Nephrotoxicity of Immunosuppressive Agents in Renal Transplantation

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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.

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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, which are derived from prostaglandins, threatening. Withdrawal of cyclosporine is the mainstay cause vasoconstriction and platelet aggregation. of treatment. Plasmapheresis and intravenous Prostaglandins also mediate vascular tone and may be immunoglobulin have been reported to confer benefit vasoconstrictors or vasodilators depending on its (6). Although subsequent resumption of cyclosporine has subtypes. Both can be altered by calcineurin inhibitors, been observed without recurrence of TMP (7), it is and the disturbed balance between prostaglandins and advisable to convert to tacrolimus if a calcineurin thromboxanes seems important in the development of inhibitor is deemed necessary (8,9). It should be noted acute nephrotoxicity. It has been demonstrated in a rat model that cyclosporine increased urinary excretion of

thromboxane B2, which correlated with reduction in renal function, manifesting as increased serum creatinine and decreased creatinine clearance (13). The administration of a thromboxane synthetase inhibitor or thromboxane receptor antagonist significantly improved renal function compared with control rats not given these agents (14,15). Similar studies investigating the potential protective effects of thromboxane synthetase inhibition in humans have yielded less conclusive results (16).

The renin-angiotensin system has been reported to have an important role in mediating the nephrotoxic effects of calcineurin inhibitors. It has been shown that plasma renin activity was increased by cyclosporine, which was Figure 2. Renal biopsy showing striped interstitial fibrosis, a associated with a decrease in kidney function and the characteristic feature of cyclosporine nephrotoxicity. development of hypertension (17). Increased production

67 Nephrotoxicity in renal transplant of angiotensin II, which has potent vasoconstrictor Endothelin is a peptide with powerful vasoconstrictor actions, may theoretically contribute to the acute properties. Calcineurin inhibitors stimulate the synthesis hemodynamic changes characteristic of acute and release of endothelin from renal cells. Endothelin nephrotoxicity. However, data to date suggest that the has been implicated in the acute hemodynamic changes role of angiotensin II may be more important in the induced by cyclosporine. It has also been proposed that pathogenesis of chronic nephrotoxicity. Angiotensin II increased endothelin may contribute toward the can promote fibrogenesis either directly or via the development of cyclosporine nephrotoxicity via the stimulation of osteopontin (18). Angiotensin II-induced induction of TGF-β1 (24) (Fig. 3). renal fibrosis is characterized by the activation of fibroblasts and increased synthesis of TGF-β1, Nitric oxide is a potent vasodilator derived from multiple fibronectin, and type I collagen (19) (Fig. 3). Blockade cell types, and is synthesized from L-arginine by a family of the renin-angiotensin system with converting enzyme of nitric oxide synthetases (NOS). Although cyclosporine inhibitor or AT-1 receptor antagonist ameliorated stimulates endothelial NOS mRNA expression in the cyclosporine-induced fibrosis, reduced the expression of renal cortex and increases NO synthesis and release, NO- TGF-β1, plasminogen activator-inhibitor type 1, and mediated vasodilatation is impaired (25-27). These data epidermal growth factor, and reduced matrix deposition suggest that the activated NOS-NO pathway is (20-22). More recently, reduced circulating levels of insufficient to overcome the vasoconstrictive effect of TGF-β1 have been demonstrated in patients with chronic calcineurin inhibitors. The potential involvement of NO allograft nephropathy who had been treated with losartan in chronic nephrotoxicity of calcineurin inhibitors is (23). Although the extent of renal preservation with renin- suggested by the protective effect of L-arginine on angiotensin blockade remains to be defined, there is cyclosporine-induced tubulointerstitial fibrosis in animal increasing evidence to support this therapeutic approach experiments (28). in the management of patients with chronic allograft nephropathy, irrespective of the relative contribution of Increased intracellular calcium concentration has been immunologic and nonimmunologic factors. observed with cyclosporine, which directly enhanced the

Figure 3. Proposed pathogenetic mechanisms leading to chronic cyclosporine nephrotoxicity and/or chronic allograft nephropathy, illustrating the important roles of TGF-β1, angiotensin II, endothelin, and other mediators.

68 Hong Kong J Nephrol 2002;4(2):65-72. KC TSE, TM CHAN contractility of mesangial cells and smooth muscle cells. usually present with progressive deterioration in renal In addition, intracellular calcium may act as an indirect function and proteinuria, but the relationship between mediator potentiating the effects of other endogenous functional manifestations and morphological lesions is vasoconstrictors, resulting in intrarenal vasoconstriction. difficult to delineate. Clinically relevant concentrations The use of a calcium antagonist has been shown to offer of cyclosporine have been reported to exert a direct toxic some protection against cyclosporine nephrotoxicity (29, effect on proximal renal tubular epithelial cells, and 30), but these studies have not demonstrated definite promote fibrogenesis by stimulating autocrine secretion benefit on graft function and survival (31). of insulin-like growth factor-I by cortical fibroblasts as well as paracrine secretion of TGF-β1 by proximal Oxidative stress leading to free-radical production has tubular epithelia (39). Excessive induction of TGF-β1 been shown to be involved in the acute nephrotoxicity and tissue fibrosis are cardinal features in both of cyclosporine (32,33). This has led to interest in the calcineurin inhibitor-induced chronic nephrotoxicity and use of antioxidants in the prevention of cyclosporine chronic allograft nephropathy (40,41). Both cyclosporine nephrotoxicity. In a rat model, N-acetylcysteine was and tacrolimus up-regulate the production of TGF-β1, - shown to significantly protect animals against β2, and -β3 (42). Anti-TGF antibody has been shown to cyclosporine-induced renal structural and functional reduce cyclosporine-induced chronic changes in the impairment (34). Similarly, lazaroid antioxidant has been kidney in an animal model (43), which suggests that reported to attenuate the acute microvascular constriction TGF-β1 has a pivotal role in pathogenesis. In this regard, in rat hydronephrotic kidneys upon exposure to TGF-β1 upregulates matrix protein and collagen cyclosporine (35). synthesis, decreases the synthesis of proteases, and stimulates protease inhibitors such as plasminogen Cyclosporine enhances the activity of the sympathetic activator-inhibitor type 1, thereby promoting the nervous system. Upregulation of the arterial baroreflex deposition and inhibiting the degradation of fibrous tissue by cyclosporine has been demonstrated in animal (44). TGF-β also increases renal sympathetic activity and experiments (36). Direct afferent arteriolar constriction the production of endothelin-1, and inhibits the synthesis mediated by the sympathetic nervous system has been of inducible NOS (45) and renin (46). More recently, observed with cyclosporine use (37). Although the renal cyclosporine has been demonstrated to stimulate the allograft is a denervated organ, it remains possible that expression of vascular endothelial growth factor in rats denervation hypersensitivity of nerve endings or placed on a low salt diet (47), and a complex inter- regeneration of renal innervation may have a role if the relationship has been demonstrated between profibrotic sympathetic nervous system is involved in acute growth factors and the renin-angiotensin system (8,9,l8, calcineurin inhibitor-induced nephrotoxicity. 19,22,47) (Fig. 3). It has been proposed that tacrolimus might have a lower fibrogenic potential compared with At the cellular level, the nephrotoxic effects of cyclosporine, based on the finding that tacrolimus cyclosporine may be related to its differential actions in administration resulted in less induction of TGF-β and the cytosol and mitochondria. Different subtypes of tissue inhibitor of metalloproteinase-1 in a rat model of cyclophilin have been described: cyclophilin A is found renal ischemia-reperfusion injury (48). Whether such in the cytosol, cyclophilin B in the mitochondrial differences can apply to humans remains obscure, as is intermembranous space, and cyclophilin D in the the long-term graft survival in patients treated with mitochondrial matrix. It has been proposed that binding tacrolimus. of cyclosporine to cytosolic cyclophilin A in T lymphocytes accounts for the immunosuppressive Management of nephrotoxicity induced effects, whereas binding to cyclophilin B and D in kidney by calcineurin inhibitors cells may be responsible for the nephrotoxic effects (38). In view of the correlation between acute nephrotoxicity and circulating blood levels of calcineurin inhibitors, Pathogenetic mechanisms involved in chronic drug level monitoring is a useful means to prevent this nephrotoxicity of calcineurin inhibitors are less well complication (49). Particular caution needs to be defined. Drug-induced nephrotoxicity, ongoing exercised in patients treated with inhibitors of hepatic immunologically mediated tissue destruction and cytochrome P450 such as diltiazem, verapamil, scarring, and nonimmunologic factors such as fluconazole, ketoconazole, macrolide antibiotics, hypertension and hyperlipidemia, are all important fluoroquinolones, or oral contraceptives; and in patients confounding variables that culminate in chronic allograft with fluctuating liver function, for example caused by nephropathy. The poor correlation with cumulative drug chronic active hepatitis B or C. In addition, increased dose underscores the multifactorial etiology. Patients nephrotoxicity is to be expected in patients receiving

69 Nephrotoxicity in renal transplant concomitant treatment with aminoglycosides, is used together with a calcineurin inhibitor, because amphotericin B, and nonsteroidal anti-inflammatory enhanced nephrotoxicity has been reported (58). agents. Once chronic nephrotoxicity or chronic allograft Alternative strategies with early cyclosporine withdrawal nephropathy is recognized, it is appropriate to reduce in a rapamycin-cyclosporine-based regimen have been the dose of calcineurin inhibitors to target at the lower advocated with beneficial effects on renal function and end of the desired circulating level (50). In this regard, prevention of nephrotoxicity (59). There is also data from recent studies on C2 monitoring of preliminary evidence that rapamycin may be of benefit cyclosporine blood level suggest that the drug dosage in patients with chronic allograft nephropathy or can be reduced in a significant proportion of long-term established chronic nephrotoxicity induced by stable patients without adverse consequences (51). The calcineurin inhibitors, in view of the ability of rapamycin addition of newer immunosuppressive agents such as to inhibit growth factor-driven proliferation of mycophenolate mofetil or rapamycin can be considered endothelial and smooth muscle cells in vitro and to disrupt when attempting to completely withdraw calcineurin signal transduction of cytokines such as epidermal growth inhibitors from an individual patient. Promising results factor and PDGE, which have been implicated in the have been observed with the latter approach, although it development of chronic allograft nephropathy (60,61). may not be easy to delineate to what extent the subsequent improvement in renal function is attributable Monoclonal (anti-CD3) and polyclonal (antithymocyte to reduced dose of calcineurin inhibitors or to these newer globulin or antilymphocyte globulin) anti-T lymphocyte immunosuppressive agents. Optimal control of blood antibodies have been used as induction therapy, pressure, and to a lesser extent hyperlipidemia, assumes especially in highly sensitized individuals, and as critical importance in the long-term preservation of renal treatment for acute steroid-resistant rejection (62-64). function in patients with chronic nephrotoxicity or They have also been used for treatment of steroid- chronic allograft nephropathy. Blockade of the renin- resistant acute rejection (64). Initial doses of these angiotensin system may confer benefits with regard to antibody preparations may induce a massive release of the amelioration of matrix deposition and fibrosis, in vasoactive substances including prostaglandins, tumor additional to its effect on blood pressure control (8,9,18, necrosis factor-α, and IL-6 (65), resulting in fever, 19,47). diarrhea, pulmonary edema, and indirectly leading to acute renal failure. Prevention is by prophylactic Other immunosuppressive agents in administration of corticosteroid and antihistamine. These renal transplantation manifestations usually become less severe with Despite the advent of new immunosuppressive agents, subsequent doses. corticosteroids are still important in the prophylaxis against rejection after renal transplantation. Although The administration of IL-2 receptor antagonists has not corticosteroids have various side effects, they are free of been associated with any nephrotoxicity. The clinical role renal toxicity. Similarly, azathioprine and mycophenolate and the side-effects profile of new immunosuppressive mofetil have not been associated with nephrotoxicity. agents such as CTLA-4 immunoglobulin, anti-CD40 Indeed, there is evidence from in vitro and animal ligand, brequinar, leflunomide, and deoxyspergualin are experiments to suggest that mycophenolate mofetil might being investigated. decrease the risk or progression of chronic allograft nephropathy through its antiproliferative effect on CONCLUSION smooth muscle cells and its inhibitory actions on fibrosis The prevention of acute renal allograft rejection has (52-55). achieved significant success in the past two decades, with consequent improvement in short-term allograft survival. Rapamycin (Sirolimus) is a macrocyclic lactone Much of this improvement can be attributed to produced by Streptomyces hygroscopicus, which acts by calcineurin inhibitors, which have assumed a pivotal role binding to the intracellular protein FKBP 25 to create a in the prophylactic immunosuppressive treatment in the complex that inhibits the target of rapamycin, a kinase majority of patients. Although acute nephrotoxicity of involved in signal transduction pathways triggered by calcineurin inhibitors seems largely reversible and IL-2 or IL-6, thereby interfering with the progression of preventable by careful attention to circulating drug levels, T lymphocytes from the G1 to the S phase of the cell the evolution of chronic nephrotoxicity induced by cycle (56). Hypomagnesemia caused by increased tubular calcineurin inhibitors, and its role in chronic allograft excretion is often observed with the use of rapamycin, nephropathy, are still being investigated. With the advent otherwise the drug per se is not nephrotoxic (57). of new and effective immunosuppressive agents, there However, caution should be exercised when rapamycin is a trend toward reduced dosage and target blood levels

70 Hong Kong J Nephrol 2002;4(2):65-72. KC TSE, TM CHAN of calcineurin inhibitors, or their total avoidance in 12.Kopp JB, Klotman PE. Cellular and molecular mechanisms of patients with compromised renal allograft function. cyclosporine nephrotoxicity. J Am Soc Nephrol 1990;1:162-79. Although this approach is likely to retard the deterioration 13. Coffman TM, Carr DR, Yarger WE, Klotman PE. Evidence that renal of renal function, therapeutic interventions that might prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity. Transplantation 1987;43:282-5. potentially reverse the morphological abnormalities 14. Gladue RP, Newborg MF. The protective effects of the thromboxane associated with chronic nephrotoxicity or chronic synthetase inhibitor Dazmegrel on nephrotoxicity in cyclosporine- allograft nephropathy remain to be established. The treated rats. Transplantation 1991;52:837-41. addition of mycophenolate mofetil or rapamycin has 15. Perico N, Rossini M, Imberti O, Malanchini B, Cornejo RP, Gaspari reduced the reliance on calcineurin inhibitors. Whether F, Bertani T, Remuzzi G. Thromboxane receptor blockade attenuates these agents might be able to prevent the deleterious long- chronic cyclosporine nephrotoxicity and improves survival in rats with term pathological changes remains to be investigated. It renal isograft. J Am Soc Nephrol 1992;2:1398-404. is likely that immunosuppressive treatment after renal 16.Smith SR, Kubacki VB, Rakhit A, Martin LL, Schaffer AV, Jasani MK, Hefty DJ, Johnston T, Cannon C, Bennett WM, et al. Chronic transplantation will be increasingly individualized to thromboxane synthetase inhibition with CGS 12970 in human maximize the benefit and minimize adverse effects cyclosporine nephrotoxicity. Transplantation 1993;56:1422-6. pertinent to the status of allograft function and the 17.Perico N, Benigni A, Bosco E, Rossini M, Orisio S, Ghilardi F, comorbidities in an individual patient. Piccinelli A, Remuzzi G. Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins? Clin Nephrol 1986;25(Suppl 1):S83-8. Acknowledgments 18.Lee DB. Cyclosporine and the renin-angiotensin axis. Kidney Int The authors acknowledge Dr. KW Chan from the 1997;52:248-60. Department of Pathology, Queen Mary Hospital, for 19. Ruiz-Ortega M, Egido J. Angiotensin II modulates cell growth-related providing the histology slide of renal biopsy for striped events and synthesis of matrix proteins in renal interstitial fibroblasts. interstitial fibrosis associated with chronic cyclosporine Kidney Int 1997;52:1497-510. toxicity in this article. 20. Johnson DW, Saunders HJ, Johnson FJ, Huq SO, Field MJ, Pollock CA. Fibrogenic effects of cyclosporine A on the tubulointerstitium: role of cytokines and growth factors. Exp Nephrol 1999;7:470-8. REFERENCES 21.Shihab FS, Bennett WM, Tanner AM, Andoh TF. Angiotensin II 1. Gjertson DW. Impact of delayed graft function and acute rejection blockade decreases TGF-beta1 and matrix proteins in cyclosporine on kidney graft survival. Clin Transpl 2000:467-80. nephropathy. Kidney Int 1997;52:660-73. 2. Christians U, Sewing KF. Cyclosporin metabolism in transplant 22.Yang CW, Ahn HJ, Kim WY, Shin MJ, Kim SK, Park JH, Kim YO, patients. Pharmacol Ther 1993;57:291-345. Kim YS, Kim J, Bang BK. Influence of the renin-angiotensin system 3. Marchetti P, Navalesi R. The metabolic effects of cyclosporin and on epidermal growth factor expression in normal and cyclosporine- tacrolimus. J Endocrinol Invest 2000;23:482-90. treated rat kidney. Kidney Int 2001;60:847-57. 4. Deppe CE, Heering PJ, Tinel H, Kinne-Saffran E, Grabensee B, 23.Campistol JM, Inigo P, Jimenez W, Lario S, Clesca PH, Kinne RK. Effect of cyclosporine A on Na+/K(+)-ATPase, Na+/K+/ Oppenheimer F, Rivera F. Losartan decreases plasma levels of 2Cl-cotransporter and H+/K(+)-ATPase in MDCK cells and two TGF-beta1 in transplant patients with chronic allograft nephropathy. subtypes, C7 and C11. Exp Nephrol 1997;5:471-80. Kidney Int 1999;56:714-9. 5. Heering P, Degenhardt S, Grabensee B. Tubular dysfunction 24.Hutchinson IV. An endothelin-transforming growth factor beta following kidney transplantation. Nephron 1996;74:501-11. pathway in the nephrotoxicity of immunosuppressive drugs. Curr 6. Pham PT, Peng A, Wilkinson AH, Gritsch HA, Lassman C, Pham Opin Nephrol Hypertens 1998;7:665-71. PC, Danovitch GM. Cyclosporine and tacrolimus-associated 25.Stroes ES, Luscher TF, de Groot FG, Koomans HA, Rabelink TJ. thrombotic microangiopathy. Am J Kidney Dis 2000;36:844-50. Cyclosporine A increases nitric oxide activity in vivo. Hypertension 7. Zent R, Katz A, Quaggin S, Cattran D, Wade J, Cardella C, Zaltzman 1997;29:570-5. J, Fenton S, Cole E. Thrombotic microangiopathy in renal transplant 26.Bobadilla NA, Gamba G, Tapia E, Garcia-Torres R, Bolio A, Lopez- recipients treated with cyclosporine A. Clin Nephrol 1997;47: Zetina P, Herrera-Acosta J. Role of NO in cyclosporin nephrotoxicity: 181-6. effects of chronic NO inhibition and NO synthases gene expression. 8. Zarifian A, Meleg-Smith S, O'donovan R, Tesi RJ, Batuman V. Am J Physiol 1998;274:791-8. Cyclosporine-associated thrombotic microangiopathy in renal 27.Assis SM, Monteiro JL, Seguro AC. L-Arginine and allopurinol allografts. Kidney Int 1999;55:2457-66. protect against cyclosporine nephrotoxicity. Transplantation 1997; 9. Young BA, Marsh CL, Alpers CE, Davis CL. Cyclosporine-associated 63:1070-3. thrombotic microangiopathy/hemolytic uremic syndrome following 28.Andoh TF, Gardner MP, Bennett WM. Protective effects of dietary kidney and kidney pancreas transplantation. Am J Kidney Dis 1996; L-arginine supplementation on chronic cyclosporine nephrotoxicity. 28:561-71. Transplantation 1997;64:1236-40. 10.Pham PT, Peng A, Wilkinson AH, Gritsch HA, Lassman C, Pham 29.Rooth P, Dawidson I, Diller K, Taljedal IB. Protection against PC, Danovitch GM. Cyclosporine and tacrolimus-associated cyclosporine-induced impairment of renal microcirculation by thrombotic microangiopathy. Am J Kidney Dis 2000;36:844-50. verapamil in mice. Transplantation 1988;45:433-7. 11. Trimarchi HM, Truong LD, Brennan S, Gonzalez JM, Suki WN. 30.Dawidson I, Rooth P, Fry WR, Sandor Z, Willms C, Coorpender L, FK506-associated thrombotic microangiopathy: report of two cases Always C, Reisch J. Prevention of acute cyclosporine-induced renal and review of the literature. Transplantation 1999;67:539-44. blood flow inhibition and improved immunosuppression with

71 Nephrotoxicity in renal transplant

verapamil. Transplantation 1989;48:575-80. potential than cyclosporin A in a model of renal ischaemia- 31.Pirsch JD, D'Alessandro AM, Roecker EB, Knechtle SJ, Reed A, reperfusion injury. Br J Surg 2000;87:1563-8. Sollinger HW, Kalayoglu M. A controlled, double-blind, randomized 49.Mahalati K, Belitsky P, West K, Kiberd B, Fraser A, Sketris I, trial of verapamil and cyclosporine in cadaver renal transplant Macdonald AS, McAlister V, Lawen J. Approaching the therapeutic patients. Am J Kidney Dis 1993;21:189-95. window for cyclosporine in kidney transplantation: a prospective 32.Wang C, Salahudeen AK. Lipid peroxidation accompanies study. J Am Soc Nephrol 2001;12:828-33. cyclosporine nephrotoxicity: effects of vitamin E. Kidney Int 1995; 50.Weir MR, Ward MT, Blahut SA, Klassen DK, Cangro CB, Bartlett 47:927-34. ST, Fink JC. Long-term impact of discontinued or reduced 33.Zhong Z, Arteel GE, Connor HD, Yin M, Frankenberg MV, calcineurin inhibitor in patients with chronic allograft nephropathy. Stachlewitz RF, Raleigh JA, Mason RP, Thurman RG. Cyclosporine Kidney Int 2001;59:1567-73. A increases hypoxia and free radical production in the rat kidney: 51.Oellerich M, Armstrong VW. Two-hour cyclosporine concentration prevention by dietary glycine. Am J Physiol 1998;275:F595-604. determination: an appropriate tool to monitor neoral therapy? Ther 34.Tariq M, Morais C, Sobki S, Al Sulaiman M, Al Khader A. N- Drug Monit 2002;24:40-6. acetylcysteine attenuates cyclosporine-induced nephrotoxicity in 52. Badid C, Vincent M, McGregor B, Melin M, Hadj-Assia A, Veysseyre rats. Nephrol Dial Transplant 1999;14:923-9. C, Hartmann DJ, Desmouliere A, Laville M. Mycophenolate mofetil 35.Krysztopik RJ, Bentley FR, Spain DA, Wilson MA, Garrison RN. reduces myofibroblast infiltration and collagen III deposition in rat Lazaroids prevent acute cyclosporine-induced renal remnant kidney. Kidney Int 2000;58:51-61. vasoconstriction. Transplantation 1997;63:1215-20. 53.Romero F, Rodriguez-Iturbe B, Parra G, Gonzalez L, Herrera- 36.Ryuzaki M, Stahl LK, Lyson T, Victor RG, Bishop VS. Acosta J, Tapia E. Mycophenolate mofetil prevents the progressive Sympathoexcitatory response to cyclosporin A and baroreflex renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999; resetting. Hypertension 1997;29:576-82. 55:945-55. 37.Remuzzi G, Perico N. Cyclosporine-induced renal dysfunction in 54. Raisanen-Sokolowski A, Vuoristo P, Myllarniemi M, Yilmaz S, Kallio experimental animals and humans. Kidney Int Suppl 1995;52:S70-4. E, Hayry P. Mycophenolate mofetil (MMF, RS-61443) inhibits 38.Simon N, Tillement JP, Albengres E, Jaber K, Hestin D, Roux F, inflammation and smooth muscle cell proliferation in rat aortic Olivier P, d'Athis P, Kessler M, Berland Y, Crevat A. Potential interest allografts. Transpl Immunol 1995;3:342-51. of anti-ischemic agents for limiting cyclosporine A nephrotoxicity. 55.Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Int J Clin Pharmacol Res 1997;17:133-42. Magee JC, Wolfe RA, Agodoa LY, Kaplan B. Mycophenolate mofetil 39.Johnson DW, Saunders HJ, Johnson FJ, Huq SO, Field MJ, Pollock reduces late renal allograft loss independent of acute rejection. CA. Fibrogenic effects of cyclosporine A on the tubulointerstitium: Transplantation 2000;69:2405-9. role of cytokines and growth factors. Exp Nephrol 1999;7:470-8. 56.Morice WG, Brunn GJ, Wiederrecht G, Siekierka JJ, Abraham RT. 40.Shin GT, Khanna A, Ding R, Sharma VK, Lagman M, Li B, Rapamycin induced inhibition of p34cdc2 kinase activation is Suthanthiran M. In vivo expression of transforming growth factor associated with G1/S-phase growth arrest in T lymphocytes. J Biol beta 1 in humans: stimulation by cyclosporine. Transplantation 1998; Chem 1993;268:3734-8. 65:313-8. 57.Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett 41.Cuhaci B, Kumar MS, Bloom RD, Pratt B, Haussman G, Laskow WM. Comparison of acute rapamycin nephrotoxicity with DA, Alidoost M, Grotkowski C, Cahill K, Butani L, Sturgill BC, cyclosporine and FK506. Kidney Int 1996;50:1110-7. Pankewycz OG. Transforming growth factor beta levels in human 58.Andoh TF, Lindsley J, Franceschini N, Bennett WM. Synergistic allograft chronic fibrosis correlate with rate of decline in renal effects of cyclosporine and rapamycin in a chronic nephrotoxicity function. Transplantation 1999;68:785-90. model. Transplantation 1996;62:311-6. 42.Border WA, Noble NA. Transforming growth factor beta in tissue 59. Velosa JA, Larson TS, Gloor JM, Stegall MD. Cyclosporine elimination fibrosis. N Engl J Med 1994;331:1286-92. in the presence of TOR inhibitors: effects on renal function, acute 43.Islam M, Burke JF Jr, McGrowan TA, Zhu Y, Dunn SR, McCue P, rejection, and safety. Am J Kidney Dis 2001;38:S3-S10. Kanalas J, Sharma K. Effect of anti-transforming growth factor-beta 60.Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in antibodies in cyclosporine-induced renal dysfunction. Kidney Int transplantation: a review of the evidence. Kidney Int 2001;59:3-16. 2001;59:498-506. 61. Kahan BD. Potential therapeutic interventions to avoid or treat chronic 44.Shihab FS, Andoh TF, Tanner AM, Noble NA, Border WA, allograft dysfunction. Transplantation 2001;71(Suppl 11):S52-7. Franceschini N, Bennett WM. Role of transforming growth factor- 62.Grundmann R, Hesse U, Wienand P, Baldamus C, Arns W. Graft beta 1 in experimental chronic cyclosporine nephropathy. Kidney survival and long-term renal function after sequential conventional Int 1996;49:1141-51. cyclosporine A therapy in cadaver kidney transplantation: a 45.Vodovotz Y, Kopp JB, Takeguchi H, Shrivastav S, Coffin D, Lucia prospective randomized trial. Klin Wochenschr 1987;65:877-84. MS, Mitchell JB, Webber R, Letterio J, Wink D, Roberts AB. 63.Grino JM, Alsina J, Sabater R, Castelao AM, Gil-Vernet S, Andres Increased mortality, blunted production of nitric oxide, and increased E, Sabate I, Mestre M, Seron D, Diaz C. Antilymphoblast globulin, production of TNF-alpha in endotoxemic TGF-beta 1 transgenic cyclosporine, and steroids in cadaveric renal transplantation. mice. J Leukoc Biol 1998;63:31-9. Transplantation 1990;49:1114-7. 46.Antoniphillai I, Le TH, Soceneantu L, Horton R. Transforming growth 64.Jogose JT, Bailey RR, Lynn KL, Robson RA, Wells JE. OKT3 for factor-beta is a renin secretagogue at picomolar concentrations. the treatment of steroid-resistant acute renal allograft rejection. Am J Physiol 1993;265:F537-41. Nephron 1997;77:298-303. 47. Shihab FS, Bennett WM, Yi H, Andoh TF. Expression of vascular 65.Wever PC, Roest RW, Wolbink-Kamp AM, Wolbink GJ, Weening endothelial growth factor and its receptors Flt-1 and KDR/Flk-1 in JJ, Hack CE, ten Berge JM. OKT3-induced nephrotoxicity is chronic cyclosporine nephrotoxicity. Transplantation 2001;72:164-8. associated with release of group II secretory phospholipase A2. 48.Jain S, Bicknell GR, Nicholson ML. Tacrolimus has less fibrogenic Eur J Clin Invest 1996;26:873-8.