HTK-N: Modified Histidine-Tryptophan-Ketoglutarate Solution—A Promising New Tool in Solid Organ Preservation

Abstract

To ameliorate ischemia-induced graft injury, optimal organ preservation remains a critical hallmark event in solid organ transplantation. Although numerous preservation solutions are in use, they still have functional limitations. Here, we present a concise review of a modified Histidine-Tryptophan-Ketoglutarate (HTK) solution, named HTK-N. Its composition differs from standard HTK solution, carrying larger antioxidative capacity and providing inherent toxicity as well as improved tolerance to cold aiming to attenuate cold storage injury in organ transplantation. The amino acids glycine, alanine and arginine were supplemented, N-acetyl-histidine partially replaced histidine, and aspartate and lactobionate substituted chloride. Several in vitro studies confirmed the superiority of HTK-N in comparison to HTK, being tested in vivo in animal models for liver, kidney, pancreas, small bowel, heart and lung transplantation to adjust ingredients for required conditions, as well as to determine its innocuousness, applicability and potential advantages. HTK-N solution has proven to be advantageous especially in the preservation of liver and heart grafts in vivo and in vitro. Thus, ongoing clinical trials and further studies in large animal models and consequently in humans are inevitable to show its ability minimizing ischemia-induced graft injury in the sequel of organ transplantation.

Ex-vivo Kidney Machine Perfusion: Therapeutic Potential

“…Moreover, it contains other impermeants (gluconate and mannitol instead of lactobionate and raffinose) and glucose. A variant of commonly used HTK (histidinetryptophan-ketoglutarate, Custodiol R ) solution Custodiol-N R supplemented with dextran 40 was used for kidney HMP in several porcine models (24). Moreover, a novel Custodiol-MP R solution has been recently developed exclusively for aerobic machine perfusion (25).…”

“…Moreover, a novel Custodiol-MP R solution has been recently developed exclusively for aerobic machine perfusion (25). Despite promising results of experimental models, further studies are necessary to prove the superiority of Custodiol-N R or Custodiol-MP R over KPS-1 R in terms of kidney graft function and transplant outcomes (24,25).…”

Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation

“…The histidine-tryptophan-ketoglutarate (HTK) organ preservation solution, which is nowadays considered one of the standard solutions used in Tx, contains 2-mmol/L tryptophan due to its antioxidant capacity and membrane stabilizing potential [ 42 ]. On the contrary, several studies have suggested that tryptophan starvation could be a protective factor against IRI.…”

“…Several attempts to use tryptophan and its metabolites as diagnostic or prognostic tools to predict graft function in a short-term or long-term period after Tx have been reported. A metabolomics study that enrolled [ 42 ] patients with or without acute kidney injury after renal Tx revealed the serum tryptophan and symmetric dimethylarginine levels to have the most significant negative correlations with blood urea nitrogen, serum creatinine and uric acid, being the most accurate markers for graft injury. When combined, these two markers reached an area under the curve of 0.901 with a sensitivity of 0.889 and a specificity of 0.831 for the diagnosis of acute kidney injury.…”

The Phenolic Antioxidant 3,5-dihydroxy-4-methoxybenzyl Alcohol (DHMBA) Prevents Enterocyte Cell Death under Oxygen-Dissolving Cold Conditions through Polyphyletic Antioxidant Actions

“…Supplementing the organ preservation solution with antioxidants reduces cold preservation and reperfusion-related injury of the small intestine [ 10 ]. However, antioxidants with different membrane permeabilities can induce different injury mitigation effects [ 11 ]. We hypothesized that an amphipathic antioxidant that can penetrate the cell membrane could reach the mitochondria in small intestinal epithelial cells exposed to the lumen.…”