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 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 2  |  Page : 21-25

Redefining acute kidney injury

1 Consultant Pediatric Intensivist, Mumbai, India
2 Clinical Assoicate, SRCC-NH Children's Hospital, Mumbai, India

Date of Submission06-Apr-2018
Date of Acceptance16-Apr-2018
Date of Web Publication30-Apr-2018

Correspondence Address:
Uma Ali
Consultant Pediatric Nephrologist, SRCC-NH Children's Hospital, Mumbai
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Source of Support: None, Conflict of Interest: None

DOI: 10.21304/2018.0502.00368

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Specific criteria using easily available biomarkers such as serum creatinine and urine output have been developed to define and stage acute kidney injury(AKI) at the bedside. The RIFLE criteria and the AKIN criteria are used for adults, the pRIFLE criteria for children and the KDIGO classification for both adults and children. The chief limitation in all the current criteria lies with the physiological limitations of using an insensitive functional marker such as serum creatinine as a surrogate marker for glomerular filtration rate (GFR). Varying methodologies for measuring serum creatinine and the lack of validation using isotope dilution mass spectrometry(IDMS), are additional technological limitations that challenge uniformity in India. Calculation of eGFR by the Schwartz formula is compromised by these technological limitations as well as by the lack of a validated k value for Indian children. Serum Cystatin C is superior to creatinine as a biomarker for GFR and appears at least 24 hours earlier than serum creatinine in the presence of AKI. However, expense and non- availability in clinical laboratories precludes its use. Urinary biomarkers appear very sensitive and reflect different stages of cell injury. Neutrophil Gelatinase associated Lipocalin (NGAL) has been shown to appear in the urine as early as 2 hours after renal injury. However, it is not specific for AKI alone and may also be increased in many inflammatory states and co-morbid conditions. The redefined criteria for AKI are invaluable in the critical care setup but need further refinement.

Keywords: RIFLE, Prifle,KDIGO,IDMS

How to cite this article:
Ali U, Krishnamurthy N. Redefining acute kidney injury. J Pediatr Crit Care 2018;5:21-5

How to cite this URL:
Ali U, Krishnamurthy N. Redefining acute kidney injury. J Pediatr Crit Care [serial online] 2018 [cited 2020 Sep 26];5:21-5. Available from: http://www.jpcc.org.in/text.asp?2018/5/2/21/281115

Acute kidney injury (AKI) occurring in the background of critical illness has a major impact on the outcome with mortality rates ranging from 9 to 67%[1]. The reported occurrence of AKI in critically ill children varies widely from 4.5-70% in various studies.[1],[2],[3] These differences may be due to heterogeneity of the patient population and or disease severity. However, some of the differences may be due to variations in defining AKI. Prior to 2004, acute renal failure had 30 different definitions.

  Rifle Criteria Top

The first attempt to redefine AKI was by the Acute Dialysis Quality Initiative group which created the RIFLE criteria for adults in 2004, based on two universally available biomarkers, serum creatinine and urine output, establishing a multidimensional, staged definition.[4] The RIFLE criteria staged the AKI into risk, injury and failure based on the duration of oliguria as well as the acute percentage rise in serum creatinine from baseline. They also added two additional stages of loss and ESRD based on the duration of the rise in creatinine or decrease in urine output. [Table 1].
Table 1: RIFLE criteria

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The RIFLE criteria made a landmark change in the way AKI was perceived and brought in uniformity in defining and staging AKI. Several studies have also validated the correlation of the staging with the length of hospital stay and mortality. However, it suffered from a few disadvantages. It relied on the percentage change in serum creatinine or GFR from baseline to define the stages. Percentage changes are less sensitive when applied to patients who have a baseline high creatinine and hence likely to miss early AKI when it is superadded on previously existing chronic kidney disease. It also needed a pre-illness creatinine. When that was not available, a default value of 75 ml per min was taken as the baseline value which may not be right for all patients. It also did not take into consideration prerenal causes of rise in creatinine.

  Akin Criteria Top

The AKI Network (AKIN) criteria, expanded the diagnosis of AKI and redefined the three stages as 1,2 and 3 and excluded loss and ESRD.[5] They included an absolute rise of 0.3 mg/dl of serum creatinine over a period of 48 hours as stage one, after correction of prerenal causes and excluding obstruction. They also did away with pre-illness creatinine. Two values of creatinine were needed in a 48 hour period after correcting prerenal factors and excluding obstruction. They included all patients on renal replacement therapy as stage 3 and did not use creatinine clearance values. As the timing of initiation of RRT varies widely in different units, based on varying protocols and resources, stage 3 as defined by AKIN is likely to be a heterogenous group. [Table 2]
Table 2: AKIN criteria

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  Prifle Criteria Top

The RIFLE criteria have been modified for use in children as the Pediatric RIFLE (pRIFLE) criteria.[6] Serum creatinine varies widely in children with age, gender and body size. Hence it is difficult to have criteria based on absolute creatinine values in children. The pRIFLE criteria therefore used estimated GFR calculated by the Schwartz formula, based on serum creatinine and height. They staged the AKI based on the percentage fall in eGFR. Where baseline GFR was not known, a default value of 100ml per min was taken as baseline. [Table 3]
Table 3: pRIFLE criteria

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Limitations of the pRIFLE criteria

The pRIFLE is based on percentage changes in the estimated GFR levels using the Schwartz equation. This has several limitations beginning with the accurate measurement of length in a critically ill child. Where baseline creatinine is not known it presumes a GFR of 100 ml per minute. This may have limitations in the Indian set up where the baseline GFR in normal children has not been established. It is well known that healthy Asian adults living in UK have a lower GFR than their Caucasian counterparts. This may be related to the lower muscle mass in this population. The baseline GFR in normal Indian children may therefore not be the same as their western counterparts and may lead to an overdiagnosis of AKI.

The original pRIFLE criteria used the old Schwartz formula with K values that varied with age and gender and creatinine measured by the Jaffes method. Since the creatinine measurements changed in the west to the enzymatic method or the kinetic Jaffe method with isotope dilution mass spectrometry (IDMS) validation, the Schwartz equation was revised and the k value changed to 0.413 for all ages and both sexes.[7] However, the validity of the new universal k value globally for all children has been questioned and suggestions have been made that each region should derive their own k value for their population.[8] The Schwartz equation has never been validated for Indian children. In India, there are variable methods of creatinine estimation which are generally non- validated. Hence the GFR calculated using the Schwartz equation may not be reliable as an absolute indicator of GFR in our population. However it is still useful as a trend marker .

Children less than 2 years of age pose a special problem. The GFR is 20 ml per min at birth and rapidly doubles by 2 weeks in full term healthy infants. Subsequently it increases gradually to reach adult values by 2 years of age. Hence baseline GFR in children less than 2 years of age cannot be presumed with certainty.

  Kdigo Criteria Top

The most recent modification, the Kidney Disease Improving Global Outcomes (KDIGO) classification system, harmonized RIFLE, AKIN, and pRIFLE and made it applicable for both adults and children.[9] The KDIGO defines the time frame for evaluation and uses the absolute value of creatinine rise for stage one. It also defines an absolute value of GFR for children less than 18 years of age, below which stage 3 should be diagnosed. KDIGO criteria can be applied to adults as well as children, thereby allowing for wider comparison of AKI data. [Table 4]
Table 4: KDIGO guidelines

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Comparison of different criteria

In a study conducted at a single centre over a 4-year span, all hospital admissions for AKI, both PICU and non-ICU were studied and evaluated based on the p RIFLE, AKIN and KDIGO staging system, using the creatinine levels for definition and not the urine output. It was noted that pRIFLE identified the largest cohort of patients in stage 1, hence was more sensitive to mild alterations in serum creatinine levels. For stage 3, AKIN showed the smallest cohort probably because its definition of stage 3 does not include the creatinine clearance but only percentage change in creatinine value. There was a greater correlation between the stages in AKIN and KDIGO criteria, as compared to AKIN and pRIFLE.[10] All the three criteria concurred on the increased mortality and increased duration of hospital stay associated with higher stages of AKI, especially in critically ill children as compared to non PICU patients. The incidence of AKI varied according the criteria used. The incidence according to pRIFLE, AKIN and KDIGO was 51.1%,37.3% and 40.3% respectively, emphasizing the need for developing one validated uniform criteria.

Limitations of the redefined criteria

The drawbacks of the staging criteria are to a large extent based on the drawbacks of serum creatinine and urine output as surrogate markers for glomerular filtration rate. This includes both physiological and technological limitations.

Serum creatinine is a functional marker and hence rises only after sufficient ultrastructural injury has already occurred. It is not a sensitive marker of renal injury and increases only after almost 50% of function is lost. The value of creatinine is also influenced by age, muscle mass, nutritional status which affect serum creatinine levels independent of the renal function. Several drugs alter the secretion of creatinine This is particularly important in critical illness as these patients receive multiple medications. As the measured value reflects the concentration, it will vary depending on the fluid status. As most patients in critical illness tend to receive a lot of fluids, the dilutional effects may lead to under estimation of serum creatinine and hence the presence and stage of AKI.

The absolute value of creatinine varies with the technology used for its measurement. The Jaffe’s picric acid method measures non-creatinine chromogens as well. The non-creatinine chromogens may account for 20% of the total measured value and is particularly misleading in children where we are looking at small changes. The Jaffes kinetic method or the enzymatic assay that is referenced to IDMS is the methodology of choice especially in neonates, infants and small children as these measure serum creatinine only and small changes can be readily appreciated.

The urine output criteria are likely to miss the non- oliguric renal failure. Almost 25% of pediatric AKI, especially the drug induced failures are likely to be non-oliguric.

Biomarkers beyond creatinine

Cystatin C

Like serum creatinine, serum cystatin C is a functional marker. The protein is excreted exclusively by GFR. It is reabsorbed and catabolized by the tubules but is not secreted. It is more sensitive to a fall in GFR than serum creatinine and rises at least 24 hours earlier than serum creatinine in AKI. However, measurements of cystatin C are expensive and not available in routine clinical laboratories.

Urinary biomarkers

Unlike serum creatinine and Cystatin C, urinary biomarkers reflect cell injury and appear earlier than the functional markers. Several urinary biomarkers like Neutrophil gelatinase associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), Interleukin-18 (IL-18), have been found useful in identifying early AKI.

The biomarkers can be grouped as

  1. Inflammatory markers like NGAL, Interleukin-6, IL-18
  2. Cell injury markers like Kidney Injury Molecule-1 (KIM-1), Sodium-Hydrogen (Na-H) Exchanger-3, Netrin-1
  3. Cell cycle markers like Urinary tissue inhibitor of Metalloproteinase-2, Insulin like Growth Factor-7.

One of the best studied biomarkers is the NGAL The urinary appearance of NGAL has been shown to occur 2 hours after the onset of renal injury and corelates well with the rise in serum creatinine 72 hours later. However, this interpretation must be made in the light of the clinical context, as NGAL may be elevated in conditions such as urinary tract infections as well as in other inflammatory states. The cell cycle markers are predictors of poor outcome and need for renal replacement therapy. However, their levels may be affected by the presence of other comorbidities.[11]

Biomarkers seem to perform best when there is a clear-cut time of renal injury and no associated comorbidities. In patients with critical illness and multiple comorbidities biomarkers may be reflecting the severity of the disease and not just AKI per se.

Although higher values may be seen in those with AKI there is often considerable overlap in the values between the groups. More studies are needed to identify a specific level of a single biomarker or a panel of biomarkers that can identify subclinical AKI in the situation where the patient’s baseline creatinine is unknown or when the creatinine value and creatinine clearance appear to be in the normal range, precluding the diagnosis of AKI if not specifically looked for.

In conclusion, the new criteria for AKI have brought in uniformity in terminology and have redefined AKI facilitating early diagnosis, assessment of severity and allows for comparison of data. However, several limitations exist largely due to the physiological and technological limitations in serum creatinine as a surrogate marker for GFR in the critical care setup. Refinement in defining AKI will continue using combinations of structural markers for early diagnosis and functional markers for staging.

Source of Funding : Nil

Conflict of Interest: Nil

  References Top

Plotz FB, Bouma AB, van Wijk JA, Kneyber MC, Bokenkamp A . Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med 2008; 34:1713-17.  Back to cited text no. 1
Bailey D, Phan V, Litalien C, Ducruet T, Merouani A, Lacroix J, Gauvin F. Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study. Pediatr Crit Care Med 2007; 8:29-35.  Back to cited text no. 2
Rustagi RS, Arora K, Das RR, Pooni PA, Singh D . Incidence, risk factors and outcome of acute kidney injury in critically ill children—a developing country perspective. Paediatr Int Child Health 2017; 37:35-41.  Back to cited text no. 3
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute Dialysis Quality Initiative workgroup. Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs. The second International Consensus Conferences of the Acute Dialysis Quality Initiative Group. Crit Care 2004; 8(4): R 204-12.  Back to cited text no. 4
Mehta RL Kellum JA, Shah SV, Molitors BA, Ronco C et al. Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury Crit Care 2007; 11:R31.  Back to cited text no. 5
Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS et al. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007; 71: 1028-35.  Back to cited text no. 6
Schwartz GJ,Muñoz A, SchneiderMF, Mak RH, Kaskel F,Warady BAFS. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20:629-637.  Back to cited text no. 7
de Souza VC, Rabilloud M, Cochat P, Selistre L, Hadj-Aissa A, Kassai B, Ranchin B, Berg U, Herthelius M, Dubourg L Schwartz formula: is one k-coefficient adequate for all children? PLoS One 2012; 7:1-7.  Back to cited text no. 8
Kidney Disease Improving Global outcome. Acute Kidney Injury Work Group.KDIGO clinical practice guidelines for acute kidney injury. Kidney Int supplement 2012; 2:1-138.  Back to cited text no. 9
Scott M. Sutherland, John J. Byrnes, Manish Kothari. AKI in Hospitalized Children: Comparing the pRIFLE, AKIN, and KDIGO Definitions Clin J Am Soc 2015; 10(4): 554-561.  Back to cited text no. 10
Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W. Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature. Nephron Dial Transplant 2012; 28:254-273.  Back to cited text no. 11


  [Table 1], [Table 2], [Table 3], [Table 4]


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