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PEDIATRICS Vol. 113 No. 4 April 2004, pp. 1084-1091

SUPPLEMENT ARTICLE

The Developing Kidney and Environmental Toxins

Michael J. Solhaug, MD*, Philip M. Bolger, PhD{ddagger} and Pedro A. Jose, MD, PhD§

* Department of Physiology, Eastern Virginia School of Medicine, Norfolk, Virginia
{ddagger} Food and Drug Administration, Washington, DC
§ Department of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, Washington, DC


   ABSTRACT
TOP
 ABSTRACT
ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 
The effects of environmental chemicals, drugs, and physical agents on the developing kidney are influenced by the state of renal development and maturation. The development of the kidney, the major excretory organ after birth, consists of 3 stages: the pronephros, or cervical kidney; mesonephros, or thoracic kidney; and metanephros, or abdominal kidney, the definitive kidney. In humans, nephrogenesis and organogenesis occur from the 6th to the 36th weeks of gestational age. After 36 weeks, nephrogenesis is complete and each kidney has a full complement of nephrons. The extent of chemical-induced renal toxicity is related, in part, to the efficiency in which the particular compound is transported by renal tubules. Because renal tubular transport capacities vary with maturation, the degree of nephrotoxicity may also vary with maturation. The signs and symptoms of nephrotoxicity can appear acutely or insidiously. Unexplained acute renal failure, chronic mild proteinuria, or even hypertension can be a manifestation of nephrotoxic agents. Species differences occur, thus the need for studies in humans.

Key Words: kidney • toxins • development • angiotensin • prostanoids

Abbreviations: RBF, renal blood flow • GFR, glomerular filtration rate • ACE, angiotensin-converting enzyme • OAT, organic anion transporter • OCT, organic cation transporter • OCTN, organic cation/carnitine transporters • PAH, p-aminohippuric acid

The effects of environmental chemicals, drugs, and physical agents on the developing kidney are influenced by the state of renal development and maturation. The unique intrauterine conditions of mammals dictate that the placenta serve as the surrogate fetal kidney in the regulation of fluid, electrolyte homeostasis, acid-base balance, elimination of waste products of metabolism and toxins, and hormone production. An important function of the fetal kidney is to maintain a urine output sufficient to maintain amniotic fluid volume. Daily urine production is approximately 30% of fetal weight. The excreted urine does not serve real excretory or homeostatic function because the urine, via the amniotic fluid, is recycled back to the fetus by swallowing (25% of fetal weight). The most striking result of impaired fetal renal function, therefore, is a significant reduction in amniotic fluid.

Human renal development involves 2 basic processes: morphologic formation and, ultimately, the acquisition of function. The anatomic formation of the human kidney occurs exclusively in utero. However, the acquisition of physiologic or functional capability begins with the earliest formation of the fetal nephron and accelerates after birth to reach adult levels. The anatomic and physiologic characteristics that distinguish the fetal and newborn kidney from the mature adult kidney present certain vulnerabilities to toxic injury. Thus, toxicity to the developing kidney may involve morphologic and functional changes that may be clinically relevant. Knowledge of the impact of toxins on the immature kidney is dependent on understanding the mechanisms of toxic injury and is useful to the practitioner.

Renal morphogenesis is a classic example of the principle that ontogeny recapitulates phylogeny. The development of the kidney, the major excretory organ after birth, has been well described and consists of 3 stages: the aglomerular pronephros, or cervical kidney; the mesonephros, or thoracic kidney, culminating in the initiation of the formation of the functional mammalian kidney; and the metanephros, or abdominal kidney. In the human, the pronephros appears at 3 weeks of gestational age and regresses by the fifth week. The pronephros is nonfunctional, but the pronephric duct becomes the mesonephric duct, which subsequently evolves into the ureteric bud. The ureteric bud is essential for nephron formation. The mesonephros, which is functional, develops caudal to the pronephros at the 3rd to 4th weeks of age and degenerates from the 5th to 12th weeks of gestational age. By the sixth week of life, the 2 essential components that trigger and sustain metanephric kidney formation are identified: the ureteric bud and the metanephric mesenchymal blastema. The definitive kidney, metanephros, develops from the interaction between the ureteric bud and the surrounding mesenchyme. Understanding the genes involved in the development of the metanephros has undergone remarkable progress.1 The metanephric blastema forms the basic structures of the functioning nephron, the glomerulus and associated tubules. The processes involve ureteric bud induction, tubular formation, glomerulogenesis, and angiogenesis/vasculogenesis. Ultimately, the ureteric bud and its branches form the epithelial structures of the collecting ducts, intrarenal collecting system, ureter, and the trigone of the bladder.

In humans, nephrogenesis, or the formation of individual nephrons, and organogenesis, or pattern formation, occur from the 6th to the 36th weeks of gestational age. After 36 weeks, nephrogenesis is complete and each kidney has a full complement of nephrons, approximately 1 000 000 nephrons per each kidney. Thus, the anatomic formation of the human kidney occurs exclusively in utero. Whether new nephrons can develop after birth in prematurely born infants remains to be determined. However, in many mammals, nephron formation continues after birth. Therefore, results of studies on renal function in rodents and other experimental models need to be interpreted carefully. Once the elemental structures are formed through differentiation, the initial process whereby primitive renal glomeruli and tubules attain their specific anatomic form, the assignment and increase of function, the process of maturation, ensues. This maturational process involves phenomenal growth as well as physiologic functional change.

A functional kidney has been observed at 6 weeks of gestational age.2 Renal blood flow (RBF) and glomerular filtration rate (GFR) progressively increase during gestation and achieve full-term levels by the 32nd to 35th weeks of gestational age.3–6 The values at term are less than those observed in adults even when corrected for body weight, kidney weight, or body surface area. For the human kidney, the period after birth is marked by striking growth and unique physiologic functional changes that facilitate not only the immediate demands for adaptation to extrauterine life but also the progressive maturation to adult renal function. The most striking postnatal transition occurs in an increase in RBF resulting in a rise in GFR. In contrast, urinary sodium output drops so that retained sodium can participate in new tissue formation in this period of rapid somatic growth. Other tubular functions, such as urinary concentration and acid-base homeostasis, more progressively approach adult levels. Adult values (ml/min/1.73 m2) for RBF, GFR, urea clearance, maximum tubular excretory capacity for p-amino hippurate transport, and maximum renal concentrating capacity are achieved by 1 to 2 years of age. In contrast, an acid urine pH is achieved by 1 week of postnatal age in term infants, and maximum urinary acidification can be achieved as early as 1 to 2 months of postnatal age.3–7 For preterm infants, renal functional maturation is influenced by conceptional age, not by postnatal age; adult values for RBF, GFR, albumin excretion, maximal concentrating ability, and kidney size are achieved sometime by 8 years of age.

Several risk factors for congenital renal disease have been identified, including in utero exposure to environmental toxins, drugs, and physical agents. Such agents may 1) stop, retard, or accelerate development; 2) promote abnormal development; and 3) interfere with orderly maturation after development. Although the developing/maturing kidney may be vulnerable to certain toxins, in other instances, the immaturity of the kidney may be "protective."


   ROLE OF HEMODYNAMICS AND RBF/GFR ON THE RENAL EFFECTS OF ENVIRONMENTAL TOXINS, DRUGS, OR STRESSES
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 
In mammals, including humans, endotoxins produce glomerular visceral epithelial and endothelial cell swelling, polymorphonuclear leukocyte and platelet accumulation in the capillary lumina, tubular interstitial edema, and focal intertubular hemorrhage. In 10- and 28-day old rats, S enteritidis endotoxin required 1/350 the dose given to young adults to induce renal histopathologic changes. This suggests that the kidney in the young may be more vulnerable to hemodynamic changes than the adult. However, 10-day-old rats, which have lower renal blood flow than 28-day-old rats, had fewer glomerular changes than the older rats.8 Thus, the low RBF and GFR in the neonate may offer protection that is lost with development. Because of a low GFR, substances that are eliminated mainly by the kidney may exert less nephrotoxicity in the young. The immature kidney has been shown to be more tolerant to the nephrotoxic effects of aminoglycosides because of the lower RBF as compared with adults.9 Conversely, this possible "protective" effect of low GFR may render the developing kidney vulnerable to the consequences of abnormal decreases in RBF, resulting in renal ischemia. The sequence of neonatal multisystem organ failure is different in the neonate than in adults. Whereas in adults the lung is typically the first organ involved, in neonates this organ is involved later in the multiorgan sequence. Instead, the immature kidney of the neonate is the first organ affected in this pathophysiologic sequence.10

Several drugs could potentially interfere with the normal development of the kidney because their target genes/proteins have been shown to be important in the development of the kidney. Two systems have been shown to be important in the development of the kidney: prostanoids and the renin-angiotensin system.

Prostanoids
Prostanoids produced by cyclo-oxygenases COX 1 and 2 regulate renal hemodynamics and tubular transport. In general, COX 1, found in the renal vasculature, glomeruli, and collecting ducts, is mainly involved in regulation of renal hemodynamics. In contrast, COX 2, found in the macula densa, thick cortical ascending limb of Henle’s loop, medullary interstitial cells, and glomerular podocytes, is mainly involved in the regulation of renal sodium and water handling.11 In general, patients with increased risk of COX inhibitor–induced renal toxicity include the elderly, patients with renal or hepatic disease, and those on diuretics or angiotensin-converting enzyme (ACE) inhibitors. Several therapeutic agents, such as nonsteroidal anti-inflammatory drugs, aspirin, and indomethacin, nonselectively inhibit both COX 1 and COX 2. Selective COX 2 inhibition leads to disruption of nephrogenesis in both mice and rats. Genetic ablation of COX 2 results in severe morphologic abnormalities, including impaired glomerulogenesis, cortical dysplasia, and diffuse tubular cyst formation. Mice lacking COX 2 have reduced viability and develop renal dysplasia.12,13 These studies confirm the potential teratogenic/developmental effects of prenatal use of nonsteroidal anti-inflammatory drugs and selective COX 2 inhibitors leading to acute renal failure and renal dysgenesis, but adverse renal effects of COX inhibitors in fetuses, neonates, and children seem to be relatively rare.14 However, the incidence of interstitial nephritis caused by COX inhibitors in children is not known.

Renin-Angiotensin System
The activity of the renin-angiotensin system is increased in the perinatal period, and the vasoconstrictor activity of angiotensin II may contribute to the low RBF in the newborn.15 Mice made deficient in angiotensinogen have a transient delay in maturation of renal glomeruli.16 Adult mice lacking angiotensinogen and ACE develop renal vascular hypertrophy, focal tubular atrophy, and marked papillary atrophy and dilated calyces.17 Mice have 2 renin genes, Ren-1 and Ren-2, and individual disruptions of these genes do not result in renal anomalies, probably because of compensation by the remaining renin gene. There are 4 angiotensin (AT) receptors, and null mutants of AT1 and AT2 receptors have been generated. Null mutations of the AT1 and AT2 receptors also have abnormal renal morphogenesis. AT1 receptor mutant mice initially have mild abnormalities in the inner medulla and papilla but subsequently develop obstructive uropathy because of poor development of the pelvis and defective ureteral peristalsis. AT2 receptors have been suggested to play a role in ureteral budding and metanephric growth. Approximately 2% to 3% of AT2 receptor mutant mice develop anomalies of the kidney and urinary tract, ranging from dysplastic kidneys to uretero-pelvic obstruction and duplicated ureters. Loss of function mutation of the AT2 gene has been associated with these congenital anomalies in humans.15,18,19 Suppression of the renin angiotensin system in the perinatal period by protein restriction or high salt intake leads to a reduced number of glomeruli, glomerular enlargement, and hypertension in the adult rat.20,21

ACE inhibitor fetopathy, which develops when ACE inhibitors are given at approximately the 26th week of gestation, does not have a counterpart in animals.12, 13 These studies confirm the potential teratogenic/developmental effects of prenatal use of nonsteroidal anti-inflammatory drugs and selective COX 2 inhibitors leading to acute renal failure and renal dysgenesis, but adverse renal effects of COX inhibitors in fetuses, neonates, and children seem to be relatively rare.14 However, the incidence of interstitial nephritis caused by COX inhibitors in children is not known.

Renin-Angiotensin System
The activity of the renin-angiotensin system is increased in the perinatal period, and the vasoconstrictor activity of angiotensin II may contribute to the low RBF in the newborn.15 Mice made deficient in angiotensinogen have a transient delay in maturation of renal glomeruli.16 Adult mice lacking angiotensinogen and ACE develop renal vascular hypertrophy, focal tubular atrophy, and marked papillary atrophy and dilated calyces.17 Mice have 2 renin genes, Ren-1 and Ren-2, and individual disruptions of these genes do not result in renal anomalies, probably because of compensation by the remaining renin gene. There are 4 angiotensin (AT) receptors, and null mutants of AT1 and AT2 receptors have been generated. Null mutations of the AT1 and AT2 receptors also have abnormal renal morphogenesis. AT1 receptor mutant mice initially have mild abnormalities in the inner medulla and papilla but subsequently develop obstructive uropathy because of poor development of the pelvis and defective ureteral peristalsis. AT2 receptors have been suggested to play a role in ureteral budding and metanephric growth. Approximately 2% to 3% of AT2 receptor mutant mice develop anomalies of the kidney and urinary tract, ranging from dysplastic kidneys to uretero-pelvic obstruction and duplicated ureters. Loss of function mutation of the AT2 gene has been associated with these congenital anomalies in humans.15,18,19 Suppression of the renin angiotensin system in the perinatal period by protein restriction or high salt intake leads to a reduced number of glomeruli, glomerular enlargement, and hypertension in the adult rat.20,21

ACE inhibitor fetopathy, which develops when ACE inhibitors are given at approximately the 26th week of gestation, does not have a counterpart in animals.22–24 ACE inhibition is associated with oligohydramnios, renal tubular dysgenesis, neonatal anuria, calvarial and pulmonary hypoplasia, mild to severe intrauterine growth retardation, persistent patent ductus arteriosus, and fetal or neonatal death. These developmental anomalies are thought to be attributable partly to a direct action of ACE inhibitors on the fetal renin-angiotensin system and partly to the ischemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrient delivery to the fetus. Use of ACE inhibitors in the first trimester has not been associated with fetal abnormalities. Angiotensin II receptor blockers that cross the placenta may produce the same defect.25,26 The effects of decreased angiotensin II levels or AT1 receptor blockade probably occurs in the fetus after the first trimester because blood pressure and, thus, tissue perfusion (including the kidneys) are maintained by the renin-angiotensin system. In the immediate newborn period, angiotensin II maintains blood pressure and contributes to the low RBF. After the immediate newborn period, maintenance of blood pressure requires angiotensin II. However, basal RBF is no longer influenced by angiotensin II. Therefore, detrimental effects in the kidney caused by interruption of the renin-angiotensin system are not evident after the immediate neonatal period.


   ROLE OF TUBULAR FUNCTION ON THE RENAL EFFECTS OF ENVIRONMENTAL TOXINS OR STRESSES
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 
Response to Anoxia and Oxidative Stress
The immature kidney tolerates anoxia to a greater extent than the mature kidney, a characteristic that is also present in immature brain and heart.27 Some antioxidant enzymes are not well expressed in the fetal kidney but are augmented after birth.28 Renal superoxide anion but not hydrogen peroxide generation is low during the early postnatal development. The levels of antioxidant enzymes and sulfhydryl content in the developing kidney are low after birth but rise with increasing age.29 The neonate may have a higher level of protection against peroxides but a lower capacity to detoxify superoxide anions.30,31

Role of Tubular Transport
The extent of chemical-induced renal toxicity can be related to the efficiency in which the particular compound is transported by renal tubules.32 Increased tubular transport generally equates with increased tubular toxicity. Because renal tubular transport capacities vary with maturation, the degree of nephrotoxicity may also vary with maturation. There are species differences, however. Thus, in several instances in which renal toxicity has been observed in humans and other experimental animals, no age-related differences in nephrotoxicity have been seen in rabbits.33


   ORGANIC ANIONS AND CATIONS
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 
Renal organic anion (OAT) and cation (OCT) transporters protect against endogenous and exogenous toxins by secreting these anionic substances into the urine.34,35 Renal OATs (OAT1, OAT2, OAT3, and OAT4) belong to the amphiphilic solute facilitator family. Another superfamily includes the OCT families (OCT1, OCT2, and OCT3) and the organic cation/carnitine transporters (OCTN1 and OCTN2). By-products of many xenobiotics are organic cations and are excreted from the body by OCTs.35 The nephrotoxicity of cephalosporins has been ascribed to effects on OCTs. Cephalosporins produce proximal tubular necrosis only after their transport into proximal tubule cells. Oxidative stress plays a major role in cephaloridine nephrotoxicity.36 Cephaloridine depletes reduced glutathione, increases oxidized glutathione, and induces lipid peroxidation in renal cortical tissue.33,36 The toxicity of cephaloridine and cefazolin is less in newborn than 2-week-old rabbits.33 The decreased nephrotoxicity of cephalosporins in the young has been ascribed to decreased tubular transport. However, competition for transport of essential nutrients by cephalosporin, eg, cephaloridine, which is transported by OCTN2, can cause carnitine deficiency.37 The excretion of both endogenous organic (aryl) acids, such as benzoic acid, and exogenous ones, such as p-aminohippuric acid (PAH), penicillin, and furosemide, is reduced in the human neonate and other immature animals. PAH is a good substrate for both OAT1 and OAT3. There is a deceased ability of the young kidney to extract PAH from the circulation.38–40 The decreased secretion of these organic acids in the developing kidney is probably related to the developmentally regulated expressions of the OATs.41 Penicillin can accelerate the maturation of organic acid transport (eg, PAH).42,43


   MYCOTOXINS
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 
The most frequent dietary toxigenic fungi are Aspergillus, Penicillium, and Fusarium species. They produce aflatoxin B1 (transformed into aflatoxin M1 in milk), as well as ochratoxins and zearalenone, fumonisin B1, T-2 toxin, HT-2 toxin, and deoxynivalenol (vomitoxin), which are of increasing concern in human health. Some of their metabolites may be involved in human diseases. They can be found in many foodstuffs, particularly grains, and many times are not completely destroyed by normal processing or cooking, particularly because they are heat stable. They can produce a variety of toxic effects (liver, kidney, and hematopoietic toxicity; immune toxicity; reproductive toxicity; fetal toxicity and teratogenicity), which have been documented mainly in experimental models; the extrapolation to levels of exposure noted in humans is many times very uncertain.44,45 Some mycotoxins can produce renal apoptosis, which subsequently may proceed to secondary necrosis. Little information is available on effects of these substances in developing kidneys.

Ochratoxin A
Ochratoxin A is produced mainly by the Aspergillus ochraceus and Penicillium verrucosum. Contamination occurs in the field, during the storage of cereals, cereal products, and other plant-derived products. It is also found in meat.46 The toxin has been classified a possible carcinogen but only after frank renal toxicity has occurred. OAT1 and OAT3 may be significantly related with the events in the development of ochratoxin-induced nephrotoxicity in the human kidney.47 Dams and fetuses that are treated with ochratoxin have visceral and skeletal anomalies; the fetuses also have lower weights.48 Age-related nephrotoxic effects of ochratoxin are not well documented.

Monocrotaline
Monocrotaline, a pyrrolizidine alkaloid, causes veno-occlusive disease of the liver, pulmonary arterial hypertension, and right ventricular hypertrophy.49–51 It also has nephrotoxic effects similar to hemolytic uremic syndrome.50

Fumonisins
The only fungi that produce significant quantities of fumonisin are Fusarium species. These species cause Fusarium kernel rot of maize, an important disease in hot climates. Fumonisins are widely distributed geographically, occurring in maize in many areas of the world; considerable annual variations in contamination have been noted. Fumonisins B1, B2, B3, and B4 are a group of structurally related compounds with B1 being the form most commonly found in corn and for which most biological studies have been performed.

Fumonisins are poorly absorbed from the digestive tract but are rapidly distributed and eliminated. The liver and kidneys retain most of the absorbed material, and fumonisin B1 persists longer in rat liver and kidney than in plasma. In pregnant rats and rabbits, very low concentrations of fumonisin B1 are recovered in the uterus and placenta. No fumonisin B1 was found in fetuses, indicating the absence of placental transfer. There is little evidence of significant transfer during lactation, and fumonisins do not seem to be metabolized in vitro or in vivo.52

Two cellular modes of action for fumonisin that are well supported by results obtained in vivo have been proposed. In both hypotheses, altered lipid metabolism is the initial biochemical mechanism. In one hypothesis, the initial biochemical lesion is presumed to be inhibition of ceramide synthase.53, 54 In the other, the biochemical lesion is attributed to disruption of the {delta}6 desaturase and cyclooxygenase metabolic pathways.55 In both hypotheses, it is assumed that other initial sites of action could contribute to the observed cellular responses. The 2 invoke similar cellular mechanisms, to the extent that fumonisin-induced imbalances in the rates of cell death and proliferation in target tissues are considered to contribute to cancer development.56 Fumonisins also affect sites of cellular regulation that seem to be independent of the disruption of lipid metabolism, but cancer and the other toxic effects in animals seem to depend on disruption of various aspects of lipid metabolism, membrane structure, and signal transduction pathways mediated by lipid second messengers. The demonstrated cellular effects include altered cell proliferation, altered rates of apoptosis, altered cell–cell communication and cell adhesion, induction of oxidative stress, and modulation of gene expression. Because the proposed biochemical mechanisms of action involve alterations in de novo biosynthetic pathways, nutritional factors could play an important role in determining the potency of FB1 and the observed toxicologic endpoints in rodents.

In many animal species, the kidney is a major target. Early renal effects include increases in free sphingoid bases, renal tubular cell apoptosis, and cell regeneration. In rodents, the toxicity of fumonisin is strain and sex dependent. For example, male BDIX rats are more sensitive to the hepatotoxic effects than male Fischer 344N, male Sprague Dawley, and male RIVM:WU rats, in which nephrotoxicity was observed at lower doses than hepatotoxicity. In mice, the liver is more sensitive than the kidney to fumonisin-induced toxicity. Female mice seem to be more sensitive than male mice. Available studies clearly indicate that renal carcinogenesis must be preceded by renal toxicity; the potential for renal carcinogenesis is subsumed by the dose–response relationship for renal toxicity. Induction of renal tubule carcinomas in male rats may be partly attributable to the continuous compensatory regeneration of renal tubule epithelial cells in response to the induction of apoptosis by fumonisin B1.45 Fumonisin B1 induces not only hepatic toxicity but also pulmonary edema and hydrothorax in pigs. Both diseases seem to occur secondary to cardiovascular dysfunction. Cardiovascular effects have also been found in other species. Field outbreaks of equine leukoencephalomalacia and porcine pulmonary edema associated with consumption of fumonisin-contaminated maize have been reported in the United States and elsewhere.57

Although there is evidence that fumonisins are embryotoxic in vitro, currently no published data exist to support the conclusion that fumonisins are developmental or reproductive toxicants in farm animals or humans. Except in 1 study in hamsters, embryotoxicity occurred in laboratory animals (rats, mice, and rabbits) secondary to maternal toxicity. A specific role for fumonisins in the development of neural tube defects has been proposed. The hypothesis includes a critical role of fumonisin in disruption of folate membrane transport, but no specific studies have been designed or performed to confirm this proposed mechanism.57


   ELEMENTAL CONTAMINANTS
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 
Infants and young children can be at an increased risk of toxicity to elemental contaminants, such as lead, because of a higher intake and a greater intestinal absorption relative to body size.58 Because renal tubular transport is decreased in the young, acute renal toxicity may be less in younger than in older individuals.59 Kidney concentrations of copper and selenium did increase with fetal age but markedly increased during the postnatal period.60 However, there were greater accumulations of mercury, cadmium, and lead in the kidney than in brain during fetal and postnatal development.61 Toxicity is influenced not only by tissue concentrations but also by deleterious cellular activities. Decreased elimination of these elements may result in greater mortality as a result of toxic effects in organs other than the kidney. Moreover, the impact on effector proteins may be less in the kidney than in other organs. Nevertheless, it has been proposed that kidney weight may be a better discriminative index of excess lead exposure than simple neurobehavioral indices.62

Lead and Cadmium
Lead is a commonly encountered nephrotoxic metal. Chronic exposure to lead at levels found in industrial exposure has been associated with the development of renal insufficiency, renal cancer, and hypertension.59,63 Rats that are exposed to lead at a younger age accumulate more lead in several organs, including the kidney, than those that are exposed at an older age that may have been related to increased gastrointestinal absorption in younger rats.58 Cadmium and arsenic are also transported in the proximal tubule, where their toxic effects are expressed. In juvenile rats, cadmium does not produce any significant alteration in renal PAH excretion, caused, likely, by the immaturity of renal tubular transport processes.64 Chronic toxicity may be expressed differently from acute toxicity. Thus, asymptomatic proteinuria as a result of interstitial fibrosis rather than proximal tubular dysfunction may be seen in chronic lead toxicity. Examples of the age-related effect of elemental contaminants on the kidney are discussed below.

Uranium
Naturally occurring uranium in drinking water is a significant health concern in several areas of North America.65 Uranyl nitrate decreased GFR and urine flow, increased fractional sodium excretion, and produced proximal tubular morphologic changes to a greater extent in older than in younger puppies. In contrast, RBF was reduced to a greater extent in younger than older puppies.66 Similarly, proteinuria, glycosuria, and hematuria were more frequent and severe in younger than in older rats. Urinary enzymes may not be reflective of tubular damage in the young.67 In rats, lactate dehydrogenase, leucine aminopeptidase, and alkaline phosphatase are reliable indicators of nephrotoxicity in the adult, but only alkaline phosphatase seems to be an indicator of nephrotoxicity in 15- to 20-day-old rats.

Mercury
The nephrotoxic effects of inorganic mercury are modified by age, gender, and concomitant exposure to other agents such as dieldrin and phenobarbital.68–70 Inorganic mercury is also transported by the proximal tubule; thus, its toxicity is expected to be less in the young. However, the dose of inorganic mercury that induced mortality in rat pups at 1 day of age was much less than that noted at 15 days of age.71 After 2 weeks of age, the decrease in blood urea nitrogen was similar to 8-week-old rats, but mortality was still greater in the youngest rats.72,73 These studies suggest that extrarenal effects of toxins may be more prominent in the young because of decreased tubular transport and, therefore, the excretion rate.

Halogenated Hydrocarbons
Maternal exposure to halogenated hydrocarbons can decrease kidney growth in the offspring.74 The diverse group of hydrocarbons that induce a specific spectrum of nephropathies include decalin, an alicyclic hydrocarbon; JP5 jet fuel, a mixture of C12–15 straight and branched-chain hydrocarbons; C10–11 isoparaffinic hydrocarbons; Stoddard solvent, a mixture of straight and branched-chain paraffins, naphthenes, and alkyl aromatic hydrocarbons; 2,2,4-trimethylpentane, a branched-chain hydrocarbon; and d-limonene, an aromatic hydrocarbon. The toxicity of halogenated hydrocarbons, like other toxins, is influenced by gender and species. Male rats but not other mammals develop nephrotoxicity on exposure to decalin. Decalin apparently produces nephrotoxicity in male rats because of the accumulation of {alpha}2 microglobulin, a protein that is seen in proximal tubules of mature male but not female rats. This is another example of animal studies that may not be applicable in humans.75

Diethylene Glycol
Idiopathic acute renal failure has been traced to contamination by diethylene glycol of glycerin, used in the formulation of medicinal syrups.76 This has occurred in many countries, including the United States.


   MANIFESTATIONS OF TOXIC NEPHROPATHY
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
CONCLUSION
 REFERENCES
 
The renal manifestations of exposure to toxic agents are similar in children and in adults. However, the extent of renal involvement and the severity of the manifestations of the direct and indirect effects of nephrotoxins are modified by the stage of renal development. For example, serum creatinine level is the best endogenous indicator of GFR. However, serum creatinine level is affected by muscle mass, to a greater extent, and to ingested sources, to a lesser extent. Immediately after birth, the neonatal serum creatinine is a reflection of maternal creatinine. Depending on the conceptual age, sometime after birth, serum creatinine levels decrease to reflect endogenous creatinine production and renal function. Because muscle mass is less in the young compared with adults, serum creatinine levels are lowest in infants and increase with age reaching adult values with accretion of muscle mass.

The effects of intrauterine or neonatal renal toxic injury may result in an impairment of glomerular filtration, tubular function, and hormonal production or catabolism. These could present as renal failure with retention of waste products of metabolism (increased blood urea and creatinine), proteinuria, aminoaciduria, glycosuria; inability to dilute and concentrate the urine, eliminate metabolically produced or ingested acids and alkali (metabolic alkalosis or acidosis), or regulate electrolyte balance; and low or high blood pressure. An early clue of renal tubular injury may be proteinuria (albuminuria, globulinuria, {alpha}1 or ß2-microglobulinuria) or the presence of abnormal urinary sediment (increased urinary levels of red blood cells, pyuria, casts, or renal tubular epithelial cells). {alpha}1-Microglobulinuria has been suggested to be a marker of cadmium exposure.77 Urinary enzymes may also reflect tubular injury. Noonan et al78 reported that in individuals 18 years and older but not in children 6 to 17 years of age, N-acetyl-ß-D-glucosamide and alanine aminopeptidase adjusted for creatinine and other potential confounders were positively associated with urinary cadmium. The utility of different biomarkers to detect nephrotoxicity has not be proved.79 The signs and symptoms of renal dysfunction may manifest acutely or insidiously. An outbreak of idiopathic acute renal failure could be caused by exposure to nephrotoxic agents. In general, however, toxic nephropathy is not a common cause of acute renal failure, the most common causes being hemolytic uremic syndrome, glomerulonephritis, sepsis, hematologic/oncologic complications, and postcardiac surgery.80


   CONCLUSION
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
REFERENCES
 
The manifestations of renal toxicity are strongly influenced by renal development. Toxic effects of xenobiotic compounds, including drugs and environmental chemicals, may be seen at a particular gestational age but not at other ages, depending on the stage of renal development. The low RBF and decreased tubular transport may serve to protect the kidneys from the effects of toxins. However, decreased tubular transport and, therefore, excretion result in accumulation of toxins and can lead to deleterious systemic, nonrenal effects that are greater than that seen in adults, whose renal function is more developed. However, many of the studies have been performed in experimental animals. There are many gaps in the characterization and understanding of the effects of drugs and environmental toxins in the developing human kidney in prenatal and postnatal life.


   ACKNOWLEDGMENTS
 
This work is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (DK52612).


   FOOTNOTES
 
Received for publication Oct 7, 2003; Accepted Oct 20, 2003.

Reprint requests to (P.A.J.) Department of Pediatrics, Georgetown University Medical Center, 3800 Reservoir Rd, NW, Washington, DC 20007. E-mail: pjose01{at}georgetown.edu


   REFERENCES
TOP
 ABSTRACT
 ROLE OF HEMODYNAMICS AND...
 ROLE OF TUBULAR FUNCTION...
 ORGANIC ANIONS AND CATIONS
 MYCOTOXINS
 ELEMENTAL CONTAMINANTS
 MANIFESTATIONS OF TOXIC...
 CONCLUSION
 REFERENCES
 

  1. Pohl M, Bhatnagar V, Mendoza SA, et al. Toward an etiological classification of developmental disorders of the kidney and upper urinary tract. Kidney Int.2002; 61 :10 –19[CrossRef][ISI][Medline]
  2. McCrory WW. Developmental Nephrology. Boston, MA: Harvard University Press; 1972
  3. Guillery EN, Nuyt A-N, Robillard JE. Functional development of the kidney in utero. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Philadelphia, PA: WB Saunders; 1998:1560–1573
  4. Jose PA, Haramati A, Fildes RD. Postnatal maturation of renal blood flow. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Philadelphia, PA: WB Saunders; 1998:1573–1578
  5. Yared A, Ichikawa I. Postnatal development of glomerular filtration rate. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Philadelphia, PA: WB Saunders; 1998:1588–1592
  6. Guignard J-P. Measurement of glomerular filtration rate in neonates. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Philadelphia, PA: WB Saunders; 1998:1593–1599
  7. Papadopoulou ZL, Tina LU, Sandler P, et al. Development of renal function. In: Johnson TR, Moore WM, Jeffries JE, eds. Children Are Different. Columbus, OH: Ross Laboratories; 1978:98–103
  8. Hurley RM, Nayyar RP, Goto M, et al. Renal lesions in young rats induced by Salmonella enteritidis endotoxin. Pediatr Nephrol.1989; 3 :156 –161[CrossRef][ISI][Medline]
  9. Cowan RH, Jukkola AF, Arant BS Jr. Pathophysiologic evidence of gentamycin nephrotoxicity in neonatal puppies. Pediatr Res.1980; 14 :1204 –1211[ISI][Medline]
  10. Avanoglu A, Ergun O, Bakirtas F, et al. Characteristics of multisystem organ failure in neonates. J Pediatr Surg.1997; 7 :263 –266[CrossRef]
  11. Harris RC Jr. Cyclooxygenase-2 inhibition and renal physiology. Am J Cardiol2002; 89 :10D –17D[ISI][Medline]
  12. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature.1995; 378 :406 –409[CrossRef][Medline]
  13. Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell.1995; 83 :473 –482[CrossRef][ISI][Medline]
  14. Cuzzolin L, Dal Cere M, Fanos V. NSAID-induced nephrotoxicity from the fetus to the child. Drug Saf.2001; 24 :9 –18[CrossRef][ISI][Medline]
  15. Norwood VF, Turfo-McReddie A, Gomez RA. Development of the renin-angiotensin system. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Philadelphia, PA: WB Saunders1998 :1579 –1587
  16. Niimura F, Labosky PA, Kakuchi J, et al. Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest.1995; 96 :2947 –2954
  17. Coffman TM. Gene targeting in physiological investigations. Am J Physiol.1998; 274 :F999 –F1005
  18. Matsusaka T, Miyazaki Y, Ichikawa I. The renin angiotensin system and kidney development. Annu Rev Physiol.2002; 64 :551 –561[CrossRef][ISI][Medline]
  19. Miyazaki Y, Ichikawa I. Role of the angiotensin receptor in the development of the mammalian kidney and urinary tract. Comp Biochem Physiol A Mol Integr Physiol.2001; 128 :89 –97[CrossRef][Medline]
  20. Woods LL, Ingelfinger JR, Nyengaard JR, et al. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult. Pediatr Res.2001; 49 :460 –467[ISI][Medline]
  21. Woods LL. Fetal origins of adult hypertension: a renal mechanism? Curr Opin Nephrol Hypertens.2000; 9 :419 –425[CrossRef][ISI][Medline]
  22. Tabacova SA, Kimmel CA. Enalapril: pharmacokinetic/dynamic inferences for comparative developmental toxicity. A review. Reprod Toxicol.2001; 15 :467 –478[CrossRef][ISI][Medline]
  23. Buttar HS. An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. Mol Cell Biochem.1997; 176 :61 –71[CrossRef][ISI][Medline]
  24. Barr M JR. Teratogen update: angiotensin-converting enzyme inhibitors. Teratology.1994; 50 :399 –409[CrossRef][ISI][Medline]
  25. Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects. Lancet.2001; 357 :363
  26. Sorensen AM, Christensen S, Jonassen TE, Andersen D, Petersen JS. Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists. Ugeskr Laegr.1998; 160 :1460 –1464
  27. Gaudio KM, Thulin G, Mann A, et al. Role of heat stress response in the tolerance of immature renal tubules to anoxia. Am J Physiol1998; 274 :F1029 –F1036
  28. Fujii T, Fujii J, Taniguchi N. Augmented expression of peroxiredoxin VI in rat lung and kidney after birth implies an antioxidative role. Eur J Biochem.2001; 268 :218 –225[ISI][Medline]
  29. Gupta A, Gupta A, Nigam D, et al. Profile of reactive oxygen species generation and antioxidative mechanisms in the maturing rat kidney. J Appl Toxicol.1999; 19 :55 –59[CrossRef][ISI][Medline]
  30. Harman AW, McKenna M, Adamson GM. Postnatal development of enzyme activities associated with protection against oxidative stress in mouse. Biol Neonate.1990; 57 :187 –193[CrossRef][ISI][Medline]
  31. Vlessis AA, Mela-Riker L. Perinatal development of heart, kidney, and liver mitochondrial antioxidant defense. Pediatr Res.1989; 26 :220 –226[ISI][Medline]
  32. Berndt WO. The role of transport in chemical nephrotoxicity. Toxicol Pathol.1998; 26 :52 –57[ISI][Medline]
  33. Wold JS, Joost RR, Owen NV. Nephrotoxicity of cephaloridine in newborn rabbits: role of the renal anionic transport system. J Pharmacol Exp Ther.1977; 201 :778 –885[Abstract/Free Full Text]
  34. Sweet DH, Bush KT, Nigam SK. The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol.2001; 281 :F197 –F205[Abstract/Free Full Text]
  35. Zhang L, Brett CM, Giacomini KM. Role of organic cation transporters in drug absorption and elimination. Annu Rev Pharmacol Toxicol.1998; 38 :431 –436[CrossRef][ISI][Medline]
  36. Goldstein RS, Smith PF, Tarloff JB, Contardi L, Rush GF, Hook J. Biochemical mechanisms of cephaloridine nephrotoxicity. Life Sci.1988; 42 :1809 –1816[CrossRef][ISI][Medline]
  37. Ganapathy ME, Huang W, Rajan DP, et al. Beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J Biol Chem.2000; 275 :1699 –1707[Abstract/Free Full Text]
  38. Calcagno PL, Rubin MI. Renal extraction of para-aminohippurate in infants and children. J Clin Invest.1963; 42 :1632
  39. Jose PA, Logan AG, Slotkoff LM, Lilienfield LS, Calcagno PL, Eisner GM. Intrarenal blood flow distribution in canine puppies. Pediatr Res.1971; 5 :335 –344
  40. Horster M, Valtin H. Postnatal development of renal function: micropuncture and clearance studies in the dog. J Clin Invest.1971; 50 :779 –795
  41. Cole BR, Brocklebank JT, Capps RG, et al. Maturation of p-aminohippuric acid transport in the developing rabbit kidney: interrelationships of the individual components. Pediatr Res.1978; 12 :992 –997[ISI][Medline]
  42. Kaplan MR, Lewy JE. Stimulation of p-aminohippurate extraction in the maturing rabbit kidney. Pediatr Res.1978; 12 :834 –837[ISI][Medline]
  43. Hirsch GH, Hook JB. Maturation of renal organic acid transport: substrate stimulation by penicillin. Science.1969; 165 :909 –910[Abstract/Free Full Text]
  44. Creppy EE. Update of survey, regulation and toxic effects of mycotoxins in Europe. Toxicol Lett.2002; 127 :19 –28[CrossRef][ISI][Medline]
  45. Howard PC, Warbritton A, Voss KA, et al. Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat. Environ Health Perspect.2001; 109(suppl 2) :309 –314
  46. Petzinger E, Ziegler K. Ochratoxin A from a toxicological perspective. J Vet Pharmacol Ther.2000; 23 :91 –98[CrossRef][ISI][Medline]
  47. Jung KY, Takeda M, Kim DK, et al. Characterization of ochratoxin A transport by human organic anion transporters. Life Sci.2001; 69 :2123 –2135[CrossRef][ISI][Medline]
  48. Abdel-Wahhab MA, Nada SA, Arbid MS. Ochratoxicosis: prevention of developmental toxicity by L-methionine in rats. J Appl Toxicol.1999; 19 :7 –12[CrossRef][ISI][Medline]
  49. Goto J, Ishikawa K, Kawamura K, et al. Heme oxygenase-1 reduces murine monocrotaline-induced pulmonary inflammatory responses and resultant right ventricular overload. Antioxid Redox Signal.2002; 4 :563 –568[CrossRef][ISI][Medline]
  50. Ecarnot-Laubriet A, Assem M, Poirson-Bichat F, et al. Stage-dependent activation of cell cycle and apoptosis mechanisms in the right ventricle by pressure overload. Biochim Biophys Acta.2002; 1586 :233 –242[Medline]
  51. Kurozumi T, Tanaka K, Kido M, et al. Monocrotaline-induced renal lesions. Exp Mol Pathol.1983; 39 :377 –386[CrossRef][ISI][Medline]
  52. Martinez-Larranaga MR, Anadon A, Diaz MJ, et al. Toxicokinetic and oral bioavailability of fumonisin B1. Vet Hum Toxicol.1999; 41 :357 –362[ISI][Medline]
  53. Merrill AH Jr, Sullards MC, Wang E, et al. Sphingolipid metabolism: roles in signal transduction and disruption by fumonisins. Environ Health Perspect.2001; 109(suppl 2) :283 –289
  54. Riley RT, Enongene E, Voss KA, et al. Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environ Health Perspect.2001; 109(suppl 2) :301 –308
  55. Gelderblom WC, Abel S, Smuts CM, et al. Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion. Environ Health Perspect.2001; 109(suppl 2) :291 –300
  56. Howard PC, Eppley RM, Stack ME, et al. Fumonisin b1 carcinogenicity in a two-year feeding study using F344 rats and B6C3F1 mice. Environ Health Perspect.2001; 109(suppl 2) :277 –282
  57. International Program on Chemical Safety/World Health Organization. Safety Evaluation of Certain Mycotoxins in Food. WHO Food Additives Series 47. Geneva, Switzerland: WHO; 2001:103–279
  58. Ziegler EE, Edwards BB, Jensen RL, Mahaffey KR, Fomon SJ. Absorption and retention of lead by infants. Pediatr Res.1978; 12 :29 –34[ISI][Medline]
  59. Fowler BA. Mechanisms of kidney injury from metals. Environ Health Perspect.1992; 100 :57 –63
  60. Vahter M, Lutz E, Lind B, et al. Concentrations of copper, zinc and selenium in brain and kidney of second trimester fetuses and infants. J Trace Elem Med Biol.1997; 11 :215 –222[ISI][Medline]
  61. Lutz E, Lind B, Herin P, et al. Concentrations of mercury, cadmium and lead in brain and kidney of second trimester fetuses and infants. J Trace Elem Med Biol.1996; 10 :61 –67[ISI][Medline]
  62. Overmann SR, Zimmer L, Woolley DE. Motor development, tissue weights and seizure susceptibility in perinatally lead-exposed rats. Neurotoxicology.1981; 2 :725 –742[ISI][Medline]
  63. Lockitch G. Perspectives on lead toxicity. Clin Biochem.1993; 26 :371 –381[CrossRef][ISI][Medline]
  64. Braunlich H, Otto R. Age-related differences in nephrotoxicity of cadmium. Exp Pathol.1984; 26 :235 –239[ISI][Medline]
  65. McDonald-Taylor CK, Singh A, Gilman A. Uranyl nitrate-induced proximal tubule alterations in rabbits: a quantitative analysis. Toxicol Pathol.1997; 25 :381 –389[ISI][Medline]
  66. Pelayo JC, Andrews PM, Coffey AK, et al. The influence of age on acute renal toxicity of uranyl nitrate in the dog. Pediatr Res.1983; 17 :985 –992[ISI][Medline]
  67. Braunlich H, Fleck C. Urinary enzyme excretion as a indicator of nephrotoxicity in dependence on age. Exp Pathol.1981; 20 :182 –187[ISI][Medline]
  68. Fowler BA, Lucier GW. Phenobarbital protection against methyl mercury nephrotoxicity. Proc Soc Exp Biol Med.1975; 149 :75 –79[Abstract]
  69. Fowler BA. The morphologic effects of dieldrin and methyl mercuric chloride on pars recta segments of rat kidney proximal tubules. Am J Pathol.1972; 69 :163 –174[ISI][Medline]
  70. Yasutake A, Hirayama K, Inouye M. Sex difference in acute renal dysfunction induced by methylmercury in mice. Ren Fail.1990; 12 :233 –240[ISI][Medline]
  71. Daston GP, Gray JA, Carver B, et al. Toxicity of mercuric chloride to the developing rat kidney. II. Effect of increased dosages on renal function in suckling pups. Toxicol Appl Pharmacol.1984; 74 :35 –45[CrossRef][ISI][Medline]
  72. Bidani A, Churchill PC, Fleischmann L, et al. HgCl2-induced acute renal failure in the developing rat. Pediatr Res.1980; 14 :183 –186[ISI][Medline]
  73. Bidani A, Churchill P. Effects of sodium intake and nephrotoxin dose on acute renal failure in the young rat. Pediatr Res.1982; 16 :277 –281[ISI][Medline]
  74. Srinivasan K, Mahadevappa KL, Radhakrishnamurty R. Effect of maternal dietary hexachlorocyclohexane exposure on pup survival and growth in albino rats. J Environ Sci Health B.1991; 26 :339 –349[Medline]
  75. Alden CL. A review of unique male rat hydrocarbon nephropathy. Toxicol Pathol.1986; 14 :109 –111[Medline]
  76. O’Brien KL, Selanikio JD, Hecdivert C, et al. Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute Renal Failure Investigation Team. JAMA.1998; 279 :1175 –1180[Abstract/Free Full Text]
  77. Pless-Mulloli T, Boettcher M, Steiner M, Berger J. {alpha}1-Microglobulin: epidemiological indicator for tubular dysfunction induced by cadmium? Occup Environ Med.1998; 55 :440 –445[Abstract]
  78. Noonan CW, Sarasua SM, Campagna D, Kathman SJ, Lybarger JA, Mueller PW. Effects of exposure to low levels of environmental cadmium on renal biomarkers. Environ Health Perspect.2002; 110 :151 –155[ISI][Medline]
  79. Price RG, Patel S, Chivers I, Milligan P, Taylor SA. Early markers of nephrotoxicity: detection of children at risk from environmental pollution. Ren Fail.1999; 21 :303 –308[ISI][Medline]
  80. Williams DM, Sreedhar SS, Mickell JJ, Chan JC. Acute kidney failure: a pediatric experience over 20 years. Arch Pediatr Adolesc Med.2002; 156 :893 –900[Abstract/Free Full Text]
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