View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Hong Kong JournalJ Nephrol of 2002;4(2):65-72.Nephrology KC TSE, TM CHAN 2002;4(2):65-72. REVIEW ARTICLE Nephrotoxicity of immunosuppressive agents in renal transplantation Kai-Chung TSE, Tak-Mao CHAN Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. Abstract The outcome of solid organ transplantation has improved significantly in the past few decades with the advent of cyclosporine and other newer immunosuppressive agents including tacrolimus, mycophenolate mofetil, interleukin-2 receptor blockers, and rapamycin. A prominent consequence of the development in posttransplant immunosuppressive regimens is the reduced incidence of acute rejections, from 30% to 40% to approximately 15% or even lower (Gjertson, Clin Transpl 2000:467-80), although it still remains an important risk factor compromising long-term renal allograft survival. The acute and chronic nephrotoxicity of immunosuppressive agents, notably calcineurin inhibitors, have attracted increasing attention, and the reduction of these untoward effects has constituted an important theme of clinical research in transplantation. The current knowledge on the spectrum and mechanisms of nephrotoxicity pertinent to immunosuppressive agents used in renal transplantation is reviewed in this article and possible strategies for prevention or amelioration of the nephrotoxicity; the future directions for investigations are also discussed. Key words: Cyclosporine/therapeutic use, Immunosuppression, Survival rate, Transforming growth factor- beta/metabolism ! !"#$%&'()*+,- !"#$%&'()$*+, JO !"#$%&'() !"#$%&'()*+,-./01234567895&':;<=>?@ABCD! !"#$%&'()*#+,-.PMBQMB !NRB dàÉêíëçåI=`äáå=qê~åëéä=OMMMW QSTJUM !"#$%&'()*+,-./01234567849:;<=>?@A !"#$%&' !" #$ %&'()*+,-./012345678%9:;<= !"#$%&'()*+,-./012345678!9:;<=>?!3@A!BCDE !"#$%&'()*+,-./012"34+56789 INTRODUCTION increasingly included. Consequently, the use of The outcome of solid organ transplantation has improved polyclonal or monoclonal anti-T lymphocyte antibodies significantly in the past few decades with the advent of has decreased accordingly. A prominent consequence of cyclosporine and other new immunosuppressive agents. the development in posttransplant immunosuppressive For renal transplantation, the combined use of regimens is the reduced incidence of acute rejections, corticosteroid and cyclosporine with or without from 30% to 40% to approximately 15% or even lower azathioprine has been the conventional prophylactic (1). Recent cohort and registry data suggest that the immunosuppressive therapy until recent years, when improvement in short-term renal allograft survival tacrolimus, mycophenolate mofetil, interleukin (IL)-2 observed with new immunosuppressive regimens could receptor blockers, and lately, rapamycin, have been lead to prolongation of long-term graft survival, although Correspondence: Prof. Tak-Mao CHAN, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Fax: (852) 2872 5828, E-mail: [email protected] ©2002 Hong Kong Society of Nephrology Hong Kong Journal of Nephrology, October 2002 65 Nephrotoxicity in renal transplant to a lesser extent. In this context, acute rejection remains Tacrolimus has a dose-related diabetogenic potential, but an important risk factor compromising long-term renal is less prone to induce gum hypertrophy or hirsutism, allograft survival. The acute and chronic nephrotoxicity and may be associated with a lower risk or severity of of immunosuppressive agents, notably calcineurin hypertension and hyperlipidemia compared with inhibitors, have thus attracted increasing attention, and cyclosporine, although the data could be confounded by the reduction of these untoward effects has constituted the drug levels targeted in the studies (3). Calcineurin an important theme of clinical research in transplantation. inhibitors have significantly decreased the risk of acute The current knowledge on the spectrum and mechanisms rejection in the early posttransplant period and improved of nephrotoxicity pertinent to immunosuppressive agents the short-term survival of renal allografts. Although they used in renal transplantation is reviewed in this article. still have a central role in prophylactic immuno- Based on these data, possible strategies for prevention suppressive protocols, novel treatment regimens free of or amelioration of the nephrotoxicity, and the future calcineurin inhibitors are being investigated, with the aim directions for investigations, are also discussed. of obviating their nephrotoxic effect, the monitoring and the early detection of which may not be easy. CALCINEURIN INHIBITORS Cyclosporine and tacrolimus represent the two calcineurin Clinicopathological manifestations inhibitors currently used in renal transplantation. Cyclo- Nephrotoxicity of calcineurin inhibitors can be acute or sporine A is a hydrophobic cyclic peptide produced by chronic (Fig. 1). Acute toxicity is dose-related, and is the fungus Tolypocladium inflatum gams (2). After related to afferent arteriolar vasoconstriction, leading to entering the cell, cyclosporine will bind to a cytosolic decreased glomerular filtration rate and acute immunophilins, cyclophilin 18 or 40, and this complex deterioration of renal function. Accordingly, this will inhibit the action of calcineurin, which is a functional, hemodynamically mediated acute toxicity is phosphatase important in intracellular signal transduction. reversible upon dosage reduction. Acute tubular Inhibition of calcineurin will reduce the transcription of dysfunction is another common side effect, manifesting cytokine, in particular IL-2, which has a pivotal role in as various electrolyte and acid-base disturbances, acute graft rejection. Tacrolimus has a similar mechanism attributed to perturbed tubular transport at the distal parts of action, except that it binds to another immunophilins, of the nephron (4). Hyperkalemia, metabolic acidosis, FK-binding protein 12, 13, or 59, instead of cyclophilin hypomagnesemia, and hyperuricemia are often seen. in the cytoplasm. The side-effect profiles of cyclosporine Treatment with sodium bicarbonate is effective in and tacrolimus are similar, and include nephrotoxicity, correcting hyperkalemia and acidosis, and helps to reduce neurotoxicity, hypertension, and hyperlipidemia. the adverse effect of acidosis on bone metabolism (5). Figure 1. Manifestations of cyclosporine nephrotoxicity. 66 Hong Kong J Nephrol 2002;4(2):65-72. KC TSE, TM CHAN Hypomagnesemia is usually mild and a magnesium that TMP has also been reported with tacrolimus (10, supplement is seldom needed. In contrast, chronic 11). With the availability of alternative agents such as nephrotoxicity is associated with irreversible structural mycophenolate mofetil and rapamycin, it may therefore changes (Fig. 2), notably striped tubulointerstitial fibrosis be safer to consider avoidance of all calcineurin inhibitors beginning in the outer medulla and progressing into in patients with a history of TMP. the medullary rays of the cortex, tubular atrophy, characteristic degenerative hyaline changes in the Mediators of acute or chronic nephrotoxicity arteriolar wall, especially afferent arterioles, sometimes induced by calcineurin inhibitors resulting in obliterative arteriolopathy, and glomerular Acute nephrotoxicity often occurs during the early sclerosis or collapse. It is often progressive, and its months after transplantation, when relatively higher relationship with blood levels of the calcineurin inhibitor target blood levels of calcineurin inhibitors were aimed is more obscure. The relationship between acute and for, and thus needs to be differentiated from other causes chronic nephrotoxicity induced by calcineurin inhibitors of acute graft dysfunction, especially acute rejection. remains to be defined. In addition, the relative Various mechanisms have been proposed to explain the contribution of immunologic and nonimmunologic intrarenal vasoconstriction (12), including altered mechanisms leading to chronic allograft dysfunction is expression of thromboxanes and prostaglandins, being investigated. endothelin, nitric oxide (NO), changes in intracellular calcium concentration, changes in the rennin-angiotensin Thrombotic microangiopathy (TMP) represents a distinct system, sympathetic over-drive, and increased oxidative form of acute vascular toxicity of cyclosporine, which stress with free-radical production. It is probable that a can affect the graft kidney. It is a rare but serious multitude of mechanisms contribute toward an excessive complication, often presenting with acute deterioration vasoconstrictor effect. Nevertheless, careful monitoring of renal function in association with thrombocytopenia to avoid excessively high blood levels remains the most and hemolytic anemia. The clinical manifestations important preventive measure. However, overexpression resemble thrombotic thrombocytopenic purpura and of transforming growth factor (TGF)-β1, over-activity hemolytic uremic syndrome. The pathogenesis involves of the renin-angiotensin system, and increased deposition endothelial damage induced by cyclosporine, with the of matrix proteins are prominent abnormalities observed consequent release of cytokines, platelet activation, and in chronic nephrotoxicity. the formation of microthrombi. It is associated with a high risk of early graft loss, and is potentially life- Thromboxanes,