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

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 <i>HBA1</i>, <i>CBR1</i>, <i>ATG5</i>, and <i>SLC6A3</i> were the top hub genes with an edge count of 7 followed by <i>GPX1</i> with an edge count of 6. Molecular docking studies revealed candesartan-<i>SLC6A3</i> to possess the highest binding affinity of −10.2 kcal/mol. In addition, simulation studies displayed empagliflozin-<i>CBR1</i> to possess the highest stability followed by candesartan-<i>ATG5</i>. A combination of β-blockers, ARBs, and SGLT2I are predicted to likely possess nephrotoxicity which may be due to the modulation of <i>HBA1</i>, <i>CBR1</i>, <i>ATG5</i>, and <i>GPX1</i>. In conclusion, candesartan and empagliflozin are most likely to cause nephrotoxicity <i>via</i> the modulation of <i>HBA1</i>, <i>CBR1</i>, <i>ATG5</i>, and <i>GPX1</i>. 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 <i>HBA1</i>, <i>CBR1</i>, <i>ATG5</i>, and <i>GPX1.</i> Candesartan and empagliflozin are most likely to cause nephrotoxicity