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# Heatwaves and plasma sodium disturbances in patients with chronic kidney disease

Adrien Flahault, Alexandre Panico, Grégory Fifre, Ziad Massy, Luc Frimat,

Florian Bayer, Marie Metzger, Natalia Alencar de Pinho, Emeline Lequy

► To cite this version:

Adrien Flahault, Alexandre Panico, Grégory Fifre, Ziad Massy, Luc Frimat, et al. Heatwaves and plasma sodium disturbances in patients with chronic kidney disease. Environment International, 2025, 204, pp.109800. 10.1016/j.envint.2025.109800. hal-05287358

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https://hal.univ-lorraine.fr/hal-05287358v1

Submitted on 28 Sep 2025

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Full length article

# Heatwaves and plasma sodium disturbances in patients with chronic kidney disease

Adrien Flahault<sup>a,b,*</sup>, Alexandre Panico<sup>a</sup>, Grégory Fifre<sup>c</sup>, Ziad A Massy<sup>d,e,f</sup>, Luc Frimat<sup>a,b</sup>, Florian Bayer<sup>g,h</sup>, Marie Metzger<sup>f</sup>, Natalia Alencar de Pinho<sup>f</sup>, Emeline Lequy<sup>f,h</sup>

## ARTICLE INFO

Handling Editor: Adrian Covaci

**Keywords:**

Hyponatremia

Heatwaves

Climate change

Kidney disease

## ABSTRACT

**Background:** Climate change and subsequent warmer temperatures may affect kidney and electrolyte-water balance, reflected by plasma sodium. Plasma sodium alterations are common among patients with chronic kidney disease (CKD).

**Objectives:** We aimed to determine whether heatwaves were associated with plasma sodium levels in this population.

**Methods:** We obtained 38,740 plasma sodium measurements from 2964 patients with moderate or severe CKD, under nephrology care, in France, prospectively followed-up in the CKD-REIN study. Patients undergoing dialysis and patients with kidney transplant were not included. We estimated multinomial odds ratios (ORs) and 95 % confidence intervals (CIs) for abnormal plasma sodium levels associated with heatwave exposure in the past 3, 8 or 15 days. We used local temperature data to assess exposure to heatwaves.

**Results:** Over a median follow-up of 5 years, 1730 (4.5 %) plasma sodium measurements were ≤ 135 mmol/L (hyponatremia) and 2797 (7.2 %) ≥ 145 mmol/L (hypernatremia). Thiazide diuretic use was associated with increased odds of hyponatremia, while loop diuretic use was associated with increased odds of both hyponatremia and hypernatremia. Summer season was associated with higher odds of hyponatremia. Exposure to at least 3 days of heatwave in the past 8 days was associated with increased odds of lower plasma sodium levels (OR [95 %CI]: 1.48 [1.10, 1.99]).

**Conclusions:** Heatwaves, particularly sustained ones, expose patients with CKD to hyponatremia. Generic recommendations to increase water intake during high temperatures may heighten this risk and are therefore inappropriate for this population. Plasma sodium monitoring should be considered for several weeks following a heatwave.

## 1. Introduction

Climate change is associated with global warming and has increased the frequency, the duration, and the intensity of heatwaves (Shukla et al., 2022) throughout the world, including in France (Shukla et al., 2022). While heatwaves have since long been associated with increased mortality (Romanello et al., 2022), their medical impact largely remains

to be delineated, especially on water metabolism.

Plasma sodium – a proxy of electrolyte-water balance – is the main contributor to plasma osmolality, and is tightly regulated in humans. While normal values for plasma sodium are 135–145 mmol/L, even small changes in plasma sodium have been related to adverse outcomes. In-hospital and 1-year mortality were increased in patients with plasma sodium outside the 138–142 mmol/L range (Thongprayoon et al., 2020).

<footnote><sup>a</sup> Centre Hospitalier Régional Universitaire de Nancy, Department of Nephrology, Nancy, France</footnote>

<footnote><sup>b</sup> Université de Lorraine, Inserm, UMR INSPIIRE, Nancy, France</footnote>

<footnote><sup>c</sup> Météo-France, 73 avenue de Paris, 94165 Saint-Mandé Cedex, France</footnote>

<footnote><sup>d</sup> Association pour l'Utilisation du Rein Artificiel dans la région parisienne (AURA), Paris, France</footnote>

<footnote><sup>e</sup> Ambroise Paré University Hospital, APHP, Department of Nephrology Boulogne-Billancourt, Paris, France</footnote>

<footnote><sup>f</sup> Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, France</footnote>

<footnote><sup>g</sup> Coordination Nationale Registre REIN, Agence de la Biomédecine, Saint-Denis, France</footnote>

<footnote><sup>h</sup> Unité "Cohortes en Population" UMS 011 Inserm/Université Paris Cité/Université Paris Saclay/UVSQ, Villejuif, France</footnote>

<footnote>* Corresponding author at: Centre Hospitalier Régional Universitaire de Nancy, Department of Nephrology, Nancy, France.
E-mail address: a.flahault@chru-nancy.fr (A. Flahault).</footnote>
The kidney is essential to maintain water and salt homeostasis, and this function is altered with chronic kidney disease (CKD), leading to more frequent alterations in plasma sodium levels in patients with CKD (Kovesdy et al., 2012). Moderate-to-severe CKD affects 1.5 to 2.1 % of the French adult population aged 18 to 74 years, representing approximately 1.6 million people in France (Olié et al., 2021, pp. 2014–2016).

Increased outdoor temperatures have been associated with metabolic disturbances in extreme conditions (Pasternak et al., 2023). Several observational studies have reported an association between in-hospital incidence of hyponatremia and summertime and/or outdoor temperatures (Kutz et al., 2020; Mannheimer et al., 2022; Pfortmueller et al., 2014; Sailer et al., 2019). A cohort study in Sweden has shown an association between severe hyponatremia < 125 mmol/L and elevated outdoor temperatures (Issa et al., 2024). No study has, to our knowledge, specifically studied the links between exposure to heatwaves and plasma sodium concentrations in an ambulatory setting in patients with CKD.

In this study, we aimed to assess whether summertime and more specifically heatwaves occurring at the local level (département) were associated with changes in plasma sodium levels in moderate-to-severe CKD patients from the CKD-REIN study, who underwent repeated, routine plasma sodium measurements over a 5-year period in France.

## 2. Material and Methods

### 2.1. Study population

The CKD-REIN (CKD-Renal Epidemiology and Information Network) cohort was launched in 2013–2016 to study care and outcomes (both clinical and patient-reported) of patients with CKD stages 3 and 4. Patients undergoing dialysis or with a kidney transplant were not included. A total of 3033 participants were recruited from 40 nationally representative nephrology clinics in France (from a geographic and public-private perspective) (Stengel et al., 2014). Those who moved to CKD stages 2 or 5 between eligibility assessment and inclusion were enrolled, assuming that this would prevent selection bias due to kidney function variability. Participants were followed prospectively by trained clinical research associates (CRAs) for up to five years, from 2013 to 2020. Data were collected through self-administered questionnaires, assessments by nephrologists, and medical examinations, including blood tests. CRAs collected medical records, interviews, and hospital or death reports. In the present analysis, participants were excluded if they had no available plasma sodium value or if they resided in a *département* (as described hereafter) with less than 5 participants, to minimize risk of reidentification. Residential history throughout the study was not available. Our study population thus included 2,964 (97.7 %) CKD-REIN participants. The French National Institute of Health and Medical Research institutional review board (IRB00003888) and ethics committee (CCTIRS12.360/CPP ID-RCB 2012-A00902-41) approved the CKD-REIN study. The study was registered at [ClinicalTrials.gov](http://ClinicalTrials.gov) (NCT03381950). All patients provided written informed consent before inclusion.

### 2.2. Exposure assessment to summer season and to heatwaves

We defined “summer season” as the period between June 21st and September 23rd, corresponding to its astronomical definition in the Northern hemisphere (between the summer solstice and the autumn equinox). Location of participants was obtained at the *département* level. In France, *départements* are administrative divisions, similar to counties in other countries. There are 96 *départements* in mainland France, with a median population of around 554,000 inhabitants in 2021 (INSEE, 2021) and a median area of 5,965 km². Heatwaves are specifically defined by Météo-France, the French meteorological agency, for each *department*, and thus determined at the local level. A heatwave is identified from a series of daily mean temperatures when the temperature exceeds the 99.5 percentile of its distribution calculated over the whole year at the

*département* level during the reference period (1981–2010). The duration of the heatwave episode is the period during which the temperature does not fall durably (two days or more) below the 97.5 percentile of the same distribution. The episode is interrupted if the temperature falls, even punctually, below the 95.0 percentile of the distribution. Temperatures corresponding to the 99.5, 97.5 and 95 percentiles for each *département* are provided in Table S1. The exposure to a heatwave in this study was defined by the occurrence of at least one day of heatwave in the past 3, 8 or 15 days prior to biological sampling date. To refine this first exposure metric, we also calculated the number of heatwave days in each of these periods, and categorized exposure length in three categories, namely, no heatwave, $\le$ median number of heatwave days, $> \text{median number of heatwave days}$.

### 2.3. Outcomes

Plasma sodium levels were obtained at baseline and over follow-up. Measurements were performed in public and private medical laboratories as part of patients’ usual care in an ambulatory setting. Furthermore, study participants were prescribed a set of laboratory measurements (recommended by health authorities, including plasma sodium) once a year as part of the study protocol. We aimed to consider mild alterations of plasma sodium; hence, we considered plasma sodium to be low (hyponatremia) when $\le 135$ mmol/L, mildly decreased when $\le 137$ mmol/L, mildly increased when $> 143$ mmol/L and high (hypernatremia) when $\ge 145$. In a sensitivity analysis, we explored associations with alternate cut-offs for hyponatremia ($\le 134$ mmol/L) and hypernatremia ($\ge 146$ mmol/L).

### 2.4. Covariables

To evaluate the association of plasma sodium levels with socio-demographic and clinical variables, and to explore possible effect modification, we used individual-level socio-demographic variables at baseline including sex, education level, area-level deprivation (French deprivation index, Fdep 2015 (Rey et al., 2009)), dichotomized according to its median value in the study population) and medical history (cancer, diabetes mellitus, cardiovascular diseases including hypertension). We also included variables available on the day of each plasma sodium determination, including age, estimated glomerular filtration rate (eGFR according to the CKD-EPI 2009 formula (Levey et al., 2009)) when performed the same day, current loop and thiazide diuretic prescription.

### 2.5. Missing data

There was no missing data on participant location and meteorological exposure, and all included patients had at least one plasma sodium determination. In univariate models studying the association between the outcome and the other exposure variables, participants with missing data were excluded. The number of participants with missing data is provided in Tables 1 and 2.

### 2.6. Statistical analyses

Participant characteristics were described with mean and standard deviation, or absolute and relative frequencies (percentage), as appropriate. As a first analytical step, we estimated the associations between summer season and plasma sodium level; then, we estimated the associations between exposure to heatwaves and plasma sodium levels. In both analyses, to account for repeated measures, we used multinomial mixed effects models. Participant identifier and *département* of residence were used as random effect variables, while exposure variables were used as fixed effects in separate models. In order to account for possible non-linear associations with plasma sodium levels, we categorized plasma sodium as previously described. When considering heatwave exposure in 3 categories (no heatwave, below and above the median
<table><caption>**Table 1**
Participant characteristics at baseline (n = 2964).</caption><thead><tr><th>Characteristic</th><th>n (%) or mean (SD)</th><th>Missing, n (%)</th></tr></thead><tbody><tr><td>Age, years</td><td>67.0 (12.8)</td><td>0 (0)</td></tr><tr><td>Sex</td><td></td><td>0 (0)</td></tr><tr><td>Male</td><td>1943 (65.6)</td><td></td></tr><tr><td>Female</td><td>1021 (34.4)</td><td></td></tr><tr><td>Hypertension</td><td>2685 (90.8)</td><td>7 (0.2)</td></tr><tr><td>Diabetes mellitus</td><td>1281 (43.3)</td><td>7 (0.2)</td></tr><tr><td>Tobacco use</td><td></td><td>22 (0.8)</td></tr><tr><td>Current smoker</td><td>349 (11.8)</td><td></td></tr><tr><td>Never smoker</td><td>1220 (41.6)</td><td></td></tr><tr><td>Former smoker</td><td>1373 (46.6)</td><td></td></tr><tr><td>History of cancer</td><td>605 (21.1)</td><td>98 (3.3)</td></tr><tr><td>Cardiovascular disease</td><td>1561 (53.3)</td><td>38 (1.3)</td></tr><tr><td>Education level (years)</td><td></td><td>35 (1.2)</td></tr><tr><td>&lt;9</td><td>439 (15.0)</td><td></td></tr><tr><td>9-11</td><td>1443 (49.3)</td><td></td></tr><tr><td>&gt;=12</td><td>1047 (35.7)</td><td></td></tr><tr><td>Chronic Kidney Disease Stage</td><td></td><td>0 (0)</td></tr><tr><td>2</td><td>67 (2.3)</td><td></td></tr><tr><td>3A</td><td>389 (13.1)</td><td></td></tr><tr><td>3B</td><td>962 (32.5)</td><td></td></tr><tr><td>4</td><td>1181 (39.8)</td><td></td></tr><tr><td>5</td><td>365 (12.3)</td><td></td></tr><tr><td>Urine albumin to creatinine ratio</td><td></td><td>113 (3.8)</td></tr><tr><td>&lt;3 mg/mmol</td><td>684 (24.0)</td><td></td></tr><tr><td>3-30 mg/mmol</td><td>1053 (36.9)</td><td></td></tr><tr><td>&gt;30 mg/mmol</td><td>1259 (39.1)</td><td></td></tr></tbody></table>

Chronic Kidney Disease (CKD) Stage is defined as follows: stage 2, eGFR between 89 and 60 ml/min/1.73 m²; stage 3A, eGFR between 59 and 45 ml/min/1.73 m²; stage 3B, eGFR between 44 and 30 ml/min/1.73 m²; stage 4, eGFR between 29 and 15 ml/min/1.73 m²; stage 5, eGFR below 14 ml/min/1.73 m². eGFR, estimated glomerular filtration rate.

number of heatwave days), we reported odd ratios with confidence intervals as well as a p-value for trend calculated using a linear trend for the ordered categorical exposure variable. We identified no additional confounding variable to be included in our models, and, thus, did not perform multivariable analysis. However, we also analyzed the univariate associations between categorized plasma sodium levels and a set of risk variables (age, sex, area-level deprivation, eGFR, and diuretic use).

Finally, we tested for interactions between exposure to heatwave, defined as the occurrence of at least one heatwave day within the specified time windows prior to plasma sodium measurements, the aforementioned set of covariates and categorized plasma sodium levels. P-values < 0.05 were considered statistically significant. All analyses were performed using R version 4.2.3(R Core Team, 2023) and the package “mclogit”(Elff, 2022).

# 3. Results

## 3.1. Participant characteristics

Characteristics of the 2964 participants at study inclusion are provided in Table 1. Briefly, mean ± standard deviation (SD) age was 67.0 ± 12.8 years. A majority (65.9 %) of participants were male. Most participants (90.8 %) had hypertension and 43.3 % had diabetes mellitus. A majority (52.8 %) had severe CKD (eGFR < 30 ml/min/1.73 m²) at baseline, and urine albumin to creatinine ratio was > 30 mg/mmol in 39.1 % of participants. Study participants resided in 46 different French départements (Fig. 1A, Table S1).

Median (Q1, Q3) plasma sodium determinations per participant was 12 (8, 17), totaling 38,740 plasma sodium values with a mean ± SD of 140.6 ± 3.0 mmol Na/L. Among these, 1730 (4.5 %) were below or equal to 135 mmol/L, 3012 (7.8 %) were 136 or 137 mmol/L, 24,492 (63.2 %) were between 138 and 142 mmol/L, 6709 (17.3 %) were 143 or 144 mmol/L and 2797 (7.2 %) were above or equal to 145 mmol/L (Table 2). Use of loop diuretics and thiazide diuretics concomitant to

<table><caption>**Table 2**
Plasma sodium determinations characteristics.</caption><thead><tr><th>Characteristic</th><th>≤135 mmol/L</th><th>136-137 mmol/L</th><th>138-142 mmol/L</th><th>143-144 mmol/L</th><th>≥145 mmol/L</th></tr></thead><tbody><tr><td></td><td>N = 1730</td><td>N = 3012</td><td>N = 24492</td><td>N = 6709</td><td>N = 2797</td></tr><tr><td></td><td>(4.5 %)</td><td>(7.8 %)</td><td>(63.2 %)</td><td>(17.3 %)</td><td>(7.2 %)</td></tr><tr><td></td><td>N (%)*</td><td>N (%)*</td><td>N (%)*</td><td>N (%)*</td><td>N (%)*</td></tr><tr><td>CKD Stage</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2</td><td>44 (2.6)</td><td>57 (1.9)</td><td>451 (1.9)</td><td>102 (1.5)</td><td>24 (0.9)</td></tr><tr><td>3A</td><td>155 (12.1)</td><td>311 (10.5)</td><td>2935 (12.1)</td><td>625 (9.4)</td><td>176 (6.3)</td></tr><tr><td>3B</td><td>388 (31.6)</td><td>908 (30.5)</td><td>7637 (31.6)</td><td>2006 (30.2)</td><td>718 (25.9)</td></tr><tr><td>4</td><td>794 (43.1)</td><td>1311 (44.1)</td><td>10,426 (43.1)</td><td>3000 (45.2)</td><td>1349 (48.6)</td></tr><tr><td>5</td><td>320 (11.4)</td><td>388 (13.0)</td><td>2757 (11.4)</td><td>908 (13.7)</td><td>506 (18.2)</td></tr><tr><td>Missing</td><td>29</td><td>37</td><td>286</td><td>68</td><td>24</td></tr><tr><td>Thiazide diuretic use</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>306 (21.0)</td><td>487 (20.0)</td><td>3634 (18.1)</td><td>889 (15.7)</td><td>366 (15.1)</td></tr><tr><td>No</td><td>1148 (79.0)</td><td>1953 (80.0)</td><td>16,482 (81.9)</td><td>4788 (84.3)</td><td>2053 (84.9)</td></tr><tr><td>Missing</td><td>276</td><td>572</td><td>4379</td><td>1032</td><td>378</td></tr><tr><td>Loop diuretic use</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>682 (47.2)</td><td>1023 (42.0)</td><td>7425 (37.0)</td><td>2473 (44.0)</td><td>1256 (52.6)</td></tr><tr><td>No</td><td>763 (52.8)</td><td>1410 (58.0)</td><td>12,625 (63.0)</td><td>3150 (56.0)</td><td>1132 (47.4)</td></tr><tr><td>Missing</td><td>285</td><td>579</td><td>4442</td><td>1086</td><td>409</td></tr></tbody></table>

* Percentages calculated excluding missing values. CKD stage and diuretic use were only considered when available on the day of plasma sodium determination. Chronic Kidney Disease (CKD) Stage is defined as follows: stage 2, eGFR between 89 and 60 ml/min/1.73 m²; stage 3A, eGFR between 59 and 45 ml/min/1.73 m²; stage 3B, eGFR between 44 and 30 ml/min/1.73 m²; stage 4, eGFR between 29 and 15 ml/min/1.73 m²; stage 5, eGFR below 14 ml/min/1.73 m². eGFR, estimated glomerular filtration rate.

plasma sodium determinations is provided in Table 2.

## 3.2. Characteristics associated with plasma sodium levels

We first evaluated potential risk factors for plasma sodium alterations in CKD patients. Summertime determination was associated with an increased risk of decreased plasma sodium levels. Diuretic use and lower eGFR were associated with a higher risk of both increased and decreased plasma sodium levels, hypertension with a higher risk of increased plasma sodium levels, and a higher age was associated with a decreased risk of lower plasma sodium levels but with an increased risk of higher plasma sodium levels (Table 3). On the other hand, sex and area-level deprivation were not associated with plasma sodium levels.

## 3.3. Summertime and exposure to heatwaves

Over the study period (2013–2020), the total number of heatwave days recorded by Météo-France ranged from 45 to 121 days, according to département of residence. Spatial distribution of the number of heatwave days is provided in Fig. 1B. Of the 38,740 plasma sodium measurements, 3090 (8.0 %) were performed in 1798 participants exposed to at least one heatwave day within the 15 days prior blood test, 2059 (5.3 %) in 1416 participants exposed to at least one heatwave day within the 8 days prior blood test and 1163 (3.0 %) in 920 participants exposed to at least one heatwave day within the 3 days prior blood test. Plasma sodium levels within the 8 days after heatwaves were most frequently
A - Spatial distribution of CKD-REIN participants

<figure><img src="image_3.png" /></figure>

Source: CKD-REIN, 2024

B - Spatial distribution of annual heat waves from 2013 to 2020

<figure><img src="image_4.png" /></figure>

Source: CKD-REIN, 2024

<caption>**Fig. 1.** Spatial distribution of participants and heatwaves in mainland France. (A) Spatial distribution of CKD-REIN participants. The circles are proportional symbols where each circle's area is directly proportional to the number of participants. Exact number of participants per *département* is provided in Table S1 (B) Spatial distribution of annual heatwaves from 2013 to 2020. Average number of heatwave days per *département* is provided in Table S1.</caption>

<table><caption>**Table 3**
Associations between exposure to several risk factors and plasma sodium levels.</caption><thead><tr><th>Factors influencing plasma sodium levels, vs 138-142 mmol/L</th><th>&le;135 mmol/L</th><th>&ge;145 mmol/L</th></tr></thead><tbody><tr><td><strong>Model 1: Seasonality</strong><br>June to September, vs October to May</td><td>1.16 (1.04, 1.30)</td><td>1.03 (0.94, 1.13)</td></tr><tr><td><strong>Model 2a: Thiazide diuretic use</strong><br>Thiazide diuretic use, vs no thiazide diuretic use</td><td>1.24 (1.03, 1.51)</td><td>0.81 (0.68, 0.96)</td></tr><tr><td><strong>Model 2b: Loop diuretic use</strong><br>Loop diuretic use, vs no loop diuretic use</td><td>1.50 (1.28, 1.77)</td><td>1.74 (1.52, 2.00)</td></tr><tr><td><strong>Model 3: eGFR</strong></td><td></td><td></td></tr><tr><td>&gt; 45 ml/min</td><td>1 (ref.)</td><td>1 (ref.)</td></tr><tr><td>30-45 ml/min</td><td>0.90 (0.72, 1.12)</td><td>1.25 (1.02, 1.52)</td></tr><tr><td>&lt; 30 ml/min</td><td>1.73 (1.40, 2.14)</td><td>1.66 (1.36, 2.02)</td></tr><tr><td><strong>Model 4: Age</strong><br>Age, per 10 additional years</td><td>1.01 (0.95, 1.08)</td><td>1.49 (1.39, 1.59)</td></tr><tr><td><strong>Model 5: Sex</strong><br>Male, vs Female</td><td>0.87 (0.73, 1.04)</td><td>0.99 (0.85, 1.17)</td></tr><tr><td><strong>Model 6: Deprivation status</strong><br>Higher deprivation (Fdep15 &ge; -0.33), vs lower deprivation (Fdep15 &lt; -0.33)</td><td>0.97 (0.82, 1.17)</td><td>1.11 (0.94, 1.30)</td></tr><tr><td><strong>Model 7: Hypertension</strong><br>Hypertension, vs no hypertension</td><td>0.84 (0.63, 1.12)</td><td>1.57 (1.18, 2.10)</td></tr><tr><td><strong>Model 8: Diabetes mellitus</strong><br>Diabetes mellitus, vs no diabetes</td><td>1.73 (1.46, 2.06)</td><td>1.16 (0.99, 1.36)</td></tr></tbody></table>

Univariate multinomial mixed-effects model; random effects were participant ID and *département*. Odds ratios with 95% confidence interval. eGFR, estimated glomerular filtration rate; vs: versus.

measured in July (n = 975), then August (n = 555), June (n = 327) and September (n = 202).

### 3.4. Associations between summer season and exposure to heatwaves and plasma sodium levels

We found that the odds of hyponatremia were higher during the summer season, while there was no association between hypernatremia and summertime (Table 3). When we used, as exposure metric, the number of days of heatwaves within the past days before plasma sodium level measurement, we estimated that a higher number of heatwaves days was associated with decreased plasma sodium level: participants with ≥ 3 days of heatwave within the past 8 days, and with ≥ 4 days of heatwave within the past 15 days, were at increased odds of hyponatremia and mildly decreased plasma sodium. We found no association between increased plasma sodium levels and heatwaves (Fig. 2, Table S2).

### 3.5. Interactions

We found no significant interaction regarding hyponatremia, the occurrence of ≥ 3 days of heatwave within the past 8 days before plasma sodium measurement, and thiazide diuretic use (p = 0.28), loop diuretic use (p = 0.38), CKD stage (p = 0.24), sex (p = 0.94) and age (p = 0.58) (Fig. 3).

### 3.6. Sensitivity analyzes

We found odds ratios of similar magnitude, although non-significant probably due to a loss of power, when restricting our analysis to plasma sodium determinations performed between June and September, when heatwaves were observed (Table S3), when adjusting plasma sodium levels to glucose levels (restricting the analysis to samples when glucose and sodium levels were measured at the same time, Table S4), and when using different cut-offs for plasma sodium values (Table S5).
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Associations between exposure to heatwaves and very low to very high plasma sodium levels according to heatwave exposure. Univariate mixed-effects model; random effects were participant ID and *département*. OR (95 %CI): Odds ratios with 95 % confidence interval, versus no heatwave. Full line and circles: ≥3 days of heatwave; dotted line and triangles: <3 days of heatwave.</figcaption></figure>

**Exposure:** ≥ 3 heat wave days in the past 8 days; **Outcome:** Plasma sodium ≤ 135 mmol/L

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Subgroup analyses. Odds ratios with 95 % Confidence Intervals (95 %CI) are provided for the whole population ("All") and after stratification for diuretic use (thiazide and loop), CKD stage, sex and age. P-value for interaction is provided. Odds ratios of plasma sodium values ≤ 135 mmol/L, vs 138–142 mmol/L, in case of an exposure ≥ 3 days of heatwave within the past 8 days. Chronic Kidney Disease (CKD) Stage is defined as follows: stage 2, eGFR between 89 and 60 ml/min/1.73 m²; stage 3A, eGFR between 59 and 45 ml/min/1.73 m²; stage 3B, eGFR between 44 and 30 ml/min/1.73 m²; stage 4, eGFR between 29 and 15 ml/min/1.73 m²; stage 5, eGFR below 14 ml/min/1.73 m². eGFR, estimated glomerular filtration rate.</figcaption></figure>

## 4. Discussion

In this study of patients with moderate to severe CKD, we showed that exposure to heatwaves was associated with plasma sodium levels. Odds of hyponatremia (plasma sodium ≤ 135 mmol/L) and mildly decreased plasma sodium levels (136–137 mmol/L) were increased after a heatwave, and this association was robust considering various windows of exposure and stronger in case of a prolonged heatwave. In contrast, we found no association between the odds of hypernatremia and heatwaves.

Plasma sodium levels are the reflection of intracellular hydration and

are very tightly regulated. Hyponatremia, a decrease in plasma sodium in CKD patients is associated with increased mortality (Huang et al., 2017; Sun et al., 2017), cardiovascular events (Huang et al., 2017), kidney disease progression (Han et al., 2015) and fracture risk (Nigwekar et al., 2019). Hence, hyponatremia represents a major burden in CKD patients, and its prevention may reduce mortality, morbidity and the financial burden associated with these complications. Previous studies aimed to identify risk factors for hyponatremia in CKD, and have shown that female sex, diabetes mellitus, hypertension and use of diuretics were associated with an increased risk of hyponatremia in CKD (Hassanein et al., 2022).
A few reports indicate that hyponatremia can occur in extreme physiological situations. For instance, individuals performing ultra-marathons are at elevated risk of acute kidney injury and hyponatremia, and these complications occur more frequently when outdoor temperatures are high (Pasternak et al., 2023). Associations between hyponatremia and higher temperatures in the general population have been reported in a few studies. In Switzerland, Kutz et al have shown an increase in the prevalence of hyponatremia among inpatients during the summer (Kutz et al., 2020), and Sailer et al have shown that increased temperatures around the hospital were associated with an increase in emergency room admissions for hyponatremia. This association was stronger in patients treated with diuretics (Sailer et al., 2019). Mannheimer et al have shown, in Sweden, that an increase in average temperature in the country was associated with a higher number of hospitalizations for hyponatremia (Mannheimer et al., 2022). Another study, also in Sweden, has shown an increased risk of severe hyponatremia (plasma sodium levels < 125 mmol/L) in case of elevated outdoor temperatures (Issa et al., 2024). It may be difficult to extrapolate results obtained from studies performed in Nordic countries; indeed, in Sweden, the risk of hyponatremia was increased in outdoor average temperatures above 15 °C, which would not meet the qualification of a heatwave in France, and highlight the need to design country- and outcome- specific exposure metrics.

One previous study similarly reported increased risk of hyponatremia, but not hypernatremia, in case of prolonged heat periods (Pfortmueller et al., 2014). However, this study reported on patients admitted to the Emergency Room, did not specifically concern patients with CKD, and included an unknown number of patients from nursing home facilities that may have inadequate access to water. When considering patients admitted to the Emergency Room, the cause of admission (ie, surgical emergency, digestive symptoms) may influence plasma sodium levels. In our study of ambulatory patients with CKD, it is unlikely that an acute medical or surgical condition may have influenced plasma sodium levels.

Increased outdoor temperature and heatwaves require physiological adaptations to maintain body temperature homeostasis. In this matter, the central nervous system, including the hypothalamus, plays a key role, by monitoring core body temperature and activating physiological responses aiming at increasing or decreasing temperature (Sladek and Johnson, 2013). More specifically, evaporative cooling through sweat is very efficient at dissipating excessive body heat, but requires regulation of water intake and loss by the kidneys. Hence, an increase in hypothalamic temperature stimulates vasopressin secretion and thirst (Forsling et al., 1975). Vasopressin acts on the collecting duct to increase free water reabsorption by the kidney. Excess reabsorption and oral intake of water may lead to lower plasma sodium levels, while insufficient water intake and water loss by the kidney may lead to increased plasma sodium levels (Flahault et al., 2017). Inadequate adaptation to outdoor temperature may lead to plasma sodium level alterations.

In our study, while we confirmed the association between hyponatremia and summer season, we further showed that heatwaves, which are extreme heat events, have the strongest association with plasma sodium in CKD patients. This association was observed in participants whom biological measurements were performed routinely during the year, reducing the risk of bias associated with inpatient measurements.

While osmotic regulation occurs within minutes (Danziger and Zeidel, 2015), our study found that the association between heatwaves and decreased plasma sodium levels was only observed in patients exposed to prolonged heatwaves (8 to 15 days prior). In contrast, recent exposure (≤3 days) to a heatwave was not associated with significant changes in plasma sodium levels. A decrease in plasma sodium levels may result from excessive water intake without adequate protein and solute intake, or from excessive vasopressin secretion (Spasovski et al., 2014). Our findings suggest that plasma sodium variations observed days after a prolonged heatwave may result from inadequate water intake, insufficient food consumption, and hormonal disruptions. Current public

health recommendations to increase water intake during heatwaves may not be sufficient—or even suitable—for patients with CKD. Our results indicate an elevated risk of low, but not high, plasma sodium levels following heatwave exposure. While increasing solute intake could theoretically mitigate this risk, its efficacy and safety in this context remain unproven and require further investigation. Importantly, our findings underscore the importance of regular plasma sodium monitoring in patients with CKD for several weeks after a heatwave. The only modifiable risk factor for plasma sodium alterations in our study was diuretic use (loop and thiazide), which increased both odds of plasma sodium increase and decrease. We found no interaction between diuretic use and heatwave exposure with respect to the odds of plasma sodium alterations, suggesting that diuretics remain a risk factor independently of heatwave exposure. Since heatwaves can be predicted, preventative measures could be considered to reduce the risk of plasma sodium alterations occurring during these extreme climatic events, such as transient diuretic suspension. Our research highlights the need for studies investigating the efficacy and safety of such interventions.

Definition of hyponatremia is not consensual in the literature; most authors and guidelines define hyponatremia as a plasma sodium value ≤ 134 mmol/L (Spasovski et al., 2014; Sterns, 2014) or ≤ 135 mmol/L (Adrogué and Madias, 2000; Hoorn and Zietse, 2017; Lee et al., 2014). In our study, we define hyponatremia as ≤ 135 mmol/L and provide a sensitivity analysis with a ≤ 134 mmol/L cut-off which yields similar results. Further, we explored the effects of heatwaves on smaller changes in plasma sodium, within the normal range. Indeed, plasma sodium levels have a U-shaped association with mortality (Mohan et al., 2013). Risk increases for plasma sodium levels < 138 mmol/L (Wald et al., 2010), leading authors to suggest « optimal » plasma sodium values as 138–142 mmol/L (Thongprayoon et al., 2020; Tong et al., 2025). We thus analyzed the association of plasma sodium changes with different categories of plasma sodium levels (≤135 [hyponatremia], 136–137 [mildly decreased], 138–142 [normal], 143–144 [mildly increased], ≥145 mmol/L [hypernatremia]) and showed an influence of heatwaves on both hyponatremia and mildly decreased plasma sodium levels.

Our study has some limitations. First, while we provide evidence of an association between water metabolism alterations and heatwaves, our study was not designed to investigate the pathophysiological mechanisms leading to these alterations. Second, the exposure assessment relies on the days of heatwaves at the "département" scale and could lead to a small degree of misclassification for participants residing close to another département with no heatwave at the time. In addition, since we did not obtain full residential history for the study participants, we cannot exclude that some of them may have moved in a different département during the study. However, it is unlikely that participants moving far away from their inclusion location would remain in the study, as yearly routine visits at the site of inclusion were required for pursuing study participation. Misclassification of exposure would result in risk estimates going towards the null. Third, these results may not be generalizable to other countries and climates. However, the obtention of local meteorological data to define heatwaves for each participant, and the geographical distribution of participants throughout France in diverse climatic areas, is a strength of this study. Further clinical and/or experimental studies are needed to investigate these mechanisms. Finally, we collected ambulatory samples, possibly excluding the most severe cases of symptomatic dysnatremia leading to direct hospital admissions. This may have biased our results towards the null.

In conclusion, heatwaves expose CKD patients to a decrease in plasma sodium levels, and this risk is more pronounced in case of a sustained exposure. The association between heatwave exposure and a decrease in plasma sodium level remains robust irrespective of the exposure window. Our results suggest that generic advice to 'drink more water' during heatwaves is inappropriate for patients with CKD, as it may exacerbate the risk of hyponatremia. We recommend close monitoring of plasma sodium levels in this population for several weeks following a heatwave.
## Authors' contributions

AF and EL designed and performed the analysis and wrote the article GF, FB, MM and NAP collected and analyzed the data. AP, ZAM and LF provided critical expertise. All authors participated to the interpretation of the results, and revised the manuscript.

## Data availability statement

Processing of the data supporting the study findings are under the responsibility of the Institut National de la Santé et de la Recherche Medicale (Inserm), France and complies with the European Regulation (EU) 2016/679 (General Data Protection Regulation) related to "the protection of natural persons with regard to the processing of personal data and rules relating to the free movement of personal data". In compliance with Inserm standard data sharing processes and the agreements obtained from the "Commission nationale de l'informatique et des libertés (CNIL_DR-2012-469)" and the ethics committee (IRB00003888 and CCTIRS12.360/CPP), the data can be made available under request to the study coordinating center via ckdrein@inserm.fr.

During the preparation of this manuscript, the author(s) used Le Chat (MISTRAL AI) to assist with language editing and proofreading, including the correction of typographical errors and the refinement of the manuscript and responses to reviewers. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article.

## CRediT authorship contribution statement

**Adrien Flahault:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
**Alexandre Panico:** Writing – review & editing, Writing – original draft, Validation, Methodology.

**Grégory Fifre:** Writing – review & editing, Visualization, Validation, Resources, Methodology, Data curation.
**Ziad A Massy:** Writing – review & editing, Project administration, Investigation, Funding acquisition.

**Luc Frimat:** Writing – review & editing, Project administration, Investigation, Funding acquisition.
**Florian Bayer:** Writing – review & editing, Visualization, Validation, Resources, Methodology, Data curation.

**Marie Metzger:** Writing – review & editing, Validation, Project administration, Methodology, Investigation.
**Natalia Alencar de Pinho:** Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization.
**Emeline Lequy:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

## Funding

CKD-REIN is funded by the Agence Nationale de la Recherche through the 2010 Cohortes-Investissements d'Avenir program (ANR-IA-COH-2012/3731) and by the 2010 national Programme Hospitalier de Recherche Clinique. CKD-REIN is also supported through a public-private partnership with GlaxoSmithKline since 2012, Boehringer Ingelheim France since 2022, Fresenius Medical Care from 2012 to 2024, Vifor France from 2018 to 2023, Sanofi-Genzyme from 2012 to 2015, Baxter and Merck Sharp & Dohme-Chibret from 2012 to 2017, Amgen from 2012 to 2020, Lilly France from 2013 to 2018, Otsuka Pharmaceutical from 2015 to 2020, and AstraZeneca from 2018 to 2021. Inserm Transfert set up and has managed this partnership since 2011. The funding sources had no role in the study design, conduct, and reporting.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ZM reports funding from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Genzyme/ Sano, Lilly, Otsuka, Boehringer and Government support for CKD-REIN PROJECT and EXPERIMENTAL PROJECTS. NAP reports funding obtained for the CKD-REIN project from 10 pharmaceutical companies as listed in the manuscript. All other authors declare they have no conflicts of interest related to this work to disclose.

## Acknowledgements

We acknowledge the CKD-REIN study coordination staff for setting up the CKD-REIN cohort (Oriane Lambert, Céline Lange, and all the clinical research associates). We also thank the participating clinical sites, patients, and investigators:

Alsace : Prs T. Hannedouche et B. Moulin (CHU, Strasbourg), Dr A. Klein (CH Colmar) Aquitaine : Pr C. Combe (CHU, Bordeaux), Dr J.P. Bourdenx (Clinique St Augustin, Bordeaux), Dr A. Keller, Dr C. Delclaux (CH, Libourne), Dr B. Vendrely (Clinique St Martin, Pessac), Dr B. Deroure (Clinique Delay, Bayonne), Dr A. Lacraz (CH, Bayonne) Basse Normandie : Dr T. Lobbedez (CHU, Caen), Dr I. Landru (CH, Lisieux) Ile de France : Pr Z. Massy (CHU, Boulogne - Billancourt), Pr P. Lang (CHU, Créteil), Dr X. Belenfant (CH, Montreuil), Pr E. Thervet (CHU, Paris), Dr P. Urena (Clinique du Landy, St Ouen), Dr M. Delahousse (Hôpital Foch, Suresnes) Languedoc - Roussillon : Dr C. Vela (CH, Perpignan) Limousin : Pr M. Essig, Dr D. Clément (CHU, Limoges) Lorraine : Dr H. Sekhri, Dr M. Smati (CH, Epinal) Dr M. Jamali, Dr B. Hacq (Clinique Louis Pasteur, Essey-les-Nancy), Dr V. Panescu, Dr M. Bellou (Polyclinique de Gentilly, Nancy), Pr Luc Frimat (CHU, Vandœuvre-les-Nancy) Midi-Pyrénées : Pr N Kamar (CHU, Toulouse) Nord-Pas-de-Calais : Prs C. Noël et F. Głowacki (CHU, Lille), Dr N. Maisonneuve (CH, Valenciennes), Dr R. Azar (CH, Dunkerque), Dr M. Hoffmann (Hôpital privé La Louvière, Lille) Pays-de-la Loire : Pr M. Hourmant (CHU, Nantes), Dr A. Testa (Centre de dialyse, Rézé), Dr D. Besnier (CH, St Nazaire) Picardie : Pr G. Choukroun (CHU, Amiens), Dr G. Lambrey (CH, Beauvais) Provence-Alpes - Côte d'Azur : Pr S. Burtey (CHU, Marseille), Dr G. Lebrun (CH, Aix-en-Provence), Dr E. Magnant (Polyclinique du Parc Rambot, Aix-en-Provence) Rhône-Alpes : Pr M. Laville, Pr D. Fouque (CHU, Lyon-Sud) et L. Juillard (CHU Edouard Herriot, Lyon), Dr C. Chazot (Centre de rein artificiel Tassin Charcot, Ste Foy-les-Lyon), Pr P. Zaoui (CHU, Grenoble), Dr F. Kuentz (Centre de santé rénale, Grenoble).

## Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.envint.2025.109800.

## Data availability

Data will be made available on request.

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