Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.

Although long-term smoking has been associated with chronic kidney disease, its effect on kidney function in early stages has not been clarified. Therefore, the proposed objectives were: (1) to identify subclinical kidney damage in smokers, through a panel of biomarkers; (2) to evaluate the progression of subclinical kidney damage after two years of consumption in these patients; and (3) study whether quitting smoking reduces kidney damage. A prospective study was carried out (patients recruited from a primary care centre and a clinical smoking unit). Kidney function was assessed using a panel of biomarkers and compared between smokers and non-smokers, taking into account potential risk factors for kidney damage. These results show, for the first time in the literature, the relationship between smoking and early (subclinical) kidney damage and provide a panel of biomarkers capable of detecting this condition (Neutrophil gelatinase-associated lipocalin, Kidney injury molecule-1, N-acetyl-beta-D-glucosaminidase, transferrin, and ganglioside-activating protein GM2). This study also indicates that subclinical damage is maintained when use continues, but can be reversed if patients stop smoking. The use of these biomarkers as diagnostic tools can be a preventive measure in the development of chronic kidney disease associated with smoking and in the prevention of acute events associated with potentially nephrotoxic pharmacological treatment in smokers. Trial registration number: NCT03850756.

Immune checkpoint inhibitors (ICIs) represent a major advance in cancer treatment due to their efficacy and safety profile. However, they are not free of side effects, including nephrotoxicity, which worsens prognosis. Diagnosis of renal injury based on clinical findings has limitations in predicting and identifying the type of damage. Biopsy remains the only definitive technique, though it is invasive and carries risks. Thus, new diagnostic approaches using urinary biomarkers are needed. Our hypothesis is that the renal damage associated with ICIs could be subclinical and not detectable by the tests used in clinical practice. Therefore, the aim was to associate the excretion of urinary biomarkers with subclinical renal damage in an experimental mouse model of treatment with ICIs and chemotherapy. A pathophysiological study was also performed to interpret the relationship between the biomarkers and the type of damage. Our results showed that the combined therapy of ICIs and cisplatin causes subclinical tubular damage, as evidenced by the excretion of albumin, NGAL and KIM-1, and suggest that cisplatin-induced renal damage is potentiated by the administration of ICIs. Diagnosis using these urinary biomarkers could be an optimal tool to detect damage at an earlier stage and improve patient management. In turn, ICIs promote an inflammatory process, as demonstrated by the biomarkers TNF-α, IL-9, CD8 and CD3, which would be involved in the development of kidney damage. Our findings open the possibility of studying their usefulness as differential diagnostic tools to identify characteristic inflammatory lesions of acute tubulo-interstitial nephritis, avoiding renal biopsy.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have generated a revolutionary approach in the treatment of cancer, but their effectiveness has been compromised by immune-related adverse events, including renal damage. Although rare, these effects are relevant because they have been related to poor patient prognoses. The objective of this review was to estimate the current incidence of nephrotoxicity in patients treated with single and double ICI therapies. Methods: A total of 1283 potential articles were identified, which were reduced to 50 after applying the exclusion and inclusion criteria. Results: This study reveals the increase in acute kidney injury associated with these drugs in the last decade and shows that, interestingly, combined therapies with ICIs does not lead to an increase in kidney damage compared with anti-CTLA-4. It also suggests that kidney damage could be underdiagnosed when it comes to interstitial nephritis, because definitive evidence requires a renal biopsy. Conclusions: In perspective, these conclusions could guide clinicians in making decisions for therapy personalization and highlight the need to search for new diagnostic systems that are more sensitive and specific to the type of damage and could replace the biopsy.

In recent years, immunotherapy has been postulated as one of the most effective strategies in the fight against cancer. The greatest success in this field has been achieved with the inhibition of molecules involved in slowing down the adaptive immune response by immune checkpoint inhibitors (ICIs). Despite its efficacy, ICI treatment has side effects. Regarding kidney damage, it is estimated that 4.9% of patients treated with ICIs develop renal injury. Furthermore, cancer patients who develop renal dysfunction have a worse prognosis. Current diagnostics are insufficient to predict the underlying renal injury and to identify the type of damage. Our hypothesis is that the renal injury could be subclinical, so the possibility of using new urinary biomarkers could be a useful diagnostic tool that would allow these patients to be managed in a preventive (risk biomarkers) and early (early biomarkers) way and even to clarify whether the renal damage is due to this therapy or to other factors (differential diagnostic biomarkers). A prospective study to validate risk and early and differential biomarkers in patients treated with ICIs is proposed to test this hypothesis. The results derived from this study will improve the clinical practice of cancer treatment with ICIs and therefore the life expectancy and quality of life of patients. Trial Registration: ClinicalTrials.gov, NCT04902846.

En las últimas décadas, los inhibidores del punto de control inmunitario (ICIs) han revolucionado el tratamiento del cáncer, aunque su eficacia se ve afectada por efectos adversos como la nefrotoxicidad, impactando negativamente el pronóstico. Nuestra hipótesis sugiere que los ICIs podrían producir daño renal subclínico, no evidenciado por pruebas clínicas habituales. El objetivo del trabajo fue estudiar la aplicación de biomarcadores urinarios en el diagnóstico temprano del daño renal asociado a los ICIs. Se realizó un estudio prospectivo en el que se reclutaron pacientes tratados con ICIs o con terapia combinada ICIs/quimioterapia. Se realizó un seguimiento de los pacientes durante 12 ciclos de tratamiento y se recogieron muestras de orina antes de iniciar el tratamiento, así como antes y después del tercer ciclo. Los pacientes se clasificaron en “casos” (si durante el tratamiento desarrollaban daño renal, según criterio KDIGO y/o aparecían alteraciones electrolíticas compatibles con el tratamiento con ICIs) y “controles” (pacientes sin daño renal durante el estudio). Se determinaron los biomarcadores A, B, C, D y E mediante la técnica de ELISA. Nuestros resultados evidenciaron una excreción significativa de A y B antes de recibir el tercer ciclo en los casos respecto a los controles. Además, se observó una tendencia de mayor excreción de C y D, incluso antes de recibir la terapia. Por tanto, estos biomarcadores podrían predecir el daño renal producido por los ICIs permitiendo un manejo preventivo y personalizado del paciente.