Checkpoint inhibitor therapy is a form of cancer immunotherapy targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), programmed cell death-1 (PD-1), and programmed cell death-ligand 1 (PD-L1) to restore immune system function (1). Immune-checkpoint inhibitors (ICI)-based combinations, such as pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib and nivolumab/ipilimumab, are now the standard of care for first-line metastatic renal cell carcinoma (mRCC) (2–4). These combinations have shown particular efficacy among intermediate- and poor-risk patients based on the International Metastatic RCC Database Consortium (IMDC). Following first-line treatment with vascular endothelium growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI), nivolumab, a PD-1 blocking antibody, is a recognized options for second-line therapy (5, 6). However, it is important to acknowledge that not all mRCC patients experience long-term benefits from ICIs, whether administered as monotherapy or in combination (7, 8).

RCC is a heterogeneous disease characterized by a highly variable clinical course, spanning from indolent to rapidly progressive disease (9, 10). Notably, one-third of RCC patients present with bone metastases (BMs) at diagnosis, which is strongly associated with a worse prognosis (11) and a median overall survival (OS) that ranges from 12 to 28 months (12).

While ICIs have demonstrated substantial efficacy against visceral disease, their effectiveness in patients with bone metastases remains insufficiently explored. Data indicates that BMs are associated with inferior progression-free survival (PFS) and OS compared to other metastatic sites during ICI treatment (13), although, additional investigations are imperative.

Consequently, identifying biomarkers to distinguish patients who are most likely to benefit from ICI from those who are not represents an unmet clinical need in practice and research. While potential biomarkers such as molecular and genomic signatures are currently under investigation, none have achieved validation for daily clinical use.

Hyponatremia, defined as a serum sodium level below 135 mEq/L, serves as an independent prognostic factor in various solid malignancies, including RCC (14–17). It has been linked to poorer prognosis and shorter cancer-specific survival in mRCC patients treated with different drug classes (18, 19). Recently, lower, but in range, sodium levels have been correlated with worse prognosis in mRCC patients receiving TKIs or nivolumab therapy (20, 21). Preclinical investigations are currently exploring the influence of sodium levels on cancer progression and the modulation of immune responses, with the potential to unveil novel concurrent therapeutic strategies in the next future (22–24).

This multicenter retrospective analysis was conducted to evaluate the impact of sodium levels on response rates and survival outcomes in RCC patients with BMs receiving nivolumab as second-line therapy or beyond.

The treatment of mRCC has seen significant advancements, particularly in the use of initial immunotherapy, which has contributed to improve patient prognosis (29). Nivolumab remains the standard of care as a second-line therapy after demonstrating superiority over everolimus in terms of response rate, PFS, OS, and quality of life in the pivotal CheckMate 025 trial (6). However, a significant portion of patients does not respond adequately to ICI therapy or experiences limited benefits. Prognostic markers for immunotherapy response identified in other tumor types have not been replicated in mRCC. The Meet-URO 15 study introduced a more accurate prognostic score incorporating clinical factors (bone metastasis) and inflammatory indices (NLR), outperforming IMDC alone (25). The presence of BMs was identified as an independent prognostic factor for lower OS. However, the study also identified a subgroup of patients with BMs (IMDC favorable-risk category and low NLR) associated with a very positive prognosis, indicating the need to consider bone metastasis prognostics within the patient’s clinical and immunological context.

Approximately one-third of mRCC patients have BMs, with median OS ranging from 12 to 28 months (12). While ICIs have shown efficacy against visceral disease, their effectiveness in patients with BMs remains insufficiently explored. The predictive and prognostic role of BM remains unclear, possibly influenced by niches and pathological bone loss hindering immune activation, affecting memory T and B lymphocytes, and cytotoxic T cell production. T-regs may play a role in balancing osteoclastic and osteoblastic activity, with potential immunosuppressive effects in the bone microenvironment (30). Limited data suggests that BMs may be associated with inferior PFS and OS during ICI treatment compared to other metastatic sites (13). Conversely, in an exploratory post hoc analysis of CheckMate 9ER study indica ted that patients with BMs experienced tumor regression with nivolumab plus cabozantinib compared to sunitinib, as did patients with other metastatic sites (31). Furthemore, subgroup analyses of the Checkmate 025 study showed a major improvement in ORR in patients with BMs treated with nivolumab compared to everolimus (26% vs. 6%, respectively) (32). However, the potential benefits of ICIs on BMs require further investigation.

Our study represents the first attempt to evaluate the prognostic significance of sodium levels in mRCC patients with BMs receiving nivolumab as a ≥2nd line therapy. We found that a pre-ICI sodium level ≥140 mEq/L correlated with significantly improved OS (p=0.04). Patients with sodium levels ≥140 mEq/L after treatment start as well as those with sodium levels ≥140 mEq/L at both pre- and post-ICI evaluation had longer PFS (p=0.05 and p<0.01, respectively) and OS (p<0.01) compared to patients with sodium levels <140 mEq/L. Notably, patients with sodium levels ≥140 mEq/L at the post-ICI evaluation and at both pre- and post-ICI evaluation displayed a better DCR (p=0.01 and p<0.01, respectively). These results align with our recent study, which demonstrated that lower sodium levels (<140 mEq/L) were associated with worse PFS and OS in mRCC patients receiving TKIs as first-line or nivolumab as second-line therapy (20, 21). It is important to note that higher baseline sodium levels do not significantly impact PFS in these patients. This may be due to the unique mechanisms of immunotherapy, including delayed response, atypical tumor responses (e.g., pseudo-progression), and establishment of long-lasting immune memory, may explain why improvements in OS are observed without immediate impacts on PFS. These factors underscore the complexity of assessing treatment efficacy and emphasize the importance of considering long-term benefits in outcome assessments.

Serum sodium levels are routinely measured but not clearly defined for prognostic proposes in mRCC. Nonetheless, previous evidence has linked hyponatremia with poor prognosis in various cancers, including RCC (14–16, 33, 34). Notably, Rinaldi et al., evaluated the prognostic impact of hyponatremia in NSCLC patients with BMs. They found that patients with BMs and hyponatremia had a mOS of 10.1 months versus 13.1 months for eunatremic patients with BMs, suggesting an important prognostic role of sodium level in the management these patients (35). Several causes of cancer-associated hyponatremia have been proposed (36–39), but the pathophysiology of hyponatremia is not yet fully understood.

Recent hypotheses suggest that upregulated sodium-transporting proteins my contribute to intracellular sodium accumulation in cancer cells, promoting invasiveness and poorer prognosis (22). Additionally, emerging evidence implicates sodium storage in immune system modulation, potentially influencing cancer treatment outcomes (23). In particular, the intake of sodium may potentially affect the activation state of the immune system by directly impacting T helper cell subtypes and innate immune cells in various tissues (23). Furthermore, it has been shown that an elevated consumption of sodium can alter the makeup of the intestinal microbiota, resulting in indirect impacts on immune cells (23). These discoveries suggest that sodium might have regulatory functions in several health conditions, including cardiovascular disease, inflammation, infection, autoimmunity, and could potentially even be relevant in the context of cancer treatment.

A recent post hoc analysis of the IMmotion151 and IMvigor 211 phase 3 clinical trials indicated that elevated baseline sodium levels are associated with a positive response to immunotherapy and improved outcomes in patients with mRCC and metastatic urothelial carcinoma receiving immunotherapy (40). Unlike other key serum electrolytes such as potassium, magnesium, and calcium, sodium alone shows a linear correlation with favorable prognosis during immunotherapy, suggesting a potentially beneficial role for increased sodium levels. Importantly, after adjusting for prognostic factors, elevated sodium levels did not improve prognosis in the comparator arms of the trials, which involved sunitinib and chemotherapy, respectively. This implies that the predictive value of baseline sodium may be specific to immunotherapy (40).

This study, in line with our previous findings (20, 21), underscores a potential correlation between elevated sodium levels and improved response to ICI in patients with RCC and BMs. These findings have the potential to enhance the management of mRCC patients. Overall, we can hypothesize that patients at low risk of developing hyponatremia before ICI treatment have a stronger likelihood of improved outcomes. Additionally, patients who maintain normal serum sodium levels after exposure to ICI tend to responde better. This raises the possibility of integrating serum sodium levels into patient risk assessments and may serve as an impetus to involve consultants, such as nephrologists, earlier, who can focus on managing natremia.

This research has various limitations, primarily due to its retrospective nature and the utilization of second-line therapy, which is no longer the standard of care, except in specific scenarios. Furthermore, the comprehensive assessment of patient comorbidities and their concurrent medications, particularly antihypertensive drugs, was omitted. Moreover, numerous factors, such as the circumstances at the time of sampling or prior nephrectomy, have the potential to impact the sodium levels in these individuals (37).

Notwithstanding these constraints, the study boasts several strengths, including participation from multiple healthcare centers, the inclusion of a substantial patient cohort, and the examination of natremia at both baseline and post-treatment initiation. Moreover, we recognized that further validation in an independent cohort could be necessary to confirm the utility of this biomarker in these patients. These findings will also be investigated in the ongoing prospective study Meet-URO 33 (41).

In summary, our investigation has unveiled that among RCC patients with BMs treated with nivolumab as a second-line therapy or beyond, the presence of a pre-ICI serum sodium level of ≥140 mEq/L is associated with extended OS compared to those with sodium levels <140 mEq/L. Furthermore, individuals who have sodium levels ≥140 mEq/L after starting treatment demonstrate superior PFS, OS, and DCR in contrast to those with levels <140 mEq/L. Additionally, patients consistently exhibiting sodium values ≥140 mEq/L both before and after ICI administration consistently display enhanced OS, PFS, and DCR relative to patients with sodium levels ≥140 mEq/L at either time point. Higher sodium levels may constitute a crucial factor linked to improved survival outcomes in RCC patients with BMs undergoing immunotherapy, implying its potential inclusion as an additional parameter in patients’ risk assessments. Further investigations are warranted to validate our findings.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Regional Ethical Committee of Liguria, under registration number 068/2019. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from primarily isolated as part of your previous study for which ethical approval was obtained. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

MaC: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. SR: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. MM: Data curation, Resources, Writing – original draft, Writing – review & editing. UG: Investigation, Writing – original draft, Writing – review & editing. SB: Supervision, Visualization, Writing – original draft, Writing – review & editing. LG: Methodology, Resources, Writing – original draft, Writing – review & editing. GF: Data curation, Writing – original draft, Writing – review & editing. PZ: Resources, Supervision, Writing – original draft, Writing – review & editing. MeC: Writing – original draft, Writing – review & editing. SC: Resources, Writing – original draft, Writing – review & editing. IZ: Writing – original draft, Writing – review & editing. SP: Writing – original draft, Writing – review & editing. RR: Data curation, Writing – original draft, Writing – review & editing. MS: Validation, Writing – original draft, Writing – review & editing, Supervision. VM: Investigation, Resources, Writing – original draft, Writing – review & editing. MT: Resources, Writing – original draft, Writing – review & editing. LF: Writing – original draft, Writing – review & editing, Resources, Supervision. VP: Resources, Writing – review & editing. OC: Resources, Validation, Writing – review & editing. FA: Conceptualization, Writing – review & editing. FM: Resources, Writing – review & editing. GP: Supervision, Writing – review & editing. FN: Resources, Supervision, Writing – review & editing. FV: Resources, Writing – review & editing. AC: Resources, Writing – original draft. MN: Resources, Writing – review & editing. AM: Resources, Writing – review & editing. EN: Supervision, Validation, Writing – review & editing. AS: Resources, Writing – review & editing. GB: Supervision, Validation, Writing – review & editing. PR: Resources, Validation, Writing – review & editing. LC: Supervision, Validation, Writing – review & editing. LA: Supervision, Validation, Writing – review & editing. GR: Conceptualization, Data curation, Formal analysis, Methodology, Software, Supervision, Validation, Writing – original draft, Writing – review & editing.