Urinary biomarkers of kidney injury in patients treated with anti-VEGF drugs

Cover Page

Cite item

Full Text

Abstract

Background. Antiangiogenic drugs are widely used in oncological practice and are aimed at inhibiting angiogenesis. Despite the high antitumor efficacy, their use may be limited by nephrotoxicity, and therefore the search for early biomarkers of kidney damage remains relevant, which will preserve a favorable safety profile of therapy.

Aim. To determine urinary biomarkers of tubular and podocyte damage in patients receiving treatment with antiangiogenic drugs.

Materials and methods. The study included patients (n=50) who received intravenous anti-VEGF drugs (aflibercept, bevacizumab, ramucirumab) in various chemotherapy regimens. Concentrations of tubular damage markers KIM-1 (Kidney Injury Molecule-1) and NGAL (Neutrophil Gelatinase-Associated Lipocalin), hypoxia marker HIF-1α (Hypoxia-Inducible Factor 1-alpha) in urine samples were determined by enzyme-linked immunosorbent assay (ELISA) before treatment, and during 8 weeks of treatment. To assess the risk factors for kidney damage, a logistic regression analysis was performed with the inclusion of the main clinical and laboratory parameters.

Results. A decrease in the calculated GFR of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Formula) of less than 60 ml/min per 1.73 m2 at week 8 of treatment was noted in 42% of patients. An increase in NGAL, KIM-1, HIF-1α and nephrin in urine during the first two weeks of therapy predicted the development of renal damage by the 8th week of follow-up. When constructing ROC-curves, the high sensitivity and specificity of these urinary indicators as prognostic markers were established. Among the clinical and laboratory indicators, independent unfavorable prognostic factors of nephrotoxicity were an initial decrease in eGFR, a history of hypertension, an increase in the concentration of KIM-1 and HIF-1α in urine during the first two weeks of therapy.

Conclusion. The predictors of renal damage in the treatment with antiangiogenic drugs were previously an increase in NGAL, KIM-1 and HIF-1α in urine during the first two weeks after the start of therapy.

About the authors

Katerina S. Grechukhina

Lomonosov Moscow State University; Loginov Moscow Clinical Scientific Center

Author for correspondence.
Email: dr.grechukhina@gmail.com
ORCID iD: 0000-0002-0616-5477

пирант каф. внутренних болезней, врач-онколог

Russian Federation, Moscow; Moscow

Natalia V. Chebotareva

Lomonosov Moscow State University; Sechenov First Moscow State Medical University (Sechenov University)

Email: dr.grechukhina@gmail.com
ORCID iD: 0000-0003-2128-8560

д-р мед. наук, проф., проф. каф. внутренних болезней, проф. каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.В. Склифосовского

Russian Federation, Moscow; Moscow

Liudmila G. Zhukova

Loginov Moscow Clinical Scientific Center

Email: dr.grechukhina@gmail.com
ORCID iD: 0000-0003-4848-6938

д-р мед. наук, проф., зам. дир. по онкологии

Russian Federation, Moscow

Tatiana V. Androsova

Sechenov First Moscow State Medical University (Sechenov University)

Email: dr.grechukhina@gmail.com
ORCID iD: 0000-0002-9951-126X

канд. мед. наук, доц. каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.В. Склифосовского

Russian Federation, Moscow

Vladimir V. Karpov

Sechenov First Moscow State Medical University (Sechenov University)

Email: dr.grechukhina@gmail.com
ORCID iD: 0000-0003-2048-3401

канд. мед. наук, доц. каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.В. Склифосовского

Russian Federation, Moscow

Tatiana N. Krasnova

Lomonosov Moscow State University; Sechenov First Moscow State Medical University (Sechenov University)

Email: dr.grechukhina@gmail.com
ORCID iD: 0000-0002-7647-3942

канд. мед. наук, зав. каф. внутренних болезней, доц. каф. внутренних болезней

Russian Federation, Moscow; Moscow

References

  1. Ferrara N, Gerber H, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669-76. doi: 10.1038/nm0603-669
  2. Zirlik K, Duyster J. Anti-Angiogenics: Current Situation and Future Perspectives. Oncol Res Treat. 2018;41(4):166-17. doi: 10.1159/000488087
  3. Pastorino A, Di Bartolomeo M, Maiello E, et al. Aflibercept Plus FOLFIRI in the Real-life Setting: Safety and Quality of Life Data From the Italian Patient Cohort of the Aflibercept Safety and Quality-of-Life Program Study. Clin Colorectal Cancer. 2018;17(3):e457-70. doi: 10.1016/j.clcc.2018.03.002
  4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539-44. doi: 10.1200/JCO.2006.09.6305
  5. Wang Z, Dabrosin C, Yin X, et al. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol. 2015;35(Suppl.):S224-43. doi: 10.1016/j.semcancer.2015.01.001
  6. Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19(5):927-34. doi: 10.1093/annonc/mdm550
  7. Qi WX, Shen Z, Tang LN, Yao Y. Risk of Hypertension in Cancer Patients Treated with Aflibercept: A Systematic Review and Meta-Analysis. Clin Drug Investig. 2014;34(4):231-40. doi: 10.1007/s40261-014-0174-5
  8. Touyz R, Herrmann S, Herrmann J. Vascular toxicities with VEGF inhibitor therapies – focus on hypertension and arterial thrombotic events. J Am Soc Hypertens. 2018;12(6):409-25. doi: 10.1016/j.jash.2018.03.008
  9. Toriu A, Sekine A, Mizuno H, et al. Renal-Limited Thrombotic Microangiopathy due to Bevacizumab Therapy for Metastatic Colorectal Cancer: A Case Report. Case Rep Oncol. 2019;12(2):391-400. doi: 10.1159/000500716
  10. Piscitani L, Sirolli V, Di Liberato L, et al. Nephrotoxicity Associated with Novel Anticancer Agents (Aflibercept, Dasatinib, Nivolumab): Case Series and Nephrological Considerations. Int J Mol Sci. 2020;21(14):4878. doi: 10.3390/ijms21144878
  11. Hanna RM, Tran NT, Patel SS, et al. Thrombotic Microangiopathy and Acute Kidney Injury Induced After Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors VEGF Blockade-Related TMA After Intravitreal Use. Front Med (Lausanne). 2020;7:579603. doi: 10.3389/fmed.2020.579603
  12. Morales E, Moliz C, Gutierrez E. Renal damage associated to intravitreal administration of ranibizumab. Nefrologia. 2017;37(6):653-5. doi: 10.1016/j.nefro.2016.10.011
  13. Florova B, Rajdl D, Racek J, et al. NGAL, albumin and cystatin C during cisplatin therapy. Physiol Res. 2020;69(2):307-17. doi: 10.33549/physiolres.934212
  14. Vaidya VS, Ford GM, Waikar SS, et al. A rapid urine test for early detection of kidney injury. Kidney Int. 2009;76(1):108-14. doi: 10.1038/ki.2009.96
  15. Vaidya VS, Ozer JS, Dieterle F, et al. Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies. Nat Biotechnol. 2010;28(5):478-85. doi: 10.1038/nbt.1623
  16. Ghadrdan E, Ebrahimpour S, Sadighi S, et al. Evaluation of urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule-1 as biomarkers of renal function in cancer patients treated with cisplatin. J Oncol Pharm Pract. 2020;26(7):1643-9. doi: 10.1177/1078155220901756
  17. Shu S, Wang Y, Zheng M, et al. Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair. Cells. 2019;3(8):207. doi: 10.3390/cells8030207
  18. Ma C, Wei J, Zhan F, et al. Urinary hypoxia-inducible factor-1alpha levels are associated with histologic chronicity changes and renal function in patients with lupus nephritis. Yonsei Med J. 2012;53(3):587-92. doi: 10.3349/ymj.2012.53.3.587
  19. Niu G, Chen X. Vascular Endothelial Growth Factor as an Anti-angiogenic Target for Cancer Therapy. Curr Drug Targets. 2010;11(8):1000-17. doi: 10.2174/138945010791591395
  20. Kazazi-Hyseni F, Beijnen J, Schellens J. Bevacizumab. Oncologist. 2010;15(8):819-25. doi: 10.1634/theoncologist.2009-0317
  21. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102(9):596-604. doi: 10.1093/jnci/djq091
  22. Steeghs N, Hovens MM, Rabelink AJ, et al. VEGF-R2 blockade in patients with solid tumors: mechanisms of hypertension and effects on vascular function. J Clin Oncol. 2006;18(Suppl.):3037. doi: 10.1200/jco.2006.24.18_suppl.3037
  23. Hayman SR, Leung N, Grande JP, Garovic VD. VEGF inhibition, hypertension, and renal toxicity. Curr Oncol Rep. 2012;14(4):285-94. doi: 10.1007/s11912-012-0242-z
  24. Bollee G, Patey N, Cazajous G, et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant. 2009;24(2):682-5. doi: 10.1093/ndt/gfn657
  25. Hauser PV, Collino F, Bussolati B, Camussi G. Nephrin and endothelial injury. Curr Opin Nephrol Hypertens. 2009;18(1):3-8. doi: 10.1097/MNH.0b013e32831a4713

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. An increase in biomarkers of renal damage NGAL (Neutrophil Gelatinase-Associated Lipocalin), KIM-1 (Kidney Injury Molecule-1), HIF-1α (Hypoxia-Inducible Factor 1-alpha) and nephrin for 8 weeks in patients treated with antitumor anti-VEGF drugs.

Download (180KB)
Indexing metadata

Copyright (c) 2022 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
 
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies