Nephrotoxicity as a cause of acute kidney injury in children
Ludwig Patzer
0
) Children's Hospital St. Elisabeth and St. Barbara
, Mauerstrasse 5, 06110 Halle/S.,
Germany
Many different drugs and agents may cause nephrotoxic acute kidney injury (AKI) in children. Predisposing factors such as age, pharmacogenetics, underlying disease, the dosage of the toxin, and concomitant medication determine and influence the severity of nephrotoxic insult. In childhood AKI, incidence, prevalence, and etiology are not well defined. Pediatric retrospective studies have reported incidences of AKI in pediatric intensive care units (PICU) of between 8% and 30%. It is widely recognized that neonates have higher rates of AKI, especially following cardiac surgery, severe asphyxia, or premature birth. The only two prospective studies in children found incidence rates of 4.5% and 2.5% of AKI in children admitted to PICU, respectively. Nephrotoxic drugs account for about 16% of all AKIs most commonly associated with AKI in older children and adolescents. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, amphotericin B, antiviral agents, angiotensin-converting enzyme (ACE) inhibitors, calcineurin inhibitors, radiocontrast media, and cytostatics are the most important drugs to indicate AKI as significant risk factor in children. Direct pathophysiological mechanisms of nephrotoxicity include constriction of intrarenal vessels, acute tubular necrosis, acute interstitial nephritis, andmore infrequentlytubular obstruction. Furthermore, AKI may also be caused indirectly by rhabdomyolysis. Frequent therapeutic measures consist of avoiding dehydration and concomitant nephrotoxic medication, especially in children with preexisting impaired renal function.
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Many different drugs and agents are currently being taken
into consideration as the causality of nephrotoxic acute
kidney injury (AKI) in children. Predisposing factors such
as age, pharmacogenetics, underlying disease, dosage of the
toxin, and concomitant medication determine and influence
the severity of nephrotoxic insult. The culprit toxins are
predominantly drugs, but exogenous (ethylene glycol,
methylene) and endogenous (hemoglobin, myoglobin)
substances and toxins from animals play a role as well.
Throughout this teaching article, incidence,
pathophysiological mechanisms, and treatment options are discussed in
general followed by characteristics of problematic drugs.
Because of the paucity of multicenter studies exploring
AKI in children, previously conceived literature of AKI in
adults ought to be considered.
Tumor lysis syndrome is not discussed. However,
calcineurin inhibitor toxicity is briefly mentioned, as it has
been respectively inclusive to the topic throughout multiple
publications [18].
Definition and incidence
Most authors define AKI as a sudden decline in glomerular
filtration rate (GFR) mirrored by doublings of serum
creatinine and azotemia. Because a precise clinical
definition remains elusive, studies comparing epidemiology and
outcome can be problematic (see Mehta et al. [9] for
review). For oncological patients being treated with
cytotoxic drugs, fractionated total body irradiation, and
stem cell transplantation, AKI is due to multiple risk
factors, with nephrotoxicity being one of the most
significant. In this group of patients, a regimen-related toxicity
score, as proposed by Bearman et al. [10], is often used.
This score is defined as follows: grade 1an increase in
creatinine up to twice the baseline; grade 2an increase in
creatinine above twice the baseline but not requiring
dialysis; grade 3renal replacement therapy required;
grade 4fatal toxicity.
In adults, the overall incidence of AKI was found to be
209 per million population (0.02%). This figure was most
likely generated by hypoxic/ischemic and nephrotoxic
insults [11, 12]. Other studies report incidence rates of
between 7% and 25% among critically ill adults [1316].
This broad range is partly due to the many different
coexisting definitions of AKI currently used, as mentioned
above.
Community-based statistics estimate the incidence of
AKI attributed to drug nephrotoxicity as being between 0%
and 7% [17, 18] and the incidence of in-hospital AKI
attributed to drug nephrotoxicity in adults at about 20% of
all AKI [1923]. Antibiotics (311%),
angiotensin-converting enzyme (ACE) inhibitors (0.57%), NSAIDs (322%),
and contrast media (212%) were noted as the most
recurrent offenders. Depending on the publication date of
the statistics, an increase in ACE inhibitors and a decrease
in contrast media as causing agents was found during recent
years (see de Broe et al. [24] for details). The trend in
claiming higher frequencies of NSAIDs and ACE inhibitors
as causes for drug-induced AKI was confirmed by a survey
in 2001 by Ronco et al. [25]. It has been observed that
hospital-acquired AKI is usually associated with one of
three renal insults: a prerenal event, exposure to
nephrotoxins, or sepsis [11]. Nephrotoxins, alone or in combination,
contribute to at (...truncated)