INTRODUCTION:

The nephron is the fundamental unit of the kidney, made up of different types of cells arranged in an organized way. The kidneys are vital for carrying out essential functions including regulating the extracellular environment, maintaining internal balance, detoxifying harmful substances, and removing waste products from the body.¹

Any factors leading to the disappearance of these cells can potentially harm or damage the kidneys. Renal failure can be attributed to either extrinsic or intrinsic causes.

Conditions like heart disease, diabetes, obesity, sepsis as well liver and lung damage are extrinsic causes. Intrinsic causes encompass stones, renal fibrosis, tubular cell death and glomerular nephritis.²

Nephrotoxicity:

Nephrotoxicity refers to the harmful impact of toxins on kidney function.³These substances may include fungus, molds, anti-chemotherapeutics like cisplatin, aminoglycosides, metals like lead, arsenic and mercury, as well as misuse drugs like cocaine. A possible sign of nephrotoxicity is a change in kidney function, which can be reflected by GFR, BUN, sCr, or urine output. Individuals with existing kidney conditions are more likely to experience the nephrotoxic effects of many medications.⁴

Mechanisms of nephrotoxicity:

Nephrotoxicity is generally cause by alterations in glomerular hemodynamics, tubular cells toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy.⁵

1. Alterations in glomerular hemodynamics:

The GFR for healthy individuals is 120ml/ min. The kidneys have the ability to adjust blood flow in the afferent and efferent arterioles to ensure a stable filtration rate and maintain intraglomerular pressure. Nephrotoxicity in the glomerulus can be induced by anti-prostaglandin drugs like diclofenac and drugs with anti-angiotensin activity such as ACE inhibitors like captopril and ARBs like valsartan.⁶

2. Tubular cell toxicity:

Drug toxicity affects renal tubules during the process of concentration and reabsorption occurring in the glomerulus.⁷Cytotoxicity is caused by damaged mitochondria in tubules, disturbed tubular transport system, and increased OS.⁸Amphotericin B, adefovir, foscarnet and cisplatin are drugs that cause cytotoxicity.

3. Inflammation:

Drugs with nephrotoxic effects, such as, NSALDs, hydralazine, gold, lithium, pamidronate and interferon can cause inflammation in the proximal tubules, glomerulus and cellular matrix around the kidneys, leading to kidney tissue fiberization. Inflammation disrupting normal renal functions and inducing toxicity includes acute, chronic interstitial nephritis and glomerulonephritis.⁹

4. Crystal nephropathy:

Some drugs form crystals that accumulate inside the distal renal tubules, causing interstitial reactions and obstruction.¹⁰Urine acidity and drug’s concentration both affect the development of insoluble crystals. Ciprofloxacin, methotrexate, sulphonamides, ampicillin, triamterene, and acyclovir are among the drugs that can cause crystal nephropathy.¹¹

5. Rhabdomyolysis:

Rhabdomyolysis occurs when skeletal muscle destruction releases muscle fiber contents into the bloodstream. This process releases serum creatine kinase and myoglobin into the circulation, degrading and impairing kidney filtration function. Heroin, methadone, ketamine, cocaine, methamphetamine, statins, and alcohol are major causes of rhabdomyolysis.¹²

6. Thrombotic microangiopathy:

Thrombotic microangiopathy occurs due to direct toxicity to renal epithelial cells or inflammation damaging organs.¹³ The immune reaction caused by drugs results in thrombotic thrombocytopenic purpura and activates platelets, ultimately leading to endothelial cytotoxicity.Medications like ticlopidine, cyclosporine, and quinine illustrate this phenomenon.¹⁴

Experimental models for nephrotoxicity:

Figure 1. Experimental Models for Nephrotoxicity

1. Acetaminophen induced nephrotoxicity:

Acetaminophen, the most commonly used antipyretic and analgesic medication globally, is considered safe when used as directed by healthcare professionals.¹⁵Studies have shown that OS contributes to kidney damage caused by acetaminophen, which is metabolized by CYP450 enzymes in the liver and kidneys. Key enzymes involved in the production of free radicals and their metabolites in renal tissues are N-deacetylase and prostaglandin synthetase. When higher doses of acetaminophen are administered, these pathways become activated, resulting in reduction of Glutathione, increased generation of ROS and RNS, and lipid peroxidation, ultimately resulting in renal failure and apoptosis.^16-19

Table 1: Different doses of Acetaminophen-induced nephrotoxicity

Animal	Dosage	Route	References
Wistar Albino Mice	750mg/kg single dose	Orally	20
Albino Rat	1000mg/kg single dose	Intraperitoneal	21
Wistar Albino Rat	200mg/kg for 2 weeks	Intraperitoneal	22
Wistar Rat	800mg/kg single dose	Orally	23
Sprague-Dawley Rats	700mg/kg single dose	Intraperitoneal	24

2. Diclofenac sodium induced nephrotoxicity:

Diclofenac is commonly used as an NSAID to alleviate arthritis related pain and inflammation. NSAIDs are frequently prescribed medications. Regrettably, the primary adverse effects of NSAIDs use is impairment of renal function. The main mechanism behind this is the inhibition of prostaglandin synthesis by NSAIDs, leading to renal ischemia. Additionally, acute interstitial nephritis may occur as a result of increased intrarenal ROS production.²⁵Diclofenac leads to elevated levels of kidney MDA and H₂O₂. The intracellular accumulation of ROS concentration results in an increase in H₂O₂ levels.²⁶

Table 2: Different doses of Diclofenac sodium-induced nephrotoxicity

Animal	Dosage	Route	References
Sprague-Dawley Rats	15mg/ kg for 2 weeks	Intraperitoneal	27
Wistar Rats	50mg/ kg for 5days	Intraperitoneal	28

3. Amphotericin B induced nephrotoxicity:

Amphotericin B is still the most effective medication for treating systemic fungal infections. However, it can result in a wide range of immediate and long-term side effects, with nephrotoxicity being the most significant. The mechanisms of kidney toxicity involve Amphotericin forming pores in membranes, leading to tubular dysfunction. Additionally, Amphotericin B causes severe vasoconstriction, resulting in reduced renal blood flow and GFR, ultimately resulting in ischemic injury.²⁹

Table 3: Different doses of Amphotericin B-induced nephrotoxicity

Animal	Dosage	Route	References
Sprague-Dawley Rats	10mg/ kg for 4 days	Intraperitoneal	30
Wistar Rats	5mg/ kg for 5 days	Intraperitoneal	31
Jcl:ICR mice	2mg, 4mg/ kg single dose	Intravenous	32
Wistar Albino Rats	50mg/ kg single dose	Intravenous	33

4. Acyclovir induced nephrotoxicity:

Acyclovir, an antiviral medication, is generally well tolerated, but it has been associated with severe nephrotoxicity.³⁴Studies have linked ACV to various symptoms of nephrotoxicity, such as acute interstitial nephritis, obstructive nephropathy, crystal nephropathy and acute tubular necrosis. It is suggested that ACV induces nephrotoxicity by directly affecting renal tubular cells and causing oxidative stress. Additionally, ACV negatively impacts the kidney's redox state by decreasing antioxidants and increasing malondialdehyde levels. The generation of OS due to ROS production by ACV may have led to a decrease in kidney antioxidant levels and the oxidation of kidney lipids, leading to increased malondialdehyde. Perhaps one of the most important marker of ACV-induced renal impairment is oxidative damage.³⁵

Table 4: Different doses of Acyclovir-induced nephrotoxicity

Animal	Dosage	Route	References
Albino Rats	150mg/ kg for 10 days	Intraperitoneal	36
Albino Rats	432mg/ kg for 1 week	Orally	37
Wistar Rats	150mg/ kg for 9 days	Intraperitoneal	38
ICR mice	600mg/ kg for 9 days	Intraperitoneal	38
Sprague-Dawley Rats	100mg, 300mg, 600mg/ kg single dose	Intravenous	39

5. Gentamicin induced nephrotoxicity:

Gentamicin is typically used to treat serious infections associated with Gram-negative bacteria.⁴⁰ Studies have indicated that around 30% of patients undergoing gentamicin treatment for over 7 days exhibit symptoms of nephrotoxicity.⁴¹The mechanisms of include the generation of free radicals, increased lipid peroxidation, and reduced natural antioxidant activity, leading to a decline in GFR and kidney function. Drug worsened tubular injury by inducing necrosis in the epithelial cells of tubule, especially in the proximal segment, and impacting the functioning of crucial cellular elements responsible for transporting water and solute.⁴²

Table 5: Different doses of Gentamicin-induced Nephrotoxicity

Animal	Dosage	Route	References
Wistar Albino Rats	100mg/ kg for 8 days	Intraperitoneal	43
Sprague-Dawley Rats	80mg/ kg for 6 days	Intramuscular	44
Sprague- Dawley Rats	150mg/ kg single dose	Intraperitoneal	45

6. Cyclosporine induced nephrotoxicity:

Cyclosporine is a commonly used immunosuppressant that significantly decreases the occurrence of rejection in kidney, heart, and liver transplants. However, the serious side effect of cyclosporine nephrotoxicity restricts its clinical use. Although the precise mechanisms of cyclosporine nephrotoxicity are not fully known, there is considerable evidence indicating that OS is a key element involved. Specifically, cyclosporine triggers ERS and boosts the generation of ROS in mitochondria, disrupting redox balance, leading to lipid peroxidation, and ultimately causing nephrotoxicity.⁴⁶

Table 6: Different doses of Cyclosporine-induced Nephrotoxicity

Animal	Dosage	Route	References
Wistar Albino Rats	20mg/ kg for 1 week	Intraperitoneal	47
Albino Rats	25mg/ kg for 3 weeks	Orally	48
Mice	30mg/kg for 16 weeks	Subcutaneous	49

7. Tacrolimus induced nephrotoxicity:

Tacrolimus, an immunosuppressive calcineurin inhibitor, is commonly used in kidney transplantation. Prolonged use of drug can lead to nephrotoxicity.⁵⁰The exact mechanisms behind tacrolimus nephrotoxicity are still not fully known. According to earlier research, Tacrolimus's nephrotoxicity has been associated with activation of the nicotinamide adenine dinucleotide phosphate oxidase pathway, which generates ROS. Apoptosis is a crucial factor in nephrotoxic agent-induced nephrotoxicity, and the caspase family, particularly caspase-3, plays a significant role in apoptosis-related kidney damage. Tacrolimus has been found to generate ROS and impede antioxidant defenses in the proximal tubules.⁵¹

Table 7: Different doses of Tacrolimus-induced Nephrotoxicity

Animal	Dosage	Route	References
Wistar Albino Rats	2mg/ kg for 2 weeks	Intraperitoneal	52
Wistar Albino Rats	0.6mg/ kg for 1 month	Intraperitoneal	53
Sprague-Dawley Rats	1.5mg/ kg for 4 weeks	Subcutaneous	54
Lewis Rats	3mg/ kg for 2 weeks	Orally	55

8. Cisplatin induced nephrotoxicity:

Cisplatin, an anti-cancer medication, is commonly used to treat ovarian, neck and head cancers, and germ cell tumors. The primary limitation is the frequent occurrence of nephrotoxicity.⁵⁶ After being exposed to cisplatin, renal dysfunction can result from various mechanisms. These include apoptosis and necrosis causing direct tubular toxicity, ROS, inflammation, calcium overload, phospholipase activation, calcium overload, decreased GSH depletion, induction of apoptosis, mitochondrial permeability transition pore (MPTP) opening, depletion of ATP and inhibition of mitochondrial respiratory chain function.^57-60

Table 8: Different doses of Cisplatin-induced nephrotoxicity

Animal	Dosage	Route	References
Wistar Albino Rats	5mg/kg for 5 days	Intraperitoneal	61
Sprague-Dawley Rats	7mg/kg single dose	Intraperitoneal	62
Sprague-Dawley Rats	10mg/kg single dose	Intraperitoneal	63

CONCLUSION:

The study demonstrates that nephrotoxicity can be induced by an overdose of drugs such as Acetaminophen, Cisplatin, Tacrolimus, Gentamicin, Amphotericin B, etc. By avoiding modifiable risk factors and closely monitoring therapeutic medication for high-risk groups, it is anticipated that the occurrence of nephrotoxicity can be minimized. Based on the study findings, it can be inferred that early identification of excessive drug doses can mitigate risks by discontinuing the drug when there is a decrease in renal function. The data above indicates that avoiding the dose at which the drug causes toxicity is essential for protecting the kidneys. Therefore, this study's overview will facilitate the identification of an appropriate nephrotoxicity model for additional research and offers guidance for future nephrotoxicity studies.

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Received on 03.10.2024 Revised on 22.02.2025

Accepted on 28.04.2025 Published on 13.01.2026

Available online from January 17, 2026

Research J. Pharmacy and Technology. 2026;19(1):446-451.

DOI: 10.52711/0974-360X.2026.00065

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.