The Potential Renoprotective Effect of Vitamin c and Coenzyme q10 Against Cisplatin Induced Nephrotoxicity in Cancer Patients
Phase: PHASE2
Conditions: Nephrotoxicity
Sponsor: Ain Shams University

 
 
 
 
 
 
 
 
"The Potential Renoprotective Effect of Vitamin C and Coenzyme q10 against 
Cisplatin-Induced Nephrotoxicity in Cancer patients" 
 
 
 
Submitted By 
 
Ghada Saied El-Seidy 
Teaching assistant of Clinical Pharmacy 
Clinical Pharmacy Department 
Faculty of Pharmacy 
Misr University for Science and Technology 
 
 
 
Under supervision of 
 
Dr. Nagwa Ali Sabri 
Professor of Clinical Pharmacy 
Clinical Pharmacy Department 
Faculty of Pharmacy 
Ain Shams University 
 
 
 
Dr. Rasha Mohamed AbdelMotagalee Aboelhassan 
Senior Oncology Consultant   
Nasser Institute for Research and Treatment 
 
 
Dr. Rana Sayed Fouad  
Lecturer of Clinical Pharmacy 
Clinical Pharmacy Department 
Faculty of Pharmacy 
Ain Shams University 
 
 
 
 
Faculty of Pharmacy 
Ain Shams University 
10-9-2025 
 
 
 
 

 Introduction: 
 
Cisplatin (Cis) is one of the most effective chemotherapeutic agents, widely used for  
the treatment of several malignant diseases including head and neck, esophageal, bladder, 
testicular, ovarian, uterine, cervical, breast, stomach, non-small and small-cell lung 
cancers[1]. 
 
Unfortunately, patients who are receiving cisplatin-based chemotherapy are at risk of severe 
adverse effects in normal tissues, including neurotoxicity, ototoxicity, nausea and vomiting 
are liming factors of cisplatin use[2].  
 
Nephrotoxicity is a major factor that negatively impacts their clinical outcomes. Cisplatin is 
mainly cleared by the kidney through glomerular filtration and tubular excretion, resulting in 
a higher concentration of this drug in the kidney than in other organs. Cisplatin-induced 
acute kidney injury (AKI), characterized by rapid deterioration of renal function 
 within days of initiating treatment, occurs in around 30% of patients who are receiving 
cisplatin chemotherapy [3]. 
 
The pathophysiology of cisplatin nephrotoxicity: An important contributor for cisplatin 
nephrotoxicity is its uptake into kidney cells which is much  higher than any tissues, 
especially in proximal tubules of the kidney where cis concentration can reach up to five 
folds higher than that of the serum[4],[5]. 
 
Cisplatin uptake in renal proximal tubular cells is mediated by membrane transporters such 
as solute carrier family 22 member 2 (SLC22A2), SLC22A6, SLC22A8, organic cation 
transporter-2 (OCT2) and copper transporter-1 (Ctr-1). After entering cells, a chloride ion of 
cisplatin is replaced with a water molecule. Hydrated cisplatin is then metabolically activated 
to the toxic form by a gamma-glutamyl transpeptidase (GGT) and kynurenine 
aminotransferase 1 (KYAT1)-dependent pathway [6],[7].  
 
Accumulation of cisplatin in renal proximal tubular cells induces DNA damage, 
mitochondrial damage, oxidative stress, endoplasmic reticulum (ER) stress, autophagy and 
cell-cycle regulation. These processes result in renal cell death, inflammation and cell 
senescence, which lead to acute kidney injury (AKI) and chronic kidney disease (CKD)[3]. 
 
The role of oxidative stress in cisplatin nephrotoxicity is well established. Cisplatin 
additionally represses the antioxidant enzymes including glutathione S-transferase, 
glutathione peroxidase, and superoxide dismutase, prompting lethal degrees of ROS inside 
the cell[4].  
 

 
Three main mechanisms of ROS generation have been proposed: rapid reaction of cisplatin 
with thiol-containing molecules during its bioactivation depletes cells of glutathione and 
related antioxidants; cisplatin-injured mitochondria produce excessive ROS and compromise 
antioxidant enzymes such as SOD and catalase, which in turn exacerbates mitochondrial 
damage, forming a vicious cycle; cisplatin induces ROS via activating cytochrome P450 
enzymes, particularly cytochrome P450 2E1 (CYP2E1) and cytochrome P450 4A11 
(CYP4A11)[3]. 
 
The consequence of ROS generated is the activation of a transcriptional factor (NF-
-
-regulated the expression of pro-inflammatory cytokines like TNF-
-18 and IL-6. 
Other studies have demonstrated that Cis promotes the intrinsic apoptotic pathway through 
activation of the proapoptotic gene Bax which binds to the mitochondrial membrane. The 
consequences of Bax activation are releasing of cytochrome-c from the mitochondria thereby 
activating cell death. Moreover, Cis induces several signal transduction pathways, such as 
those involving the p53 protein, that ends in the activation of renal tubular cell apoptosis[8]. 
 
Cisplatin nephrotoxicity is classified according to severity defined as creatinine 
increased as follows:  
 Grade : >ULN - 1.5 x ULN            Grade 2 :>1.5 - 3.0 x baseline; >1.5 - 3.0 x ULN 
 Grade 3: >3.0 x baseline; >3.0 - 6.0 x ULN                     Grade 4 : >6.0 x ULN     
Grade 5 :Death  
based on common terminology criteria for adverse events (CTCAE) version 5.0[7]. 
 
Traditional biomarkers such as serum creatinine and blood urea nitrogen (BUN) often fail 
to detect early renal damage, necessitating the use of novel biomarkers for timely diagnosis 
and intervention. The Food and Drug Administration FDA and European Medicines Agency 
(EMEA) approved seven new biomarkers used for nephrotoxicity detection that may 
influence clinical decision making: KIM-1, albumin, B2-microglobulin, cystatin C, total 
protein clusterin, and trefoil factor-3[9].  
 
Kidney injury molecule-1 (KIM-1) is a proximal tubule apical transmembrane protein. 
KIM-1 downregulates proximal tubular cell PTC cytokine secretion, modulates translational 
changes through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
pathway and interaction with phosphatidylinositol3 PI3 kinase subunit p85 . Experimentally, 
KIM-1 gene expression reflects ongoing damage in various tubulointerstitial segments and in 
the renal cortex[10] .  

For these reasons, authors began considering KIM-1 as a biomarker capable of identifying 
early AKI and may even hold a possible predictive role . interestingly, KIM-1 has a  
 
phosphatidylserine receptor which enhances apoptotic bodies and necrotic debris 
phagocytosis[9]. 
Vitamin C (ascorbic acid) is a potent antioxidant often supplemented in high amounts to 
make up for such deficiencies, it is used in the prevention and treatment of a broad spectrum 
of conditions, including diabetes, atherosclerosis, the common cold, cataracts, glaucoma, 
macular degeneration, stroke, heart disease, COVID-19, and cancer[11]. Although there is 
some toxicity reported with vitamin c with higher doses as nausea, vomiting, diarrhea, 
flushing of the face, headache, fatigue, osmotic diarrhea and disturbed sleep[12]. 
 It is capable of scavenging a wide range of reactive oxygen species and reacting with free 
radicals in aqueous environments. It forms the first line of defense against oxidant radicals in 
plasma  prevents their damaging effect to macromolecules such as lipids, DNA, and proteins. 
It has been reported to have the lowest toxicity of all vitamins[13],[14]. 
In an animal study,  the rats which were killed 7 days after cisplatin administration, it was 
observed that the treatment with vitamin C prevented the depletion of renal glutathione 
caused by cisplatin, resulting in values close to those observed in the control group. These 
results suggest the possible involvement of vitamin C-mediated protection against cisplatin 
induced depletion of renal glutathione [15].  
Coenzyme Q10 (CoQ10) as a redox-active lipophilic ROS scavenger was found in various 
cellular organelles such as mitochondria, lysosomes and Golgi vesicles. It is used as a dietary 
supplementation and as a cotherapy in conjunction with medication in a number of 
conditions, including cardiovascular diseases, cancer, muscular neurodegenerative disorders, 
and diabetes[8]. Although CoQ10 is present naturally in the human body and should 
therefore be well tolerated, a variety of adverse reactions have been reported, although 
infrequent and generally mild. These include decreased appetite, diarrhea, dizziness, 
dyspepsia, and nausea/vomiting[16]. 
 
 It participates in aerobic cellular respiration working as an electron carrier in the process 
creating energy through the formation of ATP (adenosine triphosphate). 
 Not only can it recycle and regenerate other antioxidants such as vitamins E and C, but it 
can also uniquely affect the initiation and propagation of ROS[9]. 
 

It was reported that cisplatin administration caused NF-
inflammatory reactions responsible for renal injury . Elevated TNF-
important step for activation of the NF-
oQ10  
 
treatment significantly suppressed lipid peroxidation, restored the antioxidant defense 
mechanisms, attenuated the overproduction TNF-
NF-
 
 
The nephroprotective effect of CoQ10 can be attributed to its ability to inhibit the 
activation of NF-
oxidase, TNF- and iNOS genes [8],[17].  
 
Safety assesment of Coenzyme q10: A large portion of the available published data on 
CoQ10 clinical trials at doses ranging from 30 to 3000 mg/day including the clinical safety 
study on healthy volunteers by Ikematsu et al. was reviewed. No systematic pattern of 
adverse effects was found; reports of nausea and other adverse gastrointestinal effects of 
CoQ10 cannot be causally related to the active ingredient because there is no dose-response 
relationship. In these clinical studies, 300 to 1200 mg/day of CoQ10 has been studied in a 
relative
-blind, 
placebo-controlled designed clinical trial of 16 months duration, and no adverse effects were 
found in any dose groups . This trial provides strong evidence of the lack of adverse effects 
at this dose level of CoQ10. Overall, they concluded that the observed safe level (OSL) for 
CoQ10 was 1200 mg/day[18-20]. 
 
Aim of the work : 
 
This study aims to evaluate the protective effects of  (Vitamin C and Coenzyme q10)  against 
cisplatin-induced nephrotoxicity in chemotherapy-naïve cancer patients. 
Primary Outcome 
-
induced nephrotoxicity using serum creatinine (graded by CTCAE v5.0)  
Secondary Outcomes 
* KIM-1 biomarker levels in serum in patients receiving cisplatin as an early indicator of 
acute cisplatin induced kidney injury.  
 
*Assesment of the quality of life through The EORTC QLQ-C30 questionnaire at baseline 
and by the end of the third cycle. 

*Adverse Effects from Antioxidants: Documented through structured case report forms, 
patient diaries, and adverse event reporting per CTCAE guidelines. 
 
*Time to Onset of Nephrotoxicity: Monitored through serial serum creatinine measurements 
across defined intervals. 
 
Patients and Methods: 
 
Study design: 
 
-It`s a three-arms, prospective, randomized, open label, parallel study of 75 adult cancer 
patients. Upon recruitment, Patients will be randomly assigned by permuted block 
randomization to one of the 3 study groups. 
 
Duration:3 cycles (21 days each) 
 
Study setting: 
 
Patients will be recruited from the oncology department of Nasser Institute for Research and 
Treatment. 
 
Patients:  
 
Adult patients admitted to the internal medicine department of Nasser Institute for Research 
and Treatment with proven different types of cancer mainly (lung, pancreatic and bladder 
cancers) will be assessed for eligibility. Patients who fulfilled the following inclusion and 
exclusion criteria will be included in the study and will be asked to sign an informed consent 
to be enrolled in the study. 
 
Eligible patients will be selected according to the following inclusion and exclusion 
criteria: 
 
Inclusion Criteria: 
 Chemotherapy-naïve patients diagnosed with different types of cancer.                 
 Age :adult patients (aged 18-65 years) 
 Candidates eligible for induction chemotherapy (cisplatin+gemcitabine). 
 
 
 Eastern Cooperative Oncology Group (ECOG) performance status <2. 
 Hematologic parameters 
-- 
-- 
 
 
 

 
 
 
 
Exclusion Criteria: 
 Prior chemotherapy. 
 Uncontrolled Diabetes mellitus, active infection, heart failure, or liver impairment. 
 Patients with gastritis and G-6-P deficiency 
 History of nephrotoxic drugs use over the past 3 months prior to recruitment (e.g., 
aminoglycosides, amphotericin B or vancomycin). 
 Known allergy to any study drugs. 
Sample size calculation: 
Based on a previous study of vitamin C to prevent vancomycin-induced nephrotoxicity, the 
expected effect size in GFR would be f= 0.4768[11] . To detect a similar effect size in a 
balanced ANOVA with 80% power while keeping alpha level of 0.05, a sample size of 16 
patients per group would be required. Accordingly, 25 patients will be recruited in each 
group to account for drop out. 
Study groups 
Standard of care will be given to all patients.  
The chemotherapy regimen consists of ; cisplatin+gemcitabine.  
day 1: gemcitabine+ cisplatin: 75 mg/m2 IV , or gemcitabine +fractionated cisplatin: 35 mg 
/m2 on day 1 and day 8 .This regimen will be repeated every 3 weeks for 3 cycles[7],[21]. 
All patients should receive a hydration protocol based on the chemotherapy protocol . 
 Group I (Control Group): 25 patients will receive only the standard of care.  
 Group II (Vitamin C): 25 patients will receive Vitamin C 500 mg administered orally 
once daily for 10 days. (for 2 days before day 1 for each cycle )[7],[13]. 
 Group III (Coenzyme q10): 25 patients will receive Coenzyme q10 30 mg administered 
orally once daily for 
 days. (for 2 days before day 1 for each cycle ) [22-24]. 
 
 
 
 
 

 
Ethical approval: 
The study is designed and will be carried out in accordance with the declaration of Helsinki. 
The study protocol will be submitted to the ethics committee of the Faculty of Pharmacy, 
Ain Shams University (ACUC-FP-ASU) for approval before starting the study. Moreover, 
the study will be registered on clinicaltrials.gov registry. Patients will be educated about the 
study protocol and an approval will be taken from the patient responsible physician. patients 
will be required to sign a written informed consent to be recruited in the study. 
Methodology: 
After consent, all the studied patients will be subjected to complete history taking, thorough 
clinical examination, weight and height measurement, and determination of ideal body  
weight (IBW) and body surface area (BSA). The chemotherapy dose will be calculated using 
the Mosteller body surface area (BSA) formula. 
 Sample Collection and Analysis 
Data Collection and Timeline: 
Baseline demographic data:  
age, gender, social history, medical and medication history. 
*Baseline labs:  Serum creatinine, eGFR and KIM-1 markers.  
Baseline assessment of quality of life: EORTC QLQ-30 
*Follow-ups:  
-KIM-1 :At the 3rd day of the third cycle by using double-antibody sandwich ELISA. 
-Assesment of the quality of life through The EORTC QLQ-C30 questionnaire by the end of 
the third cycle. 
-Calculation of eGFR will be done at each two cycles. 
-Serum creatinine measurements: by the end of each cycle by autoanalyzer.  
 
 
 
 

 
1. Primary Efficacy Parameter: 
 Incidence of cisplatin-induced nephrotoxicity: 
There are many side effects of cisplatin . However, nephrotoxicity is the main dose-limiting 
side effect. About 20 30% of patients experience nephrotoxicity following a single dose of 
cisplatin.  
*Measure the serum creatinine levels at baseline before administration of the first cycle then 
by the end of each cycle by calculating GFR  using serum creatinine (graded by CTCAE 
v5.0)  
Serum creatinine is a standard marker for kidney function, and a lower increase or stabilization 
in creatinine levels would suggest renal protection. 
A lower incidence of AKI in the intervention groups (Group II and Group III) compared to the 
control group (Group I) would indicate efficacy. 
 
2. Secondary Efficacy Parameters: 
 Change in Serum KIM-1 Levels: 
Measure the change in (KIM-1) levels at the baseline and then at the third day of the third 
cycle of chemotherapy. 
 
KIM-1 is a biomarker for kidney injury, and a reduction in its levels would indicate a protective 
effect of the interventions (Vitamin C, Coenzyme q10, or both) against cisplatin-induced 
nephrotoxicity. 
 
*Assesment of the quality of life through The EORTC QLQ-C30 questionnaire at baseline 
and by the end of the third cycle. 
 
*Adverse Effects from Antioxidants: Documented during weekly phone calls through 
structured case report forms, patient diaries, and adverse event reporting per CTCAE 
guidelines. 
 
*Time to Onset of Nephrotoxicity: Monitored through serial serum creatinine measurements 
across defined intervals. 
not adhering to at least 80% of their treatment regimen would be considered non-compliant 
 
 
 
 
 

3. Exploratory Efficacy Parameters: 
 Biomarker Correlation: 
Explore the correlation between changes in KIM-1 levels and serum creatinine levels to 
understand the relationship between these biomarkers in predicting kidney injury. 
 
 
Safety&Tolerability: 
Evaluate the tolerability of the chemotherapy regimen with and without the interventions, 
including the ability to complete all three cycles of chemotherapy. It will be followed up  
for 21 days until day 1 of the fourth cycle by weekly phone calls and to assess compliance 
using pill count method . 
 as the possible toxicities of Cisplatin: 
1. Renal Toxicity  
2. Gastrointestinal Toxicity (Severe nausea and vomiting -highly emetogenic) 
3. Ototoxicity 
4. Neurotoxicity 
In addition to the GIT side effects of vitamin C and Coenzyme q10 drugs. 
 
 
Statistical analysis: 
value of equal or less than 0.05 will be considered statistically significant. 
 
Statistical Tests: 
 
 
median {interquartile range(IQR)} for non-parametric data. 
groups while Kruskal Wallis test will be used for non parametric variables 
 
 
 
 

 
References : 
 
1.   
-
Induced Nephrotoxicity: A Balance on the Knife Edge Between Renoprotection and 
https://doi.org/10.1186/s12929-019-0518-9..  
 
2.   Hajian, S., M. Rafieian-
42. PMID: 28197460; PMCID: PMC5297526. 
 
3.  
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6.  
Journal of Nephrology 31 (2018): 15 25. https://doi.org/10.1007/s40620-017-0392-z. 
 
7.  Ghonaim, E., S. El-
Against Cisplatin-Induced Nephrotoxicity in Head and Neck Cancer Patients: A 
https://doi.org/10.1007/s12032-021-01558-y. 
 
8.  
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56. 
http://pharmacologyonline.silae.it. 
 
9. Tanase, D. M., E. M. Gosav, S. Radu, C. F. Costea, M. Ciocoiu, A. Carauleanu, C. M. 
Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced 
Nephroto
https://doi.org/10.3390/ijms20205238. 
 
 
 
 
 

 
10.   
-1/TIM-1 in Proximal Tubular Cell Immune 
 
 
11.  Mussa A, Mohd Idris RA, Ahmed N, Ahmad S, Murtadha AH, Tengku Din TADAA, Yean 
Mohamud R, Hassan R. High-Dose Vitamin C for Cancer Therapy. Pharmaceuticals 
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PMC9231292. 
 
12. Korah, M. C., et al. (2017). Adverse effects and side effects on vitamin therapy: A 
review. Asian Journal of Pharmaceutical and Clinical Research, 10(5), 19 26. 
https://doi.org/10.22159/ajpcr.2017.v10i5.17014 
 
13.  El-
in Reducing the Incidence of Vancomycin-Associated Nephrotoxicity in Critically Ill 
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https://doi.org/10.12688/f1000research.55619.1. 
 
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Attenuates Vancomycin-Induced Nephrotoxicity Through the Reduction of Oxidative 
Stress and Inflammation in HK-
1748 1754. https://doi.org/10.21037/apm-20-694. 
 
15.   Antunes, L. M. G., Darin, J. D. C., & Bianchi, M. L. P. (2000). Protective effects of 
vitamin C against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: 
A dose-dependent study. Pharmacological Research, 41(4), 405 411. 
https://doi.org/10.1006/phrs.1999.0600 
 
16. Raizner, A. E. (2019). Coenzyme Q10. Methodist DeBakey Cardiovascular Journal, 
15(3), 185 191. https://doi.org/10.14797/mdcj-15-3-185  
 
17. Fouad, A. A., Al-Sultan, A. I., Refaie, S. M., & Yacoubi, M. T. (2010). Coenzyme Q10 
treatment ameliorates acute cisplatin nephrotoxicity in mice. Toxicology, 274(1 3), 
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StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK493187/ 
 
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with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C 
induces epigenetic changes. Clin Epigenet 11, 143 (2019). 
https://doi.org/10.1186/s13148-019-0739-5 
 
24. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the Prevention of 
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Appendix  
EORTC QLQ-C30 (Version 3) 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year): 
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
 
1 
 
2 
 
3 
 
4 
During the past week: 
 
Not at 
 
A 
 
Quite 
 
Very
 
All 
Little 
a Bit 
Much
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
 
1 
 
2 
 
3 
 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 

 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
 
1 
 
2 
 
3 
 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
 
1 
 
2 
 
3 
 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
 
1 
 
2 
 
3 
 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
 
1 
 
2 
 
3 
 
4 
 
For the following questions please circle the number between 1 and 7 that 
best applies to you 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent