Abstract

A standardized classification of acute kidney injury (AKI) has recently been proposed with the RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) score. Such definition/classification has been applied both in adult and in paediatric patients. Neonatal definition of AKI likely results as a challenging task due to the peculiar renal pathophysiology of newborn critically ill patients. Their so-called ‘immature kidneys’ require careful management and neonatal AKI is frequently complicated by unfavourable outcomes. A recent attempt to implement the RIFLE score with a neonatal modification might lead to improvement on the knowledge of AKI incidence and epidemiology.

Although newborn kidneys are typically considered ‘immature’, they are called to a significant workload in the early phases of life. In fact, during the latter part of gestation, they essentially maintain amniotic fluid volume with a fetal urine output of 10 mL/kg/h [1]. Then, in the first week after birth, kidneys have to work hard in order to accomplish the physiologic extracellular fluid reduction (the primary reason for post-natal 10% weight loss) and to manage the large water load coming from breast-feeding [1].

Naturally, glomerular filtration rate (GFR) in neonates increases steadily from a very low level to ‘adult’ rate in about 12 months. Hence, the neonatal high levels of creatinine, reflecting maternal concentrations, tend to decrease in a relatively slow manner, depending on GFR progressive increase [1].

The urine flow is mainly regulated by tubular reabsorption that must couple a low GFR with high urine output [1]. This fascinating clinical picture essentially frames a sort of physiologic state of polyuric ‘acute’ kidney injury (AKI).

Such delicate equilibrium works perfectly unless (even small) derangements on renal blood flow or nephrogenesis occur: in such a case, kidney dysfunction leads to imbalance in water regulation, patient swelling, electrolytes disorders (hypo-natremia, hyperkalaemia) and acid–base disequilibrium (typically metabolic acidosis). Careful clinical judgment, early recognition of kidney dysfunction and super-accurate fluid and electrolyte infusion/correction are mandatory to avoid fluid overload and iatrogenic electrolyte disorders due to inappropriate management [2].

When the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria were originally conceived [3], they had the purpose of providing clinicians with a definition of AKI simply based on serum creatinine and urine output (UO) (Table 1). RIFLE was not created to identify the cause of AKI but rather to detect the presence of the syndrome in a standardized way [4]. When use of the RIFLE score began, it became clear that the severity of oliguria and creatinine increase were often displaying different behaviours. The authors were well aware of this and they suggested using the worse of the two parameters to identify the diagnosis and the staging. Nevertheless, some authors tried to examine the two criteria separately in order to see whether or not UO, with respect to creatinine criteria, achieved a better association with clinical outcomes of critically ill patients [5]. Even if a definitive answer to this point has not been provided so far, it has been remarked that both criteria have limitations and specific advantages. In particular, UO is by far one of the earliest clinical signs of acute renal impairment and it is the simplest method of diagnosing it: as a matter of fact, in paediatric, neonatal and adult populations, regardless of patient diagnosis, urinary catheterization, admission ward and citizenship, urine collection is a parameter that is always available. Oliguria is certainly a sensitive though highly a specific marker of AKI [6] but, on the other hand, creatinine alone may underestimate the severity of AKI, due to its delayed increase in the setting of rapidly evolving AKI, especially in patients with fluid overload and haemodilution [7]. Recent observational studies highlighted that UO and creatinine bring different results both important in AKI patients and not to overlook for AKI diagnosis [8]. Furthermore, awareness of milder forms of AKI, those with the potential of worsening and that should be targeted by specific treatment, is one of the most important goals of RIFLE classification.

Table 1.

Synoptic view of adult, paediatric and neonatal RIFLE

  Creatinine criteria
 
Urine output criteria
 
RIFLE pRIFLE nRIFLE RIFLE pRIFLE nRIFLE 
Risk Increased creatinine × 1.5 or GFR decreases >25% eCCl decrease by 25% UO ≤ 0.5 mL/kg/h × 6 h UO < 0.5 mL/kg/h for 8 h UO < 1.5 mL/kg/h for 24 h 
Injury Increased creatinine × 2 or GFR decreases >50% eCCl decrease by 50% UO ≤ 0.5 mL/kg/h × 12 h UO < 0.5 mL/kg/h for 16 h UO < 1.0 mL/kg/h for 24 h 
Failure Increased creatinine × 3 or GFR decreases >75% or creatinine ≥4 mg/dL (acute rise of ≥4 mg/dL) eCCl decrease by 75% or eCCl <35 mL/min/1.73 m2 UO ≤ 0.3 mL/kg/h × 24 h or anuria × 12 h UO < 0.3 mL/kg/h for 24 h or anuric for 12 h UO < 0.7 mL/kg/h for 24 h or anuric for 12 h 
Loss Persistent failure >4 weeks 
End stage Persistent failure >3 months 
  Creatinine criteria
 
Urine output criteria
 
RIFLE pRIFLE nRIFLE RIFLE pRIFLE nRIFLE 
Risk Increased creatinine × 1.5 or GFR decreases >25% eCCl decrease by 25% UO ≤ 0.5 mL/kg/h × 6 h UO < 0.5 mL/kg/h for 8 h UO < 1.5 mL/kg/h for 24 h 
Injury Increased creatinine × 2 or GFR decreases >50% eCCl decrease by 50% UO ≤ 0.5 mL/kg/h × 12 h UO < 0.5 mL/kg/h for 16 h UO < 1.0 mL/kg/h for 24 h 
Failure Increased creatinine × 3 or GFR decreases >75% or creatinine ≥4 mg/dL (acute rise of ≥4 mg/dL) eCCl decrease by 75% or eCCl <35 mL/min/1.73 m2 UO ≤ 0.3 mL/kg/h × 24 h or anuria × 12 h UO < 0.3 mL/kg/h for 24 h or anuric for 12 h UO < 0.7 mL/kg/h for 24 h or anuric for 12 h 
Loss Persistent failure >4 weeks 
End stage Persistent failure >3 months 

Question mark (‘?’) is intended to mean uncertain thresholds.

GFR, glomerular filtration rate; Ecl, estimated creatinine clearance; UO, urine output.

AKI classification in the adult population has been validated in hundreds of studies with satisfactory results [5]. Several adjusted RIFLE scores have been proposed: some authors discarded UO criteria, while others proposed disparate definitions of baseline renal function, and in some large observations, RIFLE score was evaluated only on the day of intensive care unit admission [5]. In line with the versatility of RIFLE, Akan Arikan proposed a modified RIFLE score for children (paediatric RIFLE: pRIFLE): percentage decrease of estimated creatinine clearance (instead of change of absolute creatinine levels/GFR) and slightly modified UO criteria were conceived in order to meet the paediatric low changes of creatinine levels and different urine output flows (Table 1) [9]. pRIFLE has been validated in several paediatric studies and a recent systematic review found conflicting associations between RIFLE and mortality, length of stay, illness severity and measures of kidney function [10]. It must be noted, however, that several studies of paediatric cardiac surgery patients, whose post-operative AKI occurrence is frequent, showed a satisfactory performance of pRIFLE score in AKI identification, scoring and prognosis prediction [11].

In this issue of Nephrology Dialysis Transplantation, Dr Torres de Melo and coworkers attempted, for the first time, the description of neonatal RIFLE (nRIFLE, Table 1) in a cohort of more than 300 neonates admitted to a general neonatal intensive care unit (NICU) [12]. A further modification/adaption of the original RIFLE criteria was proposed by these authors in order to cope with the peculiar physiopathology of newborn patients (Table 1). Two important merits of this contribution have to be remarked. First, very little is known on the epidemiology of AKI in premature and newborn babies. The little information that is available is far from being standardized and this first attempt is a very important starting point. Problems in the diagnosis of AKI in NICUs are essentially the relatively reduced number of creatinine measurements (due to blood sparing in these fragile patients), the uncertainty on normal creatinine levels (mostly influenced by maternal creatinine), variable GFR (secondary to ‘immature’ kidney function) and, consequently, the absence of baseline/reference values. Furthermore, as interestingly pointed out by Torres de Melo, these patients infrequently have a urinary catheter in place: hence timed diaper weight is needed to have an exact idea of UO flow. The authors show in this paper, finally, that UO flow has to be significantly ‘adjusted’ for the neonatal population, the pRIFLE urinary criteria being too restrictive: newborn and premature urine flow has to be considered normal only when higher than 1.5 mL/kg/h. The reason for this finding might be identified in the neonatal difference in body water content and in the immature tubular development. So, from a practical point of view, diaper weighing (whose accuracy is presumably dependent on scale precision) might be considered more specific with larger weight changes: in a 2.5 kg patient, a normal UO of 2 mL/kg/h measured every 3 h as in the present study results in a weight change of only 15 mg and smaller weights may easily induce ‘false positive oliguria’. When RIFLE was born, it was specifically dedicated to the adult critically ill population (admitted in the general intensive care unit, it could be also added) and its inventors had not in mind to ‘shoot’ the same RIFLE bullet for all settings. Efforts on RIFLE classification adaptation to specific settings are welcome in order not to misclassify AKI in different populations: the research on neonatal renal dysfunction diagnosis and epidemiology has to now be intensified.

There is still much work to be done, as also explained by Torres de Melo and coworkers, neonatal population ranges from very low birth weight premature patients to full-term babies with unpredictable differences in normal UO levels as well as in reference creatinine values. Then, patients with congenital diseases (with the potential for renal insult during the gestational age) may have a ‘renal behaviour’ different from that in patients with acute events (after a normal fetal development). Furthermore, it is currently unknown (and the present study did not specifically address this aspect) whether the creatinine criteria of nRIFLE should also be adjusted (Table 1).

In this light, the setting of congenital heart disease may be a wonderful field of operation, due to the high occurrence of neonatal AKI, the possibility of accurate hourly measurement of urine flow and daily creatinine levels assessment. Finally, biomarkers use in neonates and pre-term babies is currently open to in deep evaluation, provided that specific molecule and/or biomarker levels still have to be defined for these patients [13]. It is possible, given its high sensitivity and specificity and the ease of withdrawing, that urinary neutrophil gelatinase associated lipocalin will be one of the most studied biomarkers in the paediatric and neonatal setting [14, 15]; currently, however, the cost associated with novel biomarker application can only be justified for research purposes, since the benefits derived from their application on AKI management still have to be univocally showed.

In conclusion, even if neonatal RIFLE for AKI diagnosis still needs further refinements, in the proposed version it was shown to work adequately. Research on neonatal AKI epidemiology and management is currently a priority in the medical community and the main role of such new AKI classification will hopefully be able to help clinicians in diagnosis standardization, better awareness and expertise sharing. The future of nRIFLE is open to collaboration.

CONFLICT OF INTEREST STATEMENT

None declared.

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