Middle Eastern Cancer and Oncology Journal

Breast cancer is one of the most prevalent malignancies worldwide, and it continues to impose a considerable clinical and economic burden on healthcare systems, particularly in low- and middle-income countries (Perazella & Izzedine, 2015; Rosner & Perazella, 2017; Santos et al., 2020). Anthracyclines, such as doxorubicin, represent a fundamental component of systemic therapy for a wide range of solid tumours, including breast cancer. This is attributable to their robust cytotoxic effect, which is facilitated through mechanisms such as DNA intercalation, inhibition of topoisomerase II, and the production of reactive oxygen species (Drozdzik et al., 2021; Knights et al., 2013; Kwon, 2021; Perazella, 2018). Despite their recognised therapeutic importance, anthracyclines are associated with several dose-limiting toxicities, most notably cardiotoxicity; however, nephrotoxicity has also emerged as a clinically relevant but frequently under-recognised complication (C. Chen et al., 2022; Chiruvella et al., 2020).

The kidneys play a critical role in drug elimination and metabolic homeostasis, rendering them vulnerable to chemotherapeutic injury. Doxorubicin has been demonstrated to induce oxidative stress, glomerular damage, tubular apoptosis, and microvascular injury, all of which have been shown to contribute to impaired renal function and the development of acute kidney injury (AKI) (see Ingrasciotta et al., 2014; Yang et al., 2016; Yemm et al., 2019). Anthracyclines, most notably doxorubicin, are extensively utilised within the domain of oncology and are well-recognised for their cardiotoxic effects. In contrast, the issue of renal toxicity has garnered comparatively less attention. Proposed mechanisms of anthracycline-associated nephrotoxicity include oxidative stress, endothelial injury, and tubular cell damage. Despite the established presence of these mechanisms, there is a paucity of real-world data concerning the incidence and severity of acute kidney injury (AKI) following anthracycline exposure in routine clinical practice, particularly in Middle Eastern populations (Chen et al., 2019; McGowan et al., 2017). Consequently, the monitoring of renal biomarkers, including serum creatinine and estimated glomerular filtration rate (eGFR), is imperative for the early detection of nephrotoxicity during cancer treatment.

Acute kidney injury (AKI) during systemic chemotherapy is a multifactorial process influenced by patient-related factors (e.g. age, hypertension, diabetes, cardiovascular disease), treatment-related variables (e.g. cumulative anthracycline dose, combination regimens), and tumour-related factors (Johnson & Keyes, 2024; Marinello et al., 2018; Mukai et al., 2017; Savani & Skubitz, 2019). A number of studies have indicated that administration of anthracyclines may result in impaired renal perfusion and direct tubular cell damage, particularly when concomitantly administered with other nephrotoxic agents or in patients with pre-existing comorbidities (Barbosa et al., 2018; Jurczak et al., 2020; Wu et al., 2021). The KDIGO classification is widely regarded as the gold standard for defining and staging AKI. It facilitates the standardisation of reporting of renal toxicity in oncology populations (Lyrio et al., 2024).

Despite the extensive use of anthracycline-based regimens in Iraq, regional studies evaluating doxorubicin-induced nephrotoxicity remain scarce. The majority of extant literature focuses primarily on cardiotoxicity, thereby leaving an important gap regarding renal outcomes. In light of the escalating cancer burden in Iraq and the prevalent utilisation of anthracyclines in treatment protocols (Santos et al., 2020), it is imperative to comprehend the renal implications of these agents. A comprehensive understanding of this phenomenon is paramount for optimising dosing strategies, averting complications, and enhancing patient safety.

In this context, the identification of patterns and predictors of anthracycline-associated AKI is imperative for enhancing early detection and the development of supportive-care strategies. The present study aims to assess the impact of doxorubicin-based chemotherapy on renal function, evaluate changes in serum creatinine and eGFR before and after treatment, determine the incidence and severity of AKI, and identify clinical predictors associated with nephrotoxicity. This work provides valuable regional evidence to support safer anthracycline use in routine clinical practice.

Study Design and Setting

This retrospective observational study was conducted at a major oncology referral centre in Iraq, where anthracycline-based chemotherapy is routinely administered for breast cancer and other solid malignancies. A comprehensive review of the medical records of patients treated during the defined study period who received doxorubicin-containing chemotherapy regimens and had complete renal function data available before and after treatment was conducted. The retrospective design enabled the evaluation of renal outcomes in a real-world clinical setting, reflecting routine oncology practice.

Study Population

Patients were identified through institutional chemotherapy registries and electronic medical records. All adult patients who had received doxorubicin-based chemotherapy and had undergone baseline and follow-up renal laboratory assessments were screened for eligibility. The final analysis was conducted on a sample of patients who met specific criteria, namely those with complete documentation of chemotherapy exposure, cumulative anthracycline dose, and renal biomarkers.

Eligibility Criteria

Patients were eligible for inclusion if they were aged 18 years or older, had received at least one cycle of doxorubicin-containing chemotherapy, and had documented serum creatinine and estimated glomerular filtration rate (eGFR) measurements obtained both before treatment initiation and after completion of anthracycline therapy. It was imperative that patients possess comprehensive clinical records, encompassing details such as chemotherapy regimens, cumulative doses, and comorbidity profiles. Individuals suffering from pre-existing end-stage renal disease were deemed ineligible for inclusion in the study.

Patients were excluded from the study if they received concurrent nephrotoxic chemotherapy agents, such as cisplatin, that could confound renal outcomes; had advanced chronic kidney disease (stage 4–5) prior to chemotherapy; had incomplete laboratory or chemotherapy documentation; or had obstructive uropathy or renal malignancy affecting baseline renal function.

Data Collection

A comprehensive data set was extracted from patient records, encompassing demographic and clinical information. This included age, sex, and the presence of baseline comorbidities such as hypertension, diabetes mellitus, and cardiovascular disease. Treatment-related variables encompassed the chemotherapy regimen type and the cumulative doxorubicin dose. The renal biomarkers that were collected for the purpose of analysis included serum creatinine and eGFR values that had been measured prior to and following exposure to anthracyclines. The incidence and severity of acute kidney injury (AKI) were recorded for all eligible patients.

Assessment of Renal Function

The initial renal function of the patient was determined by means of serum creatinine and eGFR measurements, which were obtained within a two-week period prior to the commencement of the initial chemotherapy cycle. Follow-up renal function assessments were conducted following the completion of four cycles of doxorubicin-based chemotherapy or at the conclusion of the anthracycline component of treatment, whichever occurred first. The temporal parameters of this investigation were meticulously delineated to encompass the early manifestations of chemotherapy-induced renal changes, while concomitantly ensuring that confounding variables introduced by subsequent non-anthracycline therapeutic interventions were minimized.

Serum creatinine was measured using standardised laboratory methods, and eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation. The definition and staging of acute kidney injury was conducted in accordance with the established framework of Kidney Disease: Improving Global Outcomes (KDIGO) criteria stipulate that Stage 1 is defined as a 1.5–1.9-fold increase from baseline creatinine, Stage 2 as a 2.0–2.9-fold increase, and Stage 3 as a ≥3-fold increase or requirement for renal replacement therapy (Gounden et al., 2024).

Statistical Analysis

The statistical analysis was conducted utilising conventional descriptive and inferential methodologies. Continuous variables were summarised using means and standard deviations, while categorical variables were expressed as frequencies and percentages. A comparison of pre- and post-treatment renal biomarkers was conducted using paired t-tests. The associations between clinical variables and the occurrence of AKI were assessed using chi-square or Fisher's exact tests, as appropriate. A p-value of less than 0.05 was considered to be statistically significant.

The following section will present the demographic characteristics of the study population, the chemotherapy regimens administered, renal function changes before and after anthracycline-based treatment, and the incidence and severity of acute kidney injury (AKI). In consideration of the findings of this study, it can be concluded that there is a statistically significant correlation between exposure to anthracyclines and impairment to renal function, as well as a measurable rate of treatment-related nephrotoxicity.

Demographic and Baseline Characteristics

The present study comprised a total of 100 patients. The mean age of the subjects was 48.8 ± 14.1 years, with a median age of 52 years (range 16–73 years), thus reflecting a wide range of adult oncology patients. The majority of the participants were female (76.0%), while 24.0% were male.

The mean body mass index (BMI) was 26.5 ± 2.7 kg/m², indicating that the majority of patients were categorised as overweight. The baseline demographic factors outlined in Table 1 provide the essential clinical context for interpreting treatment-related renal outcomes.

Chemotherapy Regimens and Anthracycline Exposure

Among the 100 patients, 89.0% received combination chemotherapy regimens, while 11.0% were treated with single-agent (non-combination) therapy.

Within the combination therapy group (n = 89), the most frequently administered regimen was:

In the present study, the AC combination of Adriamycin and Cyclophosphamide was administered to 65 patients, constituting 73.0% of the total population.

ABVD: 12 patients (13.4%)

R-CHOP was administered to 11 patients, representing 12.3% of the study population.

A cisplatin-based regimen is employed. In one patient (1.1%), the following regimens were observed: all of these regimens included doxorubicin (Adriamycin), with the exception of cisplatin. This observation indicates that the cohort is predominantly exposed to anthracyclines. The substantial representation of AC-based therapy is indicative of contemporary oncological practice in Iraq. These details are summarised in Table 2.

Renal Function Changes Before and After Anthracycline Therapy

It is evident that administration of anthracycline-based chemotherapy has resulted in substantial alterations in renal function.

Serum creatinine levels increased from 0.76 ± 0.21 mg/dL prior to treatment to 0.90 ± 0.22 mg/dL following four cycles (p < 0.001). This rise indicates a measurable reduction in filtration capacity.

Concurrently, the blood urea level exhibited an increase from 35.28 ± 6.33 mg/dL at the initial baseline to 37.18 ± 5.67 mg/dL following the administration of chemotherapy (p < 0.001).

The two biomarkers exhibited statistically significant deterioration in renal function following exposure to anthracyclines, consistent with the occurrence of early drug-induced nephrotoxicity. The results of this study are presented in Table 3.

Incidence and Severity of Acute Kidney Injury

The incidence of AKI was observed in 27 out of 100 patients (27.0%), indicating a significant rate of nephrotoxicity. In the cohort of affected individuals (n = 27), the following observations were made:

• In the initial phase of the study, 21 patients (77.6%) were diagnosed with Stage I AKI.
• In the case of Stage II AKI, the number of patients was found to be six (22.4%).
• In the present cohort, no patients were observed to have Stage III AKI (0.0%). This distribution indicates that the majority of cases were mild (Stage I), with no progression to severe (Stage III) injury.

It is noteworthy that a single patient (1.0%) exhibited a non-renal complication necessitating hospitalisation, characterised by symptoms such as nausea, vomiting and diarrhea.

The remaining patients (99.0%) completed the therapeutic regimen without encountering any additional complications.

These findings underscore the fact that, while severe AKI was not present, early-stage renal impairment was prevalent and of clinical significance. The detailed values are presented in Table 4.

The present study provides real-world evidence on the occurrence and severity of acute kidney injury following anthracycline-based chemotherapy in an Iraqi oncology population. Whilst earlier studies have indicated renal toxicity associated with anthracycline exposure, the present findings are consistent with and build upon extant evidence by demonstrating that clinically meaningful AKI can occur in routine practice, outside of the confines of controlled trial settings. These results underscore the necessity to contemplate renal outcomes in conjunction with the more prevalent anthracycline toxicities (Knights et al., 2013; Kwon, 2021). Nevertheless, concerns regarding its nephrotoxic potential have increased in recent years, as mounting evidence demonstrates that anthracyclines exert harmful effects beyond their well-established cardiotoxicity. In the present study, doxorubicin-containing regimens were found to result in measurable renal function impairment, as evidenced by statistically significant elevations in serum creatinine and blood urea following treatment. These alterations provide preliminary indications of diminished renal filtration capacity, corroborating prior research associating anthracyclines with oxidative stress–mediated tubular damage, mitochondrial injury, and glomerular endothelial dysfunction (Ingrasciotta et al., 2014; Yang et al., 2016; Yemm et al., 2019).

The incidence of acute kidney injury (AKI) observed in this cohort was clinically significant, with 27% of patients meeting KDIGO criteria. The majority of cases were categorised as Stage I, with no patients demonstrating progression to Stage III AKI. This finding aligns with international observations that early-stage nephrotoxicity is more prevalent in oncology patients undergoing systemic chemotherapy (Chen et al., 2019; McGowan et al., 2017). Although severe AKI was not encountered in this study, even mild kidney injury is clinically significant because it may delay treatment cycles, prolong hospitalisation, worsen morbidity, and increase the risk of chronic kidney disease over time (Johnson & Keyes, 2024; Marinello et al., 2018). Consequently, the early identification and management of these conditions are of paramount importance in preventing treatment interruption and long-term renal consequences. From a clinical perspective, these findings carry significant implications for the delivery of oncology care in settings where resources are limited. Routine monitoring of renal function during anthracycline therapy has been shown to facilitate earlier identification of AKI, thereby enabling timely modification of dosage, the implementation of supportive interventions, and the prevention of further renal deterioration. In healthcare systems characterised by constrained access to renal replacement therapies, the employment of such strategies assumes particular significance.

It is hypothesised that renal dysfunction associated with anthracycline therapy is explained by multiple mechanistic pathways. As demonstrated in the research by Ingrasciotta et al. (2014) and Yang et al. (2016), doxorubicin has been shown to induce oxidative stress through the generation of reactive oxygen species. The result of this process is the damage of DNA, the induction of apoptosis, and the disruption of the mitochondrial function within renal tubular cells. Furthermore, the occurrence of endothelial injury and microvascular dysfunction has the potential to compromise renal perfusion, thereby exacerbating ischemic tubular injury (Yemm et al., 2019). It is important to note that the potential for confounding due to nephrotoxic exposure was minimal in this study, as only one patient received a regimen containing cisplatin. This finding serves to reinforce the hypothesis that the nephrotoxicity observed was primarily attributable to anthracycline exposure, as opposed to the combined effect of co-administered nephrotoxins.

The implementation of KDIGO criteria for AKI detection facilitates the establishment of a more uniform approach to the characterisation of nephrotoxicity within cancer populations. This, in turn, serves to enhance the comparability of findings with global oncology research (Lyrio et al., 2024). This finding also lends support to the implementation of KDIGO-guided monitoring as an integral component of chemotherapy protocols, with the aim of enhancing clinical decision-making processes. However, it is important to highlight that some patients may exhibit renal injury without meeting KDIGO threshold levels, as biochemical changes may precede clinically defined AKI. This finding indicates a necessity for a more extensive array of potential biomarkers, and potentially the incorporation of novel sensitive markers of nephrotoxicity, such as neutrophil gelatinase-associated lipocalin (NGAL) or cystatin C, in subsequent research endeavours.

The clinical implications of these findings are of particular relevance in settings such as Iraq, where anthracycline-based regimens remain widely accessible and are commonly prescribed as first-line therapy due to their cost-effectiveness and established efficacy. In light of the escalating cancer burden in Iraq, the constrained access to nephrology services, and the recurrent delays in oncology follow-up care, the undetected chemotherapy-related AKI may result in preventable complications and augmented healthcare expenditures. These contextual challenges serve to emphasise the importance of implementing low-cost monitoring strategies, including baseline and post-treatment serum creatinine assessments, hydration protocols, and dose adjustments when renal deterioration is detected.

A significant strength of this study is its real-world, retrospective design, which reflects routine oncology practice and enhances the applicability of the findings to everyday clinical settings. The findings of this study emphasise the necessity of incorporating renal safety evaluation into standard chemotherapy practice. Routine monitoring before and during anthracycline administration allows early detection of renal functional changes and enables timely intervention through hydration optimisation, treatment modification, or enhanced surveillance. The incorporation of these strategies has the potential to enhance patient safety, reduce treatment delays, prevent long-term renal damage, and support optimal therapeutic outcomes in cancer patients receiving anthracycline-based regimens.

In a real-world oncology population, there was an association between anthracycline-based chemotherapy and measurable renal impairment. The early identification of acute kidney injury through routine renal monitoring has the potential to facilitate a safer delivery of chemotherapy and to enhance the quality of supportive care. These findings underscore the significance of integrating renal surveillance into anthracycline treatment protocols, particularly in settings characterised by constrained healthcare resources.

Ethics Approval and Consent to Participate

The study protocol was approved by the Institutional Review Board of the participating oncology centre, with additional ethical clearance obtained from the Iraqi Ministry of Health. Prior to analysis, all patient data were anonymised, and confidentiality was maintained in accordance with institutional policies and the principles of the Declaration of Helsinki.

Consent for Publication

Not applicable.

Availability of Data and Material

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest / Competing Interests

The authors declare that there are no conflicts of interest.

Funding

The authors declare that this research received no external funding.

Authors’ Contributions

N.k.H.: Conceptualization, Methodology, Formal analysis, Data curation, Writing of the original draft.

A.S.A.: Conceptualization, Methodology, Resources, Writing – review & editing, Supervision.

Acknowledgment

Not applicable

Use of Generative AI and AI-Assisted Technologies

The authors declare that no generative AI or AI-assisted technologies were used in the preparation of this work.