Glucose Metabolism During Hemodialysis

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.