Nenatal Drug Induced Nephrotoxicity : Old and Next Generation Biomarkers for Early Detection and Management of Neonatal Drug-Induced Nephrotoxicity, with Special Emphasis on uNGAL

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Current Medicinal Chemistry, 2012, 19, 4595-4605 4595

Nenatal Drug Induced Nephrotoxicity : Old and Next Generation Biomarkers for

Early Detection and Management of Neonatal Drug-Induced Nephrotoxicity, with

Special Emphasis on uNGAL and on Metabolomics

V. Fanos*,1, R. Antonucci*,2, M. Zaffanello

3 and M. Mussap

4

1Department of Surgery, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section University of Cagliari, Italy;

2Division of Neonatology and Pediatrics, Ospedale Nostra Signora di Bonaria, San Gavino Monreale, Italy;

3Department of Life and

Reproduction Sciences, University of Verona, Italy; 4Department of Laboratory Medicine, University-Hospital, Genova, Italy

Abstract: For a long time, nephrotoxicity has been definitively defined as renal injury or dysfunction that arises as a direct or indirect

result of exposure to drugs and industrial or environmental chemicals. There are a number of inherent difficulties in diagnostic

procedures for toxic nephropathy, which include the absence of standard diagnostic criteria and the inability to relate exposure to a given

agent and the observed effect. Critically ill newborns represent a high risk population for developing toxic nephropathy because of

incomplete maturation of the kidney; furthermore, they are often treated with a combination of various therapeutic agents, each of them

potentially inducing renal tissue injury. Antibiotics, antifungals, and non-steroidal antiiflammatory drugs (NSAIDs) can induce

nephrotoxic damage by several, concomitant mechanisms of action on different segments of the nephron. The most common clinical

feature following a nephrotoxic effect is acute kidney injury (AKI) which, in turn, comprises a spectrum of severe tissue damages along

the nephron, leading to an abrupt decline in renal function. Because early stages of toxic nephropathy are characterized by very few

specific clinical signs and symptoms, there is the urgent need to investigate new biomarkers for predicting nephrotoxicity and localizing

the injury to a specific nephron site, in order to reduce the risk of acute renal injury and/or acute tubular necrosis. The most promising

biomarker for the early assessment of kidney injury and damage is neutrophil gelatinase-associated lipocalin (NGAL). NGAL can be

easily measured in urine by an automated analytical method, allowing its clinical use in emergency likewise creatinine. Considerable

expectations in terms of improvement of the management of newborns developing drug-induced nephropaties derive from the clinical

application of metabolomics. Keywords: Biomarkers, newborn, kidney, toxicity, uNGAL, metabolomics.

1. INTRODUCTION

Anatomical, physiological, and biochemical features make the kidney susceptible to insult from a variety of therapeutic and environmental agents. This susceptibility can be dramatic in the neonatal age, especially in preterm newborns, who are frequently exposed to drugs during active renal development. In addition, therapeutic treatment of pregnant women can be harmful for the development and maturation of fetal kidney [1], as reported elsewhere [2]. Especially preterm babies are at risk to develop toxic nephropathy following maternal assumption and/or postnatal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) [3, 4]. Finally, pharmacokinetics in critically ill very low birth weight (VLBW) preterms is substantially altered in absorption, bioavailability, distribution, metabolism, and clearance [5]. In the Neonatal Intensive Care Unit (NICU), multiple drug interactions, the acute-phase response, multiorgan dysfunction, intravenous fluids overload, and diagnostic procedures represent co-factors influencing changes in drug pharmacokinetics [6].

According to an international task group of experts selected by the World Health Organization (WHO) and the Commission of the European Communities (CEC), nephrotoxicity can be defined as renal disease or dysfunction that arises as a direct or indirect result of exposure to drugs and industrial or environmental chemicals [7]. Toxic nephropathy is characterized by three steps: a) exposure (contact); b) tissue damage, depending on both the amount of toxic substance penetrating the renal parenchyma and on the duration of its presence in the tissue; c) evidence of toxic damage with the consequent removal of its cause, namely the interruption of drug(s) administration as well as the adjustment of therapy, through individualized doses based on therapeutic drug monitoring (TDM). The extent of damage and its reversibility depend on each of the three phases, in particular on the early recognition of functional

*Address correspondence to this author at the Department of Surgery, Neonatal

Intensive Care Unit, Puericulture Institute and Neonatal Section - University of

Cagliari, Via Ospedale 119, 09124 Cagliari, Italy; Tel:/Fax: +39706093495;

E-mail: [email protected] – www.patologianeonatalecagliari.it

alterations and tissue lesions. Although it has been well established that toxic nephropaties are not restricted to a single type of renal injury, the most common clinical feature following a nephrotoxic effect is acute kidney injury (AKI) which, in turn, comprises a spectrum of severe tissue damages along the nephron, leading to an abrupt decline in renal function [8]. Up to 50% of AKI in preterm newborns may originate from exposure to potentially nephrotoxic drugs. Several pathogenic mechanisms may play a role in drug-induced nephrotoxicity, including hemodynamic changes, interstitial nephritis, glomerular disease, direct cytotoxicity resulting in tubular cell death, and intratubular precipitation of drugs leading to obstructive nephropathy [9, 10]. In particular, high delivery of blood-borne substances, as well as concentration of xenobiotics entering the tubular lumen in the course of their tubular the particular vulnerability of the kidneys to injury by clinically relevant drugs, as well as exogenous substances (contrast media, environmental toxins, etc.), specifically under conditions of dehydration. In addition, a large number of secretory transporters within the proximal tubule contribute both to high intracellular solute concentrations and to a prolonged exposure of epithelial tubular cells to very high concentrations of potential cytotoxins. This damage may be further worsened by compounds additionally reabsorbed from the tubular fluid. Thus, the proximal tubule is commonly regarded as the target of nephrotoxic pathway [11], even if nephrotoxic lesions can affect all the segments of the nephron (Table 1). Nephrotoxic injuries and damages can be also induced by the combination of two additional factors: the allergic and immunological effects of certain drugs associated with the idiosyncrasy of individuals. Penicillin can be considered a typical example of drug leading to acute interstitial nephritis [12]. Nephrotoxic effects of drug exposure, especially those from NSAIDs and antibiotics have been widely investigated in the neonate and are held to be among the most important risk factors

for renal injury and dysfunction.

The prevalence of drug-induced kidney disease is quite lower in the childhood, when compared with adulthood [13, 14]. Although controversial data exist on the correlation between age and kidney vulnerability to toxic medicaments and chemical agents, toxic

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Table 1. Partial List of Drugs that Elicit Site-Specific Toxicity in the Kidney (Partially Modified from Bonventre JV [118])

Glomerulus Proximal Tubule Distal Tubule Loop of Henle Collecting Duct

Adriamycin Cyclosporine Cyclosporine Analgesics Amphotericin B

Puromycin Tacrolimus Tacrolimus Acyclovir

Gold Cisplatin Sulfadiazine Lithium

Pamidronate Vancomycin Lithium

Penicillamine Neomycin Amphotericin B

Tobramycin

Amikacin

Ibandronate

Zoledronate

Hydroxyethyl Starch

Contrast Agents

Foscarnet

Cidofovir

Adefovir

Tenofovir

i.v. Immune Globulins

nephropathy seems to be less frequent and severe in newborns for at least three reasons: a) the ratio “renal size/body mass” is higher in newborns than in adults; b) proximal tubular uptake of proteins, drugs and other metabolites is lower in newborns than in adults, because of immaturity of tubular cells [15]; c) the immature renal parenchyma could be less susceptible to toxic compounds. However, neonatal status may itself be a risk factor for drug-induced nephrotoxicity, particularly in low birth weight infants [16, 17]. Further risk factors are the absence of oliguria during the early phases of neonatal AKI (that may retard diagnosis) and the presence of urinary tract malformations requiring long term antibiotic prophylaxis. These factors add further difficulties in diagnosing and monitoring toxic nephropathy in the perinatal age and call for a constant control of kidney function [18, 19].

There is a paucity of biological markers (biomarkers) that reliably detect nephrotoxicity. The urgent need to early recognize and accurately monitoring toxic nephropathy and the correlate risk of developing AKI has lead to the search of biomarkers identifying renal tissue injury and damage. By using a very simple definition, biomarker is anything that can be measured to extract information about a biological state or process. The National Institute of Health (NHI) Biomarkers Definitions Working Group has defined a biomarker as “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [20]. In 2006, was formed the Predictive Safety Testing Consortium (PSTC), a collaborative effort of scientists from 15 pharmaceutical companies and 2 biotech companies, four academic institutions, the Critical Path Institute, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), outlined a rolling biomarker qualification process, providing the first clear path for translation of such markers from discovery to preclinical and clinical practice [21]. Over few time, PSTC has grown to encompass around 190 industry and government scientists. After preliminary discussions among all the participants, 23 urinary biomarkers were selected and 33 studies in rats conducted at Novartis, Merck and FDA then correlated the levels of seven biomarkers as well as serum creatinine and blood urea nitrogen (BUN) with different histopathological assessment for different kidney lesions. Between June 2007 and January 2008, these data were presented to the authorities, which by April 2008

had accepted that these biomarkers outperformed the current standards [22].

This review is focused both on a brief description of next generation biomarkers for assessing drug-induced kidney toxicity and on the description of mechanisms by which the more commonly used drugs in critically ill newborns can induce nephrotoxic injury along the nephron.

2. ASSESSMENT OF NEPHROTOXIC INJURY BY

EXISTING BIOMARKERS

There are a number of inherent difficulties in diagnostic procedures for toxic nephropathy, which include the absence of standard diagnostic criteria and the inability to relate exposure to a given agent and the observed effect. Serum/plasma creatinine and blood urea have been used to detect kidney toxicity in preclinical and clinical studies as well as in routine clinical care. Unfortunately, they have severe limitations relating to sensitivity and specificity [23]. Nevertheless, nephrotoxicity (due to aminoglycosides) was previously defined on the basis of changes (20% increase from baseline) in serum creatinine [24]. Briefly, an increase in serum creatinine level of 44.2 μmol/L (0.5 mg/dL) or more in patients with basal creatininemia no higher than 265 μmol/L (3.0 mg/dL), or an increase equal to, or greater than 88 μmol/L (1.0 mg/dL) in patients with basal creatininemia above 265 μmol/L suggest the nephrotoxic action by the administered drug [25]. Serum/plasma creatinine concentration may result in a very delayed signal even after considerable kidney injury; moreover, in non steady-state conditions, such as AKI, creatinine is a retrospective, insensitive and even deceptive measure of kidney injury. In newborns, physiological (maternal rate, tubular reabsorption, non-steady state condition) and analytical (chromogens like bilirubin, cephalosporins, etc.) interfering factors also contribute to increase the inaccuracy of creatinine in assessing AKI [26].

Plasma cystatin C has been proposed for a long time as a very early and sensitive marker of changes in glomerular filtration rate (GFR); cystatin C has been extensively evaluated in the perinatal age and in childhood, confirming its clinical value at the early stage of renal impairment, during the so-called “creatinine blind time”

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[27-29]. However, plasma cystatin C may reflect only drug toxicity targeted to the glomerulus but not that targeted to more distal part of the nephron. Taking into account that most drug-induced injuries affect the proximal tubule, plasma cystatin C limitations become obvious. On the other hand, urine excretion of cystatin C may be considered a promising biomarker of kidney injury.

3. FUTURE PERSPECTIVES FROM NEXT GENERATION BIOMARKERS: THE ROLE OF URINARY NGAL AND

METABOLOMICS

Toxic nephropathy calls for improving early therapeutic intervention, in order to reduce the risk of acute renal injury and/or acute tubular necrosis. In most cases, early stages of toxic nephropathy are characterized by very few specific clinical signs and symptoms as well as by no significant variation in conventional serum markers of kidney injury. By contrast, a timely diagnosis of nephrotoxic injury is mandatory, particularly in the newborn, in order to avoid further iatrogenic damages either by adjusting drug dosing or by changing therapy, since drug-induced kidney injuries are mainly reversible when recognized at the early stages [30]. The earlier the recognition, the greater the likelihood for a complete recovery, with "restitutio ad integrum" of the damaged tissue. The application of functional genomics to human and animal models of AKI has led to the discovery of novel gene products that have utility as biomarkers [31]. Several alternatives to serum creatinine and blood urea have been proposed in response to the urgent need for biomarkers capable to predict nephrotoxicity and to localize the injury to a specific nephron site. Urine biomarkers seem to better fulfil the need of an early recognition of toxic damage for preventing the development of AKI [32-34]. Currently, a number of promising, non-invasive urine biomarkers for the early assessment of kidney injury have been proposed in the literature, most of them capable to identify the site of the injury (Table 2). Promising biomarkers list includes neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), clusterin, fatty acid binding protein-liver type (L-FABP),

osteopontin, sodium transporter Na+/H

+ exchanger isoform 3 (NHE-

3), netrin-1 [35, 36].

The most investigated next-generation biomarker is NGAL. Experimental animal studies have elucidated the role of this low-molecular mass protein both during AKI [37] and as inducer of apoptosis and epithelial-to-mesenchymal transition (fibrosis) during chronic kidney disease (CKD) [38, 39]. Human NGAL, also known as human neutrophil lipocalin (HNL), lipocalin-2/24p3 (Lcn2), and siderocalin, is a ubiquitous 25-kDa glycoprotein consists of 178 amino acid residues. NGAL was originally isolated and purified from human neutrophils. Stressful conditions, such as oxidative stress, cytokines, ischemia, infection and inflammation, cancer, intoxication, and other conditions leading to cellular necrosis, apoptosis, and death induce the rapid up-regulation of NGAL synthesis in epithelial cells of various human tissues (liver, lung, trachea, salivary gland, prostate, uterus, stomach, colon), including the kidney. During the early phases of AKI, a rapid and massive up-regulation of NGAL mRNA takes place in the thick ascending limb of Henle’s loop and in the collecting ducts, originating the so-called “NGAL renal pool” [40]; the accumulation of NGAL in the distal nephron leads to a significant increase in urine NGAL excretion, which is the major fraction of urinary NGAL (uNGAL). Concomitantly, AKI induces an increased NGAL mRNA expression in distant organs, particularly liver and lung; the overexpressed NGAL protein is most likely released into the circulation, originating the so-called “NGAL systemic pool”. Finally, uNGAL may originate both from circulating NGAL and from distal nephron, and this hypothesis has been recently reported as “two-compartment model of NGAL trafficking during AKI” [41]. Experimental studies and clinical trials have demonstrated that: a) during AKI, the timing and the intensity of kidney NGAL mRNA expression and uNGAL excretion are correlated with each other; b) both kidney NGAL mRNA expression and uNGAL excretion are dependent on the extent and severity of tissue injury; c) uNGAL concentration originates from the kidney (specifically NGAL monomer and the heterodimer NGAL/MMP-9); d) uNGAL is an autonomous feature of the injured nephron or the result of

Table 2. Nephron Segment-Specific Biomarkers of Kidney Injury (Partially Modified from Bonventre JV [118])

Glomerulus Proximal Tubule Distal Tubule Loop of Henle Collecting Duct

Total Proteins Kim-1 Osteopontin Osteopontin Calbindin D28

Cystatin C Clusterin Clusterin NHE-3

2-Microglobulin NGAL GST-μ/

1-Microglobulin GST- NGAL

Albumin 2-Microglobulin H-FABP

1-Microglobulin Calbindin D28

NAG

Osteopontin

Cystatin C (urinary)

Netrin-1

RPB

IL-18

HGF

Cyr 61

NHE-3

L-FABP

Albumin

Fetuin A (Exosomal)

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localized signaling among damaged nephrons; e) uNGAL fraction originated from the kidney is independent from the amount of plasma NGAL and from the uptake of the filtered protein by proximal tubular cells; f) kidney NGAL mRNA expression is unaffected by neutrophil deletion. In summary, NGAL measurement may significantly improve the outcome of babies with established AKI and may reduce neonatal morbidity and mortality, being able to assess early injuries within 2-6 hours after an insult. Similarly, a set of potential biomarkers with a time- and dose-response with respect to the progression of proximal tubular toxicity has been reported [42].

Considerable expectations in terms of improvement of the management of newborns developing drug-induced nephropaties derive from the clinical application of metabolomics. Metabolomics may play a strategic clinical role in various clinical conditions: we have found very significant results in children with nephrouropathies [43], in the early prediction of developing CKD in young adults [44], and in newborns with intrauterine growth retardation [45]. Metabolomics represents the passage from a descriptive medicine to a predictive medicine, and it has the potential to translate bench top research to real clinical benefits since it is the best indicator of an organism’s phenotype: in fact it is so close to the phenotype to be considered the phenotype itself [46]. In pediatrics and neonatology, metabolomics appears to be an essential tool that can also be used as non-invasive technique by collecting urine samples only [47].

4. ANTIBIOTICS

4.1. Aminoglycosides

Aminoglycosides (AMGs) are still widely employed, despite their low therapeutic index [48, 49]. Gentamicin is probably the most investigated nephrotoxic drug. Among antibiotic-induced AKIs, 80% are related to the AMGs (60% in single-drug therapy and 20% in combination with cephalosporins) [11]. AMGs are eliminated without any metabolic transformation almost exclusively by the kidneys by glomerular filtration. After filtration, a small amount of AMG (5%) is uptaken within tubular cells, in the S1 and S2 segments (first step towards nephrotoxicity). Subsequently, high AMG concentrations accumulate in the lysosomes, where they interfere with protein reabsorption, protein synthesis in the endoplasmatic reticulum, mitochondrial respiration and sodium-potassium pump (second step towards nephrotoxicity) [11]. It has been demonstrated that megalin, a giant endocytic receptor abundantly expressed at the apical membrane of renal proximal tubules, plays an important role in binding and endocytosis of AMGs into the proximal tubular cells [50]. The related structural damage may result in cell necrosis associated with corresponding changes detectable by either optical microscopy or electron microscopy (formation of multilaminated membrane structures, myeloid bodies). Myeloid bodies development within tubular cell lysosomes is the most characteristic early cytotoxic effect.

From a clinical point of view, after one or two days of AMG therapy a conspicuous urinary loss of microglobulins occurs (functional tubular damage). After the third day, a sharp increase in urinary N-Acetyl- -D-Glucosaminidase (NAG) enzyme is observed (structural tubular damage). After 6 days of therapy, cylindruria, proteinuria, polyuria and reduced urine concentration capacity may be present. In the presence of other risk factors, these alterations may occur earlier.

AMG-induced tubulotoxicity is frequent, but is generally reversible when discontinuing the drug. The newborn and infant with renal failure are usually nonoliguric. However, it should be considered that renal damage may alter the pharmacokinetics of the antibiotic, prolonging half life, reducing renal excretion and creating a dangerous vicious circle. Serum creatinine

characteristically rises 5 to 10 days after the start of therapy, but other less frequent clinical features include an increased urinary excretion of ions (sodium, potassium, magnesium, and phosphorus), uric acid, amino acids and glucose. Selected cases may end up with a full picture of Fanconi syndrome. AKI may appear only at a later stage. Various factors contribute significantly to AMG nephrotoxicity; some of them due to the antibiotic itself, others related to the patient and his associated pathology, as well as further pharmacologic factors, as summarized below.

Aminoglycoside Intrinsic Toxicity

AMG-induced glomerular toxicity shows the following breakdown: gentamicin > tobramycin > amikacin > netilmicin [51]. The higher renal tubular safety of netilmicin was also confirmed in newborns with the employ of enzymuria.

Aminoglycoside Administration Modalities

The modalities of AMG administration, continuous or intermittent infusion, once-daily administration, twice daily administration or multiple daily doses significantly influence the renal accumulation kinetics (RAK) of AMGs and, in turn, their nephrotoxicity. Experimentally, gentamicin and netilmicin present a saturable RAK. By contrast, tobramycin shows a non-saturable RAK. In the case of amikacin, RAK is mixed, being saturable at low serum concentrations and non-saturable at high concentrations [52]. A review examining the available data from randomized and non randomized studies confirmed the lower nephrotoxicity of extended interval dosing compared to conventional dosing in newborns [53].

In adults patients, therapeutic efficacy and toxicity of AMGs correlate well with serum concentrations [54]. Therapeutic drug monitoring (TDM) has two major objectives: a) to ensure therapeutic concentrations; b) to avoid toxicity. Most investigators relate the nephrotoxicity of AMGs to high trough levels (measured immediately before the next administration). Serum concentrations should be kept below 10 mg/L for amikacin and below 2 mg/L for the other AMGs. Peak levels (obtained 30 minutes after an intravenous administration, 60 minutes after an intramuscular administration) of gentamicin, tobramycin and netilmicin should be maintained from 5 to 8 mg/L while those of amikacin from 15 to 25 mg/L. Even if the need of routine TDM in the first week of life has been debated [55, 56], neonates often require TDM and an individually adjusted therapeutic regimen, especially preterm infants [6, 57]. However, AMG nephrotoxicity can occur even with proper TDM.

Other Risk Factors

Prolonged therapy, malnutrition, volume depletion, liver disease, preexisting renal disease, potassium and magnesium depletion, concomitant exposure to other nephrotoxic drugs such as amphotericin B, cyclosporine, vancomycin and NSAIDs are all risk factors. Clinical conditions commonly observed in the newborn and potentially amplifying AMG nephrotoxicity are neonatal anoxia, respiratory distress syndrome (RDS), mechanical ventilation, and hyperbilirubinaemia. Sepsis due to gram-negative bacteria is also associated with AMG-induced kidney damage especially in presence of renal hypoperfusion, fever and endotoxinaemia [8].

4.2. Glycopeptides

The mechanism of vancomycin nephrotoxicity is not well understood. It is commonly believed that the main mechanism is a tubular transport (energy-dependent) of the glycopeptide from blood to tubular cell across the basolateral membrane; similarly to some AMGs, a saturation of this tubular transport would occur at a particular concentration [58]. There is a lysosomal accumulation of vancomycin in proximal tubular cells but this is not similar to the behaviour of AMG. Nephrotoxicity relates to the combined effect

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of a large area under the concentration-time curve and duration of therapy. A relationship between the time of administration and vancomycin toxicity has been observed, morning administration being associated with less toxicity than evening doses [59]. In most cases, vancomycin-associated nephrotoxicity is reversible, even after high doses. Until 1980, vancomycin-related nephrotoxicity, observed in about 25% of treated adults [60] and in 11% of children receiving vancomycin alone [61], was attributed to impurities present in the old preparations (the so called “Mississipi Mud”. The current preparations of vancomycin may have less potential for nephrotoxicity than earlier. Risk factors comprise essentially high trough values (>15 mg/L) and prolonged therapy [62]. Otherwise, there is no evidence that transient high peak concentrations (>40mg/L) are associated with toxicity. However, it is not clear whether elevated serum trough levels are the cause or the consequence of renal failure. High baseline serum creatinine concentration, liver disease, neutropenia and peritonitis are also considered significative risk factors [59].

An analysis of the literature reveals that vancomycin-induced nephrotoxicity in newborns, infants and children is rare and often reversible, without a linear correlation with its serum levels. However, the combination AMG-vancomycin should be used with caution when an alternative association is possible, when TDM of both drugs is impracticable, and in VLBW [63]. Compared to vancomycin, teicoplanin-induced nephrotoxicity is lower in paediatric patients too [64].

4.3. Beta-Lactams

4.3.1. Cephalosporins

The nephrotoxicity of cephalosporins depends on two main factors: a) the intra-cortical concentration of the drug; b) the intrinsic reactivity of the drug [65]. The intra-cortical concentration of cephalosporins, which is the result of the equilibrium created at the tubular cell level between active transport, secretion and reabsorption, is crucial for the development of nephrotoxicity. The importance of an antiluminal active organic acid transport is well known: a) nephrotoxicity due to cephalosporins is limited to those compounds transported by this system; b) prevention of damage is possible by inhibiting this transport; c) toxicity increases together with rising intracellular uptake of cephalosporins [66]. The intrinsic reactivity of cephalosporins is linked to its potential negative interaction with the intracellular targets at three levels: a) lipid peroxidation; b) acylation and inactivation of tubular proteins; c) competitive inhibition of mitochondrial respiration. Cephaloridine and cephaloglycin are the only cephalosporins able to cause kidney damage at therapeutic doses.

Transcriptomic data revealed several characteristic expression patterns of genes associated with specific cellular processes, including oxidative stress response and proliferative response, upon exposure to cephaloridine, allowing a better understanding of cephalosporin -induced nephrotoxicity [67]. Compared to other cephalosporins, renal damage can occur only at extremely high doses, much greater than the routine therapeutic doses [68].

In vivo, nephrotoxicity of cephalosporins decreases as follows: cephaloglycin > cephaloridine > cefaclor > cephazolin > cephalothin >>> cephalexin > ceftazidime. The latter shows good renal safety even when renal safety is detected with early markers of nephrotoxicity, such as urinary enzymes. Third generation cephalosporins, such as ceftazidime, cefotaxime and ceftriaxone, widely used in pediatrics, commonly induce a direct significant increase in serum creatinine in less than 2% of treated cases, with the exception of cefoperazone (5%) [69]. Ceftriaxone is forbidden in the neonatal period, due to fatal reactions. An interesting characteristic of cefotaxime is its low sodium content (about 1/5 and 1/4 of ceftazidime and ceftriaxone, respectively): this could be useful in newborns and children with hypernatremia and/or fluid

overload [70]. Finally, it is well known that cephalosporins may act as interfering chromogens during the in vitro Jaffe reaction, affecting accuracy in serum creatinine measurement by colorimetric methods based on this reaction [71]. Recent efforts in creatinine assay standardization have lead to a significant reduction in inaccuracy and imprecision, making results between laboratories strictly comparable [72].

4.3.2. Carbapenems

Carbapenems present a significative potential for nephrotoxicity, higher than cephalosporins and penicillins. Together with cephaloridine and cephaloglycin, imipenem and panipenem are the most nephrotoxic beta-lactam compounds [73]. Carbapenems nephrotoxicity has been demonstrated in various experimental animal studies, specifically in rabbits [74]. The beta-lactam ring and the basicity of the C-2 side chain play an important role in the nephrotoxicity of carbapenem antibiotics. Carbapenems induce mitochondrial injury by acylating and inactivating the mitochondrial transporters [75] while the beta-lactam ring of carbapenems is essential for the acylation of the target protein that leads to nephrotoxicity. Moreover, the carbapenem skeleton itself has much higher reactivity due to strained chemical structure than cephalosporin skeleton. Imipenem is hydrolized by a brush-border enzyme (dehydropeptidase I) giving rise to more toxic and less active metabolites. Imipenem administered together with cilastatin (in a 1:1 ratio), a specific inhibitor of dehydropeptidase I, aims at preventing nephrotoxicity. A lower potential for nephrotoxicity was observed with meropenem.

5. ANTIFUNGALS

5.1. Amphotericin B

As regards amphotericin B-induced nephrotoxicity, different mechanisms have been proposed. These include the vehicle (deoxycholate) in which amphotericin is administered [76], ischemic injury due to a reduction of renal blood flow and GFR [77, 78], increase in salt concentrations at the macula densa leading to enhanced stimulation of tubule-glomerular feedback and vasoconstriction [79]. Moreover, interaction of amphotericin B with cholesterol on the human tubular cell membrane has also been postulated [75] and apoptosis in proximal tubular cells and medullary interstitial cells has been documented [80]. However, AKI that is the most serious complication of antifungal agents, is rare. More frequent is tubulotoxicity, which includes potassium and magnesium loss in urine, renal tubular acidosis and loss of urinary concentrating ability. Hypokalemia can be significant in children and neonates [11]. Risk factors include the amphotericin B cumulative dose and the average daily dose, abnormal baseline creatinine values and concomitant administration of potentially nephrotoxic drugs. However, in neonates, unlike in other age groups, an increase in creatininemia appears not to be related to the total cumulative dose of the drug, and may show up after the first few doses. Discontinuation of treatment for a few days can lead to hospitalization. New lipid formulations of amphotericin B, introduced with the aim to prevent nephrotoxicity, effectively share a considerable reduction of nephrotoxicity in adults, but information are limited in children and newborns. Presently, the use of such agents should be restricted to those subjects who are intolerant or refractory to amphotericin B. Discontinuation of treatment for a few days may lead to hospitalization. Amphotericin B should be used with caution in newborns treated with other nephrotoxic drugs, such as aminoglycosides or vancomycin. The concomitant administration of dopamine and/or furosemide was not found to be effective.

5.2. Other Antifungals

Alternative antifungals are currently available for clinical use in newborns: the azoles (itraconazole, fluconazole, voriconazole), the

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fluorinated pyrimidines (flucytosine), the echinocandins (caspofungin, micafungin, anidulafungin). Among azoles, fluconazole is by far the most widely used and has been reported to be relatively well tolerated, even at renal level [81-85]. Data regarding safety of voriconazole in newborns are very limited and mostly reported as case reports [86-88]. Flucytosine, due to the evidence of primary and acquired resistance in some strains, should not be used as monotherapy [89] and its use in newborns is limited [90].

As regards echinocandins, abnormalities in laboratory tests (serum creatinine and blood urea elevations, hypokalemia) are uncommon, although seem to be more frequent with caspofungin, the first echinocandin approved for treatment of patients unresponsive to conventional antifungal therapies [91-98].

As regards the other echinocandins, micafungin seems to have very good renal safety profile in neonates, superior to other classes of antifungals (such as the polyenes). Withdrawal of this drug due to adverse effects is very rare; however, transaminase monitoring is recommended during treatment, as well as evaluation of the risk-benefit balance in patients with liver disease or concomitant administration of hepatotoxic drugs [99-102]. In some countries, like Italy, micafungin is the only label drug for antifungal infection in the newborn.

6. NONSTEROIDAL ANTIIFLAMMATORY DRUGS

(NSAIDs)

NSAIDs are used in the neonatal period to favor closure of patent ductus arteriosus (PDA) and to reduce polyuria in subjects with congenital salt-losing tubulopathies [103]. The nephrotoxic effects of NSAIDs are related to their mechanism of action: by blocking prostaglandin synthesis through the inhibition of cyclooxygenase (COX) enzymes. These drugs may induce kidney damage that may result in AKI with or without oliguria, CKD, significant proteinuria, fluid metabolism alterations and hyperkalemia. Two of the COX isoforms, COX-1 and COX-2 have been widely acknowledged, displaying a similar structure differing each other by a side pocket in the hydrophobic substrate-binding channel. However, the site of action, selectivity, and intracellular localization of the two isoforms are quite distinct. COX-1, the “constitutive” isoform, is ubiquitous and constitutively expressed in

all tissues under basal conditions, being implicated in the maintenance of normal physiological functions in numerous organs, e.g. stomach and kidney. COX-2 has been termed “inducible” in view of its more restricted basal expression and upregulation during inflammation. It is undetectable in most mammalian tissues, although expression can be rapidly induced by different inflammatory stimuli (cytokines, endotoxins, hypoxia and growth factors) in fibroblasts, endothelial cells, macrophages, synovial tissue, chondrocytes, osteoblasts and ovarian follicles. Identification of the two isoforms has given rise to the so-called “COX hypothesis”: COX-1-derived prostaglandins should be involved in physiological functions, whereas COX-2-derived prostaglandins should play a major role during inflammation or tissue damage [104].

At birth, many organ systems undergo important processes of adaptation to extrauterine life. Prostaglandins play a prominent role in postnatal cardiovascular adaptation in general, and particularly in renal adaptation both in normal [105] and in pathological newborns [106]. The perinatal kidney may be considered as being under a condition of permanent stress owing to the high preglomerular and postglomerular vascular resistances. After birth, prostaglandin-induced vasodilation at afferent arterioles, in combination with persistent vasoconstriction at efferent arterioles under the control of the renin-angiotensin system, modifies glomerular filtration pressure, thus contributing towards a postnatal increase of GFR [104, 107]. The immature kidney would appear to be programmed expecially depending on glomerular and tubular actions of prostaglandins in the perinatal and neonatal period [108].

Interestingly, urinary excretion of PGE2 and PGI2 in preterm infants has been found to be significantly higher than that observed in term infants and in subjects over the age of 1 month, thereby supporting the concept that renal prostaglandin activity is inversely related to gestational age [105]. For many years, indomethacin was the drug of choice in the treatment and prophylaxis of PDA in premature neonates. Among its side-effects, transient or permanent alterations in renal function have been frequently reported [109]. Reduction of urinary volume and glomerular filtrate usually are reversible within 48 h by discontinuation of therapy, while oliguria may persist for two weeks. Strategies to minimize the renal side-effects of indomethacin, such as its association with furosemide or with low doses of dopamine or the use of prolonged low doses,

Table 3. Main Mechanisms of Drug-Induced Nephrotoxic Injury

Drug Nephron Segment Mechanism of Toxic Damage

Aminoglycosides Convolute Proximal Tubule

Vessels

Accumulation within lysosomes (from the lumen)

Interference with protein synthesis

Interference with protein reabsorption

Interference with Na/K pump

Interference with oxidative phosphorilation

Vasocostriction

Glycopeptides (vancomicin) Convolute proximal tubule Accumulation within lysosomes (from the blood)

Cephalosporins Convolute proximal tubule Imbalance between passive reabsorption (from the lumen) and active secretion

(blood and brush border)

Carbapenems Mitochondria

Proximal tubule

Acylation and inactivation of the mitochondrial transporters

Imipenem is hydrolized by a brush-border enzyme (dehydropeptidase I) giving

rise to more toxic and less active metabolites

Antifungals (conventional amphotericin B) Glomerulus

Proximal tubule

Medullary interstitial cells

Vessels

Reduction of renal blood flow leading to ischemic injury

Oxidative interaction with tubular cell membrane cholesterol; apoptosis; hole

generation through the brush border with potassium depletion

Apoptosis

Intense vasoconstriction

NSAIDs Glomerulus Block of prostaglandin synthesis by inhibiting cyclooxygenase (COX) enzymes;

imbalance between vasoconstriction (increased) and vasodilatation (decreased).

Vasoconstrictors are vasoaggressive, vasodilators are vasoprotective

Nenatal Drug Induced Nephrotoxicity Current Medicinal Chemistry, 2012 Vol. 19, No. 27 4601

have not been successful. In any case, indomethacin seems to have no major long-term renal effects, since some authors showed that kidney function was restored after one month following acute renal impairment.

Ibuprofen has been shown to close successfully the ductus arteriosus in animals and newborns without affecting renal hemodynamics. In a prospective randomised study considering the effectiveness and the side-effects of ibuprofen and indomethacin in the treatment of PDA, it has been observed a marked influence of indomethacin on serum creatinine. In another randomized trial involving five NICUs in Belgium, the authors confirmed that ibuprofen was significantly less likely to induce oliguria and to increase serum creatinine, as also reported in other studies after intravenous and oral administration. In conclusion, no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found, but ibuprofen was associated with lower nephrotoxicity. However, numerous issues pertaining to the use of these drugs in neonatology remain. Recently, during an International Congress devoted to this topic [110], a research on the actual use on NSAIDs in European newborns was presented [111]. The study underlies the extreme variety in using NSAIDs in the different European countries.

Administration of an unvaried dose of indomethacin or ibuprofen to newborns despite their gestational and/or postnatal age is a paradox, overlooking displayed specific clearance rates based on the age of the infants. The two ibuprofen enantiomers are characterized by different half- lives (enantiomer S, t 25 hours; enantiomer R, t 10 hours), efficacy and probably toxicity [112]. Moreover, the influence produced by genetic polymorphism on the metabolism of these drugs has been well documented, revealing the presence of extensive metabolisers and poor metabolisers of the isoenzyme CYP2C9 [113]. Compared to indomethacin, ibuprofen seems to reduce the risk of oliguria and is associated with lower serum creatinine levels following treatment [114]. However, when toxicity is detected with urinary biomarkers such as PGE2, considered early as indicators of nephrotoxicity, a dramatic decrease in urinary PGE2 has been observed with both drugs. In fact, studies performed on both animals (neonatal piglets) and humans (preterm infants with PDA) have shown a reduction in urinary excretion of PGE2 following indomethacin administration. We reported a significant decrease in urinary PGE2 levels following ibuprofen treatment in preterm infants with PDA, revealing a dramatic fall in PGE2 particularly in infants developing significant side- effects (intraventricular haemorrhage, acute renal failure, intestinal perforation) [115]. Therefore, the role of PGE2 should be taken into account in all situations in which the balance between vasoconstrictors (aggressive) and vasodilators (vasoprotective) is essential for the neonatal kidney. From a practical point of view, the measurement of urinary PGE2 in premature infants would be helpful in the following situations: a) if urinary PGE2 values are low (<35 pg/ml) prior to ibuprofen treatment one should consider not to treat; b) if PGE2 values are rapidly decreasing during ibuprofen treatment, then the decision to continue with a second or third dose should be reconsidered; c) if urinary PGE2 values are very low (<5 pg/ml) during and/or after ibuprofen treatment significant adverse renal effects should be anticipated [115].

New strategies regarding a tailored dosage of ibuprofen in the first week of life to optimize dosing regimen, reaching an optimal peak level and avoiding toxicities, have been proposed [116]. However further studies are needed to confirm this approach [104, 115, 117].

7. METABOLOMICS AND NEPHROTOXICITY

Metabolomics could be very important for early diagnosis, increased choice of therapy and identification of new metabolic pathways that could potentially be targeted in kidney disease.

However, despite its enormous potential in the fields of nephrology, so far metabolomics has been used fairly little to study the kidney, namely in pediatrics. In fact it can be considered in a pionieristic application in this field. Metabolomics analysis of the urine will probably result in biomarkers that reflect the altered metabolic function of these cells better than other “omics” technique, namely proteomics. A feature unique to kidney diseases is that most of the components of this organ system are bathed in urine. Furthermore, as the kidney is a primary site of drug metabolism and urine is frequently a repository of specific drug metabolites, metabolomics can identify drug assumption and thereby indicate nephrotoxicity by measuring the metabolic signatures of the drugs. Metabolomics strategies to assess drug toxicity have been developed as early as in the 1980s with a focus mainly on hepato and nephrotoxicity [118-121]. Several studies have utilized metabolomics to study acute kidney injury (AKI) induced by nephrotoxins (especially aminoglycosides) in rats. Prediction models for early detection of nephrotoxicity comprise leucine, isoleucine and valine and the citric acid cycle (glucose, lactate, acetoacetate and 3-hydroxybutyrate [122, 123]. Other studies have utilized a variety of metabolomics techniques to examine AKI attributable to nephrotoxins not used in the newborn and infants and will not be considered.

Metabolomic approaches are useful to identify: the kidney as target organ or region of toxicity; the biochemical mechanism contributing to toxicity, molecular marker profiles of nephrotoxicity in plasma and urine; moreover metabolomics is usefull to monitor the time course of nephrotoxicity, its dose dependency and its recovery.

The following metabolite signatures in urine have been associated with injury to specific regions of the kidney [124-126]:

• Proximal straight tubules (via D serine): increase of lactate, phenylala nine, tryptophan, tyrosine and valin.

• Proximal convolute tubules (via gentamicin): increase of glucose; reduction of trimethylamine N oxide, xanthurenic acid and kynurenic acid.

• Cortical injury (via mercuric chloride): increased glucose, alanine, valine, lactate and hippurate and decreased citrate, succinate and oxoglutarate.

• Papilla and medulla (via bromoethanamide): increase of glutaric acid, creatine and adipic acid; reduction of citrate, succinate, oxoglutarate and trimethylamine N oxide.

The changes of urine metabolite patterns found in several key nephrotoxicity studies in the rat are summarized in Tables available in literature. Although an attractive concept and although there is promising feasibility data, there are many obstacles that have prevented this technology from becoming a widely accepted drug development tool in the industry and for regulatory submissions. Metabolomics has resulted in potential biomarkers for several renal diseases, but to become true biomarkers, validation is still needed.

8. CONCLUSIONS

Although nephrotoxic injury may be frequently reversible in many patients [126], there is a need to improve the early diagnosis of drug-induced kidney disease, especially in the neonatal age, characterized by an incomplete maturation of the nephron. Clinical surveillance is of particular importance because critically ill newborns are often treated with a combination of various therapeutic agents, each of them potentially being nephrotoxic. Such nephrotoxicity may be either a dose-dependent or a dose-independent phenomenon, resulting from an immuno-allergic or vasoactive effect. Predisposing factors such as gestational age, post natal age, maternal diseases, pharmacogenetics, changes in hemodynamic, underlying disease, dosage of the microbial toxin, and concomitant medications determine and influence the severity

4602 Current Medicinal Chemistry, 2012 Vol. 19, No. 27 Fanos et al.

of the nephrotoxic insult. Intravascular haemolysis, rabdomyolysis and prolonged hyperbilirubinaemia should be carefully taken into account as additional factors leading to nephrotoxic injury reinforcing the nephrotoxic effects of drugs [127].

Constant and careful surveillance and very early diagnosis are two key factors for the management of newborns at risk for developing drug-induced nephrotoxic injury. The most important step in treating drug-induced nephropathy is to stop the responsible drug as soon as possible; this intervention represents a successfull treatment in most of prerenal, intrinsic and obstructive renal failure. Thus, preventing iatrogenic nephrotoxicity is not only possible and desirable, but strictly mandatory. How can one avoid nephrotoxicity? It is possible to summarize some practical rules of particular importance in clinical practice. These rules should be taken into account to prevent kidney impairment and damage: a) don’t use nephrotoxic drugs, if you have alternatives; b) choose the less nephrotoxic compound; c) use therapeutic drug monitoring, if needed; d) don’t use concomitant nephrotoxic drugs; e) pay attention to the duration of treatment; f) perform an early diagnosis of renal damage and in this case stop the administration of the drug, if there is damage; g) use new drugs with caution in neonatology [128]. Given the insensitivity of current methods for diagnosing and monitoring nephrotoxicity, there is the need to identify next generation of biomarkers that are more sensitive and specific than serum creatinine. These markers should be also used as “translational” biomarkers to substantially improve prediction of nephrotoxicity in preclinical studies, by identifying kidney injuries in all stages of the drug-development process. Recently, PSTC has pointed out ideal features of biomarkers used to detect drug-induced nephrotoxicity [129]. These criteria included (a) the early identification of kidney injury, before the renal reserve becomes dissipated and levels of creatinine increase, (b) the correlation between their concentration and the degree of toxicity, in order to characterize dose dependencies, (c) the capacity to display similar reliability across multiple species, including humans, (d) the capacity to localize the site of kidney injury, (e) the possibility to track progression of injury and recovery from damage, (f) accessibility in readily available body fluids or tissues, and finally (g) the full characterization of each biomarker with respect to limitations of its capacities. It is obvious that new biomarkers make sense when they provide better or different information than current used biomarkers. Their use may have analytical, non-clinical or clinical advantages, or may simply expand the existing information derived from biomarkers evaluated so far [130]. In the next future, new approaches like metabolomics could help in individualizing therapies in neonatology [131]. We must say that at the moment Pharma-metabolomics in Neonatology is a dream, in the next few years there will probably be a dramatic increase in the applications of metabolomics for the study of drugs in the neonatal period, coupling noninvasiveness with the prediction of pharmacological efficacy/safety before using drugs [132-135].

CONFLICT OF INTEREST

The author(s) confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENT

Declared none.

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Received: January 15, 2012 Revised: March 24, 2012 Accepted: April 07, 2012