The influence of calcineurin inhibitors on renal medullary microcirculation: a novel approach to nephrotoxicity

The calcineurin inhibitors (CNIs), cyclosporine A (CsA) and tacrolimus (FK506), have revolutionized solid organ transplantation with their unprecedented ability to increase graft and patient survival. However, they have a plethora of unwanted side effects, of which nephrotoxicity is predominant. Renal cortical blood flow is majorly suppressed with administration of CsA and FK506, however the impact of these drugs on medullary blood flow is still unclear.

It was previously thought that renal medullary blood flow (RMBF) was regulated upstream by the larger arterioles of the cortex, however new evidence suggests that a local regulation of blood flow exist and is partially controlled through the vasoconstriction of renal pericytes on descending vasa recta (DVR) capillaries. Renal pericytes have been shown to contract and/or dilate in response to a variety of endogenous and exogenous factors suggesting they have the ability to locally regulate RMBF and respond accordingly after insult or in stress situations.

The first chapter of this thesis demonstrates the ability of CNIs to induce pericyte-mediated vasoconstriction of DVR. A significant decrease of DVR diameter likely results in decreased blood flow in vivo and contributes to increased ischemia. Furthermore, an alternative immunosuppressant, rapamycin, a mammalian target of rapamycin inhibitor (mTOR-i) failed to induce any significant vasoconstriction.

The following chapter investigates the use of antihypertensives in combination with CNIs and highlights a mechanism for their potential beneficial use in combating the progression of CNI-induced hypertension and nephrotoxicity.

The third results chapter sets out to establish a perfusion method for DVR in situ. The results demonstrate the feasibility of in situ perfusion within the established live kidney slice model, and also the impact of perfused CNIs on the vasoconstriction of vasa recta as defined in chapter 1. The data presented here further demonstrates how CNIs may augment the known nephrotoxic effect but, also how they may instigate medullary ischemia.

The final results chapter emphasises how the generation of reactive oxygen species (ROS) induced by CNIs could be a foremost mechanism in pericyte-mediated vasoconstriction of DVR. In addition, prevention of ROS production, rather than it’s scavenging, could be an enhanced approach for the inhibition of CNI induced renal damage and nephrotoxicity.

Taken together, the data presented here suggests a role of RMBF in the pathogenesis of CNI nephrotoxicity. Given that our understanding of RMBF is only now coming to light, its role in many disease states, including CNI nephrotoxicity, may have a greater impact than previously assumed and potentially offer a novel therapeutic approach for the prevention of renal decline.