Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Renal effects of targeted anticancer therapies

Nature Reviews Nephrology volume 11, pages 354–370 (2015)Cite this article

Subjects

Key Points

  • Adverse events from novel anticancer targeted agents represent a growing problem for oncologists and nephrologists, who should cooperate to recognize, understand and adequately treat toxic effects

  • The management of novel targeted anticancer agents in patients with chronic kidney disease or receiving haemodialysis is challenging because of a shortage of specific data

  • Recognition and prompt and proactive management of kidney toxic effects is necessary to aid in the proper administration of life-prolonging oncological treatments

  • Nephrologists and oncologists should initially treat renal toxic effects related to targeted anticancer agents according to available guidelines, because oncological patients do not necessarily differ from other patients with nephropathy

  • A subspeciality of onconephrology urgently needs to develop, as only close cooperation and cultural change will improve the management and outcomes of patients with both cancer and kidney disease

Abstract

The use of novel targeted anticancer agents has led to overall improvement in the prognosis of many patients affected by various malignancies, but has also been associated with an increased risk of poorly characterized toxic effects to different organs, including the kidneys. The high prevalence of kidney impairment in the general population complicates the issue further. Nephrologists most frequently work with patients with cancer when they are asked to investigate kidney function to assess the need for dose adjustments in anticancer therapy. A thorough knowledge of the renal safety profile of novel life-prolonging anticancer therapies, specific features of their metabolism, and pharmacokinetic and pharmacodynamic properties (under normal circumstances as well as in the setting of renal replacement therapy) is, therefore, necessary to preserve kidney function as far as possible and to ensure optimum treatment. In this Review we summarize the present knowledge of renal toxic effects from novel targeted anticancer agents and discuss whether the management of patients' treatment needs to be modified. We also advocate the development of a new onconephrology subspeciality.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Launay-Vacher, V. et al. Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: the Renal Insufficiency and Anticancer Medications (IRMA) study. Cancer 110, 1376–1384 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Launay-Vacher, V. Epidemiology of chronic kidney disease in cancer patients: lessons from the IRMA study group. Semin. Nephrol. 30, 548–556 (2010).

    Article  PubMed  Google Scholar 

  3. Christiansen, C. F., Johansen, M. B., Lengeberg, W. J., Fryzek, J. P. & Sørensen, H. T. Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study. Eur. J. Intern. Med. 22, 399–406 (2011).

    Article  PubMed  Google Scholar 

  4. Maw, T. T. & Fried, L. Chronic kidney disease in the elderly. Clin. Geriat. Med. 29, 611–624 (2013).

    Article  Google Scholar 

  5. Murthy, V. H., Krumholz, H. M. & Gross, C. P. Participation in cancer clinical trials: race, sex, and age-based disparities. JAMA 291, 2720–2726 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Unger, J. M. et al. Comparison of survival outcomes among cancer patients treated in and out of clinical trial. J. Natl. Cancer Inst. 106, dju002 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  7. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0 [online], (2009).

  8. Porta, C. et al. Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries. Cancer Med. 3, 1517–1526 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Chu, Q. S. Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin. Biol. Ther. 9, 263–271 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Chow, L. Q. & Eckhardt, S. G. Sunitinib: from rational design to clinical efficacy. J. Clin. Oncol. 25, 884–896 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Sonpavde, G. & Hutson, T. E. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr. Oncol. Rep. 9, 115–119 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Bukowski, R. M. Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma. Front. Oncol. 2, 13 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Izzedine, H., Rixe, O., Billemont, B., Baumelou, A. & Deray, G. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am. J. Kidney Dis. 50, 203–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Syrigos, K. N., Karapanagiotou, E., Boura, P., Manegold, C. & Harrington, K. Bevacizumab-induced hypertension: pathogenesis and management. Biodrugs 25, 159–169 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Sugimoto, H. et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J. Biol. Chem. 278, 12605–12608 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Stylianou, K. et al. Crescentic glomerulonephritis associated with vascular endothelial growth factor (VEGF) inhibitor and bisphosphonate administration. Nephrol. Dial. Transplant. 26, 1742–1745 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. George, B. A., Zhou, X. J. & Toto, R. Nephrotic syndrome after bevacizumab: case report and literature review. Am. J. Kidney Dis. 49, e23–e29 (2007).

    Article  PubMed  Google Scholar 

  19. Eremina, V. et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358, 1129–1136 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zachary, I. Signaling mechanism mediating vascular protective actions of vascular endothelial growth factor. Am. J. Physiol. 280, C1375–C1386 (2001).

    Article  CAS  Google Scholar 

  21. Mourad, J. J., des Guetz, G., Debbabi, H. & Levy, B. I. Blood pressure rise following angiogenesis inhibition by bevacizumab: a crucial role for microcirculation. Ann. Oncol. 19, 927–934 (2008).

    Article  PubMed  Google Scholar 

  22. Yao, S. K. et al. Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation 86, 1302–1309 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Hicklin, D. J. & Ellis L. M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 23, 1011–1027 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Mancia, G. et al. 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J. Hypertens. 25, 1751–1762 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Izzedine, H. et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann. Oncol. 20, 807–815 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. BC Cancer Agency Cancer Management Guidelines. Management guidelines of bevacizumab-related side effects in patients with colorectal cancer [online], (2006).

  27. Porta, C., Paglino, C., Imarisio, I. & Bonomi, L. Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents: the case of sorafenib and sunitinib. Clin. Exp. Med. 7, 127–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. MacFarlane, R. et al. The impact of kidney function on the outcome of metastatic renal cell carcinoma patients treated with vascular endothelial growth factor-targeted therapy. Cancer 118, 365–370 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Khosravan, R. et al. Pharmacokinetics and safety of sunitinib malate in subjects with impaired renal function. J. Clin. Pharmacol. 50, 472–481 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Gupta, S. et al. Safety and efficacy of targeted agents in metastatic kidney cancer patients with renal dysfunction. Anticancer Drugs 22, 794–800 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Méndez-Vidal, M. J., Martínez Ortega, E., Montesa Pino, A., Pérez Valderrama, B. & Viciana, R. Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma. Cancer Metastasis Rev. 31 (Suppl. 1), S19–S27 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Garnier-Viougeat, N. et al. Pharmacokinetics of bevacizumab in haemodialysis. Nephrol. Dial. Transplant. 22, 975 (2007).

    Article  PubMed  Google Scholar 

  33. Izzedine, H., Etienne-Grimaldi, M. C., Renée, N., Vignot, S. & Milano, G. Pharmacokinetics of sunitinib in hemodialysis. Ann. Oncol. 20, 190–192 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Masini, C. et al. Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey. BJU Int. 110, 692–698 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Shetty, A. V. et al. Outcomes of patients with metastatic renal cell carcinoma and end-stage renal disease receiving dialysis and targeted therapies: a single institution experience. Clin. Genitourin. Cancer 12, 348–353 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Porta, C., Paglino, C., Imarisio, I. & Ferraris, E. Sorafenib tosylate in advanced kidney cancer: past, present and future. Anticancer Drugs 20, 409–415 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Wilhelm, S. M. et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Crona, D. J., Keisler, M. D. & Walko, C. M. Regorafenib: a novel multitargeted tyrosine kinase inhibitor for colorectal cancer and gastrointestinal stromal tumors. Ann. Pharmacother. 47, 1685–1696 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Ryan, A. J. & Wedge, S. R. ZD6474–a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br. J. Cancer 92 (Suppl. 1), S6–S13 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bellini, E. et al. Sorafenib may induce hypophosphatemia through a fibroblast growth factor-23 (FGF23)-independent mechanism. Ann. Oncol. 22, 988–990 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Mir, O., Coriat, R., Boudou-Rouquette, P., Durand, J. P. & Goldwasser, F. Sorafenib-induced diarrhea and hypophosphatemia: mechanisms and therapeutic implications. Ann. Oncol. 23, 280–281 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Shen, H., Yang, Z., Zhao, W., Zhang, Y. & Rodrigues, A. D. Assessment of vandetanib as an inhibitor of various human renal transporters: inhibition of multidrug and toxin extrusion as a possible mechanism leading to decreased cisplatin and creatinine clearance. Drug Metab. Dispos. 41, 2095–2103 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Morrissey, K. M., Stocker, S. L., Wittwer, M. B., Xu, L. & Giacomini, K. M. Renal transporters in drug development. Annu. Rev. Pharmacol. Toxicol. 53, 503–529 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Miller, A. A. et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J. Clin. Oncol. 27, 1800–1805 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Parsa, V., Heilbrun, L., Smith, D., Sethi, A. & Vaishampayan, U. Safety and efficacy of sorafenib therapy in patients with metastatic kidney cancer with impaired renal function. Clin. Genitourin. Cancer 7, E10–E15 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Khan, G. et al. Sunitinib and sorafenib in metastatic renal cell carcinoma patients with renal insufficiency. Ann. Oncol. 21, 1618–1622 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Ferraris, E. et al. Use of sorafenib in two metastatic renal cell cancer patients with end-stage renal impairment undergoing replacement hemodialysis. Tumori 95, 542–544 (2009).

    Article  PubMed  Google Scholar 

  48. Kennoki, T. et al. Clinical results and pharmacokinetics of sorafenib in chronic hemodialysis patients with metastatic renal cell carcinoma in a single center. Jpn. J. Clin. Oncol. 41, 647–655 (2011).

    Article  PubMed  Google Scholar 

  49. Weil, A. et al. Pharmacokinetics of vandetanib in subjects with renal or hepatic impairment. Clin. Pharmacokinet. 49, 607–618 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Buchdunger, E., O'Reilly, T. & Wood, J. Pharmacology of imatinib (STI571). Eur. J. Cancer 38 (Suppl. 5), S28–S36 (2002).

    Article  PubMed  Google Scholar 

  51. Wang-Rosenke, Y. et al. Tyrosine kinase inhibition by imatinib slows progression in chronic ant-thy1 glomerulosclerosis of the rat. BMC Nephrol. 14, 223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Elmholdt, T. R., Buus, N. H., Ramsing, M. & Olesen, A. B. Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: an open-label non-randomized, uncontrolled clinical trial. J. Eur. Acad. Dermatol. Venereol. 27, 779–784 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Wallace, E. & Gewin, L. Imatinib: novel treatment of immune-mediated kidney injury. J. Am. Soc. Nephrol. 24, 694–701 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Wallace, E., Fogo, A. B. & Schulman, G. Imatinib therapy for non-infection-related type II cryoglobulinemia with membranoproliferative glomerulonephritis. Am. J. Kidney Dis. 59, 122–125 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Chandran, S. et al. Imatinib in the treatment of nephrogenic systemic fibrosis. Am. J. Kidney Dis. 53, 129–132 (2009).

    Article  PubMed  Google Scholar 

  56. Savikko, J., Rintala, J. M., Rintala, S. E., Koskinen, P. K. & von Willebrand. E. Early short-term imatinib treatment is sufficient to prevent the development of chronic allograft nephropathy. Nephrol. Dial. Transplant. 26, 3026–3032 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Iyoda, M. et al. Long and short-term treatment with imatinib attenuates the development of chronic kidney disease in experimental anti-glomerular basement membrane nephritis. Nephrol. Dial. Transplant. 28, 576–584 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Peng, B., Lloyd, P. & Schran, H. Clinical pharmacokinetics of imatinib. Clin. Pharmacokinet. 44, 879–894 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Gibbons, J. et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J. Clin. Oncol. 26, 570–576 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Judson, I. R. Imatinib for patients with liver or kidney dysfunction: no need to modify the dose. J. Clin. Oncol. 26, 521–522 (2008).

    Article  PubMed  Google Scholar 

  61. Tong, W. G. et al. Imatinib front-line therapy is safe and effective in patients with chronic myelogenous leukemia with pre-existing liver and/or renal dysfunction. Cancer 116, 3152–3159 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Demetri, G. D. et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J. Clin. Oncol. 31, 2485–2492 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Porta, C., Paglino, C. & Mosca, A. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol. 4, 64 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Vogelbacher, R., Wittmann, S., Braun, A., Daniel, C. & Hugo, C. The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation 84, 1492–1499 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Baas, M. C. et al. Cyclosporine versus everolimus: effects on the glomerulus. Clin. Transplant. 27, 535–540 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Keller, K. et al. Everolimus inhibits glomerular endothelial cell proliferation and VEGF, but not long-term recovery in experimental thrombotic microangiopathy. Nephrol. Dial. Transplant. 21, 2724–2735 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Nakagawa, S., Nishihara, K., Inui, K. & Masuda, S. Involvement of autophagy in the pharmacological effects of the mTOR inhibitor everolimus in acute kidney injury. Eur. J. Pharmacol. 696, 143–154 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Hiatt, W. R., Nissen, S. E. & Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration. New drug application 21–628, Certican (everolimus), for the proposed indication of prophylaxis of rejection in heart transplantation: report from the Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration, November 16, 2005, Rockville, Md. Circulation 113, e394–e395 (2006).

    Article  PubMed  Google Scholar 

  69. Bertoni, E. et al. Posttransplant proteinuria associated with everolimus. Transplant Proc. 41, 1216–1217 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Schmidinger, M. & Bellmunt, J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat. Rev. 36, 416–424 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Oroszlán, M. et al. Sirolimus and everolimus reduce albumin endocytosis in proximal tubule cells via an angiotensin II-dependent pathway. Transpl. Immunol. 23, 125–132 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Rodriguez-Pascual, J., Cheng, E., Maroto, P. & Duran, I. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs 21, 478–486 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Barthélémy, P. et al. mTOR inhibitors in advanced renal cell carcinomas: from biology to clinical practice. Crit. Rev. Oncol. Hematol. 88, 42–56 (2013).

    Article  PubMed  Google Scholar 

  74. Porta, C. et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur. J. Cancer 47, 1287–1298 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Aapro, M. et al. Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. Ann. Oncol. 25, 763–773 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Thiery-Vuillemin, A. et al. Hemodialysis does not affect everolimus pharmacokinetics: two cases of patients with metastatic renal cell cancer. Ann. Oncol. 23, 2992–2993 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. van Rooijen, J. M. & de Vries, E. G. Hemodialysis: no reason to withhold everolimus. Cancer Chemother. Pharmacol. 71, 273–274 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Lunardi, G. et al. Comparison of temsirolimus pharmacokinetics in patients with renal cell carcinoma not receiving dialysis and those receiving hemodialysis: a case series. Clin. Ther. 31, 1812–1819 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Rosell, R. et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958–967 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Ciardiello, F. & Tortora, G. Anti-epidermal growth factor receptor drugs in cancer therapy. Expert Opin. Investig. Drugs 11, 755–768 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Voets, T. et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J. Biol. Chem. 279, 19–25 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Groenestege, W. M. et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J. Clin. Invest. 117, 2260–2267 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fakih, M. G., Wilding, G. & Lombardo, J. Cetuximab-induced hypomagnesemia in patients with colorectal cancer. Clin. Colorectal Cancer 6, 152–156 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Tejpar, S. et al. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol. 8, 387–394 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Schrag, D., Chung, K. Y., Flombaum, C. & Saltz, L. Cetuximab therapy and symptomatic hypomagnesemia. J. Natl. Cancer Inst. 97, 1221–1224 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Izzedine, H. et al. Electrolyte disorders related to EGFR-targeting drugs. Crit. Rev. Oncol. Hematol. 73, 213–219 (2010).

    Article  PubMed  Google Scholar 

  87. Fakih, M. G. Management of anti-EGFR-targeting monoclonal antibody-induced hypomagnesemia. Oncology 22, 74–76 (2008).

    PubMed  Google Scholar 

  88. Maliakal, P. & Ledford. A. Electrolyte and protein imbalance following anti-EGFR therapy in cancer patients: a comparative study. Exp. Ther. Med. 1, 307–311 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Dimke, H. et al. Effects of the EGFR inhibitor erlotinib on magnesium handling. J. Am. Soc. Nephrol. 21, 1309–1316 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Costa, A., Tejpar, S., Prenen, H. & Van Cutsem, E. Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents. Target. Oncol. 6, 227–233 (2011).

    Article  PubMed  Google Scholar 

  91. Krens, L. L. et al. Pharmacokinetics and safety of cetuximab in a patient with renal dysfunction. Cancer Chemother. Pharmacol. 73, 1303–1306 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Aldoss, I. T., Plumb, T., Zhen, W. K., Lydiatt, D. D. & Ganti, A. K. Cetuximab in hemodialysis: a case report. Head Neck 31, 1647–1650 (2009).

    Article  PubMed  Google Scholar 

  93. Fontana, E., Pucci, F. & Ardizzoni, A. Colorectal cancer patient on maintenance dialysis successfully treated with cetuximab. Anticancer Drugs 25, 120–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Koch, T. et al. Antibody-dependent cellular cytotoxicity in patients on chronic hemodialysis. Am. J. Nephrol. 38, 379–387 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Rossi, A. et al. Safety profile of gefitinib in advanced non-small cell lung cancer elderly patients with chronic renal failure: two clinical cases. Lung Cancer 47, 421–423 (2005).

    Article  PubMed  Google Scholar 

  96. Del Conte, A. et al. Complete metabolic remission with gefitinib in a hemodialysis patient with bone metastases from non-small cell lung cancer. Anticancer Res. 34, 319–322 (2014).

    CAS  PubMed  Google Scholar 

  97. Togashi, Y. et al. Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis. J. Thorac. Oncol. 5, 601–605 (2010).

    Article  PubMed  Google Scholar 

  98. Bersanelli, M., Tiseo, M., Artioli, F., Lucchi, L. & Ardizzoni, A. Gefitinib and afatinib treatment in an advanced non-small cell lung cancer (NSCLC) patient undergoing hemodialysis. Anticancer Res. 34, 3185–3188 (2014).

    CAS  PubMed  Google Scholar 

  99. Thomas, N. E. BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Res. 16, 97–103 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Regnier-Rosencher, E. et al. Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas. Br. J. Dermatol. 169, 934–948 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Launay-Vacher, V. et al. Acute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients. Cancer 120, 2158–2163 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Ascierto, P. A. et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J. Clin. Oncol. 31, 3205–3211 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Hauschild, A. et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380, 358–365 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Green, J. S., Norris, D. A. & Wisell, J. Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases. Br. J. Dermatol. 169, 172–176 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Iddawela, M. et al. Safety and efficacy of vemurafenib in end stage renal failure. BMC Cancer 13, 581 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF v600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Goldenberg, M. M. Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin. Ther. 21, 309–318 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Harbeck, N. et al. HER2 dimerization inhibitor pertuzumab—mode of action and clinical data in breast cancer. Breast Care (Basel) 8, 49–55 (2013).

    Article  Google Scholar 

  110. Burris, H. A. 3rd. Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9 (Suppl. 3), 10–15 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Boyraz, B. et al. Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Curr. Med. Res. Opin. 29, 405–414 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Russo, G. et al. Role of renal function on the development of cardiotoxicity associated with trastuzumab-based adjuvant chemotherapy for early breast cancer. Intern. Emerg. Med. 7, 439–446 (2012).

    Article  PubMed  Google Scholar 

  113. Kaufman, B. et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J. Clin. Oncol. 27, 5529–5537 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Slamon, D. et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273–1283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Micallef, R. A., Barrett-Lee, P. J., Donovan, K., Ashraf, M. & Williams, L. Trastuzumab in patients on haemodialysis for renal failure. Clin. Oncol. (R. Coll. Radiol.) 19, 559 (2007).

    Article  CAS  Google Scholar 

  117. Piacentini, F., Omarini, C. & Barbieri, E. Lapatinib and renal impairment: a case report. Tumori 99, e134–e135 (2013).

    Article  PubMed  Google Scholar 

  118. Costa Reis, A. P., Russo, P., Gallucci, S. & Sullivan, K. E. Control of cell proliferation in lupus nephritis: the role of miRNAs and HER2 [abstract]. Arthritis Rheumatol. 66 (Suppl. S3), S194 (2014).

    Article  Google Scholar 

  119. Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  120. Spanou, Z. et al. Involvement of drug-specific T cells in acute drug-induced interstitial nephritis. J. Am. Soc. Nephrol. 17, 2919–2927 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Voskens, C. J. et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS ONE 8, e53745 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Izzedine, H. et al. Kidney injuries related to ipilimumab. Invest. New Drugs 32, 769–773 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. Fadel, F., El Karoui, K. & Knebelmann, B. Anti-CTLA4 antibody-induced lupus nephritis. N. Engl. J. Med. 361, 211–212 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Weber, J. S. et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26, 5950–5956 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. O'Day, S. J. et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann. Oncol. 21, 1712–1717 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Rodig, S. J. & Shapiro, G. I. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr. Opin. Investig. Drugs 11, 1477–1490 (2010).

    CAS  PubMed  Google Scholar 

  128. Camidge, D. R. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13, 1011–1019 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Seimetz, D., Lindhofer, H. & Bokemeyer, C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 36, 458–467 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Brosnan, E. M. et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 120, 664–674 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Martín Martorell, P., Huerta Alvaro, M., Solís Salguero, M. A. & Insa Molla, A. Crizotinib and renal insufficiency: a case report and review of the literature. Lung Cancer 84, 310–313 (2014).

    Article  PubMed  Google Scholar 

  133. Gastaud, L. et al. Acute kidney injury following crizotinib administration for non-small-cell lung carcinoma. Lung Cancer 82, 362–364 (2013).

    Article  PubMed  Google Scholar 

  134. Lin, Y. T. et al. Development of renal cysts after crizotinib in advanced ALK-positive non-small-cell lung cancer. J. Thorac. Oncol. 9, 1720–1725 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Heigener, D. F. & Reck, M. Crizotinib. Recent Results Cancer Res. 201, 197–205 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Houk, B. E. et al. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother. Pharmacol. 66, 357–371 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Levey, A. S. et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150, 604–612 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Janus, N. et al. Management of anticancer treatment in patients under chronic dialysis: results of the multicentric CANDY (CANcer and DialYsis) study. Ann. Oncol. 24, 501–507 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Porta, C. & Szczylik, C. Tolerability of first-line therapy for metastatic renal cell carcinoma. Cancer Treat. Rev. 35, 297–307 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Finkel, K. W. & Howard, S. C. Onco-nephrology: an invitation to new field. J. Clin. Oncol. 32, 2389–2390 (2014).

    Article  PubMed  Google Scholar 

  141. Perazella, M. A., Berns, J. S. & Rosner, M. H. Cancer and the kidney: the growth of onco-nephrology. Adv. Chronic Kidney Dis. 21, 4–6 (2014).

    Article  PubMed  Google Scholar 

  142. Zhu, X., Wu, S., Dahut, W. L. & Parikh, C. R. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am. J. Kidney Dis. 49, 186–193 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Wu, S., Kim, C., Baer, L. & Zhu, X. Bevacizumab increases risk for severe proteinuria in cancer patients. J. Am. Soc. Nephrol. 21, 1381–1389 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ranpura, V., Pulipati, B., Chu, D., Zhu, X. & Wu, S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am. J. Hypert. 23, 160–168 (2010).

    Article  CAS  Google Scholar 

  145. Van Cutsem, E. et al. Addition of aflibercept to fluorouracil, leucovorin and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 30, 3499–3506 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Qi, W. X., Shen, Z., Tang, L. N. & Yao, Y. Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis. Clin. Drug Investig. 34, 231–240 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Zhu, X., Stergiopoulos, K. & Wu, S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol. 48, 9–17 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Qi, W. X. et al. Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis. Cancer Chemother. Pharmacol. 71, 431–439 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Zhang, Z. F., Wang, T. Liu, L. H. & Guo, H. Q. Risks of proteinuria associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a systematic review and meta-analysis. PLoS ONE 9, e90135 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Qi, W. X., He, A. N., Shen, Z. & Yao, Y. Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br. J. Clin. Pharmacol. 76, 348–357 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Li, Y. et al. Incidence and risk of Sorafenib-induced hypertension: a systematic review and meta-analysis J. Clin. Hypertens. (Greenwich) 16, 177–185 (2014).

    Article  CAS  Google Scholar 

  152. Funakoshi, T., Latif, A. & Galsky, M. D. Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. J. Hum. Hypertens. 27, 601–611 (2013).

    Article  CAS  PubMed  Google Scholar 

  153. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  154. Llovet, J. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Yao, J. C. et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Hudes, G. et al. Temsirolimus, interferon α, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2781 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Chen, P., Wang, L., Li, H., Liu, B. & Zou, Z. Incidence and risk of hypomagnesemia in advanced cancer patients treated with cetuximab: a meta-analysis. Oncol. Lett. 5, 1915–1920 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Cao, Y., Liao, C., Tan, A., Liu, L. & Gao, F. Meta-analysis of incidence and risk of hypomagnesemia with cetuximab for advanced cancer. Chemotherapy 56, 459–465 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Petrelli, F., Borgonovo, K., Cabiddu, M., Ghilardi, M. & Barni, S. Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies. Expert Opin. Drug Saf. 11 (Suppl. 1), S9–19 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Cao, Y., Liu, L., Liao, C., Tan, A. & Gao, F. Meta-analysis of incidence and risk of hypokalemia with cetuximab-based therapy for advanced cancer. Cancer Chemother. Pharmacol. 66, 37–42 (2010).

    Article  CAS  PubMed  Google Scholar 

  164. Kim, E. S. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372, 1809–1818 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Wan, H. L. & Yao, N. S. Acute renal failure associated with gefitinib therapy. Lung 184, 249–250 (2006).

    Article  PubMed  Google Scholar 

  166. Kumasaka, R. et al. Side effects of therapy: case 1. Nephrotic syndrome associated with gefitinib therapy. Clin. Oncol. 22, 2504–2505 (2004).

    Article  Google Scholar 

  167. Miller, V. A. et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 13, 528–538 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This Review is the result of a Joint Italian Association of Medical Oncology (AIOM)/Italian Society of Nephrology (SIN) Working Group on Onco-Nephrology.

Author information

Authors and Affiliations

  1. Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Piazzale C. Golgi 19, 27100, Pavia, Italy

    Camillo Porta & Paolo Pedrazzoli

  2. Nephrology and Dialysis, Istituti Ospitalieri Cremona, Largo Priori 1, 26100, Cremona, Italy

    Laura Cosmai & Fabio Malberti

  3. Nephrology and Dialysis, San Carlo Borromeo Hospital, University of Milano, Via Pio II, 3, 20153, Milan, Italy

    Maurizio Gallieni

Authors
  1. Camillo Porta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Cosmai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maurizio Gallieni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Pedrazzoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fabio Malberti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.P. and L.C. researched the data, wrote the article and reviewed and/or edited the manuscript before submission. All authors made substantial contributions to discussion of content.

Corresponding author

Correspondence to Camillo Porta.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Common terminology criteria for reporting of adverse events of treatment-related kidney toxicities.7 (DOCX 21 kb)

Supplementary Table 2

Approved oncological indications for eight classes of cancer-targeted agents (DOCX 20 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Porta, C., Cosmai, L., Gallieni, M. et al. Renal effects of targeted anticancer therapies. Nat Rev Nephrol 11, 354–370 (2015). https://doi.org/10.1038/nrneph.2015.15

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2015.15

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing