Abstract
Cyclosporine A (CsA) is a widely used calcineurin inhibitor essential for immunosuppression in solid organ and hematopoietic stem cell transplantation (HSCT), immune-mediated bone marrow failure, and autoimmune diseases. Although highly efficacious as an immunosuppressive agent, its use is associated with clinically significant cardiovascular and metabolic adverse effects, most prominently hypertension and hyperlipidemia. These adverse effects arise through well-characterized mechanisms, including renal vasoconstriction, endothelial dysfunction, and alterations in lipid metabolism. Advanced practice providers (APPs) play a crucial role in the longitudinal care of patients receiving cyclosporine and must possess a comprehensive understanding of these complications to optimize patient outcomes. While CsA also has notable effects of nephrotoxicity, hepatotoxicity, and neurotoxicity, these will not be discussed in this review. Synthesizing current peer-reviewed literature, this practical guide examines the pathophysiologic mechanisms underlying CsA-induced hypertension and hyperlipidemia, outlines evidence-based monitoring strategies, and provides clinically actionable management recommendations tailored to the APP’s scope of practice across oncology, transplant, and immunology settings.
References
Asberg, A., Christensen, H., Hartmann, A., Carlson, E., Molden, E., & Berg, K. J. (1999). Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients. European Journal of Clinical Pharmacology, 55(5), 383–387. https://doi.org/10.1007/s002280050644
Avdonin, P. V., Cottet-Maire, F., Afanasjeva, G. V., Loktionova, S. A., Lhote, P., & Ruegg, U. T. (1999). Cyclosporine A up-regulates angiotensin II receptors and calcium responses in human vascular smooth muscle cells. Kidney International, 55(6), 2407–2414. https://doi.org/10.1046/j.1523-1755.1999.00481.x
Bader, F. M., Hagan, M. E., Crompton, J. A., & Gilbert, E. M. (2005). The effect of beta-blocker use on cyclosporine level in cardiac transplant recipients. The Journal of Heart and Lung Transplantation, 24(12), 2144–2147. https://doi.org/10.1016/j.healun.2005.05.002
Ballantyne, C. M., Radovancevic, B., Farmer, J. A., Frazier, O. H., Chandler, L., Payton-Ross, C., Cocanougher, B., Jones, P. H., Young, J. B., & Gotto, A. M. (1992). Hyperlipidemia after heart transplantation: Report of a 6-year experience, with treatment recommendations. Journal of the American College of Cardiology, 19(6), 1315–1321. https://doi.org/10.1016/0735-1097(92)90340-S
Bleck, J. S., Thiesemann, C., Kliem, V., Christians, U., Hecker, H., Repp, H., Frei, U., Westhoff-Bleck, M., Manns, M., & Sewing, K. F. (1996). Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients. British Journal of Clinical Pharmacology, 41(6), 551–556. https://doi.org/10.1046/j.1365-2125.1996.34412.x
Carey, R. M., Calhoun, D. A., Bakris, G. L., Brook, R. D., Daugherty, S. L., Dennison-Himmelfarb, C. R., Egan, B. M., Flack, J. M., Gidding, S. S., Judd, E., Lackland, D. T., Laffer, C. L., Newton-Cheh, C., Smith, S. M., Taler, S. J., Textor, S. C., Turan, T. N., & White, W. B. (2018). Resistant hypertension: Detection, evaluation, and management: A scientific statement from the American Heart Association. Hypertension, 72(5), e53–e90. https://doi.org/10.1161/HYP.0000000000000084
Chambers, H. E., Reinschmidt, K., Smith, G., Agudelo, E., Brodahl, K., Herriman, E., Hoy, H., Pont, K., Seawright, A., Stearns, E., Torres, A. M., Weldon, E., & Blackstock, D. M. (2021). Examining the critical role of advanced practice providers on a multidisciplinary transplant team. American Journal of Transplantation, 21(12), 3840–3846. https://doi.org/10.1111/ajt.16715
Cross, N. B., Webster, A. C., Masson, P., O’Connell, P. J., & Craig, J. C. (2009). Antihypertensive treatment for kidney transplant recipients. Cochrane Database of Systematic Reviews, 2009(3), Article CD003598. https://doi.org/10.1002/14651858.CD003598.pub2
Curtis, J. J. (1992). Cyclosporine and posttransplant hypertension. Journal of the American Society of Nephrology, 2(12 Suppl.), S243–S245. https://doi.org/10.1681/ASN.V212s243
Esposito, C., Fornoni, A., Cornacchia, F., Bellotti, N., Fasoli, G., Foschi, A., Mazzucchelli, I., Mazzullo, T., Semeraro, L., & Dal Canton, A. (2000). Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures. Kidney International, 58(1), 123–130. https://doi.org/10.1046/j.1523-1755.2000.00147.x
Grundy, S. M., Stone, N. J., Bailey, A. L., Beam, C., Birtcher, K. K., Blumenthal, R. S., Braun, L. T., de Ferranti, S., Faiella-Tommasino, J., Forman, D. E., Goldberg, R., Heidenreich, P. A., Hlatky, M. A., Jones, D. W., Lloyd-Jones, D., Lopez-Pajares, N., Ndumele, C. E., Orringer, C. E., Peralta, C. A., . . . Yeboah, J. (2019). 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation, 139(25), e1082–e1143. https://doi.org/10.1161/CIR.0000000000000625
Halloran, P. F. (2004). Immunosuppressive drugs for kidney transplantation. The New England Journal of Medicine, 351(26), 2715–2729. https://doi.org/10.1056/NEJMra033540
Holdaas, H., Fellström, B., Jardine, A. G., Holme, I., Nyberg, G., Fauchald, P., Grönhagen-Riska, C., Madsen, S., Neumayer, H. H., Cole, E., Maes, B., Ambühl, P., Olsson, A. G., Hartmann, A., Solbu, D. O., & Pedersen, T. R. (2003). Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial. The Lancet, 361(9374), 2024–2031. https://doi.org/10.1016/S0140-6736(03)13638-0
Hoorn, E. J., Walsh, S. B., McCormick, J. A., Fürstenberg, A., Yang, C. L., Roeschel, T., Paliege, A., Howie, A. J., Conley, J., Bachmann, S., Unwin, R. J., & Ellison, D. H. (2011). The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nature Medicine, 17(10), 1304–1309. https://doi.org/10.1038/nm.2497
Kang, N. R., Lee, J. E., Huh, W., Kim, S. J., Kim, Y. G., Kim, D. J., & Oh, H. Y. (2009). Minimal proteinuria one year after transplant is a risk factor for graft survival in kidney transplantation. Journal of Korean Medical Science, 24(Suppl. 1), S129–S134. https://doi.org/10.3346/jkms.2009.24.S1.S129
Kaye, D., Thompson, J., Jennings, G., & Esler, M. (1993). Cyclosporine therapy after cardiac transplantation causes hypertension and renal vasoconstriction without sympathetic activation. Circulation, 88(3), 1101–1109. https://doi.org/10.1161/01.CIR.88.3.1101
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. (2009). KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation, 9(Suppl. 3), S1–S155. https://doi.org/10.1111/j.1600-6143.2009.02834.x
Knight, S. R., & Morris, P. J. (2007). The clinical benefits of cyclosporine C2-level monitoring: A systematic review. Transplantation, 83(12), 1525–1535. https://doi.org/10.1097/01.tp.0000268306.41196.2c
Kobashigawa, J. A., & Kasiske, B. L. (1997). Hyperlipidemia in solid organ transplantation. Transplantation, 63(3), 331–338. https://doi.org/10.1097/00007890-199702150-00001
Leenen, F. H. H., Coletta, E., & Davies, R. A. (2007). Prevention of renal dysfunction and hypertension by amlodipine after heart transplant. The American Journal of Cardiology, 100(3), 531–535. https://doi.org/10.1016/j.amjcard.2007.03.058
Lucini, D., Milani, R. V., Ventura, H. O., Mehra, M. R., Messerli, F., & Pagani, M. (2000). Study of arterial and autonomic effects of cyclosporine in humans. Hypertension, 35(6), 1258–1263. https://doi.org/10.1161/01.HYP.35.6.1258
Lungu, A. O., Jin, Z. G., Yamawaki, H., Tanimoto, T., Wong, C., & Berk, B. C. (2004). Cyclosporin A inhibits flow-mediated activation of endothelial nitric-oxide synthase by altering cholesterol content in caveolae. Journal of Biological Chemistry, 279(47), 48794–48800. https://doi.org/10.1074/jbc.M313897200
Mangray, M., & Vella, J. P. (2011). Hypertension after kidney transplant. American Journal of Kidney Diseases, 57(2), 331–341. https://doi.org/10.1053/j.ajkd.2010.10.048
Marshall, A. L., Masselink, L. E., Kouides, P. A., Davies, F. E., Farooqui, A., Nagalla, S., Herrera, A., Mortier, N., Brodsky, R., & Erikson, C. E. (2024). Advanced practice providers in hematology: Actionable findings from national paired APP and physician surveys. Blood Advances, 8(5), 1179–1189. https://doi.org/10.1182/bloodadvances.2023011927
Meyer-Lehnert, H., & Schrier, R. W. (1989). Potential mechanism of cyclosporine A-induced vascular smooth muscle contraction. Hypertension, 13(4), 352–360. https://doi.org/10.1161/01.HYP.13.4.352
Momoniat, T., Ilyas, D., & Bhandari, S. (2019). ACE inhibitors and ARBs: Managing potassium and renal function. Cleveland Clinic Journal of Medicine, 86(9), 601–607. https://doi.org/10.3949/ccjm.86a.18024
Muduma, G., Saunders, R., Odeyemi, I., & Pollock, R. F. (2016). Systematic review and meta-analysis of tacrolimus versus ciclosporin as primary immunosuppression after liver transplant. PLOS ONE, 11(11), Article e0160421. https://doi.org/10.1371/journal.pone.0160421
Navarro-Antolín, J., Redondo-Horcajo, M., Zaragoza, C., Alvarez-Barrientos, A., Fernández, A. P., León-Gómez, E., Rodrigo, J., & Lamas, S. (2007). Role of peroxynitrite in endothelial damage mediated by cyclosporine A. Free Radical Biology and Medicine, 42(3), 394–403. https://doi.org/10.1016/j.freeradbiomed.2006.11.008
Neuvonen, P. J., Niemi, M., & Backman, J. T. (2006). Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance. Clinical Pharmacology & Therapeutics, 80(6), 565–581. https://doi.org/10.1016/j.clpt.2006.09.003
Novartis Pharmaceuticals Corporation. Sandimmune (cyclosporine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
Ojo, A. O. (2006). Cardiovascular complications after renal transplantation and their prevention. Transplantation, 82(5), 603–611. https://doi.org/10.1097/01.tp.0000235527.81917.fe
Pascual, M., Curtis, J., Delmonico, F. L., Farrell, M. L., Williams, W. W., Kalil, R., Jones, P., Cosimi, A. B., & Tolkoff-Rubin, N. (2003). A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation. Transplantation, 75(9), 1501–1505. https://doi.org/10.1097/01.TP.0000061606.64917.BE
Penninga, L., Møller, C. H., Gustafsson, F., Steinbrüchel, D. A., & Gluud, C. (2010). Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: Systematic review with meta-analyses and trial sequential analyses of randomised trials. European Journal of Clinical Pharmacology, 66(12), 1177–1187. https://doi.org/10.1007/s00228-010-0902-6
Pickard, T., Williams, S., Tetzlaff, E., Petraitis, C., & Hylton, H. (2023). Team-based care in oncology: The impact of the advanced practice provider. American Society of Clinical Oncology Educational Book, 43, Article e390572. https://doi.org/10.1200/EDBK_390572
Rangaswami, J., Mathew, R. O., Parasuraman, R., Tantisattamo, E., Lubetzky, M., Rao, S., Yaqub, M. S., Birdwell, K. A., Bennett, W., Dalal, P., Kapoor, R., Lerma, E. V., Lerman, M., McCormick, N., Bangalore, S., McCullough, P. A., & Dadhania, D. M. (2019). Cardiovascular disease in the kidney transplant recipient: Epidemiology, diagnosis and management strategies. Nephrology Dialysis Transplantation, 34(5), 760–773. https://doi.org/10.1093/ndt/gfz053
Scherrer, U., Vissing, S. F., Morgan, B. J., Rollins, J. A., Tindall, R. S., Ring, S., Hanson, P., Mohanty, P. K., & Victor, R. G. (1990). Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. The New England Journal of Medicine, 323(11), 693–699. https://doi.org/10.1056/NEJM199009133231101
Tantisattamo, E., Molnar, M.Z., Ho, B.T., Reddy, U. G., Dafoe, D. C., Ichii, H., Ferrey, A. J., Hanna, R. M., Kalantar-Zadeh, K., & Amin, A. (2020). Approach and management of hypertension after kidney transplantation. Frontiers in Medicine, 7, Article 229, https://doi.org/10.3389/fmed.2020.00229
Textor, S. C., Canzanello, V. J., Taler, S. J., Wilson, D. J., Schwartz, L. L., Augustine, J. E., Raymer, J. M., Romero, J. C., Wiesner, R. H., & Krom, R. A. (1994). Cyclosporine-induced hypertension after transplantation. Mayo Clinic Proceedings, 69(12), 1182–1193. https://doi.org/10.1016/S0025-6196(12)65772-3
Vaziri, N. D., Ni, Z., Zhang, Y. P., Ruzics, E. P., Maleki, P., & Ding, Y. (1998). Depressed renal and vascular nitric oxide synthase expression in cyclosporine-induced hypertension. Kidney International, 54(2), 482–491. https://doi.org/10.1046/j.1523-1755.1998.00014.x
Vaziri, N. D., Liang, K., & Azad, H. (2000). Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions. Journal of Pharmacology and Experimental Therapeutics, 294(2), 778–783.
Whelton, P. K., Carey, R. M., Aronow, W. S., Casey, D. E., Collins, K. J., Dennison Himmelfarb, C., DePalma, S. M., Gidding, S., Jamerson, K. A., Jones, D. W., MacLaughlin, E. J., Muntner, P., Ovbiagele, B., Smith, S. C., Spencer, C. C., Stafford, R. S., Taler, S. J., Thomas, R. J., Williams, K. A., . . . Wright, J. T. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 71(19), e127–e248. https://doi.org/10.1016/j.jacc.2017.11.006
Wiggins, B. S., Saseen, J. J., Page, R. L., II, Reed, B. N., Sneed, K., Kostis, J. B., Lanfear, D., Virani, S., & Morris, P. B. (2016). Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: A scientific statement from the American Heart Association. Circulation, 134(21), e468–e495. https://doi.org/10.1161/CIR.0000000000000456
