Renal Toxicity of Tumor Immunotherapy

Renal Toxicity of Tumor ImmunotherapyThe nephrotoxicity of anti-tumor therapy is becoming more and more common in clinical practice, and it has gradually developed into a subspecialty of "tumor nephropathy". Antitumor Immunotherapy, the use of drug-mediated immunity to recognize tumor cells and attack them. So what are the effects of these anti-tumor immunotherapies on the kidneys? Mark A. Perazella, of Yale University in the us, reported in the recent American Journal of Nephrology.

Interferon IFN-α therapy

Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) that reflects podocyte injury and thrombotic microangiopathy (TMA) that reflect vascular endothelial injury, are common in tumor patients treated with IFN-α therapy. FSGS and MCD with acute renal injury (AKI) and high levels of proteinuria are common after 3 months to 6 years of IFN-α therapy. In the presence of FSGS, this type is generally less responsive to discontinuation and steroid therapy, while MCD is more effective for discontinuation and steroid therapy. TMA generally appears after about 35 months of IFN-α treatment, accompanied by severe AKI and high mortality, and timely withdrawal is the key to the prognosis.

Interleukin IL-2 therapy

High doses of IL-2 cause cytokine-mediated capillary leakage syndrome, leading to reduced intravascular volume, decreased fluid in the third compartment, and renal toxicity. The leakage of capillaries leads to prerenal azotemia, leading to AKI. However, severe hypotension can also cause ischemic acute tubular injury (ATI). IL-2 can also cause cytokine mediated immune kidney damage. Therefore, renal function and urine volume should be monitored in patients receiving high-dose IL-2 therapy. Although in most cases AKI can be alleviated after drug withdrawal, the recovery of renal function may be slowed down if intrinsic renal damage has been caused.

Checkpoint inhibitor (CPI) therapy

A meta-analysis of 48 procedural death receptor-1 (pd-1) inhibitors suggested that the overall incidence of AKI was 2.1%, and the incidence of electrolyte abnormalities was 0.6% ~ 1.3%. AKI usually appears within 3 to 12 months after treatment with CPI. Therefore, renal injury tests such as serum creatinine and urine analysis are required at baseline, 3 months, 12 months after treatment and annually thereafter.

CPI - related AKI was evaluated according to the degree of kidney injury. If patients are stage 1 AKI defined by kidney disease improving global outcomes (KDIGO), reversible causes such as decreased volume, urinary obstruction, and drug-related AKI need to be monitored and evaluated. For patients with stage 2/3 AKI with or without proteinuria, consult a nephrologist to assess the cause of AKI and whether renal biopsy is required. Tests included renal ultrasound, urine analysis/urinoscopy, and urinary protein creatinine ratio.

If the urine microscopy has aseptic purulent urine and leukocyte tubular type, it indicates inflammatory kidney injury. However, due to the lack of specificity and sensitivity of blood and urine tests to acute interstitial nephritis (AIN), renal biopsy is recommended to clarify the lesion type if the cause of AKI is unclear. For stage 2/3 AKI, this anti-tumor therapy should be continued before renal biopsy results.

Renal biopsy has guiding significance for treatment, because CPI-mediated AIN is usually sensitive to drug withdrawal and glucocorticoid therapy, and other AKI lesions such as ATI, TMA and FSGS are generally not sensitive to drug withdrawal and steroid therapy. This will reduce unnecessary and potentially side effects of glucocorticoid therapy (hypertension, edema, hyperglycemia, etc.). If AKI is not caused by immunotherapy, CPI treatment may be continued.

If AIN is found, the patient's medication needs to be reviewed and the medication that is known to cause AIN should be discontinued. If AKI is not severe enough to require dialysis or renal function is restored after treatment with glucocorticoid for AKI, the CPI therapy may be resumed after withdrawal. However, even with other types of CPI, AKI rarely does not reoccur. CPI re-use can only be done if it is clearly life-saving and only after a discussion with the oncologist and nephrologist.

Chimeric antigen receptor T cell (CAR-T) therapy

The risk of complications from CAR-T therapy can be predicted by tumor burden and expected tumor response. Prevention includes pretreatment chemotherapy to reduce tumor burden and glucocorticoid to reduce inflammatory responses (table 1). Fluid resuscitation and hyperbaric drugs maintain hemodynamic stability and renal perfusion. For severe grade 3/4 cytokine release syndrome and catecholamine-dependent hypotensive shock, trastuzumab (a monoclonal anti-IL-6 receptor antibody) can be used to improve blood pressure and reduce multi-organ failure. In addition, glucocorticoids may be used in patients with only partial efficacy of trastuzumab or recurrent symptoms.

Table 1. Nephrotoxicity of chimeric antigen receptor T cell (CAR-T) therapy


Prerenal AKI/ acute renal tubular injury

Cytokine release syndrome with capillary leakage and hypotension

Hemophagocytic lymphocytosis is associated with inflammation

Acute cardiac insufficiency with low cardiac output and hypotension

Insufficient blood vessel volume due to fever, nausea, vomiting, and diarrhea

Oncolytic syndrome

-Electrolyte disturbance

Hypokalemia, hypophosphatemia and hyponatremia

-Prevention/treatment of toxicity

Chemotherapy reduces tumor burden

Glucocorticoids reduce inflammation

Supportive treatment of hypotension, such as hypertensive drugs, intravenous fluids, and oxygen

For cytokine releasing syndrome and cytophagic lymphocyte hyperplasia, the IL-6 pathway is blocked by trastuzumab

In conclusion, although new Immunotherapy provides effective tumor treatment, it is also accompanied by potential kidney damage. The nephrotoxicity of IFN and high dose IL-2 has been well known as traditional Immunotherapy. Novel Immunotherapies, such as checkpoint suppression therapy with acute interstitial nephritis, and CAR-T therapy may be associated with AKI and electrolyte abnormalities.


***Please seek professional medical advise for the diagnosis or treatment of any ailment, disease or medical condition. This article is not intended to be a substitute for the advice of a licensed medical professional.***

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