Risk factors for renal alterations in patients with hematological cancer undergoing antineoplastic treatment


 Purpose Antineoplastic treatments, mainly chemotherapy, affect the kidneys, causing toxicity, and can trigger acute and long-term chronic kidney injury. The objective of this study was to analyze the prevalence of renal disorders in patients with oncohematological neoplasms under antineoplastic treatment. Methods This is a retrospective cohort study involving 75 patients affected by hematological cancer who underwent chemotherapy between 2012 and 2108 in the Hematology Sector of the Walter Cantídeo University Hospital of the Federal University of Ceará. Sociodemographic and clinical data, blood biochemical assessment, and Glomerular Filtration Rate (GFR) were analyzed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The data were tabulated, transferred to the Statistical Package for the Social Sciences software, version 20.0, and analyzed using Fisher's exact test or Pearson's chi-square test, followed by the Mann-Whitney test. Additionally, the variables were treated using a multinomial logistic regression model (p <0.05). Results The prevalence of renal disorders was 52.4%, considering the episodes of GFR through the CKD-EPI equation. There was an association between the reduction in GFR and the variables: female gender (p = 0.002), diagnosis of multiple myeloma (p = 0.008), start of treatment within 40 days (p = 0.005), protocol Cyclophosphamide, Oncovin, Prednisone (p = 0.026), Idarubicin (p = 0.032), Vidaza protocol, Dexamethasone, Cyclophosphamide (p <0.001), Zoledronate (p <0.001) and Pamidronate (p = 0.012). It was also observed that the Cancer and Leukemia Group B protocol (p <0.001) is inversely associated with a reduction in GFR. Conclusions The prevalence of renal disorders is high in the service evaluated, requiring periodic monitoring of the evaluation of renal function, since the reduction in GFR is statistically associated with different protocols used.


Introduction
For the basal creatinine value, the rst measurement found in the medical records of each patient was adopted, following the recommendations of KDIGO, and to estimate GFR, the formula CKD-EPI was used because of its accuracy is more effective than when compared with the others [13], and thus the outcome variable was determined.
Categorical data were expressed as absolute frequency, considering the patient as the sample unit. The clinical evaluation event was adopted as the sample unit for the assessment of CKD risk factors, which were crossed using Fisher's exact test or Pearson's chi-square test. Examination data were expressed as means and standard deviations and analyzed using the Mann-Whitney test (non-parametric data).
After identifying the clinical variables signi cantly associated with increased risk of CKD-EPI, these were divided into two levels: clinical-epidemiological variables and therapeutic variables. At each level, these variables were analyzed using a multinomial logistic regression model, and after that, the variables independently associated with CKD-EPI were selected at each level for multilevel analysis using the same model. For all analyzes, p < 0.05 was considered statistically signi cant.

The research is in accordance with ethical principles, and the Ethics Committee for Research on Human
Beings of the Faculty of Medicine (UFC) was rstly approved with CAAE 87952818.7.0000.5054 and then by the Ethics Committee of the Walter Cantídeo University Hospital (UFC) ) under CAAE number 87952818.7.3001.5045.
Almost the entire population had a normal initial renal function, 70 patients (93.3%), and 74 did not use hemodialysis (98.7). Regarding the place where the treatment was applied, the vast majority of patients were administered at the outpatient clinic, 67 (89.3%) and concerning the start of medications, part of the patients started after 40 days after diagnosis, representing 38 (50, 7%) ( Table 2).
Regarding the clinical and admission pro le of the patients, it was observed that SAH (p < 0.001), DM (p < 0.001), coronary disease (p = 0.002), other comorbidities (p < 0.001) of the most varied, grade I obesity (p < 0.001) are directly associated with a reduction in CKD-EPI. Although the lack of dental follow-up did not show statistical signi cance (p = 0.056), there is a trend when associated with a decrease in GFR (Table 2).
Acyclovir (p = 0.014), uconazole (p = 0.001) and levo oxacin (p = 0.011) were inversely associated with a decrease in CKD-EPI whereas, the use of bactrim (p < 0.001) and other drugs (p < 0.001) showed a direct relationship with this change. According to renal function, patients who started treatment with AKI or CKD (p = 0.003) also had more episodes of reduced GFR as well as hemodialysis (p = 0.032) and progression to CKD (p < 0.001) ( Table 2).
Patients who underwent treatment at the outpatient clinic (p < 0.001) were directly associated with renal dysfunction. It should be noted, however, that the sample studied consisted almost entirely of outpatients. There was also a higher number of dysfunctional episodes (p = 0.048) in patients who started treatment within 40 days after diagnosis (Table 2).
Therapeutic pro le of the sample and in uence of the scheme on the incidence of CDK-EPI episodes The 75 patients participating in the research totaled 985 episodes of analysis (data collection), with a mean of 6.6 ± 6.8 and a median of 4 events per patient with a minimum and maximum of 1 to 46 events, respectively. Most patients underwent 1 to 2 cycles of CT, totaling 302 (30.7%) ( Table 3).  When the multivariate analysis of the variables that showed signi cant relevance of the sociodemographic and clinical admission aspects was performed, it was found that being female increased the chance of episodes with a reduction in the CKD-EPI index by 18.75 times. Also, the diagnosis of MM increased this prevalence by 4,111.01 times, as well as the initiation of treatment within  When performing the same procedure with the variables involved in the treatment, it was found that the use of COP, Idarubicin, CalgB, and others were inversely associated, reducing by 0.09, 0.12, 0.09 and 0.32 times, in this order, the prevalence of episodes with decreased CKD-EPI, independently of the others.
Finally, another analysis of the variables described above was made, highlighting that, independently, the female gender and the diagnosis of MM are associated with a greater probability of occurring episodes with renal dysfunction in 2.26 and 5.75 times, respectively. This fact also happened with the use of Vidaza, Zoledronate, and Pamidronate, increasing the chances by 10.64, 3.20, and 3.86 times, respectively. On the other hand, the use of CalgB was inversely associated with the occurrence of episodes with low GFR, reduced by 0.23 times (Table 5).

Discussion
Renal impairment in patients with oncological hematology mainly comes from nephrotoxicity caused by the excretion of chemotherapy drugs. The dysfunctionality of this organ relates to the suspension of antineoplastic treatment, increased costs, reduced quality of life, and, among others, the increase in mortality [14,11,15,16].
The present research, evaluated in episodes, found that 52.4% of the participants had reduced GFR according to the result of the CKD-EPI formula. One study showed that, in patients with CLL, approximately 15% of the patients developed some degree of renal dysfunction [17].
The signi cance of females with a higher number of episodes of reduced GFR may be associated with MM, and this fact is rea rmed by other studies in which women are predominant with this disease [18][19][20] and patients with MM are more prone to kidney injury [21,22]. Research shows that, in developing countries, this scenario is visualized, but when it comes to rst world countries, there is a balance between the sexes in the diagnosis of MM [23].
The in uence of the diagnosis of MM with renal impairment has a broad scienti c basis since 20 to 40% of patients with MM have renal dysfunction at the time of diagnosis. There are reports that the chemotherapy plan can reverse this dysfunctionality even in patients with low GFR rates [24]. However, the interaction of MM with renal dysfunction impacts on the survival time of affected patients, presenting an average of two years when renal function is normal and, in the presence of failure, the time is reduced by 50% [25][26][27].
The CalgB protocol is applied in hematological neoplasms, mainly in leukemias and their various aspects. The scheme in question in the present study is composed of oncovin, dexamethasone, and doxorubicin showing relation with GFR. Oncovin is a chemotherapy that has the main adverse effect on neurotoxicity [28,29]. Dexamethasone is a potent anti-in ammatory used in the treatment of numerous diseases whose mechanism of action is aimed at minimizing the in ammatory state (attenuating chemokines and cytokines) and increasing vascular permeability [30][31][32]. It has been reported that its activity decreases the breakdown of the glycocalyx and improves renal perfusion, thereby reducing renal dysfunction [33,34]. Doxorubicin, on the other hand, is a versatile and effective anticancer used in several types of neoplasms. However, it triggers cardiotoxicity, hepatotoxicity, nephrotoxicity, pulmonary, and hematological toxicity [35,36]. After performing the multivariate and multilevel analysis, it was found that the therapeutic set is inversely associated with a reduction in GFR, that is, its use is less harmful to the kidneys, causing mild protection. This fact can occur due to the bene cial action of dexamethasone in protecting and recovering from kidney damage. There is still a de cit of scienti c ndings speci cally about this protocol. However, when drugs are analyzed separately, there is a greater collection.
The VCD protocol was statistically relevant in the analyses, being independently related to the decrease in GFR, causing an impact more than ten times. The proteasome inhibitor antineoplastic, such as Vecalde present in the VCD protocol, is widely used for the treatment of MM and mantle cell lymphoma. Its action consists of the degradation of proteins, essential for cell hemostasis, and the accumulation of these fragments triggers the process of cell death [37]. In addition, it also has the effect of minimizing the action of the immune system [38,39]. There are reports of its bene ts in the kidney, causing an improvement in renal function. Another study points out that there is a need for further analysis about the dosage of the drug to verify its e ciency [40]. The second member of the scheme is dexamethasone, whose bene cial action on the renal system reduces the possibilities of dysfunction and progression to the installation of CKD [35]. Cyclophosphamide is the last component of the VCD protocol, being conceptualized as an immunosuppressive and antineoplastic drug that has ample potential for nephrotoxicity. This research showed a direct association between renal dysfunction and the use of this protocol (VCD), which, despite comprising a drug considered nephroprotective, has more dominant characteristics of the action of the two drugs that are harmful to the kidneys. The properties of Vecalde support the ndings in which most patients are in the rst and second chemotherapy cycles.
The use of bisphosphonates stands out as harmful to the kidneys with a decrease in GFR, and this risk can vary between 3 to almost 4 times. Bisphosphonates, zoledronate, and pamidronate are used to restore bone mineral density, minimizing the possibility of fractures and treating malignant hypercalcemia [41]. In the context of cancers, bisphosphonates hinder malignant osteolysis, neoplastic growth, and bone destruction, and, in particular, zoledronate has antitumor and antiangiogenic characteristics [42]. This pharmacological group can be used in patients with MM and bone metastases due to breast, prostate, lung, and other soft tissue cancer [43]. It should be noted that nitrogenous bisphosphonates do not have speci c enzymes that recognize and metabolize them, causing an accumulation of bisphosphonates in the cortex and renal medulla [44]. When the drug cannot be absorbed, it is excreted unchanged by the kidney, damaging it, a fact that can be modi ed according to the dose administered [45]. About 63% of patients with MM developed renal dysfunction due to the use of this drug [46]. The literature largely reinforces the present research above, con rming the harmful action of bisphosphonates in the kidneys. Its use must be accompanied by more rigorous monitoring of renal function at each cycle and/or application with veri cation of serum creatinine, urea, electrolyte values, in addition to the calculation of GFR.
In oncohematological patients, the prevalence of renal disorders is high, affecting women more, increasing the probability of the event by more than two times, and the diagnosis of MM has an independent in uence, increasing the chance of episodes with reduced GFR by 5.75 times. The pharmacological protocol CalgB is inversely associated with GFR reduction events, minimizing the chances of renal dysfunction by 0.23 times. On the other hand, the VDC, zoledronate and pamidronate therapeutic regimens are related to higher chances of episodes of reduced GFR, and speci cally, the VDC protocol increases the chances of occurring this change by more than ten times. Helena Pitombeira and Jacqueline Holanda de Sousa designed the model, conducted the research, revised the text and read and approved the nal version.