feature of patients with end-stage renal disease (ESRD). Furthermore, the prevalence of diabetes mellitus in the ESRD population is high resulting in a marked increased morbidity and mortality. Several hormones responsible of a stable blood glucose including insulin, glucagon, and the gastrointestinal insulinotropic hormones Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Peptide (GIP) are elevated and dysregulated in patients with ESRD. Newly developed antidiabetic medications such as the dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) increase the concentrations of these hormones making the effect of these treatments difficult to predict in patients with ESRD.

During the history of hemodialysis the treatment has been refined to increase the removal of the various substances that accumulate when the kidney function declines. The focus has primary been on the removal of smaller molecules such as creatinine and urea, but in recent decades the focus has moved to medium-sized molecules (molecular weight of 300 to 12,000 Da) which are suspected of causing various uremic complications such as amyloidosis and neuropathy. The dialysis technique has therefore been optimized such that relatively large molecules are removed, but the dialysis filter does not distinguish between wanted and unwanted substances. Thus, in contrast to the functioning kidney there is a risk of removing important molecules including hormones, which are essential for maintaining a normal glucose metabolism.

Insulin, glucagon and the incretin hormones, GLP-1 and GIP are all peptides with a molecular weight of 3300 to 5800 Da. This means that they theoretically have a size where they can be removed under hemodialysis with so-called high-flux filters and by hemodiafiltration, both of which are common standards of care for patients with ESRD. It has been shown that insulin is removed in significant quantities during a hemodialysis, but this is probably due to adsorption to the filter and not filtration. Whether glucagon and the incretin hormones are eliminated by high effective hemodialysis and hemodiafiltration is never investigated. Previous studies have primarily observed unchanged glucagon and GIP concentrations in the blood after conventional hemodialysis. One study showed a 30% decrease in GIP concentration after hemodialysis, but the detected change probably reflects altered metabolism due to the treatment as the dialysis technique at the time was too inefficient to remove peptides significantly. Assays for the analysis of incretin hormones have also become considerably more specific and now differentiate between the active hormones and their inactive intermediate metabolites.

In recent years there has been a growing development of drugs that increase the endogenous produced incretin hormones. Linagliptin, launched in 2011, is the only one that is approved for patients with ESRD since it is not cleared renally and therefore does not require a change in dosage. However, the elimination of incretin hormones in dialysis patients is sparingly studied both during and between dialysis treatments.

This study will determine the effect of high efficient dialysis treatment on a number of hormones regulating the blood glucose. Significant elimination of these hormones during dialysis can have therapeutic implications for the treatment of dialysis patients with incretin based therapies.

PURPOSE OF THE STUDY

The purpose of this study is to determine whether several blood glucose-regulating hormones and their metabolites are removed during hemodialysis and hemodiafiltration in patients with dialysis-dependent renal insufficiency. The hypothesis is that the dialysis treatment results in a significant removal, thereby reducing the plasma concentration of each hormone.

METHODS

10 patients with ESRD undergoing either chronic hemodialysis or chronic hemodiafiltration will be included. The study will be carried out on two separate days which are planned two days after their previous dialysis. On the two study days each participant will be treated with a 4 hour hemodialysis or hemodiafiltration. Besides the dialysis modality (hemodialysis and hemodiafiltration) the two study days will be alike.

The participant will be examined in the morning in a 10 hour fasting state (including smoking) without any alcohol consumption within the last 24 hours and strenuous physical activity within the last 2 hours. Weight, Height, blood pressure and pulse will be measured and the dialysis access is prepared. An initial blood sample will be analyzed immediately for sodium, bicarbonate and ionized calcium and the dialysate of the dialyzer will be adjusted to match the measured concentrations as close as possible. The ultrafiltration will be set according to the patients dry weight and no sodium or ultrafiltration profiles will be allowed. The blood flow will be held constant not exceeding the half of the flow of the arteriovenous fistula.

Each participant at each study day will receive the dialysis fasting for one hour after which a standardized liquid meal with 1.5 mg Paracetamol added will be administered.

During the dialysis blood samples will be measured repeatedly and analyzed for insulin, glucagon, GLP-1 and GIP. Blood samples will be drawn both before and after the dialysis filter to calculate the clearance and samples from the spend dialysate are collected to determine the amount of adsorption of the hormones to the dialysis filter.

Participants undergo an optional third examination day receiving the standardized meal test without dialysis. Blood samples are collected at the same time intervals as during the examination days with dialysis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Aged 18-90 years

• Dialysis-dependent ESRD for more than 3 months

• Regular treatment with either hemodialysis or hemodiafiltration

• A well functioning arteriovenous fistula

• Fistula flow = 400 ml/min

Exclusion Criteria:

• Diabetes mellitus

• Impaired fasting glucose (fasting plasma glucose = 6.1 mmol/l)

• Current illness requiring admission to the hospital

• Significant acidosis before dialysis (standardized bicarbonate < 20 mmol/l)

• Anemia (B-Hemoglobin < 6,0 mmol/l)

• Known allergy to Paracetamol

• Medical treatment with compounds of known diabetogenic and / or insulin secretion inhibitory effect, including steroids and calcineurin inhibitors.

• Bowel resection or other major surgery of the gastrointestinal tract

• Current malignancy not including basal cell carcinoma

Study Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• ESRD

Intervention

Procedure:
• Hemodialysis
A 4 hour hemodialysis with a standardized liquid meal after one hour
• Hemodiafiltration
A 4 hour hemodiafiltration with a standardized liquid meal after one hour
• Meal test
A 3 hour standardized liquid meal test without dialysis

Locations

Country	Name	City	State
Denmark	Nephrology department, Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Bo Feldt-Rasmussen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clearance of total GLP-1	Clearance,K, is defined as; K=Qb*(Ca-Cv)/Ca+Qf*Cv/Ca; where Qb is the effective blood flow, Ca is the concentration before the filter, Cv is the concentration after the filter and Qf is the ultrafiltration flow.	2 hours into dialysis	No
Primary	Clearance of total GIP	Clearance,K, is defined as; K=Qb*(Ca-Cv)/Ca+Qf*Cv/Ca; where Qb is the effective blood flow, Ca is the concentration before the filter, Cv is the concentration after the filter and Qf is the ultrafiltration flow.	2 hours into dialysis	No
Primary	Clearance of glucagon	Clearance,K, is defined as; K=Qb*(Ca-Cv)/Ca+Qf*Cv/Ca; where Qb is the effective blood flow, Ca is the concentration before the filter, Cv is the concentration after the filter and Qf is the ultrafiltration flow.	One hour into dialysis	No
Secondary	Change of insulin clearance at 2 hours into dialysis	Clearance,K, is defined as; K=Qb*(Ca-Cv)/Ca+Qf*Cv/Ca; where Qb is the effective blood flow, Ca is the concentration before the filter, Cv is the concentration after the filter and Qf is the ultrafiltration flow.	Baseline and 2 hours into dialysis	No
Secondary	Change of hormone concentrations		Baseline and 1 hour into dialysis	No
Secondary	The percentage of cleared hormone present in the dialysate		One or two hours into the dialysis	No
Secondary	Change of insulin clearance at 3 hours into dialysis	Clearance,K, is defined as; K=Qb*(Ca-Cv)/Ca+Qf*Cv/Ca; where Qb is the effective blood flow, Ca is the concentration before the filter, Cv is the concentration after the filter and Qf is the ultrafiltration flow.	Baseline and 3 hours into dialysis	No
Secondary	Change of insulin clearance at 4 hours into dialysis	Clearance,K, is defined as; K=Qb*(Ca-Cv)/Ca+Qf*Cv/Ca; where Qb is the effective blood flow, Ca is the concentration before the filter, Cv is the concentration after the filter and Qf is the ultrafiltration flow.	Baseline and 4 hours into dialysis	No