Different Effects of Tacrolimus and Cyclosporine on Renal Hemodynamics and Blood Pressure in Healthy Subjects. Transplantation 2002; 73: 732.

Abstract

RELATIVE NEPHROTOXICITY OF TACROLIMUS VERSUS CYCLOSPORINE The cyclic oligopeptide, cyclosporine, has been the pivotal immunosuppressive agent since its anti-T-cell properties were discovered in 1972. On its introduction in the 1980s, it improved 1-year kidney survival rates from 64% to 80% by reducing acute rejection rates (1). The use of this potent calcineurin blocker spread rapidly to all fields of transplantation, and it has proven phenomenally successful in preventing early graft loss. However, the major problems facing long-term use of this agent in all spheres is its nephrotoxicity. The initial launch of tacrolimus, a macrolide-calcineurin inhibitor, onto the world of transplantation in the 1980s was heralded by initial claims that tacrolimus was less toxic than cyclosporine. It was launched at a time when drug monitoring was still being optimized and at a high initial dose with intravenous protocols during the induction stage. This led to the rapid realization that nephrotoxicity was as bad as, if not worse, in patients treated with tacrolimus. However, as time has moved on, the dose of tacrolimus used has been decreased, such that current recommended oral doses are effective and safe. Cyclosporine and tacrolimus both have acute and chronic toxic effects. Acute toxic effects are reversible and dose related, causing a rapid reduction of renal blood flow and glomerular filtration rate after administration. With respect to cyclosporine, many mediators have been proposed to account for this effect, including adenosine, thromboxane A2, cysteinyl leukotrienes, endothelin-1, angiotensin II, and platelet-derived growth factor (2). In addition, altered activity of the sympathetic nervous system or the synthesis of vasodilatory prostaglandins or nitric oxide may also play a part. Although most work has been performed with regard to cyclosporine, most studies suggest that similar changes are seen with tacrolimus (3). Histology and clinical data are poorly correlated, but histological changes of vascular toxicity involve demonstration of light microscopical changes in afferent arterioles, showing endothelial swelling and nodular hyaline thickening and narrowing of the vascular lumen. This is often seen with evidence of downstream damage with ischemic-looking collapsed glomeruli and gross tubular vacuolation. Cyclosporine- and tacrolimus-induced chronic nephrotoxicity is progressive and leads to interstitial scarring that starts in the outer medulla and “striped fibrosis.” It is not known whether this is the result of recurrent and subclinical vascular microischemia or has a separate pathology. Certainly there is histological data to suggest that at least some of the chronic lesions have their basis in ischemia. However the tubulointerstitial lesions are patchy and not always in the territory supplied by affected arterioles. Implicating calcineurin inhibitors as the immediate cause of renal dysfunction in transplant patients is not always easy due to the complex nature of things, such as pretransplant conditions, preexistent renal dysfunction, drug interactions, and the use of drugs with nephrotoxic potential. Animal studies suggest that cyclosporine or tacrolimus are the most likely causative agents. However, there are problems extrapolating animal data to humans, because animals are relatively resistant to cyclosporine nephrotoxicity (4). Most studies have suggested that the nephrotoxic potential of both tacrolimus and cyclosporine is similar, and the recognition that nephrotoxicity is a major problem in transplantation medicine has led to the introduction of calcineurin blocking-free regimes as standard in many liver units. Other approaches of using calcium antagonists and other agents to protect the kidney against these vascular effects have been tried but with variable results. In this issue of Transplantation, Klein et al. (5) reported their data in a simple but clear study comparing the acute effects of tacrolimus and cyclosporine in normal human subjects. This study confirmed previous data showing that cyclosporine is vasoactive at these doses, with increases in baseline creatinine and blood pressure and a reduction in renal plasma flow and glomerular filtration rate in otherwise in normal kidneys. However, this is the first study to show that tacrolimus does not share these vasoconstrictor properties at the current recommended doses. This slightly surprising result may be related to the relative doses and potencies. The “guilt by association” usually linking these agents may be unfair, because the real differences between the two agents are now becoming clearer. Most data now suggests that tacrolimus may have a cleaner vascular side-effect profile at currently recommended trough levels than cyclosporine. This study did not address the effects of these agents on lipid or glucose metabolism, areas in which concerns have been raised and which may be pertinent to long-term graft survival. Does the current evidence suggest that we should keep a long-term place for cyclosporine in allograft immunosuppression regimes? In this respect, the link between acute reduction in renal blood flow and chronic nephrotoxicity is crucial. If one takes the view that chronic toxicity is due at least in part to microischemia, then patients should probably be transferred onto agents that cause less vasoconstriction. The problem with this approach is that in some studies there were appreciable rejection episodes associated with cyclosporine removal (6). In other studies, some benefit was derived from the switch from cyclosporine to tacrolimus (7). Although the study by Klein et al. (5) was small and concentrated on the acute period, it highlighted the relative vasoactive potency in the normal kidney. However, it may be that these data merely highlight the inadequacy of our current therapeutic monitoring using trough concentrations. Perhaps the side effects of cyclosporine could be ameliorated by better tailoring of doses. Measurement of cyclosporine concentrations at 2 hours post-administration, rather than the trough levels, gives a better indication of peak concentrations, and has been advocated by the manufacturer. However, many units have found the practical difficulties of switching to monitoring at 2 hours post-dose to be overwhelming. Moreover, because all patients differ in their T-cell sensitivity to calcineurin blocking agents, we urgently need an inexpensive and reliable lymphocyte sensitivity assay, which may allow a much more individual dosing regime than current therapy allows. In summary, because the vascular effects of cyclosporine are likely to be contributory to its nephrotoxicity, they remain the major drawback to its use in transplantation and autoimmune disease. This study showed that tacrolimus seems to be less vasoactive in normal subjects. Although it is difficult to extrapolate this data to transplant patients, there is now more of an argument for replacing cyclosporine with tacrolimus in the short term. In the long term, replacing calcineurin blocking agents completely with drugs such as rapamycin or switching early to mycophenolate mofetil-based regimes may be the way ahead.