Chronic cyclosporine A-nephrotoxicity: functional characteristics, pathology and clinical manifestations in long-term kidney graft recipients

The results of 99 kidney transplant biopsies performed in Moscow research Institute of Transplantation and Artificial Organs and Moscow City Nephrological center (Municipal hospital № 52) are discussed. Indications for biopsy were graft dysfunction and/or proteinuria in all cases. Pathology findings were compared with cyclosporine A (CsA) pharmacokinetic profile (area under the curve, AUC) and sodium tubular transport measured by fractional lithium clearance (Cli/Ccr). Peripheral nodular arteriolohyalinosis was considered as main morphological marker of chronic CsA toxicity. There was statistically significant correlation between degree of peripheral nodular arteriolohyalinosis and AUC or Cli/Ccr. There was no correlation between degree of non-specific arteriolohyalinosis and AUC or Cli/Ccr. These results confirm the significance of peripheral nodular arteriolohyalinosis as marker of chronic CsA toxicity. The diagnosis of chronic CsA-nephropathy was extracted and validated from chronic allograft nephropathy diagnosis. CsA-nephropathy was present in 33,3% of transplant biopsies and was characterized by interstitial fibrosis, tubular atrophy and peripheral nodular arteriolohyalinosis morphologically, and by severe hypertension and moderate proteinuria clinically.

трансплантация почки, циклоспорин А, фармакокинетика, патоморфология нефротоксичности, артериологиалиноз, проксимальный канальцевый транспорт натрия

1. Котенко О.Н. Ренальная дисфункция почечного аллотрансплантата при применении циклоспорина А. Автореф. дисс. … канд. мед. наук. М., 1997.

2. Малов И.П. Гистологическое и иммуноморфологическое исследование аллотрансплантированных почек в позднем послеоперационном периоде. Автореф. дисс. … канд. мед. наук. М., 2002.

3. Никоненко Т.Н., Гриценко С.Н., Поляков Н.Н. Морфологический мониторинг аллотрансплантированных трупных почек. Вестник трансплантологии и искусств. органов 2002; 2: 28-33.

4. Ратнер М.Я., Серов В.В., Томилина Н.А. Ренальные дисфункции. М.: Медицина, 1977.

5. Столяревич Е.С. Хроническая трансплантационная нефропатия: клинико-морфологические сопоставления и факторы прогрессирования. Автореф. дисс. … канд. мед. наук. М., 2002.

6. Трансплантология. Руководство под ред. В.И. Шумакова. М.: Медицина, 1995.

7. Ader J.L., Tack I., Lloveras J.J., Tran-Van T. et al. Renal functional reserve in cyclosporin-treated recipients of kidney transplant. Kidney Int 1994; 45 (6): 1657-1667.

8. Benigni A., Bruzzi I., Mister M. et al. Nature and mediators of renal lesions in kidney transplant patients given cyclosporine for more than one year. Kidney Int 1999; 55 (2): 674-685.

9. Bennett W.B., deMattos A., Meyer M.M. et al. Chronic cyclosporine nephropathy: The Achille’s heel of immunosuppressive therapy. Kidney Int 1996; 50: 1089-1100.

10. Chomette G., Auriol M., Beaufils H. et al. Morphology of cyclosporine nephrotoxicity in human heart transplant recipients. J Heart Transplant 1986; 5 (4): 273-278.

11. Chomette G., Auriol M., Beaufils H. et al. C. Renal lesions induced by cyclosporin. Apropos of 4 renal biopsies and 22 necropsies of recipients of heart transplant Ann Pathol 1986; 6 (1): 29-36.

12. Feria I., Pichardo I., Juarez P. et al. Therapeutic benefit of spironolactone in experimental сhronic cyclosporine A nephrotoxicity. Kidney Int 2003; 63 (1): 43-52.

13. Feutren G., Mihatsch M.J. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N Engl J Med 1992; 326: 1654-1660.

14. Haas M., Meehan S.M., Josephson M.A. et al. Smooth muscle-specific actin levels in the urine of renal transplant recipients: correlation with cyclosporine or tacrolimus nephrotoxicity. Am J of Kidney Dis 1999; 34 (1): 69-84.

15. Halloran P., Melk A., Barth C. Rethinking Chronic Allograft Nephropathy The Concept of Accelerated Senescence. J Am Soc Nephrol 1999; 10: 167-181.

16. Kirk A.J.B., Omar I., Bateman D.N., Dark J.H. Cyclosporine-associated hypertension in cardiopulmonary transplantation. Transplantation 1989; 48: 428-430.

17. Kumar K.V., Naidu M.U., Shifow A.A. et al. Melatonin: an antioxidant protects against cyclosporine-induced nephrotoxicity. Transplantation 1999; 67 (7): 1065-1068.

18. Laine J., Krogerus L., Jalanko H. et al. Renal allograft histology and correlation with function in children on triple therapy. Nephrol Dial Transplant. 1995; 10 (1): 95-102.

19. deMattos A.M., Olyaei A.J., Bennett W.M. Nephrotoxicity of immunosuppressive drugs: Long-term consequences and challenges for the future. Am J Kidney Dis 2000; 35; 21: 333-334.

20. Mihatsch M.J., Gudat F., Ryffel B., Thiel G. Cyclosporine Nephropathy in Renal Pathology with Clinical and Functional Correlations, 2-n edition, J.B. Lippincott Company, Philadelphia: 1994: 1660.

21. Mihatsch M.J., Morozumi K., Strom E.H. et al. Renal transplant morphology after long-term therapy with cyclosporine. Transplant Proc 1995; 27: 39.

22. Monaco A.P., Burke J.F., Ferguson R.M., Halloran P.F. et al. Current thinking on chronic renal allograft rejection: Issues, concerns, and recommendations from a 1997 round table discussion Am J of Kidney Diseases 1999; 33; 1: 150-160.

23. Morozumi K., Thiel G., Albert F.W. et al. Studies on morphological outcome of cyclosporine-associated arteriolopathy after discontinuation of cyclosporine in renal allografts. Clin Nephrol 1992; 38 (1): 1-8.

24. Pilmore H.L., Dittmer I.D. Calcineurin inhibitor nephrotoxicity: reduction in dose results in marked improvement in renal function in patients with coexisting chronic allograft nephropathy. Clin Transplant 2002; 16 (3): 191-194.

25. Racusen L.C., Solez K., Colvin R.B., Bonsib S.M. et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55 (2): 713-723.

26. Shihab F.S. Cyclosporine nephropathy: pathophysiology and clinical impact. Semin Nephrol 1996; 16 (6): 536-547.

27. Shihab F.S., Andon T.F., Tanner A.M. et al. Role of transforming growth factor-β1 in experimental chronic cyclosporine nephropathy. Kidney Int 1996; 49: 1141-1151.

28. Shibab F.S., Bennett W.M. et al. Angiotensin II blockade decreases TGF-β1 and matrix proteins in cyclosporine nephropathy. Kidney Int 1997, 52: 660-673.

29. Strom E.H., Thiel G., Mihatch M.J. Prevalence of cyclosporine-associated arteriolopathy in renal transplant biopsies from 1981 to 1992. Transplant Proc 1994; 26: 2585-2586.

30. Takeda A., Uchida K., Haba T. et al. Chronic cyclosporin nephropathy: long-term effects of cyclosporin on renal allografts. Clin Transplant 2001; 15 Suppl 5: 22-29.

31. Toki K., Kyo M., Takahara S., Morozumi K. et al. Arteriolopathy in non-episode biopsies of renal transplant allograft. Clin Transplant 2000; 14 Suppl 3: 21-24.

32. Thomsen K., Schou M. Renal lithium clearance in man. Am J Physiol 1969; 215: 823-827.

33. Young B.A., Burdmann E.A., Johnson R.J. et al. Cyclosporine A induced arteriolopathy in a rat model of chronic cyclosporine nephropathy. Kidney Int 1995; 48 (2): 431-438.UNOS-Transplantation Resource (http://www.unos.org/).