
==== Front
Clin Kidney J
Clin Kidney J
ckj
Clinical Kidney Journal
2048-8505
2048-8513
Oxford University Press

10.1093/ckj/sfae234
sfae234
Original Article
AcademicSubjects/MED00340
Effects of SGLT2 inhibitors on parameters of renal venous congestion in intrarenal Doppler ultrasonography
https://orcid.org/0000-0002-1162-4682
Wallbach Manuel Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany
German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Germany

Ajrab Jamil Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany

Bayram Bilgin Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany

Pieper Dennis Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany

Schäfer Ann-Kathrin Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany

Lüders Stephan Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany
Department of Nephrology, St.-Josefs-Hospital, Cloppenburg, Germany

Delistefani Fani Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany

Müller Dieter GIZ Nord Poison Centre, Göttingen, Germany

Koziolek Michael Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany
German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Germany

Correspondence to: Manuel Wallbach; E-mail: manuel.wallbach@med.uni-goettingen.de
9 2024
14 8 2024
14 8 2024
17 9 sfae23423 5 2024
10 9 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.
2024
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 (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

ABSTRACT

Background

Cardiorenal syndrome is a common condition in clinical practice in which renal venous congestion (VC) plays an important role. Intrarenal Doppler ultrasound (IRD) is a non-invasive method to assess and quantify renal VC. The current study aims to investigate the effects of SGLT2 inhibitor (SGLT2i) therapy on IRD parameters of renal VC.

Methods

This prospective observational study included patients with chronic kidney disease (CKD) with or without type 2 diabetes mellitus and/or heart failure (HF) with reduced and preserved ejection fraction who had an indication for standard of care SGLT2i therapy. IRD, assessing venous impedance index (VII), and intrarenal venous flow pattern (IRVF) analysis were performed within the interlobar vessels of the right kidney before and 6 months after initiation of SGLT2i therapy.

Results

A number of 64 patients with CKD and a cardiorenal risk profile were included (mean eGFR 42.9 ml/min/1.73 m2; 56% with HF, and 38% with type 2 diabetes mellitus). 17 patients exhibited signs of VC in the IRD. VII was significantly correlated with levels of NT-proBNP, female gender, NYHA class, and was significantly negative correlated with body mass index. After 6 months, a notable decrease in the mean VII of the right interlobar veins by 0.13 (P < .01) was observed. Stratification according to IRVF pattern showed a significant shift towards reduced renal VC pattern after 6 months (P = .03).

Conclusions

In this study, SGLT2i therapy resulted in a reduction in renal VC as assessed by IRD. These findings underscore the potential haemodynamic benefits of SGLT2 inhibitors in cardiorenal syndrome and warrant further investigation into their clinical implications.

Graphical Abstract

Graphical Abstract

congestive nephropathy
estimated glomerular filtration rate
heart failure
intrarenal Doppler sonography
renal venous congestion
==== Body
pmcKEY LEARNING POINTS What was known:

Renal venous congestion (VC) is an accumulation of fluid that attenuates the forward flow in the renal veins and leads to a leakage of fluid from the intravascular to the interstitial space. Moreover, VC can be also be due to right-sided heart failure in the absence of fluid overload. This might cause compression of the tubules, which could weaken the transglomerular gradient and potentially reduce the glomerular filtration rate (GFR).

Intrarenal Doppler sonography (IRD) is a non-invasive method used for the assessment and quantification of renal VC. IRD enables the determination of the intrarenal venous flow profile and venous impedance index, which serves as an indicator of changes in intravascular volume and renal VC.

Several randomized controlled trials have demonstrated significant renoprotective effects of SGLT2i. It has been postulated that SGLT2i therapy reduces VC, so this study was done to explore, whether IRD parameters associated with VC improve in patients receiving SGLT2i treatment for renal and/or cardiac conditions.

This study adds:

After 6 months of SGLT2i treatment, renal VC improved significantly, which was reflected in a reduced venous impedance index and a shift in the intrarenal venous flow pattern towards a reduced congestion pattern.

Potential impact:

The present study contributes to the evolving narrative surrounding the nephroprotective effects of SGLT2i by highlighting their potential role in improving renal VC. This mechanism, elucidated through IRD assessments, offers a novel perspective on the intricate interplay between SGLT2i, cardiac function, and renal haemodynamics.

INTRODUCTION

Venous congestion (VC) is an accumulation of fluid in the intravascular and interstitial space caused by increased renal sodium and water retention, partly stimulated by activation of the renin angiotensin aldosterone system (RAAS) and sympathetic nervous system [1]. Moreover, VC can be also be due to right-sided heart failure (HF) in the absence of fluid overload. The resulting volume expansion causes a decrease in venous compliance and an increase in pressure in the inferior vena cava (IVC), which in turn weakens the forward flow in the interlobar veins of the kidneys [2]. In the kidneys, VC causes fluid leakage from the intravascular space into the interstitial space [1]. It is hypothesized that an increase in renal interstitial pressure may lead to compression of the tubules. This compression could potentially attenuate the transglomerular gradient and thereby reduce the glomerular filtration rate (GFR) [3] Moreover, renal VC causes inflammation, oxidative stress, and renal ischaemia, resulting in intrinsic tubular damage [4]. Congestive nephropathy (CN) is a subtype of cardiorenal syndrome, characterized by potentially reversible kidney dysfunction due to impaired renal venous outflow, commonly resulting from right-sided HF or intra-abdominal hypertension [5]. HF is probably the most common condition associated with CN, but others include pulmonary hypertension, isolated tricuspid regurgitation, and congenital heart disease [5].

Measurement of right atrial pressure by right heart catheterization is considered the gold standard for the assessment of VC [1]. Intrarenal Doppler sonography (IRD) is a non-invasive method used for the assessment and quantification of renal VC [2, 6, 7]. IRD enables the determination of the intrarenal venous flow profile (IRVF) [7], which can manifest as either continuous (indicative of no VC) or discontinuous (suggestive of VC), with the discontinuous profile further categorized into pulsatile, biphasic, and monophasic [6]. Additionally, the venous impedance index (VII), another Doppler sonographic parameter, serves as an indicator of changes in intravascular volume and renal VC [2]. Given that in a discontinuous flow profile there is a cessation of flow at the end of diastole (resulting in zero end-diastolic flow velocity), the VII is uniformly equal to 1 across pulsatile, biphasic, and monophasic flow profiles.

In recent years, several randomized controlled trials have demonstrated significant renoprotective effects of SGLT2i therapy in the treatment of diabetes, HF, and/or chronic kidney disease (CKD). These included reductions in glomerular hyperfiltration and hypertension [8], albuminuria [9], improvements in metabolic status, tubular oxygen delivery [10], and renal function [11]. The reduction in various endpoints, including the reduction in hospitalization for HF, observed in large clinical trials of SGLT2i is clear and impressive [12–16]. However, long-term changes in total plasma volume and general haemodynamics may not be the main mechanism contributing to the large clinical benefit of SGLT2i. It has been postulated that SGLT2i therapy reduces VC by reducing the water and salt content in the interstitial space [17]. This study aimed to explore IRD parameters associated with VC in patients receiving SGLT2i treatment for renal and/or cardiac conditions.

MATERIALS AND METHODS

Study design and participants

This is a non-randomized, monocentric, prospective, observational study. Patients admitted to the Department of Nephrology of the University Medical Center of Göttingen between January 2022 and March 2023 and fulfilling inclusion criteria were prospectively enrolled. The inclusion criteria encompassed individuals with CKD, with or without diabetes mellitus type 2, and individuals experiencing HF with reduced ejection fraction (HFrEF), coupled with CKD, and demonstrating an indication for the commencement of a novel SGLT2i therapy within standard of care treatment. Patients with pregnancy, breastfeeding, after kidney transplantation, or requiring dialysis, with CKD stage >G4, autosomal dominant polycystic kidney disease, current acute kidney injury, postrenal obstruction, pulmonary hypertension due to causes other than HF, diabetes mellitus type 1, active malignant disease, inflammatory or autoimmune disease affecting renal function, circumstances that could interfere with the results of the Doppler sonographic evaluation [e.g. significantly respiratory diseases with current symptoms, body mass index (BMI) >40 kg/m2, etc.], or patients with known non-adherence were excluded. As per approval by the European Medicines Agency, dapagliflozin was started up to an eGFR of 25 ml/min/1.73 m2 and empagliflozin up to an eGFR of 20 ml/min/1.73 m2. Study visits were performed 1 day before the start of SGLT2i therapy (dapa- or empagliflozin, each 10 mg/day) and 6 months ± 14 days thereafter. The study complies with the principles of the Declaration of Helsinki and local ethical committee approved the study protocol (Ethical vote number 38/6/21). All patients provided written informed consent. The study was prospectively registered at the German Clinical Trials Register (DRKS00026098).

Laboratory analyses and medication

NT-proBNP, haemoglobin, haematocrit, sodium, potassium, fractional excretion of sodium (FeNa), aldosterone, plasma renin activity (PRA), HbA1c, serum creatinine, cystatin C, eGFR determined by the CKD-EPI formula based on creatinine, and urinary albumin-creatinine ratio (UACR) were assessed at baseline and follow-up, as well as adherence by gas chromatography-mass spectrometry [18]. At each visit, all medications were assessed. Medication changes between visits were recorded. In the case of diuretics, the cumulative diuretic dose was calculated as follows: [(dose of diuretic 1/maximum dosage of diuretic 1) × 100 + (dose of diuretic 2/maximum dosage of diuretic 2) × 100 + ... + (dose of diuretic n/maximum dose of diuretic n) × 100]/number of diuretics.

Intrarenal Doppler sonography and inferior vena cava assessment

The Doppler sonographic examinations were carried out using the LOGIQ E10s device from GE HealthCare (Chicago, IL, USA) and were always performed by the same three trained physicians, who had at least 2 years of experience in renal ultrasound. The examination was performed after 5 minutes of rest in the lateral position. Patients underwent IRD assessment, as detailed in previous publications [2, 7, 19]. IRD was conducted as a routine part of clinical practice in our department, utilizing a standard convex transducer designed for abdominal sonography, operating within a frequency range of 1–6 MHz. IRD parameters of the right kidney were analysed with each subject positioned in the left semi-lateral decubitus posture. When there was no sufficient image quality on the right side, parameters of the left kidney were analysed. Colour Doppler images were employed to identify interlobar vessels. The renal resistance index (RI) at an interlobar artery was calculated using the formula RI = (Vmax − Vmin)/Vmax [2]. The venous impedance index (VII) for venous flow was calculated in a manner analogous to RI in the arterial system: VII = (Vmax − Vmin)/Vmax [2]. Furthermore, Doppler waveforms of the venous flow were categorized into four flow patterns as previously described [6]: continuous venous flow (stage 0, no congestion), pulsatile flow (stage 1 congestion), biphasic flow (stage 2 congestion), and monophasic flow (stage 3 congestion). Congestion stages 1 to 3 were defined as discontinuous flow, considered abnormal, indicating a venous flow at the nadir of zero or even a positive venous flow value. Consequently, if the nadir of the venous flow was zero or positive, the VII was defined as 1, resulting in a VII range between 0 and 1. All values were recorded as means based on at least three measurements in different interlobar vessels within the kidney. In cases of atrial fibrillation, an index beat (the beat following two preceding cardiac cycles of equal duration) was utilized for each measurement [6]. At baseline and follow-up, IVC was identified in B-mode sonography with a phased array transducer (2–8 MHz) for the heart and then the M-mode Doppler was applied to capture at least three respiratory cycles for diameter measurement. Additionally, for HF classification, in all patients, echocardiography was carried out at baseline or, if available from the previous 6 months, those results were applied. The parameters investigated included left ventricular ejection fraction (LVEF) and systolic pulmonary artery pressure (PAPsys). Patients with symptoms and signs of HF with preserved LVEF (≥50%) and elevated NT-proBNP > 125 pg/ml (or >365 pg/ml if atrial fibrillation) and LAVI > 34 ml/m2 and/or LVMI ≥ 115 g/m2 (men) or 95 g/m2 (women) and/or E/e´ ≥ 9 were classified as patients with HFpEF [20].

Statistical analysis

The data were analysed using GraphPad Prism Version 10 (GraphPad Software, San Diego, CA, USA). The presence of a normal distribution was tested graphically. To assess time-dependent changes in the investigated variables, paired two-sided t-test, Wilcoxon signed rank, or sign test were used, where appropriate. Differences between subgroups were compared by an independent t-test or Mann–Whitney U-test for continuous variables or the Pearson's chi square test or Fisher's exact test for categorical values. In analysis with more than two groups Kruskal–Wallis analysis with Dunn's test for pairwise post hoc comparisons was performed. Data are presented as mean ± standard deviation (SD), median and interquartile range (IQR) or number (N) and % (%). The significance level was set to alpha = 5% for all statistical tests.

RESULTS

Baseline characteristics

The baseline characteristics of the study population, consisting of 64 participants, are summarized in Table 1 to provide a comprehensive overview of demographic, clinical, and medical history parameters. Among the participants, 26 (41%) were female, and the average age was 67 ± 12 years. The average BMI was 28.8 ± 5.5 kg/m2. A detailed exploration of medical history revealed a prevalence of various comorbidities within the cohort. Atrial fibrillation was observed in 22 (34%) of participants, arterial hypertension in all 64 (100%), hyperlipoproteinaemia in 47 (73%), diabetes mellitus type 2 in 24 (38%), cerebrovascular diseases in 11 (17%), chronic obstructive pulmonary disease (COPD) in 10 (16%), and a history of smoking in 47 (73%). Additionally, 31 (48%) participants had a history of coronary artery disease. In terms of HF classification based on LVEF, 17 (27%) of the participants had HFrEF, while none fell into the HF with mid-range ejection fraction (HFmrEF) category, and 19 (30%) had HF with preserved ejection fraction (HFpEF). Regarding CKD stage, a high degree of patients showed advanced stage CKD, with stage G3-4 in 56 patients (88%) and 38 patients (59%) showing at least A2 albuminuria (i.e. >30 mg/g creatinine). A number of 15 patients (23%) showed even eGFR < 30 ml/min/1.73 m2 and 17 patients (27%) showed A3 albuminuria (>300 mg/g creatinine) (Table S1). Patients took on average 3.47 ± 1.17 haemodynamic-active cardiovascular medications at baseline. The individual drug classes are listed in Table 2. Correlation analysis revealed significant associations between the VII and various clinical parameters, as summarized in Table 3. VII was significantly correlated with levels of NT-proBNP, female gender, and NYHA class, and was significantly negatively correlated with BMI. In contrast to that, age, LVEF, UACR, PAPsys, PRA, aldosterone levels, presence of diabetes mellitus, and eGFR, based on CKD-EPI creatinine, did not show statistically significant correlations with VII. Most patients did not show elevated PAPsys and only nine patients had an elevated PAPsys of >36 mmHg.

Table 1: Baseline characteristics.

Parameter	N = 64	
Female	26 (41%)	
Age (years)	67 ± 12	
BMI (kg/m2)	28.8 ± 5.5	
Atrial fibrillation	22 (34%)	
Arterial hypertension	64 (100%)	
Hyperlipoproteinemia	47 (73%)	
Diabetes mellitus type 2	24 (38%)	
CKD stage 3–4	56 (88%)	
Cerebrovascular diseases	11 (17%)	
COPD	10 (16%)	
History of smoking	47 (73%)	
Coronary artery disease	31 (48%)	
Congestive heart failure	36 (57%)	
 HFrEF	17 (27%)	
 HFmrEF	0 (0%)	
 HFpEF	19 (30%)	
BMI, CKD, number (No.), COPD, HFmrEF, HFpEF, HFrEF. Values are expressed as mean ± SD or n (%).

Table 2: Haemodynamic active, CV-medication.

	V1	V2	P	
No. of medication	3.47 ± 1.17	3.42 ± 1.19	.61	
ACE inhibitor	19 (33%)	19 (33%)	1.0	
ARB	26 (46%)	26 (46%)	1.0	
ARNI	9 (16%)	9 (16%)	1.0	
Renin-inhibitor	1 (2%)	1 (2%)	1.0	
Beta-blocker	45 (79%)	45 (79%)	1.0	
Thiazid diuretic	10 (18%)	9 (16%)	1.0	
Loop diuretic	36 (63%)	37 (65%)	1.0	
MRA	12 (21%)	11 (19%)	1.0	
Alpha-blocker	11 (19%)	6 (11%)	.29	
CCB	29 (51%)	26 (46%)	.71	
Cumulative diuretic doses (%)	10.0 (2.9–16.9)	11.3 (4.3–28.8)	.21	
Abbreviations: ARNI, angiotensin receptor-neprilysin inhibitor; ARB, angiotensin-2-receptor-blocker; CCB, calcium channel blocker; MRA, mineralococorticoid receptor antagonist; No., number (). Values are expressed as mean ± SD, n (%) or median (IQR).

Table 3: Bivariate correlation between VII and clinical parameters.

Parameter	Correlation coefficient rho	95% CI	P	
BMI (kg/m2)	−.300	[−0.508; −0.058]	.02	
Age (years)	.184	[−0.064; 0.412]	.15	
Gender (female)	.310	[0.070; 0.517]	.01	
LVEF (%)a	−.214	[−0.447; 0.047]	.11	
Diabetes mellitus	−.086	[−0.325; 0.163]	.50	
eGFR (ml/min/1.73 m2)	.013	[−0.234; 0.258]	.92	
NYHA class	.369	[0.134; 0.565]	<.01	
NT-proBNP (ng/l)	.583	[0.394; 0.725]	<.01	
IVC min	.254	[0.003;0.476]	.05	
UACRb	.094	[−0.186;0.360]	.51	
PAPsysc	−.041	[−0.402;0.330]	.83	
Aldosterone (ng/l)d	−.156	[−0 389;0.095]	.222	
PRA (µIu/ml)e	−.224	[−0.449–0.027]	.080	
LVEF, eGFR, based on CKD-EPI creatinine UACR, IVC, pulmonary arterial pressure (PAP), PRA. N = 64, different sample sizes are indicated: an = 58; bn = 51, cn = 29; dn = 63, en = 62.

Doppler sonographic parameters of renal venous congestion

A total of seven patients (11%) were excluded from IRD analysis due to missing 6 months data [one patient (2%) died due to ischaemic stroke, five patients (8%) cancelled the study within the first 6 months and one patient (2%) could not adhere to breathing commands during IRD at month 6], so that IRD was performed at baseline and month 6 in 57 patients. With the exception of starting SGLT2i therapy, the number of cardiovascular, haemodynamic-active medications remained unchanged over the observation period (3.47 ± 1.17 vs. 3.42 ± 1.19, P = .61). The cumulative diuretic doses also remained stable [median 10.0% of the maximum daily dose (IQR 2.9–16.9) at the beginning and 11.3% (IQR 4.3–28.8) at the end of the study period, P = .21, see Table 2]. Regarding the renal arterial system, RI in the interlobar artery did not change significantly from baseline to month 6 (0.76 ± 0.07 vs. 0.75 ± 0.05; P = .43). Compared to baseline, VII in the right interlobar veins was significantly reduced from a median of 0.51 (IQR 0.35–1.0) to 0.38 (0.26–0.59) (P < .01) after 6 months of SGLT2i treatment (Fig. 1). Regarding stratification by different variable, there was no difference in change in VII between baseline and 6-month follow-up: intake of thiazides (P = .15) or loop diuretics (P = .35), occurrence of peripheral oedema (P = .64), presence of arterial hypertension (P = .11), and sex (P = .46). Evaluation of the IVC was performed in 53 patients (93%) at baseline and follow-up. Between baseline and follow-up, there was no change neither in the IVC in expiration (maximum width) (1.6 ± 0.5 cm vs. 1.5 ± 0.4 cm, P = .30) and in inspiration (minimal width) (0.8 ± 0.4 cm vs. 0.7 ± 0.3 cm, P = .47) nor in the respiratory responsiveness (50.6% ± 20.6% vs. 55.7% ± 14.8%, P = .13). Stratification according to IRVF pattern showed a significant shift towards a reduced renal VC pattern after 6 months of SGLT2i therapy (P = .03) (Fig. 2). At baseline, 41 patients (72%) showed continuous venous flow, which was considered as normal IRVF pattern. After 6 months of SGLT2i therapy, 14 (out of 16 patients with preexisting VC) patients (25% of total and 88% of those with initial existing VC) exhibit an improvement of IRVF pattern and four patients (7%) exhibit a deterioration of IRVF pattern. A number of 50 patients (88%) showed continuous venous flow after 6 months of SGLT2i therapy. The study observed significant changes in various clinical and laboratory parameters over the 6-month observational period (Table 4). Between baseline and month 6, creatinine levels increased from 1.65 ± 0.55 mg/dl to 1.76 ± 0.64 mg/dl (P = .03), while eGFR demonstrated a decrease from 42.9 ± 15.5 ml/min/1.73 m2 to 40.1 ± 15.1 ml/min/1.73 m2 (P = .03). Cystatin C levels significantly increased from 2.05 ± 0.59 to 2.27 ± 0.72 (P < .01), and eGFR Cystatin C decreased from 33.0 ± 12.8 ml/min/1.73 m2 to 30.0 ± 12.1 ml/min/1.73 m2 (P < .01). Initially, the median UACR was 50 mg/g creatinine (15.3–323.0), and it remained stable throughout the follow-up period (P = .29). PRA also significantly increased from 102.6 µIU/ml (18.7–213.1) to 129.8 µIU/ml (33.4–334.3) (P < .01). Markers of glycaemic control and haemodynamics without statistically significant changes included aldosterone (P = .30), the aldosterone-renin ratio (P = .29), HbA1c (P = .32), and blood pressure (BP) (P = .35 for systolic and P = .09 for diastolic BP). Body weight (P = .19) as well as NT-pro BNP levels did not exhibit a statistically significant change (P = .48).

Figure 1: (a) VII and (b) RI at baseline (BL) and after 6 months of SGLT2i therapy. Lines represent median, boxes represent lower and upper quartile, whiskers represent 1.5 × IQR and dots indicate outliers.

Figure 2: Distribution of IRVF pattern at baseline (BL) and after 6 months of SGLT2i therapy. Values indicate absolute numbers of patients (%).

Table 4: Changes of clinical and laboratory parameters.

Parameter	Baseline	Month 6	P	
Serum creatinine (mg/dl)	1.65 ± 0.55	1.76 ± 0.64	.03	
eGFR (ml/min/1.73 m2)	42.9 ± 15.5	40.1 ± 15.1	.03	
Cystatin C	2.05 ± 0.59	2.27 ± 0.72	<.01	
eGFR cystatin C (ml/min/1.73 m2)	33.0 ± 12.8	30.0 ± 12.1	<.01	
Albumin (g/dl)	3.7 ± 0.6	3.9 ± 0.5	.02	
Haemoglobin (g/dl)	13.3 ± 1.3	13.8 ± 2.0	<.01	
Haematocrit (%)	39.5 ± 5.6	41.3 ± 5.4	<.01	
Sodium (mmol/l)	139.5 ± 2.8	139.9 ± 2.7	.24	
Potassium (mmol/l)	4.3 ± 0.4	4.4 ± 0.4	.22	
FeNa (%)	1.9 ± 1.5	2.1 ± 1.9	.25	
Aldosterone (ng/l)	125.0 (71.9–176.0)	132.0 (105.0–200.0)	.30	
PRA (µIU/ml)	102.6 (18.7–213.1)	129.8 (33.4–334.3)	<.01	
ARR	2.0 (0.8–7.7)	1.9 (0.8–6.3)	.29	
HbA1c (%)	6.1 ± 0.7	6.1 ± 0.7	.32	
Office BP				
SBP (mmHg)	136.5 ± 20.7	134.4 ± 20.8	.35	
DBP (mmHg)	77.3 ± 12.9	74.9 ± 13.6	.09	
Body weight (kg)	87.3 ± 19.1	86.5 ± 18.3	.19	
NT-pro BNP (ng/l)	564 (199–1659)	471 (194–1727)	.48	
Oedema	34 (53%)	12 (21%)	<.01	
Pleural effusion	0	0	>.99	
Abbreviations: systolic BP (SBP) and diastolic BP (DBP).

VII in patients with and without heart failure

Patients with HF showed higher VII compared to patients without HF [0.37 (IQR 0.29–0.60) vs. 0.57 (IQR 0.44–1.0) P < .01, Figure 3a]. The comparison of the three groups no HF, HFpEF, HFrEF showed a significant intergroup difference (P = .01, Figure 3b). Post hoc-analysis revealed a significant higher VII in patients with HFrEF with a median of 0.54 (IQR 0.47–1.0) compared to patients without HF showing a median of 0.37 (IQR 0.30–0.56: P = .02) and a trend to higher VII in patients with HFpEF with a median of 0.58 (IQR 0.51–0.63) compared to patients without HF (P = .075) without reaching statistical significance. No differences were observed between patients with HFpEF and HFrEF in respect to their baseline VII levels (P = .616).

Figure 3: Venous impedance index in patients with and without HF at baseline. (a) Comparison between patients with and without HF. (b) Comparison between patients with HFpEF, HFrEF, and patients without HF. Lines represent median, boxes represent lower and upper quartile, whiskers represent 1.5 × IQR and dots indicate outliers.

Adherence to SGLT2i treatment

A total of 52 patients were treated with dapagliflozin and six patients were treated with empagliflozin. Adherence testing was performed with direct biochemical methods such as the GC-MS method in 49 patients. In nine patients, adherence testing was performed by analysing glucosuria using a urine dipstick. Adherence testing demonstrated the presence of dapagliflozin in 46 patients. In three patients, the direct adherence testing revealed non-adherence (5.1%). However, in two out of these three patients, marked elevated glucosuria of >1000 mg/dl was detected, indicating adherence to SGLT2i therapy. The remaining nine patients for whom no direct biochemical adherence testing was conducted (including the six patients receiving empagliflozin, not captured by the applied methodology), also exhibited glucosuria at the second visit. Thus, a high adherence rate of 98% (57 out of 58 patients) can be assumed.

DISCUSSION

The most notable finding of the present study is the reduction of renal VC under treatment with SGLT2i. This is supported by a decrease in the VII and a transition towards a less congested IRVF pattern observed via IRD. To the best of our knowledge, this is the first study to investigate the effects of SGLT2i on renal VC in humans, apart from a case report showing improvement of IRVF pattern in a single patient with HFpEF during a 1-month course of SGLT2i therapy [21]. Specifically, among the subgroup displaying discontinuous flow at baseline, 82% of patients exhibited improvement after 6 months.

Several studies have reported that diuretic and natriuretic effects of SGLT2 inhibitors are only transient [22–27]. At the beginning of SGLT2i therapy, a hybrid diuretic effect occurs due to the inhibition of proximal tubule sodium uptake and the absence of activation of compensatory mechanisms in the distal tubule. This results in both natriuresis and glycosuria [25, 28]. The early diuretic effect of SGLT2i may contribute to cardioprotective properties, leading to a reduction in preload and myocardial stretch [29]. Over time, the body reaches a new stable state of sodium balance [25]. In our cohort, there was no change in FeNa after 6 months. However, there was a slight increase in PRA, as well as in the aldosterone levels and aldosterone-to-renin ratio (ARR). This is in line with previous clinical studies investigating the long-term effects of SGLT2 inhibitors on sodium excretion, urine volume, and hormone levels within the RAAS axis [25, 30–33]. While glucosuria remains present during SGLT2i treatment, the initial rise in urine volume tends to normalize over time. This normalization could be attributed to urea generation and renal accumulation in response to altered energy metabolism [34, 35].

In a rat model of HF, canagliflozin was found to deplete fluids from both intravascular and renal medullary interstitial compartments [36]. Furthermore, a mathematical model demonstrated that dapagliflozin use in healthy subjects led to a 2-fold greater reduction in interstitial fluid volume compared to blood volume [37]. Consistent with these findings, other studies have indicated a preferential removal of interstitial fluid over intravascular fluid, potentially aiding in the amelioration of renal interstitial oedema and tubular cell oedema, consequently increasing renal blood flow [38].

It is hypothesized that this distinct volume modulation by SGLT2i, which favours interstitial over intravascular regulation, could help attenuate neurohumoral activation associated with intravascular volume depletion [39, 40]. SGLT2i therapy thus emerges as a promising treatment option for congestion, as it reduces interstitial volume more evenly than blood volume, without compromising arterial filling or renal perfusion. This balanced approach to congestion management holds potential for optimizing patient outcomes.

However, other surrogates of fluid balance must also be considered. In this study, changes in serum albumin, haemoglobin, and haematocrit can only be used to a limited extent as they are influenced by various SGLT2i-related effects. The increase in serum albumin levels might be explained by the known effect of SGLT2i in reducing albuminuria. The elevation in haemoglobin and haematocrit levels could be attributed to the previous observed increase in haematopoiesis resulting from SGLT2i therapy [41]. NT-proBNP levels remained unchanged after 6 months of SGLT2i treatment, consistent with several previous studies investigating the effect of SGLT2i on natriuretic peptides [42, 43]. However, in established HFrEF, the SGLT2i-treated group showed only a modest reduction in NT-proBNP levels (8% after 8 months and 13% after 1 year) compared to the placebo group [15, 44]. This suggests that the therapeutic effect of SGLT2i on cardiorenal outcomes is not accurately reflected by changes in NT-proBNP concentration.

The prevalence of congestion in clinically stable patients with HF remains uncertain. However, even subclinical congestion, as assessed by ultrasound, is associated with worse clinical outcomes [45]: ∼50% of patients with HF suffer CKD at a stage ≥3 [46]. It is not only possible but also realistic that congestion contributes to the decline in renal function, at least in part. The present cohort study found that 28% of patients showed VC expressed by an intermittent flow in the IRVF at baseline, which ameliorates after 6 months of SGLT2i therapy. So, the current findings suggest that SGLT2i therapy can exert a notable influence on the haemodynamic aspects of fluid balance in cardiorenal patients without altering NT-proBNP levels and IVC width. Hence, evaluating IRD parameters could represent a valuable approach to elucidating the haemodynamic changes and their clinical implications induced by SGLT2i treatment.

Limitations

The present study has several limitations as it was not blinded and not randomized. Although the parameters of IRD and renal VC are of interest, a further randomized trial seems very unlikely to take place, given the fact that there are already convincing data on the cardiorenal vascular benefits of SGLT2i therapy. The observational nature of this study, featuring a single follow-up point, leaves it vulnerable to confounding factors. Future research should incorporate more frequent measurements and correlate changes in echocardiographic parameters with changes in renal VC. Variations in clinical management and patient behaviours, such as diet, physical activity, and fluid intake, during the follow-up period could have influenced the study outcomes. Additionally, the study's patient cohort is limited, particularly regarding those treated with empagliflozin, and many patients did not exhibit renal VC in IRD at baseline. While the subgroup with overt CN was small, the study aimed to explore preliminary observations in a broader population with diabetes mellitus and HF. This may even have led to an underestimation of the anticongestive effect in the population of those with VC at the start of SGLT2i treatment. In future studies, preselection of patients with a discontinuous IRVF pattern may be preferable to more specifically highlight the effects of SGLT2i on IRD parameters.

Conclusion

The present study offers preliminary insights into the potential nephroprotective effects of SGLT2i, suggesting a role in improving renal VC observed through IRD assessments. This suggests a novel perspective on the interplay between SGLT2i, cardiac function, and renal haemodynamics. However, further research is necessary to confirm and expand on these findings, including long-term implications for managing cardiorenal patients.

Supplementary Material

sfae234_Supplemental_File

ACKNOWLEDGEMENTS

We acknowledge support by the Open Access Publication Funds of the Göttingen University.

The study protocol was approved by the ethical committee of the university medicine Göttingen.

FUNDING

Open Access funding enabled and organized by Projekt DEAL. This study was a prospectively designed cohort study planned by M.W. and M.J.K. All study related procedures were financed by own resources of the participating department.

CONFLICT OF INTEREST STATEMENT

M.W. declares lecture fees from AstraZeneca. M.J.K. declares lecture fees from Boehringer Ingelheim, Lilly, and AstraZeneca. For the present study, there are no conflict of interest from any of the other authors.

AUTHORS' CONTRIBUTIONS

Research idea and study design: M.W., M.J.K.; data acquisition: M.W., J.A., B.B., D.P., A.C.S., S.L., F.D., D.M., M.J.K.; statistical analysis: M.W., J.A., M.J.K.; interpretation of data: M.W., J.A., A.C.S., S.L., F.D., D.M., M.J.K.; supervision or mentorship: M.W., M.J.K. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

DATA AVAILABILITY STATEMENT

Patients did not agree for their individual data to be shared publicly.
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