Cyclophosphamide-induced nephrotoxicity: a mini-review

Chhayala Raut; Varsha Dhurvey; Aashikkumar Nagwanshi; Dharita Joshi

Cyclophosphamide-induced nephrotoxicity: a mini-review

Chhayala Raut Varsha Dhurvey Aashikkumar Nagwanshi Dharita Joshi

Журнал: Журнал стресс-физиологии и биохимии @jspb

Статья в выпуске: 2 т.22, 2026 года.

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Cyclophosphamide (CP) is a widely used alkylating chemotherapeutic and immunosuppressive drug for treating malignancies, autoimmune disorders, and renal diseases. However, its clinical use is limited by nephrotoxicity caused by toxic metabolites such as phosphoramide mustard and acrolein. These metabolites induce oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis in renal tissues. CP administration results in elevated renal biomarkers including serum creatinine, blood urea nitrogen, cystatin-C, KIM-1, and NGAL, along with severe histopathological damage. Activation of inflammatory cytokines and NF-κB pathways further aggravates renal injury. Various antioxidants and pharmacological agents have shown potential renoprotective effects.

Cyclophosphamide \ Nephrotoxicity \ Oxidative stress \ Renal biomarkers \ Inflammation \ Apoptosis

Короткий адрес: https://sciup.org/143186138

IDS: 143186138

Текст научной статьи Cyclophosphamide-induced nephrotoxicity: a mini-review

Cyclophosphamide (CP) is a widely used alkylating agent belonging to the oxazaphosphorine class and is extensively employed in the treatment of malignant disorders as well as autoimmune and inflammatory diseases due to its potent cytotoxic and immunosuppressive properties. ( hosh et al., 1999; Abraham and Isaac, 2011). CP is a prodrug that undergoes hepatic biotransformation by cytochrome P450 enzymes to generate active metabolites, including phosphoramide mustard and acrolein, which are responsible for its antineoplastic efficacy as well as systemic toxicity ( hosh et al., 1999; Haque et al., 2003). Despite its therapeutic importance, CP administration is associated with significant dose-limiting adverse effects, among which nephrotoxicity represents a clinically relevant complication affecting both glomerular and tubular structures (Hauritz et al., 2001; Abraham et al., 2007). Experimental studies have demonstrated that CP-induced renal injury is closely linked to oxidative stress, characterized by increased lipid peroxidation, depletion of endogenous antioxidants, and disruption of redox homeostasis within renal tissues (Ayhanci et al., 2009; Abraham and Rabi, 2009). Elevation of biochemical markers such as malondialdehyde and alterations in antioxidant enzyme activities have been consistently reported following CP exposure, indicating enhanced reactive oxygen species generation (Abraham and Sugumar, 2008; unes et al., 2017). In addition to oxidative damage, CP-induced nephrotoxicity involves inflammatory responses, leukocyte infiltration, and enzymatic leakage, contributing to progressive renal dysfunction ( ashlan et al., 2013; Kocahan et al., 2017). Ultrastructural investigations have further revealed that CP causes profound subcellular alterations, including mitochondrial deformation, lysosomal depletion, peroxisome proliferation, and endoplasmic reticulum dilation, underscoring the organelle-specific nature of CP-mediated renal injury (Abraham and Isaac, 2011). Collectively, these findings establish cyclophosphamideinduced nephrotoxicity as a multifactorial process involving oxidative stress, inflammation, and organelle dysfunction, thereby justifying continued investigation into protective and therapeutic strategies (Adikwu et al., 2019; Alghamdi et al., 2024) (Fig. 1).

EFFECTS OF CYCLOPHOSPHAMIDE ONKIDNEY

Cyclophosphamide-induced nephrotoxicity is multifactorial, involving biochemical, structural, inflammatory, and mitochondrial disturbances. Rodent studies consistently show elevated serum creatinine, BUN, uric acid, and cystatin-C after CP exposure, indicating sharp impairment in renal filtration ( unes et al., 2016). These functional changes correlate with increased oxidative stress, as evidenced by elevated MDA levels and suppression of endogenous antioxidants including SH, SOD, CAT, and Px (Ayhanci et al., 2010).

Histopathological studies reveal clear renal damage such as tubular necrosis, loss of brush border, glomerular shrinkage, epithelial desquamation, and interstitial inflammation (Alabi et al., 2022). Some investigations also report mesangial proliferation, Bowman’s space widening, and glomerulonephritis-like changes (Zonozi et al., 2021). Inflammatory activation is a major factor in CP nephrotoxicity. CP upregulates pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and activates NF-κB signaling, resulting in prolonged renal inflammation (Dobrek et al., 2017) CP further induces apoptosis, indicated by increased Bax, p53, and caspase-3 expression and decreased Bcl-2 levels, contributing to tubular cell loss (Tohamy et al., 2021). Recent mechanistic insights highlight early mitochondrial membrane damage, ROS overproduction, ATP depletion, and autophagy– apoptosis imbalance as critical contributors to kidney deterioration (Jiang et al., 2020).

EARLY BIOMARKERS OFNEPHROTOXICITY

Traditional markers like serum creatinine rise only after major nephron loss. Clinical proteomic approaches using N AL, KIM-1, clusterin, and urinary protein fragments allow early and more accurate detection of CP-induced renal damage, improving patient monitoring and intervention timing (Kim et al., 2015).

METHODOLOGY

The author followed PRISMA, the Preferred Reporting Items for systematic Reviews and Meta-Analyses.

Recommendations are a minimal collection of things based on evidences. The author focused on both experimental and non-experimental studies, using four internet databases, including oogle scholar, PubMed, and Science Direct Research articles published between and were searched for using search engines. Research articles published between were searched for using search engines. Research articles published between 2001 and 2025 were searched for using search engines.

BIOCHEMICAL CHANGES

Cyclophosphamide (CP) administration has been consistently associated with marked biochemical disturbances reflecting renal dysfunction and oxidative stress. Experimental studies in rodents demonstrated significant elevations in serum creatinine, blood urea nitrogen (BUN), and urea levels following CP exposure, indicating impaired glomerular filtration and renal clearance (Bhat et al., 2018; Adikwu et al., 2019; Al-Salih et al., 2019; Yadav et al., 2021). CP treatment also induced pronounced oxidative stress, evidenced by increased malondialdehyde (MDA) levels and reactive oxygen species (ROS), accompanied by depletion of endogenous antioxidant defenses such as superoxide dismutase, catalase, glutathione, and glutathione peroxidase (Elwakeel et al., 2021; Tohamy et al., 2021; Ahmad et al., 2021). Furthermore, elevated levels of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, along with activation of apoptotic markers such as caspase-3, were reported, highlighting the role of inflammation and apoptosis in CP-induced nephrotoxicity (Jiang et al., 2020; Alghamdi et al., 2024). Similar biochemical impairments have also been observed in clinical settings, where prolonged CP therapy was associated with progressive renal functional decline (Cortazar et al., 2017; Sedhain et al., 2018).

HISTOLOGICAL CHANGES

Histopathological evaluation of kidney tissues following cyclophosphamide exposure revealed extensive structural damage affecting both tubular and glomerular compartments. Common histological alterations included tubular epithelial degeneration, tubular necrosis, loss of brush border, epithelial desquamation, and disruption of normal tubular architecture (Bhat et al., 2018; Olukole et al., 2020; Tohamy et al., 2021). lomerular changes such as shrinkage, congestion, distortion of Bowman’s capsule, and glomerular atrophy were frequently observed, along with interstitial edema and vascular congestion (Elwakeel et al., 2021; Yadav et al., 2021). Severe inflammatory cell infiltration and apoptotic features, including nuclear pyknosis and cellular fragmentation, were evident in high-dose or prolonged CP exposure models, confirming progressive renal injury (Jiang et al., 2020; Ahmad et al., 2021; Eldien and Alenzi, 2023; Kabil et al., 2023; Seker et al., 2024). These histological findings strongly correlate with the observed biochemical abnormalities and collectively confirm that cyclophosphamide induces nephrotoxicity through oxidative stress–mediated inflammation and apoptosis, leading to structural and functional deterioration of the kidney.

PROTECTIVE TREATMENTS AGAINSTCYCLOPHOSPHAMIDE NEPHROTOXICITY

A wide range of natural antioxidants and pharmacological agents have shown promising Reno protective effects in experimental models. Melatonin, quercetin, gallic acid, Selen methionine, caffeic acid phenethyl ester, royal jelly, hesperidin, vitamins C and E, and several plant-derived extracts (e.g., Ocimum gratissimum , Phoenix dactylifera seed extract) demonstrated significant reversal of oxidative injury, restoration of antioxidant enzymes, and improvement in tubular architecture (Ayhanci et al., 2010).

Compounds such as NAC (N-acetylcysteine), diosmin, zinc oxide nanoparticles, sesamin, baicalein, and bioactive saponins showed dual antioxidant and anti-inflammatory effects (Tohamy et al., 2021). Advanced regenerative strategies, including mesenchymal stem cells (MSCs), have been particularly effective in repairing renal injury by suppressing inflammation and promoting tissue regeneration (Eldien and Alenzi 2023). L-carnitine has also been shown to stabilize mitochondria and reduce renal and neural toxicity during CP or combination chemotherapy (Kocahan et al., 2016)

Major Clinical Limitation: Dose-Limiting Toxicities

1. Myelosuppression
2. Hemorrhagic Cystitis

Caused by acrolein accumulation in the bladder; prevented with MESNA and hydration (Sedhain et al., 2018).
3. Nephrotoxicity
4. Cardiotoxicity (High Dose)

The most common dose-limiting toxicity causing neutropenia, anemia, and thrombocytopenia (Hauritz et al., 2001).

Nephrotoxicity Leads to oxidative stress, tubular necrosis, inflammation, and renal (Morid et al., 2023).

High-dose CP can cause acute cardiomyopathy and arrhythmias (Hauritz et al., 2001).

Therefore, the present review aims to provide a comprehensive analysis of the cyclophosphamideinduced nephrotoxicity effects and renal risks of this widely used anticancer drug.

Figure 1. Cyclophosphamide. (Source:

Table 1 . Comparative analysis of biochemical changes

Model organism	Dose of CP	Duration	Major biochemical changes observed	References
Rats ( Rattus norvegicus )	200 mg/kg	10–14 days	Increased oxidative stress markers (increase MDA), decreased antioxidant enzymes (decrease SOD, CAT, SH)	Bhat et al., (2018)
Rats ( Rattus norvegicus )	150 mg/kg	10 days	Oxidative stress–mediated kidney damage, altered renal biomarkers	Adikwu et al., (2019)
Rats ( Rattus norvegicus )	150 mg/kg	7–14 days	Altered renal biochemistry (increase serum urea, creatinine)	Al-Salih et al., (2019)
Rats ( Rattus norvegicus )	200 mg/kg	14 days	Elevated inflammatory markers and oxidative stress parameters	Olukole et al., (2020)
Mice ( Mus musculus )	200 mg/kg	24–72 hours	Acute oxidative stress, depletion of antioxidant defense	Jiang et al., (2020)
Rats ( Rattus norvegicus )	150 mg/kg	14 days	Increased renal inflammatory cytokines and oxidative damage	Elwakeel et al., (2021)
Rats ( Rattus norvegicus )	150 mg/kg	7–10 days	Oxidative stress–mediated nephrotoxicity	Yadav et al., (2021)
Rats ( Rattus norvegicus )	200 mg/kg	14 days	Activation of apoptotic pathways and inflammatory mediators	Ahmad et al., (2021)
Rats ( Rattus norvegicus )	50 mg/kg	21 days	Persistent oxidative stress and altered renal enzymes	Alaqeela and Al-Hariri, (2023)
Rats (Sprague Dawley)	150 mg/kg	19 days	Oxidative stress, inflammation, and apoptosis-related biochemical alterations	Alghamdi et al., (2024)

Table 2. Comparative analysis of histological damage

Model organism	Dose of CP	Duration	Major histopathological changes observed	References
Rats ( Rattus norvegicus )	200 mg/kg	10–14 days	Renal structural damage, tubular degeneration	Bhat et al., (2018)
Rats ( Rattus norvegicus )	150 mg/kg	7–14 days	Tubular necrosis and glomerular damage	Al-Salih et al., (2019)
Rats ( Rattus norvegicus )	200 mg/kg	14 days	Tubular injury and inflammatory cell infiltration	Olukole et al., (2020)
Mice ( Mus musculus )	200 mg/kg	24–72 hours	Early tubular necrosis and epithelial damage	Jiang et al., (2020)
Rats ( Rattus norvegicus )	200 mg/kg	10 days	Tubular injury and renal tissue degeneration	Tohamy et al., (2021)
Rats ( Rattus norvegicus )	200 mg/kg	14 days	Apoptosis, inflammation, and renal architectural distortion	Ahmad et al., (2021)
Rats ( Rattus norvegicus )	70 mg/kg (single dose)	4–10 days	Severe renal injury with inflammatory infiltration and tissue damage	Eldien and Alenzi, (2023)
Mice ( Mus musculus )	175 mg/kg	30 days	Marked kidney injury and deterioration of renal histoarchitecture	Kabil et al., (2023)
Rats ( Rattus norvegicus )	50 mg/kg	21 days	Tubular damage and loss of normal renal morphology	Alaqeela and Al-Hariri, (2023)
Mice ( Mus musculus )	200 mg/kg	14 days	Renal dysfunction with histopathological alterations	Seker et al., (2024)

Table 3. Comparative analysis of Ameliorative effects

Protective Agent / Strategy	Nature of Agent	Major Protective Mechanisms	Observed Reno protective Effects	References
Melatonin	Endogenous hormone / Antioxidant	Free radical scavenging, enhancement of antioxidant enzymes	Reduced lipid peroxidation, restoration of renal antioxidant status, improved tubular histology	Ayhanci et al., (2010)
Quercetin	Flavonoid (Natural antioxidant)	Antioxidant, antiinflammatory	Decreased oxidative stress, improved renal architecture	Ayhanci et al., 2010
allic acid	Phenolic compound	ROS scavenging, inhibition of oxidative injury	Protection of renal tubular cells, normalization of biochemical markers	Ayhanci et al., 2010
Selen methionine	Organic selenium compound	Boosts glutathione peroxidase, antioxidant defense	Reduced renal oxidative damage, improved kidney function	Ayhanci et al., 2010
Caffeic Acid Phenethyl Ester (CAPE)	Polyphenolic compound	Anti-inflammatory, antioxidant	Preservation of renal structure, reduction in inflammatory damage	Ayhanci et al., 2010
Royal Jelly	Natural bee product	Antioxidant, immunomodulatory	Attenuation of tubular degeneration and oxidative stress	Ayhanci et al., 2010
Hesperidin	Citrus flavonoid	Antioxidant, antiinflammatory	Restoration of antioxidant enzymes, reduced nephron injury	Ayhanci et al., 2010

Vitamin C	Water-soluble antioxidant	ROS neutralization	Reduced CP-induced oxidative renal injury	Ayhanci et al., 2010
Vitamin E	Lipid-soluble antioxidant	Prevention of lipid peroxidation	Protection of renal membranes and tubular integrity	Ayhanci et al., 2010
Ocimum gratissimum extract	Medicinal plant extract	Antioxidant, antiinflammatory	Improved renal histology and antioxidant status	Ayhanci et al., 2010
Phoenix dactylifera seed extract	Plant-derived antioxidant	Free radical scavenging	Reduction in biochemical and histopathological damage	Ayhanci et al., 2010
N-Acetylcysteine (NAC)	Synthetic antioxidant	lutathione replenishment, antiinflammatory	Reduced oxidative stress and inflammation in renal tissue	Tohamy et al., 2021
Diosmin	Flavonoid glycoside	Antioxidant, antiinflammatory	Improved renal biochemical parameters	Tohamy et al., 2021
Zinc oxide nanoparticles	Nanoparticlebased antioxidant	Reduction of oxidative and inflammatory responses	Protection against CP-induced renal damage	Tohamy et al., 2021
Sesamin	Lignan (Sesame-derived)	Antioxidant, antiinflammatory	Attenuation of renal oxidative stress	Tohamy et al., 2021
Baicalein	Flavone (Herbal origin)	Suppression of inflammatory mediators	Reduced tubular injury and oxidative stress	Tohamy et al., 2021
Bioactive saponins	Plant secondary metabolites	Antioxidant, antiinflammatory	Improved renal function and histology	Tohamy et al., 2021
Mesenchymal Stem Cells (MSCs)	Regenerative therapy	Anti-inflammatory, tissue regeneration	Repair of renal tissue, suppression of CP-induced inflammation	Eldien and Alenzi, 2023
L-Carnitine	Mitochondrial stabilizer	Mitochondrial protection, antioxidant	Reduced renal and neural toxicity, improved energy metabolism	Kocahan et al., 2016

CONCLUSION

From the available literature, it is evident that cyclophosphamide induces significant nephrotoxicity. Although cyclophosphamide is a highly effective anticancer and immunosuppressive agent, its clinical use is limited by dose-dependent renal toxicity. The severity of kidney injury varies with species, dosage, duration of exposure, metabolic capacity, and route of administration. Cyclophosphamide-induced nephrotoxicity is characterized by oxidative stress, inflammation, tubular and glomerular damage, and impaired renal function. Overall, the combination of cyclophosphamide therapy with appropriate nephroprotective agents or optimized dosing strategies may significantly improve renal safety and reduce kidney damage. Further investigations are essential to elucidate the long-term renal effects of cyclophosphamide and to develop effective therapeutic interventions for minimising its nephrotoxic potential.

CONFLICTS OF INTEREST

The author declares no conflicts of interest.