Analysis of the therapeutic effect of online haemodiafiltration on delayed methotrexate excretion combined with acute kidney injury in children: a real-world study

Abstract

Background

To evaluate the efficacy and feasibility of online haemodiafiltration (HDF) in the treatment of delayed methotrexate (MTX) excretion and acute kidney injury (AKI) in children with hematological malignancies after chemotherapy.

Methods

Children diagnosed with hypermethotrexatemia combined with acute kidney injury and receiving blood purification treatment during high-dose methotrexate(HD-MTX) chemotherapy for leukemia/lymphoma in a hospital from January 2019 to August 2023 were divided into CRRT group and HDF group. The rate of decrease in MTX blood concentration, drug-related adverse reactions, renal function recovery time and hospitalization related economic costs were compared between the HDF group and CRRT group.

Results

There was no significant differences (P > 0.05) between the HDF group and the CRRT group in terms of drug concentration after 45 h of MTX treatment, time required for MTX concentration to return to normal, time required for renal function to return to normal, length of hospital stay and the primary clinical endpoints between HDF and CRRT groups. In terms of total hospitalization costs and blood purification related expenses, the HDF group was significantly lower than the CRRT group (P < 0.05).

Conclusion

In children with hypermethotrexatemia and AKI who cannot effectively clear MTX through conservative internal medicine treatment. online HDF appears to be a safe and cost-effective alternative to CRRT for MTX clearance in paediatric patients with delayed excretion and AKI, with similar clinical outcomes and lower associated costs.

Clinical trial number

Not applicable.

Methotrexate (MTX) is an organic compound with a structure similar to folate. MTX interferes with intracellular folate metabolism and inhibits cellular DNA and RNA synthesis and is widely used in antitumour therapy. High-dose methotrexate (HD-MTX) can significantly increase blood MTX concentration, which can not only cross the blood-brain barrier, but also reach solid tumours which lack of blood supply and enter the cytoplasm by passive diffusion. MTX is an important component treatment for children with acute lymphoblastic leukemia (ALL), lymphoma and osteosarcoma. However, delayed MTX excretion in some children can cause multiple adverse effects, including acute kidney injury (AKI), liver impairment, myelosuppression and mucositis. Currently, the treatment of delayed MTX excretion is still based on hydration and urinary alkalinisation and increasing the dose and frequency of the rescue drug, calcium folinate (CF). For patients with limited effectiveness of above treatments or combined with AKI, receiving blood purification treatment can rapidly reduce blood MTX concentration [1]. In this study, we analysed the therapeutic effects of different blood purification modes in treating oncology children with delayed MTX excretion after HD-MTX chemotherapy and combined with AKI, and explored the efficacy of online haemodialysis filtration (HDF) in the treatment of delayed MTX excretion, expecting to provide more choices for children with delayed MTX excretion combined with AKI.

Material and methods

Patients

Inclusion criteria: paediatric patients aged 1–18 years(28 patients, aged 4–16 years, were actually included in this study), diagnosed with acute ALL or non-Hodgkin’s lymphoma (NHL) at a hospital hematology-oncology centre from January 2019 to August 2023, who developed hypermethotrexatemia combined with AKI during HD-MTX chemotherapy, and received blood purification treatment in addition to conventional therapy. The diagnosis of hypermethotrexatemia were based on the “Evidence-based Practice Guideline of Medication Therapy of High-dose Methotrexate in China” [2], The diagnosis of AKI was based on the KDIGO AKI staging criteria [3]. The specific criteria were as follows: 1) Patients aged 1–18 years; 2) Diagnosis of ALL or NHL requiring HD-MTX therapy; 3) MTX concentration remains above 10 umol/l for 45 hours after a conventional rescue therapy; 4) combined with AKI; 5) patients who gave informed consent for enrolment.

Exclusion criteria: (1) paediatric patients with sepsis or multiple organ failure/multiple organ dysfunction; (2) paediatric patients with shock; (3) patients with heart failure; (4) patients who refuse to participate in this study.

Research methods

Research methods

Patients were divided into two groups, based on the treatment prescribed by different doctors: the online haemodiafiltration treatment group (HDF group), and the continuous renal replacement therapy group (CRRT group). The treatment protocols were as follows:

1. General treatment: all patients received standard hydration and alkalinisation therapy and CF rescue. The details were as follows: HD-MTX administration: the starting dose was 3g/m²~ 5g/m², 1/10 of dose was given over 0.5h on day 1, and the remaining dose was given over the following 23.5h. Hydration and alkalinisation therapy: start hydration (24h total volume of 3L/m²) and urinary alkalinisation (24h intravenous infusion of 5% sodium bicarbonate solution 150ml/m²) on day 0 to maintain urinary pH at 7-8. CF was initiated 42h after start of the MTX infusion(15mg/m²each time, once every 6h for 3 times). Blood MTX concentration was measured at 45h of MTX application. Drugs that affect MTX metabolism were discontinued during MTX administration.

2. Blood purification treatment:

HDF group: double-pump haemodialysis machine (Gambro AK200 UltraS), dialysis filter is hollow fibre haemodialysis filter (RESENIUS, AV400S, AV600s), < 30 kg to AV400s, > 30 kg to AV600s. Blood flow rate 4 ~ 6 ml/kg-min, each treatment duration 4 h, dialysate flow rate: 500 ml/min. Post-replacement solution volume is 1/3 of the blood flow rate; for pre-replacement solution, the volume is twice as much as for post-replacement.

CRRT group: bedside haemofiltration machine (Gambro Prismaflex), CVVHDF mode, the filter is disposable haemodialysis filter (Gambro M60, M100), blood flow rate: 2 ~ 5 ml/kg-min, dialysate rate: 30-40 ml/kg-h, the rate of replacement solution is the same as the rate of the dialysate; the rate of dehydration 0-2 ml/kg-h.

Timing of end of the blood purification treatment: blood MTX concentration were below 0.1 umol/l.

Observation indicators

Data was collected for the children’s age, sex, weight, body surface area(BSA), blood MTX concentrations at 45, 69, 93, 117, 141, 165, 199 and 213 h after administration, white blood cells (WBC), haemoglobin (Hb), platelets (PLT), serum blood urea nitrogen (BUN), serum creatinine (Scr), alanine aminotransferase (ALT), aspartate aminotransferase (AST),γ-glutamyltransferase (γ- GGT), the time for MTX concentrations and Scr to return to normal, and clinical outcomes. Total hospitalisation and blood purification treatment costs were recorded, as well as adverse events. Adverse events will be evaluated according to the National Cancer Institute’s Common Terminology Criteria Adverse Events version 5.0.

(CTCAEv5.0,https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50)

Statistical analysis

Quantitative data that follows or approximates a normal distribution was described using the mean ± SD(±𝑠)for central tendency description, and comparisons between two groups were statistically analysed by independent samples t-test, and comparisons between categorical variable were analysed by χ² test. Count data was presented as n (%), analysed using the Fisher’s exact test. Statistical analysis was performed using SPSS 23.0. A P-value < 0.05 was considered statistically significant.

Results

General information

28 children were included, with 22 males and 6 females. The average age was 9.28 years (4.7 ~ 18.0 years) and the average weight was 34.94 kg (16.0 ~ 101.7 kg). There were 20 cases of ALL and 8 cases of NHL. 16 cases in the HDF group and 12 cases in the CRRT group.

Baseline comparison

There were no significant differences between the two groups in terms of age, sex, body weight, BSA, 45 h blood MTX concentration, Scr just prior to initiation of RRT, fold increase in Scr, urine output in the preceding 6 h, adverse events, including liver impairment, myelosuppression, and mucositis. The results are presented in Tables 1 and 2.

Table 1.

General clinical profile of children with delayed MTX excretion combined with AKI

	CRRT(n = 12)	HDF(n = 16)	t /χ2	P
Age(years)±s	10.5 ± 3.9	9.2 ± 3.2	0.946	0.353
Sex male(n,% )	10(83.3)	13(81.3)		1
Weight(kg)±s	37.8 ± 22.3	36.6 ± 18	0.156	0.878
BSA(m2)	1.14 ± 0.27	1.13 ± 0.33	0.036	0.97
45 h blood MTX concentration(umol/L)	23.42 ± 6.9	18.14 ± 7.1	1.98	0.58
Urine volume in the preceding 6 h(ml)	517.5 ± 98.6	746.8 ± 78.9	1.84	0.078
Fold increase in Scr	5 ± 1.97	3.68 ± 1.98	1.75	0.09
Scr just prior to initiation of RRT	99.6 ± 30.2	106.9 ± 56.8	0.405	0.66

Table 2.

Adverse events of liver impairment, myelosuppression and mucositis in children with delayed MTX excretion combined with AKI

adverse reaction	CRRT group(n = 12)				HDF group(n = 16)				P
	Level 1	Level 2	Level 3	Level 4	Level 1	Level 2	Level 3	Level 4
Elevated ALT	0	9	3	0	0	11	5	0	0.291
Elevated AST	0	9	3	0	0	11	5	0	0.291
Elevated γGGT	0	9	3	0	0	11	5	0	0.291
Decreased WBC	2	10	0	0	8	8	0	0	0.174
Decreased Neutrophils	10	2	0	0	15	1	0	0	0.399
Decreased Hb	1	11	0	0	0	16	0	0	0.262
Decreased PLT	9	1	2	0	10	6	0	0	0.203
Muscositis	4	8	0	0	3	13	0	0	0.746

Note: Adverse reactions were graded and diagnosed using the U.S. Department of Health and Human Services Common Adverse Event Evaluation Criteria v5.0, Fisher’s test.

Treatment efficacy comparison

Comparison of treatment effects

Comparing the HDF group and the CRRT group after the treatment, the average time needed for blood MTX concentration to return to normal was 12.9 days for the CRRT group and 12.4 days for the HDF group, with no significant difference. The average time of serum creatinine to return to normal was 13.08 days for the CRRT group and 11.75 days for the HDF group, and with no significant difference between the groups. The average hospitalisation duration in the CRRT group was 14.42 days, and in the HDF group was 12.75 days, with no significant difference between the groups. The results are presented in Table 3.

Table 3.

Treatment outcome in children with delayed MTX excretion with AKI

	CRRT (n = 12)	HDF (n = 16)	t	P
Time taken for blood MTX concentration to decrease to normal (days)	12.9 ± 1.78	12.44 ± 3.18	0.47	0.64
Time taken for kidney function to return to normal (days)	13.08 ± 3.12	11.75 ± 3.38	1.07	0.30
Hospitalisation for this treatment (days)	14.42 ± 2.02	12.75 ± 3.07	1.63	0.12

The blood MTX concentration in both groups showed a rapid decrease at 69 h, and a slow decrease after 93 h. At 117 h, 141 h, 165 h and 189 h after the treatment, the average blood MTX concentration in the HDF group was lower than that in the CRRT group, with significant differences, and at 213 h, there were no significant differences between the groups (showed in Table 4; Fig. 1 for details).

Table 4.

Comparison of blood MTX concentration (umpl/L) at different time points in children with delayed MTX excretion with AKI

	69 h	93 h	117 h	141 h	165 h	189 h	213 h
CRRT(n = 12)	5.18 ± 2.55	2.65 ± 1.69	2.11 ± 0.77	2.51 ± 0.02	1.81 ± 1.27	1.34 ± 0.93	0.71 ± 0.31
HDF(n = 16)	4.99 ± 2.97	2.30 ± 1.24	1.44 ± 0.83	1.26 ± 0.68	0.93 ± 0.45	0.71 ± 0.42	0.57 ± 0.38
t	0.18	0.78	2.17	2.51	2.29	2.15	0.94
P	0.86	0.44	0.039	0.019	0.039	0.049	0.36

Fig. 1.

Decrease in blood MTX concentration at different time points in children with delayed MTX excretion with AKI

Economic cost comparison

Comparing the economic cost of hospitalisation between the HDF group and the CRRT group, the total costs of hospitalisation for the children were 31,900 ± 980,0 yuan in the HDF group and 43,600 ± 1,330,0 yuan in the CRRT group. The costs of blood purification treatment were 3500 ± 2300 yuan in the HDF group and 7500 ± 3400 yuan in the CRRT group. The total hospitalisation cost and blood purification treatment cost of children in HDF group were both lower than those in CRRT group, t = 2.69, P = 0.012 (P < 0.05); t = 3.7, P = 0.001 (P < 0.05), showing significant differences. The results are presented in Table 5 and Fig. 2.

Table 5.

Comparison of the cost of hospitalisation for children in the HDF and CRRT groups

	CRRT	HDF	t	P
Total hospitalisation costs (10,000 yuan)	4.36 ± 1.33	3.19 ± 0.98	2.69	0.012
Blood purification treatment costs (10,000 yuan)	0.75 ± 0.34	0.35 ± 0.23	3.70	0.001

Fig. 2.

Comparison of costs in patients with delayed MTX excretion with AKI

Comparison of complications

The common adverse reaction during blood purification treatment is ion disorder which were mild, and were corrected just in 6 h after the treatment. Hypokalemia occurred in 5 cases (2 cases in CRRT group and 3 cases in HDF group), hypocalcemia occurred in 4 cases (1 case in CRRT group and 3 cases in HDF group); There were 3 cases of hypophosphatemia (1 cases in CRRT group and 2 cases in HDF group) and 3 cases of hypomagnesemia (1 cases in CRRT group and 2 cases in HDF group). The results are presented in Table 6.

Table 6.

Comparison of the serum levels of potassium, calcium, phosphorus, and magnesium in the HDF and CRRT groups (Fisher’s test)

	CRRT(n = 12)	HDF(n = 16)	P
hypokalemia(n,%)	2(16.7)	3(18.7)	0.99
hypocalcemia(n,%)	1(8.3)	3(18.7)	0.613
hypophosphatemia(n,%)	1(8.3)	2(12.5)	0.99
hypomagnesemia(n,%)	1(8.3)	2(12.5)	0.99

There are no serious systemic adverse events such as arrhythmias, hypotension, hypertension, gastrointestinal bleeding, catheter-related infections occurred during the blood purification treatment in either groups.

Discussion

The molecular weight of MTX is 454.4 Da, the binding rate with plasma protein is 50%, insoluble in water, the volume of distribution is 0.4 ~ 0.9 L/kg, mainly metabolized and excreted through the kidney and its toxicity is related to the extracellular concentration [4], when the blood MTX concentration is 5 ~ 10µmol/L in 24 h,>1µmol/L in 48 h, and > 0.1µmol/L in 72 h, adverse reactions can occur [5].It mainly causes liver and kidney injury, myelosuppression and mucositis. Once the child has AKI, the MTX excretion will be significantly reduced, which may cause blood MTX at high levels continuously, leading to severe adverse reactions, including myelosuppression, liver impairment, mucositis, gastrointestinal discomfort, and even life-threatening [6, 7]. So it is particularly important to rapidly decrease the blood MTX concentration.

Blood purification treatment can rapidly decrease blood MTX concentration and minimize the risk of adverse effects. There are guidelines or protocols all recommend blood purification for the treatment of delayed MTX excretion [1, 2, 8].According to the molecular features of MTX, traditional low flux normal haemodialysis can only partially remove free extracellular MTX, and it has been reported that its clearance of MTX is only (38 ~ 40) ml/min [9].Due to the low clearance of MTX by low flux haemodialysis and the unsatisfied efficacy of blood purification treatment [10], current guidelines and expert consensus recommend high flux haemodialysis (HF-HD) [1, 2]. HF-HD refers to the application of dialyzers with larger membrane pore size and higher ultrafiltration coefficient for haemodialysis [11].It is a more efficient dialysis method [12]. HF-HD has a stronger effect on urotoxic clearance and also removes MTX more adequately, reducing MTX by up to 76% at 4 h [5]. So HF-HD is more widely used in adult patients. However, because suitable HF-HD dialyser for children are not yet available in some areas, so they are not widely used in all of the countries till now.

HDF is a combination of haemodialysis and haemofiltration, applying high-flow and convective technologies [13]. HDF uses convection and diffusion in the treatment of MTX intoxication, it is combination of the two methods of molecules’ removal, compared with haemodialysis, it may has a more effective clearance in molecules. The substitution fluid of online HDF is generated online directly on the dialysis machine, which can increase the clearance of molecules by 87 mL/min with a treatment time of 4 h and 21 L of substitution fluid [14]. Fewer studies have been reported on the usage of online HDF for MTX clearance, most are case reports. Yun-yun Yang et al. reported a 20-year-old Hodgkin’s lymphoma patient who was diagnosed with hypermethotrexate accompanied by acute kidney injury after receiving high-dose MTX treatment. After routine hydration alkalization and folic acid rescue treatment, he received 10 sessions of HDF treatment, and MTX was quickly cleared and kidney function was restored[15]. Abdelsalam et al. reported that in lymphoma adult patients with hypermethotrexatemia combined with AKI, blood MTX concentration rapidly decreased by 80% after 3 times treatment with online HDF [16]. Razan et al. reported that 3 adult patients with delayed MTX excretion with AKI had a rapid decrease of 80% after online HDF and HF-HD treatment, the results showed that online HDF could clear 65% MTX in 4.4 h, achieving the same clearance effect as HF-HD [17]. As early as 2004, scholars compared the effectiveness of different blood purification modes in clearing MTX, including HDF, HF-HD, peritoneal dialysis, and plasma exchange. They found that the use of HDF(4 cases) resulted in the largest decrease in MTX concentration (median, 82%; range, 44–98%), with an increase of 25–43% in postoperative MTX rebound, while the use of HF-HD(9 cases) led to a decrease in plasma MTX concentration (median, 75.7%; range, 42–94%), with an increase of ≥ 50% in postoperative MTX rebound levels [18]. But online HDF, like HF-HD, requires repeated treatment due to the MTX blood concentration rebound caused by the redistribution of MTX. In this study, 16 children with delayed MTX excretion with AKI were treated with HDF for 1 ~ 7 times (median number of 3 times), blood MTX concentration decreased from 18.14µmol/L to 4.99µmol/L and 1.44µmol/L in 69 h and 93 h, which decreased by up to 72.2% and 87.3% respectively, achieving rapid clearance. And in 117–189 h, HDF has shown a superior concentration lowering effect than CRRT.

CVVHDF is a mode of CRRT, which clears toxic molecules slowly and continuously and maintains haemodynamic stability through diffusion and convection. Because of its continuous and slow clearance, continuous treatment can reduce MTX rebound, and it is one of the most widely used modes of blood purification treatment to rescue MTX poisoning in children [19, 20]. In this study, 12 children with delayed MTX excretion with AKI were treated with CVVHDF for 18 h ~ 118 h, and blood MTX concentration decreased by up to 77.7% at 45 h and 88.6% at 93 h, which showed a better clearance rate of MTX. However, CRRT needs to be performed at the patient’s bedside, which requires specialized care and a high nurse-to-patient ratio (nurse-to-patient ratio of 1:1–1:2 for children’s CRRT, and 1:4 − 1:5 for children’s normal dialysis and HDF), and the price of filters and tubing is relatively high, 3–6 times higher than that of normal dialysis and HDF, so it adds a certain amount of economic cost at the patient’s level and human resources at the hospital’s level.

In this study, the HDF group and CRRT group showed same effect on the time for MTX to return to normal and for renal function to recover. There were no statistically significant differences in the primary clinical endpoints between HDF and CRRT groups. However, the HDF group showed lower concentration at 117 h, 141 h, 165 h and 189 h after the treatment, and the overall cost was significantly lower than that in the CRRT group. Additionally, during the blood purification treatments, there are no adverse reactions such as hypotension or arrhythmia caused by the treatment were observed in any of the groups.

There are several limitations in the study. First, the sample size in this study is small, with only 28 patients, and the study is non-randomized design that patients were assigned by physician preference, introducing potential bias. Second, its retrospective nature inherently limits ability to prove causality. Third, only short-term outcomes were assessed, with no data on long-term kidney function, relapse, or survival. Finally, there was no standardization of dialysis parameters or dose intensity beyond basic protocol. More detailed and comprehensive evaluation of the efficacy and safety of online HDF requires further confirmed by more high-quality, large-scale prospective randomized controlled trails.

In conclusion, in children with hypermethotrexatemia combined with AKI after chemotherapy, when medical treatments such as hydration, alkalization, and CF infusion are ineffective, combination with blood purification treatment should be considered. For children without severe complications and with stable haemodynamic, online HDF appears to be a safe and cost-effective alternative to CRRT with similar clinical outcomes, so it can be one of the optimal choices for treating paediatric patients.

Abbreviations

HDF

Haemofiltration

CRRT

Continuous renal replacement therapy

HF-HD

High flux haemodialysis

MTX

Methotrexate

HD-MTX

High-dose methotrexate

AKI

Acute kidney injury

ALL

Acute lymphoblastic leukemia

NHL

Non-Hodgkin's lymphoma

CF

Calcium folinate

Authors' contributions

Huixin Xue, Na Tian and Mingxu Wang collected data. Xiaolu Nie, Nan Li and Xue Liu performed the data analysis and inter- pretation. Bo Zhang wrote the manuscript. Ying Wu, Zheng Li and Qiang Sun revised the manuscript critically and contributed to interpretation of the scores and reported outcomes. All authors read and approved the final manuscript. Authors contributed to making critical revisions related to important intellectual content of the manuscript; all authors approved the version of the article to be published.

Funding

This study was supported by Beijing Municipal Hospital Research and Cultivation Program (PX2024044).

Data availability

The datasets generated and/or analyzed during this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in line with the principles of the Declaration or Helsinki. The Ethics Committee of Beijing Children’s Hospital approved this study [2025]-E-010-R. We have obtained informed consent to participate from the parents or legal guardians of any participant under the age of 16.

Competing interests

The authors declare no competing interests.