Nephrotoxicity as a cause of acute kidney injury in children

Pediatric Nephrology, Dec 2008

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, and—more infrequently—tubular 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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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. - 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)


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Ludwig Patzer. Nephrotoxicity as a cause of acute kidney injury in children, Pediatric Nephrology, 2008, pp. 2159-2173, Volume 23, Issue 12, DOI: 10.1007/s00467-007-0721-x