Guideline directed medical therapy induced nephrotoxicity in HFrEF patients; an insight to its mechanism

Abstract

Guideline Directed Medical Therapy (GDMT) has been the standard pharmacotherapy for the treatment of Heart Failure patients with reduced Ejection Fraction (HFrEF) recommended by the European Society of Cardiology (ESC). However, patients on GDMT are likely to possess nephrotoxicity as an adverse effect. We utilized multiple system biology tools like ADVER-Pred, gene enrichment analysis, molecular docking, molecular dynamic simulations, and MMPBSA analysis to predict a possible molecular mechanism of how selected combinations of GDMT may cause nephrotoxicity. As per the ACC/AHA/ESC guidelines, we categorized the drugs as category 1 including β-blockers (BB), angiotensin receptor blockers (ARB), and sodium-glucose cotransporter-2 inhibitors (SGLT2I), category 2 includes BB’s, SGLT2I, and angiotensin receptor-neprilysin inhibitors (ARNI), and category 3 includes BB’s, SGLT2I, and angiotensin-converting enzyme (ACE) inhibitors. Enrichment analysis predicted category 2 drugs to possess the highest number of proteins to be involved in the development of nephrotoxicity i.e. 79.41%. The targets HBA1, CBR1, ATG5, and SLC6A3 were the top hub genes with an edge count of 7 followed by GPX1 with an edge count of 6. Molecular docking studies revealed candesartan-SLC6A3 to possess the highest binding affinity of −10.2 kcal/mol. In addition, simulation studies displayed empagliflozin-CBR1 to possess the highest stability followed by candesartan-ATG5. A combination of β-blockers, ARBs, and SGLT2I are predicted to likely possess nephrotoxicity which may be due to the modulation of HBA1, CBR1, ATG5, and GPX1. In conclusion, candesartan and empagliflozin are most likely to cause nephrotoxicity via the modulation of HBA1, CBR1, ATG5, and GPX1.

Communicated by Ramaswamy H. Sarma

HIGHLIGHTS

• GDMT drugs were predicted to possess nephrotoxicity as an adverse effect

• Category 2 drugs BB’s, SGLT2I, and ARNI were assessed to possess highest number of proteins to be involved in the development of nephrotoxicity which may be by modulating HBA1, CBR1, ATG5, and GPX1.

• Candesartan and empagliflozin are most likely to cause nephrotoxicity

Keywords:

• GDMT
• HFrEF
• Molecular docking
• Molecular mechanism
• Nephrotoxicity

Acknowledgments

Authors are heartily thankful to NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Nitte (Deemed to be University), for providing facilities for molecular dynamic simulations.

Authors’ contributions

A.P. and P.S.R. set the hypothesis, performed the work, gathered & analyzed data, and prepared the manuscript. C.S. and B.U. helped with hypothesis setup, supervised the work, and helped in drafting & reviewing the manuscript.

Ethical approval

This work does not include any animal or human work.

Disclosure statement

The authors report there are no competing interests to declare

Data availability statement

The data that support the findings of this study are available from the corresponding author, AP & CSS, upon reasonable request.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.