A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics

Capolongo, Giovanna; Capasso, Giovambattista; Viggiano, D.

doi:10.3390/ijms23073915

Cited by 12 publications

(6 citation statements)

References 85 publications

(108 reference statements)

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“…RAS inhibitors and sodium-glucose co-transporter 2 inhibitors cause a transient decrease in eGFR in the early phase of their administration and a subsequent slower decrease in eGFR. Although this phenomenon is known to have no clinical relevance [44], long-term evidence is lacking for esaxerenone. Additionally, patients with early DKD and a slow rate of eGFR decline were not enrolled in the study, and the long-term safety in patients with early DKD remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study

et al. 2022

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Introduction Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. Methods In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. Results In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (− 11.6/− 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (− 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was − 4.8 mL/min/1.73 m 2 . Conclusion Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. Clinical Trial Registration jRCTs06119002. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02294-z.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study

et al. 2022

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“…Besides the hemodynamic effect of RAS-Inhibitors, immunomodulatory properties have been discussed 24 , 25 . Inflammation is generally present in patients with decompensated liver cirrhosis and plays a crucial role in the genesis of kidney injury 26 .…”

Section: Discussionmentioning

confidence: 99%

Effects of renin–angiotensin inhibitors on renal function and the clinical course in patients with decompensated cirrhosis

Tergast,

Griemsmann,

Wedemeyer

et al. 2023

Sci Rep

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Patients with decompensated cirrhosis are at risk of developing acute kidney injury (AKI). Studies have suggested that inhibition of the Renin-Angiotensin System (RAS) has certain nephro- and hepatoprotective effects in patients with compensated liver disease. This study aimed to investigate the clinical impact of RAS-Inhibitors in individuals with decompensated liver cirrhosis. Overall, 1181 consecutive hospitalized patients with ascites that underwent paracentesis were considered for this retrospective study. In total, 667 patients with decompensated cirrhosis fulfilled the inclusion criteria and were finally analyzed. RAS-Inhibitor intake was documented in 41 patients (7%). First, 28-day incidences of AKI and grade III AKI of all patients with RAS-Inhibitors were compared to those without intake. Afterwards, propensity score matching was conducted in a 3:1 manner. Here, incidence of further renal endpoints such as need of hemodialysis were analyzed in detail. In the unmatched setting, intake of RAS-Inhibitors was not associated with an increased 28 day-incidence of AKI (P = 0.76) or LTx-free survival (P = 0.60). However, 28 day-incidence of grade III AKI was significantly lower in patients with RAS-Inhibitor intake (P < 0.001). In the matched setting, 28 day-incidence of AKI did not differ (P = 0.81), while grade III AKI was significantly less frequent in the RAS-Inhibitor group (P < 0.001). Need for hemodialysis was also significantly lower in patients with RAS-Inhibitors (P = 0.03) and LTx-free survival was comparable between both groups (P = 0.52). Thus, this study suggests that intake of RAS-Inhibitors is associated with decreased incidences of grade III AKI and need of hemodialysis in patients with decompensated liver disease.

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“…However, the highest resistance to the intratubular flow is within the thin descending limbs where the smallest tubular section can be observed [ 34 ]. These authors also predict that proximal diuretics (acetazolamide and SGLT2-inhibitors) give a substantial back pressure in Bowman’s capsule, decreasing the glomerular filtration rate [ 35 ].…”

Section: Laplace’s Law In Kidney Tubules: Hypothesis On Adpkdmentioning

confidence: 99%

Wall Tension and Tubular Resistance in Kidney Cystic Conditions

Corte

Viggiano

2023

Biomedicines

Self Cite

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The progressive formation of single or multiple cysts accompanies several renal diseases. Specifically, (i) genetic forms, such as adult dominant polycystic kidney disease (ADPKD), and (ii) acquired cystic kidney disease (ACKD) are probably the most frequent forms of cystic diseases. Adult dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by multiple kidney cysts and systemic alterations. The genes responsible for the condition are known, and a large amount of literature focuses on the molecular description of the mechanism. The present manuscript shows that a multiscale approach that considers supramolecular physical phenomena captures the characteristics of both ADPKD and acquired cystic kidney disease (ACKD) from the pathogenetic and therapeutical point of view, potentially suggesting future treatments. We first review the hypothesis of cystogenesis in ADPKD and then focus on ACKD, showing that they share essential pathogenetic features, which can be explained by a localized obstruction of a tubule and/or an alteration of the tubular wall tension. The consequent tubular aneurysms (cysts) follow Laplace’s law. Reviewing the public databases, we show that ADPKD genes are widely expressed in various organs, and these proteins interact with the extracellular matrix, thus potentially modifying wall tension. At the kidney and liver level, the authors suggest that altered cell polarity/secretion/proliferation produce tubular regions of high resistance to the urine/bile flow. The increased intratubular pressure upstream increases the difference between the inside (Pi) and the outside (Pe) of the tubules (∆P) and is counterbalanced by lower wall tension by a factor depending on the radius. The latter is a function of tubule length. In adult dominant polycystic kidney disease (ADPKD), a minimal reduction in the wall tension may lead to a dilatation in the tubular segments along the nephron over the years. The initial increase in the tubule radius would then facilitate the progressive expansion of the cysts. In this regard, tubular cell proliferation may be, at least partially, a consequence of the progressive cysts’ expansion. This theory is discussed in view of other diseases with reduced wall tension and with cysts and the therapeutic effects of vaptans, somatostatin, SGLT2 inhibitors, and potentially other therapeutic targets.

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A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics

Cited by 12 publications

References 85 publications

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study

Effects of renin–angiotensin inhibitors on renal function and the clinical course in patients with decompensated cirrhosis

Wall Tension and Tubular Resistance in Kidney Cystic Conditions

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