Research ArticleClinical Studies
Open Access

Serum Zinc Levels and Skin-related Adverse Events During Systemic Therapy for Renal Cell Carcinoma

SHINPEI SAITO, TOMOKAZU SAZUKA, HIROAKI SATO, YURI WATANABE, FUMIYA YOKOCHI, KOHEI TOMA, YUSUKE ONODA, KOTARO NAGAOKA, SANGJON PAE, KODAI SATO, KEISUKE ANDO, YASUTAKA YAMADA, YUSUKE IMAMURA and SHINICHI SAKAMOTO
In Vivo January 2026, 40 (1) 333-340; DOI: https://doi.org/10.21873/invivo.14196

Abstract

Background/Aim: This study aimed to evaluate the association between serum zinc levels and skin-related adverse events in patients with advanced or metastatic renal cell carcinoma receiving systemic drug therapy.

Patients and Methods: This retrospective observational study included 25 patients with unresectable or metastatic renal cell carcinoma (RCC) who initiated systemic therapy between September 2018 and September 2023. Serum zinc levels were measured at multiple time points during treatment, and skin-related adverse events were graded according to CTCAE version 5.0.

Results: The median age was 73 years, and 76% of patients were male. Skin-related adverse events occurred in 12 patients (48%), with grade 3 or higher events in four patients (16%). A progressive decline in zinc levels was observed in 15 patients (60%) during treatment. Among seven patients with zinc levels measured at the time of adverse event occurrence, six (85.7%) exhibited decreased zinc levels compared to baseline.

Conclusion: This study provides preliminary evidence of an association between zinc depletion and skin-related adverse events in patients with renal cell carcinoma receiving systemic therapy. Zinc monitoring may represent an underutilized strategy for optimizing patient care.

Keywords:

Introduction

Over the past two decades, systemic therapy for advanced and metastatic renal cell carcinoma (RCC) has evolved significantly with the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), resulting in substantial improvements in patient outcomes (1). Current first-line treatments include ICI–TKI combinations, dual ICIs, or TKI monotherapy, depending on patient risk and clinical characteristics (2-6).

Despite their efficacy, these treatments frequently cause adverse events, with skin-related toxicities being particularly common and detrimental to quality of life (7, 8). These include rash, pruritus, hand–foot syndrome, xerosis, and other inflammatory conditions, occurring in 30% to 80% of patients, depending on the specific therapy (9).

Although the underlying mechanisms of these toxicities remain unclear, zinc deficiency has been proposed as a potential contributing factor. Zinc is essential for numerous biological processes, including skin maintenance, immune regulation, and wound healing (10, 11). The epidermis contains high concentrations of zinc, which are necessary for keratinocyte function and maintenance of skin barrier integrity (12). Zinc deficiency is associated with various skin disorders, such as acrodermatitis enteropathica and delayed wound healing, and is common among patients with cancer due to factors such as reduced dietary intake, malabsorption, and treatment-related effects (13, 14).

However, the association between serum zinc levels and skin toxicities in patients with RCC undergoing systemic therapy remains unclear. We hypothesized that lower serum zinc levels may be associated with an increased incidence of skin-related toxicities. This retrospective study aimed to assess that association in patients with advanced RCC receiving systemic therapy, as well as to explore longitudinal changes in serum zinc levels and differences across treatment regimens.

Patients and Methods

Study design and patient population. This retrospective observational study was conducted at our institution following approval by the Institutional Review Board of Chiba University (Approval No. 2554). We identified all patients with unresectable or metastatic RCC who initiated systemic therapy at our center between September 2018 and September 2023. Inclusion criteria were as follows: 1) histologically confirmed RCC with unresectable locally advanced or metastatic disease; 2) initiation of systemic therapy ICIs, TKIs, or combination regimens; 3) availability of serum zinc level measurements at two or more time points during treatment; and 4) adequate follow-up data for adverse event assessment. Exclusion criteria were: 1) prior systemic therapy for RCC; 2) concurrent zinc supplementation at treatment initiation; 3) significant comorbidities known to affect zinc metabolism; and 4) incomplete clinical or laboratory data.

From an initial cohort of 28 patients who met the inclusion criteria, 25 had serum zinc levels measured at two or more time points and were included in the final analysis. All patients were notified via opt-out public notice regarding the content of the ethical review associated with this study.

Treatment regimens and patient management. Patients received systemic therapy in accordance with current clinical guidelines and institutional protocols. Treatment regimens included: 1) dual ICI combination therapy (nivolumab plus ipilimumab); 2) ICI plus TKI combination therapy (pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, or avelumab plus axitinib); and 3) TKI monotherapy (pazopanib). Treatment selection was based on patient performance status, comorbidities, risk stratification, and physician discretion, in alignment with standard clinical practice.

Patients were monitored according to standard institutional protocols with regular clinical assessments, laboratory evaluations, and imaging studies. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Skin-related adverse events included rash, pruritus, xerosis, hand–foot syndrome, mucositis, and other dermatological toxicities. Dose modifications, treatment interruptions, and supportive care measures were implemented as clinically indicated.

Serum zinc level assessment. Serum zinc levels were measured using atomic absorption spectrophotometry or inductively coupled plasma mass spectrometry at the institutional laboratory. The Japanese Society of Clinical Nutrition (JSCN) defines the normal range as 80–130 μg/dl. Zinc levels were measured at baseline and at regular intervals during treatment as part of routine monitoring or when clinically indicated.

For analysis purposes, zinc decline was defined as a decrease in the final zinc measurement compared to baseline. Baseline zinc deficiency was defined as an initial serum zinc level below 80 μg/dl. The temporal relationship between zinc level changes and the occurrence of skin-related adverse events was assessed by comparing zinc levels at baseline and at the time of adverse event onset.

Statistical analysis. Descriptive statistics were used to summarize patient demographics, treatment characteristics, and clinical outcomes. Continuous variables are expressed as medians and ranges, while categorical variables are presented as frequencies and percentages. The association between changes in zinc levels and the occurrence of skin-related adverse events was evaluated using Fisher’s exact test for categorical variables and the Mann–Whitney U test for continuous variables. A p-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using JMP Pro 18.0.1 (SAS Institute, Cary, NC, USA).

Results

Patient characteristics. Twenty-five patients with unresectable or metastatic RCC were included in the analysis. Patient demographics and baseline characteristics are summarized in Table I. The median age was 73 years (range=40–85 years), and 19 patients (76%) were male. The median serum zinc level at the time of the first measurement was 69 μg/dl (range=47–124 μg/dl). Among eight patients who had zinc levels measured prior to treatment initiation, the median baseline serum zinc level was 63 μg/dl (range=47–124 μg/dl).

View this table:
Table I.

Patient characteristics.

With respect to initial treatment regimens, 10 patients (40%) received dual ICI combination therapy (ICI–ICI), 14 patients (56%) received ICI plus TKI combination therapy (ICI–TKI), and one patient (4%) received TKI monotherapy.

Skin-related adverse events. Skin-related adverse events occurred in 12 patients (48%) during the observation period. The spectrum of skin toxicities included rash, pruritus, xerosis, hand–foot syndrome, and mucositis. Grade 3 or higher skin-related adverse events were observed in four patients (16%).

Temporal changes in serum zinc levels. The median follow-up period for serum zinc level monitoring was 18 months. Figure 1 illustrates the temporal course of serum zinc levels during treatment. Among all 25 patients, 15 (60%) demonstrated a progressive decline in serum zinc levels over the course of treatment. This decline was observed across different treatment regimens and appeared to be a common phenomenon during systemic therapy for RCC.

Figure 1.
Figure 1.

Temporal trends in serum zinc levels during systemic therapy.

Serum zinc level changes at the time of adverse event occurrence. Figure 2 presents the changes in serum zinc levels at the time of skin-related adverse event onset. Among seven patients who had serum zinc levels measured at the time of adverse event development, six (85.7%) exhibited decreased zinc levels compared to their baseline or previous measurements. This finding provides further support for a temporal relationship between zinc depletion and the development of skin toxicities.

Figure 2.
Figure 2.

Changes in serum zinc levels at the onset of skin-related adverse events (AEs).

Treatment-specific analysis. Table II presents a comparison of the associations between zinc level decline and skin-related adverse events stratified by initial treatment regimen. Among patients receiving dual ICI combination therapy (ICI–ICI), 66.7% of those who developed skin-related adverse events also experienced a decline in serum zinc levels. Similarly, among patients receiving ICI plus TKI combination therapy (ICI–TKI), 66.7% of those with skin-related adverse events exhibited concurrent zinc level decline. The objective response rate (ORR) was 60.0% in all patients, and 66.7% among those who experienced skin-related adverse events in the ICI–ICI group. In the ICI–TKI group, the ORR was 78.6% overall and 83.3% among those with skin-related adverse events.

View this table:
Table II.

Association between serum zinc level decline and skin-related adverse events by treatment regimen.

Discussion

This retrospective study represents the first systematic investigation of the relationship between serum zinc levels and skin-related adverse events in patients with advanced RCC receiving modern systemic therapies. The findings offer several important insights that may have significant clinical implications for the management of treatment-related skin toxicities.

The most notable observation was the high prevalence of zinc depletion during systemic therapy for RCC, with 60% of patients exhibiting a progressive decline in serum zinc levels over time. This finding is consistent with prior reports suggesting that cancer treatments may disrupt zinc homeostasis through multiple mechanisms (15, 16). Patients with cancer are at increased risk of zinc deficiency due to decreased dietary intake, impaired absorption, elevated metabolic demands, and treatment-related factors (17). In particular, gastrointestinal toxicities associated with systemic cancer therapies can significantly impair zinc absorption and contribute to progressive depletion (16).

The temporal association between zinc depletion and skin-related adverse events was particularly compelling. Among patients who had serum zinc levels measured at the time of adverse event onset, 85.7% exhibited decreased zinc levels compared to baseline. Although this finding is based on a small subgroup, it provides supportive evidence for a temporal relationship between zinc depletion and the development of skin toxicities. This association is consistent with the well-established role of zinc in maintaining skin barrier integrity and supporting cellular repair mechanisms (18). Zinc deficiency is known to impair wound healing, reduce collagen synthesis, and compromise epithelial integrity, all of which may predispose patients to treatment-related skin toxicities (17-19).

Our analysis revealed numerical trends suggesting higher rates of skin-related adverse events in patients with declining zinc levels. The clinical relevance of this trend should not be dismissed, particularly given that 75% of patients with grade 3 or higher skin toxicities exhibited concurrent declines in serum zinc levels. These severe toxicities often necessitate dose modifications or treatment interruptions, which may compromise therapeutic efficacy (20). Previous studies in other cancer populations have demonstrated that maintaining adequate zinc levels can help preserve treatment intensity and improve patient outcomes (21, 22).

Immune checkpoint inhibitors are known to trigger immune-mediated inflammation and can affect multiple organ systems through autoimmune mechanisms (9). ICI-induced immune activation may increase zinc consumption via enhanced inflammatory responses and tissue repair processes.

Furthermore, recent clinical evidence in RCC and immuno-oncology supports the notion that host nutritional and physiologic factors may modulate both therapeutic outcomes and toxicity risks. Bekku et al. examined patients with advanced RCC treated with the nivolumab/ipilimumab combination and reported that higher BMI was correlated with improved objective response and survival compared to lower BMI groups (23). This BMI-outcome correlation suggests that systemic metabolic reserves or nutritional status may influence both tolerability and efficacy of ICI therapy, which aligns with our focus on zinc as a modifiable micronutrient factor. Meanwhile, Suto’s review on ICI rechallenge emphasizes that decisions to resume immunotherapy after prior irAEs must carefully balance anticipated benefits and risks, taking into account the severity and organ involvement of the initial toxicity (24). In the specific context of skin toxicities, this underscores the importance of identifying predictive biomarkers or modifiable risk factors –such as zinc status– that might help stratify patients for safe rechallenge or prophylactic strategies.

The clinical implications of these findings may be significant. Zinc supplementation represents a relatively simple, safe, and cost-effective intervention that could help prevent or mitigate treatment-related skin toxicities. One report has described the efficacy of zinc supplementation in preventing chemotherapy-induced skin toxicities and enhancing wound healing in patients with cancer (25). However, the optimal timing, dosing, and duration of zinc supplementation in patients with RCC require further investigation through prospective clinical trials.

From a mechanistic standpoint, zinc’s role in skin homeostasis involves multiple biological pathways that may be relevant to treatment-related toxicities (26, 27). Zinc is essential for DNA synthesis, protein synthesis, and cell division, all of which are critical for maintaining skin integrity during exposure to cytotoxic or immunemodulating therapies (28). Additionally, zinc possesses anti-inflammatory properties and supports antioxidant defenses, which may help protect against treatment-induced oxidative stress and inflammation (29). Zinc deficiency has been shown to impair T-cell function and natural killer (NK) cell activity, potentially exacerbating immune-mediated skin toxicities associated with ICI therapy (30).

The baseline zinc deficiency observed in most patients with pre-treatment measurements suggests that patients with RCC may be particularly susceptible to zinc depletion. This susceptibility could be related to the underlying malignancy, nutritional status, or other patient-specific factors. Patients with advanced cancer often exhibit compromised nutritional status due to decreased appetite, metabolic alterations, and systemic inflammation, all of which may contribute to micronutrient deficiencies (11). However, a subset of patients with low baseline serum zinc levels did not develop skin-related adverse events. In most patients who developed skin-related adverse events, serum zinc levels declined further from baseline, suggesting that not only absolute zinc deficiency, but also the reduction itself, may contribute to the development of these adverse events. Aguiari et al. recently reviewed the latest advances in prognostic and predictive molecular biomarkers in clear cell renal cell carcinoma, highlighting the growing importance of tumor-immune interactions and host-related factors in treatment outcomes (31). As immune checkpoint inhibitors have become integral to systemic therapy for renal cell carcinoma, immune-related adverse events (irAEs) have emerged as a clinically significant issue. Considering that zinc plays essential roles in immune regulation and epithelial repair, alterations in zinc homeostasis may influence both the efficacy and toxicity profiles of immunotherapy. Therefore, evaluating serum zinc levels could provide additional insight into the biological mechanisms underlying irAE development, particularly cutaneous manifestations, and help identify patients at higher risk during systemic treatment.

Study limitations. The retrospective design limits the ability to establish causality and introduces the possibility of selection bias. The relatively small sample size, particularly for severe adverse events, limits the statistical power and generalizability of the findings. Serum zinc level measurements were not standardized across patients, and the timing of measurements varied based on clinical indications rather than protocol-defined intervals. Additionally, potential confounding factors –such as nutritional status, concurrent medications, or comorbidities that may affect zinc metabolism or skin toxicity risk– were not controlled for. Furthermore, not all patients with skin-related adverse events underwent dermatological evaluation, precluding detailed characterization of specific skin toxicities.

Despite several limitations, the present study provides valuable preliminary evidence of an association between serum zinc status and skin-related adverse events in patients with RCC. The therapeutic utility of zinc supplementation has been reported in various dermatologic conditions, supporting the rationale for further investigation in this context (32). Future research should include prospective observational studies employing standardized zinc monitoring protocols, randomized controlled trials evaluating the efficacy of zinc supplementation for the prevention of skin toxicities, and mechanistic studies to elucidate the pathways linking zinc metabolism to treatment-related adverse events.

Conclusion

In conclusion, this study suggests that it may not be the baseline serum zinc concentration alone, but rather the decline over time, that contributes to the development of skin-related adverse events. Therefore, changes in serum zinc concentrations during systemic therapy for RCC may serve as a useful marker for predicting the occurrence of skin-related adverse events.

Acknowledgements

The Authors thank the members of the Department of Urology, Chiba University School of Medicine, for their dedicated clinical efforts.

Footnotes

  • Authors’ Contributions

    Conceptualization: TS; Interpretation or Analysis of Data: SS, HS; Data Curation: SS, TS, HS, YW, FY, KT, YO, KN, SP, KA, KS, YY, YI, SS; Supervision: SS, TS; Visualization: SS; Investigation; Writing – original draft; Writing – review and editing: SS; All Authors have read and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    This research received no external funding.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received September 20, 2025.
  • Revision received October 12, 2025.
  • Accepted October 13, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Serum Zinc Levels and Skin-related Adverse Events During Systemic Therapy for Renal Cell Carcinoma
SHINPEI SAITO, TOMOKAZU SAZUKA, HIROAKI SATO, YURI WATANABE, FUMIYA YOKOCHI, KOHEI TOMA, YUSUKE ONODA, KOTARO NAGAOKA, SANGJON PAE, KODAI SATO, KEISUKE ANDO, YASUTAKA YAMADA, YUSUKE IMAMURA, SHINICHI SAKAMOTO
In Vivo Jan 2026, 40 (1) 333-340; DOI: 10.21873/invivo.14196
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