Acute Kidney Injury Associated with Anticancer Therapies: Small Molecules and Targeted Therapies

Abstract

Molecular targeted therapy has revolutionized cancer treatment by significantly improving patient survival compared with standard conventional chemotherapies. The use of these drugs targets specific molecules or targets, which block growth and spread of cancer cells. Many of these therapies have been approved for use with remarkable success in breast, blood, colorectal, lung, and ovarian cancers. The advantage over conventional chemotherapy is its ability to deliver drugs effectively with high specificity while being less toxic. Although known as "targeted," many of these agents lack specificity and selectivity, and they tend to inhibit multiple targets, including those in the kidneys. The side effects usually arise because of dysregulation of targets of the inhibited molecule in normal tissue. The off-target effects are caused by drug binding to unintended targets. The on-target effects are associated with inhibition toward the pathway reflecting inappropriate inhibition or activation of the intended drug target. Early detection and correct management of kidney toxicities is crucial to preserve kidney functions. The knowledge of these toxicities helps guide optimal and continued utilization of these potent therapies. This review summarizes the different types of molecular targeted therapies used in the treatment of cancer and the incidence, severity, and pattern of nephrotoxicity caused by them, with their plausible mechanism and proposed treatment recommendations.

Figure 1

Overview of the molecular targeted therapy mechanism. Molecular targeted therapy on cancer focuses on targeting specific cancer-associated molecules that are highly expressed in cancer cells or by modulating the tumor microenvironment related to tumor vasculature, metastasis, or hypoxia. These lead to the inhibition of tumor cell proliferation, cell survival, cell cycle progression, angiogenesis, and cell invasion and metastasis. (Adapted from ref. 1). (Figure generated using BioRender.)

Figure 2

Molecular targets in tumor cells that act as sites of action for chemotherapy. Adapted with permission from ref. . ALK, anaplastic lymphoma kinase; BCL-2, B-cell lymphoma 2 gene; BCR-ABL, gene sequence; BRAF, v-Rapidly accelerated fibrosarcoma viral oncogene homolog B1; CD30, lymphocyte activation antigen; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptors; HER, human epidermal growth factor; MEK, mitogen-activated protein kinase; MMAE, monomethyl auristatin E; mTOR, mechanistic target of rapamycin; PARP, poly-adenosine diphosphate-ribose polymerase; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor. (Figure generated using BioRender.)

Figure 3

Molecular targets expressed in the kidney. Adapted with permission from ref. . MET, mesenchymal–epithelial transition; VEGF, vascular endothelial growth factor. (Figure generated using BioRender.)

Figure 4

Potential mechanisms of kidney injury and HTN induced by antiangiogenic treatment. Systemic vascular endothelial cell dysfunction and localized kidney effects (glomerular endothelial cells and podocytes) of antiangiogenesis drugs lead to clinical kidney syndromes. NO, nitric oxide; ET, endothelin; HTN, hypertension; TKI, tyrosine kinase inhibitor. (Figure generated using BioRender.)

Figure 5

Kidney biopsy findings in a patient on anti-VEGF therapy: TMA. Histological examination of kidney biopsy showing TMA in a patient on anti-VEGF treatment. (A) The yellow arrow illustrates in high magnification (200 μm) a thrombosed vessels with fibrinoid necrosis of the vessel wall in trichrome staining. (B) The yellow arrow illustrates in high magnification (200 μm) a congested glomerulus in trichrome staining. (C) The yellow arrow illustrates in high magnification (200 pm) a preglomerular arteriole thrombotic lesion in AFOGH staining. AFOGH, acid–fuchsin orange G; TMA, thrombotic microangiopathy.

Figure 6

Kidney biopsy findings in a patient on PI: acute granulomatous tubule-interstitial nephritis. H&E, hematoxylin and eosin; PAS, periodic acid–Schiff; PI, proteosome inhibitor.