Successful Treatment of Bilateral-Obstructive Renal Fungal Balls with Continuous Liposomal Amphotericin B Irrigation Using Pairs (Upper and Lower Pole) of Percutaneous Nephrostomy Tubes in an Extremely Low Birth Weight Infant

Extremely low birth weight infants (ELBWIs) are at high risk for invasive fungal infections, resulting in significant morbidity and mortality.1 In the urinary tract, Candida may be present ranging from isolated candiduria to severe disease (formation of a fungal ball known as fungal accretions or bezoars). Obstructive uropathy caused by fungal balls is rare but frequently leads to the development of hydronephrosis, acute renal failure, and permanent renal damage.2 Bilateral obstructing renal fungal balls in ELBWIs are potentially life-threatening and require prompt drainage by the placement of percutaneous nephrostomy (PCN) or surgical intervention. However, therapeutic procedures are technically challenging because of their small anatomical proportions. We describe a case of an ELBWI with extensive bilateral obstructive renal fungal balls successively treated by continuous antifungal agent instillation and drainage through the upper and lower pole-paired PCN tubes.

A 25 3/7 weeks of gestation age, birth weight of 640 g, female baby delivered by cesarean section because of fetal heart rate decelerations, was admitted to Neonatal Intensive Care Unit (NICU). The mother was a 33-year-old woman (gravida 1, para 0), and the delivery was complicated by preterm labor and elevation of high-sensitivity C-reactive protein (hsCRP). The infant underwent intubation and was administered surfactant. The patient was started on parenteral nutrition through a peripherally inserted central catheter (PICC). The patient was treated empirically with amoxicillin/clavulanate for the risk of early-onset sepsis. On day 7, because progressive pulmonary infiltrates and elevated hsCRP levels were observed, vancomycin and piperacillin/tazobactam were started. The blood culture was positive for methicillin-resistant Staphylococcus aureus. The PICC was removed and antibiotic treatment continued. On day 21, while maintaining the antibiotics, the patient developed a bloodstream C. albicans infection. Although the strain appeared to be sensitive to fluconazole in the susceptibility test, candidemia persisted after a week course of fluconazole. On day 30, we changed the antifungal agent to liposomal amphotericin B (LAmB, AmBisome®; Gilead Sciences Inc., San Dimas, CA, USA). The blood culture became negative after three days of LAmB administration. On day 41, although the preload and cardiac output on echocardiography was normal and the mean arterial pressure was maintained above 40 mmHg, the patient showed oliguria, elevation of serum creatinine level (3.6 mg/dL), and yeast in urine sediment microscopy. The patient rapidly deteriorated and was completely anuric within 48 hours.

Ultrasonography of the kidneys identified heterogeneous hyperechoic lesions within both the dilated renal pelvis and ureteropelvic junction obstruction. The sizes of the lesions were approximately 15 mm and 11 mm on the right and left sides, respectively (Fig. 1). Since both fungal balls completely blocked the passage of urine, immediate intervention was required. Because she was too small and hemodynamically unstable for open surgery, we decided to insert four PCN tubes on the upper and lower poles of both kidneys for direct antifungal irrigation and drainage. On day 43, using ultrasound guidance, pairs of 5-Fr nephrostomy tubes were placed percutaneously and bilaterally under general anesthesia by a radiologist (Dr. JH Kim) (Fig. 2, 3). The patient was managed with continuous instillation of LAmB via each upper pole tube and free drainage via each lower pole tube simultaneously while continuing at a dose of 5 mg/kg/day of intravenous LAmB. Because the patient had previous treatment failure of fluconazole and severe renal impairment, we decided to keep using LAmB because it is known to be less nephrotoxic and has a better urine sterilizing effect than fluconazole in the renal pelvis.3 We determined the dosage of LAmB continuously instilled via both upper PCN tubes by adjusting the LAmB concentration in the renal pelvis to be the same as the serum peak concentration of systemic administration. We supposed two presumptions: first, the volume of the renal pelvis is so small that it does not affect the concentration of LAmB and second, the amount of urine produced from both kidneys is about 4 mL/kg/h. Considering the serum peak concentration when LAmB was administered intravenously at 5 mg/kg/day was 83 mcg/mL, the dosage of LAmB was 15,936 mcg/day in a 1.0-kg infant when it was administered to each kidney at 2 mL/h continuously. The dosage was calculated by multiplying the sum of the amount of urine (4 mL/h×24 h/day=96 mL/day) and the amount of infused fluid (2×2 mL/h×24 h/day=96 mL/day) by the serum peak concentration of LAmB (83 mcg/mL). The concentration of infused LAmB was 166 mcg/mL diluted in 5% dextrose, and 2 mL/kg/h was administered via each upper pole tube continuously. Changes in drug concentration due to changes in urine volume were not considered.

Fig. 1
Both kidneys appear to be diffusely increased (measuring about 4.3 cm) in its parenchymal echogenicity with dilatation of both renal pelvocalyces. Lobulated border of the heterogeneous hyperechoic and non-shadowing mass consistent with the fungal balls are both noted within the dilated renal pelvis and measured about 15 mm and 11 mm in its maximal length on the right (A) and left (B) side, respectively.

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Fig. 2
Intraprocedural bilateral antegrade nephrostogram showed severe hydronephrosis and an ureteropelvic obstruction (A) and After procedural picture of infant (B).

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Fig. 3
Four percutaneous nephrostomy tubes were placed on the upper and lower poles of the kidneys bilaterally. Infantogram of the infant.

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After two weeks of continuous irrigation, the urine culture became sterile, and the serum creatinine level was normalized. On serial ultrasonography, the size of the fungal balls gradually shrunk. On day 62, when ureteral patency was fully recovered, we removed both lower pole tubes while continuous antifungal instillation through both upper pole tubes was reduced to half. On day 68, the fungal ball in the right kidney disappeared entirely, and the right upper pole tube was removed. On day 94, we confirmed a complete resolution of the fungus ball in the left kidney by renal ultrasonography (Fig. 4); simultaneously, the Perinatologylast PCN tube was removed. Intravenous antifungal therapy was maintained for three more days after PCN tube removal. The PCN tubes were kept for seven weeks without any obstruction or displacement. The total administration period of systemic LAmB was nine weeks (seven weeks after the first negative blood culture). Renal function, liver function, and complete blood cell counts were monitored once a week during antifungal treatment. No adverse effects were noted. At four months of age, the baby was discharged home. Over the subsequent two years, serum creatinine levels and renal ultrasonography have remained normal, and urine specimens were consistently negative for yeast.

Fig. 4
Longitudinal section of the right (A) and left (B) kidney showing complete resolution of hydronephrosis and the fungal ball.

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We described the use of a combination of systemic LAmB and direct irrigation via dual PCN tubes that successfully eliminated bilateral-obstructing renal fungal balls in an ELBWI with progressive renal failure. To our knowledge, our case represents the first report of continuous irrigation through paired PCN tubes in a preterm infant with infected, obstructed kidneys. Only one case report of a renal pelvic-ureteric fungal ball successfully managed by the placement of two nephrostomy tubes has been reported in an adult patient.4 The type of drainage should be determined by local technical expertise and availability and patient-specific factors.5 The significance of this case lies in the fact that dual PCN tubes were successfully inserted into an ELBWI, and continuous administration of antifungals and free drainage through paired PCN tubes was relatively safe and more effective than a single tube in anuric conditions. In our case, the patient rapidly deteriorated and was hemodynamically unstable for surgical removal. Emergent drainage was urgently needed because the fungal balls were too large and entirely blocked the passage of urine. To avoid the risk of urinary obstruction and increase of intra-pelvic pressure during antifungal flushing with clamping of the tube, we attempted to insert two nephrostomy tubes into each kidney. This may have been possible because of the dilated, obstructed collecting system that allowed two tubes to be placed in the pelvis of the 1.0 kg infant. We assumed that continuous administration of antifungals and free drainage through paired tubes was more physiologic and safer for a small patient than intermittent antifungal flushing, indwelling, and drainage because of a slower infusion rate, smaller volume remaining in the renal pelvis, and continuous natural drainage. Considering continuous urine discharge of the patient, it was expected that a high concentration of antifungal agents could be maintained in the renal pelvis more effectively through continuous irrigation than with intermittent irrigation. In addition, the continuously infused flow to the renal pelvis would have helped the destruction of the fungal balls. As described in the report, the target concentration of LAmB in the renal pelvis was set to equal the serum peak concentration when intravenously administered at 5 mg/kg/day. This led to prompt recovery of renal function and urine output. We decided to continue irrigation through the upper tube until the renal fungal ball completely disappeared on ultrasonography. Combination therapy with continuous irrigation through paired PCN tubes and systemic antifungal treatment resulted in shrinkage of the fungal balls in a relatively short period and obviated the need for further surgical intervention.

Prematurity is increasingly recognized as a high risk for invasive Candida infection. Candidemia is the leading cause of late-onset sepsis and has a high rate of mortality.1 The indwelling of a central venous catheter and use of broad-spectrum antibiotics, parenteral nutrition, and intravenous hydrocortisone increase the risk of systemic candidiasis.6, 7 Although urinary candidiasis is relatively common in NICUs, invasive renal candidiasis leading to a fungal ball is uncommon. However, prevalence of renal candidiasis in premature infant with systemic candida infection lead up to 61–70%.8 Renal fungal balls can cause obstruction and dilatation of the upper renal tract or bladder outflow tract obstruction, leading to high morbidity and mortality.2, 6

Recently published therapeutic options for obstructive renal candidiasis vary greatly as a consensus regarding the optimal antifungal agent, dosage, mode of administration, and duration of therapy is not yet available. Although there are some cases in which an obstructive renal fungal ball has been managed by medical treatment alone, surgical interventions are almost always needed.9, 10, 11, 12

If the obstruction is partial, conservative medical treatment may be sufficient to treat renal infection. Amphotericin B (AmB) is the oldest antifungal drug and has been considered a first-line treatment for neonates with disseminated candidiasis and candidemia. However, AmB is well known for its nephrotoxicity through direct toxicity to proximal and tubular cells.13 Recently fluconazole is used in patients who have not received fluconazole prophylaxis.14 Since >80% of fluconazole is excreted into urine as its active form and its high concentration is maintained, fluconazole can be an excellent agent for the treatment of renal candidiasis.15 However, because of failure to achieve adequate concentrations in urine, fluconazole has lower efficacy for obstructions or renal failure. The alternative use of LAmB for neonatal candidiasis due to the high risk of nephrotoxicity of AmB was suggested by recent studies.13, 14, 16 However, it should be used with caution because candidemia in infants is often accompanied by renal candidiasis due to its low urinary clearance.14 Therefore, if LAmB is used as a treatment for candidemia, monitoring for complications of the kidney, such as urine analysis and kidney ultrasonography, may be necessary. In our case, if we had regularly observed urine culture or renal ultrasonography while using LAmB, we might have detected and treated invasive renal candidiasis early before renal drainage was indicated.

When a renal fungal ball causes obstruction of urine output and alteration in renal function, prompt drainage or surgical removal is required to relieve the obstruction.10 The first treatment option is a drainage procedure with or without local antifungal irrigation. The advantages of drainage by PCN include prompt drainage of the obstructed renal pelvis or ureter, direct access to obtain specimens from the renal pelvis to confirm the diagnosis, and direct irrigation of the fungal balls with an antifungal agent.17 However, interventions in preterm infants can be complicated because of the small renal pelvis and overall small size of the preterm neonate. In such situations, open surgical methods may be considered primarily.11 Local irrigation with fluconazole or AmB has proven to be effective.18 To our knowledge, there are no reports in the literature on the use of LAmB for local irrigation to treat obstructive renal candidiasis. Although LAmB administration alone is ineffective for the treatment of urinary tract infection because of the low urinary clearance of LAmB, we had no choice but to continue using LAmB in this patient with previous fluconazole failure and severe renal impairment. We continued systemic and local LAmB administration until complete resolution of the renal fungal balls was achieved. The endpoint of therapy is often ill-defined in neonates.14 One reported suggestion is that local treatment is usually continued until blood, urine, and nephrostomy cultures are negative.6 If there is no response to local irrigation with antifungal medication through a PCN tube, streptokinase and a fibrinolytic agent can be infused locally through the PCN tube.6 Endoscopic or open surgical removal of fungal balls may be a challenging procedure in preterm neonates, so it should be selected when the response to the abovementioned method is inadequate and the size of the fungal ball is not reduced.6, 18

A recently published therapeutic protocol for the management of these rare cases is helpful to clinicians.6, 18 However, clinicians still decide the individual options in different clinical situations. In our case, the combination of systemic LAmB and direct continuous irrigation via paired PCN tubes successfully eliminated bilateral-obstructing renal fungal balls in an ELBWI with progressive renal failure. The suggested method of treatment can be considered a valid option in ELBWI with bilateral urinary obstruction. Above all, in this high-risk group for invasive candidiasis, a high degree of suspicion and thorough multisystem evaluation are indispensable for the early diagnosis of invasive fungal infection and detection of complications.