Amphotericin B (AmphoB) remains the preferred therapy for invasive fungal infections despite many side effects, such as nephrotoxicity and electrolyte imbalance. Our previous study suggested that high sodium (Na) intake >4 mEq/kg per day may be associated with lower nephrotoxicity in extremely premature infants treated with AmphoB. Subsequently, it became a standard of care in our unit to administer Na >4 mEq/kg per day to extremely premature infants treated with AmphoB. The purpose of this study was to evaluate the effect of high Na intake > 4 mEq/kg per day on the incidence of AmphoB-induced nephrotoxicity among extremely premature infants with birth weight <1250 gm. All extremely premature infants with birth weight <1250 gm born between 1992 and 2004 and treated with AmphoB for systemic fungal infections were included in the study. The study infants were divided into two groups: a control (CL) group (1/1992–12/1999, n = 21) consisting of extremely premature infants given a maintenance Na intake during AmphoB therapy, and a high sodium intake (High Na) group (1/2000–12/2004, n = 16) consisting of extremely premature infants given a high Na intake >4 mEq/kg per day during AmphoB therapy. Nephrotoxicity was defined as serum creatinine levels >1 mg/dl, urinary output (UOP) < 1 ml/kg per hour or a decrease in UOP of 50%, compared with the previous 2 days, and persisting for at least 2 days. Invasive fungal infection was diagnosed in 5.7% of the infants (44/763 infants). Thirty-seven infants were eligible for the study and seven were excluded. There were no differences between the two groups in gestational age, birth weight, age at fungal infection diagnosis, length of AmphoB therapy, daily fluid intake or hyponatremia. Nephrotoxicity was significantly higher in the CL group than in the High Na group (13/21 vs. 3/16; P = 0.02). In the CL group, nephrotoxicity occurred at (mean ± SD) 1.9 ± 3.2 days after the initiation of AmphoB treatment and lasted for 5.5 ± 4.7 days. In this group, nephrotoxicity occurred in two of the 13 infants before the initiation of AmphoB therapy. In the High Na group, nephrotoxicity occurred before the start of AmphoB therapy in two of the three infants. In the third infant, nephrotoxicity lasted for 1 day. Mean Na intake was not different between the two groups during the 4-day period prior to AmphoB therapy. Mean Na intake during the first 10-day period of AmphoB therapy was significantly lower in the CL group (3.7 vs 6.2; P < 0.001). Conclusion: High Na intake was associated with a reduction in the incidence of AmphoB-induced nephrotoxicity in extremely premature infants with birth weight <1250 gm. We recommend the use of a high Na intake of >4 mEq/kg per day for extremely premature infants during Amphotericin B therapy.
Survival of extremely premature infants has improved significantly with recent advances in neonatal intensive care . However, increased survival is associated with complications related to exposure to invasive treatment modalities [2–4]. Among these complications, infection continues to be an important cause of mortality and morbidity. The causes of infection are changing over time, with Candida emerging as one of the leading causes of morbidity and mortality among extremely premature infants [4–11]. Amphotericin B (AmphoB) remains the treatment of choice for invasive candidiasis because of its fungicidal effects . Side effects of AmphoB include various infusion reactions, nephrotoxicity and electrolyte imbalance . AmphoB seems to induce renal damage by enhancement of the tubuloglomerular feedback (TGF) or systemic and afferent arteriolar vasoconstriction . The use of a amphotericin–lipid formulation can prevent some of the renal side effects, but conventional AmphoB is preferred since it achieves higher concentrations in renal tissue . Also, previous studies of animals and human adults have demonstrated that salt loading before AmphoB therapy ameliorates the nephrotoxicity [15–24].
In our previous study, we examined the effects of fluid and electrolyte management on AmphoB-induced nephrotoxicity among extremely premature infants . The results of this study suggested that sodium (Na) intake >4 mEq/kg per day was associated with a decrease in the incidence of AmphoB-induced nephrotoxicity. The mechanism by which Na reduces AmphoB-induced nephrotoxicity is not well understood, but changes in membrane permeability and drug-induced pre-glomerular vasoconstriction seem to play a role . After our study results were published, it became a standard of care in our unit to administer Na >4 mEq/kg per day to extremely premature infants treated with AmphoB. The purpose of the study reported here was to evaluate the effect of high Na intake (>4 mEq/kg per day) on the prevention of AmphoB-induced nephrotoxicity among extremely premature infants with birth weight <1250 gm.
This is a retrospective cohort study including all infants with birth weight <1250 gm who were treated with AmphoB for systemic fungal infection between 1992 and 2004. These infants were admitted to the Neonatal Intensive Care Unit at Sparrow Hospital, Lansing, Michigan. The study was approved by the institutional review boards at Michigan State University, East Lansing, Michigan and Sparrow Hospital, Lansing, Michigan, USA.
The patients were divided into two groups: a control (CL) group consisting of a historical control group that involved infants born 1/1992–12/1999 (n = 21) when high Na administration was not a routine treatment during AmphoB therapy, and a high sodium intake (High Na) group consisting of infants born 1/2000–12/2004 (n = 16) when Na intake >4 mEq/kg per day was implemented for all infants with invasive fungal infection during AmphoB therapy. Demographic, clinical and laboratory information was collected for the study infants. Data were analyzed for two time periods (similar to the previous study): during the 4 days before the initiation of AmphoB treatment and during the10 days after its initiation. Demographic data included gestational age, birth weight, gender, race and Apgar scores. The following data were collected to assess the risk factors for developing systemic fungal infections: number of ventilator days, number of central line days, postnatal corticosteroid use, number of transfusions, amount of intralipid administered and use of antibiotics before the diagnosis of fungal infection. The following data regarding fungal infection were recorded: age of infant at time of diagnosis, Candida species, infection site, number of positive cultures and time to achieve negative cultures. All urine cultures were obtained by suprapubic bladder tap or catheterization. If the quantitative urine culture became positive, culture was repeated daily until it became negative.
The clinical data reviewed were related to the signs and symptoms of fungal infection and treatment side effects. Infants diagnosed with fungal infection, including the infants with positive tracheal aspirate cultures or positive urine culture, had invasive fungal infection documented by worsening of their clinical status with at least two of the following clinical manifestations: increased ventilatory support, worsening apnea and bradycardia, acidosis (pH < 7.20), hypotension [persistent low mean blood pressure (<30 mmHg) associated with decrease peripheral perfusion], leukopenia (decrease in total white blood cells <4 × 103/mm3), neutropenia (absolute neutrophil count <1500/mm3), thrombocytopenia (platelet count <100 × 103/mm3) or hyperglycemia (blood glucose >150 mg/dl). The following clinical data were recorded: number of ventilator days, central line days, postnatal corticosteroids use, transfusions, amount of intralipid administered and use of antibiotics or other antifungals before or concomitant with AmphoB.
During the study period there was a change in the dose and frequency of AmphoB treatment between the two groups. The initial AmphoB regimen was 0.1–0.25 mg/kg per dose once and then daily doubling until 1 mg/kg per dose had been reached. After 1996, infants with fungal infection were started on AmphoB at 0.5 mg/kg per day for 1 day and doubled to 1 mg/kg per day in the second and subsequent days of therapy. The duration of AmphoB treatment and the use of other nephrotoxic drugs before and during the AmphoB therapy were recorded. Both the diagnosis and the treatment of invasive fungal infection were at the discretion of the attending neonatologist responsible for the care of these infants.
Nephrotoxicity was defined as serum creatinine levels >1 mg/dl and a urinary output (UOP) <1 ml/kg per hour or a decrease in UOP of 50%, compared with the previous 2 days and persisting for at least 2 days. The following data were collected: daily fluid intake and urinary output, electrolyte intake, serum electrolyte and creatinine levels, as obtained at the discretion of the attending neonatologist. Sodium intake included intravenous intake and enteral intake if the patient was on oral feeding.
All data collected for the two groups were examined and reported as mean ± standard deviation (SD), mean and 95% CI (confidence interval) as well as median and range. We used Student’s t test to compare continuous data with a normal distribution. If the data failed the normality test we used the Mann–Whitney rank sum test. Repeated-measures data were compared by a one-way analysis of variance (ANOVA) followed by all pair-wise multiple comparison procedures (Student Newman–Keuls method). Categorical data were compared using chi-square or Fisher’s exact test. Statistical significance was accepted at P < 0.05.
A total of 763 infants with birth weights of <1250 gm were admitted during the study period. Candida species were isolated from blood, urine or tracheal aspirates of 44 patients (5.7%). All cerebrospinal fluid cultures yielded negative results. Seven infants were excluded: three were not treated with AmphoB (two received liposomal amphotericin and one received fluconazole); three were treated for less than 5 days and then changed to other antifungal medications according to the sensitivity results (two to fluconazole and one to caspofungin); one was excluded for ambiguous genitalia and associated renal malformation. Consequently, 37 infants were ultimately included in the study. All cases of invasive candidiasis were included. There were no cases of invasive fungal infection during the study period that were diagnosed postmortem or based upon histopathology of surgical specimens. Three of the infants included in the study died; none had positive fungal cultures at the time of death. Two of the infants who expired were in the CL group: one expired on day 7 after diagnosis of invasive fungal infection and initiation of AmphoB treatment because of overwhelming infection and acute renal failure; the second infant died after AmphoB therapy had been completed, and death was unrelated to fungal infection. The third infant was in the high Na group and expired as a result of septic shock with multiple organ failure, after 15 days of AmphoB therapy. Data for all three infants were included in the analyses.
There was no significant difference between the two groups in terms of gestational age, birth weight, sex or survival, as summarized in Table 1. The evaluation of the risk factors associated with fungal sepsis or renal impairment showed no statistically significant differences between the groups in number of ventilator days, number of central line days, postnatal corticosteroid use, number of blood transfusions, amount of intralipid administered before AmphoB therapy or prior or concomitant use of antibiotics or nephrotoxic drugs, as seen in Table 1.
There was no statistically significant differences between the two groups in terms of their clinical characteristics at the time of fungal diagnosis, as summarized in Table 2, and there was no significant difference between the groups in terms of the mean postnatal age at the time of fungal infection diagnosis [14 ± 9 (CL) vs. 23 ± 20 days; P = 0.07] or the mean length of AmphoB therapy [18 ± 10 (CL) vs. 20 ± 11 days; P = 0.5]. Candida albicans was the most common fungal species isolated among the study patients in both groups [16/21 cases (CL) vs. 9/16 cases; P = 0.35]. Candida parapsilosis was more frequently isolated in the High Na group than in the CL group, but the difference did not reach statistical significance (2/21 cases vs. 6/16 cases; P = 0.06). The fungal species isolated from the remaining three infants in the CL group were C. tropicalis, C. lambica and one unidentified Candida species. Both C. albicans and C. parapsilosis were isolated from one patient in the High Na group. There was no significant difference between the two groups in terms of the numbers of infants from whom fungus was isolated from multiple sites [11/21 (CL) vs. 7/16 infants; P = 0.37], as summarized in Table 3. There were only six infants (6/37) with a single positive fungal culture among the study patients, with no difference between the groups in the number of infants with single positive culture (4/21 vs. 2/16; P = 0.68). There also was no difference between the two groups in the numbers of renal fungal infections (13/21 vs. 6/6 infants; P = 0.32). Among the infants with renal fungal infection, a total of 18 infants (18/19 infants) had multiple positive urine cultures. The number of positive urine cultures ranged between two and five. For one patient in the CL group, fungal balls were identified using renal ultrasonography. In addition, one patient in the CL group had both renal and ophthalmic evidence of fungus. None of the patients demonstrated cardiac vegetation. All infants with positive tracheal aspirate cultures had clinical evidence of invasive fungal infection associated with multiple positive cultures.
The number of patients who developed nephrotoxicity was significantly higher in the CL group than in the high Na group (13/21 vs. 3/16, respectively; P = 0.02) as seen in Table 2. All 16 infants with nephrotoxicity had a serum creatinine >1 mg/dl. Eight patients had a serum creatinine level of 1.1–1.5 mg/dl (six in the CL group and two in the High Na group), and eight infants had serum creatinine >1.5 mg/dl (seven in the in the CL group and one in the High Na group). A total of five babies (four in the CL group and one in the High Na group) had UOP < 1 ml/kg per hour for more than 2 days. There was no statistical difference between the two groups in the incidence of nephrotoxicity prior to initiation of AmphoB therapy. In the CL group, nephrotoxicity occurred at 1.9 ± 3.2 days after the initiation of AmphoB and lasted for 5.5 ± 4.7 days. In this group, two of the 13 infants had the onset of nephrotoxicity before the initiation of AmphoB therapy. In the High Na group, nephrotoxicity occurred before the start of AmphoB therapy in two of the three infants and lasted throughout AmphoB therapy. The third infant with nephrotoxicity in the High Na group had increased serum creatinine 1 day after AmphoB was started, which returned to normal within 24 h. The incidence of nephrotoxicity was significantly higher among the patients with C. albicans than in those with C. parapsilosis infection [56% (14/25) vs. 13% (1/8); P = 0.04]. The high Na intake was most likely protective against the development of nephrotoxicity because among the 25 patients with C. albicans infection, the incidence of nephrotoxicity was higher in the CL group than in the High Na group [11/16 (69%) vs. 3/9 (33%); P = 0.14]. While the renal fungal infection was higher in the CL group than in the High Na group [13/21 (62%) vs. 6/16 (38%); P = 0.26], the high Na intake was most likely protective against the development of nephrotoxicity because among the patients with renal fungal infection, the incidence of nephrotoxicity was higher in the CL group than in the high Na group [8/13 (62%) vs. 1/6 (14%); P = 0.14]. In addition, the mean total dose of AmphoB was significantly higher in the High Na group than in the CL group (21 vs. 12 mg/kg; P = 0.03), as seen in Table 2. The study is not powered to probe whether nephrotoxicity was impacted by having renal fungal infection or different Candida species. There was no difference between the groups in the serum creatinine levels before the initiation of AmphoB treatment. Mean daily serum creatinine levels tended to be higher in the CL group than in the High Na group, but the difference did not achieve statistical significance, as seen in Fig. 1.
Sodium, potassium and fluid intake and urine output were evaluated as mean intake for a 4-day period before the initiation of AmphoB treatment and then for a 10-day period after its initiation (Table 4).
There was no significant difference in the mean Na intake between the groups during the 4-day period prior to initiation of AmphoB therapy [3.5 (CL) vs. 4.5 mEq/kg per day; P = 0.13], as seen in Table 4. The mean Na intake was significantly higher in the High Na group than in the CL group during the first 10-day period of AmphoB therapy (6.2 vs. 3.7 mEq/kg per day, respectively; P < 0.001) (Table 4). Interestingly, in the CL group, although eight infants had Na intake >4 mg/kg per day, only two (25%) developed nephrotoxicity. In addition, 13 infants in the CL group had Na intake <4 mg/kg per day, of which 11 (85%) developed nephrotoxicity.
Despite the higher Na intake, there was no significant difference in serum Na between the two groups (Fig. 1). Hyponatremia (serum Na <130 mEq/dl) occurred in six of 21 patients in the CL group and one of 16 patients in the High Na group (P = 0.11).
There was no significant difference between the two groups in terms of mean fluid intake (Table 4) during AmphoB therapy. None of the study infants had a mean total fluid intake <120 ml/kg per day except for three infants who developed nephrotoxicity and whose fluid was reduced to <120 ml/kg per day during the management of their renal compromise.
Mean potassium intake during the 4-day period before the initiation of AmphoB therapy was not different between the two groups, as shown in Table 4. During AmphoB therapy, there was significantly higher potassium intake in the High Na group on days 1, 2, 3 and 5 of therapy (P < 0.05). In the subsequent days of treatment, there was no difference between the two groups in terms of average daily potassium intakes. When the mean potassium intake was evaluated for the first 10-day period of AmphoB therapy, there was a statistically significant difference between the two groups [2.2 (CL) vs 2.9 mEq/kg per day; P = 0.02]. There was no difference between the groups in terms of serum potassium levels (Fig. 1) or incidence of hypokalemia (serum potassium <3 mEq/dl) [2/21 (CL) vs. 1/16; P = NS].
Extremely premature infants are at risk for nosocomial infections because of their immature immune system and the extensive number of procedures needed to support them. Among nosocomial infections, invasive fungal infection continues to be of significant concern, especially with the increased use of broad spectrum antibiotics. In our unit, during the study period 1992–2004, the overall incidence of invasive fungal infection was 5.7% in infants <1250 gm. Amphotericin B remains the drug of choice for treating systemic candidiasis, despite its side effects, mainly renal toxicity . Our previous study showed that AmphoB-induced nephrotoxicity was not influenced by concomitant use of antibiotics and/or nephrotoxic drugs with AmphoB .
Other risk factors, such as the number of central catheter days, number of ventilation days, number of transfusions, postnatal corticosteroid use and intralipid use were not found to influence the incidence of AmphoB nephrotoxicity in our previous or this study .
The use of lipid-associated preparations of AmphoB is more costly, and the renal penetration and concentration may be lower. Salt loading before AmphoB administration can reduce nephrotoxicity effectively, as demonstrated in animal and human adult studies, and it is inexpensive [14–22, 32–33]. The exact mechanism by which Na reduces the incidence and severity of AmphoB-induced nephrotoxicity has not been clearly delineated. The two postulated mechanisms of nephrotoxicity suggested in the literature include changes in membrane permeability and drug-induced pre-glomerular vasoconstriction . Most of the studies published regarding salt-loading approaches to prevent AmphoB-induced nephrotoxicity in adults are case reports; there is one randomized study .
To date, our previous study has been the only one that has examined Na intake and its influence on renal toxicity in extremely premature infants treated with AmphoB . The results of our study suggested that Na intake >4 mEq/kg per day was associated with a decrease in the incidence of AmphoB-induced nephrotoxicity . Based on these results, it subsequently became the standard of care in our unit to ensure a Na intake of at least 4 mEq/kg per day during the AmphoB therapy. This was achieved either by administering additional normal saline to infants who could tolerate excess fluid or by increasing the amount of Na administered in parenteral nutrition (TPN). As a reflection of this intervention, the Na intake in our High Na group is significantly higher than that in our CL group, reported as mean intake over the 4-day period before AmphoB therapy was initiated and over the 10-day period thereafter. If normal saline was used, this was a temporary action until new TPN was adjusted, and it did not influence the overall fluid intake, as seen in Table 4. The Na intake during the 4 days prior to AmphoB initiation was not significantly different between the two groups. In the CL group, eight of the 21 patients had an average Na intake higher than 4 mEq/kg per day for the 4-day period prior to the initiation of AmphoB therapy; of these eight patients, only two developed nephrotoxicity. The remaining 13 infants in the CL group had an average Na intake <4 mEq/kg per day, and 11 of the 13 developed nephrotoxicity. This observation may be important in evaluating the impact of overall Na balance at the beginning of the AmphoB therapy on AmphoB-induced nephrotoxicity. Our study is retrospective, and we could not specify if Na intake before the initiation of AmphoB therapy is a determinant of AmphoB-induced nephrotoxicity. Previous animal studies have shown that Na depletion was associated with AmphoB-induced nephrotoxicity, while Na loading prior to AmphoB therapy was associated with a significant increase in urinary Na excretion and the prevention of AmphoB-induced nephrotoxicity [17–18]. These studies suggest that the prevention of AmphoB-induced nephrotoxicity is mediated by increased in urinary Na excretion and inhibition of tubuloglomerular feedback (TGF) [17–18]. The findings of our study are in agreement with this suggestion. In addition, we speculate that serum Na levels were similar in both groups because of the increase in urinary Na excretion in the High Na intake group. However, we did not measure urinary Na excretion in our retrospective study. Large, prospective, randomized, blinded trials are warranted to answer these questions.
In addition, all infants in the High Na group received 1 mg/kg per day AmphoB by the second day of life, with overall significantly higher mean total dose of AmphoB correlated with a significantly lower incidence of nephrotoxicity. These results support the start of AmphoB therapy at 1 mg/kg, especially when combined with Na intake >4 mEq/kg per day to avoid nephrotoxicity.
We did not identify any difference in the fluid intake before or after AmphoB treatment was initiated. This finding is consistent with the results of our previous study that also showed no association between hydration and AmphoB-induced nephrotoxicity .
Other electrolytes, such as potassium, have been implicated in nephrotoxicity [23, 34]. Bernado et al.  reported in a rat model that potassium depletion augmented AmphoB-induced toxicity to the renal tubules. Their study also showed that potassium depletion did enhance urinary Na excretion and enhanced the development of renal tubular toxicity. In our study, there was no difference in the potassium intake during the 4-day period prior to AmphoB therapy, but we noticed a significantly higher potassium intake during the first 10 days of AmphoB therapy. This difference was evident when data were expressed as mean intake for the 10-day period. The evaluation of average daily potassium intake revealed an overall trend of higher potassium intake in the High Na group compared with the CL group during the first 4 days of AmphoB therapy. Among adults, salt loading resulted in increased urinary potassium loss. In our study, higher Na intakes were not associated with a decrease in serum potassium levels (Fig. 1). It is unclear whether the increase in potassium intake is an incidental finding or whether the finding can be attributable to differences in tubular function among extremely premature infants. However, the effects of higher Na intake on potassium homeostasis were difficult to evaluate because urine electrolyte levels were not measured for these infants.
We acknowledge the limitations of the study reported here. First, this is a retrospective study. In light of the previous study results, with good evidence that higher Na intake may help to prevent AmphoB-induced nephrotoxicity, it was difficult to design a prospective randomized trial and assign patients to low Na intake. The use of historical controls (CL group) can be a disadvantage, but the neonatology team in our neonatal intensive care unit had a consistent management approach for treatment of fungal infection in extremely premature infants. In addition, the fluid and electrolyte management was similar for all infants included in the study during this entire time except for the use of high Na intake >4 mEq/kg per day during the second period of the study (the High Na intake group). The relative small number of patients in the study, deriving from the relative low incidence of the problem studied, did not allow us to answer additional questions, such as the definitive influence of prior Na balance or potassium intake on AmphoB-induced nephrotoxicity. Long-term outcome data were not collected for the study patients. Consequently, the effect of nephrotoxicity on the long-term outcome (persistent renal dysfunction, growth and development) requires further study.
Our data confirm the findings of previous animal and human adult studies, indicating that higher Na intakes >4 mEq/kg per day among extremely premature infants with birth weight <1250 gm were associated with a reduction in the incidence of AmphoB-induced nephrotoxicity. In times of limited resources, cost-effective treatment options are pivotal in improving the outcome of extremely premature infants. In the absence of a prospective randomized clinical trial, we recommend the use of conventional AmphoB therapy in combination with sodium intake of >4 mEq/kg per day to decrease the incidence of AmphoB-induced nephrotoxicity among extremely premature infants with birth weight <1250 gm.
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Turcu, R., Patterson, M.J. & Omar, S. Influence of sodium intake on Amphotericin B-induced nephrotoxicity among extremely premature infants. Pediatr Nephrol 24, 497–505 (2009). https://doi.org/10.1007/s00467-008-1050-4
- Amphotericin B
- ELBW infants
- Extremely premature infants
- Fungal infection
- High sodium intake