PDE5i Use in Renal Transplant Recipients

1. Purpose Renal ischemia-reperfusion injuries (IRI) are the result of multifactorial mechanisms. During ischemia, the kidney is subject to reduced blood flow, oxygen delivery, and nutrients. This leads to the accumulation of nitrogenous waste products (i.e. creatinine and blood urea nitrogen) that can lead to cellular damage, depending on the extent and duration of the ischemia. Moreover, when the kidney is reperfused there is additional damage caused by reactive oxygen radicals and inflammatory processes.

IRI is a common feature in the presentation of a diverse range of presentations: trauma, shock, sepsis, renal transplantation, cardiovascular surgery, partial nephrectomy, and other urologic complications. Moreover, IRI of the kidney specifically can lead to acute kidney injury (AKI), acute renal failure (ARF), and subsequent chronic renal failure. In the context of renal transplantation, IRI is associated with primary nonfunction, delayed graft failure, increased acute rejection, and allograft dysfunction. It has been postulated that interventions designed at increasing vasodilation during early reperfusion could reduce the effects of IRI through improving blood flow to the transplanted kidney.

Phosphodiesterase-5 (PDE5) inhibitors, like sildenafil citrate (Viagra) and tadalafil, are drugs generally used to treat erectile dysfunction (ED) and pulmonary hypertension. These drugs prevent the breakdown of nitric oxide (NO) by increasing levels of cyclic guanosine monophosphate (cGMP). Besides causing smooth muscle relaxation and systemic vasodilation, NO and cGMP are both believed to help reduce the extent of IRI. NO has protective vasodilatory effects; while cGMP is an important mediator in the body that causes neutrophil degranulation, inhibits platelet aggregation, regulates intracellular calcium levels, and opens mitochondrial K+ATP channels.

A number of different studies have been undertaken that support the use of PDE5 inhibitors as a pretreatment to prevent IRI in kidneys. In particular, sildenafil's antioxidant, anti-inflammatory, and antiapoptotic properties have been shown to be renoprotective in some renal injury models. However, the majority of literature is based from animal studies; there is very little information about the clinical use of PDE5 inhibitors during human kidney transplantation. Previous studies have proven that these drugs are safe for impotent males with significant comorbidities, including those on dialysis and those who underwent kidney transplants (>6 months post-op). They have also proven that sildenafil does not affect immunosuppressive drugs (i.e. tacrolimus and cyclosporine), despite these drugs sharing a common elimination pathway; Tacrolimus' pharmacokinetics, trough levels, and half-life are not significantly changed when administered with sildenafil. However, tacrolimus does change the pharmacokinetics (increase in Cmax and half-life) of sildenafil when both are administered together.

These studies prove that PDE5 inhibitors are renoprotective, generally well-tolerated, and do not impact immunosuppressants. However, what they have not shown is the effect of PDE5 inhibitors administered early in human kidney transplantation and their effect on the transplanted kidney. Our study will try to amend this by looking at utility of perioperative administration of sildenafil in early effects on the transplanted allograft. 2. Hypothesis A.) PDE5 inhibitors given perioperatively will decrease ischemia reperfusion injury and lead to consequently improved function in the transplanted kidney. 3. Justification In 2018, 133 transplants were performed by the Vancouver General Hospital (VGH) Kidney Transplant program. 38 of these kidneys were from living donors (LD), while the remaining 95 were cadaveric donations. This data supports that the majority of renal transplants are done using kidneys from deceased donors (DD) as opposed to LDs. However, the quality of these donated organs can vary drastically and DD organs are more likely to have poorer outcomes relative to LD. This is because the DD kidney undergoes warm ischemia (WIT) after the blood circulation is stopped and then cold ischemia (CIT) when subjected to hypothermic conditions meant to preserve the organ. The combined effects of WIT and CIT inflict cellular damage and may impair renal blood flow to cause primary renal dysfunction, delayed graft failure, increased acute rejection, and allograft dysfunction. Increased renal perfusion in this critical phase through vasodilation may counteract some of these negative effects of procurement and implantation