Antineoplastic agents can exert nephrotoxic effects through diverse mechanisms, including direct tubular damage, glomerular injury, and alterations in renal hemodynamics. Over the years, the spectrum of kidney diseases in cancer patients has changed, mainly as a result of modifications to the cancer treatment regimens.6 Nephrotoxicity can occur with various classes of antineoplastic agents, such as platinum-based compounds (e.g., cisplatin), anthracyclines (e.g., doxorubicin), alkylating agents (e.g., ifosfamide), and targeted therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICPI).4,7,8 Cisplatin is classically notorious for its nephrotoxic potential, causing dose-dependent renal tubular injury and apoptosis, particularly in the proximal tubules.9 Other agents, such as methotrexate, may lead to nephrotoxicity through crystalluria and obstructive nephropathy,4 whereas drugs like bevacizumab, a vascular endothelial growth factor inhibitor, can induce thrombotic microangiopathy, which results in glomerular injury.7,10 In addition to these, TKI and ICPI are two of the most expanding drug groups in oncology, whose nephrotoxic properties are being thoroughly studied, both causing AKI through several mechanisms. While the most common mechanisms of AKI due to TKI are podocytopathies and thrombotic microangiopathy,11 ICPI causes primarily immune-mediated acute tubulointerstitial nephritis, although other mechanisms may also be implied, whether tubular, vascular, or glomerular in nature.12

The complex interplay between cancer treatment, nephrotoxicity, and AKI underscores the importance of early identification and management of renal complications in oncology patients. Several strategies have been proposed to mitigate the risk of nephrotoxicity, including dose adjustments, hydration protocols, and using nephroprotective agents such as amifostine to prevent cisplatin nephrotoxicity.13 Despite these measures, the prevention of AKI remains challenging and once established, AKI significantly worsens patient outcomes.

In cancer patients, the decision to initiate dialysis is particularly complex, as it must account not only for the severity of renal dysfunction but also for the patient's overall prognosis and cancer trajectory. Patients with AKI who require HD in oncology settings have significantly higher mortality rates than those who do not.14 The need for RRT is further complicated by the common presence of factors such as infection, tumor lysis syndrome, or concurrent administration of other nephrotoxic agents.3,15 Moreover, oncologic treatments may have to be delayed or adjusted in patients requiring dialysis, potentially affecting cancer outcomes.2

While RRT can be lifesaving by managing the complications of severe AKI, its use in cancer patients is associated with substantial morbidity, prolonged hospital stays, and increased healthcare costs. Additionally, the initiation of dialysis in patients with terminal cancer or poor performance status is a subject of ethical debate, as the burden of dialysis may outweigh the potential benefits in these cases.

A poor prognosis is generally observed in cancer patients who develop nephrotoxic AKI, especially those requiring HD. In critically ill cancer patients, mortality rates associated with AKI are significantly high, with studies indicating in-hospital mortality rates ranging from approximately 50% to as high as 70%, particularly among patients with metastatic disease, sepsis, or multi-organ failure. Haematologic malignancies and high SOFA scores (indicating organ dysfunction severity) are also linked to poorer outcomes. Patients with solid tumors requiring RRT or intensive care unit (ICU) admission experience mortality rates exceeding 70% in some cases, exacerbated by conditions like tumor lysis syndrome and exposure to nephrotoxic treatments.3,16,17

Data from drug-related AKI in cancer patients is scarce. In this setting, we aim to review the profile of moderate to severe nephrotoxic AKI in patients admitted to an oncology hospital over the last two decades, explore the clinical scenarios in which AKI progresses to require RRT, and examine the associated mortality rates in cancer patients. Understanding these dynamics is crucial for clinicians in oncology, as preventing or mitigating nephrotoxicity could enhance patient outcomes, maintain continuity of cancer treatment, and reduce the burden on healthcare systems.

In this retrospective cohort study, we included all patients hospitalised in a comprehensive cancer center during the period from January 2002 to December 2021 with the diagnosis of AKI KDIGO≥2 needing evaluation by the Nephrology Department, which primary etiology was drug-induced nephrotoxicity. We excluded all patients for whom complete data could not be collected and patients enrolled in randomized controlled trials. A sub-analysis of the two decades of study time (first decade, 2002–2011 vs second decade, 2012–2021) was carried out (see Supplementary material: Fig. S1).

The data was collected from the hospital information system. In descriptive analyses, we analyzed sociodemographic data, oncological data, nephrotoxicity data, clinical factors associated with AKI, and hospitalization outcomes. The normality test Kolmogorov–Smirnov was performed for continuous variables, demonstrating a non-normal distribution. Comparative analysis of all variables was made using non-parametric tests: bivariate inferential analysis was made with Mann–Whitney U test for continuous variables and Pearson's Chi-squared test for categorical variables; multivariate analysis was made with logarithmic regression with stepwise forward method, assessing the models’ goodness of fit with Nagelkerke pseudo-R2. Statistical significance was considered for p-value<0.05. Statistical analysis was conducted using SPSS® version 28.0.

The study was approved by the institution's Medical Ethics Committee (ref. no. 015/024). No data on patients’ personal information was recorded, and their identities were protected.

Fig. S1 (Supplementary material) depicts the flow chart for sample selection. We collected data on 2042 inpatients whose diagnosis of AKI KDIGO≥2 were made and selected 584 in which the primary etiology for AKI was drug-induced nephrotoxicity. In total, 174 were excluded due to incomplete data. The final study population was 410 patients; the sub-analysis comparing the two decades of the study comprised 137 patients in the first decade and 273 patients in the second decade. There was an asymmetric eligibility between the study's first and second decade, as seen in Fig. S1 (Supplementary material).

Table 1 summarizes demographic and clinical data.

Every demographic and clinical variable was evaluated as possible risk factor for the need for RRT.

Regarding the sample baseline characteristics, there was no significant difference in gender (p=0.536) or cancer distribution (p=0.906) between the two decades of the study, with only a slightly older sample in the second decade (median 59 [IQR 43–69] vs 62 [IQR 51–71] years old, p=0.002).

There were significant differences, however, in the available/used treatments for these patients, either by the appearance of new drugs or by the change in incidence of AKI with classically known nephrotoxic drugs. There was a decrease in cases involving platinum-based drugs (10.2% vs 8.1%, p=0.020) and an increase in cases involving a combination of multiple drugs without cancer-directed therapy, mainly due to combinations of antibiotics, antivirals, or antifungals (17.5% vs 28.6%, p=0.011). This trend may reflect advancements in cancer treatment protocols (e.g. intravenous hydration protocols), allowing for safer drug administrations with fewer adverse effects, particularly nephrotoxicity, for which clinicians are increasingly aware and able to treat. In fact, in a comprehensive cancer center, most AKI cases do not need a specialized nephrology evaluation and are managed by the oncology assistant team or referred to the nephrology outpatient clinic. Only a small proportion of AKI cases, usually KDIGO 2 or 3, need hospitalization with follow-up by the nephrology team; those are the ones represented in this study (Fig. 1). In addition, novel therapies like ICPI and TKI have become more prevalent, bringing new aspects to drug monitoring and side effects while allowing for less usage of classically known toxic chemotherapies. ICPIs and TKIs accounted for 4.8% and 1.5% of nephrotoxicity cases in the second decade, respectively, aligning with studies that report these agents’ emerging role in inducing renal complications.4,7,8 Kitchlu et al. reported similar findings, demonstrating an increase in AKI cases related to modern cancer therapies, particularly with the introduction of targeted therapies like TKI.15 Our findings also resonate with the work of Perazella et al., which highlights the nephrotoxic potential of these new oncologic agents and underscores the necessity for vigilant renal monitoring in cancer patients receiving these treatments.18

Fig. 1.

Follow-up of AKI cancer patients in a comprehensive cancer center. AKI, acute kidney injury.

(0.08MB).

The nephrological profile identified in our population is similar to the outpatient nephrotoxic profile regarding cancer therapy as described in the study by Alonso et al.19 However, differences in the drug-induced nephrotoxicity profile were also identified since hospitalised patients, particularly those with critical illness or requiring intensive care, are exposed to a broader array of nephrotoxic agents beyond antineoplastic drugs, including antimicrobials and other supportive therapies. In fact, regardless of the decade in analysis, cancer-directed therapy accounted for around one-fifth of the drug-induced AKI cases, with an overall percentage of 16.1% caused by a single nephrotoxic agent and 5.6% in combination with other nephrotoxic drugs. The most common nephrotoxic agents were NSAIDs and antibiotic drugs, with an overall representation of 19.3% and 15.9% as single nephrotoxic agents, respectively, also contributing to a large proportion of cases involving multiple drugs without cancer-directed therapy, making grossly one-quarter of all nephrotoxicity cases. These findings prove interest in showing that most cases of drug-induced AKI in a comprehensive cancer center are not caused by antineoplastic agents, highlighting the complexity of oncologic patients and the awareness for the surveillance of cancer treatments.

One of the significant findings of our study is the increase in the need for RRT over the two decades, rising from 25.5% to 36.6% (p=0.024). This could reflect an increase in the complexity and severity of AKI cases, driven in part by the intensified use of nephrotoxic drug combinations and the longer survival of cancer patients. Patients with AKI who require RRT face significantly worse outcomes, including higher mortality rates, which is consistent with our findings, specifically in drug-induced AKI.

To begin, we ran a bivariate analysis, which showed several variables to be associated with a higher need for RRT, such as younger age, haematologic cancer, BMT, severe clinical complications like GVHD, IMV, and sepsis, and some drugs (antiviral, CNI, and the use of multiple drugs without cancer-directed therapy). On the other hand, most of the solid cancers, reversible clinical complications such as pre and post-renal AKI, and some drugs, particularly NSAID, platinum-based drugs, ICPI, and the use of multiple drugs with cancer-directed therapy, were associated with lower need for RRT. Although multivariate analysis cleared some of these predictors as confounding factors, several thoughts can be made regarding this. Firstly, the need for RRT is higher when the measured factor implies greater severity of clinical status, such as haematologic cancers and several drugs. Interestingly, drugs other than antimicrobials and immunosuppressives do not seem to increase the need for RRT, as those are not expected to lead to irreversible AKI or bad prognosis; furthermore, there is tight surveillance over cancer therapy safety. Also noteworthy, younger patients had a higher need for RRT, which may be counterintuitive, although it may be explained by underlying oncologic disease profiles, such as a higher prevalence of haematologic cancer.

Notwithstanding, multivariate analysis summed up the predictors for the need for RRT to only three factors – haematologic cancer, IMV, and sepsis. Some of the predictors for the need for RRT, namely IMV and sepsis, are in line with other studies,5,20–24 which also identified these factors as strong indicators of severe AKI from all causes, requiring dialysis in critically ill general and cancer patients. Furthermore, we also found haematologic cancer as a risk factor for the need for RRT, which is generally associated with a worse prognosis than solid tumors. The practice of BMT, in some cases, leads to associated immunosuppression and risk of infectious diseases, prone to the need for nephrotoxic drugs such as several antimicrobials.

The overall mortality rate in our cohort was high (29.5%), a finding that echoes the results of similar studies in cancer patients with AKI.25 The need for RRT was a significant predictor of mortality, reinforcing the link between severe AKI and poor patient outcomes.

As was seen for the need for RRT (see above), grossly the same factors were predictors of higher or lower risk for mortality, also expressing relation to underlying disease severity and treatment complications. Once more, no cancer therapy was associated with higher mortality.

Furthermore, multivariate analysis revealed that IMV, multiple nephrotoxic without cancer-directed therapy, RRT, and sepsis were the strongest predictors of death. Our findings are supported by other reports that found that cancer patients requiring RRT have markedly higher mortality rates than those with milder forms of AKI.2,26 These authors also emphasized the impact of AKI on disrupting cancer treatment, contributing to disease progression and further worsening patient prognosis. This is consistent with the increased mortality observed in our cohort, where AKI likely interrupted cancer-directed therapy, reducing the effectiveness of cancer management. Nevertheless, prospective studies with follow-up after hospital discharge or studies addressing outpatient long-term implications of drug-induced AKI would better ascertain the causality nexus regarding worse clinical outcomes.

While the global trend toward more intensive cancer therapies has contributed to improved cancer survival, it has also resulted in increased rates of AKI and the need for interventions such as HD. Our study's findings emphasize the importance of balancing the oncological benefits of newer therapies with their potential for nephrotoxicity. The increase in AKI due to non-antineoplastic drugs, particularly antimicrobials, highlights the need for caution when prescribing these agents in the oncologic setting, especially in patients already at risk of renal impairment. Similar preventive measures like rigorous hydration protocols and dose adjustments for high-risk drugs like cisplatin to mitigate nephrotoxicity are suggested in various studies and recommendations. The use of nephroprotective agents, such as amifostine, has shown some promise in reducing cisplatin-induced renal damage, though their use remains limited due to cost and side effects.9,27,28 Notwithstanding, although this study showed many cases of drug-induced AKI due to cancer-directed therapy, it also showed that its effects seem to be reversible, without a strong association with the need for RRT or mortality and, in some cases, these drugs were associated to lower odds for these adverse events.

Our findings highlight the need for future research. The high mortality rates in patients requiring HD, particularly those with sepsis and IMV, suggest the need for more refined clinical tools to assess when dialysis should be initiated. The role of biomarkers in predicting AKI in cancer patients is also an area of growing interest. Biomarkers such as neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 have shown potential in identifying early kidney damage, allowing for timely interventions.29 Incorporating these biomarkers into clinical practice could help oncologists and nephrologists to personalize treatment plans, balancing cancer efficacy with renal safety.

This is one of the few studies in the literature that gives an insight into drug-induced AKI in cancer patients, comprising a large sample of patients in an extended cohort. However, several limitations should be considered. First, the retrospective study design has inherent limitations, as evidenced by the large number of excluded cases and the lack of information regarding comorbidities and cancer status, particularly in the first decade of the cohort. Second, we did not account for heterogeneity in cancer stage and disease aggressiveness, which are relevant confounders when analysing predictors of RRT and mortality. That is also true for the ECOG scale and baseline chronic kidney disease, a known risk factor for AKI. Third, we did not analyze long-term mortality and chronic kidney disease development due to the lack of follow-up data, which would give greater insight into the implications of AKI in the oncologic therapy and outcome.