Thrombotic Microangiopathy Associated with Pazopanib in a Kidney Transplant Recipient

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.

Tyrosine kinase inhibitor-induced immune hemolytic anemia; three different drugs in three separate cases

“…6 Several cases diagnosed with sorafenib, sunitinib, and pazopanib-induced coombs-negative microangiopathic hemolysis were reported. 7, 8 Another mechanism of TKI-associated anemia is drug-induced coombs-positive IHA that was described with cases under imatinib, erlotinib, and afatinib previously. 7, 9, 10 TKIs are presumed to interfere with B-cell activation causing humoral response by their off-target multikinase inhibitory effect.…”

Late renal toxicity in patient with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib: A case report and literature review

“…Supportive treatment, including cessation of the offending drugs and blood pressure control demonstrated good results. 6,11,12…”

“…Supportive treatment, including cessation of the offending drugs and blood pressure control demonstrated good results. 6,11,12 TMA and diabetic nephropathy TMA has been reported in patients with diabetic nephropathy; it is thought that TMA is induced by decreased VEGF expression levels. VEGF promotes survival of endothelial cells and maintains podocyte integrity.…”

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation

“…Although the focus here was on VCA transplants, it is likely B.PSel-Crry would be an equally suitable therapy in solid organ transplantation. Microvascular thrombosis is a common complication early and late post-transplantation (40)(41)(42)(43), particularly in extended criteria donors, and thus application of B.PSel-Crry could represent a novel therapeutic intervention.…”