Prevention of complications from use of conventional immunosuppressants: a critical review

  • Claudio PonticelliEmail author
  • Richard J. Glassock


Synthetic immunosuppressive drugs are largely used in immune-related renal diseases and in kidney transplantation. Most of these drugs have a low therapeutic index (the ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective), which means that the drug should be dosed carefully and the patient monitored frequently. In this review, we consider the categories of synthetic immunosuppressive agents more frequently and conventionally used in clinical nephrology: glucocorticoids, Aalkylating agents (cyclophosphamide, chlorambucil), purine synthesis inhibitors (azathioprine, mycophenolate salts) and calcineurin inhibitors (cyclosporine, tacrolimus). For each category the possible side effects will be reviewed, the general and specific measures to prevent or treat the adverse events will be suggested, and the more common mistakes that may increase the risk of toxicity will be described. However, the efficacy and safety of immunosuppressive agents depend not only on the pharmacologic characteristics of single drugs but can be influenced also by the clinical condition and genetic characteristics of the patient, by the typology and severity of the underlying disease and by the interaction with other concomitantly used drugs.


Glucocorticoids Calcineurin inhibitors Cyclophosphamide Mycophenolic acid Immunosuppression 


Compliance with ethical standards

Conflict of interest

Dr Ponticelli has no conflict of interest to disclose. Dr. Glassock is a compensated consultant to Bristol-Myers Squibb, Genentech, Chemocentryx, Mallinckrodt, Apellis, Ionis, Achillion, Omeros. He also receives a stipend from Wolters -Kluwer (UpToDate) and Karger Publications (American Journal of Nephrology and Nephrology Viewpoints) for Editorial Services. He owns stock in REATA, Inc. (Bardoxolone).

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.


  1. 1.
    Granner DK, Wang JC, Yamamoto KR (2015) Regulatory actions of glucocorticoid hormones: from organisms to mechanisms. Adv Exp Med Biol 872:3–31CrossRefPubMedGoogle Scholar
  2. 2.
    Panettieri RA, Schaafsma D, Amrani Y, Koziol-White C, Ostrom R, Tliba O (2019) Non-genomic effects of glucocorticoids: an updated view. Trends Pharmacol Sci 40(1):38–49CrossRefPubMedGoogle Scholar
  3. 3.
    Tornatore KM, Logue G, Venuto RC, Davis PJ (1997) Cortisol pharmacodynamics after methylprednisolone administration in young and elderly males. J Clin Pharmacol 37(4):304–311CrossRefPubMedGoogle Scholar
  4. 4.
    Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden YM, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G (2013) Reduced cortisol metabolism during critical illness. N Engl J Med 368(16):1477–1488CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Moroni G, Ponticelli C (2014) Rapidly progressive crescentic glomerulonephritis: early treatment is a must. Autoimmun Rev 13(7):723–729CrossRefPubMedGoogle Scholar
  6. 6.
    Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J, Darzy K, Merke DP, Arlt W, Ross RJ (2009) Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 94:1548–1554CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Peckett AJ, Wright DC, Riddell MC (2011) The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism 60:1500–1510CrossRefPubMedGoogle Scholar
  8. 8.
    Shen Y, Roh HC, Kumari M, Rosen ED (2017) Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding. Mol Metab 6(10):1150–1160CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kim HJ, Cha JY, Seok JW, Choi Y, Yoon BK, Choi H, Yu JH, Song SJ, Kim A, Lee H, Kim D, Han JY, Kim JW (2016) Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis. Sci Rep 6:28648CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Berthon BS, MacDonald-Wicks LK, Wood LG (2014) A systematic review of the effect of oral glucocorticoids on energy intake, appetite, and body weight in humans. Nutr Res 34:179–190CrossRefPubMedGoogle Scholar
  11. 11.
    Cannon CP, Kumar A (2009) Treatment of overweight and obesity: lifestyle, pharmacologic, and surgical options. Clin Cornerstone 9(4):55–68CrossRefPubMedGoogle Scholar
  12. 12.
    Liu XX, Zhu XM, Miao Q, Ye HY, Zhang ZY, Li YM (2014) Hyperglycemia induced by glucocorticoids in nondiabetic patients: a meta-analysis. Ann Nutr Metab 65(4):324–332CrossRefPubMedGoogle Scholar
  13. 13.
    Burt MG, Willenberg VM, Petersons CJ, Smith MD, Ahern MJ, Stranks SN (2012) Screening for diabetes in patients with inflammatory rheumatological disease administered long-term prednisolone: a cross-sectional study. Rheumatology (Oxford) 51(6):1112–1119CrossRefGoogle Scholar
  14. 14.
    Trinkley KE, Anderson HD, Nair KV, Malone DC, Saseen JJ (2018) Assessing the incidence of acidosis in patients receiving metformin with and without risk factors for lactic acidosis. Ther Adv Chronic Dis 9(9):179–190CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Donnan K, Segar L (2019) SGLT2 inhibitors and metformin: dual antihyperglycemic therapy and the risk of metabolic acidosis in type 2 diabetes. Eur J Pharmacol 5(846):23–29CrossRefGoogle Scholar
  16. 16.
    Gunaratne K, Austin E, Wu PE (2018) Unintentional sulfonylurea toxicity due to a drug–drug interaction: a case report. BMC Res Notes 11(1):331CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Villanueva G, Baldwin D (2005) Rosiglitazone therapy of posttransplant diabetes mellitus. Transplantation 80:1402–1405CrossRefPubMedGoogle Scholar
  18. 18.
    Shorter DE, Armstrong PW (2000) Adverse effects of corticosteroids on the cardiovascular system. Can J Cardiol 16(4):505–511Google Scholar
  19. 19.
    Meng X, Chen X, Wu L, Zheng S (2017) The hyperlipidemia caused by overuse of glucocorticoid after liver transplantation and the immune adjustment strategy. J Immunol Res 2017:3149426CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Choi HK, Seeger JD (2005) Glucocorticoid use and serum lipid levels in US adults: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 53:528–535CrossRefPubMedGoogle Scholar
  21. 21.
    Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H (2013) A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 9(1):30CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM, REDUCE-it investigators (2019) Cardiovascular risk reduction with Icosapent Ethyl Hypertriglyceridemia. N Engl J Med 380(1):11–22CrossRefPubMedGoogle Scholar
  23. 23.
    Coelho MC, Dos Santos CV, Vieira Neto L, Gadelha MR (2014) Adverse effects of glucocorticoids: coagulopathy. Eur J Endocrinol 173:M11–M21CrossRefGoogle Scholar
  24. 24.
    Mantero F, Boscaro M (1992) Glucocorticoid-dependent hypertension. J Steroid Biochem Mol Biol 43(5):409–413CrossRefPubMedGoogle Scholar
  25. 25.
    Sato A, Funder JW, Okubo M, Kubota E, Saruta T (1995) Glucocorticoid-induced hypertension in the elderly. Relation to serum calcium and family history of essential hypertension. Am J Hypertens 8(8):823–828CrossRefPubMedGoogle Scholar
  26. 26.
    Yang S, Zhang L (2004) Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2(1):1–12CrossRefPubMedGoogle Scholar
  27. 27.
    Slama M, Susic D, Frohlich ED (2002) Prevention of hypertension. Curr Opin Cardiol 17(5):531–536CrossRefPubMedGoogle Scholar
  28. 28.
    Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP (2009) Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Meatab 102(5):703–708Google Scholar
  29. 29.
    Walker BR (2007) Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157:545–559CrossRefPubMedGoogle Scholar
  30. 30.
    Borst O, Schaub M, Walker B, Schmid E, Münzer P, Voelkl J, Alesutan I, Rodríguez JM, Vogel S, Schoenberger T, Metzger K, Rath D, Umbach A, Kuhl D, Müller II, Seizer P, Geisler T, Gawaz M, Lang F (2015) Pivotal role of serum- and glucocorticoid-inducible kinase 1 in vascular inflammation and atherogenesis. Arterioscler Thromb Vasc Biol 35:547–557CrossRefPubMedGoogle Scholar
  31. 31.
    Wei L, MacDonald TM, Walker BR (2004) Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 141:764–770CrossRefPubMedGoogle Scholar
  32. 32.
    Christiansen CF, Christensen S, Mehnert F, Cummings SR, Chapurlat RD, Sørensen HT (2009) Glucocorticoid use and risk of atrial fibrillation or flutter: a population-based, case–control study. Arch Intern Med 169:1677–1683CrossRefPubMedGoogle Scholar
  33. 33.
    Moretti R, Torre P, Antonello RM, Zorzon M, Cazzato G (2000) Recurrent atrial fibrillation associated with pulse administration of high doses of methylprednysolone: a possible prophylactic treatment. Eur J Neurol 7(1):130CrossRefPubMedGoogle Scholar
  34. 34.
    Stuck AE, Minder CE, Frei FJ (1989) Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 11(6):954–963CrossRefPubMedGoogle Scholar
  35. 35.
    Wolfe F, Caplan L, Michaud K (2006) Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 54(2):628–634CrossRefPubMedGoogle Scholar
  36. 36.
    Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG (2017) Prevention and management of glucocorticoid-induced side effects: A comprehensive review: Infectious complications and vaccination recommendations. J Am Acad Dermatol 76(2):191–198CrossRefPubMedGoogle Scholar
  37. 37.
    Herrou J, De Lastours V (2018) Predictive factors of pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids. Ann Rheum Dis. (Epub ahead of print)
  38. 38.
    Conn HO, Poynard T (1994) Corticosteroids and peptic ulcer: meta-analysis of adverse events during steroid therapy. J Intern Med 236:619–632CrossRefPubMedGoogle Scholar
  39. 39.
    Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM (2015) Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab 100:2171–2180CrossRefPubMedGoogle Scholar
  40. 40.
    West S, Kenedi C (2014) Strategies to prevent the neuropsychiatric side-effects of corticosteroids: a case report and review of the literature. Curr Opin Organ Transpl 19(2):201–208CrossRefGoogle Scholar
  41. 41.
    Frenkel B, White W, Tuckermann J (2015) Glucocorticoid-induced osteoporosis. Adv Exp Med Biol 872:179–215CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Buckley L, Humphrey MB (2018) Glucocorticoid-induced osteoporosis. N Engl J Med 379(26):2547–2556CrossRefPubMedGoogle Scholar
  43. 43.
    Ding H, Wang T, Xu D, Cha B, Liu J, Li Y (2015) Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation. Biochem Biophys Res Commun 460:157–163CrossRefPubMedGoogle Scholar
  44. 44.
    Allen CS, Yeung JH, Vandermeer B, Homik J (2016) Bisphosphonates for steroid-induced osteoporosis. Cochrane Database Syst Rev 10:Cd001347Google Scholar
  45. 45.
    Khaleeli AA, Edwards RH, Gohil K, McPhail G, Rennie MJ, Round J, Ross EJ (1983) Corticosteroid myopathy: a clinical and pathological study. Clin Endocrinol (Oxf) 18:155–166CrossRefGoogle Scholar
  46. 46.
    Pereira RM, Freire de Carvalho J (2011) Glucocorticoid-induced myopathy. Joint Bone Spine 78:41–44CrossRefPubMedGoogle Scholar
  47. 47.
    Carli L, Tani C, Querci F, Della Rossa A, Vagnani S, Baldini C, Talarico R, d’Ascanio A, Neri R, Tavoni AG, Bombardieri S, Mosca M (2013) Analysis of the prevalence of cataracts and glaucoma in systemic lupus erythematosus and evaluation of the rheumatologists’ practice for the monitoring of glucocorticoid eye toxicity. Clin Rheumatol 32(7):1071–1073CrossRefPubMedGoogle Scholar
  48. 48.
    Richmond E, Rogol AD (2016) Treatment of growth hormone deficiency in children, adolescents and at the transitional age. Best Pract Res Clin Endocrinol Metab 30(6):749–755CrossRefPubMedGoogle Scholar
  49. 49.
    Luo X, Hou L, Liang L, Dong G, Shen S, Zhao Z, Gong CX, Li Y, Du ML, Su Z, Du H, Yan C (2017) Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies. Eur J Endocrinol 177(2):195–205CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zhai JL, Ge N, Zhen Y, Zhao Q, Liu C (2016) Corticosteroids significantly increase serum cystatin c concentration without affecting renal function in symptomatic heart failure. Clin Lab 62(1–2):203–207PubMedGoogle Scholar
  51. 51.
    Reichert LJ, Koene RA, Wetzels JF (1999) Acute haemodynamic and proteinuric effects of prednisolone in patients with a nephrotic syndrome. Nephrol Dial Transpl 14(1):91CrossRefGoogle Scholar
  52. 52.
    Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V, Sbardella E, Gianfrilli D, Pozza C, Pasqualetti P, Morrone S, Santoni A, Naro F, Colao A, Pivonello R, Lenzi A (2018) Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diab Endocrinol 6(3):173–185Google Scholar
  53. 53.
    Ponticelli C, Locatelli F (2018) Glucocorticoids in the treatment of glomerular diseases: pitfalls and pearls. Clin J Am Soc Nephrol 13(5):815–822CrossRefPubMedGoogle Scholar
  54. 54.
    Liu J, Li X, Fan L, Yang J, Wang J, Sun J, Wang Z (2019) Proton pump inhibitors therapy and risk of bone diseases: an update meta-analysis. Life Sci 218:213–223CrossRefPubMedGoogle Scholar
  55. 55.
    Helsby NA, Hui CY, Goldthorpe MA, Coller JK, Soh MC, Gow PJ, De Zoysa JZ, Tingle MD (2010) The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation. Br J Clin Pharmacol 70(6):844–853Google Scholar
  56. 56.
    Ponticelli C, Escoli R, Moroni G (2018) Does cyclophosphamide still play a role in glomerular diseases? Autoimmun Rev 17(10):1022–1027CrossRefPubMedGoogle Scholar
  57. 57.
    Martin F, Lauwerys B, Lefèbvre C, Devogelaer JP, Houssiau FA (1997) Side-effects of intravenous cyclophosphamide pulse therapy. Lupus 6(3):254–257CrossRefPubMedGoogle Scholar
  58. 58.
    Woytala PJ, Morgiel E, Łuczak A, Czesak-Woytala K, Wiland P (2016) The safety of intravenous cyclophosphamide in the treatment of rheumatic diseases. Adv Clin Exp Med 25(3):479–484CrossRefPubMedGoogle Scholar
  59. 59.
    Herbert LA, Rovin BH (2010) Oral cyclophosphamide is on the verge of extinction as therapy for severe autoimmune diseases (especially lupus): should nephrologists care? Nephron Clin Pract 117(1):c8–c14CrossRefGoogle Scholar
  60. 60.
    Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group (2009) Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 20(5):1103–1112CrossRefGoogle Scholar
  61. 61.
    Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, Baslund B (2008) Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol 35:100–105PubMedGoogle Scholar
  62. 62.
    Yilmaz N, Emmungil H, Gucenmez S, Ozen G, Yildiz F, Balkarli A, Kimyon G, Coskun BN, Dogan I, Pamuk ON, Yasar S, Cetin GY, Yazici A, Ergulu Esmen S, Cagatay Y, Yilmaz S, Cefle A, Sayarlioglu M, Kasifoglu T, Karadag O, Pehlivan Y, Dalkilic E, Kisacik B, Cobankara V, Erken E, Direskeneli H, Aksu K, Yavuz S (2015) Incidence of cyclophosphamide-induced urotoxicity and protective effect of mesna in rheumatic diseases. J Rheumatol 42:1664–1666CrossRefGoogle Scholar
  63. 63.
    Kim S, Choi HJ, Jo CH, Park JS, Kwon TH, Kim GH (2015) Cyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney. Am J Physiol Renal Physiol 309:F474–F483CrossRefPubMedGoogle Scholar
  64. 64.
    Esposito P, Domenech MV, Serpieri N, Calatroni M, Massa I, Avella A, La Porta E, Estienne L, Caramella E, Rampino T (2017) Severe cyclophosphamide-related hyponatremia in a patient with acute glomerulonephritis. World J Nephrol 6:217–220CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Sterns RH, Silver SM (2006) Brain volume regulation in response to hypo-osmolality and its correction. Am J Med 119(Suppl 1):S12–S16CrossRefPubMedGoogle Scholar
  66. 66.
    Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E; Hyponatraemia Guideline Development Group (2014) Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transpl 29[Suppl 2]: i1–i39Google Scholar
  67. 67.
    Appenzeller S, Blatyta PF, Costallat LT (2008) Ovarian failure in SLE patients using pulse cyclophosphamide: comparison of different regimes. Rheumatol Int 28:567–571CrossRefPubMedGoogle Scholar
  68. 68.
    Tamirou F, Husson SN, Gruson D, Debiève F, Lauwerys BR, Houssiau FA (2017) Brief report: the euro-lupus low-dose intravenous cyclophosphamide regimen does not impact the ovarian reserve, as measured by serum levels of anti-müllerian hormone. Arthritis Rheumatol 69:1267–1271CrossRefPubMedGoogle Scholar
  69. 69.
    Latta K, von Schnakenburg C, Ehrich JH (2001) A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Ped Nephrol 16:271–282CrossRefGoogle Scholar
  70. 70.
    Meistrich ML (2009) Male gonadal toxicity. Pediatr Blood Cancer 53:261–266CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Ghobadi E, Moloudizargari M, Asghari MH, Abdollahi M (2017) The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents. Expert Opin Drug Metab Toxicol 13:525–536CrossRefPubMedGoogle Scholar
  72. 72.
    Koyama H, WadaT Nishikawa Y, Iwanaga T, Aoki Y (1977) Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 39(4):1403–1409CrossRefPubMedGoogle Scholar
  73. 73.
    Hasky N, Uri-Belapolsky S, Goldberg K, Miller I, Grossman H, Stemmer SM, Ben-Aharon I, Shalgi R (2015) Gonadotrophin-releasing hormone agonists for fertility preservation: unraveling the enigma? Hum Reprod 30:1089–1101CrossRefPubMedGoogle Scholar
  74. 74.
    Nishikawa T, Miyahara E, Kurauchi K, Watanabe E, Ikawa K, Asaba K, Tanabe T, Okamoto Y, Kawano Y (2015) Mechanisms of Fatal cardiotoxicity following high-dose cyclophosphamide therapy and a method for its prevention. PLoS ONE 10:e0131394CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Usui Y, Aida H, Kimula Y, Miura H, Aoyagi Y, Nakayama M, Takayama S (1992) A case of cyclophosphamide-induced interstitial pneumonitis diagnosed by bronchoalveolar lavage. Respiration 59(2):125–128CrossRefPubMedGoogle Scholar
  76. 76.
    Barnes H, Holland AE, Westall GP, Goh NS, Glaspole IN (2018) Cyclophosphamide for connective tissue disease-associated interstitial lung disease. Cochrane Database Syst Rev 1:CD010908Google Scholar
  77. 77.
    Ochoa R, Bejarano PA, Glück S, Montero AJ (2012) Pneumonitis and pulmonary fibrosis in a patient receiving adjuvant docetaxel and cyclophosphamide for stage 3 breast cancer: a case report and literature review. J Med Case Rep 6:413Google Scholar
  78. 78.
    Shang W, Ning Y, Xu X et al (2015) Incidence of cancer in ANCA-associated vasculitis: a meta-analysis of observational studies. PLoS One 10:e0126016CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hemminki K, Liu X, Ji J, Försti A (2016) Origin of B-cell neoplasms in autoimmune disease. PLoS One 11:e0158360CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Ponticelli C, Escoli R, Moroni G (2018) Fetal toxicity of immunosuppressive drugs in pregnancy. J Clin Med 17(10):1022–1027Google Scholar
  81. 81.
    Staatz CE, Tett SE (2007) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 46(1):13–58CrossRefPubMedGoogle Scholar
  82. 82.
    Zhang D, Chow DS (2017) Clinical Pharmacokinetics of mycophenolic acid in hematopoietic stem cell transplantation recipients. Eur J Drug Metab Pharmacokinet 42(2):183–189CrossRefPubMedGoogle Scholar
  83. 83.
    de Jong DJ, Goullet M, Naber TH (2004) Side effects of azathioprine in patients with Crohn’s disease. Eur J Gastroenterol Hepatol 16(2):207–212CrossRefPubMedGoogle Scholar
  84. 84.
    Moran GW, Dubeau MF, Kaplan GG, Yang H, Eksteen B, Ghosh S, Panaccione R (2015) Clinical predictors of thiopurine-related adverse events in Crohn’s disease. World J Gastroenterol 21(25):7795–7804Google Scholar
  85. 85.
    Regueiro M, Mardini H (2002) Determination of thiopurine methyltransferase genotype or phenotype optimizes initial dosing of azathioprine for the treatment of Crohn’s disease. J Clin Gastroenterol 35(3):240–244CrossRefPubMedGoogle Scholar
  86. 86.
    Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE (1993) Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 34(8):1081–1085CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Corominas H, Domènech M, González-Juan D, González-Suárez B, Díaz C, Pujol J, Vázquez G, Baiget M (2000) Aplasia after azathioprine administration: role of the thiopurine methyltransferase genetic polymorphism. Med Clin (Barc) 115(8):299–301CrossRefGoogle Scholar
  88. 88.
    Pruijt JF, Haanen JB, Hollander AA, den Ottolander GJ (1996) Azathioprine-induced pure red-cell aplasia. Nephrol Dial Transpl 11(7):1371–1373Google Scholar
  89. 89.
    Ohmann EL, Burckart GJ, Brooks MM, Chen Y, Pravica V, Girnita DM, Zeevi A, Webber SA (2010) Genetic polymorphisms influence mycophenolate mofetil-related adverse events in pediatric heart transplant patients. J Heart Lung Transpl 29(5):509–516CrossRefGoogle Scholar
  90. 90.
    Varnell CD, Fukuda T, Kirby CL, Martin LJ, Warshaw BL, Patel HP, Chand DH, Barletta GM, Van Why SK, VanDe Voorde RG, Weaver DJ, Wilson A, Verghese PS, Vinks AA, Greenbaum LA, Goebel J, Hooper DK (2010) Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: influence of genes and drugs. Pediatr Transpl 21(7).
  91. 91.
    Rerolle JP, Szelag JC, Le Meur Y (2007) Unexpected rate of severe leucopenia with the association of mycophenolate mofetil and valganciclovir in kidney transplant recipients. Nephrol Dial Transpl 22(2):671–672Google Scholar
  92. 92.
    Hardinger KL, Brennan DC, Lowell J, Schnitzler MA (2004) Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int 17(10):609–616CrossRefPubMedGoogle Scholar
  93. 93.
    Manger B, Hiepe F, Schneider M, Worm M, Wimmer P, Paulus EM, Schwarting A (2015) Impact of switching from mycophenolate mofetil to enteric-coated mycophenolate sodium on gastrointestinal side effects in patients with autoimmune disease: a Phase III, open-label, single-arm, multicenter study. Clin Exp Gastroenterol 8:205–213CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Siramolpiwat S, Sakonlaya D (2017) Clinical and histologic features of Azathioprine-induced hepatotoxicity. Scand J Gastroenterol 52:876–880CrossRefPubMedGoogle Scholar
  95. 95.
    Musumba CO (2013) Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy. Aliment Pharmacol Ther 38:1025–37Google Scholar
  96. 96.
    Hantash B, Fiorentino D (2006) Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil. Arch Dermatol 142:109–110PubMedGoogle Scholar
  97. 97.
    Loupy A, Anglichaeu D, Mamzer-Bruneel MF, Martinez F, Thervet E, Legendre C, Serpaggi J, Pol S (2006) Mycophenolate sodium-induced hepatotoxicity: first report. Transplantation 82(4):581CrossRefPubMedGoogle Scholar
  98. 98.
    Kawasaki Y (2009) Mizoribine: a new approach in the treatment of renal diseases. Clin Dev Immunol 2009:681482CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Floyd A, Pedersen L, Nielsen GL, Thorlacius-Ussing O, Sorensen HT (2003) Risk of acute pancreatitis in users of azathioprine: a population-based case-control study. Am J Gastroenterol 98:1305–1308PubMedGoogle Scholar
  100. 100.
    Elli A, Aroldi A, Montagnino G, Tarantino A, Ponticelli C (1998) Mycophenolate mofetil and cough. Transplantation 66(3):409CrossRefPubMedGoogle Scholar
  101. 101.
    Maes B, Oellerich M, Ceuppens JL, Armstrong VW, Evenepoel P, Kuypers D, Messiaen T, Shipkova M, Wieland E, Vanrenterghem Y (2002) A new acute inflammatory syndrome related to the introduction of mycophenolate mofetil in patients with Wegener’s granulomatosis. Nephrol Dial Transpl 17:923–926CrossRefGoogle Scholar
  102. 102.
    Moreso F, Seron D, Morales JM, Cruzado JM, Gil-Vernet S, Pérez JL, Fulladosa X, Andrés A, Grinyó JM (1998) Incidence of leukopenia and cytomegalovirus disease in kidney transplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses. Clin Transpl 12:198–205Google Scholar
  103. 103.
    Borni-Duval C, Caillard S, Olagne J, Perrin P, Braun-Parvez L, Heibel F, Moulin B (2013) Risk factors for BK virus infection in the era of therapeutic drug monitoring. Transplantation 95(12):1498–1505CrossRefPubMedGoogle Scholar
  104. 104.
    Aleissa M, Nicol P, Godeau M, Tournier E, de Bellissen F, Robic MA, Livideanu CB, Mazereeuw-Hautier J, Paul C (2017) Azathioprine hypersensitivity syndrome: two cases of febrile neutrophilic dermatosis induced by azathioprine. Case Rep Dermatol 9:6–11CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Volgger B, Marth C, Zeimet A, Müller-Holzner E, Ruth N, Dapunt O (1997) Fulminant course of a microinvasive vulvar carcinoma in an immunosuppressed woman. Gynecol Oncol 65(1):177–179CrossRefPubMedGoogle Scholar
  106. 106.
    Weaver JL (2012) Establishing the carcinogenic risk of immunomodulatory drugs. Toxicol Pathol 40:267–271CrossRefPubMedGoogle Scholar
  107. 107.
    Perez HC, Benavides X, Perez JS, Pabon MA, Tschen J, Maradei-Anaya SJ, Lopez L, Lozano E (2017) Basic aspects of the pathogenesis and prevention of non-melanoma skin cancer in solid organ transplant recipients: a review. Int J Dermatol 56(4):370–378CrossRefPubMedGoogle Scholar
  108. 108.
    Casetta I, Iuliano G, Filippini G (2007) Azathioprine for multiple sclerosis. Cochrane Database Syst Rev 4:CD003982Google Scholar
  109. 109.
    Dun B, Sharma A, Teng Y, Liu H, Purohit S, Xu H, Zeng L, She JX (2013) Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways. PLoS One 8:e81702CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Ponticelli C, Moroni G (2015) Immunosuppression in pregnant women with systemic lupus erythematosus. Expert Rev Clin Immunol 11(5):549–552CrossRefPubMedGoogle Scholar
  111. 111.
    O’Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O’Neill EA (1992) FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357:692–694CrossRefPubMedGoogle Scholar
  112. 112.
    Staatz CE, Goodman LK, Tett SE (2010) Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin Pharmacokinet 49(3):141–175CrossRefPubMedGoogle Scholar
  113. 113.
    Vanhove T, Annaert P, Kuypers DR (2016) Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metab Rev 48(1):88–112CrossRefPubMedGoogle Scholar
  114. 114.
    Vanhove T, Remijsen Q, Kuypers D, Gillard P (2017) Drug-drug interactions between immunosuppressants and antidiabetic drugs in the treatment of post-transplant diabetes mellitus. Transpl Rev (Orlando) 31(2):69–77CrossRefGoogle Scholar
  115. 115.
    Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier A, Ponticelli C, Saito T, Choukroun G, Nachman P, Praga M, Yoshikawa N (2007) Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome: workshop recommendations. Kidney Int 72(12):1429–1447Google Scholar
  116. 116.
    Naesens M, Kuypers DR, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4(2):481–508Google Scholar
  117. 117.
    Burdmann EA, Andoh TF, Yu L, Bennett WM (2003) Cyclosporine nephrotoxicity. Semin Nephrol 23:465–476CrossRefPubMedGoogle Scholar
  118. 118.
    Griffiths MH, Crowe AV, Papadaki L, Banner NR, Yacoub MH, Thompson FD, Neild GH (1996) Cyclosporin nephrotoxicity in heart and lung transplant patients. QJM 89(10):751–763Google Scholar
  119. 119.
    Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM (1996) Chronic cyclosporine nephropathy: the Achilles’ heel of immunosuppressive therapy. Kidney Int 50(4):1089–1100CrossRefPubMedGoogle Scholar
  120. 120.
    Issa N, Kukla A, Ibrahim HN (2013) Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am J Nephrol 37(6):602–612CrossRefPubMedGoogle Scholar
  121. 121.
    Curtis JJ (2002) Hypertensinogenic mechanism of the calcineurin inhibitors. Curr Hypertens Rep 4(5):377–380CrossRefPubMedGoogle Scholar
  122. 122.
    Blankenstein KI, Borschewski A, Labes R et al (2017) Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms. Am J Physiol Renal Physiol 312:F489–F501CrossRefPubMedGoogle Scholar
  123. 123.
    Robert N, Wong GW, Wright JM (2010) Effect of cyclosporine on blood pressure. Cochrane Database Syst Rev 1:CD007893Google Scholar
  124. 124.
    Grześk E, Malinowski B, Wiciński M et al (2016) Cyclosporine-A, but not tacrolimus significantly increases reactivity of vascular smooth muscle cells. Pharmacol Rep 68:201–205CrossRefPubMedGoogle Scholar
  125. 125.
    Klein IH, Abrahams A, van Ede T, Hene RJ, Koomans HA, Ligtenberg G (2002) Different effects of tacrolimus andcyclosporine on renal hemodynamic and blood pressure in healthy subjects. Transplantation 73:732CrossRefPubMedGoogle Scholar
  126. 126.
    Ponticelli C, Cucchiari D (2017) Renin-angiotensin system inhibitors in kidney transplantation: a benefit-risk assessment. J Nephrol 30(2):155–157CrossRefPubMedGoogle Scholar
  127. 127.
    Kuypers DR, Neumayer HH, Fritsche L, Budde K, Rodicio JL, Vanrenterghem Y (2004) Lacidipine Study Group. Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study. Transplantation 78(8):1204–1211Google Scholar
  128. 128.
    Øzbay LA, Smidt K, Mortensen DM Carstens J, Jørgensen KA, Rungby J (2011) Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. Br J Pharmacol 162: 136–146Google Scholar
  129. 129.
    Chakkera HA, Kudva Y, Kaplan B (2017) Calcineurin inhibitors: pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus. Clin Pharmacol Ther 101:114–120CrossRefPubMedGoogle Scholar
  130. 130.
    Li Z, Sun F, Zhang Y, Chen H, He N, Chen H, Song P, Wang Y, Yan S, Zheng S (2015) Tacrolimus induces insulin resistance and increases the glucose absorption in the jejunum: a potential mechanism of the diabetogenic effects. PLoS One 10:e0143405CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Triñanes J, Rodriguez-Rodriguez AE, Brito-Casillas Y, Wagner A, De Vries APJ, Cuesto G, Acebes A, Salido E, Torres A, Porrini E (2017) Deciphering tacrolimus-induced toxicity in pancreatic β cells. Am J Transpl 17(11):2829–2840CrossRefGoogle Scholar
  132. 132.
    Rao SR, Sundararajan S, Subbarayan R, Murugan Girija D (2017) Cyclosporine-A induces endoplasmic reticulum stress and influences pro-apoptotic factors in human gingival fibroblasts. Mol Cell Biochem 429:179–185CrossRefPubMedGoogle Scholar
  133. 133.
    Nash MM, Zalztman JS (1998) Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients. Transplantation 65(12):1611–1615CrossRefPubMedGoogle Scholar
  134. 134.
    Hirsch R, Deng H, Laohachai MN (2012) Azithromycin in periodontal treatment: more than an antibiotic. J Periodontal Res 47(2):137–148Google Scholar
  135. 135.
    Sen A, Callisen H, Libricz S, Patel B (2019) Complications of solid organ transplantation: cardiovascular, neurologic, renal, and gastrointestinal. Crit Care Clin 35(1):169–186CrossRefPubMedGoogle Scholar
  136. 136.
    Ponticelli C, Campise R (2005) Neurological complications in kidney transplant recipients. J Nephrol 18:521–528PubMedGoogle Scholar
  137. 137.
    Song T, Rao Z, Tan Q, Qiu Y, Liu J, Huang Z, Wang X, Lin T (2016) Calcineurin inhibitors associated posterior reversible encephalopathy syndrome in solid organ transplantation: report of 2 cases and literature review. Medicine (Baltimore) 95:e3173CrossRefGoogle Scholar
  138. 138.
    Kockx M, Glaros E, Leung B, Ng TW, Berbée JF, Deswaerte V, Nawara D, Quinn C, Rye KA, Jessup W, Rensen PC, Meikle PJ, Kritharides L (2016) Low-density lipoprotein receptor-dependent and low-density lipoprotein receptor-independent mechanisms of cyclosporin a-induced dyslipidemia. Arterioscler Thromb Vasc Biol 36(7):1338–1349CrossRefPubMedGoogle Scholar
  139. 139.
    Suk HY, Zhou C, Yang TT, Zhu H, Yu RY, Olabisi O, Yang X, Brancho D, Kim JY, Scherer PE, Frank PG, Lisanti MP, Calvert JW, Lefer DJ, Molkentin JD, Ghigo A, Hirsch E, Jin J, Chow CW (2013) Ablation of calcineurin Aβ reveals hyperlipidemia and signaling cross-talks with phosphodiesterases. J Biol Chem 288:3477–3488CrossRefPubMedGoogle Scholar
  140. 140.
    Fuhrmann A, Lopes P, Sereno J, Pedro J, Espinoza DO, Pereira MJ, Reis F, Eriksson JW, Carvalho E (2014) Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model. Biochem Pharmacol 88:216–228CrossRefPubMedGoogle Scholar
  141. 141.
    Brocks DR, Chaudhary HR, Ben-Eltriki M, Elsherbiny ME, El-Kadi AO (2014) Effects of serum lipoproteins on cyclosporine. A cellular uptake and renal toxicity in vitro. Can J Physiol Pharmacol 92:140–148CrossRefPubMedGoogle Scholar
  142. 142.
    Clarke H, Ryan MP (1999) Cyclosporine A-induced alterations in magnesium homeostasis in the rat. Life Sci 64(15):1295–1306CrossRefPubMedGoogle Scholar
  143. 143.
    Lea JP, Sands JM, McMahon SJ, Tumlin J (1994) Evidence that the inhibition of Na+/K(+)-ATPase activity by FK506 involves calcineurin. Kidney Int 46:647–652Google Scholar
  144. 144.
    Osorio JM, Bravo J, Pérez A, Ferreyra C, Osuna A (2010) Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transpl Proc 42(8):2910–2913Google Scholar
  145. 145.
    Stamp L, Searle M, O’Donnell J, Chapman P (2005) Gout in solid organ transplantation: a challenging clinical problem. Drugs 65(18):2593–2611CrossRefPubMedGoogle Scholar
  146. 146.
    Piccoli GB, Cabiddu G, Attini R, Gerbino M, Todeschini P, Perrino ML, Mone AM, Piredda GB, Gnappi E, Caputo F et al (2016) Pregnancy outcomes after kidney graft in Italy: are the changes over time the result of different therapies or of different policies? A nationwide survey (1978–2013). Nephrol Dial Transpl 31:1957–1965CrossRefGoogle Scholar
  147. 147.
    Thiagarajan KM, Arakali SR, Mealey KJ, Cardonick EH, Gaughan WJ, Davison JM, Moritz MJ, Armenti VT (2013) Safety considerations: breastfeeding after transplant. Prog. Transpl 23:137–146CrossRefGoogle Scholar
  148. 148.
    Euvrard S,Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, Broeders N, del Marmol V, Chatelet V, Dompmartin A, Kessler M, Serra AL, Hofbauer GF, Pouteil-Noble C, Campistol JM, Kanitakis J, Roux AS, Decullier E, Dantal J; TUMORAPA Study Group (2014). Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 367(4):329–339Google Scholar
  149. 149.
    Liacini A, Seamone ME, Muruve DA, Tibbles LA (2010) Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation 90:1450–1457CrossRefPubMedGoogle Scholar

Copyright information

© Italian Society of Nephrology 2019

Authors and Affiliations

  1. 1.Division of NephrologyIstituto Scientifico Ospedale MaggioreMilanItaly
  2. 2.MilanItaly
  3. 3.The David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA

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