Nephrotoxicity of Anti-Angiogenic Therapies

Wynsberghe, Margaux Van; Flejeo, Joanne; Sakhi, Hamza; Ollero, Mario; Sahali, Dil; Izzedine, Hassan; Hénique, Carole

doi:10.3390/diagnostics11040640

Cited by 23 publications

(24 citation statements)

References 184 publications

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“…Kidney side effects from cancer immunotherapies and targeted therapies will frequently present with similar clinical findings (i.e., proteinuria and AKI) requiring a biopsy for diagnosis. The patient presented on third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor), which, in itself, has known kidney toxicities ( 12 , 13 ). Lenvatinib is a multi-TKI that notably targets vascular endothelial growth factor (VEGF) receptor 1, 2, and 3 among other tyrosine kinase receptors.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

et al. 2022

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BackgroundDiagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy.Case presentationA 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy.ConclusionThis report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment.

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Section: Discussionmentioning

confidence: 99%

Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

et al. 2022

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Section: Discussionmentioning

confidence: 99%

“…The RAF/ MAPK/ERK pathway is affected by dabrafenib. [19] In the glomerulus, VEGF is expressed and secreted by podocytes, and VEGF receptors are expressed on the surfaces of both endothelial cells and podocytes. [20] Therefore, interruption of VEGF-mediated podocyte-endothelial crosstalk compromises the efficiencies of the glomerular filtration barrier and glomerular capillary endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…[20] Therefore, interruption of VEGF-mediated podocyte-endothelial crosstalk compromises the efficiencies of the glomerular filtration barrier and glomerular capillary endothelial cells. [7,19] The pathological impacts of kidney VEGF inhibition can be seen in patients with pre-eclampsia. [21,22] In pre-eclampsia, a soluble Fms-like tyrosine kinase-1 antagonizes VEGF and excess soluble Fms-like tyrosine kinase-1 triggers maternal endothelial dysfunction, hypertension, glomerular endotheliosis, and proteinuria; this combination of problems progresses to thrombotic microangiopathy.…”

Section: Discussionmentioning

confidence: 99%

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Dabrafenib- and trametinib-associated glomerular toxicity

Rhee

2022

Medicine

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Rationale: Combined treatment with dabrafenib, a B-RAF inhibitor, and trametinib, a mitogen-activated protein kinase inhibitor, is an effective option for patients with metastatic melanoma. A few cases of acute kidney injury associated with tubulointerstitial nephritis and 1 case of nephrotic syndrome have been reported in patients on this drug combination; however, progressive renal injury has not been reported. In this case study, we report a patient with metastatic melanoma who developed glomerular capillary endothelial toxicity and progressive glomerular sclerosis during combination therapy. Patient concern: Our patient was an 80-year-old woman with a history of type 2 diabetes and chronic kidney disease. Diagnosis and intervention: She was diagnosed with metastatic melanoma and commenced combination therapy with dabrafenib and trametinib. Outcomes: Her renal function progressively deteriorated; by month 20 after treatment commencement, her serum creatinine level had increased from 1.59 to 3.74 mg/dL. The first kidney biopsy revealed marked glomerular and endothelial cell damage. Her medication was stopped, but no improvement was evident. At 5 months after the first biopsy, her serum creatinine level had increased to 5.46 mg/dL; a second kidney biopsy revealed focal segmental glomerular sclerosis and marked tubulointerstitial fibrosis. She was started on hemodialysis. Lessons: We describe a patient with a metastatic melanoma who developed progressive kidney failure during treatment with dabrafenib and trametinib. The most prominent microscopy findings were glomerular endothelial damage in the initial kidney biopsy and accelerated glomerular sclerosis and tubulointerstitial fibrosis in the follow-up biopsy. We hypothesize that a decreased renal reserve and impairment of kidney repair capacity caused by inhibition of B-RAF, a downstream mediator of vascular endothelial growth factor, may explain the progressive kidney injury.

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“…Genetic knockout of VEGF, or pharmacological blockade induces the loss of endothelial fenestrations in glomerular capillaries leading to proteinuria [ 92 ], and the reason is related to nephrin expression downregulation, which is an important cytoskeletal protein of glomerular slit diaphragm [ 93 ]. Secondly, VEGF inhibitors induce the disruption of autophagy and podocyte loss via antagonizing PI3K/AKT/mTOR pathway [ 94 ]. Some hypertensive patients receiving VEGF-targeted therapy were also accompanied by proteinuria.…”

Section: Vegf-targeted Therapymentioning

confidence: 99%

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases

et al. 2022

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Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-β: transforming growth factor-β; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response

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Nephrotoxicity of Anti-Angiogenic Therapies

Cited by 23 publications

References 184 publications

Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

Dabrafenib- and trametinib-associated glomerular toxicity

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases

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