Glucose Metabolism During Hemodialysis
Condition: ESRD
Study type: Observational

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.
    

Detailed 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.
    

Intervention name(s): Hemodialysis; Hemodiafiltration; Meal test
Intervention type(s): Procedure; Procedure; Procedure
Intervention description(s): A 4 hour hemodialysis with a standardized liquid meal after one hour; A 4 hour hemodiafiltration with a standardized liquid meal after one hour; A 3 hour standardized liquid meal test without dialysis
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with ESRD undergoing chronic hemodialysis/hemodiafiltration and with a normal
        fasting glucose
      
Biospecimen description: 
      Serum of blood specimens will be retained for analysis at the end of the study
    
Keywords: Dialysis; Incretin hormones