Tolvaptan- and Tolvaptan-Metabolite-Responsive T Cells in Patients with Drug-Induced Liver Injury

Gibson, Andrew; Hammond, Sean; Jaruthamsophon, Kanoot; Roth, Sharin E.; Mosedale, Merrie; Naisbitt, Dean J.

doi:10.1021/acs.chemrestox.0c00328

Cited by 13 publications

(11 citation statements)

References 8 publications

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“… 39 Furthermore, in vitro evidence has suggested that liver injury may be mediated by tolvaptan-induced T-cell activation and the subsequent release of specific cytokines, especially interferon-γ, interleukin-13 and granzyme-B. 40 Transcriptomic analysis using Collaborative Cross mice showed that tolvaptan may contribute to liver oxidative stress, mitochondrial dysfunction and activation of innate immunity. Interestingly, susceptibility to liver injury correlated with the mRNA expression and plasma levels of secretory leukocyte peptidase inhibitor, indicating its potential role as a predictive factor of hepatotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Bellos¹

2021

TCRM

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Autosomal dominant polycystic kidney disease constitutes the most prevalent hereditary kidney disease, associated with high rates of morbidity leading eventually to end-stage renal disease. Tolvaptan is a selective vasopressin antagonist and has emerged as a promising therapeutic option for patients with autosomal dominant polycystic kidney disease. The present review summarized current evidence regarding the safety profile of tolvaptan in patients with the disease. Consistent with its pharmacological action, aquaretic adverse events represent the most common side effects of tolvaptan, consisting of polyuria, pollakiuria and polydipsia. Gradual dose titration based on urinary osmolality, as well as dietary interventions aiming to reduce solute excretion, have been proposed as potential strategies to mitigate polyuria. In addition, tolvaptan administration may be complicated by liver injury, characterized by alanine aminotransferase and bilirubin elevations. Hepatotoxicity has been suggested to be triggered by impaired biliary clearance, activation of innate immunity and increased oxidative stress. Frequent monitoring of liver function tests has been shown to be effective in preventing Hy’s Law and liver failure cases. Uric acid elevation due to reduced renal excretion may lead to hyperuricemia and gout, although no drug discontinuations have been linked to these events. Future studies should confirm the safety profile of tolvaptan in large-scale real-world studies, clarify the pathogenetic pathways leading to hepatotoxicity and define its role in special populations, especially pediatric patients.

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Section: Resultsmentioning

confidence: 99%

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Bellos¹

2021

TCRM

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“…The application of TVP is associated with a risk of liver injury in a small portion of ADPKD patients. 22 To examine the potential hepatotoxicity of the benzodiazepine derivatives, wild-type C57BL/6 mice were treated with 5 mg/kg compound 25 or TVP once daily for 12 consecutive days. Serum alanine aminotransferase (ALT) was selected as a surrogate marker to evaluate the potential hepatotoxicity.…”

Section: ■ Resultsmentioning

confidence: 99%

Benzodiazepine Derivatives as Potent Vasopressin V₂ Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease

et al. 2022

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Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V2 receptor (V2R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V2R. Among these derivatives, compound 25 exhibited potent binding affinity to the V2R (K i = 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC50 = 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound 25 in a murine model of ADPKD demonstrated a significantly improved in vivo efficacy compared with the reference compound tolvaptan. Overall, compound 25 holds therapeutic potential for the treatment of ADPKD.

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“…Similarly, Tolvaptan has some effect on T-cells, although this has been correlated with the adverse effect of the drug onto the liver [ 72 ].…”

Section: Vra and Egfr Reductionmentioning

confidence: 99%

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

Capolongo

Capasso

Viggiano

2022

IJMS

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A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these factors derives from the effects of so-called nephroprotective drugs. Thirty years after the introduction of Renin-Angiotensin-system inhibitors (RASi) into clinical practice, two new families of nephroprotective drugs have been identified: the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the vasopressin receptor antagonists (VRA). Even though the molecular targets of the three-drug classes are very different, they share the reduction in the glomerular filtration rate (GFR) at the beginning of the therapy, which is usually considered an adverse effect. Therefore, we hypothesize that acute GFR decline is a prerequisite to obtaining nephroprotection with all these drugs. In this study, we reanalyze evidence that RASi, SGLT2i, and VRA reduce the eGFR at the onset of therapy. Afterward, we evaluate whether the extent of eGFR reduction correlates with their long-term efficacy. The results suggest that the extent of initial eGFR decline predicts the nephroprotective efficacy in the long run. Therefore, we propose that RASi, SGLT2i, and VRA delay kidney disease progression by controlling maladaptive glomerular hyperfiltration resulting from circulating immunological factors. Further studies are needed to verify their combined effects.

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Tolvaptan- and Tolvaptan-Metabolite-Responsive T Cells in Patients with Drug-Induced Liver Injury

Cited by 13 publications

References 8 publications

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Benzodiazepine Derivatives as Potent Vasopressin V₂ Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease

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

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Tolvaptan- and Tolvaptan-Metabolite-Responsive T Cells in Patients with Drug-Induced Liver Injury

Cited by 13 publications

References 8 publications

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Benzodiazepine Derivatives as Potent Vasopressin V2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease

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

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Benzodiazepine Derivatives as Potent Vasopressin V₂ Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease