Assessment of kidney injury during immune-targeted therapy (pembrolizumab + axitinib) in patients with metastatic renal cell carcinoma and solitary kidney

Aim. To assess the rate and type of kidney injury in the first 28 weeks of pembrolizumab and axitinib therapy after nephrectomy in patients with metastatic renal cell carcinoma and solitary kidney.

Materials and methods. The retrospective study included 50 patients who previously underwent nephrectomy due to stage III–IV stage renal cell carcinoma. After nephrectomy prior to the start of antitumor therapy for cancer progression, 84 % of the patients were diagnosed with stage II and higher chronic kidney disease.

Results. During antitumor drug treatment, acute kidney injury 14 and 28 weeks after the start of immune-targeted therapy was diagnosed in 4 % and 6 % of patients, respectively. Dynamics of the change in acute kidney injury in 28 weeks were not statistically significant (p = 0.983). Changes in serum creatinine, urea, and glomerular filtration rate were also insignificant. Statistically significant elevation of hemoglobin and hematocrit was observed during the 28 weeks of observation. Hemoglobin level increased from 128.1 g/L before the treatment to its maximal value of 141.7 g/L after the third injection of pembrolizumab (p <0.001).

Conclusion. No significant kidney injury was observed during 28 weeks of observation in this single cohort study of patients with metastatic renal cell carcinoma after nephrectomy receiving pembrolizumab and axitinib.

1. Cancer Taday. Available at: https://gco.iarc.fr/today/home

2. Powles T., Albiges L., Bex A. et al. Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2024;35(8):692–706. DOI: 10.1016/j.annonc.2024.05.537

3. Siegel R.L., Miller K.D., Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67(1):7–30. DOI: 10.3322/caac.21387

4. Ko J., Xie W., Heng D. et al. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model as a prognostic tool in metastatic renal cell carcinoma (mRCC) patients previously treated with first-line targeted therapy (TT). J Clin Oncol 2014;32:398. DOI: 10.1200/jco.2014.32.4_suppl.398

5. Heng D.Y.C., Wells J.C., Rini B.I. et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66(4):704–10. DOI: 10.1016/j.eururo.2014.05.034

6. Attalla K., Weng S., Voss M.H., Hakimi A.A. Epidemiology, risk assessment, and biomarkers for patients with advanced renal cell carcinoma. Urol Clin North Am 2020;47(3):293–303. DOI: 10.1016/j.ucl.2020.04.002

7. Wang Y., Suarez E.R., Kastrunes G. et al. Evolution of cell therapy for renal cell carcinoma. Mol Cancer 2024;23(1):8. DOI: 10.1186/s12943-023-01911-x

8. Narang A., Gebrael G., Jo Y. et al. Effectiveness of second-line Cabozantinib in metastatic clear cell renal cell carcinoma patients after first-line treatment with immune checkpoint inhibitor-based combinations. Kidney Cancer J 2024;8(1):135–42. DOI: 10.3233/KCA-240016

9. Barragan-Carrillo R., Saad E., Saliby R.M. et al. First and second-line treatments in metastatic renal cell carcinoma. Eur Urol 2025;87(2):143–54. DOI: 10.1016/j.eururo.2024.10.019

10. Powles T., Plimack E.R., Soulières D. et al. Pembrolizumab plus Axitinib versus Sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21(12):1563–73. DOI: 10.1016/S1470-2045(20)30436-8

11. Chau V., Bilusic M. Pembrolizumab in combination with Axitinib as first-line treatment for patients with renal cell carcinoma (RCC): evidence to date. Cancer Manag Res 2020;12:7321–30. DOI: 10.2147/CMAR.S216605

12. Grünwald V., Voss M.H., Rini B.I. et al. Axitinib plus immune checkpoint inhibitor: evidenceand expert-based consensus recommendation for treatment optimisation and management of related adverse events. Br J Cancer 2020;123(6):898–904. DOI: 10.1038/s41416-020-0949-9

13. Rini B.I., Atkins M.B., Plimack E.R. et al. Characterization and management of treatment-emergent hepatic toxicity in patients with advanced renal cell carcinoma receiving first-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial. Eur Urol Oncol 2022;5(2):225–34. DOI: 10.1016/j.euo.2021.05.007

14. Rosellini M., Tassinari E., Marchetti A. et al. An update on safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma. Expert Opin Drug Saf 2023;22(4):279–91. DOI: 10.1080/14740338.2023.2203486

15. Liu C., Wei W., Yang L. et al. Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol 2023;14:1173952. DOI: 10.3389/fimmu.2023.1173952

16. Levin A., Ahmed S.B., Carrero J.J. et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the evaluation and management of chronic kidney disease: known knowns and known unknowns. Kidney Int 2024;105(4):684–701. DOI: 10.1016/j.kint.2023.10.016

17. Levey A.S., Stevens L.A., Schmid C.H. et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9): 604–12. DOI: 10.7326/0003-4819-150-9-200905050-00006

18. 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 2007;49(2):186–93. DOI: 10.1053/j.ajkd.2006.11.039

19. Perazella M.A., Sprangers B. AKI in patients receiving immune checkpoint inhibitors. Clin J Am Soc Nephrol 2019;14(7):1077–9. DOI: 10.2215/CJN.02340219

20. El Rassy E., Bakouny Z., Yared F. et al. The nephrotoxicity of immune checkpoint inhibitor-based combinations. Eur J Cancer 2018;103:274–8. DOI: 10.1016/j.ejca.2018.07.126

21. Manohar S., Kompotiatis P., Thongprayoon C. et al. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis. Nephrol Dial Transplant 2019;34(1):108–17. DOI: 10.1093/ndt/gfy105

22. Wang S., Yan L., Yu J., Lu C. Comparative safety of immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma: a systematic review and network meta-analysis. Eur Arch Otorhinolaryngol 2024;281(7):3385–95. DOI: 10.1007/s00405-024-08517-z

23. Rini B.I., Atkins M.B., Choueiri T.K. et al. Time to resolution of Axitinib-related adverse events after treatment interruption in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2021;19(5):e306–e12. DOI: 10.1016/j.clgc.2021.03.019

24. Gökyer A., Küçükarda A., Köstek O. et al. Contrast nephropathy in cancer patients receiving anti-VEGF therapy: a prospective study. Int J Clin Oncol 2020;25(10):1757–62. DOI: 10.1007/s10147-020-01729-3

25. Stachyra-Strawa P., Szatkowska-Sieczek L., Cisek P. et al. Cardiac and nephrological complications related to the use of antiangiogenic and anti-programmed cell death protein 1 receptor/programmed cell death protein 1 ligand therapy. Genes 2024;15(2):177. DOI: 10.3390/genes15020177

26. Hanna P.E., Anumolu R.K., Motwani S.S. et al. Risk factors for severe hypertension and proteinuria after treatment with vascular endothelial growth factor signaling pathway inhibitors among patients with cancer. Kidney Int Rep 2024;9(6):1897–902. DOI: 10.1016/j.ekir.2024.03.005

27. Rini B.I., Escudier B., Tomczak P. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378(9807):1931–9. DOI: 10.1016/S0140-6736(11)61613-9

28. Zakharia Y., Thomaidou D., Li B. et al. Real-world therapy management and outcomes of first-line Axitinib plus Pembrolizumab in patients with advanced renal cell carcinoma in the United States. Front Oncol 2022;12:861189. DOI: 10.3389/fonc.2022.861189

29. Rini B.I., Plimack E.R., Stus V. et al. Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380(12):1116–27. DOI: 10.1056/NEJMoa1816714

30. Atkins M.B., Plimack E.R., Puzanov I. et al. Axitinib in combination with Pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol 2018;19(3):405–15. DOI: 10.1016/S1470-2045(18)30081-0

31. Atkins M.B., Plimack E.R., Puzanov I. et al. Axitinib plus Pembrolizumab in patients with advanced renal-cell carcinoma: long-term efficacy and safety from a phase Ib trial. Eur J Cancer 2021;145:1–10. DOI: 10.1016/j.ejca.2020.12.009

32. Johnson A.C., Matias M., Boyle H. et al. Haemoglobin level increase as an efficacy biomarker during Axitinib treatment for metastatic renal cell carcinoma: a retrospective study. BMC cancer 2017;17(1):355. DOI: 10.1186/s12885-017-3312-7

33. Wood L.S., Ornstein M.C. Toxicity management of front-line Pembrolizumab combined with Axitinib in clear cell metastatic renal cell carcinoma: a case study approach. JCO Oncol Pract 2020;16(2):15s–9s. DOI: 10.1200/JOP.19.00647