Chronic Calcineurin Inhibitor Nephrotoxicity—Lest We Forget

Abstract

Calcineurin inhibitor (CNI) nephrotoxicity was recognized in Cambridge in the late 1970s. The vasoconstrictor impact of cyclosporine (CsA) and to a lesser extent tacrolimus, in both acute and chronic settings, results from a decrease in vasodilators and increase in vasconconstrictors while direct tubular toxicity results from blockade of mitochondrial permeability transition pores and inhibition of prolyl isomerase. A biopsy of native kidneys of recipients of CNIs reveals nephrotoxicity as the most common pathological diagnosis with chronic CNI toxicity and hypertension the primary problems. A long-term study of randomized clinical trials with up to 20 years of follow-up shows inferiority of both renal function and graft survival for continuous CsA compared to either CsA withdrawal or continuous azathioprine and prednisolone. Pathological hallmarks of chronic CNI nephrotoxicity include stripped interstitial fibrosis, arteriolar hyalinosis and glomerular sclerosis, but with the exception of nodular arteriolar hyalinosis the findings are non specific. The model for chronic renal allograft loss must be multifactorial with both immune and nonimmune factors operating dependent upon an individual's risk factors for cell and/or antibody-mediated rejection, CNI nephrotoxicity and recurrent disease. Better outcomes will require early diagnosis and individualization of therapy dependent upon the dominant mechanisms impacting each patient. The revisionist view put forward by some senior, experienced and thoughtful individuals, challenges the concept of chronic CNI nephrotoxicity as an important clinical entity. By implication, the view that appears to be promoted is as follows: we need not fear-prolonged exposure to CNIs, and in seeking better long-term solutions for transplant recipients, we have forgotten alloimmunity. It is thus apparent that we must revisit the data and again question the basis for chronic CNI nephrotoxicity in current clinical practice. This contribution to the debate will focus on the evidence that CNIs are nephrotoxic and that their impact needs to be limited if we are to improve long-term outcomes after transplantation, leaving others to promote the contrary perspective and perhaps also to reflect on the largely unproven impact of the steroid avoidance and other minimization strategies so prevalent today.

MicroRNA-494 Promotes Cyclosporine-Induced Nephrotoxicity and Epithelial to Mesenchymal Transition by Inhibiting PTEN

“…Long-term use of CsA is associated with significant nephrotoxicity (1,(19)(20)(21). Major components of CsA nephrotoxicity include tubular epithelial cell apoptosis and EMT (6)(7)(8), however it is unclear how these responses are regulated.…”

Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A

“…Later, however, CsA was found to be nephrotoxic, causing stripped tubulointerstitial fibrosis, tubular atrophy and afferent arteriolopathy [15,16].…”

Molecular Diagnostics of Calcineurin-Related Pathologies

“…Both angiotensin II and aldosterone may independently aggravate these pathologic effects because of their stimulating effects on TGF-␤ production (75,77,78 ). Tacrolimus has a similar nephrotoxic profile, although it is seemingly somewhat less severe (79 ).…”