#5436 CHARACTERIZATION OF KIDNEY FUNCTIONAL DAMAGE ASSOCIATED TO CO-TREATMENT WITH IMMUNE CHECKPOINT INHIBITORS AND CISPLATIN

Abstract

Abstract Background and Aims Advances in the knowledge of the immune response against tumors and the evasion mechanisms of these have led to develop new cancer therapies focused on improving the immune response and thus increasing patient survival. This is the case of immunotherapeutic treatment based on immune checkpoint inhibitors (ICI). However, treatment based on these antibodies is associated with autoimmune side effects, in most of the body organs, that limit their use. Although nephrotoxicity is rare, renal effects have been shown to worsen the prognosis of cancer patients. Recently, therapies based on the combination of immuno and chemotherapy have been approved. They have improved efficacy but have increased the risk of suffering nephrotoxic adverse effects. Our hypothesis is that kidney damage associated with ICIs could be subclinical and not evidenced by the parameters used in clinical practice (mainly plasma creatinine). The aim of this work was to characterize functional kidney damage associated with ICI (anti-CTLA-4) in combination with chemotherapy (cisplatin) in a murine model. Method C57BL/6 mice were treated with combined therapy of cisplatin (10 mg/kg, single dose) and anti-CTLA-4 (10 or 15 mg/kg/day, for 6 days) administrated by intraperitoneal injection. In addition, groups treated with drug monotherapies and a control group were included. Urine and blood samples were collected at baseline, on day 3 and on day 6 (sacrifice). Biomarkers of subclinical kidney damage were determined by ELISA in urine samples. There were albumin, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1). Blood samples were centrifuged to obtain plasma, in which creatinine and urea were measured using colorimetric techniques. Data were analyzed with the statistical software SPSS®. Results Plasma creatinine and urea were elevated in the combined therapy groups with respect to the monotherapies. However, these parameters were similar to the normal range, so they do not reflect obvious kidney injury. It was evidenced a statistically significant elevation of biomarkers of subclinical kidney damage in the combined therapy groups with respect to monotherapies and control group. Conclusion This study suggests that the combination of anti-CTLA-4 with cisplatin could cause a potenciation effect on subclinical kidney damage compared to monotherapies. This experimental model would make possible to study the nephrotoxicity mechanisms of ICI. Moreover, it could have a potential diagnostic utility through the identification of biomarkers of subclinical kidney damage, that would avoid biopsy.