Case of iatrogenic neonatal acute kidney injury requiring dialysis and review of literature

Abstract

A full-term male baby was administered furosemide and enalapril for treatment of cardiac failure secondary to a ventricular septal defect. He also received piperacillin-tazobactam and amikacin for 7 days for suspected early-onset neonatal sepsis. He developed anuria and raised creatinine and was referred with acute kidney injury (AKI)—neonatal KDIGO (Kidney Disease Improving Global Outcomes) stage 3 on day 20. Urine output and renal parameters improved after discontinuing drugs and peritoneal dialysis. This case report highlights the importance of serial monitoring of kidney function tests while using nephrotoxic drugs and ensuring correct dosage and titration. In the early stages, AKI can be treated with conservative therapy but once established, renal replacement therapy might be required. It can also lead to chronic kidney disease.

Background

Acute kidney injury (AKI) is commonly seen in babies admitted to neonatal intensive care units (NICU) and is associated with increased mortality and morbidity in these babies.¹ Nephrotoxic drugs lead to 16% of all paediatric AKI cases.² Common causes of AKI in neonates include asphyxia, sepsis, drug-induced, inborn errors of metabolism and obstructive causes like a posterior urethral valve. In this case report, we describe a case of drug-induced AKI managed with peritoneal dialysis (PD) and subsequently discharged after complete recovery.

Case presentation

A term baby born to a primigravida mother by caesarian section was referred to us from an outside hospital on day 20. He had respiratory distress at birth. In view of prolonged rupture of membranes, the possibility of early-onset sepsis was considered. He was treated with intravenous antibiotics piperacillin-tazobactam (100 mg/kg/dose two times a day) and amikacin (15 mg/kg/day one time a day) for 7 days. A systolic murmur was noted on examination. Echocardiography showed an 8 mm atrial septal defect (ASD) with a 5 mm peri-membranous ventricular septal defect (VSD) (figure 1). Furosemide (2 mg/kg/day) and enalapril (0.1 mg/kg/day) were initiated for congestive cardiac failure. Serial renal function tests (RFTs) showed a rising trend in creatinine values. He was discharged on day 18 of life on the medications mentioned above. On day 20, the baby was referred with nil urine output and a creatinine of 6.8 mg/dL.

Figure 1.

(A) Echocardiography and (B) colour Doppler showing atrial septal defect with ventricular septal defect.

Investigations

At admission, the baby was anuric and had deranged RFTs—urea 163 mg/dL, creatinine 8.3 mg/dL, and hyponatraemia—Na 129 meq/L. The trend in serum creatinine and urine output during the hospital course is shown in figure 2. Ultrasound kidney and bladder showed normal echogenicity, size and echotexture.

Figure 2.

Trend in serum creatinine and urine output in our case. DOL, Day of life.

Differential diagnosis

Differentials for AKI causation were kept as medications, sepsis, or underlying congenital anomalies of the kidney and urinary tract. Ultrasound kidney was normal and the sepsis screen was negative. With an antecedent history of administration of nephrotoxic drugs, AKI secondary to nephrotoxic drugs was considered more likely. Amikacin, piperacillin-tazobactam, enalapril and furosemide were the implicated drugs. However, the serum drug levels of amikacin could not be obtained due to the lack of resources. This would have made amikacin toxicity even more likely.

Treatment

As the baby presented with stage 3 AKI as per neonatal KDIGO (Kidney Disease Improving Global Outcomes) classification, PD was initiated. Drugs were discontinued.

PD using a pigtail catheter was started with 1.7% dextrose fluid, fluid volume 20 mL/kg, and 1 hour cycles. There was a serial fall in creatinine levels to 2.1 mg/dL. Urine output was re-established on day 4 of hospitalisation (figure 2). PD was continued for 108 hours. PD fluid was sent for analysis every 48 hours. Subsequently, the peritoneal fluid analysis showed features of peritonitis with cells 1248/c mm and 94% polymorphonuclear cells. Fluid culture grew Enterococcus and Enterobacter. According to the sensitivity report, the baby was treated with vancomycin.

On day 35, he had respiratory distress with hepatomegaly suggestive of congestive heart failure (CHF). ECHO showed fenestrated ASD and 5 mm VSD. Spironolactone (2 mg/kg/day) was started. He responded well to decongestive measures and respiratory distress settled.

Outcome and follow-up

At discharge, urea was 22, creatinine 0.4 mg/dL and blood pressure 58/35 (between the 5th and 50th centile). On follow-up, the baby had adequate weight gain. Renal parameters were normal.

Discussion

AKI is defined based on urine output and serum creatinine as per the neonatal KDIGO classification.³ According to this classification, stage 1 is defined as the absolute rise in serum creatinine levels≥0.3 mg/dL within 48 hours or a rise in creatinine 1.5–1.9 times from the baseline or urine output<0.5 mL/kg/hour for 6–12 hours. A rise in creatinine 2.0–2.9 times from the baseline or urine output<0.5 mL/kg/hour for≥12 hours is suggestive of stage 2. Lastly, stage 3 is described by the rise in sCreatinine more than three times from the baseline or absolute creatinine≥2.5 mg/dL or receipt of dialysis. Urine output<0.5 mL/kg/hour ≥ 24 hours or anuria for 12 hours is also considered stage 3 AKI. Different classifications like AKIN, nRIFLE and modified KDIGO have been proposed for defining AKI, but KDIGO has been adopted universally to maintain consistency across studies and regions. Serum creatinine is the most commonly used marker for AKI, but creatinine levels are not reliable in the initial few weeks of life. AKI is associated with increased mortality and length of hospital stay.¹ The incidence of AKI in NICU-admitted babies is around 30%.⁴

The dynamic changes in renal blood flow occurring postnatally predispose neonates to AKI. Preterm and low birth weight (LBW) babies are at increased risk for AKI as most nephrons are formed in the last trimester. Incidence varies between 48% in extreme preterm babies to 37% in term babies.¹ Other predisposing factors include babies with cardiac surgery, hypoxic-ischaemic encephalopathy, necrotising enterocolitis and exposure to nephrotoxic drugs.⁴

Nephrotoxic drugs not only cause AKI but also disrupt nephron development after birth. This predisposes preterm/LBW babies to develop chronic kidney disease after an acute insult. Drugs like amikacin, gentamicin, indomethacin and vancomycin have been associated with AKI.^{5 6}

Rhone et al studied nephrotoxic drug exposure in VLBW babies and found that at least one drug was used in 86% of cases with mean nephrotoxin days of 14.⁵ In the index case, the baby was administered piperacillin, amikacin, furosemide and enalapril, all of which had a detrimental effect on the kidneys. A retrospective study of 276 preterm infants by Barhight et al showed that antimicrobials constituted 80% of all nephrotoxic drugs administered.⁶ Gentamicin was the most commonly implicated drug in patients with AKI, followed by nafcillin and indomethacin. Piperacillin was used in 24% of cases with AKI. Endo et al observed nephrotoxicity in 21% of neonates once daily versus 36% on every 48-hour administration of amikacin.⁷ With every addition of a nephrotoxic drug, the odds of AKI increased by 1.83 times. A nested case-control study by Slater et al in 914 children admitted to PICU showed that furosemide increased the odds of AKI by 1.9 times and gentamicin by 1.8 times.⁸ Furosemide, a commonly used drug to treat CHF in infants can cause prerenal AKI by reducing preload. In the absence of monitoring of fluid balance, it may precipitate renal AKI. In the index case, the cause of AKI was attributed to the use of multiple nephrotoxic drugs and poor oral intake, thus, leading to dehydration and worsening renal parameters. Angiotensin inhibitor, enalapril, is another commonly used drug in CHF. The incidence of AKI is more in preterm/LBW babies with concomitant use of diuretics and postoperative cases. Mechanisms postulated in renal injury include direct nephrotoxic effect, efferent arteriolar vasodilatation leading to reduction in a GFR, and systemic hypotension resulting in decreased renal perfusion. Thus, volume depletion with the use of diuretics makes them more vulnerable to AKI. Previous reports on drug-induced AKI in neonates and the management strategies have been included in table 1.

Table 1.

Case reports of drug-induced neonatal AKI and its management

Reported by	Year	Drug/dose used	Age of presentation	Management
Busuttil et al.13	1973	Cephaloridine+gentamicin	DOL 11 (Day 2 of therapy)	Conservative
Levine et al.14	1985	Intravenous epinephrine (intra-aortic)	DOL 10 (immediate after drug administration)	Conservative
Schubiger et al.15	1988	Enalapril in mother	17 days prior to delivery (baby had anuria since birth)	Peritoneal dialysis
Dutta et al.16	2003	Oral enalapril-0.1 mg/kg/day	DOL 7 Day 4 of treatment	Peritoneal dialysis
Shinomiya et al.17	2003	Phenylephrine eye drops	DOL 29	Conservative
Erdeve et al.18	2008	Oral Ibuprofen 10-5-5 mg/kg	DOL 5 Day 2 of treatment	Fluid/dopamine infusion
Essid et al.19	2010	Cefotaxime+gentamicin	Third week	Discontinuation of drugs
Tan et al.20	2011	Oral captopril 0.3 mg/kg/day + Furosemide 1 mg/kg/dose Three times a day	DOL 21 Day 3 of treatment	Discontinuation of drug

AKI, acute kidney injury; DOL, Day of life.

Medical management remains the mainstay of therapy in AKI. Common indications of renal replacement therapy (RRT) include fluid overload, uraemia, hyponatraemia, hyperkalaemia and severe metabolic acidosis. In AWAKEN study, RRT was required in 4% of cases.¹ Different modalities include PD, and continuous renal replacement therapy.^{9 10} Being a simple procedure without the need for vascular access, PD is preferred in neonates for RRT. Usually, Tenckhoff catheters are used. Due to their large size and more risk of injury, alternative devices are gaining popularity. In the index case, PD was performed with a pigtail catheter. Others have used intravascular cannula, Flex-Neck catheter, or Cook catheter in small babies.

A systematic surveillance programme–baby NINJA (Nephrotoxic Injury negated by just-in-time action) was shown to reduce the incidence of AKI by 78%.¹¹ Under medication stewardship adopted by the ICU (Intensive care unit) team, daily creatinine levels were measured in babies who received prolonged (>3 days) duration of aminoglycosides. The Renal Angina Index (RAI) is also a validated scoring system for predicting the risk of AKI in critically ill children. It is calculated based on two variables-AKI risk levels and evidence of renal injury. An RAI score≥8 has high predictability of AKI.⁹ Novel biomarkers like neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, cystatin-C, interleukin 18, and liver-type fatty acid binding protein have shown promising results in rapid detection of AKI.¹² Thus, AKI is preventable if nephrotoxic drugs are used cautiously with appropriate dosage and monitoring of adverse effects. Follow-up is necessary in all cases for early detection of chronic kidney disease.

Learning points.

• Nephrotoxic drugs should be used judiciously and correct dosage should be ensured.

• Serial monitoring of renal function tests is mandatory while administering antibiotics and diuretics.

• When detected early, acute kidney injury resolves with conservative management and discontinuation of the drug.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s)