Age and baseline creatinine as risk factors for methotrexate nephrotoxicity in children with acute lymphoblastic leukemia in resource-limited countries

doi:10.21203/rs.3.rs-1770424/v1

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Age and baseline creatinine as risk factors for methotrexate nephrotoxicity in children with acute lymphoblastic leukemia in resource-limited countries

https://doi.org/10.21203/rs.3.rs-1770424/v1

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Introduction. The search for risk factors for high-dose methotrexate (MTX)–induced nephrotoxicity in children with acute lymphoblastic leukemia (ALL) has been complex in the context of resource-limited countries where serum levels of MTX are not always available.

Objective. To analyze the demographic, clinical, and biochemical factors associated with MTX-induced nephrotoxicity in children with ALL.

Methodology. Case-control study in children with ALL from a General Hospital in Mexico over a four-year period (2016–2020). Kidney damage was defined with KDIGO criteria and the following variables were analyzed: sex, age, weight, height, creatinine, urea, transaminases, hematic cytometry, vomiting, mucositis, dermatitis, and number of MTX applications.

Results: Fifty eight children were studied, 22 females (38%) and 36 males (62%), ages 1 to14 years. The incidence of nephrotoxicity was 5.8% in 238 events of MTX administration. The children in the group with nephrotoxicity were older (average age 9.5 vs 5, p = 0.036), had higher baseline creatinine (0.5 mg/dL vs 0.4 mg/dL p = 0.006), and had lower baseline hemoglobin (10.1 g/dL vs 11.3 g/dL, p = 0.034). Mucositis, dermatitis, and febrile neutropenia were more frequent in the group with kidney damage (p < 0.001). A cut-off value for age of 8 years (AUC of 64%) had a higher frequency of nephrotoxicity. Baseline creatinine value higher than 0.44 mg/dL was a risk factor for developing kidney damage (OR 4.1).

Conclusions: The incidence of MTX nephrotoxicity in children with ALL was 5.8%,

slightly higher than that reported by other authors. The risk was greater for children older than 8 years and baseline creatinine higher than 0.44 mg/dL.

methotrexate

nephrotoxicity

children

lymphoblastic leukemia.

Cancer is one of the main causes of death among children and adolescents worldwide, and the most common type is ALL (1). Hence, during its treatment, it is important to reduce associated adverse effects inherent to the drug itself and its administration. Among the most important is the deterioration of renal function, which has an important influence on the morbidity and mortality of the cancer patient (2, 3, 4).

There are several factors that enhance the risk of nephrotoxicity: drug-related factors including its renal clearance, host-specific factors considering characteristics as age and pre-existing kidney damage, and therapeutic-intervention-related factors as those caused by radiotherapy and surgery. Among the drugs reported with greater renal toxicity is MTX (1.8–12%) with data showing an increase of up to 20% when administered at high doses to children with ALL without previously diagnosed renal disease (3–6).

Methotrexate is the most widely used antimetabolite in childhood cancer due to its effectiveness in the treatment of ALL and other types of cancers (7). MTX is a structural analog of folic acid which acts as its antagonist interfering with the replication of the leukemic cell. It is administered on an intermittent schedule and by diverse routes, including intrathecal and intravenous. Described as a high-dose infusion when the administration exceeds 500 mg/m2, which is the indicated to avoid cellular resistance and promote its arrival at sanctuary sites such as the testicles and the central nervous system (4), MTX can usually be administered safely. However, it has occasionally been associated with kidney toxicity (2, 3–6), defined as a manifestation of reduced glomerular filtration rate fluid, electrolyte imbalance, or acute kidney injury (3, 6, 8).

There are various markers of kidney damage in children, but in the clinical setting serum creatinine levels and uresis are still the most used (9). Acute kidney injury staging is currently determined according to the Kidney Disease: Improving Global Outcomes (KDIGO) 2013 criteria, which distinguishes 3 categories – Grade I, II, and III- depending on the levels of serum creatinine and urinary volume (11). These markers of kidney injury are easily accessible and highly affordable. Nevertheless, it is also important to underline that there are some more accurate ones such as cystatin C levels. Unfortunately, they are not widely accessible due to their high cost and the limited number of units equipped to process them (12).

Several studies have searched for an ideal biochemical marker that denotes early kidney damage and its correlation with methotrexate plasma levels (4, 9, 13, 14). Likewise, changes have been proposed in the nephroprotection strategy, urinary surveillance, and the monitoring of serum methotrexate levels adjusting the time and number of doses in order to find the ideal moment of determination and correlation with early kidney damage (15, 16). This is beneficial for medical facilities in limited-resource countries such as those in our region, in which we may lack the necessary biochemical means to monitor both serum drug levels and kidney function. Therefore, in order to minimize the risk of nephrotoxicity, and due to the limited resources available, there is a need to determine if there is a correlation between the risk factors associated with methotrexate nephrotoxicity and the commonly used biochemical parameters to assess renal function. This will have a positive impact in the treatment as it will make possible to carry out timely interventions to increase the long-term survival and to improve the quality of life of the pediatric cancer patient while the material and financial resources available are optimized (16, 17).

Patient population

A retrospective case-control study was carried out with the records of patients under 18 years of age with acute lymphoblastic leukemia who received high-dose MTX (0.5–8 g/m2 of body surface area) in the Pediatric Oncology Department of the Hospital General León from 2016 to 2020. Cases were defined as those who presented acute kidney injury according to the KDIGO 2013 criteria (10). Records of patients with kidney damage prior to MTX administration or who did not have complete records of creatinine levels and/or uresis were excluded. Clinical and biochemical variables were measured at baseline and 7 days after MTX administration. When any clinical manifestation of MTX toxicity occurred, the measurement was made 48–72 hours after administration.

Diagnosis of acute kidney injury

Acute kidney injury was classified into 3 categories according to the increase in creatinine levels and/or the decrease in uresis:

Grade I:
- Baseline creatinine x 1.5–1.9 o increase > 0.3 mg / dL in 48 hours or
- Urinary output < 0.5 ml / kg / hour x 6–12 hours
Grade II:
- Basal creatinine x 2-2.9 or
- Urinary output < 0.5 ml / kg / hour x 12 hours
Grade III:
- Baseline creatinine > x 3 o Serum creatinine > 4 mg / dL or
- Renal replacement therapy or in children under 18 years of age, glomerular filtration < 35 ml / minute / 1.73m2
- Urinary output < 0.3 ml / kg / hour for 24 hours or anuria for 12 hours

According to the Common Terminology Criteria for Adverse Events (CTCAE) classification, grade I acute kidney injury corresponds to CTCAE-3 (hospitalization indicated) and grade II and III to CTCAE-4 (life-threatening consequences; dialysis indicated) (17).

Statistical analysis

Descriptive statistics with mean and standard deviation were applied for the numerical variables that had a normal distribution according to the kurtosis test; with median and interquartile range for the numerical variables that did not have a normal distribution, and with percentages for the nominal variables.

To compare the groups, a univariate analysis was carried out with Student's T for the numerical variables with normal distribution, with the Mann-Whitney U for the numerical variables that did not have normal distribution, with Chi-squared for the polytomous nominal variables, and with the exact test of Fisher for dichotomous nominal variables that had expected values less than 5.

A multivariate analysis with backward step-by-step logistic regression was performed to obtain odds ratio (OR) values with 95% confidence intervals. A value of p < 0.05 was considered significant. Finally, an analysis of ROC curves with an empirical model was performed to determine cut-off points for risk of nephrotoxicity of the variables that showed significance in the multivariate analysis. The NCSS statistical package was used.

Ethical considerations.

The protocol was approved by the research ethics committee of the Hospital General León and was granted registration number PR0026.

The records of 62 patients who received high-dose MTX were reviewed. All patients received the same hydration, that is, 2 times the baseline requirement and fixed doses of folinic acid as rescue based on the Total Therapy XV protocol. Four patients were excluded from the study as they continued their treatment and follow-up in another unit. Therefore, the records of 58 patients with 238 high-dose MTX application events were analyzed. There were 14 events of kidney damage, which corresponds to an incidence of 5.8%, of which 57% were grade I, 28% grade II, 14% grade III. According to the CTCAE classification there were 8 cases grade 3, and 6 cases grade 4. One of them required dialysis therapy. Acute kidney injury occurred in 8% of the first application events (5 vs 57) and in 5% of subsequent doses. (9 vs 167) (p = 0.3).

Table 1 shows the demographic, clinical, and basal biochemical characteristics of the groups with and without acute kidney injury. As it is shown, the patients with kidney damage were older, had a higher baseline creatinine level, and a lower hemoglobin level. It must also be noted that in the evaluation after the administration of MTX, there were no differences in the hematic cytometry parameters associated with acute kidney injury (Table 2).

Table 1

– Demographic, clinical and basal biochemical characteristics
VARIABLE	ACUTE KIDNEY INJURY		p
VARIABLE	NO n = 224	YES n = 14	p
Age (years)	5 (3–10) ^a	9.5 (4.5–14) ^a	0.036 ^b
Male (%)	61%	64%	0.5 ^c
Weight (kg)	21 (15–31) ^a	32 (18–43) ^a	0.07 ^b
Height (cm)	117 (97–137) ^a	137 (111–155) ^a	0.06 ^b
Body mass index • Low weight • Normal • Overweight • Obesity	42 138 30 14	3 9 2 0	0.81^d
Diagnosis • ALL pre B cells • ALL T cells	201 14	12 2	0.24 ^c
Creatinine (mg/dL)	0.4 ± 0.1 ^e	0.5 ± 0.1 ^e	0.006 ^f
Urea (mg/dL)	18 (13–24) ^a	22 (17.5–24) ^a	0.13 ^b
Leukocytes (x10⁹/L)	4 (2.8–5.4) ^a	4 (2.5–6.5) ^a	0.34 ^b
Lymphocytes (x10⁹/L)	1.5 (1.1-2) ^a	1.5 (0.9-2) ^a	0.4 ^b
Neutrophils (x10⁹/L)	1.1 (0.6–1.9) ^a	1.2 (0.4–2.3) ^a	0.4 ^b
Hemoglobin (g/dL)	11.3 (10.2–12.3) ^a	10.1 (8.9–11.8) ^a	0.034 ^b
Platelets (x10⁹/L)	247 (159–382) ^a	320 (202–461) ^a	0.12 ^b
^aMedian and interquartile range, ^bMann-Whitney U test, ^cFisher's exact test, ^dChi square, ^emean and standard deviation, ^fStudent's t test Variables with p < 0.05 are shown in bold font

Table 2

– Biochemical characteristics post MTX administration
VARIABLE	ACUTE KIDNEY INJURY		p
VARIABLE	NO n = 224	YES n = 14	p
Creatinine (mg/dL)	0.4 (0.3–0.5) ^a	0.8 (0.6–0.9) ^a	< 0.001 ^b
Urea (mg/dL)	19 (14–25) ^a	24 (20–35) ^a	0.004 ^b
Leukocytes (x10⁹/L)	3.4 (2.4–4.8) ^a	3 (1.1–4.1) ^a	0.09 ^b
Lymphocytes (x10⁹/L)	1.3 (0.8–1.8) ^a	1 (0.3-2) ^a	0.11 ^b
Platelets (x10⁹/L)	210 (135–290) ^a	215 (153–274) ^a	0.4 ^b
^aMedian and interquartile range, ^bMann-Whitney U test Variables with p < 0.05 are shown in bold font

Of the side effects of MTX, fever and neutropenia (50% vs 16%, p = 0.009), mucositis (50% vs 7%, p < 0.001), and dermatitis (35% vs 2%, p < 0.001) showed greater frequency in cases with kidney damage.

The baseline variables that had a significant difference in the univariate analysis were analyzed with logistic regression, and baseline creatinine was the only one that remained in the model (Table 3). Figure 1 shows the ROC curve with an empirical model of the behavior of baseline creatinine levels with an area under the curve (AUC) of 68% and a cut-off point of 0.44 mg/dL while Fig. 2 shows the age with an AUC of 64% and a cut-off point of 8 years. With these cut-off points the risk of developing acute kidney injury was calculated, and it was found that creatinine greater than 0.44 mg/dL had an OR of 4.1 (95% CI 1.3–12.8) (Table 4).

TABLE 3

Multivariate analysis of factors associated with MTX nephrotoxicity

STEP 1

VARIABLE	REGRESSION COEFFICIENT	WALD Z-VALUE	p	ODDS RATIO	CONFIDENCE INTERVAL 95%
Age	0.07	0.8	0.4	1.1	0.9 – 1.2
Basal creatinine	3.9	1.6	0.11	48.3	0.4 – 5694
Basal hemoglobin	-0.3	-1.9	0.06	0.7	0.6 – 1

STEP 2

VARIABLE	REGRESSION COEFFICIENT	WALD Z-VALUE	p	ODDS RATIO	CONFIDENCE INTERVAL 95%
Basal creatinine	5	2.5	0.01	149.2	2.8 – 7934
Basal hemoglobin	-0.3	-1.9	0.05	0.7	0.6 – 1

STEP 3

VARIABLE	REGRESSION COEFFICIENT	WALD Z-VALUE	p	ODDS RATIO	CONFIDENCE INTERVAL 95%
Basal creatinine	4.8	2.4	0.02	128	2.5 – 6495

Backward stepwise regression

Variables with p <0.05 are shown in bold font

TABLE 4

Risk of nephrotoxicity by age and baseline hemoglobin level

STEP 1

VARIABLE	REGRESSION COEFFICIENT	WALD Z-VALUE	p	ODDS RATIO	CONFIDENCE INTERVAL 95%
Age > 8 years	0.4	0.7	0.5	1.5	0.5 – 5
Basal creatinine > 0.44 mg/dL	1.3	2	0.04	3.5	1.04 – 11.8

STEP 2

VARIABLE	REGRESSION COEFFICIENT	WALD Z-VALUE	p	ODDS RATIO	CONFIDENCE INTERVAL 95%
Basal creatinine > 0.44 mg/dL	1.4	2.5	0.01	4.1	1.3 – 12.8

Backward stepwise regression

Variables with p <0.05 are shown in bold font

In this study we found a methotrexate nephrotoxicity of 5.8%, which is

slightly higher than that reported by other authors (1.8–18%). One of the most important articles about it is that from Schmidt et al., who conducted a study with 218 ALL pediatric patients reporting a 3.2% of moderate to severe delayed elimination incidence when they were exposed to high-dose MTX with 5g/m2. This frequency was 4.2 times higher when 8g/m2 doses were used (4).

It is important to note that the relationship between nephrotoxicity and other side effects of MTX treatment was striking, showing that the damage caused by the drug provokes a retarded elimination leading to high concentrations of MTX itself. This occurs despite the rescue measures, such as an optimal hydration and folinic acid use. Thus, as a consequence of the high levels concentration of MTX, some other adverse effects like myelosuppression, mucositis, liver toxicity, and dermatitis increase (3, 18).

Even though few hospitals in Mexico have access to serum methotrexate determination levels, our hospital does not. Due to this, we use fixed doses of folinic acid as rescue based on the Total Therapy XV protocol, which are only modified when some clinical data suggest a drug elimination delay (mucositis, oliguria, rising creatinine, history of severe toxicity, etc.)

One of the most important findings of this study was to identify that the nephrotoxicity risk was higher in children older than 8 years of age. This is relevant because although several studies have shown that there is a greater number of nephrotoxicity cases at older ages in both children and adults, a cut-off point to determine the exact risk age has not been established. (4, 8, 19–21). Some researchers have suggested using the same cut-off age used in determining the relapse risk in ALL that is 10 years. Thommy Svahn et al. found that the MTX elimination time was shorter in those with a body surface area of less than 1 m2 (p < 0.004), and thus, a greater risk of retarded elimination and acute renal injury with inherent complications such as mucositis (18%) and dermatosis (6%) (18).

Close monitoring of kidney function and its correlation with MTX levels has been subject of research in several publications. Creatinine measurement has been described as a marker of acute kidney injury; however, the cut-off point for the absolute value and the time of measurement after the administration of the methotrexate infusion is still discussed. We found that the nephrotoxicity risk was higher from an absolute value of 0.44 mg/dl, which is similar to that reported by Schmidt et al. of 0.3 mg/dl or 1.5 times the baseline value (4). It is well known that young children have less muscle mass and thus less ability to raise creatinine. Thus, finding slightly elevated levels of creatinine in determinations is of great risk, as is finding a creatinine clearance less than 100 ml/min prior to methotrexate infusion; having lower creatinine clearance levels correlates with high risk of delayed elimination of the drug and with concomitant kidney injury. This was shown in this study as higher baseline creatinine levels were found in those with renal injury. It was proved that a fall in the glomerular filtration rate of 10–30 ml/min or a reduction to 50–60 ml/min was also sufficient to determine nephrotoxicity. (4, 5, 8, 20). The main weakness of this study is that it was retrospective and it was conducted in a single center. Nevertheless, it has the strength of having analyzed a considerable number of events with an adequate data record and a 100% patient follow-up.

This topic requires further prospective studies for monitoring the variation in nitrogen levels depending on the hours elapsed after methotrexate infusion to identify early data more accurately about nephrotoxicity.

Several efforts have been made to prevent the appearance of the nephrotoxic effects of MTX. Some of them focused on the acceleration of the renal excretion of the drug through modifications in the sodium concentration in hydration solutions and reducing dosing intervals in the administration of bicarbonate to favor the clearance and renal tubular excretion of MTX (15). Our results support that for centers in which the measurement of serum MTX levels is not possible, it is important to make a more frequent measurement of creatinine levels after the administration of MTX in order to identify kidney damage early and give longer schedules of hyperhydration to patients older than 8 years and / or baseline creatinine greater than 0.44 mg / dL.

Recent studies have discovered various mechanisms of renal protection in animal models. Through the administration of a compound that acts at the level of the cells of the renal tubular epithelium, it is possible to reduce the destruction of the organic anion transporters (OAT's) whose function is the elimination of MTX, in particular OAT3. This could guide future studies in the search for substances that promote the excretion of the drug without the risk of reducing the efficacy of the treatment (22).

The incidence of methotrexate nephrotoxicity in children with ALL was 5.8%. The findings of the current study are sufficient to justify close monitoring of children older than 8 years of age and those with baseline creatinine greater than 0.44 mg/dl due to their higher risk of developing methotrexate nephrotoxicity (OR 4.1).

mM micromole

7-OH-methotrexate 7-hydroxy-methotrexate

ALL acute lymphoblastic leukemia

AUC area under the curve

CI confidence interval

DAMPA 4-deoxy-4-aminoN¹⁰-methylpteroic acid

g/dl grams/deciliter

KDIGO Kidney Disease: Improving Global Outcomes

m² Square meter

mg/dl milligrams/deciliter

mg/m² milligrams/square meter

ml/kg/hour milliliters/kilograms/hour

ml/min millimeters/minute

ml/minute/1.72m² milliliters/minute/1.73 square meter

MTX methotrexate

NCSS Number Cruncher Statistical Software

OAT’s organic anion trnasporters

OAT3 organic anion transporter-3

OR odds ratio

ROC Receiver Operating Characteristic

Ethics approval.

This work was approved by the Research Committee and the Research Ethics Committee of the Hospital General León and obtained the registration number PR0026 from the Ministry of Health of the State of Guanajuato, Mexico

Consent to participate.

Not applicable.

Consent for publication.

All authors gave their consent for publication. No further consent is required.

Availability of data and material

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors have no conflict of interests to declare.

Funding

No funding was obtained for this study.

Authors’ contributions

IMAC, JALE and MCRJ contributed to the conception, design and edition of the manuscript. All the authors contributed to the literature search, revised the article and approved its final version.

Acknowledgment

The authors would like to thank the staff and fellows of the Pediatric Oncology Department and the staff of the Health Information Department of Hospital General León for the support provided in the gathering of information for this research.

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No competing interests reported.

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Age and baseline creatinine as risk factors for methotrexate nephrotoxicity in children with acute lymphoblastic leukemia in resource-limited countries

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Abstract

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Introduction

Patients And Methods

Patient population

Diagnosis of acute kidney injury

Statistical analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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