Peritoneal Dialysis for Stroke: Amazing, but Promising!

Peritoneal dialysis (PD) applies the principles of diffusion and osmosis across the peritoneal membrane to restore electrolyte and fluid balance in patients with acute renal failure and end-stage renal disease. In addition to its role as a renal replacement therapy, an increasing body of evidence suggests that PD can help to treat fluid overload in refractory heart failure patients, thereby relieving their symptoms and reducing hospitalization rates. A recent study published in the Journal of Clinical Investigation (1) suggests that stroke might, in the future, be added to the list of nonrenal indications for PD.

Stroke is one of the leading causes of death world-wide and a major source of disability among survivors. Ischemic stroke results from a reduction in cerebral blood flow restricted to the territory of a major brain artery. Thrombolytic therapy with recombinant tissue plasminogen activator is currently the only effective strategy to reverse vessel obstruction and improve outcomes (2). Unfortunately, that approach is restricted to relatively few patients. Recent progress in the understanding of the fundamental mechanisms of neuronal cell death has contributed to the development of novel alternative therapeutic perspectives (3).

The ischemic peri-infarct zone is now considered to be a main target for therapy, because this region is functionally impaired and at risk for irreversible structural damage, but still salvageable. In this peri-infarct zone, glutamate, the most abundant neurotransmitter in mammals, was shown to play a critical role in the propagation of ischemic brain damage by a mechanism called excitotoxicity (3). In the ischemic brain, glutamate abnormally accumulates in the extracellular space as a consequence of energy and ion pump failure, and a failure of reuptake mechanisms. Glutamate overload exerts toxic effects on metabolically viable tissue through sustained activation of postsynaptic receptors, leading to a massive influx of calcium, sodium, and water into neurons. That influx in turn triggers a cascade of intracellular events—specifically, production of reactive oxygen species, inflammation, and uncoupling of oxidative phosphorylation—eventually leading to apoptosis and cell death. The local release of glutamate after stroke also enhances brain-to-blood efflux, leading to a transient increase in the blood concentration, a finding that has been associated with disease progression in a large cohort of patients with acute ischemic stroke (4).

In their study, Godino Mdel et al. (1) tested the hypothesis that PD could lower blood levels of glutamate, thereby preventing the progression of ischemic brain damage. In a rat model of stroke, the authors showed that PD using glucose-based dialysis solution—two consecutive dwells for a total of 2 hours, beginning 2.5 hours or 5 hours after occlusion of the middle cerebral artery—was effective in attenuating the transient increase in blood levels of glutamate after stroke. That attenuation was associated with a reduced cerebral infarct size measured 24 hours after the arterial occlusion: 12.1% ± 2.2% in treated rats versus 23.3±1.3% in rats not receiving PD. The addition of glutamate to the dialysis solution completely abrogated the reduction in blood glutamate levels and the beneficial effect of PD on infarct size, demonstrating the critical role of glutamate clearance by diffusion across the peritoneum. The benefits of PD were further evaluated 2 weeks after the ischemic insult by functional magnetic resonance imaging and an evaluation of limb-use asymmetry. Both techniques demonstrated significant improvement in tissue viability and function among rats treated with PD, reducing the degree of disability. Lastly, the demonstration of effective glutamate clearance across the peritoneum of end-stage renal disease patients on PD after a 4-hour dwell suggested the potential clinical benefit of the findings (1).

The ingenious idea of applying PD to enhance transperitoneal diffusion and clearance of a transient excess of glutamate opens perspectives for improving functional outcome after stroke. Achieving glutamate clearance by promptly initiating PD could indeed extend the window of opportunity for intervention in patients with stroke. However, the optimal timing of PD, and the modalities of PD catheter insertion and PD prescription, will need to be carefully addressed to ensure the efficiency of such an intervention, while avoiding early—that is, mechanical—complications.

Glutamate has been shown to play a pivotal role not only in ischemic stroke, but also in the physiopathology of many neurologic diseases such as hemorrhagic stroke and seizures. Enhancing glutamate clearance could therefore potentially be of benefit in those conditions as well (1). The effect on outcomes after stroke or other neurologic disorders with the decreased clearance and higher blood levels of glutamate seen in patients with end-stage renal disease (5) have not yet been investigated. Given the small size of the glutamate molecule (169 Da), hemodialysis would presumably also be as effective as PD in removing it; however, the hemodynamic stability and lack of a need for anticoagulation represent advantages of PD over hemodialysis in the setting of acute stroke. The relevance of the animal studies of Godino Mdel et al. and the possibility of adding a new indication for PD need now to be rigorously tested in patients with stroke.

Disclosures

The authors have no financial conflicts of interest to declare.