Renal complications after heart transplantation

Abstract

THE PATHOGENESIS of chronic cyclosporine nephrotoxicity is unknown, although experimentally a model has been produced that mimics the clinical pathologic features of this lesion. This model is produced by salt depletion in a rat or mouse even with modest doses of cyclosporine. Said another way, clinically relevant cyclosporine doses in a salt-depleted animal can produce chronic cyclosporine nephrotoxicity, while massive pharmacologic doses in a salt-replete animal produces hemodynamic change without pathologic lesions. There is now a considerable body of evidence that the renin angiotensin system is involved directly or indirectly in the renal scarring process as well as the vascular lesions. Blockade of the renin angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists can reverse the vasculopathy and interstitial fibrosis independent of changes in the glomerular filtration rate. There is also substantial evidence that angiotensin stimulates the production of increased interstitial matrix by its effects on transforming growth factor beta and its inhibition of matrix breakdown. Furthermore, cyclosporine and probably tacrolimus are known to reduce constitutive nitric oxide formation. Cyclosporine nephrotoxicity of the chronic variety is worsened by nitric oxide synthase inhibitors and is markedly improved by the infusion or administration of L-arginine. Finally, it has been shown recently that cyclosporine may induce renal tubular cell apoptosis by activation of the fas, fas-ligand pathway with the ultimate formation of caspases, which result in cell dropout and disappearance. How all of these pathways relate to clinical renal disease is best seen in successful heart transplant recipients. The frequency of cyclosporine nephrotoxicity is unknown and is very difficult to study in a renal transplant situation where rejection is always a confounding variable.