Acute kidney injury adversely affects the clinical course of acute myeloid leukemia patients undergoing induction chemotherapy

In this single-center study, we retrospectively included all patients aged ≥ 18 with AML (excluding acute promyelocytic leukemia) who underwent intensive induction chemotherapy between 2007 and 2019. AKI was defined and stratified as recommended by the KDIGO Clinical Practice Guideline (https://​kdigo.​org/​wp-content/​uploads/​2016/​10/​KDIGO-2012-AKI-Guideline-English.​pdf). AML patients with an increase in serum creatinine (SCr) by ≥ 0.3 mg/dl within 48 h or an increase in SCr to ≥ 1.5 times baseline within the prior 7 days during the hospital stay of induction chemotherapy were defined as AML patients with AKI. SCr increase 1.5–1.9 times baseline or ≥ 0.3mg/dl was defined as AKI stage 1, and SCr 2.0–2.9 times baseline was defined as AKI stage 2 and SCr 3.0 times baseline or increase in serum creatinine to ≥ 4.0 mg/dl or initiation of renal replacement therapy was defined as AKI stage 3 (Table S1). All other patients were defined as AML patients without AKI. The baseline SCr was defined as the value measured at day 1 of induction chemotherapy. AML patients with a baseline SCr ≥ 1.5 mg/dl were excluded from this study. Urine output was not considered for definition and stratification of AKI. Standard induction chemotherapy was the so-called 7+3-regime; cytarabine 100 mg/m² given intravenous (IV) continuously for 7 days is combined with daunorubicin 60mg/m² given as a 30-min IV infusion on days 3, 4, and 5 [9]. Patients under the age of 60 received a second induction therapy with 7+3 if early blast clearance was achieved in d15 bone marrow blood evaluation or with HAM protocol (cytarabine 3000 mg/m² was administered by 3-h IV infusion every 12 h on day 1 through 3 and mitoxantrone 10 mg/m² by 30-min IV infusion on days 3, 4, and 5) if blast clearance was not achieved on d15 bone marrow blood evaluation [10]. Patients above the age of 60 received only a second induction chemotherapy with HAM (with reduced cytarabine dose of 1000 mg/m²), if the first induction therapy cycle was not sufficient to achieve bone marrow blast clearance on d15 [11]. In case of a complete remission (CR) after induction chemotherapy with 7+3 alone or with 7+3 and HAM, patients went on to receive a consolidation treatment with either high-dose cytarabine or with an allogenic SCT. Response assessment was performed in accordance with the European Leukemia Net (ELN) recommendations from 2010 [12]. Patients received routinely antimicrobial prophylaxis with levofloxacin and posaconazole daily as suggested by current guidelines [13, 14]. A day with fever was defined as a body temperature increase above ≥ 38.3 °C once or ≥ 38.0 °C on two consecutive days [15]. If fever or a significant increase of C-reactive protein (CRP) (doubling of CRP level and absolute value above 5 mg/dl, norm < 0.5 mg/dl) was found, antibiotic prophylaxis was replaced by intravenous broad-spectrum antibiotics. Blood testing (hematology, liver and kidney function, coagulation, inflammation markers) was performed every other day routinely.

The study was performed in accordance with the 2013 Helsinki declaration. Patients provided informed written consent to retrospective data extraction from patient charts and patient data was provided after approval by the local Ethics Committee (approval number SHN-01-2020). The ethics committee waived the requirement for informed consent for deceased patients. In addition, the majority of patients were also enrolled in the AML registry of the Study Alliance Leukemia (approval number EK 98032010). After ethics approval, patient data was retrieved from the clinical cancer registry of the University Cancer Center (UCT) Frankfurt, complemented by data directly from the medical records and fully anonymized. Data analysis was performed on anonymized data.

Median age was 61 years (range 24–78) in AML patients with AKI and 58 years (range 18–82) in AML patients without AKI (p = 0.014) (Table 1). The fraction of AML patients older than 60 years of age was 51.4% in AML patients with AKI and 41.6% in AML patients without AKI (p = 0.149). The median albumin level on the day of admission was 3.7 g/dl (2–4.9) in AML patients with AKI and 3.8 g/dl (2–5.2) in AML patients without AKI (p = 0.015). There was no significant difference between both cohorts with respect to gender, WHO classification, blood counts, and other blood test results [16]. AML risk groups according to the European Leukemia Net (ELN) recommendations from 2010 were equally distributed between the two cohorts (p = 0.923) [12]. Thirty-one (43.1%) of the AML patients with AKI suffered from AKI KDIGO stage 1, 30 (41.7%) from AKI KDIGO stage 2, and 11 (15.3%) from AKI KDIGO stage 3 (Table 2). Median days to the first AKI episode during induction chemotherapy were 18.5 days (1–120). In median, AML patients with AKI suffered from 1 AKI episode (range 1–3).

There was no significant difference between the two cohorts with respect to the length of the hospital stay for induction chemotherapy (46 days vs. 49 days, p = 0.237) (Table 3). AML patients with AKI had a median of 7 (0–23) days with fever compared to 5 (0–31) days with fever in AML patients without AKI (p = 0.028). Thirty-three (45.8%) AML patients with AKI required treatment on ICU, significantly more than AML patients without AKI (n = 35, 10.6%, p < 0.001). During the hospital stay of induction chemotherapy, AML patients with AKI received 12 (0–53) RBC transfusion and 11 (2–73) platelet concentrates compared to 10 (0–35) RBC transfusion and 8 (0–33) platelet concentrates (p = 0.152 and p = 0.100 respectively). The percentage of patients receiving two cycles of induction chemotherapy was significantly lower in AML patients with AKI, (33.3% vs. 53.8%, p < 0.001). Thirty-four (47.2%) AML patients with AKI received allogenic SCT as consolidation therapy compared to 193 (58.7%) AML patients without AKI (p = 0.088). Only 39 (54.2%) AML patients with AKI achieved a CR after completion of induction chemotherapy, whereas in AML patients without AKI, 254 (77.2%) received a CR after completion of induction chemotherapy (p = 0.005).

Median hemoglobin levels and platelet counts measured throughout the hospital stay of induction chemotherapy did not differ significantly in AML patients with and without AKI (Table 4). AML patients with AKI had lower albumin levels (3.2 g/dl, range 2.1–4.0, vs. 3.4 g/dl, range 2.25–4.25, p < 0.001) and higher CRP levels during the hospital stay of induction chemotherapy than AML patients without AKI (5.94 mg/dl, range 0.61–34.66, vs. 3.69 mg/dl, range 0.19–87.6, p < 0.001). Median SCr levels during the hospital stay of induction chemotherapy were 0.83 mg/dl (0.45–3.03) in AML patients with AKI and 0.71 mg/dl (0.37–1.27) in AML patients without AKI (p < 0.001). SCr levels remained higher in AML patients with AKI at discharge (1.02 mg/dl, range 0.37–2.40, vs. 0.71 mg/dl, range 0.33–1.21, p < 0.001) and on day 90 after initiation of induction chemotherapy (0.98 mg/dl, range 0.37–1.72, vs. 0.72 mg/dl, range 0.2–3.42, p < 0.001).

All p-values reported are two-sided, and statistical significance was defined as p ≤ 0.05

The distribution of anti-infective agents used in AML patients with and without AKI is illustrated in Table 5. Sixty-one (84.7%) AML patients with AKI had exposure to fluoroquinolones compared to 304 (92.4%) AML patients without AKI (p = 0.065). Exposure to other antibiotics (acylaminopenicillin + ß-lactamase inhibitor, carbapenems, and glycopeptides) did not differ between AML patients with and without AKI. Sixty (83.3%) AML patients with AKI received azole antifungals during the hospital stay, significantly less than 303 (92.1%) AML patients without AKI (p = 0.027). Liposomal amphotericin B was more often used in AML patients with AKI than in AML patients without AKI (23.6% vs. 10.9%, p = 0.007). Exposition to angiotensin-converting enzyme (ACE) inhibitors was significantly higher in AML patients with AKI than in AML patients without AKI (n = 24, 36.1%, vs. n = 63, 19.1%, p = 0.003).

All p-values reported are two-sided, and statistical significance was defined as p ≤ 0.05

To further analyze risk factors for AKI in AML patients undergoing induction chemotherapy, a uni- and multivariate logistic regression model was performed. The nominal dichotome variables age above 60 years, male sex, > 5 days with fever, treatment on ICU, treatment with ACE inhibitors, and treatment with liposomal amphotericin B were included in this model. As shown in Table 6, treatment on ICU and treatment with ACE inhibitors or liposomal amphotericin B were independent risk factors for AKI in AML patients undergoing induction chemotherapy.

Risk factors AKI were determined using a uni- and multivariate binary logistic regression model. All p-values reported are two-sided, and statistical significance was defined as p ≤ 0.05

We analyzed the survival of both patient cohorts. Overall and 90-day mortality were significantly higher in AML patients with AKI, 45 (62.5%) vs. 130 (39.5%) and 22 (30.6%) vs. 11 (3.3%) respectively (p = 0.001 and < 0.001 respectively) (Table 3). For AML patients without AKI during the hospital stay of induction chemotherapy, median OS was not reached. For AML patients with AKI during the hospital stay of induction chemotherapy, median OS was 402 days (95% confidence interval 87–718). We further analyzed OS with respect to the different KDIGO stages of AKI. The median OS for AML patients with AKI KDIGO stage 1 was not reached, for AML patients with KDIGO stage 2 366 days (95% confidence interval 0–1065), and for AML patients with KDIGO stage 3 220 days (95% 0–451). The Kaplan-Meier estimates with a stepwise increase of mortality with increasing AKI severity are displayed in Fig. 1.

To further analyze AKI as a prognostic parameter in AML patients undergoing intensive induction chemotherapy, a uni- and multivariate Cox regression model with forward stepwise likelihood ratio was performed. The nominal dichotome variables age above 60 years, male sex, adverse-risk AML, treatment on ICU, CR after induction chemotherapy, allogenic SCT as consolidation therapy, and AKI during induction chemotherapy were included in this model. As shown in Table 7, age above 60 years, adverse-risk AML, treatment on ICU, CR after induction chemotherapy, allogenic SCT as consolidation therapy, and AKI during induction chemotherapy were independently associated with OS. Importantly, AKI remained as an independent risk factor for OS, when censored for AKI grade 3.

CI, confidence interval; HR, hazard ratio. All p-values reported are two-sided, and statistical significance was defined as p ≤ 0.05