Renoprotective Effects of Metformin

Metformin, used in the management of blood glucose, may provide a renoprotective effect through inhibition of inflammation and apoptosis. 

Metformin is one of the most commonly used oral medications for the management of type 2 diabetes mellitus. In addition to lowering blood glucose, metformin has the potential to reduce plasma lipids and body weight. Scientists reported the benefit of metformin on nonalcoholic fatty liver disease and polycystic ovarian syndrome, and its reno-protective effect in renally impaired patients. However, the use of metformin in renal disease has been hampered by its ability to produce lactic acidosis. This article intends to present the use of metformin in patients with kidney impairment. 

Acute kidney injury (AKI) is a decline in renal function over a given period. The leading causes of AKI include urinary tract obstruction, reduced blood flow to the kidneys, and nephrotoxic medications. Gentamycin, cisplatin, and NSAID are examples of known nephrotoxic medications. AKI can be quantified by measurement of the urinary output or evaluation of the serum creatinine. Chronic kidney disease (CKD) is diagnosed for patients who experience sustained loss of kidney functions for three months or more. Patients with CKD who do not respond to treatment develop a more complicated form of kidney impairment known as an end-stage renal disease (ESRD). 

Glycerol’s administration induces renal vasoconstriction and tubular necrosis. The mechanism of nephrotoxicity involves inhibition of mitochondrial electron transport and respiratory chain, which cause inflammation and apoptosis of the cells (Ladeira et al., 11). Various agents such as potassium dichromate, L-cysteine, sepsis infection, and radiocontrast reduce renal blood flow and induce AKI. In addition, these agents cause apoptosis by forming free radicals that alter the body’s defense against oxidative agents.  

The majority of diabetic kidney disease is influenced by type 2 diabetes mellitus through insulin resistance and glucose intolerance. Given the number of patients with kidney failure and kidney transplantation, clinicians are developing additional strategies to diagnose and manage kidney failure, mainly because early discovery limits complication and enhances the chance for reversal. Current guidelines recommend stopping the nephrotoxic agents and administering fluid for the initial management of AKI. However, early diagnosis of AKI is challenging because most patients do not have a baseline or have not had a doctor visit for a while. Some of those issues might justify why there is an increased number of patients diagnosed or living with kidney disease.  

In the search for a new drug to manage kidney impairment, metformin is a promising option. Decleves and colleagues report that metformin could stimulate the adenosine monophosphate-activated protein kinase (AMPK). The latter decreases the stress response and reduces apoptosis thus, provides kidney protection while lowering insulin resistance (Song et al., 3). Metformin was suggested to alleviate the nephrotoxic effect of medications such as cisplatin. Metformin is effective in the management of diabetes-induced kidney disease by suppressing inflammation and oxidative stress. Roussel and colleagues found that metformin reduces mortality in stage 3 chronic kidney disease, while there is no benefit in stage 4 because metformin acts by reducing inflammation and apoptosis. 

Fortez and colleagues report that cyst development in polycystic kidney disease involves two essential contributors: cyst proliferation using the mechanistic target of rapamycin (mTOR) pathway and fluid secretion through a chloride channel. Metformin inhibits cystic growth by blocking fluid secretion tough the chloride channel and inhibiting the mTOR pathway. The combination of metformin and 2-deoxy-glucose improves renal function by regulating glucose metabolism and cell growth. In addition, the anti-inflammatory effect of metformin inhibits polycystic kidney disease and protects renal function. A 3-year follow-up study conducted by Pisani and colleagues found that metformin lowers the glomerulus filtration rate compared to the control group and restores the kidney function in adult patients with polycystic kidney disease. 

Another common cause of AKI is the calcification in the urinary tract and obstruction of the urinary flow, which causes postrenal AKI. This phenomenon has become very prevalent. Turney and colleagues show that metformin alters the formation of reactive oxygenated species and free radicals, inhibits stone formation, and protects the renal tubule by suppressing crystal formation and oxidative mediators. Metformin was also reported to be effective in renal carcinoma, where it causes cell cycle arrest and induces apoptosis. 

 Practice pearls: 

• Metformin provides a renoprotective effect through inhibition of inflammation inhibition and apoptosis. 
• Metformin can inhibit the nephrotoxic effect of medications such as cisplatin, thus protecting kidney function and structure. 
• Metformin alters the formation of reactive oxygenated species and free radicals, inhibits stone formation, and protects the renal tubule by suppressing crystal formation and oxidative mediators. 

References for “Renoprotective Effects of Metformin”:
Ladeira L.C.M., Dos Santos E.C., et al. Green Tea Infusion Prevents Diabetic Nephropathy Aggravation in Recent-onset Type 1 Diabetes Regardless of Glycemic Control. J Ethnopharmacol. 2021 Jun 28;274:114032. doi: 10.1016/j.jep.2021.114032. Epub 2021 Mar 15. PMID: 33737142.  

Song A., Zhang C. et al. Mechanism and Application of Metformin in Kidney Diseases: An Update. Biomed Pharmacother. 2021 Jun;138:111454. doi: 10.1016/j.biopha.2021.111454.  

 Pierre Djemgou, PharmD candidate class of 2022, University of South Florida 

Related: studies have examined whether drugs other than metformin have renoprotective effects.