Introduction Chemotherapy is one of the fundamental pillars in the treatment of malignant tumors; however, its use is frequently accompanied by adverse effects on multiple organs. The kidneys are among the most vulnerable organs due to their pivotal role in the filtration and excretion of drugs and their metabolites. Numerous chemotherapeutic agents can cause acute or chronic kidney injury, potentially limiting optimal therapeutic doses and affecting treatment outcomes. Studies indicate that the prevalence of renal disorders among patients receiving antineoplastic therapies may reach a notable proportion, particularly in cases of hematological malignancies. Chemotherapeutic Agents Most Commonly Associated with Kidney Injury Platinum Compounds (Cisplatin and Carboplatin) Platinum compounds, particularly cisplatin, are among the chemotherapeutic agents most frequently associated with kidney injury. Cisplatin is used in the treatment of 40–80% of solid tumors, but it causes acute kidney injury (AKI) in a significant proportion of patients. The mechanism of injury involves the accumulation of cisplatin within the mitochondria of renal tubular epithelial cells, leading to structural and functional mitochondrial damage, increased production of reactive oxygen species (ROS), and induction of apoptosis. Cisplatin is also associated with the formation of covalent bonds with DNA (DNA adducts), causing DNA damage and mitochondrial dysfunction, ultimately resulting in renal tubular necrosis and kidney failure. Clinical manifestations of cisplatin-induced kidney injury include decreased glomerular filtration rate, hypomagnesemia, salt wasting, and acute tubular injury. Ifosfamide Ifosfamide causes a distinctive renal tubular injury known as Fanconi syndrome. The mechanism involves the production of a highly toxic metabolite called chloroacetaldehyde (CAA) within tubular cells, leading to depletion of mitochondrial ATP stores and failure of Na⁺/K⁺-ATPase pumps on cell membranes. Consequently, proximal tubular cells lose their ability to reabsorb glucose, amino acids, bicarbonate, potassium, and phosphate, resulting in substantial urinary loss of these substances. Children receiving ifosfamide are considered particularly at risk of bone deformities and growth disturbances due to chronic phosphate loss. Methotrexate High-dose methotrexate is used in the treatment of osteosarcoma and acute lymphoblastic leukemia. The nephrotoxicity of methotrexate lies in its physicochemical properties: it and its primary metabolite (7-hydroxymethotrexate) have very low solubility in acidic media. When urine pH is low, methotrexate precipitates as crystals within the distal tubules and collecting ducts, causing obstruction and acute kidney injury. This injury leads to decreased methotrexate excretion and elevated serum levels, causing life-threatening systemic toxicities such as bone marrow suppression and mucosal ulceration. Prevention and Protective Strategies Given the severity of chemotherapy-associated nephrotoxicity, prevention and protective strategies are considered an urgent necessity. The most prominent of these strategies include: · Intensive hydration: Aggressive intravenous hydration is considered the most important intervention for preventing nephrotoxicity associated with cisplatin and methotrexate. Fluid volumes administered typically range from 3000–4500 mL/m² per day. · Urine alkalinization: For methotrexate, raising urine pH (pH ≥ 7) is an essential preventive measure to prevent crystal precipitation in the renal tubules. · Magnesium supplementation: Cisplatin is associated with urinary magnesium loss, so intravenous magnesium supplementation is recommended for patients. · Dose adjustment: Patients with pre-existing renal impairment may require adjustment of chemotherapeutic drug doses to reduce risks. · Regular monitoring: Regular monitoring of renal function (creatinine, urinary protein, blood pressure, electrolytes) is recommended during and after the treatment period, particularly for patients who have received nephrotoxic agents. · Avoidance of concurrent nephrotoxic drugs: Caution should be exercised when using other drugs that may increase the risk of kidney injury, such as non-steroidal anti-inflammatory drugs or certain antihypertensive agents. Conclusion Chemotherapy-induced kidney injury represents a complex clinical challenge requiring close collaboration among oncologists, nephrologists, and pharmacists. The pattern and severity of renal injury vary according to the type of drug used, with mechanisms ranging from direct accumulation of toxins in tubular cells, to crystal precipitation, immune-mediated reactions, and vascular dysregulation. Despite advances in understanding these mechanisms, further research is still needed to develop targeted preventive strategies and safer drugs. Early detection of kidney injury markers using sensitive biomarkers may allow for faster and more effective interventions to preserve renal function in cancer patients. Al-Mustaqbal University The First University in Iraq