Cyclosporin nephrotoxicity following cardiac transplantation.

The greatest change in GFR in response to treatment with cyclosporin occurs in the first 3-6 months and the magnitude of the decrement in the first year (or perhaps the first few months) appears to be a vital indicator of future problems. However, the apparent stabilization of renal function, particularly when monitored only by plasma creatinine, can conceal progressive tubulointerstitial injury, and increasing proteinuria is an ominous sign. Although lower doses of cyclosporin and careful monitoring of renal function may be helpful, there is at present no pharmacological intervention to protect or reverse the reduction in GFR that occurs. We believe that the vascular lesion induced by cyclosporin is fundamental, with early and initially reversible cyclosporin-induced vasospasm leading to progressive vascular damage with activation of endothelial cells and increased platelet interactions. Amongst other determinants, the renal response to this vasculopathy will depend on the balance between the presence of vasoactive factors with the vasoconstrictors promoting interstitial fibrosis and the vasodilators inhibiting proliferation. It is likely that the kidneys of heart-transplant recipients are chronically ischaemic and as a consequence their renin-angiotensin systems massively activated, which may further sensitize their kidneys to cyclosporin. Overproduction of angiotensin II, associated with the DD ACE genotype, has already been associated with poor prognosis in diabetic and IgA nephropathy. It is interesting to speculate that this ACE genotype, which is associated with a poor outcome in non-ischaemic heart disease can influence renal sensitivity to cyclosporin and predict the development of morphological injury. Extension of these experimental findings into the clinical arena with a placebo-controlled trial of early introduction of ACE inhibitor therapy in recipients of cardiac transplants would be timely.

RCT Entities:   Population Interventions Outcomes