Cardiovascular Journal of Africa: Vol 31 No 4 (July/August 2020)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 31, No 4, July/August 2020 AFRICA 209
undergoing cardiac surgery, who had displayed serum creatinine
levels above the normal threshold pre-operatively.7
The use of serum creatinine levels in diagnosing AKI is not
without its limitations. Inconsistencies still arise in the application
of the diagnostic criteria and not only for the KDIGO criteria
but also for the RIFLE score and AKIN criteria.5 Creatinine
measurements require many hours and days to identify any
evidence of renal injury, and at the same time, mild renal injury
can be missed as the kidneys might still maintain normal GFR.11
It is therefore evident that AKI is a continuum from initial
injury to the kidneys, to the development of the disease and then
eventual kidney failure.44
In the hope of increasing awareness about the mortality
and morbidity burden of AKI among clinicians, Kellum et
al.42 introduced a new concept known as ‘kidney attack’. They
proposed five steps that are important in improving outcomes
in patients with AKI.42The first two steps offer a window period
to intervene and possibly prevent further injury. They are known
as the risk-assessment and early-detection steps. The other steps
are early management, organ support and the recovery phase.42
When the initial attack occurs to the kidneys, molecular changes
follow, which result in cellular damage. This leads to a variety of
cellular markers known as biomarkers to be expressed and released
by cells.47 Clinical evidence has proven that biomarkers are present
two days prior to the development of AKI,48 therefore allowing
for the subclinical diagnosis of renal injury.44 This demonstrates
that cellular and molecular biomarkers have the potential to be
superior during the early diagnosis of AKI.44
Biomarkers in the diagnosis of AKI
The ADQI working group recommended the use of renal injury
biomarkers in the diagnosis of AKI to supplement the RIFLE
and AKIN scores.49
Neutrophil gelatinase-associated lipocalin (NGAL)
NGAL is a biomarker that can be measured in both the urine
and plasma.47 It is an acute-phase reactant protein released by
inflammatory cells as well as leukocytes and epithelial cells of
the loop of Henle and the collecting ducts of the renal tubules.47
Urinary NGAL was shown to be superior to plasma NGAL
in the early diagnosis of CSA-AKI.1 Mishra et al.50 found that
urinary NGAL increased up to 25-fold within the first two
hours following cardiac surgery, making it a highly sensitive and
specific predictor of CSA-AKI.
It has however been shown that urinary NGAL levels can
also be elevated in other inflammatory conditions, making it less
specific.47 In a study by Wagener et al .,51 high levels of urinary
NGAL correlated to the duration of CPB and aortic cross clamp.
Interleukin-18 (IL-18)
IL-18 is an inflammatory marker released by dendritic cells,
monocytes and macrophages. 47 Urinary IL-18 was shown to peak
six hours post cardiac surgery.3 Urinary IL-18, together with
NGAL and kidney injury molecule (KIM-1), are less sensitive
and less specific in patients with co-morbid disease. 47
Cystatin C
Cystatin C is a low-molecular weight protein released by all the
nucleated cells of the body, and its levels can be measured in both
the urine and plasma.47 It is an inhibitor of cysteine proteases, 52
and an early diagnostic biomarker of AKI.47 Cystatin C is freely
filtered at the glomerulus, which renders it an appropriate
marker for GFR. 52,53 This biomarker has been researched in the
paediatric population admitted for cardiac surgery.52,53 It was
demonstrated by Hassinger et al .53 to be a good early predicter
of AKI after CPB in children. 53
Plasma cystatin C was shown to be more specific and sensitive
in the early diagnosis of AKI compared to serum creatinine in
infants undergoing cardiac surgery under bypass. 52 Cystatin C
has however also been shown to be less specific and sensitive in
patients with co-morbid diseases and sepsis.54
Insulin-like growth factor binding protein 7 (IGFBP-7)
and tissue inhibitor of metalloproteinases-2 (TIMP-2)
Urinary IGFBP-7 and TIMP-2 are cell cycle-arrest proteins.47 In
a study assessing the risk of AKI in 50 patients who had cardiac
surgery on CPB, both IGFBP-7 and TIMP-2 showed specificity
and sensitivity in predicting AKI as early as four hours following
surgery.55 In a systematic review and meta-analysis by Liu et al., 34
it was shown that these two biomarkers are reliable in the early
detection of AKI in adult patients.34 IGFBP-7 and TIMP-2 have
emerged as novel biomarkers of AKI compared to the others, as
cell cycle arrest is considered the pathophysiological mechanism
in the development of AKI.47
In 2014 the Food and Drug Administration (FDA) approved
the marketing of the nephrocheck test, a laboratory instrument
that detects the presence of IGFBP-7 and TIMP-2 proteins
in the urine of patients at risk of developing AKI following
cardiac surgery.56 This apparatus is the first of its kind (Fig. 2).
Table 2.The classification and staging of the RIFLE, AKIN and KDIGO criteria as modified by Machado et al.7
Class RIFLE SCr or GFR Stage AKIN SCr Stage KDIG0 SCr
Risk Increases Scr X 1.5 or GFR decrease > 25%
(within 7 days)
1 Increase in SCr ≥ 0.3 mg/dl or ≥ 150–200%
(1.5–2-fold) from baseline (within 48 hours)
1 Increase in SCr by ≥ 0.3 mg/dl within 48 hours
or increase in SCr 1.5–1.9 times baseline,
which is known or presumed to have occurred
within the previous 7 days
Injury Increase Scr X 2.0 or GFR decrease > 50% 2 Increase in SCr to more than 200 to 300%
(> 2–3-fold) from baseline
2 Increase in SCr to 2.0–2.9 times baseline
Failure Increase Scr X 3.0 or GFR decrease > 75% or
SCr ≥ 4.0 mg/dl or acute increase ≥ 0.5 mg/dl
3 Increase in SCr to more than 300% (> 3-fold)
from baseline or SCr ≥ 4.0 mg/dl with an
acute increase of at least 0.5 mg/dl or the
initiation of renal replacement therapy
3 Increase in SCr to 3.0 times baseline or
increase in SCr to ≥ 4.0 mg/dl or initiation of
renal replacement therapy
Loss Persistent acute renal failure = complete loss
of kidney function > 4 weeks
End-stage
kidney
disease
End stage of kidney disease (> 3 months)