Application of Biomarkers of Renal Damage in Patients Treated With Immune Checkpoint Inhibitors

During the last decade, advances in the knowledge of both the immune response to tumors, as well as the understanding of their evasion mechanisms, has made it possible to design treatments aimed at improving said response and increasing patient survival in figures up to now unthinkable. The greatest success in this field has been achieved through the inhibition of molecules involved in the braking of the adaptive immune response: the so-called CTLA-4 (cytotoxic T-lymphocyte antigen-4) and PD-1 (programmed cell death protein-1), with their respective ligands. The compounds capable of blocking the action of these molecules constitute the so-called "immune checkpoint inhibitors" (ICI).

As with conventional therapies, the adverse effects that these drugs develop in many cases limit their use. Although nephrotoxicity is less common than other complications (liver, gastrointestinal, skin, and lung toxicity), kidney effects have been shown to worsen prognosis in cancer patients who develop kidney dysfunction. In addition, therapies based on ICI combinations have recently been promoted to avoid the resistance acquired by the tumor to treatment, and have even been associated with chemotherapy, which has improved the response, but has increased the risk of nephrotoxic adverse events.

Kidney injury due to immunotherapy treatment is characterized by acute kidney damage, proteinuria, electrolyte disturbances, tubular injuries, glomerular injuries, and more frequently acute tubulointerstitial nephritis, the toxic mechanisms underlying these events are largely unknown. The usual clinical procedure when kidney damage appears is to suspend immunotherapy treatment and administer systemic corticosteroids. However, discontinuation of treatment may not be appropriate without diagnostic confirmation of the progression of kidney damage, but continuation of treatment if the diagnosis is subsequently confirmed may lead to definitive and irreversible kidney damage.

At present, the diagnosis of kidney injury based on clinical findings and laboratory tests is insufficient to predict the underlying kidney injury and identify the type of damage, since serum markers such as creatinine or urea only provide information when the damage is already established. In addition, it must be taken into account that kidney injuries, such as ischemic and / or nephrotoxic tubular injury, paraneoplastic kidney injury, glomerular injuries, and tubular obstruction can occur in cancer patients as a consequence of their pathology and associated therapy. . Therefore, a careful evaluation of the possible causes should be made to make the correct diagnosis in patients undergoing treatment with ICI (for example, interstitial nephritis due to ICI versus other types of damage by other drugs) and based on that, proceed to the management of the patient optimally. In this scenario, renal biopsy is presented as the only alternative to definitively diagnose the lesion and potentially guide therapy. Although it is the definitive diagnostic method, it is an invasive technique, not without complications, therefore the possibility of using biomarkers capable of identifying the type of damage (differential diagnosis biomarkers) would represent a highly relevant diagnostic advance.

Another important approach in diagnosis is the identification of damage early, since creatinine levels (a commonly used marker) do not show a significant increase until kidney function has already decreased by 50%. Currently, the usefulness of biomarkers of early kidney damage associated with drug treatment has been described. These markers are components or metabolic derivatives, degradation compounds or remains of them that appear in the urine as a consequence of damage to kidney structures, showing subclinical damage.