New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Abstract

Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.

Molecular Diagnostics of Calcineurin-Related Pathologies

“…Long-term exposure to CsA is associated with histologic damage to all compartments of the kidney [reviewed in (74 )]. TGF-␤-induced tubulointerstitial fibrosis is thought to be the primary mechanism driving progression of CsA nephropathy, which is characterized by loss of tubular epithelial cells and deposition of extracellular matrix in the tubulointerstitium (75 ). Another pathologic hallmark is arteriolar vasoconstriction, which leads to glomerular ischemia (76 ).…”

Diabetic Nephropathy: Role of Aldosterone and Benefits of Therapy with Aldosterone Receptor Blocker

“…The renoprotective effects of spironolactone or epleronone had been seen in many other animal models of renal injury not limited to diabetic nephropathy, as noted in a recent review by Nishiyama et al (46) These models included streptozotocin-induced and other forms of diabetic rats and mice, obese SHR rats, murine lupus nephritis, unilateral ureteral obstruction, ischemia reperfusion injury, 5/6 th nephrectomised rats and rats treated with AngII infusion, NO synthase inhibitor or cyclosporine (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). In these animal models, treatment with aldosterone blockers had no effect on systemic blood pressure.…”

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

“…In a single study, inhibition of RAS by ACE inhibitors has limited development of cyclosporine nephrotoxicity 124 and administration of angiotensin II blockers led to a significant reduction in plasma levels of TGF-β and endothelin 125,126 . In an experiment, application of spironolactone eliminated many of the RAS-and aldosterone-induced effects occurring during CI therapy 11 ; studies confirming these finding in humans are however not available.…”

“…It has been demonstrated that vasoconstriction is induced by activation of the renin-angiotensin system (RAS) and increase in levels of the vasoconstricting factors, endothelin and thromboxane, as well as suppression of synthesis of vasodilating prostacyclin, prostaglandin E2, and nitric oxide (NO) [9][10][11] . Interindividual susceptibility to cyclosporine-induced vasoconstriction also plays an important role 12 .…”