Acquired Bartter-like syndrome association with netilmicin therapy in an extremely low birth weight infant

Abstract

Aminoglycosides are commonly used antibiotics with excellent renal parenchymal penetration. Their clinical effectiveness is counter balanced with the risk of renal toxicity, which develops in a dose-dependent fashion. Aminoglycoside-induced renal tubular dysfunction could result in diffuse damage or manifest as a Fanconi-like syndrome, Bartter-like syndrome (BLS), or distal renal tubular acidosis.^1–4 Although tubulopathy associated with amikacin and gentamicin was reported in adults and rarely children, to the best of our knowledge, netilmicin-associated BLS neither in adults nor in children has been reported in the literature. We here report a 30-week, 770 g male preterm infant who developed BLS just after netilmicin treatment for neonatal sepsis and recovered 6 weeks after the drug cessation.

• Acquired Bartter-like syndrome
• netilmicin
• preterm infant

Case report

A male baby weighing 770 g was born to 28 years old, gravida 1, and para 1 mother. Antenatal ultrasound showed anhydramnios and intrauterine growth retardation. At 30 weeks of gestation, the mother underwent caesarean section for premature labor and fetal distress. At the delivery room, first minute APGAR score was 6 and fifth minute APGAR score was 8, spontaneous respiration was insufficient, there was subcostal, intercostal retractions and nasal flaring. Immediately after birth, the baby developed severe respiratory distress and was intubated and ventilated. Anteroposterior chest radiographs showed diffuse bilateral reticulogranular opacities, and air bronchograms, findings consistent with severe RDS. He received surfactant therapy twice, due to severe RDS. Umbilical vein catheter was inserted and empirical antibiotherapy (ampicillin 25 mg/kg/dose × 2 and netilmicin 5 mg/kg/day) was started.

On postnatally first day; hemogram, biochemical parameters (renal and liver function tests, ions, blood glucose), coagulation parameters were normal. Acute phase reactants and TORCH viral titers were negative. On day third of intensive care, the infant was less active and had apneic episodes, with tachycardia and he had poor peripheric circulation. The blood culture and urine culture were performed. Chest X-ray demonstrated pneumonic infiltration of both lower lobes. Cranial and abdominal sonography was normal. Laboratory analyses were as follows: hemoglobin 13.3 g/dL, white blood cells count 13,300/mm³ and platelets count 68,000/mm³. Biochemical findings were as follows: blood urea nitrogen 10 mg/dL, creatinine 1.03 mg/dL, total protein 3.7 g/dL, albumin 2.8 g/dL, sodium 133 mmol/L, potassium 3.59 mmol/L, calcium 8.5 mg/dL and magnesium 2.3 mg dL. Aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase values were normal. C-reactive protein was 14.6 mg/L (normal: 0–6 mg/L).

Meropenem and vancomycin therapies (meropenem 20 mg/kg every 12 h and vancomycin 15 mg/kg every 18 h) were added to netilmicin treatment. Ampicillin was stopped. On the sixth day of netilmicin therapy, hypokalemia (2.7 mmol/L), hyponatremia (123 mmol/L), hypomagnesemia (1.4 mg/dL) and hypocalcemia (7.2 mg/dL) were determined in the routine biochemical examination. Serum urea nitrogen level was 19 mg/dL, serum creatinine was 0.5 mg/dL and bicarbonate concentration was 31.2 mmol/L. Urine amount was 2.5 cc/kg/day, urine Na: 128 mmol/L, urine K: 50 mmol/L, urine Cl: 92 mmol/L, urine Mg²⁺: 7.3 mg/dL, urine Ca²⁺: 41.3 mg/dL, urine creatinine: 26.6 mg/dL and urine osmolality: 271 (50–1200 mOsm/kg). Fractional excretion of Na, K and Mg was elevated at 4.2% (normal, <1%), 17% (normal, 8.5 ± 3.8) and 12% (normal, 1.6–8.1%), respectively. Serum hormonal assays on blood drawn on the same day revealed: normal plasma renin activity 31 ng/mL/h (2–35 ng/mL/h) and normal serum aldosterone concentration 140 pg/dL (38–313 pg/mL).

The blood culture yielded a methicillin resistant coagulase negative Staphylococcus aureus demonstrated susceptibility to aminoglycosides, vancomycin and linezolid. Treatment with meropenem and vancomycin were continued. Follow-up blood cultures were sterile. Antibiotics were administered duration of 10 days.

Hypokalemia, metabolic alkalosis, hypocalcemia, hypercalciuria and hypomagnesemia were consistent with an acquired Bartter-like syndrome. Potassium, calcium and magnesium supplements initially were given with intravenous potassium chloride, calcium gluconate and magnesium sulfate. Later, oral tablets were used when the patient’s condition stabilized. However, prolonged and fluctuating electrolyte imbalance continued for 6 weeks.

Discussion

The nephrotoxic potential of various aminoglycosides depends upon the number of free amino groups on their surface. The nephrotoxicity of various aminoglycosides in the decreasing order is neomycin > gentamicin > tobramycin > amikacin > netilmicin > streptomycin.5,6 Various risk factors predisposing to aminoglycoside nephrotoxicity such as fluid depletion, potassium and magnesium deficiency, endotoxemia, pre-existing renal disease, newborn, prematurity, advanced age, co-administration of other nephrotoxins, lengthy duration of treatment repeated courses of aminoglycosides, liver disease, obesity and male sex.7 Bartter-like syndrome characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia and normal kidney function has been described in patients treated with aminoglycosides. A small number of pediatric case reports have documented the association between aminoglycoside therapy and Bartter-like syndrome. All of these cases were gentamicin induced Bartter-like syndrome.8–10

We reported an extremely low birth weight infant with Bartter-like syndrome induced netilmicin therapy. Our patient developed hypokalemic metabolic alkalosis, hypocalcemia, hyponatremia and hypomagnesemia after a 6-day treatment with netilmicin, 3.85 mg, every 48 h (total 11.5 mg). Coexisting risk factors of this case included immaturity, co-administration of another nephrotoxic antibiotic (vancomycin) and male sex. None had evidence of primary renal disease. Previously he did not use any diuretic.

Bartter-like syndrome are still unclear, some authors have proposed mechanisms based on inherited Bartter syndrome, including dysfunction of the Na-K-2Cl co-transporter NKCC2, the apical adenosine triphosphate (ATP)-dependent potassium channel ROMK (encoded by KCNJ1), the chloride channel ClC-Kb (encoded by CLCNKB), and inappropriate activation of the basolateral calcium-sensing receptor (CaSR).4

In the thick ascending limb of the loop of Henle, the entry of sodium chloride primarily occurs through NKCC2 in the luminal membrane, which is driven by the adenosine triphosphatase (ATPase) sodium-potassium pump (Na-K-ATPase) in the basolateral membrane. The reabsorbed sodium and chloride ions return to systemic circulation through Na-K-ATPase and the C1C-Kb chloride channel, respectively.

Recycling of potassium ion to the lumen through ROMK leads to a positive potential there, which results in the paracellular reabsorption of divalent cations, such as calcium and magnesium. Reabsorption of sodium and calcium ions is linked closely in this nephron segment, and the activities of both NKCC2 and ROMK are influenced by CaSR.11–14

Our patient shows the ability of netilmicin to cause multiple renal tubular abnormalities. The initial laboratory data in this case [i.e., predominant urinary calcium and magnesium and sodium wasting (with hypocalcemia, hypomagnesemia hypokalemia and hyponatremia)] are identical to those in patients with gain-of-function mutations of CaSR, NKCC2 or ROMK. Follow-up urinary chemistry data in this patient showed persistent urinary potassium, calcium and magnesium wasting. One possible explanation for this set of observations is persistence of dysfunction of CaSR, NKCC2 or ROMK. We suggested that netilmicin administration was associated with decreased NKCC2, CaSR and ROMK function in the ascending limb of the loop of Henle.

Bartter-like syndrome, Fanconi syndrome and Gitelman syndrome are among the differential diagnoses. Fanconi syndrome was not likely because of the absence of metabolic acidosis, hypouricemia, hypophosphatemia and glycosuria. Gitelman syndrome would be unusual in the presence of hypercalciuria. Our case had hypokalemia, hyponatremia, hypocalcemia and hypomagnesemia. There were no metabolic acidosis, hypouricemia, hypophosphatemia and glycosuria in our case.

The transient nature of the electrolyte and acid–base abnormalities as well as prompt response to appropriate electrolyte supplementation are typical features of aminoglycoside-induced Bartter-like syndrome.15 Our patient had netilmicin-induced Bartter-like syndrome with delayed recovery of as long as 6 weeks.

In summary, this report of an extremely low birth weight infant presenting with Bartter-like syndrome after netilmicin therapy suggests that this syndrome is caused by netilmicin that induces multiple renal tubular abnormalities. Preterm newborns receiving netilmicin therapy should be monitored for complication with acquired Bartter-like syndrome. Prompt diagnosis and correction of these electrolyte and acid–base imbalances can reduce the risk of potentially life-threatening complications.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.