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Ren Fail
Ren Fail
Renal Failure
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Taylor & Francis

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10.1080/0886022X.2024.2406392
2406392
Version of Record
Brief Report
Hemodialysis and Peritoneal Dialysis
Harnessing the eccrine sweat glands for the management of interdialytic weight gain – a pilot study
Z. A. Armaly et al.
Armaly Zaher A. ab
Nitzan Yaacov c
Chernin Gil de
Aronson Doron f
a Departement of Nephrology, EMMS (Scottish) Hospital, Nazareth, Israel
b Bar-Ilan University, Ramat Gan, Israel
c AquaPass Medical Ltd, Shefayim, Israel
d Department of Nephrology and hypertension, Kaplan Medical Center, Rehovot, Israel
e School of Medicine, Hebrew University, Jerusalem, Israel
f Department of Cardiology, Rambam Health Care Campus and the Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2024.2406392.

CONTACT Doron Aronson daronson@technion.ac.il Department of Cardiology, Rambam Medical Center, POB 9602, Haifa 31096, Israel
23 9 2024
2024
23 9 2024
46 2 240639220 6 2024
12 9 2024
14 9 2024
KnowledgeWorks Global Ltd.20 9 2024
published online in a building issue20 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Hemodialysis patients are susceptible to excess volume accumulation, particularly over the 2-day interval (long interdialytic gap), resulting in higher interdialytic weight gain (IDWG). We thought to determine whether a novel device designed to enhance fluid and salt loss by activating the eccrine sweat glands can mitigate IDWG. Patients eligible for the study were undergoing regular hemodialysis for ≥3 months, without residual renal function, and with IDWG (as a percentage of IDWG/dry body weight) ≥2.5%. Treatments were administered at the patient’s home. The primary performance endpoint was differences in weight gain over long interdialytic period with the device compared to the control period. Secondary exploratory endpoints included the need for ultrafiltration (UF) rate > 10 mL/kg/h in the post-interval dialysis. Five patients were enrolled into the pilot study (age range 26 to 69 years, 3 women). The hourly mean weight loss from sweat was 186 ± 45 g/h. The average procedure length was 4.5 h with an average fluid loss of 899 ± 283 grams per procedure. The average least-squares mean absolute difference of IDWG between the control and treatment periods was −2.0%; (95% confidence interval [CI], −2.9% to −1.2%, p < 0001). The reduction in IDWG was associated a reduction in UF rates, from 9.23 ± 3.7 mL/kg/h to 5.55 ± 2.45 mL/kg/h between the control and treatment periods (p < 0.001), resulting in a safe UF rate (<10 mL/kg/h) in all post-treatment sessions. We conclude that enhancing sweat rate can mitigate IDWG in hemodialysis patients.

Keywords

Eccrine glands
hemodialysis
interdialytic weight gain
sweat
ultrafiltration rate
AquaPass Ltd. The study was funded by AquaPass Ltd.
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pmcIntroduction

Volume overload is prevalent among patients undergoing hemodialysis and is associated with diminished quality of life and adverse outcomes including systemic hypertension, left ventricular hypertrophy, hospitalizations, and mortality [1, 2]. These patients are vulnerable to excessive fluid accumulation, especially during the 2-day interval between dialysis sessions (the long interdialytic gap), leading to significant interdialytic weight gain (IDWG) [1–5].

IDWG is closely associated with elevated ultrafiltration rates. Rapid ultrafiltration rate due to excessive IDWG during the long interdialytic gap promotes non-physiological fluid shifts and hemodynamic instability, pre-syncope/syncopal events, and symptoms such as cramping and postdialysis fatigue [6]. The downstream consequences include ischemic organ injury associated with high ultrafiltration rates include rapid loss of residual kidney function [7], cerebral ischemia, brain white matter damage and dementia [8, 9], myocardial stunning with maladaptive cardiac structural changes [10], arrhythmia, cardiac sudden death, mesenteric ischemia with gut related systemic endotoxemia [10, 11] and overall mortality [12]. Thus, there exists a narrow therapeutic window to avoids both excessive IDWG and high UF rates, along with the resulting complications of both volume depletion and overload [5].

Interest in the use of sweat glands to treat renal diseases has been noted in the nephrology literature for decades [13–15]. It has been reported that the least IDWG occurs on dry-hot weekends [16]. The eccrine sweat glands can produce large amounts of fluid in addition to other constituents including sodium, chloride, potassium, phosphorous, and ammonium [17]. We have recently shown that enhancing sweat rate was safe and resulted in a clinically meaningful fluid removal rates in heart failure patients [18]. In this pilot study, we thought to determine whether a novel device designed to enhance fluid loss by activating of the eccrine sweat glands can mitigate IDWG in hemodialysis patients [19].

Methods

The AquaPass system (AquaPass Medical Ltd., Shefayim, Israel) is designed to enhance fluid and salt loss via the eccrine sweat glands [18–21]. The System consists of three main components: a microclimate generator, a connecting hose, and a wearable suit (Supplementary Figure 1). The microclimate generator, which includes a convective warming unit and control interface, provides a continuous source of heated filtered air that is delivered to the wearable suit via a flexible hose at a rate of 1.6 m3/min. The microclimate generator is equipped with temperature and humidity sensors at both the inlet and outlet, ensuring precise control of the treatment environment.

The wearable is a loose body-contacting cloth, designed to accommodate the patient’s body from the foot and the entire torso, in standing, sitting, or supine positions. The wearable fits loosely around the patient such that once warm air moves over the entire body surface area enclosed by the wearable, a gap is created between the body surface and the capsule measuring 5 to 10 cm. The wearable maintains a homogeneous warm temperature environment leading to increased skin temperature that activates the eccrine glands and initiates perspiration. The sweat evaporates instantaneously, thus avoiding elevation of core temperature and the awareness of perspiration by the patient, enabling long durations of treatments.

The microclimate generator controls temperature inside the wearable. The system is programmed to maintain an air temperature between 44 °C and 47 °C with relative humidity below 30% within the wearable suit. This ensures that the patient’s skin temperature remains within a safe range of 33 °C to 39 °C. Within this skin temperature range, the slope of the relationship between temperature and sweat production is linear and discomfort or thermal injury does not occur [22].

A user interface enables the operator to set the air flow rate and skin temperature within allowed range of values. The system software can also calculate the fluid removal rate based on humidity differentials and airflow measurements [18], providing feedback on treatment efficacy. In a first-in-human study of stable heart failure patients, the median hourly weight loss induced by the device was 215 g/h (interquartile range, 165–285; range, 100–344 g/h) [18].

With increased sweat rate, the majority of the fluid removed is from the interstitial compartment as interstitial fluid is the precursor fluid for sweat (in contrast to mobilization of fluid from the intravascular space with hemodialysis).

The study was conducted with the approval of the institutional review boards at the Nazareth Hospital EMMS, Nazareth, Israel. Written informed consent was obtained from all study participants. The protocol was registered at ClinicalTrials.gov (Unique identifier: NCT06358365).

Patients eligible for the study were undergoing regular hemodialysis for ≥3 months, without residual renal function (RKF), and with IDWG (as a percentage of IDWG/dry body weight) ≥2.5%. Primary safety endpoint was device related serious adverse events. The primary performance endpoint was differences in weight gain over long interdialytic period with the device compared to the control period. Secondary exploratory endpoints included the need for ultrafiltration rate > 10 mL/kg/h in the post-interval dialysis, hypotension in the post-interval dialysis session, systolic blood pressure pre-dialysis after the interdialytic interval; Quality of life as assessed by the Kansas City Cardiac Questionnaire-12 (KCCQ-12); changes in hemoglobin, BUN, and electrolytes, and changes in biomarkers of congestion (NT-proBNP).

The study design is depicted in Supplementary Figure 2. Patients entered a 3-week observation period, followed by a 4-week treatment period. In addition to the regular planned hemodialysis sessions, each patient underwent 2 weekly procedures (∼4 h) with the AquaPass device during the weekend at the patient’s home. Blood pressure and heart rate was measured before and after each treatment session.

We used repeated measurements ANOVA to determine differences in IDWG and UF rates over time, with weighted contrast between the first 3 and last 4 repeated measurements. All other statistical comparisons were exploratory.

Results

Five patients were enrolled into the pilot study (age range 26 to 69 years, 3 women). The mean IDWG during the control period was 3.4 ± 1.3%. During the home therapy, the hourly mean weight loss from sweat was 186 ± 45 g/h. The average procedure length was 4.5 h with an average fluid loss of 899 ± 283 g per procedure. There were no procedure-related adverse events.

During the treatment period patients had lower IDWG than in the control period (Figure 1A). The average least-squares mean absolute difference between the periods was −2.0%; (95% confidence interval [CI], −2.9% to −1.2%, p < 0001). The reduction in IDWG was associated a reduction in UF rates from 9.23 ± 3.7 mL/kg/h to 5.55 ± 2.45 mL/kg/h. The least-squares mean difference in UF rates between the control and treatment periods was −3.2 mL/kg/h [95% CI −4.6 to −1.8](p < 0.001), resulting in a safe UF rate in all post-treatment sessions (Figure 1B). AquaPass therapy was also associated with a reduction in potassium levels (least-squares mean difference −0.28 mmol/L [95 CI −0.56 to −0.04, p = 0.025]. We also observed an increase in hemoglobin and calcium levels and a reduction in NT-proBNP (Table 1). The KCCQ-12 score increased from a baseline of 67 ± 12 to 86 ± 11 at the end of the study (Supplementary Figure 3).

Figure 1. (A) Box-and-whisker plot and scatter plot of IDWG% during the control (C) and treatment (T) phases. The line within the box denotes the median and the box spans the interquartile range (25–75th percentiles). Whiskers extend from the 5th to 95th percentiles; (B) Percent of patients in the 3 categories of ultrafiltration rate in the control and treatment phases.

Table 1. Laboratory tests in the control and treatment periods.

Test	Least square mean difference of treatment vs. control (95% CI)	P value*	
Hemoglobin (g/dl)	0.5 [0.3 to 0.8]	<0.001	
BUN (mg/dl)	−4.7 [-9.2 to −0.2]	0.04	
Sodium (mmol/L)	1.0 [-0. 4 to 2.3]	0.15	
Potassium (mmol/L)	−0.3 [-0. 5 to 0.0]	0.025	
Magnesium (mmol/L)	0.0 [-0.2 to 0.2]	0.84	
Calcium (mmol/L)	0.5 [0.3 to 0.7]	<0.001	
Phosphorous (mmol/L)	−0.1 [-0.4 to 0.2]	0.56	
Uric acid (mg/dL)	0.1 [-0.6 to 0.4]	0.69	
NT-proBNP (pg/mL)	−1912 [-3117 to −708]	0.002	
*Repeated measures ANOVA.

There was a significant reduction in systolic blood pressure during the procedure from 142 ± 32 mm Hg to 124 ± 19 mm Hg (p = 0.002). There was no significant change in diastolic blood pressure (70 ± 17 mm Hg vs. 71 ± 17 mm Hg, p = 0.61). The heart rate increased during the procedure from 66 ± 6 BPM to 69 ± 7 BPM (p = 0.04). The systolic blood pressure pre-dialysis after the interdialytic interval was 134 ± 9 mm Hg in the treatment period vs. 143 ± 10 mm Hg in the control period (p = 0.50).

After the 4th weekend treatments, the scheduled hemodialysis was deferred by an additional 24 h in all patients.

Discussion

While achieving normovolemia is a central element of dialysis prescription, it is notoriously difficult to accomplish in clinical practice. The clinical hallmarks of high IDWG are diminished quality of life and repeated cycles of fluid overload leading to increased cardiovascular hospitalizations and increased mortality rates [4]. Attempts to alleviate volume overload using dialysis time extension or additional dialysis sessions have been poorly accepted by patients. Therefore, high IDWG imposes more aggressive volume reduction during hemodialysis with high UF rate.

The study represents the first step in the clinical evaluation of a novel strategy to remove fluid by increasing sweat rate as a potential solution for IDWG. Fluid removal rates with the device were comparable to normal subjects and patients with chronic heart failure,12 and led to reductions in IDWG thus enabling lower and safer UF rates. In addition, our preliminary data suggest a significant reduction in potassium levels. Given the observed safety and clinical performance of the device, this study supports further evaluation of this concept in hemodialysis patients.

Because sweat is hypotonic, there is a tendency for serum sodium to increase. We observed a median increase of 1 mmol/l in serum sodium, consistent with the amount of total sweat volume removed. The overall increase in plasma osmolarity is <1%. Thus, we did not observe an increase in thirst.

Previous studies have used other methods to increase perspiration, including sauna and hot baths [14, 15]. The technology presented in the current study can generate higher fluid removal rates in a more predictable manner and can be used comfortably by the patients at home.

With IDWG, the excess fluid initially redistributes into the extravascular space [2, 20]. With increased sweat rate, the fluid is removed from the interstitial compartment because interstitial fluid is the precursor fluid for primary sweat. Removing fluids directly from the interstitial space protects the intravascular compartment from underfilling prior to the subsequent hemodialysis.

In conclusion, increasing fluid loss by activating of the eccrine sweat glands may provide important health benefits in hemodialysis patients by lowering IDWG and mitigating chronic volume overload. Together with thrice weekly HD, this therapy more closely approximates the capacity of the native kidney to regulate extracellular volume and solute composition, similar to patients with substantial RKF. This approach may also address long interdialytic gaps in resource-poor regions with limited access to thrice weekly hemodialysis.

Supplementary Material

Suppl Data.pdf

Ethics statement

This study was reviewed and approved by the Nazareth Hospital EMMS institutional independent review. Written informed consent was obtained in all study participants.

Disclosure Statement

Doron Aronson is a consultant for AquaPass. Yaacov Nitzan is the CEO of AquaPass Ltd.

Data availability statement

The data underlying the findings described in this manuscript are proprietary and not publicly available. Further inquiries can be directed to Dr. Doron Aronson at daronson@technion.ac.il
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