OBJECTIVE

Limited studies describe acute kidney injury (AKI) in children receiving trimethoprimsulfamethoxazole (SXT). The primary objective of this study was to describe AKI with SXT use in pediatric patients. Secondary objectives included describing the incidence of hyperkalemia and blood dyscrasias with SXT use.

METHODS

In this retrospective, single-center observational study, inpatient electronic medical records were reviewed for patients younger than 18 years of age who received at least 5 days of SXT for treatment of a bacterial infection. Patients were excluded if serum creatinine data prior to and after initiation of SXT were unavailable, they had AKI or were on hemodialysis prior to SXT initiation, or they were admitted to an oncology unit.

RESULTS

Of 98 patients who met inclusion criteria, 24 (24.5%) experienced stage I AKI and 16 (16.3%) experienced stage II or III AKI. The mean treatment duration with SXT at time of AKI development was 5.9 days. Coadministration of SXT with other nephrotoxic medications increased the risk of development of AKI (OR, 1.7; 95% CI, 1.2–2.4). Hyperkalemia was noted in 29 patients (29.6%), anemia in 39 patients (39.8%), thrombocytopenia in 30 (30.6%), and neutropenia in 39 (39.8%).

CONCLUSIONS

Changes in renal function suggestive of AKI occur frequently in pediatric patients receiving at least 5 days of treatment with SXT, particularly when using serum creatinine as a marker of AKI. In contrast, when using urine output rather than serum creatinine, the incidence is much lower and may be more reflective of a true change in renal function. Coadministration of nephrotoxic agents increases the risk of development of AKI. Anemia and hyperkalemia are common in patients receiving SXT and not associated with development of AKI. Further prospective study is warranted to validate these results.

Trimethoprim-sulfamethoxazole (SXT) is commonly prescribed due to its effectiveness in treating bacterial infections, including urinary tract and skin and soft tissue infections.1,2  It is also used in pediatric patients for prophylaxis against Pneumocystis pneumonia3,4  and treatment of community acquired pneumonia,5  amongst other indications. Despite being generally well tolerated, the medication can affect patient renal function.1,6  Trimethoprim decreases tubular secretion of creatinine, causing elevations in serum creatinine concentrations.1,7  However, this change in serum creatinine has not been shown to result in a decrease in glomerular filtration rate.8 

Several case series and case reports in the adult population have described an elevation in serum creatinine associated with use of SXT regardless of patient baseline kidney function. A retrospective study showed a mean elevation in serum creatinine of 2.6 mg/dL and a reduction in creatinine clearance in 16 patients treated with SXT for a mean of 10 days.9  Shouval et al.10  described similar results in 6 patients with baseline normal kidney function. A study in 2012 reported 11.2% of participating middle-aged veterans who received SXT therapy for a minimum of 6 days had an increase in serum creatinine that met the Acute Kidney Injury Network criteria11  for acute kidney injury (AKI).12  Other studies in adults have reported similar results and suggested that trimethoprim was responsible for the increase in serum creatinine observed following SXT therapy.13,14  Similarly, a cohort study in older adults showed that trimethoprim is associated with a greater risk of AKI compared with other antibiotics used to treat urinary tract infections.15  However, as noted above, transient increases in serum creatinine seen with trimethoprim use complicates assessing AKI when using serum creatinine alone to estimate renal function.

The primary objective of this study was to describe AKI with use of SXT in the pediatric population assessing both serum creatinine and urine output. Secondary objectives included duration of SXT use at time of development of AKI and incidence of hyperkalemia and blood dyscrasias associated with SXT use in pediatric patients.

This institutional review board approved, retrospective, single-center observational study was conducted in patients admitted from February 1, 2013, until October 31, 2019, who received SXT as treatment for bacterial infections. Electronic medical records were reviewed for patients younger than 18 years of age. Patients were excluded for the following: 1) preexisting renal impairment or AKI; 2) unavailable data on baseline and end-of-treatment serum creatinine; 3) duration of treatment less than 5 days; 4) admission to an oncology unit. For patients with multiple AKI events during treatment with SXT, each event was considered an independent event and was included as a separate data point.

Demographic data and information regarding administration of SXT were collected. Formulation of SXT was recorded as the formulation on which the patient was initiated at start of therapy. Serum creatinine, white blood count, hemoglobin, and platelets were noted from 1 day before the start of SXT (“baseline”) to 3 days after discontinuation of therapy (“follow up”). Data were also collected at these time points for urine output and serum potassium. Concurrently administered nephrotoxic medications were noted.

Acute kidney injury was classified using the Kidney Disease Improving Global Outcomes 2012 criteria.16  Stage 1 AKI is defined as a serum creatinine 1.5 to 1.9 times baseline or at least a 0.3-mg/dL increase. Similarly, a patient with a urine output of less than 0.5 mL/kg/hr for 6 to 12 hours is classified with Stage 1 AKI. Stage 2 AKI is defined as a serum creatinine 2.0 to 2.9 times baseline or a urine output of less than 0.5 mL/kg/hr for more than 12 hours. Stage 3 AKI is defined as a serum creatinine at least 3 times baseline, an increase in serum creatinine to greater than 4 mg/dL, initiation of dialysis, or a decrease in estimated glomerular filtration rate to less than 35 mL/min/1.73m2 in pediatric patients. A urine output of less than 0.3 mL/kg/hr for at least 24 hours or anuria for at least 12 hours also qualifies for AKI Stage 3.

Analysis was conducted for patients experiencing AKI as measured by serum creatinine or urine output. Hyperkalemia was classified as serum potassium greater than 5 mmol/L. White blood count and platelets were recognized as below normal if less than 4500 bil/L and 150,000 bil/L, respectively. Patients aged 1 to 23 months were considered to have anemia if hemoglobin was less than 10.5 g/dL; patients aged 2 to 9 years old and 10 to 17 years old were deemed to have anemia with a hemoglobin less than 11.5 g/dL and 12.5 g/dL, respectively.

Data analysis was conducted using SPSS version 25 (IBM SPSS, Inc, Armonk, NY) with the level of significance set at α = 0.05. Continuous data were summarized using means with SDs and analyzed with an independent t test. Categorical data were reported using frequency and percentages and analyzed with a chi-square or Fisher exact test. Binary logistic regression was used to assess the association of use of nephrotoxic agents with AKI.

Ninety-eight patients met inclusion criteria and were included in analysis. The majority of patients in this study were male (56.1%), Hispanic (67.3%), and in the intensive care unit at time of SXT initiation (65.3%). The most common indication for SXT use was pneumonia (45.9%). The majority (n = 81, 82.7%) of patients received 3 or more unique nephrotoxic medications during the SXT course. Patient demographics can be found in Table 1.

Table 1.

Patient Demographics

Patient Demographics
Patient Demographics

Primary Objective. Data regarding development of AKI during treatment with SXT are found in Table 2. When looking at change in serum creatinine as the diagnosing factor of AKI, 36 (36.7%) patients were determined to have AKI, with 6 (6.1%) having Stage II or III AKI. When using change in urine output as the diagnostic criterion for AKI, 12 (12.2%) patients had AKI, of which 11 (11.2%) had Stage II or III AKI. Patients who were in the intensive care unit at time of SXT initiation were more likely to experience AKI of any stage than patients who were not (p = 0.037). However, using multivariate logistic regression, patients who were receiving concomitant nephrotoxic medications were more likely to experience any stage of AKI (OR, 1.7; 95% CI, 1.2–2.4) after adjusting for demographic and clinical factors (Table 3).

Table 2.

Incidence of AKI

Incidence of AKI
Incidence of AKI
Table 3.

Binary Logistic Regression for the Association of Nephrotoxic Agents With AKI *

Binary Logistic Regression for the Association of Nephrotoxic Agents With AKI
						*
Binary Logistic Regression for the Association of Nephrotoxic Agents With AKI
						*

Although mean serum creatinine was not significantly different at baseline between patients with and without AKI (Table 4), the mean urine output was lower in patients with any stage of AKI compared with patients without AKI (2.1 vs 2.7 mL/kg/day, p = 0.036). Dose and frequency of SXT administration were not associated with development of AKI.

Table 4.

SXT Dosing and Patient Information

SXT Dosing and Patient Information
SXT Dosing and Patient Information

Secondary Objectives. Mean time to development of AKI of any stage was 5.9 days (SD, 2.3). Hyperkalemia was noted in 29 patients (29.6%) (Table 5). A greater percentage of patients with any stage AKI had hyper-kalemia compared with those who had no AKI or Stage I AKI (40% vs 22.4%), though this difference was not statistically significant (p = 0.061).

Table 5.

Secondary Outcomes

Secondary Outcomes
Secondary Outcomes

Anemia was noted in 39 patients (39.8%), of which 19 (48.7%) already had a hemoglobin less than 10.5 g/dL at initiation of SXT. Thrombocytopenia was noted in 30 patients (30.6%), of which 27 patients (90%) already had thrombocytopenia upon initiation of SXT. Neutropenia was documented in 12 patients (12.2%), of which 9 patients (75%) were neutropenic at initiation of SXT. There was no difference in mean hemoglobin at initiation of SXT between patients with and without AKI (p = 0.453). None of the secondary outcomes were associated with development of AKI.

Approximately 40% of pediatric patients in this study experienced apparent AKI with at least 5 days of SXT therapy, with 40% of these patients experiencing Stage II or III AKI. This is in agreement with studies conducted in adult patients10,1214  and occurred in patients without preexisting renal insufficiency. It is interesting to note that when using urine output as an indicator of AKI, our incidence of AKI was far less than when using only serum creatinine (12.2% vs 36.7%). As noted, this discrepancy is most likely due to the elevation of serum creatinine due to trimethoprim,17  and as other authors have shown, is not indicative of renal dysfunction. These data combined with ours calls into question the use of serum creatinine as a primary measure of renal function or dysfunction in patients receiving SXT combination or trimethoprim therapy.

There was no association between dose administered or the frequency of SXT administration and the likelihood of developing AKI. However, this study did show that patients who developed AKI had a statistically significantly lower urine output than those who did not develop AKI. This may provide additional evidence that urine output is a valuable marker in assessing early signs of renal insufficiency,18  particularly in patients receiving SXT therapy. One noted factor that did increase the likelihood of AKI was the use of concomitant nephrotoxic medications—each additional medication increased the odds of AKI occurring by 70%. This may emphasize the need for monitoring for AKI, especially in patients who are receiving other nephrotoxic medications simultaneously. A retrospective case-control study in pediatric hospitalized non-critically ill patients aged 1 day to 18 years found that patients exposed to nephrotoxic medications, including SXT, for a longer period of time were more likely to develop AKI.19  This reinforces data shown in this study, where AKI did not develop until after several days of therapy.

Most patients experiencing Stage III AKI in this study had decreased urine output or anuria. This may be due to a true decrease in urine output or to the limitations in charting in the medical record. Similarly, if the patient had surgery or went for a procedure, urine output may not have been documented accurately. The discrepancy between the decrease in urine output and the increase in serum creatinine in patients with AKI calls this further into question.

Hyperkalemia occurred in approximately 30% of patients receiving at least 5 days of SXT. Literature varies in regards to the frequency of hyperkalemia with administration of SXT, from 3%20  to 36%.21 Documentation of hyperkalemia in pediatric patients receiving SXT is rare; the results of this study indicate that monitoring of serum potassium in pediatric patients receiving SXT may be warranted.

Concern about thrombocytopenia and leukopenia with use of SXT has persisted throughout the life of this medication.22  Evidence in adults shows that leukopenia, thrombocytopenia, and anemia occur with treatment with SXT.23  A study of 25 pediatric patients with HIV infection treated with SXT showed that 20% of patients had neutropenia.24  In a study conducted by Asmar et al.25  of 50 children treated with SXT, 34% developed neutropenia and 12% developed thrombocytopenia. Data in this study regarding incidence of blood dyscrasias correspond with what has been shown in literature, indicating that anemia is a common occurrence and neutropenia and thrombocytopenia, while less likely, occur without relationship to development of AKI and in 7% to 12% of patients. The results of this study are in contrast to those of Feldman et al.,26  who found that pediatric patients receiving SXT had a negligible incidence of leukopenia, thrombocytopenia, and anemia. When accounting for patients who had blood dyscrasias at initiation of SXT, fewer patients experienced leukopenia, thrombocytopenia, and anemia (3.7%, 8.6%, and 42%, respectively). This study suggests that thrombocytopenia and leukopenia are not common with use of SXT, whereas concern for anemia persists with SXT use. Monitoring of blood counts for patients receiving more than 5 days of therapy with SXT may be warranted.

The retrospective nature of this study leads to limitations. One limitation is that laboratory values indicating development of syndrome of inappropriate anti-diuretic hormone (SIADH) (e.g., serum and urine sodium, urine osmolality) were not collected. Because many patients in this study were diagnosed with pneumonia, and SIADH is a possible sequalae of pneumonia, without collection of these values SIADH cannot be ruled out as a potential cause of low urine output. Also, it is challenging to determine if the decrease in urine output found in some patients with AKI is due to true AKI or a lack of documentation of urine output. Similarly, because the Kidney Disease Improving Global Outcomes criteria note an increase in serum creatinine of 50% to be evidence of Stage I AKI, a large percentage of patients were categorized as having Stage I AKI, despite the fact that they may have experienced a change in serum creatinine from 0.2 mg/dL to 0.3 mg/dL, for example. This is especially true because many patients had a low serum creatinine prior to initiation of SXT. Trimethoprim use may also temporarily increase serum creatinine without indicating a true AKI.17  This study reported AKI due to both increased serum creatinine and decreased urine output to mitigate this effect. The small sample size of the study, lack of consistent documentation of fluid and electrolyte intake, as well as the inclusion of critically ill patients and patients receiving concomitant nephrotoxic medications, also makes it challenging to determine if the documented AKI was due to use of SXT alone or in concert with other risk factors.

Approximately 41% of pediatric patients experienced AKI with administration of at least 5 days of treatment with SXT. Coadministration of SXT with other nephrotoxic medications increases the risk of development of AKI. Anemia and hyperkalemia are common in pediatric patients receiving SXT. The results of this study suggest that patients receiving at least 5 days of therapy with SXT should be monitored for the development of AKI, hyperkalemia, and blood dyscrasias. Moreover, our data also suggest that use of urine output to assess renal function may be preferred to serum creatinine-based methodologies in patients receiving SXT due to the trimethoprim-induced increase in serum creatinine. Further prospective data are warranted to validate these results.

AKI

acute kidney injury

SIADH

syndrome of inappropriate anti-diuretic hormone

SXT

trimethoprim-sulfamethoxazole

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Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Ethical Approval and Informed Consent. Institutional review board approval was obtained for this retrospective study.