Novel Addition to Kidney Preservation Could Reduce Transplant Rejects

Nancy A. Melville

March 10, 2020

The relatively simple addition of a first-in-class nitrosylating agent to the fluid used in preserving donor kidneys shows the potential to significantly improve function and expand the supply of much-needed organs that are viable for transplantation.

"Inclusion of ethyl nitrite in the renal preservation solution holds promise to increase the number and quality of kidneys available for transplant," say Lin Zhu, MD, PhD, and colleagues in their research published online in the Annals of Surgery.

"S-nitrosylation therapy (with ethyl nitrite) restored the microcirculation and thus improved overall organ perfusion," they add.

Kidneys donated by deceased donors are typically preserved during storage with active perfusion to provide a constant inflow of nutrients to the kidney. However, up to 20% of those organs wind up ultimately failing to be viable for transplant because of reductions in flow and/or increases in fluid resistance, which are linked to poorer outcomes for the recipient.

Zhu, of the Institute for Transformative Molecular Medicine at Case Western Reserve University, in Cleveland, Ohio, and coauthors hypothesized that in many cases the lack of function occurs because current preservation solutions do not adequately correct the injury to donor kidneys that is sustained as the result of brain death in deceased donors.

Specifically, brain death causes a disruption in systemic S-nitrosothiol (SNO) homeostasis, which is critical in regulating microvascular blood flow and inflammatory responses in the kidney.

The team was able to determine that ethyl nitrite, when added to the kidney preservation solution, in fact generates SNO molecules, which can help regulate tissue oxygen delivery.

Senior author James D. Reynolds, PhD, also of Case Western, told Medscape Medical News: "We hypothesized that inclusion of an S-nitrosylating agent into the pumping milieu would confer benefit with respect to improving measures of ex vivo kidney function."

Reversing the Damage Caused by Current Standard of Care

Reynolds and his team had performed previous proof-of-concept experiments on swine kidneys showing encouraging results, so the team extended the research.

In the current study, 27 human kidneys determined unsuitable for transplantation were stored in a preservation solution that was aerated with 50 ppm of S-nitrosylating agent ethyl nitrite (ENO).

The kidneys were compared with seven control deceased donor kidneys that were stored according to the current standard of care, pumped at 4°C.

A recording of flow rate and perfusion for the 10 hours following biochemical analysis of the kidney tissue showed that in the control kidneys, the rate of perfusion was constant during the monitoring period, with the flow rate remaining low and vascular resistance staying high.

However, in the kidneys exposed to the addition of ethyl nitrite, there were "significant and sustained" reductions in resistance and increases in flow rate (P < .05 for each).

"These kidneys had been pumped and deemed nontransplantable, but we were able to recover them such that the parameters focusing on flow rate and resistance corrected to the extent of making them transplantable," Reynolds said.

Previous attempts to improve preservation solutions for donor kidneys have included the addition of agents such as oxygen, vasodilators, and nitric oxide, but those efforts have had limited effect in improving perfusion status.

"None of the agents trialed to date have been directed towards correcting the systemic disruptions in nitric oxide bioactivity and SNO homeostasis that occur after brain death," Reynolds explained.

Intervention Easy but Work Needed to See if Transplant Performs Well

The authors note that with ethyl nitrite, the intervention is relatively easy to execute, with one envisioned scenario including preloading ethyl nitrite into the preservative mix during manufacturing. The intervention is furthermore compatible with current pumping technology.

A key question moving forward is whether the use of the ethyl nitrite solution could in fact help improve graft performance in the kidney transplant recipient. And although further studies are needed, Reynolds noted that previous research involving the use of ethyl nitrite in other conditions has been encouraging.

"We have conducted previous studies...[where we have] successfully administered ethyl nitrite to humans under different conditions of dysfunction in oxygenation, such as pulmonary hypertension, and not observed adverse effects," he said.

For the current study, "the biggest limitation right now is we didn't transplant these kidneys, so we don't know if they are functional, but this is the first step in hopefully a long project," Reynolds concluded.

The study was funded, in part, by grants from the US Organ Donor Research Consortium, the Roche Organ Transplant Research Foundation, and the US Army Medical Research and Materiel Command. Reynolds and coauthor Jonathan S. Stamler, MD, hold patents related to renitrosylation. The other authors have reported no relevant financial relationships.

Ann Surg. Published online December 05, 2019. Abstract

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