Thrombotic Microangiopathy Associated with Pazopanib in a Kidney Transplant Recipient

Main Article Content

Shabana Kalla
Robert J Ellis
Scott Campbell
Brian Doucet
Nicole Isbel
Bibiana Tie
Dev Jegatheesan

Keywords

thrombotic microangiopathy, vascular endothelial growth factor inhibitors, pazopanib, kidney transplant

Abstract

Thrombotic microangiopathy (TMA) is characterised by abnormalities in the walls of arterioles and capillaries, precipitated by hereditary or acquired characteristics, and culminating in microvascular thrombosis because of dysregulated complement activity. A number of drugs can precipitate TMA, including vascular endothelial growth factor (VEGF) inhibitors, because of their effects on endothelial repair. Pazopanib is a VEGF inhibitor used for the treatment of renal cell carcinoma (RCC); it is uncommonly associated with TMA. A 52-year-old male, 5 years post his second kidney transplant secondary to immunoglobulin (Ig) A nephropathy, presented with hypertension, fluid overload, and worsening graft function (peak creatinine 275 µmol/L, baseline 130–160 µmol/L) and nephrotic range proteinuria 2 months after commencing pazopanib for metastatic RCC. His maintenance immunosuppression included ciclosporin, mycophenolate, and prednisolone. Haematological parameters were unremarkable. Allograft biopsy demonstrated glomerular and arteriolar changes consistent with chronic active TMA, with overlying fea-tures of borderline cellular rejection. He was treated with intravenous methylprednisolone 250 mg for 3 days and commenced on irbesartan 75 mg daily. Drug-induced TMA from pazopanib was suspected, particularly given the documented association with other tyrosine kinase inhibitors (TKIs). In consultation with his medical oncologist, pazopanib was ceased, and an alternate TKI cabozantinib was commenced. Serum creatinine remained <200 µmol/L 3 months after admission. This is the first reported biopsy-proven case of TMA attributed to pazopanib in a kidney transplant recipient. With increasing clinical indications for and availability of TKIs, clinicians need to be aware of their association with TMA events in kidney transplant recipients, who are already susceptible to TMA due to abnormal vasculature, infectious triggers, ischaemia-reperfusion injury, and use of calcineurin inhibitor.

Abstract 121 | PDF Downloads 54 XML Downloads 29 HTML Downloads 15

References

1. George JN, Nester CM. Syndromes of thrombotic microangiop-athy. N Engl J Med. 2014;371(7):654–66. https://doi.org/10.1056/ NEJMra1312353
2. Brocklebank V, Wood KM, Kavanagh D. Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol. 2018;13(2):300–17. https://doi.org/10.2215/CJN.00620117
3. Babaian RJ, Swanson DA. Serum haptoglobin: A non-specific tumor marker for renal cell carcinoma. Southern Med J. 1982;75(11):1345–8. https://doi.org/10.1097/00007611-198211000-00010
4. Del Vecchio SJ, Ellis RJ. Cabozantinib for the management of metastatic clear cell renal cell carcinoma. J Kidney Cancer VHL. 2018;5(4):1–5. https://doi.org/10.15586/jkcvhl.2018.109
5. La Manna G, Baraldi O, Corradetti V, Comai G. Cabozantinib-induced renal thrombotic microangiopathy. Nephrology. 2018;23(1):96–7. https://doi.org/10.1111/nep.13086
6. Vigneau C, Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Laguerre B, et al. All anti-vascular endothelial growth factor drugs can induce “pre-eclampsia-like syndrome”: A RARe study. Nephrol Dial Transplant. 2014;29(2):325–32. https://doi.org/10.1093/ndt/gft465
7. Izzedine H, Escudier B, Lhomme C, Pautier P, Rouvier P, Gueutin V, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): An 8-year observational study at a single center. Medicine. 2014;93(24):333–9. https:// doi.org/10.1097/MD.0000000000000207
8. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: A systematic review of published reports. Blood. 2015;125(4):616–8. https://doi. org/10.1182/blood-2014-11-611335
9. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic micro-angiopathy. N Engl J Med. 2008;358(11):1129–36. https://doi. org/10.1056/NEJMoa0707330
10. Estrada CC, Maldonado A, Mallipattu SK. Therapeutic inhibition of VEGF signaling and associated nephrotoxicities. J Am SocNephrol. 2019;30(2):187–200. https://doi.org/10.1681/ ASN.2018080853
11. Qi WX, Lin F, Sun YJ, Tang LN, He AN, Yao Y, et al. Incidence and risk of hypertension with pazopanib in patients with cancer: A meta-analysis. Cancer Chemother Pharmacol. 2013;71(2):431–9. https://doi.org/10.1007/s00280-012-2025-5
12. Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. Lancet Oncol. 2010;11(10):962– 72. https://doi.org/10.1016/S1470-2045(10)70203-5
13. Zhang ZF, Wang T, Liu LH, Guo HQ. Risks of proteinuria associated with vascular endothelial growth factor receptor tyro-sine kinase inhibitors in cancer patients: A systematic review and meta-analysis. PloS ONE. 2014;9(3):e90135. https://doi. org/10.1371/journal.pone.0090135
14. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff  J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8. https://doi.org/10.1200/ JCO.2009.23.9764
15. Sorich MJ, Rowland A, Kichenadasse G, Woodman RJ, Mangoni AA. Risk factors of proteinuria in renal cell carcinoma patients treated with VEGF inhibitors: A secondary analysis of pooled clinical trial data. Brit J Cancer. 2016;114(12):1313–7. https://doi.org/10.1038/bjc.2016.147
16. Kandula P, Agarwal R. Proteinuria and hypertension with tyrosine kinase inhibitors. Kidney Int. 2011;80(12):1271–7. https:// doi.org/10.1038/ki.2011.288
17. Novartis Pharmaceuticals Corporation. Votrient® [Internet]. [updated Aug 2020]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. Available from: https://www.hcp. novartis.com/products/votrient/
18. Négrier S, Pérol D, Bahleda R, Hollebecque A, Chatelut E, Boyle  H, et al. Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors. BMC Cancer. 2017;17(1):547. https://doi.org/10.1186/s12885-017-3527-7
19. Maruyama K, Nakagawa N, Suzuki A, Kabara M, Matsuki M, Shindo M, et al. Pazopanib-induced endothelial injury with podocyte changes. Int Med. 2018;57(7):987–91. https://doi. org/10.2169/internalmedicine.9576-17
20. Syed U, Wahlberg KJ, Douce DR, Sprague JR. Thrombotic thrombocytopenic purpura associated with pazopanib. Case Rep Hematol. 2018;2018:4327904. https://doi. org/10.1155/2018/4327904
21. Reynolds JC, Agodoa LY, Yuan CM, Abbott KC. Thrombotic microangiopathy after renal transplantation in the United States. Am J Kidney Dis. 2003;42(5):1058–68. https://doi.org/10.1016/j. ajkd.2003.07.008
22. Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K. De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev. 2018;32(1):58–68. https://doi.org/10.1016/j. trre.2017.10.001
23. Ponticelli C. De novo thrombotic microangiopathy. An underrated complication of renal transplantation. Clin Nephrol. 2007;67(6):335–40. https://doi.org/10.5414/CNP67335
24. Sartelet H, Toupance O, Lorenzato M, Fadel F, Noel LH, Lagonotte E, et al. Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys. Am J Transplant. 2005;5(10):2441–7. https://doi.org/10.1111/j.1600-6143.2005.01047.x
25. Izzedine H, Massard C, Soria JC. Unlikely association of nephrectomy post-mRCC with anti-VEGF-induced renal TMA. NDT Plus. 2011;4(1):78–9. https://doi.org/10.1093/ndtplus/ sfq178
26. Person F, Rinschen MM, Brix SR, Wulf S, Noriega MLM, Fehrle W, et al. Bevacizumab-associated glomerular microangiopathy. Modern Pathol. 2019;32(5):684–700. https://doi. org/10.1038/s41379-018-0186-4
27. Zuber J, Le Quintrec M, Morris H, Frémeaux-Bacchi V, Loirat C, Legendre C. Targeted strategies in the prevention and management of atypical HUS recurrence after kidney trans-plantation. Transplant Rev. 2013;27(4):117–25. https://doi. org/10.1016/j.trre.2013.07.003
28. Müsri FY, Mutlu H, Ery?lmaz MK, Salim DK, Cos¸kun H. Experience of bevacizumab in a patient with colorectal cancer after renal transplantation. J Cancer Res Ther. 2015;11(4):1018– 20. https://doi.org/10.4103/0973-1482.168996
29. Sorafenib/tacrolimus. React Wkly. 2019;1756(1):314. https://doi. org/10.1007/s40278-019-63193-9
30. Cutler C, Henry NL, Magee C, Li S, Kim HT, Alyea E, et al. Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(7):551–7. https://doi.org/10.1016/j. bbmt.2005.04.007
31. Paramesh AS, Grosskreutz C, Florman SS, Gondolesi  GE, Sharma S, Kaufman SS, et al. Thrombotic microangiopathy associated with combined sirolimus and tacrolimus immunosuppression after intestinal transplantation. Transplantation. 2004;77(1):129–31. https://doi.org/10.1097/01. TP.0000092522.36410.D0
32. Shayani S, Palmer J, Stiller T, Liu X, Thomas SH, Khuu T, et al. Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2013;19(2):298–304. https://doi. org/10.1016/j.bbmt.2012.10.006
33. Langer RM, Van Buren CT, Katz SM, Kahan BD. De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination. Transplantation. 2002;73(5):756–60. https://doi. org/10.1097/00007890-200203150-00017
34. Faes S, Santoro T, Demartines N, Dormond O. Evolving significance and future relevance of anti-angiogenic activity of mTOR inhibitors in cancer therapy. Cancers. 2017;9(11):152. https:// doi.org/10.3390/cancers9110152