Most of the drugs we use are metabolized by the liver and excreted by the kidneys. During this process, drug prodrugs and metabolites may cause impaired liver and kidney function, and this effect can be exacerbated if there are some specific body types (hypersensitivity to drugs, or reduced tolerance).
With the development of antineoplastic drugs, patients have more access to multiple drugs, long-term therapy, and a similarly increased risk of liver and kidney impairment. So which drugs hurt the liver and kidneys during lung cancer treatment and what to do about it?
What drugs “hurt the liver”?
What drugs hurt the liver?
Serological indicators related to liver function include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), r-glutamyl transpeptidase (r-GT), total serum bilirubin (TBIL), and direct bilirubin (DBIL). Changes in these indicators suggest possible liver damage.
Table 1, Common Terminology Criteria Adverse Events (CTCAE) liver function-related index scores
| Adverse Events | Grade 1 | Grade 2 | Level 3 | Level 4 | Grade 5 |
| ALT elevated | >ULN~3x ULN | >3~5x ULN | >5~20x ULN | >>20x ULN | – |
| ALP increase | >ULN ~ 2.5x ULN | >2.5 to 5 times ULN | >5~20x ULN | ＞20x ULN | – |
| AST increase | >ULN to 3x ULN | >3 to 5 times ULN | >5~20x ULN | >>20x ULN | – |
| TBIL increase | >ULN ~ 1.5x ULN | >1.5 to 3 times ULN | >3~10x ULN | >10x ULN | – |
| r-GT increase in height | >ULN ~ 2.5x ULN | >2.5 to 5 times ULN | >5~20x ULN | ＞20x ULN | – |
Note: ULN: upper limit of normal
Anti-tumor drugs cause hepatotoxicity through three main pathways:
- Direct damage to hepatocytes;
- Exacerbation of underlying liver disease, especially viral hepatitis;
- Underlying liver disease affects antitumor drug metabolism, leading to prolonged metabolism and increased side effects.
Common drugs with hepatotoxicity are as follows:
1. chemotherapy drugs
- Gicitabine: usually causes transient (temporary) transaminase elevations that are not exacerbated by continued dosing and generally do not require dose reduction; if the patient has a pre-existing bilirubin elevation and is at increased risk for hepatotoxicity, the physician may consider dose reduction in this situation.
- Vincristine analogs and etoposide: are metabolized primarily in the liver and excreted through the bile. Vincristines can cause transient transaminase elevations; etoposide is usually not hepatotoxic at standard doses and can cause elevations in bilirubin, transaminases, and ALP at high doses, usually without causing permanent damage. If the patient has pre-existing poor liver function, the dose should be reduced.
- Platinums: Standard doses of cisplatin may cause mild elevation of transaminases and occasionally hepatocellular steatosis and cholestasis.
- Iritecan: metabolized in the liver and cleared from the liver primarily in its native form. Mild, transient elevations in aminotransferase and bilirubin levels may occur following drug administration. Severe transaminase elevations typically occur in patients with preexisting liver metastases from cancer.
.
2. Targeted agents
Targeted drugs can all cause mild to moderate transaminase abnormalities, sometimes requiring adjustment or suspension of the drug. Usually, a degree 1 elevation can still be continued; a degree 2 requires close monitoring of liver function and liver protection therapy; if the elevation reaches a degree 3, the drug needs to be suspended to treat the liver impairment and can only be continued when it returns to a degree 1. If degree 3 liver impairment persists for 1 month, the drug needs to be permanently discontinued.
What drugs “hurt the kidneys”?
What drugs hurt the kidneys?
The indicators of kidney function are creatinine (CREA), uric acid (URIC), urea (UREA), and the indicators in routine urinalysis.
Table 2, CTCAE renal function-related index scores
| Adverse events | Grade 1 | Grade 2 | Level 3 | Level 4 | Grade 5 |
| Creatinine elevation | >1 to 1.5 times baseline value; >ULN to 1.5 times ULN | >1.5 to 3x baseline value; >1.5 to 3x ULN |
>>3x baseline values, >>3 to 6 times ULN |
>>6x ULN | – |
| Definition: biological sample with elevated creatinine levels as demonstrated by laboratory tests | |||||
| Hyperuricemia | >ULN-10mg/dL (0.59nmol/L) without physiological abnormalities | – | >ULN-10mg/dL (0.59nmol/L), with physiological abnormalities | >10mg/dL; >0.59nmol/L; life-threatening | Death |
| Definition: laboratory tests showing higher than normal uric acid concentration | |||||
| Hematuria | Asymptomatic, seen only by clinical observation or judgment, no treatment required | Mildly symptomatic, requiring catheter or bladder cleaning; interferes with daily exercise | massive hematuria requiring blood transfusion, intravenous drug administration, or hospitalization; requiring elective endoscopy, radiation therapy, or surgery; limited personal self-care | Life-threatening; requires urgent treatment | Death |
| Definition: blood in urine found on laboratory tests | |||||
| Hemoglobinuria | Asymptomatic, seen only on clinical examination or diagnosis; no treatment needed | – | – | – | – |
| Definition: laboratory test reveals hemoglobin in urine | |||||
| Proteinuria | Proteinuria 1+, 24-hour urine protein <1.0 g | Adults: proteinuria 2+, 24-hour urine protein 1.0 to 3.4 g, children: urine protein, creatinine ratio 0.5 to 1.9 | Adults: 24-hour urine protein ≥3.5g, children: urine protein, creatinine ratio >1.9 | – | – |
| Definition: Laboratory finding of excess protein in the urine, primarily albumin but also globulin. | |||||
| Acute kidney injury | increase in creatinine level >0.3 mg/dl; or more than 1.5 to 2.0 times baseline | Creatinine exceeds baseline by 2 to 3 times | Creatinine 3x above baseline or >4.0 mg/dl; hospitalization required | Life-threatening, requiring dialysis treatment | death |
| Definition: disorders caused by acute impairment of renal function, mainly classified as pre-renal (less blood flow), renal (kidney damage), and post-renal (outlet blockage) | |||||
| Chronic kidney disease | Glomerular filtration rate or creatinine clearance <60ml/min/1.72m, proteinuria 2+; urine protein quantification >0.5 | Glomerular filtration rate or creatinine clearance 59-30ml/min/1.73m | Glomerular filtration rate or creatinine clearance 29-15ml/min/1.73m | Glomerular filtration rate or creatinine clearance less than 5 ml/min/1.73m, requiring dialysis or kidney transplantation | Death |
| d Definition: progressive and (usually) permanent decompensation of renal function until renal failure. | |||||
Anti-tumor drugs damage the kidney in two main ways:
- Direct damage to urinary tract cells, which is more common;
- After the killing of tumor cells sensitive to chemotherapeutic agents, they rapidly disintegrate in large quantities, and intracellular substances (such as potassium, phosphate and nucleic acids) are excreted via the kidneys, which may cause renal impairment, mainly in the form of acute uric acid nephropathy (UAN, characterized by acute oliguric or anuric renal failure) and tumor lysis syndrome (TLS, characterized by tumor lysis (TLS, characterized by hyperuricemia, etc.).
The drugs that commonly cause nephrotoxicity are listed below.
1. Chemotherapeutic drugs
- Cisplatin: All platinum drugs have some nephrotoxicity, and cisplatin is particularly prominent. It mainly damages the renal tubules and may cause “clear tubular urine” (urine with a colorless, clear, cylindrical protein component) and elevated blood urea nitrogen and creatinine markers. Its nephrotoxicity is closely related to the dose, with small doses (<50 mg/m2) causing no nephrotoxicity or only reversible nephrotoxicity; at >50 mg/m2, the incidence of nephrotoxicity is about 20%. Therefore, cisplatin is routinely treated with a large infusion of fluid (what doctors often call “hydration”) and a diuretic to reduce its concentration in the urine and reduce its binding to the renal tubules, thereby reducing nephrotoxicity.
- Pemetrexed: excreted primarily by the kidneys, the drug is normally excreted in its original form primarily in the urine within 24 hours of administration; if the kidneys are not functioning, this affects drug excretion, causing the drug to accumulate in the body and bring about toxicity. Pemetrexed is usually combined with platinum, which increases the potential for renal impairment, but even with pemetrexed alone, there is still a risk of renal impairment. Therefore, renal function needs to be routinely monitored during drug administration.
2. Targeted drugs
Bevacizumab: may cause nephrotic syndrome (manifested by massive proteinuria, hyperlipidemia, etc.). Patients with nephrotic syndrome should discontinue this drug. It is inconclusive whether the drug is safe to use in patients with moderate to severe proteinuria. Drug instructions recommend discontinuation when 24-hour proteinuria is ≥2 grams and recovery to <2 grams before consideration of reintroduction of the drug [6].
Renal function needs to be routinely monitored during the use of other targeted drugs, and physicians adjust the dose or recommend discontinuation or change of treatment regimen depending on the degree of renal injury.
Summary
Before prescribing a drug, your doctor needs to know your medical history, especially about liver and kidney-related diseases and what medications you have used. If you have these medical histories, tell your doctor in detail, and choose carefully for drugs that may cause liver or kidney toxicity. Doctors are familiar with the indications for use or the toxicity of combination regimens and will avoid combining drugs that are also hepatotoxic or nephrotoxic whenever possible. In addition, liver and kidney function needs to be tested prior to treatment.
If liver or kidney damage occurs after treatment, the physician will adjust the drug and dose according to the extent of the damage. Liver and kidney function needs to be monitored closely both during and after treatment, and if abnormalities occur, the drug in question needs to be discontinued and liver or kidney protective therapy administered.
Hepatoprotective drugs may include N-acetylcysteine, but also reduced glutathione, licorice, silymarin, polyenylphosphatidylcholine, ursodeoxycholic acid, and glucocorticoids if necessary. For patients with pre-existing renal impairment, in addition to appropriate hydration, physicians will use nonsteroidal anti-inflammatory drugs, aminoglycosides, and cephalosporin antibiotics with caution, and contrast agents with caution during imaging.
As a patient, you need to follow your doctor’s orders for medication, cooperate with dose and regimen adjustments, and inform your doctor if you experience any abnormalities during medication use.
Co-authors: Dr. Bai Xiaoyan, Guangdong Provincial People’s Hospital, Guangdong Lung Cancer Institute Dr. Gao Xin