Extracorporeal methods of blood glutamate scavenging: a novel therapeutic modality

Abstract

Pathologically elevated glutamate concentrations in the brain’s extracellular fluid are associated with several acute and chronic brain insults. Studies have demonstrated that by decreasing the concentration of glutamate in the blood, thereby increasing the concentration gradient between the brain and the blood, the rate of brain-to-blood glutamate efflux can be increased. Blood glutamate scavengers, pyruvate and oxaloacetate have shown great promise in providing neuroprotection in many animal models of acute brain insults. However, glutamate scavengers’ potential systemic toxicity, side effects and pharmacokinetic properties may limit their use in clinical practice. In contrast, extracorporeal methods of blood glutamate reduction, in which glutamate is filtered from the blood and eliminated, may be an advantageous adjunct in treating acute brain insults. Here, we review the current evidence for the glutamate-lowering effects of hemodialysis, peritoneal dialysis and hemofiltration. The evidence reviewed here highlights the need for clinical trials.

Keywords:

• blood glutamate scavenging
• extracorporeal methods
• hemodialysis
• hemofiltration
• neuroprotection
• peritoneal dialysis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• In recent years, there has been much focus on better understanding the brain’s inherent mechanisms of removing excess glutamate from the extracellular fluid during pathological states.

• By establishing a favorable brain-to-blood glutamate efflux, the rate of reducing pathologically elevated glutamate in the brain’s extracellular fluid can be dramatically increased.

• Various pharmacological blood glutamate scavengers have been demonstrated to successfully reduce brain glutamate and provide neuroprotection in animal models of brain injury including stroke, traumatic brain injury and subarachnoid hemorrhage.

• Extracorporeal methods, including hemodialysis (HD), peritoneal dialysis and continuous hemofiltration (HF), offer unique advantages over pharmacological methods of blood glutamate reduction including irreversible glutamate removal, as well as fewer peripheral effects and side effects.

• Humans with end-stage renal failure have been shown to have higher concentrations of blood glutamate compared with healthy controls, and HD has been effective in eliminating this excess plasma glutamate.

• Peritoneal dialysis, which neither impacts the hemodynamic stability of critically ill patients nor requires heparin, has been effective in reducing blood glutamate in humans and animal studies.

• HF may be superior to dialysis in clearing medium and larger sized molecules, and may be a surrogate for HD to decrease blood glutamate concentrations.

• Currently, two clinical studies are underway that better study the blood glutamate-lowering effects of HF: the first study is investigating the effects of continuous HF in critically ill patients, and the second study is a Phase II, prospective, double-blinded randomized control trial evaluating the effect of HF in the treatment of acute ischemic stroke.