The study received approval from the institutional review board of the King Abdullah International Medical Research Center (KAIMRC), Saudi Arabia, IRB approval number (IRB/1117/22), approved study number (NRJ22J/065/04) in June 2022. The study adhered to the principles outlined in the Declaration of Helsinki as well as both national and institutional standards. In consideration of the study's retrospective observation design that didn’t interfere with patient care at any level, and in accordance with institutional/national guidelines, written informed consent was not required.

AKI was determined on the basis of the Kidney Disease Improving Global Outcomes (KDIGO 2012) criteria: an increase in serum creatinine of ≥ 0.3 mg/dL (≥ 26.5 mmol/L) within 48 hours. The increase in serum creatinine to ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days. The urine volume was < 0.5 mL/kg/hour for 6 hours. Adequate hydration is defined as receiving continuous hydration daily during the whole course of acyclovir, including any type of intravenous fluid with at least 1500 mL. A volume of less than 1500 mL may be acceptable if the patient’s medical condition requires fluid restriction, for example, for patients who have heart failure and edema.

A list of patients who received IV acyclovir generated in an Excel sheet. Patient demographic data and laboratory test data were extracted from the patients’ electronic medical records. The laboratory tests included the collection of SCr and BUN and reported their baseline and peak values during the administration of IV acyclovir. Descriptive statistical analysis is presented, depicting categorical outcomes through frequencies and percentages, whereas continuous outcomes are represented as the means with standard deviations (SDs). Univariate descriptive analysis, the chi-square test and Fisher's exact test were used for categorical variables, whereas the t test was used for normally distributed numeric variables. To assess potential differences in acute kidney status between patients with and without hydration, a multiple binary logistic regression model was applied. To improve the regression model, a forward stepwise selection model technique has been used to select significant predictors (McCarthy RV, et al., 2022). Only significant predictors with specified significant level remain in the final model. For further model selection step, we also used the area under the curve to assure the specificity and sensitivity of our selected model. The threshold for statistical significance was set at P < 0.05 (two-sided). All analyses were executed via SAS 9.4(McCarthy RV, et al., 2022).

Among the 281 screened patients, 201 were included; of those patients, 33 had repeated courses, so 266 courses were assessed for primary and secondary outcomes. The reasons for excluding the remaining 80 participants are shown in Fig. 1.

Two hundred fifty patients received hydration, while 16 patients did not receive hydration. Table 1 summarizes the demographic data and baseline characteristics of the participants. The baseline characteristics of the two groups were similar. The mean age of the patients in the hydrated group was 47 years, whereas that in the nonhydrated group was 52 years. In total, 152 (60.8%) out of 250 patients in the hydrated group had underlying diseases (i.e., diabetes, hypertension, diarrhea, heart failure, and chronic kidney disease), and 13 (81.25%) out of 16 patients in the nonhydrated group had other comorbidities. Eighty-eight percent of the hydrated patients received other nephrotoxic medications (i.e., nonsteroidal anti-inflammatory drugs, vancomycin, aminoglycoside, beta-lactam, amphotericin, trimethoprim sulfamethoxazole, colistin, and radiocontrast dye), whereas 94% of the nonhydrated patients did. Most of the patients in both groups received the appropriate dose of IV acyclovir (68%), with 171 patients in the hydrated group and 11 patients in the nonhydrated group. Patients who received hydration had a mean duration of 8.9 days of acyclovir treatment, whereas nonhydrated patients had a mean duration of 5.8 days of acyclovir treatment. The mean baseline BUN and SCr levels were relatively similar in both groups.

The estimated incidence of AKI was 11.6% in the hydrated group versus 18.8% in the nonhydrated group, with no statistically significant difference between the two groups (P = 0.39). See table 2. According to the multiple logistic regression model, there was a 19% lower odds of AKI in patients who received adequate hydration than in those who received inadequate hydration, but this difference was not statistically significant (OR = 0.81, 95% CI (0.31–2.17)). The model performance is shown in Fig. 2. We assessed the impact inadequate hydration on SCr, BUN and urine output compared to patients who received adequate hydration. A statistically significant increase in the odds of anuria (OR = 3.64, 95% CI (1.02–13.01)) and the serum creatinine level (OR = 1.06, 95% CI (1.001, 1.12)) was reported as summarized in table 3.

In this retrospective observational study, the incidence of acute kidney injury was greater among patients who received IV acyclovir and who were nonhydrated or did not receive adequate hydration; however, the differences were not statistically significant. Anuria and elevated serum creatinine were significantly greater among patients who received inadequate hydration.

Acyclovir-induced acute kidney injury has been well documented and is most likely due to crystal precipitation.

In our cohort, the dose was considered appropriate if it was dosed maximally at 10 mg/kg on the basis of actual body weight (ABW) (BMI < 30 kg/m2) or if (ABW < IBD) and adjusted body weight (AdjBW) for obese patients (BMI > 30 kg/m2), with adjustment of the frequency on the basis of creatinine clearance.

In the present study, the failure to detect differences in AKI between the two groups could be attributed to the small number of patients who did not receive hydration and the low incidence of AKI in our sample. Moreover, the relatively small incidence of AKI could be related to the preparation of IV acyclovir at our institution. Most treatment doses of acyclovir are prepared in at least 250 mL of suitable fluid. Although one retrospective study revealed that the preparation of acyclovir at 250 mL was not associated with a significant decrease in the incidence of AKI, it was associated with a significant decrease in the doubling of serum creatinine. (Dubrofsky, L., et al. 2016)

Our findings highlight the importance of maintaining daily continuous hydration in patients who receive IV acyclovir to prevent acyclovir-associated kidney injury. Our results are in line with those of published studies (Guo, X., et al., 2002; Lee, Eun Ju, et al., 2018; Kim, S., et al., 2015). However, the present study has several limitations. First, this was a single-center retrospective study, and we did not have the opportunity to standardize the amount of IV fluid used. Second, the number of patients who were compared in the study was relatively small. Third, there is no established literature definition for adequate hydration, so we set our specific definition by considering the hydration status of those patients.

The present study highlights that maintaining continuous daily hydration may be essential for preventing acyclovir-induced nephrotoxicity. Although there was no statistically significant difference in the overall incidence of AKI between hydrated and nonhydrated patients, our findings showed that inadequate hydration during IV acyclovir administration led to a statistically significant increase in serum creatinine levels and cases of anuria.

The study received approval from the institutional review board of the King Abdullah International Medical Research Center, Saudi Arabia (IRB/1117/22), in June 2022. The study adhered to the principles outlined in the Declaration of Helsinki as well as both national and institutional standards. In consideration of the study's retrospective design, and no active intervention or interference with regular patient care, informed consent was not obtained from the participants.

Not applicable

The authors declare that they have no competing interests