Evaluation of Thiosulfate Enhanced Organ Preservation Solution in Kidney Transplantation

The rise in the incidence of end stage renal disease (ESRD) is a global concern. Renal transplantation is the best available treatment for established renal failure, as it not only improves survival, but also improves patient quality of life and is cost effective [1-3]. Unfortunately, there is a widening discrepancy between the incidence of ESRD and the number of available organs for transplantation. While living donor organs have traditionally been preferred, the number of living donors has never been sufficient for all of the patients on the transplant waiting lists. This deficit in organ allocation is expected to rise over the next 20 years due to an increased incidence of ESRD risk factors such as obesity, diabetes and hypertension. This has necessitated increasing the donor pool, with use of organs from extended criteria donors, neurologically deceased donors (NDD), and donation after cardiac death donors (DCD) [4-9].

As expected, maximizing usable organs for transplant with NDD and DCD kidneys comes an increased risk for delayed graft function (DGF) and graft loss. The NDD and DCD kidneys have inherently longer warm ischemic times during the recovery operation, and often have longer cold ischemia times due to the need to transport organs between donor and recipient sites. This results in an increased risk for ischemia-reperfusion injury (IRI). IRI is a complex biological process involving cell death, microcirculatory compromise, altered transcription, inflammation and immune activation [14-16]. While these processes affect all grafts, the effect appears to be greatest in DCD and NDD cohorts. DCD kidneys have up to a 30% risk of graft loss at 5 years and up to 50% in 10 years [10-13].

Significant efforts have been applied to preclinical and clinical settings to develop strategies to ameliorate the negative effects of IRI during organ transplantation. However, there is currently no active pharmacological agent used during transplantation to reduce the impact of IRI. Current strategies include either pulsatile (machine perfusion) or static storage of donor kidneys in various preservation solutions at hypothermic (4ºC) conditions during the peri-transplant period [17]. Hypothermia slows cellular metabolism and subsequent ATP depletion during the ischemic period [18], while organ preservation solutions contain a myriad of electrolytes and other solutes which help to maintain osmotic conditions, scavenge free radicals, and stimulate cellular metabolism upon reperfusion [17]. University of Wisconsin (UW) solution is the most commonly used preservation solution and has been shown to be effective at decreasing the risk of DGF [17].

The addition of a protective pharmacological agent to UW solution may improve graft preservation. Hydrogen sulfide (H2S) has been known for its unsavory "rotten eggs" smell and toxic effects at high concentrations. However, it is also endogenously produced in mammalian cells through the metabolism of L-cysteine and elevated levels are found in hibernating animals. H2S is believed to have a number of cytoprotective effects through anti-inflammatory, anti-oxidative, and anti-apoptotic events. In the kidney, H2S has a direct vasodilatory effect and increased glomerular filtration rate. H2S acts as an endothelium derived relaxing factor that uses Sulphydration mechanisms on vascular smooth muscle cells, interferes with renin production and works synergistically with nitric oxide to upregulate the production of cyclic guanosine monophosphate.

Various H2S donation strategies have been developed and tested in vitro and in vivo. The two most common sources are both sulphide salts, sodium hydrosulfide (NaHS) and sodium sulphide (Na2S) [23]. They dissociate rapidly at physiological pH to generate H2S. However, the resulting bolus of instantly generated H2S does not mimic the endogenous, constitutive enzymatic synthesis of small amounts of H2S. It also has difficulty reaching the mitochondrial target site, which contributes principally to IRI of the renal graft. Other H2S donor compounds such as GYY4137, AP39 and AP123, have offered alternatives but unfortunately are not clinically viable [24,25].