Nephrotoxicity in cancer treatment: An overview

Table 1 Relationship between anticancer drug class, its nephrotoxic effects and mechanism of action of its lesion

Class	Drugs	Nephrotoxicity	Mechanism of action
Alkylating agents	Bendamustine; Cyclophosphamide; Ifosfamide; Melfalano; Nitrosureasnts	AKI; Hemorrhagic cystitis; Inflammatory lesion; SIADH; Hyponatremia; Fanconi's syndrome; Interstitial nephritis; Diabetes	Damage to proximal and distal tubular structures by action of metabolites and increased cellular oxidative stress
Antimetabolites	Chlopharabine; Methotrexate; Pemetrexed; Gemcitabine; Pentostatin	AKI; Decreased GFR; Interstitial edema; Tubular acidosis; Diabetes insipidus; Microangiopathic hemolytic anemia; SIADH; Hyponatremia	Decreased GFR due to vasoconstrictor action on afferent renal arteries; Crystal precipitation in tubules and induction of tubular injury
Anti-microtubular agents	Paclitaxis; Vincristine; Vinblastine; Vinorelbine	SIADH	Inhibits synthesis of genetic material or causes irreparable DNA damage
Antitumor antibiotics	Daunorubicin; Doxorubicin; Mitomycin	Nephrotic syndrome; Focal segmental glomerular sclerosis; TMA; AKI; Hemolytic uremic syndrome	Epithelial lesions (podocytes)
Platinum agents	Cisplatin; Carboplatin; Ocaliplatin	AKI; Anemia; Hypomagnesemia; Proximal tubular dysfunction; TMA	Drug accumulation in the proximal renal tubules
Cytotoxic agents	Arsenic trioxide; Etoposide; Irinotecan; Topotecan	Tubulointerstitial disease; Rhabdomyolysis; AKI	Increased exposure can be toxic; Higher levels of hematologic toxicity
Immunomodulatory drugs	Thalidomide; Lenalidomide; Pomalidomide	Hypercalcemia; Decreased GFR; Nephrolithiasis	Unclear, depending on the drug, may be related to its type of metabolism
Proteasome inhibitors	Bortezomib; Carfilzomib; Ixazomib	TMA; Acute interstitial nephritis; AKI	Prerenal causes (e.g., hypovolemia); Tumor lysis-like syndrome
EGFR pathway inhibitors	Cetuximab; Panitumumab; Afatinib; Erlotinib; Gefitinib	Electrolyte disturbance; AKI; Diffuse proliferative glomerulonephritis; Nephrotic syndrome	Inhibition of EGFR signaling at the distal convoluted tubule, which regulates transepithelial magnesium transport; AKI mechanism is unclear, however, EGFR plays a role in the maintenance of tubular integrity
HER-2 inhibitors	Trastuzumab; Ado-trastuzumab emtansine; Pertuzumab	Proteinuria; AKI; Decreased GFR; Electrolyte disturbance; Hypertension	Unclear
BCL-2 inhibitors	Venetoclax; Obituzumab; Ofatumumab	AKI	Tumor lysis syndrome
ALK inhibitors	Crizotinib; Alectinib; Brigatinib	Decreased GFR; Development of complex renal cysts; Electrolyte disturbance	Unclear
BRAF inhibitors	Vemurafenib; Dabrafenib; Trametinib; Cobimetinib	Decrease GFR; AKI; Glomerulonephritis; Hyponatremia; Hypertension	Unclear
MTOR inhibitors	Temsirolimus	Glomerulopathy; AKI; Proteinuria	Unclear
BCR-ABL1 and KIT inhibitors	Bosutinib; Dasatinib; Imatinib	Hypophosphatemia; Decreased GFR; AKI; Proteinuria; Nephrotic syndrome; CKD	Rhabdomyolysis; Thrombotic thrombocytopenic purpura; Alterations in glomerular podocytes; Tumor lysis syndrome; Acute tubular injury
Anti-angiogenesis drugs (VEGF pathway inhibitors and TKI)	Bevacizumab; Ramucirumab; Aflibercept; Sunitinib; Sorafenib; Pazopanib; Ponatinib; Others	Hypertension; Proteinuria; Nephrotic syndrome; Decreased GFR; TMA; Glomerulopathy; Electrolyte disturbance	Endothelial cell dysfunction and dysregulation of podocyte
Inhibitor of Bruton’s tyrosine kinase	Ibrutinib	AKI	Unclear, but tumor lysis syndrome might be contributory
Immune checkpoint inhibitors (PD-1, PD-L1, CTLA-4)	Ipilimumab; Pembrolizumab; Nivolumab	Acute tubulointerstitial nephritis; Immune complex glomerulonephritis; TMA; Electrolyte disturbance; AKI (rare)	Unclear, but development of autoantibodies that are pathogenic to the kidney might be contributory
Cytokine	INF-a	Proteinuria; Glomerulopathy; TMA; AKI	Minimal change disease or focal segmental glomerulosclerosis
Cytokine	IL-2	AKI	Capillary leak syndrome leading to AKI
Peptide receptor radioligand	Lutetium Lu-177 dotatate	Decreased GFR	Kidney irradiation

AKI: Acute kidney injury; CKD: Chronic kidney disease; GFR: Glomerular filtration rate; SIADH: Syndrome of inappropriate antidiuretic hormone secretion; TKI: Tyrosine kinase inhibitor; TMA: Thrombotic microangiopathy.