The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Calcineurin Inhibitor Nephrotoxicity

The present article reviews, in detail, the current knowledge of the oral and dental aspects of chronic renal failure (CRF). Worldwide, increasing numbers of persons have CRF; thus, oral health care staffs are increasingly likely to provide care for patients with such disease. Chronic renal failure can give rise to a wide spectrum of oral manifestations, affecting the hard or soft tissues of the mouth. The majority of affected individuals have disease that does not complicate oral health care; nevertheless, the dental management of such individuals does require that the clinician understand the multiple systems that can be affected. The clinician should also consider the adverse side-effects of drug therapy and appropriate prescribing, in view of compromised renal clearance.

Oral and Dental Aspects of Chronic Renal Failure

Everolimus With Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial

Cyclosporine A delivery to the eye: a pharmaceutical challenge.

In some cases, the slow rotational movement underlying peptide bond cis/trans isomerizations is found to control the biological activity of proteins. Peptide bond cis/trans isomerases as cyclophilins, Fk506-binding proteins, parvulins, and bacterial hsp70 generally assist in the interconversion of the polypeptide substrate cis/trans isomers, and rate acceleration is the dominating mechanism of action in cells. We present evidence disputing the hypothesis that some of the molecular properties of these proteins play an auxiliary role in enzyme function.

Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes

Ciclosporine-A (CSA) has been in clinical use as an immunosuppressive drug in transplant recipients for over a decade. Unfortunately, CSA also has major side-effects (including nephrotoxic ones). In an attempt to find safer agents, tacrolimus (TAC) has been introduced recently. Despite major differences in the chemical structure, TAC and CSA seem to have many effects in common. This phenomenon can be explained by the inhibition of the calcineurin pathway characteristic for both drugs. The aim of our brief review was to compare personal observations regarding side-effects encountered under CSA or TAC therapy with data reported previously. We found that the profile of side-effects both under CSA and TAC was nearly identical. In particular, morphologic changes associated with toxic drug effects in the kidney were indistinguishable from one another, i.e. tubular lesions, arteriolopathy, HUS-like changes in glomeruli and vessels. The prevalence of defined nephrotoxic lesions was very similar. Some differences were found regarding the prevalence of clinical side effects. Hypertension, hypertrichosis and gingival hyperplasia were less pronounced in the TAC group and an elevated blood glucose level in the CSA group. We conclude that TAC and CSA are closely related immunosuppressive drugs with regard to adverse effects.

B Ryffel

Papers

The side-effects of ciclosporine-A and tacrolimus.