Cyclosporine chronic nephrotoxicity

Compared with previously available therapy, the adverse effects associated with cyclosporine are much less severe but still worthy of concern. Nephrotoxicity, which can occur in up to 75% of patients, ranges from severe tubular necrosis to chronic interstitial nephropathy. This effect is generally reversible with dosage reduction. Vasoconstriction appears to be an important aspect of cyclosporine-induced nephrotoxicity. Hypertension occurs in 25% of the patients and more frequently in patients with some degree of renal dysfunction the concomitant use of antihypertensive drugs may prove useful. Hyperglycemia, hyperlipidemia, transient liver dysfunction, and unwanted hair growth are also observed. 

Mobb GE, Veitch PS, Bell PR. Are serum creatinine levels adequate to identify the onset of chronic cyclosporine A nephrotoxicity Transplant Proc 1990 22(4) 1708-10. 

Lipkorvitz GS, Madden RL, Mulhern J, Braden G, O Shea M, O Shaughnessy J, Nash S, Kurbanov A, Freeman J, Rennke H, Germain M. Long-term maintenance of therapeutic cyclosporine levels leads to optimal graft survival without evidence of chronic nephrotoxicity. Transpl Int I999 I2(3) 202-7. 

Pei Y, Scholey JW, Katz A, Schachter R, Murphy GF, Cattran D. Chronic nephrotoxicity in psoriatic patients treated with low-dose cyclosporine. Am J Kidney Dis 1994 23(4) 528-36. 

Prevot A, Llet JM, Semama DS, Justrabo E, Guignard JP, Gouyon JB. Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity. Pediatr Nephrol 2002 17 418-424. 

Ramirez C, Olmo A, O Valle F, Masseroli M, Aguilar M, Gomez-Morales M, Revelles F, Garcia-Chicano MJ, Arrebola F, Reguero ME, del Moral RG. Role of Intrarenal endothelin 1, endothelin 3,and angiotensin II expression in chronic cyclosporin A nephrotoxicity in rats. Exp Nephrol 2000 8 161-172. 

Dieterle A, Gratwohl A, Nizze FI, Fluser B, Mihatsch MJ, Thiel G, Tichelli A, Signer E, Nissen C, Speck B. Chronic cyclosporine-associated nephrotoxicity in bone marrow transplant patients. Transplantation 1990 49 1093-1100. 

Kolkin S, Nahman NS, Jr., Mendell JR. Chronic nephrotoxicity complicating cyclosporine treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 1987 37 147-149. 

Araujo IM, Mendes GEF, Baptista MAF, Burdmann EA. Effects of mycophenolate mofetil (MMF) on chronic cyclosporine (CSA) nephrotoxicity. J Am Soc Nephrol 2001 12 797A. 

Andoh TF, Lindsley J, Franceschini N, Bennett WM. Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 1996 62 311-316. 

Burdmann EA, Rosen S, LindsleyJ, Elzinga L, Andoh T, Bennett WM. Production of less chronic nephrotoxicity by cyclosporine G than cyclosporine A in a low salt rat model. Transplantation 1993 55 969-966. 

The ABCBl genotype of the donor, but not of the recipient, may be a major risk factor for cyclosporine-related chronic nephrotoxicity in recipients of renal transplants. The ABCBl 3435TT genotype, which is associated with lower Pgp... 

Qiao, B.P., X.D. Tang, and Q. Ruan. 2001. [Experimental study of compound salvia injection in preventing and treating chronic nephrotoxicity induced by cyclosporine A in rats.] Zhongguo Zhong Xi Yi Jie He Za Zhi 21(8) 611-614. 

The beneficial effect of curcumin in preventing the acute renal failure and related oxidative stress caused by chronic administration of cyclosporine was examined in rats (Tirkey et al. 2005). Curciunin administered concurrently with for 21 days effectively attenuated cyclosporine induced nephrotoxicity through its antioxidant activity as revealed by markedly countered elevated levels of TEARS, attenuated renal dysfunction, and increased levels of antioxidant enzymes. 

Methotrexate has been used successfully with cyclosporine, either concurrently34 or in rotation. Rotational therapy is particularly effective since it minimizes the serious adverse effects of both agents hepatotoxidty from methotrexate and hypertension and nephrotoxicity from cyclosporine. Having an overlapping treatment period may not be necessary and patients have been successfully switched after a 1-week washout period.21,35 This is a very useful combination of systemic agents in the longterm management of this chronic disease. 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

Chamey, D., Solez, K., Rascusen, L. (2004). Nephrotoxicity of cyclosporine and other immunosuppressive and immunothera-peutic agents. In Toxicology of Kidney, 3rd edition (J.B. Hook, J.B. Tarloff, L.H. Lash, eds). CRC Press, Boca Raton FL. Choie, D.D., Longnecker, D.S., Del Capmo, A.A. (1981). Acute and chronic cisplatin nephropathy in rats. Lab. Invest. 44(5) 397 02. 

N. A. Bobadilla, G. Gamba, E. Tapia, R. Garcia-Torres, A. Bolio, P. Lopez-Zetina, et al.. Role of No in Cyclosporin Nephrotoxicity Effects of Chronic No Inhibition and No Synthases Gene Expression, Am J Physiol 11A (1998) F791-8. 

Extensive expression of KlM-1 has been found in proximal tubule cells in biopsies from patients with acute tubular necrosis [302]. KlM-1 is also expressed in other conditions where proximal tubules are dedifferentiated, including renal cell carcinoma [303, 304], chronic cyclosporine nephrotoxicity [305], a protein-overload model of tubulointerstitial disease [306], polycystic kidney disease [307], and contrast nephropathy. In several chronic conditions, KlM-1 has been found primarily expressed at the luminal side of dedifferentiated proximal tubules, in areas with fibrosis and inflammation. Independent of the specific disease, renal KIM-1 correlated positively with the extent of renal damage and negatively with renal function. In these patients, urinary levels of KIM-1 were and correlated positively with tissue KIM-1 and negatively with renal function. Thus, KIM-1 is upregulated in renal disease and is associated with renal fibrosis and inflammation. Urinary KIM-1 is also associated with inflammation and renal function, and reflects tissue KIM-1. 

Perez-Rojas J, Blanco JA, Cruz C, Trujillo J, Vaidya VS, Uribe N, Bonventre JV, Gamba G, Bobadilla NA Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am J Physiol Renal Physiol 292 FI 31 -FI 39,... 

Yang CW, Faulkner GR, Wahba IM, Christianson TA, Bagby GC, Jin DC, Abboud HE, Andoh TF, and Bennett WM. Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice. Am JTransplant 2 391-399,2002. 

Bobadilla NA, Gamba G,Tapia E, Garcia-Torres R, Bolio A, Lopez-Zetina P, Herrera-Acosta J. Role of NO in cyclosporin nephrotoxicity effects of chronic NO inhibition and NO synthases gene expression. Am J Physiol 1998 274 F791-F798. 

AndohTF, Gardner MP, Bennett WM. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity.Transplantation 1997 64 1236-1240. 

Coffman TM, Carr DR, Yarger WE, Klotman PE. Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity.Transplantation 1987 43 282-285. 

Flunley TE, Fogo A, Iwasaki S, Kon V. Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity. J Am Soc Nephrol 1995 5 1718-1723. 

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