Hypertension (HTN) and chronic kidney disease (CKD) are pressing global health concerns, with increasing prevalence rates and significant implications for morbidity and mortality (1, 2). Moreover, patients with CKD frequently face the challenge of polypharmacy, with 48% taking 5–9 medications, and 29% ≥ 10 medications (3). Over 30% of patients with CKD have poor adherence to antihypertensive therapy, which is associated with poor blood pressure (BP) control (4). Therefore, there is an urgent need for hypertension treatments that are safe for use in individuals with CKD, effective in managing BP, do not adversely affect kidney function or electrolyte balance (e.g., hyperkalemia), can be administered under medical supervision, and do not add to the pharmaceutical treatment burden.

One of the emerging alternatives to pharmacotherapy are device-based interventions such as renal denervation (RDN) (5), baroreflex activation therapy (BAT) (6) or cardiac neuromodulation (7). RDN is now considered as an option for patients with true resistant hypertension (RH), as well as patients who are nonadherent and/or intolerant to medical therapy (5). While successful, these procedures are invasive, require skilled and well-trained operators, and rely on iodine contrast administration directly to the kidney, raising concerns of nephrotoxicity in patients with CKD.

Electro-hydraulic acoustic therapy (eHAT) represents a promising frontier in HTN management, offering a non-invasive, non-pharmaceutical, ambulatory, and potentially transformative approach to modulating BP (8). eHAT delivers an acoustic wave characterized by an abrupt spike; this type of wave exhibits high peak pressure, typically up to 19.6 MPa (Nephrospec user manual) and a short life cycle lasting approximately 1 µs. The specific energy parameters for eHAT were selected based on preclinical studies demonstrating that low-intensity shock waves at 0.09 mJ/mm² with 200–300 impulses optimize cellular viability, enhance expression of angiogenic factors, and minimize apoptosis, thereby promoting tissue repair without detrimental effects (9, 10). eHAT targets tissues directly, using electro-hydraulically generated acoustic waves to induce mechanotransduction in renal and vascular structures. It has been postulated that this therapy may stimulate nitric oxide signaling, microvascular remodeling, and better renal perfusion, all without nerve or parenchyma damage—especially important in CKD. In contrast, renal denervation lowers BP via thermal ablation of sympathetic nerves (11, 12). However, the extent to which eHAT therapy reduces BP in individuals with CKD and its safety in terms of the kidney function in this high-risk population remains unknown.

To fill this gap in the literature, we tested the hypothesis that eHAT reduces BP while maintaining renal function in hypertensive individuals with CKD in the pilot prospective clinical cohort study.

Between February 2022 and July 2023, we screened 24 patients, with 21 enrolled and 20 completing the eHAT regimen. Four patients subsequently dropped out of the study for various reasons before reaching the primary endpoint (unrelated surgery, inability to adhere to follow-up visit schedules). One patient was disqualified due to inadvertent errors in BP measurements and therefore inaccurate reading. Final analysis therefore included 15 subjects who completed study protocol (Supplementary Figure S2).

Table 1 depicts the baseline characteristics of the 15 analyzed subjects. Overall, there were more males than females, with a mean age (SD) of 69.5 (9) and 60% had diabetes. Fourteen subjects were on BP medications, and 5/15 (33%) had a history of RH. One subject who was not on anti-hypertensive therapy had OBP of 148/82 mmHg at baseline and 130/71 mmHg at the primary efficacy endpoint (12 weeks from EOT). None of the patients had renal artery stenosis. Mean OBP systolic (SD) and diastolic (SD) were 139.2 mmHg (15.7) and 77.4 mmHg (7.8) respectively. Mean eGFR (SD) was 45.6 (14) mL/min/1.73m².

This study showed that eHAT therapy improved OBP in subjects with HTN and CKD, although ABPM did not confirm the results. Therapy was overall well tolerated without major safety concerns. Hypertension is highly prevalent in individuals with CKD and constitutes both a cause and consequence of CKD progression. Despite advancements in treatment, as many as 40% of patients with CKD have been shown to have apparent treatment-RH, defined as BP ≥140/90 mm Hg on ≥3 antihypertensives, or use of ≥4 antihypertensive drugs based on Chronic Renal Insufficiency Cohort (CRIC) data (15). Others showed that over half of patients with CKD may have apparent treatment-RH when the currently recommended by Kidney Disease Improving Global Outcomes goal of BP <120 (16) is applied, underscoring the urgent need for innovative therapeutic modalities. Many patients either do not tolerate or prefer to avoid multiple medications, and the complexity of treatment increases the likelihood of non-adherence to prescribed regimens (17). Procedures such as RDN, baroreflex activation therapy, and arteriovenous anastomosis can be effective, but may be too invasive for many patients with CKD, DM, or obesity (18). In contrast, eHAT presents a promising option, but it's safety and efficacy need to be established in the larger number of patients.

The reduction in the number and dosage of antihypertensive agents following eHAT therapy, as measured by MedIndex, along with the observed decrease in BP, supports the possible role of eHAT in BP control. Therefore, eHAT could be used alongside or instead of blood pressure medications for patients with uncontrolled hypertension if future randomized controlled trials confirm its effectiveness.

The use of this device may be particularly advantageous for individuals who struggle with adherence to therapy, experience side effects from BP medications, or face a high treatment burden (19) (20) (21).Currently, the possible ways that eHAT may reduce BP are mostly uncertain and based mainly on animal research, not studies involving humans. It is hypothesized that eHAT could reduce BP through denervation of the kidney by delivering energy to the renal nerves, in a manner analogous to the RDN procedures used by RECOR (19) (acoustic) and MEDTRONIC (radiofrequency) (20). Supporting this hypothesis, previous research in pigs has shown a decrease in renal norepinephrine release following eHAT treatment (21); however, these findings have not yet been demonstrated in humans.

OBP was lower than the baseline up to 48 weeks of follow up. Long term anti-hypertensive effect of RDN was also previously demonstrated (up to 36 months of follow up) (22, 23), and real world evidence confirmed sustained BP lowering effect up to 10 years post procedure (24). Further studies are required to clarify whether the lower OPB was truly related to eHAT therapy and the mechanisms behind sustained BP improvement in these subjects.

Our data showed that both attended and unattended OBP improved after eHAT therapy more than ABPM. These findings align with previous reports that antihypertensive treatment in hypertensive patients results in a greater reduction in OBP compared to ABPM. This effect is observed in both SBP and DBP, with the treatment effect captured by OBP being 36% greater for SBP and 33% greater for DBP compared to 24-hour measurements (25). The treatment's impact is influenced by several factors that may have a differential impact on OBP vs. ABPM. For example, the “white-coat effect” affects OBP but not ABPM, and “the regression to the mean” phenomenon (where extreme measurements tend to move closer to the average upon remeasurement) affects single or few OBP measurements more than the 24-hour average of day and night measurements (25). Measurement bias in OBP and absence of blinding may have also contributed to stronger in-office responses. Overall, the small number of participants in this study does not allow for subgroup analysis to further elucidate individual characteristics predictive or larger ambulatory daytime SBP response. Moreover, the results may be affected by natural fluctuations in BP and by the influence of participating in a clinical trial, as earlier randomized controlled trials on antihypertensive treatments have shown that even patients assigned to placebo experienced documented BP improvements (19).

Importantly, patients experienced either transient or no side effects. In particular, kidney function remained stable over time. Urinary protein excretion, an important prognostic factor for kidney function decline (26), showed no change, and we found no negative impact of eHAT on eGFR that remained stable for up to 48 weeks of follow up. Indeed, eHAT has been recently shown to be safe in patients with diabetic nephropathy (27). Whether and through which mechanism eHAT might slow down deterioration of kidney function has not been fully explored in the current pilot study.

This study has several limitations that should be acknowledged. It was non-randomized and did not include a sham-treated control group. The severity of HTN was not considered for enrollment, with recruited participants ranging from no medications (one patient) to RH. The BP regimen at baseline was not standardized, and anti-hypertensive medications were changed by primary care providers. In addition, the protocol requires a 3-week regimen that might be impractical for some patients. Strengths of the study include its prospective design and longitudinal follow-up of up to 48 weeks, but the results should be considered hypothesis generating and require confirmation. eHAT.

In conclusion, eHAT should be explored for treatment of HTN in patients with CKD. Efficacy cannot be firmly attributed to eHAT without randomized sham-controlled trials.

Supplementary Figure S1 Study design. Participants underwent a screening process to assess eligibility, followed by baseline evaluation prior to intervention. Eligible participants received six sessions of electro-hydraulic acoustic therapies. The end of treatment evaluation was conducted shortly after the last therapy session. Subsequently, follow-up assessments were scheduled at 4-, 12-, 24-, and 48-weeks post-treatment to monitor outcomes over time. In all follow-ups, office and unattended office blood pressure was measured. In every follow-up laboratory blood and urine samples were taken to evaluate eGFR and uPCR. At 12- and 48-weeks post treatment ambulatory blood pressure monitoring was conducted.

Supplementary Figure S2 Study recruitment flowchart. Flowchart depicting the recruitment and follow-up process of recruiting study participants. Of 24 patients screened, 21 consented to participate, while 3 failed screening. One patient revoked consent, leaving 20 who completed all eHAT assessments. Of these, 4 dropped out during follow-ups, resulting in 16 completing all follow-ups. One patient was removed due to errors in BP readings, yielding 15 patients with complete and usable results.

Supplementary Figure S3 Medindex. Change in MedIndex-2 post electro-hydraulic acoustic therapy treatment: baseline to 48-week follow-up. MedIndex is a method used to quantify the use of antihypertensive medications. MedIndex-1 calculates the sum of the ratios of prescribed doses to standard doses, weighted by drug class. MedIndex-2 multiplies this sum by the number of medications, thereby capturing both the dosage and the number of prescribed medications. We calculated the mean of MedIndex-2 at each time point. The figure shows that MedIndex-2 decreased over time, indicating a reduced need for antihypertensive medications.

Supplementary Figure S4 eGFR. Change in eGFR post electro-hydraulic acoustic therapy treatment. Serum creatinine was taken at every timepoint from baseline to 48 weeks post treatment. Serum creatinine was used to calculate eGFR using CKD- EPI 2021 equation. In figure 4 we see a delta (change) between all time points and baseline.