TY - JOUR
AU - Morales, Ana, Isabel
AB - Abstract As in the case of other heavy metals, a considerable body of evidence suggests that overexposure to uranium may cause pathological alterations to the kidneys in both humans and animals. In the present work, our aim was to analyze the available data from a critical perspective that should provide a view of the real danger of the nephrotoxicity of this metal for human beings. A further aim was to elaborate a comparative compilation of the renal pathophysiological data obtained in humans and experimental animals with a view to gaining more insight into our knowledge of the mechanisms of action and renal damage. Finally, we address the existing perspectives for the improvement of diagnostic methods and the treatment of intoxications by uranium, performing an integrated analysis of all these aspects. uranium, nephrotoxicity, chronic, acute, diagnosis, treatment Human beings are constantly exposed to a certain amount of uranium because it is heterogeneously present in natural form in food, the air, the soil, and water. The repercussions of this natural exposure as regards human physiology and pathophysiology are not completely known. However, the evidence gathered so far suggests that overexposure to uranium may result in toxicity, which is derived from an excessive accumulation of the element in the organism. This accumulation, in turn, depends on the route of entry, the duration of the exposure, the dose and the chemical compound of which it forms part, and its absorption (Maynard and Hodge, 1949; Stokinger et al., 1953). Natural exposure, overexposure, and intoxication can occur by ingestion, inhalation, or skin contact (Fig. 1). In any case, a small portion of the uranium gains access to the circulation from which it distributes throughout the body. Uranium accumulates mainly in the bones (66%), kidneys (8%), and liver (16%) (ICRP, 1996), and it is eliminated with the urine, rapidly from the blood and slowly from organ depots (ICRP, 1996; La Touche et al., 1987). FIG. 1. Open in new tabDownload slide Possible mechanisms involved in uranium nephrotoxicity. U, Uranium; Na/K ATPase, sodium-potassium pump; Na ATPase, sodium pump; Na, sodium; Pi, inorganic phosphate. FIG. 1. Open in new tabDownload slide Possible mechanisms involved in uranium nephrotoxicity. U, Uranium; Na/K ATPase, sodium-potassium pump; Na ATPase, sodium pump; Na, sodium; Pi, inorganic phosphate. Human beings may be subjected to pathological overexposure to the metal, both acutely and chronically, as a consequence of (1) contamination of the usual sources of normal exposure with high amounts of uranium arising from the anisotropy of the distribution of the metal in the earth’s crust, as in ground veins or water masses in contact with them, or from human dumping and (2) direct contact with new sources of exposure originated by human activity and enriched in the element, such as in materiel and aeronautics or in the fields of mining and industry. The main industrial use of uranium is for fuel in nuclear reactors, which produce 17% of the world’s electricity (Uranium Institute, 1996). Many countries are being driven into nuclear energy generation as a consequence of (1) the energy demand escalation, (2) the limited reserve of fossil fuels, (3) the scarce development of alternative sources, (4) the climate change, and (5) the regulation imposed by the Kyoto treaty. In this sense, uranium is one of the most useful fuels for nuclear energy production; it is reasonably inexpensive and complies with the Kyoto protocol. Other industrial uses of the element include the manufacture of aircraft stabilizers, in satellites, and in naval architecture (Wilkinson, 1962); in inertial orientation devices and gyroscopes (ATSDR/CDC, 1990); in green or yellow glasses (Peeks et al., 2002; Rossol, 1997); and in certain luminous devices, in highly penetrating gun ammunitions and in the production of high-energy x-rays (EPA, 1985). For years, it was used in the manufacture of dental porcelain (Thompson, 1976). The long half-life of the 238U isotope (4.51 × 109 years) is a good proxy for estimating the age of igneous rocks and in other types of radiometric dating (ATSDR, 1999). The toxicity of the metal depends on several factors, such as sex, age, the body mass index (Kurttio et al., 2006), and species. Of all the mammals studied, humans seem to be the least sensitive to uranium (Kathren and Burklin, 2008). An interspecies order of sensitivity has been proposed: rabbit > rat > guinea pig > pig > mouse > dog > cat > human (Orcutt, 1949; Tannenbaum et al., 1951). Uranium is responsible for both radiological and chemical toxicity. The radiological toxicity has been theoretically associated with the production of cancer. However, because the specific radioactivity of natural uranium is low, there seems to be no evident danger of cancer from radiological effects. The results of different studies carried out on animals and humans are consistent with this notion (Morris et al., 1990; Muller et al., 1967; Sanders, 1986; Stokinger et al., 1953). On the other hand, the chemical toxicity has been associated with hepatic, lung, and renal injury (UNSCEAR, 1988). It has also been suggested that the net effects caused by this metal in the kidneys and lungs could be because of cooperation between the chemical and radiological properties through a complementary mechanism of action, although this relationship has not been demonstrated experimentally (Ballou et al., 1986; Filippova et al., 1978; Spiegel, 1949; Spoor and Hursh, 1973; Stokinger et al., 1953). No significant toxicity of uranium has been evidenced at the cardiovascular (Boice et al., 2007; Dygert, 1949; Gilman et al., 1998c), muscle-skeletal (Gilman et al., 1998c), endocrine (Boice et al., 2007; Dygert, 1949; ,Gilman et al., 1998c; Maynard and Hodge, 1949; Stokinger et al., 1953), gastrointestinal (Boice et al., 2007; ,Gilman et al., 1998c; Maynard and Hodge, 1949), and skin (Boice et al., 2007; Spiegel, 1949) levels. No effects on reproduction have been reported in humans (Mays et al., 1985; McDiarmid et al., 2007). In contrast, in animal experimentation, relatively high doses of uranium have been reported to elicit reproductive abnormalities, manifested as a decrease in sperm counts (Llobet et al., 1991), fetal toxicity (Domingo et al., 1989), and testicular lesions (Maynard et al., 1953). In this article, the available information on the nephrotoxicity of uranium upon acute and chronic intoxication is thoroughly analyzed. For this purpose, both data from human as well as animal studies are critically compared. Human studies are scarcer and less controlled than animal studies. As such, information from experimental animals can, to a certain extent, be processed and extrapolated into the framework delineated by data obtained from human beings, in order to create a more complete picture of the pathophysiological aspects of the nephrotoxicity of uranium and the real risk posed by this metal to the human being. NEPHROTOXICITY BECAUSE OF ACUTE OVEREXPOSURE Acute Nephrotoxicity in Animal Models Pathophysiological Studies In animals, it has been possible to characterize the renal damage caused by the element in detail, under predetermined and controlled experimental conditions. Several studies have reported decreases in creatinine clearance (Banday et al., 2008; Haley, 1982; Sanchez et al., 2001; Shim et al., 2009), which is indicative of a reduction in the glomerular filtration rate (GFR). Congruently, with the decrease in the GFR, a significant increase in the plasma concentration of creatinine and blood ureic nitrogen (BUN) has been reported after uranium administration (Banday et al., 2008; Fukuda et al., 2005b; Sanchez et al., 2001; Shim et al., 2009; Taulan et al., 2006; Yapar et al., 2010; Zimmerman et al., 2007). It is unknown whether such a decrease in the GFR is because of (1) the glomerular effects of uranium, (2) the tubuloglomerular feedback brought about after tubular insult in order to prevent an uncontrolled loss of water and electrolytes, or (3) a combination of both. In this sense, in animals acutely intoxicated with uranium, functional tubular alterations have been observed. These are reflected in a significant increase in electrolyte excretion (sodium, potassium, magnesium, calcium, and inorganic phosphate) (Banday et al., 2008; Haley, 1982), proteins (Haley, 1982; Sanchez et al., 2001), β-2-microglobulin (Fukuda et al., 2008), and glucose (Nomiyama et al., 1974; Taulan et al., 2006). Increases in the urinary activity of several enzymes indicating tissue lesion have also been reported. At least in part, this could be explained by the functional tubular alterations. Still, it is not possible to rule out a direct effect of the metal on transport mechanisms or tubular cell functions, independently of cell viability. Among the increased urinary enzymes are N-acetyl glucosaminidase (NAG) (Diamond et al., 1989; Fukuda et al., 2005b, 2008; Sanchez et al., 2001) and alkaline phosphatase (ALP) (Banday et al., 2008; Nomiyama et al., 1974). The increase in ALP in urine has been linked to the loss of microvilli in the proximal tubules, where this enzyme is mainly located (Yuile, 1973). Increases in the activities of other enzymes in the urine, such as gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and acid phosphatase (Banday et al., 2008; Diamond et al., 1989; Sanchez et al., 2001; Taulan et al., 2006), have been described, pointing to the presence of tissue lesions. LDH is a nonspecific marker of renal tissue lesion, but NAG, ALP, and GGT are mainly markers of proximal tubule insult (Emeigh Hart, 2005). Other effects of uranium on the kidneys possibly related to the function and viability of renal structures include (1) alterations in the activities of several enzymes associated with glycolysis (aldolase and phosphoglycerokinase), the tricarboxylic acid cycle (isocitrate, succinate, and malate dehydrogenases), and gluconeogenesis (FBPase and G6Pase) (Banday et al., 2008); (2) disturbances in the oxidative balance (Schramm et al., 2002), potentially related to increases in the activity of superoxide dismutase (SOD) (Banday et al., 2008; Schramm et al., 2002); and (3) increases in the plasma renin levels, associated with increases in blood pressure (Kato et al., 1994; Mendelsohn and Smith, 1980). Table 1 summarizes the most relevant data obtained from the acute intoxications with uranium carried out in experimental animals, with regard to the alterations in renal function and structure observed; the animal species; and the dose, route, and duration of the exposure. The diversity of route of administration, uranium type, and other factors introduces some complexity when comparing the results from different studies. Most of them have been done with rats, a species very sensitive to uranium’s toxicity. Regardless of strain and route of administration, single doses of a few (> 2) milligram per kilogram are consistently and overtly nephrotoxic, as demonstrated by alterations in classical parameters of renal function (serum creatinine, BUN, etc.) and renal tissue status (e.g., urinary excretion of NAG), during the immediate days after exposure. This is also true for other less sensitive species, such as mice and dogs. There are fewer studies using lower doses, which were all conducted in rats. However, it is evident that, at least when uranium is administered ip, the toxic threshold for single-dose exposures is set around 0.5 mg/kg. In the case of the im administration, at least doses of or over 1 mg/kg induce a renal injury that is still detectable 28 days after exposure (Fukuda et al., 2005b). Because this is the only study monitoring renal parameters so late after an acute exposure, there is not enough evidence to know whether this is rather specific of the im route or it can also be observed upon intoxication by other routes. TABLE 1 Studies of Acute Intoxication in Experimental Animals Reference Species Uranium type Dose Route Exposure Time of analysis Observations Serum parameters Urine parameters Others Zimmerman et al. (2007) SD rats DU 0.1 mg/kg ip 1 dose 3 and 7 days _ Crs, BUN, albumin Fukuda et al. (2005b) Wistar rats DU 0.2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP, Prot., Ca, BUN, Crs, erythrocyte, hematocrit < hemoglobin (slightly) Zimmerman et al. (2007) SD rats DU 0.3 mg/kg ip 1 dose 3 and 7 days _ Albumin > Crs, BUN (slightly) Banday et al. (2008) Wistar rats UN 0.5 mg/kg ip 1 dose 5 days > Cr, BUN, cholesterol, phospholipids > UF, Glc, Na, K, Ca, Mg, Pi, GGT, ALP, LDH < Clcr Shim et al. (2009) SD rats UN 0.5 mg/kg ip 1 dose 6 days before dose > Crs, BUN < Clcr Diamond et al. (1989) Long-Evans rats UO2F2 0.66 mg/kg ip 5 doses 6 days before last dose _ UF, NAG, Gluc. > LDH, AST, Prot., albumin, alfa-amino nitrogenuria _ Kidney weights, body weights Fukuda et al. (2005b) Wistar rats DU 1 mg/kg im 1 dose 28 days _ GOT, GPT, protein, Ca > BUN, Crs, ALP < erythrocyte, hemoglobin _ hematocrit Zimmerman et al. (2007) SD rats DU 1 mg/kg ip 1 dose 3 and 7 days > Crs BUN, albumin Diamond et al. (1989) Long-Evans rats UO2F2 1.32 mg/kg ip 5 doses 6 days before last dose _ UF > LDH, AST, NAG, Prot., albumin, alfa-amino nitrogenuria, Glc. _ Kidney weights, body weights Fukuda et al. (2005a) Wistar rats DU 2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP Crs, BUN, Ca, Prot., erytrhocyte, hemoglobin, hematocrit Fukuda et al. (2005b) Wistar rats DU 2 mg/kg im 1 dose 28 days > BUN, Crs > NAG < Body weight Sanchez et al. (2001) SD rats UA 2.5 mg/kg ip 1 dose 1 day _ protein, uric acid > Crs, BUN, LDH _Cr, urea > UF, Prot., LDH, GGT, NAG < Body weight < Clcr Fukuda et al. (2008) Wistar rats DU 4 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc., Ca, BUN > Crs GPT _ NAG Kato et al. (1994) SD rats UA 5 mg/kg iv 1 dose 2 days > Crs, BUN, FENa, plasma renin activity < Body weight Sanchez et al. (2001) SD rats UA 5 mg/kg ip 1 dose 1 day > Crs, BUN, LDH _ Prot., uric acid < Clcr > UF, Prot., LDH, GGT, NAG _Cr, urea < Body weight, Clcr Tolson et al. (2005) SD rats UA 5 + 10 mg/kg ip 2 doses 5 days before the dose > Crs, BUN Haley et al. (1982) SD rats UN 10 mg/kg ip 1 dose 5 days > Na, Prot. < GFR Tolson et al. (2005) SD rats UA 10 mg/kg ip 1 dose 5 days > Crs BUN Fukuda et al. (2008) Wistar rats DU 16 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc, Ca > Crs, BUN, GPT > NAG Fukuda et al. (2005a) Wistar rats DU 7.9; 15.8; 31.5; 63; and 126 mg/kg im 1 dose 3–7 days < Body weight (rats die at 3–7 days) Taulan et al. (2006) C57 Bl/6J mice UN 5 mg/kg ip 1 dose 2 days > Crs, BUN > GGT, Glc. Yapar et al. (2010) Albino Swiss mice UA 5 mg/kg ip 1 dose 5 days > Crs, BUN, AST, ALT Martinez et al. (2003) Balb-C mice UN 350 mg/kg bw Oral 3 days 2 days > Crs BUN Died day 3 postintoxication Nomiyama et al. (1972) Rabbits UA 0.2 mg/kg iv 1 dose 2 days > ALP, GOT, GPT, LDH > ALP, GOT, GPT, Glc, LDH Stefanovic et al. (1987) Dogs UN 10 mg/kg ip 1 dose > Ca, Pi Reference Species Uranium type Dose Route Exposure Time of analysis Observations Serum parameters Urine parameters Others Zimmerman et al. (2007) SD rats DU 0.1 mg/kg ip 1 dose 3 and 7 days _ Crs, BUN, albumin Fukuda et al. (2005b) Wistar rats DU 0.2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP, Prot., Ca, BUN, Crs, erythrocyte, hematocrit < hemoglobin (slightly) Zimmerman et al. (2007) SD rats DU 0.3 mg/kg ip 1 dose 3 and 7 days _ Albumin > Crs, BUN (slightly) Banday et al. (2008) Wistar rats UN 0.5 mg/kg ip 1 dose 5 days > Cr, BUN, cholesterol, phospholipids > UF, Glc, Na, K, Ca, Mg, Pi, GGT, ALP, LDH < Clcr Shim et al. (2009) SD rats UN 0.5 mg/kg ip 1 dose 6 days before dose > Crs, BUN < Clcr Diamond et al. (1989) Long-Evans rats UO2F2 0.66 mg/kg ip 5 doses 6 days before last dose _ UF, NAG, Gluc. > LDH, AST, Prot., albumin, alfa-amino nitrogenuria _ Kidney weights, body weights Fukuda et al. (2005b) Wistar rats DU 1 mg/kg im 1 dose 28 days _ GOT, GPT, protein, Ca > BUN, Crs, ALP < erythrocyte, hemoglobin _ hematocrit Zimmerman et al. (2007) SD rats DU 1 mg/kg ip 1 dose 3 and 7 days > Crs BUN, albumin Diamond et al. (1989) Long-Evans rats UO2F2 1.32 mg/kg ip 5 doses 6 days before last dose _ UF > LDH, AST, NAG, Prot., albumin, alfa-amino nitrogenuria, Glc. _ Kidney weights, body weights Fukuda et al. (2005a) Wistar rats DU 2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP Crs, BUN, Ca, Prot., erytrhocyte, hemoglobin, hematocrit Fukuda et al. (2005b) Wistar rats DU 2 mg/kg im 1 dose 28 days > BUN, Crs > NAG < Body weight Sanchez et al. (2001) SD rats UA 2.5 mg/kg ip 1 dose 1 day _ protein, uric acid > Crs, BUN, LDH _Cr, urea > UF, Prot., LDH, GGT, NAG < Body weight < Clcr Fukuda et al. (2008) Wistar rats DU 4 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc., Ca, BUN > Crs GPT _ NAG Kato et al. (1994) SD rats UA 5 mg/kg iv 1 dose 2 days > Crs, BUN, FENa, plasma renin activity < Body weight Sanchez et al. (2001) SD rats UA 5 mg/kg ip 1 dose 1 day > Crs, BUN, LDH _ Prot., uric acid < Clcr > UF, Prot., LDH, GGT, NAG _Cr, urea < Body weight, Clcr Tolson et al. (2005) SD rats UA 5 + 10 mg/kg ip 2 doses 5 days before the dose > Crs, BUN Haley et al. (1982) SD rats UN 10 mg/kg ip 1 dose 5 days > Na, Prot. < GFR Tolson et al. (2005) SD rats UA 10 mg/kg ip 1 dose 5 days > Crs BUN Fukuda et al. (2008) Wistar rats DU 16 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc, Ca > Crs, BUN, GPT > NAG Fukuda et al. (2005a) Wistar rats DU 7.9; 15.8; 31.5; 63; and 126 mg/kg im 1 dose 3–7 days < Body weight (rats die at 3–7 days) Taulan et al. (2006) C57 Bl/6J mice UN 5 mg/kg ip 1 dose 2 days > Crs, BUN > GGT, Glc. Yapar et al. (2010) Albino Swiss mice UA 5 mg/kg ip 1 dose 5 days > Crs, BUN, AST, ALT Martinez et al. (2003) Balb-C mice UN 350 mg/kg bw Oral 3 days 2 days > Crs BUN Died day 3 postintoxication Nomiyama et al. (1972) Rabbits UA 0.2 mg/kg iv 1 dose 2 days > ALP, GOT, GPT, LDH > ALP, GOT, GPT, Glc, LDH Stefanovic et al. (1987) Dogs UN 10 mg/kg ip 1 dose > Ca, Pi Note. >, increase; <, decrease; _ no changes; DU, depleted uranium; UN, uranyl nitrate; UO2F2, uranyl fluoride; UA, uranyl acetate; SD, Sprague-Dawley; Crs, serum creatinine; BUN, blood ureic nitrogen; GOT, glutamic oxalo transaminase; GPT, glutamic piruvic transaminase; Prot., protein; Ca, calcium; UF, urinary flow; Glc, glucose; Na, sodium; K, potasium; Mg, magnesium; Pi, inorganic phosphate; GGT, gamma-glutamil-transpeptidase; Clcr, creatinine clearance; NAG, N-acetyl-β-D-glucosaminidase; AST, aspartate aminotransferase; FENa, fractional excretion rate of sodium, bw, body weight. Open in new tab TABLE 1 Studies of Acute Intoxication in Experimental Animals Reference Species Uranium type Dose Route Exposure Time of analysis Observations Serum parameters Urine parameters Others Zimmerman et al. (2007) SD rats DU 0.1 mg/kg ip 1 dose 3 and 7 days _ Crs, BUN, albumin Fukuda et al. (2005b) Wistar rats DU 0.2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP, Prot., Ca, BUN, Crs, erythrocyte, hematocrit < hemoglobin (slightly) Zimmerman et al. (2007) SD rats DU 0.3 mg/kg ip 1 dose 3 and 7 days _ Albumin > Crs, BUN (slightly) Banday et al. (2008) Wistar rats UN 0.5 mg/kg ip 1 dose 5 days > Cr, BUN, cholesterol, phospholipids > UF, Glc, Na, K, Ca, Mg, Pi, GGT, ALP, LDH < Clcr Shim et al. (2009) SD rats UN 0.5 mg/kg ip 1 dose 6 days before dose > Crs, BUN < Clcr Diamond et al. (1989) Long-Evans rats UO2F2 0.66 mg/kg ip 5 doses 6 days before last dose _ UF, NAG, Gluc. > LDH, AST, Prot., albumin, alfa-amino nitrogenuria _ Kidney weights, body weights Fukuda et al. (2005b) Wistar rats DU 1 mg/kg im 1 dose 28 days _ GOT, GPT, protein, Ca > BUN, Crs, ALP < erythrocyte, hemoglobin _ hematocrit Zimmerman et al. (2007) SD rats DU 1 mg/kg ip 1 dose 3 and 7 days > Crs BUN, albumin Diamond et al. (1989) Long-Evans rats UO2F2 1.32 mg/kg ip 5 doses 6 days before last dose _ UF > LDH, AST, NAG, Prot., albumin, alfa-amino nitrogenuria, Glc. _ Kidney weights, body weights Fukuda et al. (2005a) Wistar rats DU 2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP Crs, BUN, Ca, Prot., erytrhocyte, hemoglobin, hematocrit Fukuda et al. (2005b) Wistar rats DU 2 mg/kg im 1 dose 28 days > BUN, Crs > NAG < Body weight Sanchez et al. (2001) SD rats UA 2.5 mg/kg ip 1 dose 1 day _ protein, uric acid > Crs, BUN, LDH _Cr, urea > UF, Prot., LDH, GGT, NAG < Body weight < Clcr Fukuda et al. (2008) Wistar rats DU 4 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc., Ca, BUN > Crs GPT _ NAG Kato et al. (1994) SD rats UA 5 mg/kg iv 1 dose 2 days > Crs, BUN, FENa, plasma renin activity < Body weight Sanchez et al. (2001) SD rats UA 5 mg/kg ip 1 dose 1 day > Crs, BUN, LDH _ Prot., uric acid < Clcr > UF, Prot., LDH, GGT, NAG _Cr, urea < Body weight, Clcr Tolson et al. (2005) SD rats UA 5 + 10 mg/kg ip 2 doses 5 days before the dose > Crs, BUN Haley et al. (1982) SD rats UN 10 mg/kg ip 1 dose 5 days > Na, Prot. < GFR Tolson et al. (2005) SD rats UA 10 mg/kg ip 1 dose 5 days > Crs BUN Fukuda et al. (2008) Wistar rats DU 16 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc, Ca > Crs, BUN, GPT > NAG Fukuda et al. (2005a) Wistar rats DU 7.9; 15.8; 31.5; 63; and 126 mg/kg im 1 dose 3–7 days < Body weight (rats die at 3–7 days) Taulan et al. (2006) C57 Bl/6J mice UN 5 mg/kg ip 1 dose 2 days > Crs, BUN > GGT, Glc. Yapar et al. (2010) Albino Swiss mice UA 5 mg/kg ip 1 dose 5 days > Crs, BUN, AST, ALT Martinez et al. (2003) Balb-C mice UN 350 mg/kg bw Oral 3 days 2 days > Crs BUN Died day 3 postintoxication Nomiyama et al. (1972) Rabbits UA 0.2 mg/kg iv 1 dose 2 days > ALP, GOT, GPT, LDH > ALP, GOT, GPT, Glc, LDH Stefanovic et al. (1987) Dogs UN 10 mg/kg ip 1 dose > Ca, Pi Reference Species Uranium type Dose Route Exposure Time of analysis Observations Serum parameters Urine parameters Others Zimmerman et al. (2007) SD rats DU 0.1 mg/kg ip 1 dose 3 and 7 days _ Crs, BUN, albumin Fukuda et al. (2005b) Wistar rats DU 0.2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP, Prot., Ca, BUN, Crs, erythrocyte, hematocrit < hemoglobin (slightly) Zimmerman et al. (2007) SD rats DU 0.3 mg/kg ip 1 dose 3 and 7 days _ Albumin > Crs, BUN (slightly) Banday et al. (2008) Wistar rats UN 0.5 mg/kg ip 1 dose 5 days > Cr, BUN, cholesterol, phospholipids > UF, Glc, Na, K, Ca, Mg, Pi, GGT, ALP, LDH < Clcr Shim et al. (2009) SD rats UN 0.5 mg/kg ip 1 dose 6 days before dose > Crs, BUN < Clcr Diamond et al. (1989) Long-Evans rats UO2F2 0.66 mg/kg ip 5 doses 6 days before last dose _ UF, NAG, Gluc. > LDH, AST, Prot., albumin, alfa-amino nitrogenuria _ Kidney weights, body weights Fukuda et al. (2005b) Wistar rats DU 1 mg/kg im 1 dose 28 days _ GOT, GPT, protein, Ca > BUN, Crs, ALP < erythrocyte, hemoglobin _ hematocrit Zimmerman et al. (2007) SD rats DU 1 mg/kg ip 1 dose 3 and 7 days > Crs BUN, albumin Diamond et al. (1989) Long-Evans rats UO2F2 1.32 mg/kg ip 5 doses 6 days before last dose _ UF > LDH, AST, NAG, Prot., albumin, alfa-amino nitrogenuria, Glc. _ Kidney weights, body weights Fukuda et al. (2005a) Wistar rats DU 2 mg/kg im 1 dose 28 days _ GOT, GPT, ALP Crs, BUN, Ca, Prot., erytrhocyte, hemoglobin, hematocrit Fukuda et al. (2005b) Wistar rats DU 2 mg/kg im 1 dose 28 days > BUN, Crs > NAG < Body weight Sanchez et al. (2001) SD rats UA 2.5 mg/kg ip 1 dose 1 day _ protein, uric acid > Crs, BUN, LDH _Cr, urea > UF, Prot., LDH, GGT, NAG < Body weight < Clcr Fukuda et al. (2008) Wistar rats DU 4 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc., Ca, BUN > Crs GPT _ NAG Kato et al. (1994) SD rats UA 5 mg/kg iv 1 dose 2 days > Crs, BUN, FENa, plasma renin activity < Body weight Sanchez et al. (2001) SD rats UA 5 mg/kg ip 1 dose 1 day > Crs, BUN, LDH _ Prot., uric acid < Clcr > UF, Prot., LDH, GGT, NAG _Cr, urea < Body weight, Clcr Tolson et al. (2005) SD rats UA 5 + 10 mg/kg ip 2 doses 5 days before the dose > Crs, BUN Haley et al. (1982) SD rats UN 10 mg/kg ip 1 dose 5 days > Na, Prot. < GFR Tolson et al. (2005) SD rats UA 10 mg/kg ip 1 dose 5 days > Crs BUN Fukuda et al. (2008) Wistar rats DU 16 mg/kg sc 1 dose 1 day _ GOT, ALP, Glc, Ca > Crs, BUN, GPT > NAG Fukuda et al. (2005a) Wistar rats DU 7.9; 15.8; 31.5; 63; and 126 mg/kg im 1 dose 3–7 days < Body weight (rats die at 3–7 days) Taulan et al. (2006) C57 Bl/6J mice UN 5 mg/kg ip 1 dose 2 days > Crs, BUN > GGT, Glc. Yapar et al. (2010) Albino Swiss mice UA 5 mg/kg ip 1 dose 5 days > Crs, BUN, AST, ALT Martinez et al. (2003) Balb-C mice UN 350 mg/kg bw Oral 3 days 2 days > Crs BUN Died day 3 postintoxication Nomiyama et al. (1972) Rabbits UA 0.2 mg/kg iv 1 dose 2 days > ALP, GOT, GPT, LDH > ALP, GOT, GPT, Glc, LDH Stefanovic et al. (1987) Dogs UN 10 mg/kg ip 1 dose > Ca, Pi Note. >, increase; <, decrease; _ no changes; DU, depleted uranium; UN, uranyl nitrate; UO2F2, uranyl fluoride; UA, uranyl acetate; SD, Sprague-Dawley; Crs, serum creatinine; BUN, blood ureic nitrogen; GOT, glutamic oxalo transaminase; GPT, glutamic piruvic transaminase; Prot., protein; Ca, calcium; UF, urinary flow; Glc, glucose; Na, sodium; K, potasium; Mg, magnesium; Pi, inorganic phosphate; GGT, gamma-glutamil-transpeptidase; Clcr, creatinine clearance; NAG, N-acetyl-β-D-glucosaminidase; AST, aspartate aminotransferase; FENa, fractional excretion rate of sodium, bw, body weight. Open in new tab All together, these data indicate that several species acutely intoxicated with uranium undergo some degree of renal damage in a dose-dependent and route-independent manner. Doses of 5 mg/kg U (or higher) are overtly nephrotoxic for rats, mice, and dogs. Doses higher than 0.5 mg/kg U are nephrotoxic at least for rats. “Documented Human Cases” section presents the evidence on acute intoxication of humans gathered in documented cases and compares the information with that obtained in animals. Morphological Renal Modifications As far as we are aware, there are no histological studies about the acute effects of uranium on kidney structure in human beings. In contrast, its effects on the kidney structures of laboratory animals are fairly well documented because uranyl nitrate has been widely used as an experimental nephrotoxic agent (Domingo et al., 1989; Haley, 1982; Haley et al., 1982; Kobayashi et al., 1984; McDonald-Taylor et al., 1997; Sun et al., 2002). Modifications in the color and smoothness of the kidney surface have been described (Fukuda et al., 2005a). At toxic doses (5–20 mg/kg), ip injected uranyl nitrate elicits specific damage to the S2 and S3 segments of the proximal tubule (,Gilman et al., 1998c; Haley, 1982; Haley et al., 1982; Oliver, 1915), cell vacuolization (Gilman et al., 1998c; Haley, 1982; Haley et al., 1982; Martinez et al., 2000; Taulan et al., 2006), loss of the brush border membrane (Taulan et al., 2006; Haley, 1982; Haley et al., 1982; Schwartz and Flamenbaum, 1976), and in the S1 segment, an increase in lysosomal and vacuolar mass. In other studies, reports have also been made of variations in mitochondrial mass (Haley, 1982; McDonald-Taylor et al., 1997). At very high doses (5–10 mg/kg body weight, ip), it is also possible to observe necrosis of the proximal tubules (Haley et al., 1982; Hirsch, 1976; Taulan et al., 2006), especially in the corticomedullary area (,Fukuda et al., 2005a; Shim et al., 2009; Sun et al., 2002). When the dose of uranyl nitrate administered is not very high (0.5 mg/kg), the glomerulus is apparently left intact (Taulan et al., 2006). However, if the dose is very high (∼10 mg/kg), adherences and congestion are seen in the glomerular epithelium (Haley, 1982) together with a decrease in the glomerular surface (Shim et al., 2009). Once exposure has ceased, the uranium bound to the tubular cells is eliminated in the urine (Leggett, 1989) and a process of tubular re-epithelization begins (Zager et al., 1994). It is believed that interstitial myofibroblasts and macrophages could play an important role in regeneration after acute insult owing to their role in scarring (Leibovich and Ross, 1975; Powell et al., 1999). The appearance of myofibroblasts and monocytes/macrophages in the renal interstitium of rats has been observed following injections of uranyl nitrate at toxic doses (Sun et al., 2002). A network of myofibroblasts surrounding the tubular basal membranes has been observed; this persists until cellular re-epithelization has been fully completed (Sun et al., 2002). It is thought that this formation may serve to provide contractile capacity and to prevent nephron collapse, as well as to reinforce the extracellular matrix and promote the production of cytokines that favor re-epithelization (Sun et al., 2002). This regenerated tubular epithelium seems to be more resistant to the toxicity of uranium than the original one (Hodge et al., 1973). Documented Human Cases Acute overexposure to uranium in humans is very rare and unlikely, such that few cases have been documented. Table 2 shows a summary of the main studies addressing acute exposure to the metal. The information comes from a case of intended suicide (Pavlakis et al., 1996), several controlled administration of uranium (via oral) with research purposes on volunteers (Bassett et al., 1948; Butterworth, 1955; Hursh and Spoor, 1973), and professional accidents in which individuals were exposed through inhalation (Bijlsma et al., 2008; Fisher et al., 1990; Kathren and Moore, 1986; Lu and Zhao, 1990). In most of these cases of acute intoxication in humans, there is clear evidence of acute nephrotoxicity. A decrease in the GFR (as assessed by the measurement of creatinine clearance) (Kathren and Moore, 1986; Tanigawara et al., 1990), or consequences of this, such as increases in plasma creatinine levels (Pavlakis et al., 1996), has been reported. Increases in the urinary excretion of proteins (Friberg et al., 1986; Lu and Zhao, 1990), amino acids (Lu and Zhao, 1990), and urinary catalase (Bassett et al., 1948; Friberg et al., 1986) have also been reported. Other studies have described increases in the excretion of certain proteins, such as albumin (in amounts in the microalbuminuria range) (Butterworth, 1955), and β-2-microglobulin (Butterworth, 1955). In those studies, the origin of the proteinuria was not determined, such that it could reflect glomerular or tubular alterations (or both). In other cases, it has been reported that uranium affects both the reabsorption of filtered solutes and the excretion of other solutes. All the above findings suggest that, depending on the effective dose, acute intoxication with uranium may lead to kidney impairment of varying intensity, which is strongly dependent on the circumstances of the exposure. TABLE 2 Documented Cases of Acute Intoxication with Uranium in Humans Study Participants number Exposure source Uranium amount and type Study moment Observations Bassett et al. (1948) 6 volunteers iv 6.3–70.9 μg/kg UN (0.44–4.96 mg/kg)a During exposure > Urinary catalase > Prot. (for the highest dose used) Butterworth (1955) 1 volunteers Oral 1 g UN (14.3 mg/kg)a During exposure Vomiting, diarrhea > microalbuminury Hursh and Spoor (1973) 4 patients Oral 10.9 mg UN (0.16 mg/kg)a During exposure Without kidney damage Pavlakis et al. (1996) 1 attempted suicide Oral 15 g UN (214.3 mg/kg)a After cessation All renal parameters altered Kathren and Moore (1986) 3 men Inhalation UF6 Sortly after the accident < Clcr Fisher et al. (1990) 31 enrichment plant workers Inhalation 0.47–24 mg/m3 UF6 After cessation > U in urine Lu and Zhao (1990) 1 Inhalation NU 1 week after cessation > Prot., NNP, aminoacidury > U in urine Bijlsma et al. (2008) 2499 firefighters, police and airport workers Inhalation NU and DU 8.5 years after cessation No > U in urine; No differences in the other renal parameters Study Participants number Exposure source Uranium amount and type Study moment Observations Bassett et al. (1948) 6 volunteers iv 6.3–70.9 μg/kg UN (0.44–4.96 mg/kg)a During exposure > Urinary catalase > Prot. (for the highest dose used) Butterworth (1955) 1 volunteers Oral 1 g UN (14.3 mg/kg)a During exposure Vomiting, diarrhea > microalbuminury Hursh and Spoor (1973) 4 patients Oral 10.9 mg UN (0.16 mg/kg)a During exposure Without kidney damage Pavlakis et al. (1996) 1 attempted suicide Oral 15 g UN (214.3 mg/kg)a After cessation All renal parameters altered Kathren and Moore (1986) 3 men Inhalation UF6 Sortly after the accident < Clcr Fisher et al. (1990) 31 enrichment plant workers Inhalation 0.47–24 mg/m3 UF6 After cessation > U in urine Lu and Zhao (1990) 1 Inhalation NU 1 week after cessation > Prot., NNP, aminoacidury > U in urine Bijlsma et al. (2008) 2499 firefighters, police and airport workers Inhalation NU and DU 8.5 years after cessation No > U in urine; No differences in the other renal parameters Note. UN, uranyl nitrate; UF6, uranium hexafluoride; NU, natural uranium; DU, depleted uranium; Prot., proteinuria; Clcr, creatinine clearance; NNP, nonprotein nitrogen; U, uranium. a Values between brackets represent the estimated dose (milligram per kilogram) for a 70-kg individual. Open in new tab TABLE 2 Documented Cases of Acute Intoxication with Uranium in Humans Study Participants number Exposure source Uranium amount and type Study moment Observations Bassett et al. (1948) 6 volunteers iv 6.3–70.9 μg/kg UN (0.44–4.96 mg/kg)a During exposure > Urinary catalase > Prot. (for the highest dose used) Butterworth (1955) 1 volunteers Oral 1 g UN (14.3 mg/kg)a During exposure Vomiting, diarrhea > microalbuminury Hursh and Spoor (1973) 4 patients Oral 10.9 mg UN (0.16 mg/kg)a During exposure Without kidney damage Pavlakis et al. (1996) 1 attempted suicide Oral 15 g UN (214.3 mg/kg)a After cessation All renal parameters altered Kathren and Moore (1986) 3 men Inhalation UF6 Sortly after the accident < Clcr Fisher et al. (1990) 31 enrichment plant workers Inhalation 0.47–24 mg/m3 UF6 After cessation > U in urine Lu and Zhao (1990) 1 Inhalation NU 1 week after cessation > Prot., NNP, aminoacidury > U in urine Bijlsma et al. (2008) 2499 firefighters, police and airport workers Inhalation NU and DU 8.5 years after cessation No > U in urine; No differences in the other renal parameters Study Participants number Exposure source Uranium amount and type Study moment Observations Bassett et al. (1948) 6 volunteers iv 6.3–70.9 μg/kg UN (0.44–4.96 mg/kg)a During exposure > Urinary catalase > Prot. (for the highest dose used) Butterworth (1955) 1 volunteers Oral 1 g UN (14.3 mg/kg)a During exposure Vomiting, diarrhea > microalbuminury Hursh and Spoor (1973) 4 patients Oral 10.9 mg UN (0.16 mg/kg)a During exposure Without kidney damage Pavlakis et al. (1996) 1 attempted suicide Oral 15 g UN (214.3 mg/kg)a After cessation All renal parameters altered Kathren and Moore (1986) 3 men Inhalation UF6 Sortly after the accident < Clcr Fisher et al. (1990) 31 enrichment plant workers Inhalation 0.47–24 mg/m3 UF6 After cessation > U in urine Lu and Zhao (1990) 1 Inhalation NU 1 week after cessation > Prot., NNP, aminoacidury > U in urine Bijlsma et al. (2008) 2499 firefighters, police and airport workers Inhalation NU and DU 8.5 years after cessation No > U in urine; No differences in the other renal parameters Note. UN, uranyl nitrate; UF6, uranium hexafluoride; NU, natural uranium; DU, depleted uranium; Prot., proteinuria; Clcr, creatinine clearance; NNP, nonprotein nitrogen; U, uranium. a Values between brackets represent the estimated dose (milligram per kilogram) for a 70-kg individual. Open in new tab There seems to be some divergence of results regarding the renal effects of exposure to uranium because the available information is extremely varied as regards the route of exposure, the dose (sometimes unknown), and the type of uranium used, the time of analysis, etc. None of the studies in which renal function was evaluated after several years has reported altered parameters. In analyses carried out during or immediately after acute intoxication, in addition to increased urinary uranium levels, an alteration of different renal parameters has been observed after both oral and inhalation intoxication. Through oral administration, only in one case of exposure to low doses, in the range of a few milligram of uranium (Hursh and Spoor, 1973) corresponding to an estimated dose of 0.16 mg/kg, was renal function apparently unaltered. For higher doses, more serious alterations were observed as the dose increased, ranging from simple microalbuminuria with a dose of 14.3 g/kg in Butterworth (1955) to alterations in all the renal parameters measured in Pavlakis et al. (1996), after an estimated dose of about 214.3 mg/kg. It therefore seems that acute exposure (at least through the oral route) to more than about 15 mg/kg is required for renal alterations to start appearing. Along with ingestion, inhalation is the other most likely potential route through which humans can be overexposed to uranium. We have found four studies reporting overexposure to uranium though inhalation. One of them (Bijlsma et al., 2008) studied renal function parameters 8.5 years after the exposure and found no alteration other than higher urinary excretion of uranium. The other three studied renal function immediately after the exposure. Kathren and Moore (1986) found reduced creatinine clearance, Lu and Zhao (1990) proteinuria and increased serum non protein nitrogen (NPN), and Fisher et al. (1990) only higher excretion of uranium. Except in Fisher et al. (1990), the concentration of uranium in the air is not known (see Table 2). Accordingly, it is impossible to draw conclusions on toxic dosage or sensitivity through this route and much less to make comparisons with other exposure routes. However, it is clear that feasible accidents or sporadic circumstances can overexpose the human being to uranium through inhalation resulting in some degree of nephrotoxicity. In conclusion, animal studies diverge from human studies in the exposure route, which is a key determinant of uranium bioavailability, and blood and tissue levels. However, it is clear that acute intoxication with uranium leads to nephrotoxicity in both animals and humans, in a dose-dependent manner. Yet one study in rats (Kato et al., 1994) and another one in humans (Bassett et al., 1948) of acute intoxication via iv with similar doses yield interesting information. Humans exposed to ∼5 mg/kg U showed proteinuria as the most significant renal alteration, whereas both serum creatinine and BUN increased in rats subject to the same dose. This indicates that humans underwent some degree of renal alteration (probably in tubular reuptake) that did not end up in the renal dysfunction seen in rats. This highlights the lower sensitivity to U toxicity of humans when compared with rats. Through the iv route, uranium surpasses interspecies differences posed by different absorption and different influence of other physical barriers working upon exposure through other routes. Finally, it should be noted that it is not known whether acute intoxication with uranium is able to trigger chronic renal lesions that will progress irreversibly and autonomously regardless of the presence of the metal, consistent with the well-known fact that the concurrence of several acute renal insults may drive the kidneys to enter an autonomous chronic degenerative process (Basile, 2008). The few data available concerning acute intoxications in human beings, together with the lack of this type of study in animals, make it impossible to draw conclusions. As a possible indication, the work of Bijlsma et al. (2008) (see Table 2), in which renal function was assessed years after the acute exposure, suggests that this would not be the case, although the intensity of those exposures is not known. NEPHROTOXICITY BECAUSE OF CHRONIC OVEREXPOSURE Under certain circumstances, humans are chronically overexposed to uranium. It remains largely unknown whether such exposure may elicit kidney damage and neither are the determinants of the possible nephrotoxicity known. It is also unknown whether the possible nephrotoxicity is triggered (1) as a subacute effect when a certain level of tissue accumulation after a more or less long exposure time has been surpassed or in contrast (2) as chronic renal damage that gradually develops into irreversible degeneration that is even independent of the presence of uranium, as occurs with most of the causes of chronic renal impairment (CRI) (Remuzzi et al., 2006). In this section, we attempt to shed some light on these aspects. Pathophysiological Studies with Animal Models In general, studies carried out in laboratory animals have used higher doses of uranium than those found in human exposure, although the time of exposure was much shorter (months instead of years). Table 3 summarizes the most relevant data obtained from the chronic exposure to uranium in experimental animals, with regard to the alterations in renal function, the animal species, uranium type, the estimated dose (milligram per kilogram), and the route and duration of the exposure. As commented above, the toxicity of uranium depends on sex, age, the body mass index, and species. Data from Table 3 are not in agreement with the interspecies sensitivity classically reported (Orcutt, 1949; Tannenbaum et al., 1951). Indeed, after chronic oral exposure, the rat seems to be more sensitive than the rabbit. Rabbits showed no biochemical changes in the estimated dose range 0.048–30 mg/kg during 3 months of exposure. However, rats subject to even milder conditions (exposure of 1 month and a lower dosage range [0.02–16 mg/kg]) showed renal alterations, including glucosuria and increased leucine aminopeptidase activity. Comparison with the mouse is more controversial because exposure time was longer (4 months), which may have induced a higher accumulation resulting in greater kidney damage. The importance of exposure time has been evidenced by the studies of Berradi et al. (2008) and Tissandie et al. (2008), which show major renal alterations owing to longer time of exposure. TABLE 3 Studies of Chronic Intoxication in Experimental Animals Reference Species Uranium type Dose Estimated dose Route Exposure Observations Serum parameters Urine parameters Others Gilman et al. (1998c) SD rats UN 0.96 mg/l 0.02 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Gilman et al. (1998c) SD rats UN 4.8 mg/l 0.32 mg/kga Oral 3 months _ hemoglobin, erythrocytes > leucine aminopeptidase, Glc. _ Body weight Ortega et al. (1989) SD rats UA 2 mg/kg 2 mg/kg Oral 1 month > Glc. Berradi et al. (2008) SD rats UN 40 mg/l 2.67 mg/kga Oral 9 months _ Leucocytes < hemoglobin, hematocrit (sligthly) < RBC Tissandie et al. (2008) SD rats EU 40 mg/l 2.67 mg/kga Oral 9 months _ ALT, AST, Crs, BUN, PTH, Pi > Ca _ Body weight, kidney weight Ortega et al. (1989) SD rats UA 4 mg/kg 4 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 8 mg/kg 8 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 16 mg/kg 16 mg/kg Oral 1 month > Glc. Gilman et al. (1998c) SD rats UN 600 mg/l 400 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Taulan et al. (2004) Mice UN 80 mg/l 13.33 mg/kgb Oral 4 months _ BUN > Crs _ Glc., GGT _ Kidney weight Taulan et al. (2004) Mice UN 160 mg/l 26.67 mg/kgb Oral 4 months _ BUN > Crs _ Glc. > GGT _ Kidney weight Gilman et al. (1998b) Rabbits UN 0.96 mg/l 0.048 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 4.8 mg/l 0.24 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilmanm et al. (1998b) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Stokinger et al. (1953) Dogs UO2 0.05 mg U/m3 Inhalation 12–24 months _ NPN _ Prot. > catalase < Clcr Pozzani (1949) Dogs UO2 0.13 mg U/m3 Inhalation > NPN > Prot., catalase < Clcr Maynard and Hodge (1949) Dogs UO2F2 37.5 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Maynard and Hodge (1949) Dogs UO2F2 187 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Reference Species Uranium type Dose Estimated dose Route Exposure Observations Serum parameters Urine parameters Others Gilman et al. (1998c) SD rats UN 0.96 mg/l 0.02 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Gilman et al. (1998c) SD rats UN 4.8 mg/l 0.32 mg/kga Oral 3 months _ hemoglobin, erythrocytes > leucine aminopeptidase, Glc. _ Body weight Ortega et al. (1989) SD rats UA 2 mg/kg 2 mg/kg Oral 1 month > Glc. Berradi et al. (2008) SD rats UN 40 mg/l 2.67 mg/kga Oral 9 months _ Leucocytes < hemoglobin, hematocrit (sligthly) < RBC Tissandie et al. (2008) SD rats EU 40 mg/l 2.67 mg/kga Oral 9 months _ ALT, AST, Crs, BUN, PTH, Pi > Ca _ Body weight, kidney weight Ortega et al. (1989) SD rats UA 4 mg/kg 4 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 8 mg/kg 8 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 16 mg/kg 16 mg/kg Oral 1 month > Glc. Gilman et al. (1998c) SD rats UN 600 mg/l 400 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Taulan et al. (2004) Mice UN 80 mg/l 13.33 mg/kgb Oral 4 months _ BUN > Crs _ Glc., GGT _ Kidney weight Taulan et al. (2004) Mice UN 160 mg/l 26.67 mg/kgb Oral 4 months _ BUN > Crs _ Glc. > GGT _ Kidney weight Gilman et al. (1998b) Rabbits UN 0.96 mg/l 0.048 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 4.8 mg/l 0.24 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilmanm et al. (1998b) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Stokinger et al. (1953) Dogs UO2 0.05 mg U/m3 Inhalation 12–24 months _ NPN _ Prot. > catalase < Clcr Pozzani (1949) Dogs UO2 0.13 mg U/m3 Inhalation > NPN > Prot., catalase < Clcr Maynard and Hodge (1949) Dogs UO2F2 37.5 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Maynard and Hodge (1949) Dogs UO2F2 187 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Note. >, increase; <, decrease; _ no change; SD, Sprague-Dawley; UN, uranyl nitrate; UA, uranyl acetate; UO2, uranium dioxide; UO2F2, uranyl fluoride; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Crs, serum creatinine; BUN, blood ureic nitrogen; PTH, parathyroid hormone; Ca, calcium; NPN, nonproteic nitrogen; Prot., proteins; Glc., glucose; EU, enriched uranium. a Estimated dose assuming that rat median weight of 300 g and daily intake of water 20 ml/day. b Estimated dose assuming that mice median weight of 30 g and daily intake of water 5 ml/day. c Estimated dose assuming rabbit median weight of 4 kg and daily intake of water 200 ml/day. Open in new tab TABLE 3 Studies of Chronic Intoxication in Experimental Animals Reference Species Uranium type Dose Estimated dose Route Exposure Observations Serum parameters Urine parameters Others Gilman et al. (1998c) SD rats UN 0.96 mg/l 0.02 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Gilman et al. (1998c) SD rats UN 4.8 mg/l 0.32 mg/kga Oral 3 months _ hemoglobin, erythrocytes > leucine aminopeptidase, Glc. _ Body weight Ortega et al. (1989) SD rats UA 2 mg/kg 2 mg/kg Oral 1 month > Glc. Berradi et al. (2008) SD rats UN 40 mg/l 2.67 mg/kga Oral 9 months _ Leucocytes < hemoglobin, hematocrit (sligthly) < RBC Tissandie et al. (2008) SD rats EU 40 mg/l 2.67 mg/kga Oral 9 months _ ALT, AST, Crs, BUN, PTH, Pi > Ca _ Body weight, kidney weight Ortega et al. (1989) SD rats UA 4 mg/kg 4 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 8 mg/kg 8 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 16 mg/kg 16 mg/kg Oral 1 month > Glc. Gilman et al. (1998c) SD rats UN 600 mg/l 400 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Taulan et al. (2004) Mice UN 80 mg/l 13.33 mg/kgb Oral 4 months _ BUN > Crs _ Glc., GGT _ Kidney weight Taulan et al. (2004) Mice UN 160 mg/l 26.67 mg/kgb Oral 4 months _ BUN > Crs _ Glc. > GGT _ Kidney weight Gilman et al. (1998b) Rabbits UN 0.96 mg/l 0.048 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 4.8 mg/l 0.24 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilmanm et al. (1998b) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Stokinger et al. (1953) Dogs UO2 0.05 mg U/m3 Inhalation 12–24 months _ NPN _ Prot. > catalase < Clcr Pozzani (1949) Dogs UO2 0.13 mg U/m3 Inhalation > NPN > Prot., catalase < Clcr Maynard and Hodge (1949) Dogs UO2F2 37.5 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Maynard and Hodge (1949) Dogs UO2F2 187 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Reference Species Uranium type Dose Estimated dose Route Exposure Observations Serum parameters Urine parameters Others Gilman et al. (1998c) SD rats UN 0.96 mg/l 0.02 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Gilman et al. (1998c) SD rats UN 4.8 mg/l 0.32 mg/kga Oral 3 months _ hemoglobin, erythrocytes > leucine aminopeptidase, Glc. _ Body weight Ortega et al. (1989) SD rats UA 2 mg/kg 2 mg/kg Oral 1 month > Glc. Berradi et al. (2008) SD rats UN 40 mg/l 2.67 mg/kga Oral 9 months _ Leucocytes < hemoglobin, hematocrit (sligthly) < RBC Tissandie et al. (2008) SD rats EU 40 mg/l 2.67 mg/kga Oral 9 months _ ALT, AST, Crs, BUN, PTH, Pi > Ca _ Body weight, kidney weight Ortega et al. (1989) SD rats UA 4 mg/kg 4 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 8 mg/kg 8 mg/kg Oral 1 month > Glc. Ortega et al. (1989) SD rats UA 16 mg/kg 16 mg/kg Oral 1 month > Glc. Gilman et al. (1998c) SD rats UN 600 mg/l 400 mg/kga Oral 3 months _ hemoglobin, erythrocytes, Glc. > leucine aminopeptidase _ Body weight Taulan et al. (2004) Mice UN 80 mg/l 13.33 mg/kgb Oral 4 months _ BUN > Crs _ Glc., GGT _ Kidney weight Taulan et al. (2004) Mice UN 160 mg/l 26.67 mg/kgb Oral 4 months _ BUN > Crs _ Glc. > GGT _ Kidney weight Gilman et al. (1998b) Rabbits UN 0.96 mg/l 0.048 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 4.8 mg/l 0.24 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilmanm et al. (1998b) Rabbits UN 24 mg/l 1.2 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998a) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Gilman et al. (1998b) Rabbits UN 600 mg/l 30 mg/kgc Oral 3 months No biochemical changes Stokinger et al. (1953) Dogs UO2 0.05 mg U/m3 Inhalation 12–24 months _ NPN _ Prot. > catalase < Clcr Pozzani (1949) Dogs UO2 0.13 mg U/m3 Inhalation > NPN > Prot., catalase < Clcr Maynard and Hodge (1949) Dogs UO2F2 37.5 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Maynard and Hodge (1949) Dogs UO2F2 187 mg U/m3 Inhalation 1–24 months > Crs, BUN > Prot. Note. >, increase; <, decrease; _ no change; SD, Sprague-Dawley; UN, uranyl nitrate; UA, uranyl acetate; UO2, uranium dioxide; UO2F2, uranyl fluoride; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Crs, serum creatinine; BUN, blood ureic nitrogen; PTH, parathyroid hormone; Ca, calcium; NPN, nonproteic nitrogen; Prot., proteins; Glc., glucose; EU, enriched uranium. a Estimated dose assuming that rat median weight of 300 g and daily intake of water 20 ml/day. b Estimated dose assuming that mice median weight of 30 g and daily intake of water 5 ml/day. c Estimated dose assuming rabbit median weight of 4 kg and daily intake of water 200 ml/day. Open in new tab Regarding inhalation exposure to uranium, renal damage has been reported in studies from 1 to 24 months mainly in dogs. Stokinger et al. (1953), in a study conducted at low doses (0.05 mg U/m3 air), observed that NPN levels in plasma were normal, and there were no differences in the excretion of urinary proteins, whereas a decrease in creatinine clearance and an increase in urinary catalase were observed. At higher doses (0.13 mg U/m3), an increase in protein excretion and NPN (Pozzani, 1949) was observed. In other studies conducted during a similar exposure time but with higher dose, changes in the usual markers of renal function (serum creatinine, BUN, and urinary proteins) were observed. Importantly, similar results were obtained in a wide range of doses (37.5–187 mg U/m3) (Maynard and Hodge, 1949). It is difficult to compare the results obtained in oral and inhalation exposure because, among many other factors, the absorption process in each route is different. Generally, when exposure occurs with high doses of uranium, the markers of renal damage, such as plasma creatinine and nonprotein nitrogen in plasma, are found to be altered, but when exposure occurs at lower doses, these markers are not altered or at least their alteration is not dose dependent. In the case of oral exposure, an increase in glucosuria has also been observed in several studies, whereas in the case of the inhalation route, no alteration in glucose excretion has been described. It is also important to note that the work carried out on oral exposure has focused more on the nephrotoxicity of uranium than studies carried out on the inhalation route, in which many of the markers of renal damage were not analyzed. Accordingly, it is not possible to rule out that certain parameters, such as glucosuria, might be altered because of chronic uranium exposure through this route. These factors presumably determine the accumulation of the metal in the various compartments of the organism; hypothetically, such accumulation could be an important component of the renal toxicity of uranium. Data Sources of Human Cases Several epidemiological studies have attempted to link chronic exposure to uranium and renal damage, which is usually determined through alterations in parameters, such as microalbuminuria, glucosuria, and β-2-microglobulinuria. There are few studies from which epidemiological information can be drawn and they are incomplete and biased (Table 4). This is because it is difficult to know (1) the number of people exposed, (2) whether they in fact underwent some degree of renal damage, (3) the characteristics of each episode of exposure are highly variable (duration, dose, route of exposure, etc.), and (4) the possible existence of other comorbility factors, known or not. TABLE 4 Documented Cases of Chronic Intoxication with Uranium in Humans Study Participants number Male Female Ages Exposure source Exposure time Uranium amount and type Study moment Observations Shiraishi et al. (1992) —; general population — — — Oral (water) 10 years approximately 1.07–42.6 ng/dm3 NU During exposure No clinical effects Zamora et al. (1998) 30; 20 10; 7 20; 13 13–87; 16–68 Oral (water); oral (water) 3 years approximately High dose (2–780 μg/l); Low dose (< 1 μg/l) NU During exposure > U in urine (exposed); > LDH, ALP and GGT (slightly); > Glc.; No changes in Prot. and NAG Kurttio et al. (2002) 325; general population — — 15–82 Oral (water) 1–34 years High dose (> 100 μg/l); low dose (10–100 μg/l) During exposure > U in urine; > Ca, Phosphate and glc in urine; No changes in Clcr. Albumin, BMG, Crs. Pinney et al. (2003) —; residents near uranium plant — — — Oral (water) Years —; NU During exposure > U in urine; > microalbuminury; > red cells and hematocit in blood Orloff et al. (2004) 105; general population 50 55 15–79 Oral (water) Months High dose (620 μg/l) NU 6–10 months after cessation > U in urine Karpas et al. (2005) 205; general population 102 103 18–81 Oral (water) Years 0.03–2.775 μg/day NU During exposure > U in urine Wyatt et al. (2008) 156; general population — — — Oral (water) Years > 30 μg/l NU 1 year after cessation > Crs and BUN; > U in urine Kurttio et al. (2006) 193; general population 95 98 18–81 Oral (water) 16 years approximately 25 μg/l NU During exposure > Glc and ALP in urine; > U in urine; No changes in NAG, LDH, GGT, Ca, Prot, phosphates, Glc, Crs Magdo et al. (2007) 2 adults + 5 children; general population 5 2 3–37 Oral (water) 5 years approximately 866 and 1.160 μg/l NU 3 months after cessation > BMG; > U in urine Oeh et al. (2007) —; workers during Balcans War — — — Oral Years 17.7 μg/l NU 2–6 years after cessation No differences in uranium excretion Selden et al. (2009) 453; general population 227 226 18–74 Oral (water) Years 6.7–25.2 μg/l NU During exposure > U in urine; < NAG (exposed); > (tendency) BMG, kappa chains, HC protein; No changes in urinary Glc, phosphates, calcium, Prot., Cr. Zamora et al. (2009) 54 39 15 12–73 Oral (water) Years 0,4–845 μg/l NU During exposure > GGT, ALP, LDH, NAG and BMG in urine; No changes in Prot., and glc. Anderson et al. (2007) 581; gas plant workers — — Inhalation Years 73 μg/m3 NU and EU During exposure > U in urine Boice et al. (2007) 2161; workers and residents near uranium factory 1368 796 > 18 Inhalation > 1 year —; NU During exposure > U in urine Parrish et al. (2008) —; residents near uranium factory — — — Inhalation Years 300 μg/ g U, DU 20 years after cessation > U in urine McDiarmid et al. (2001) 15; Gulf war veterans — — — Inhalation; dermal Years —; DU 8 years after cessation > U in urine; > phosphates; < Clcr; No change in Crs, BUN, BMG, Cru y Prot. McDiarmid et al. (2006) 31; Gulf War veterans — — — Inhalation; dermal Years —; DU 12 years after cessation > U in urine; No change in Crs, BUN, Ca, RBP, BMG, NAG, ALP, phosphates, Clcr Squibb and McDiarmid (2006) 102; Gulf War veterans — — — Dermal Years —; DU 15 years after cessation > U in urine; No change in Crs, BUN, Clcr, Ca, Glc Phosphates, BMG, Prot., RBP, ALP, NAG Squibb et al. (2005) 16; Gulf War veterans — — — Dermal; oral; inhalation 6–10 years 25–190 μg DU (dermal) 6–10 years after cessation > U in urine; > Prot., RBP;No change in Crs, ALP, NAG McDiarmid et al. (2007) 108; Gulf War veterans — — — Dermal; oral; inhalation Years —; DU Years after cessation > U in urine; > Phosphates and Ca in urine; No change in Crs, BUN, Clcr, Ca, pot, BMG, RBP, ALP, NAG Helmer et al. (2007) 56; Gulf War veterans — — — Oral; inhalation; dermal Years —; DU Years after cessation > U in urine Study Participants number Male Female Ages Exposure source Exposure time Uranium amount and type Study moment Observations Shiraishi et al. (1992) —; general population — — — Oral (water) 10 years approximately 1.07–42.6 ng/dm3 NU During exposure No clinical effects Zamora et al. (1998) 30; 20 10; 7 20; 13 13–87; 16–68 Oral (water); oral (water) 3 years approximately High dose (2–780 μg/l); Low dose (< 1 μg/l) NU During exposure > U in urine (exposed); > LDH, ALP and GGT (slightly); > Glc.; No changes in Prot. and NAG Kurttio et al. (2002) 325; general population — — 15–82 Oral (water) 1–34 years High dose (> 100 μg/l); low dose (10–100 μg/l) During exposure > U in urine; > Ca, Phosphate and glc in urine; No changes in Clcr. Albumin, BMG, Crs. Pinney et al. (2003) —; residents near uranium plant — — — Oral (water) Years —; NU During exposure > U in urine; > microalbuminury; > red cells and hematocit in blood Orloff et al. (2004) 105; general population 50 55 15–79 Oral (water) Months High dose (620 μg/l) NU 6–10 months after cessation > U in urine Karpas et al. (2005) 205; general population 102 103 18–81 Oral (water) Years 0.03–2.775 μg/day NU During exposure > U in urine Wyatt et al. (2008) 156; general population — — — Oral (water) Years > 30 μg/l NU 1 year after cessation > Crs and BUN; > U in urine Kurttio et al. (2006) 193; general population 95 98 18–81 Oral (water) 16 years approximately 25 μg/l NU During exposure > Glc and ALP in urine; > U in urine; No changes in NAG, LDH, GGT, Ca, Prot, phosphates, Glc, Crs Magdo et al. (2007) 2 adults + 5 children; general population 5 2 3–37 Oral (water) 5 years approximately 866 and 1.160 μg/l NU 3 months after cessation > BMG; > U in urine Oeh et al. (2007) —; workers during Balcans War — — — Oral Years 17.7 μg/l NU 2–6 years after cessation No differences in uranium excretion Selden et al. (2009) 453; general population 227 226 18–74 Oral (water) Years 6.7–25.2 μg/l NU During exposure > U in urine; < NAG (exposed); > (tendency) BMG, kappa chains, HC protein; No changes in urinary Glc, phosphates, calcium, Prot., Cr. Zamora et al. (2009) 54 39 15 12–73 Oral (water) Years 0,4–845 μg/l NU During exposure > GGT, ALP, LDH, NAG and BMG in urine; No changes in Prot., and glc. Anderson et al. (2007) 581; gas plant workers — — Inhalation Years 73 μg/m3 NU and EU During exposure > U in urine Boice et al. (2007) 2161; workers and residents near uranium factory 1368 796 > 18 Inhalation > 1 year —; NU During exposure > U in urine Parrish et al. (2008) —; residents near uranium factory — — — Inhalation Years 300 μg/ g U, DU 20 years after cessation > U in urine McDiarmid et al. (2001) 15; Gulf war veterans — — — Inhalation; dermal Years —; DU 8 years after cessation > U in urine; > phosphates; < Clcr; No change in Crs, BUN, BMG, Cru y Prot. McDiarmid et al. (2006) 31; Gulf War veterans — — — Inhalation; dermal Years —; DU 12 years after cessation > U in urine; No change in Crs, BUN, Ca, RBP, BMG, NAG, ALP, phosphates, Clcr Squibb and McDiarmid (2006) 102; Gulf War veterans — — — Dermal Years —; DU 15 years after cessation > U in urine; No change in Crs, BUN, Clcr, Ca, Glc Phosphates, BMG, Prot., RBP, ALP, NAG Squibb et al. (2005) 16; Gulf War veterans — — — Dermal; oral; inhalation 6–10 years 25–190 μg DU (dermal) 6–10 years after cessation > U in urine; > Prot., RBP;No change in Crs, ALP, NAG McDiarmid et al. (2007) 108; Gulf War veterans — — — Dermal; oral; inhalation Years —; DU Years after cessation > U in urine; > Phosphates and Ca in urine; No change in Crs, BUN, Clcr, Ca, pot, BMG, RBP, ALP, NAG Helmer et al. (2007) 56; Gulf War veterans — — — Oral; inhalation; dermal Years —; DU Years after cessation > U in urine Note. NU, natural uranium; DU, depleted uranium; U, uranium; Glc, gucosuria; Crs, serum creatinine; BUN, blood urea nitrogen; BMG, β-2-microglobulin; Cru, urinary creatinine; Prot., proteinuria; Ca, calcium; Clcr, creatinine clearance; NAG, N-acetyl-β-D-glucosaminidase; GGT, gamma-glutamyl-transpeptidase; EU, enriched uranium. Open in new tab TABLE 4 Documented Cases of Chronic Intoxication with Uranium in Humans Study Participants number Male Female Ages Exposure source Exposure time Uranium amount and type Study moment Observations Shiraishi et al. (1992) —; general population — — — Oral (water) 10 years approximately 1.07–42.6 ng/dm3 NU During exposure No clinical effects Zamora et al. (1998) 30; 20 10; 7 20; 13 13–87; 16–68 Oral (water); oral (water) 3 years approximately High dose (2–780 μg/l); Low dose (< 1 μg/l) NU During exposure > U in urine (exposed); > LDH, ALP and GGT (slightly); > Glc.; No changes in Prot. and NAG Kurttio et al. (2002) 325; general population — — 15–82 Oral (water) 1–34 years High dose (> 100 μg/l); low dose (10–100 μg/l) During exposure > U in urine; > Ca, Phosphate and glc in urine; No changes in Clcr. Albumin, BMG, Crs. Pinney et al. (2003) —; residents near uranium plant — — — Oral (water) Years —; NU During exposure > U in urine; > microalbuminury; > red cells and hematocit in blood Orloff et al. (2004) 105; general population 50 55 15–79 Oral (water) Months High dose (620 μg/l) NU 6–10 months after cessation > U in urine Karpas et al. (2005) 205; general population 102 103 18–81 Oral (water) Years 0.03–2.775 μg/day NU During exposure > U in urine Wyatt et al. (2008) 156; general population — — — Oral (water) Years > 30 μg/l NU 1 year after cessation > Crs and BUN; > U in urine Kurttio et al. (2006) 193; general population 95 98 18–81 Oral (water) 16 years approximately 25 μg/l NU During exposure > Glc and ALP in urine; > U in urine; No changes in NAG, LDH, GGT, Ca, Prot, phosphates, Glc, Crs Magdo et al. (2007) 2 adults + 5 children; general population 5 2 3–37 Oral (water) 5 years approximately 866 and 1.160 μg/l NU 3 months after cessation > BMG; > U in urine Oeh et al. (2007) —; workers during Balcans War — — — Oral Years 17.7 μg/l NU 2–6 years after cessation No differences in uranium excretion Selden et al. (2009) 453; general population 227 226 18–74 Oral (water) Years 6.7–25.2 μg/l NU During exposure > U in urine; < NAG (exposed); > (tendency) BMG, kappa chains, HC protein; No changes in urinary Glc, phosphates, calcium, Prot., Cr. Zamora et al. (2009) 54 39 15 12–73 Oral (water) Years 0,4–845 μg/l NU During exposure > GGT, ALP, LDH, NAG and BMG in urine; No changes in Prot., and glc. Anderson et al. (2007) 581; gas plant workers — — Inhalation Years 73 μg/m3 NU and EU During exposure > U in urine Boice et al. (2007) 2161; workers and residents near uranium factory 1368 796 > 18 Inhalation > 1 year —; NU During exposure > U in urine Parrish et al. (2008) —; residents near uranium factory — — — Inhalation Years 300 μg/ g U, DU 20 years after cessation > U in urine McDiarmid et al. (2001) 15; Gulf war veterans — — — Inhalation; dermal Years —; DU 8 years after cessation > U in urine; > phosphates; < Clcr; No change in Crs, BUN, BMG, Cru y Prot. McDiarmid et al. (2006) 31; Gulf War veterans — — — Inhalation; dermal Years —; DU 12 years after cessation > U in urine; No change in Crs, BUN, Ca, RBP, BMG, NAG, ALP, phosphates, Clcr Squibb and McDiarmid (2006) 102; Gulf War veterans — — — Dermal Years —; DU 15 years after cessation > U in urine; No change in Crs, BUN, Clcr, Ca, Glc Phosphates, BMG, Prot., RBP, ALP, NAG Squibb et al. (2005) 16; Gulf War veterans — — — Dermal; oral; inhalation 6–10 years 25–190 μg DU (dermal) 6–10 years after cessation > U in urine; > Prot., RBP;No change in Crs, ALP, NAG McDiarmid et al. (2007) 108; Gulf War veterans — — — Dermal; oral; inhalation Years —; DU Years after cessation > U in urine; > Phosphates and Ca in urine; No change in Crs, BUN, Clcr, Ca, pot, BMG, RBP, ALP, NAG Helmer et al. (2007) 56; Gulf War veterans — — — Oral; inhalation; dermal Years —; DU Years after cessation > U in urine Study Participants number Male Female Ages Exposure source Exposure time Uranium amount and type Study moment Observations Shiraishi et al. (1992) —; general population — — — Oral (water) 10 years approximately 1.07–42.6 ng/dm3 NU During exposure No clinical effects Zamora et al. (1998) 30; 20 10; 7 20; 13 13–87; 16–68 Oral (water); oral (water) 3 years approximately High dose (2–780 μg/l); Low dose (< 1 μg/l) NU During exposure > U in urine (exposed); > LDH, ALP and GGT (slightly); > Glc.; No changes in Prot. and NAG Kurttio et al. (2002) 325; general population — — 15–82 Oral (water) 1–34 years High dose (> 100 μg/l); low dose (10–100 μg/l) During exposure > U in urine; > Ca, Phosphate and glc in urine; No changes in Clcr. Albumin, BMG, Crs. Pinney et al. (2003) —; residents near uranium plant — — — Oral (water) Years —; NU During exposure > U in urine; > microalbuminury; > red cells and hematocit in blood Orloff et al. (2004) 105; general population 50 55 15–79 Oral (water) Months High dose (620 μg/l) NU 6–10 months after cessation > U in urine Karpas et al. (2005) 205; general population 102 103 18–81 Oral (water) Years 0.03–2.775 μg/day NU During exposure > U in urine Wyatt et al. (2008) 156; general population — — — Oral (water) Years > 30 μg/l NU 1 year after cessation > Crs and BUN; > U in urine Kurttio et al. (2006) 193; general population 95 98 18–81 Oral (water) 16 years approximately 25 μg/l NU During exposure > Glc and ALP in urine; > U in urine; No changes in NAG, LDH, GGT, Ca, Prot, phosphates, Glc, Crs Magdo et al. (2007) 2 adults + 5 children; general population 5 2 3–37 Oral (water) 5 years approximately 866 and 1.160 μg/l NU 3 months after cessation > BMG; > U in urine Oeh et al. (2007) —; workers during Balcans War — — — Oral Years 17.7 μg/l NU 2–6 years after cessation No differences in uranium excretion Selden et al. (2009) 453; general population 227 226 18–74 Oral (water) Years 6.7–25.2 μg/l NU During exposure > U in urine; < NAG (exposed); > (tendency) BMG, kappa chains, HC protein; No changes in urinary Glc, phosphates, calcium, Prot., Cr. Zamora et al. (2009) 54 39 15 12–73 Oral (water) Years 0,4–845 μg/l NU During exposure > GGT, ALP, LDH, NAG and BMG in urine; No changes in Prot., and glc. Anderson et al. (2007) 581; gas plant workers — — Inhalation Years 73 μg/m3 NU and EU During exposure > U in urine Boice et al. (2007) 2161; workers and residents near uranium factory 1368 796 > 18 Inhalation > 1 year —; NU During exposure > U in urine Parrish et al. (2008) —; residents near uranium factory — — — Inhalation Years 300 μg/ g U, DU 20 years after cessation > U in urine McDiarmid et al. (2001) 15; Gulf war veterans — — — Inhalation; dermal Years —; DU 8 years after cessation > U in urine; > phosphates; < Clcr; No change in Crs, BUN, BMG, Cru y Prot. McDiarmid et al. (2006) 31; Gulf War veterans — — — Inhalation; dermal Years —; DU 12 years after cessation > U in urine; No change in Crs, BUN, Ca, RBP, BMG, NAG, ALP, phosphates, Clcr Squibb and McDiarmid (2006) 102; Gulf War veterans — — — Dermal Years —; DU 15 years after cessation > U in urine; No change in Crs, BUN, Clcr, Ca, Glc Phosphates, BMG, Prot., RBP, ALP, NAG Squibb et al. (2005) 16; Gulf War veterans — — — Dermal; oral; inhalation 6–10 years 25–190 μg DU (dermal) 6–10 years after cessation > U in urine; > Prot., RBP;No change in Crs, ALP, NAG McDiarmid et al. (2007) 108; Gulf War veterans — — — Dermal; oral; inhalation Years —; DU Years after cessation > U in urine; > Phosphates and Ca in urine; No change in Crs, BUN, Clcr, Ca, pot, BMG, RBP, ALP, NAG Helmer et al. (2007) 56; Gulf War veterans — — — Oral; inhalation; dermal Years —; DU Years after cessation > U in urine Note. NU, natural uranium; DU, depleted uranium; U, uranium; Glc, gucosuria; Crs, serum creatinine; BUN, blood urea nitrogen; BMG, β-2-microglobulin; Cru, urinary creatinine; Prot., proteinuria; Ca, calcium; Clcr, creatinine clearance; NAG, N-acetyl-β-D-glucosaminidase; GGT, gamma-glutamyl-transpeptidase; EU, enriched uranium. Open in new tab The first documented data concerning chronic exposure date back to the 19th century, before the discovery of insulin, because uranium was then used as a treatment for diabetes mellitus (Hodge et al., 1973). Thus, the treated population could provide data about the chronic toxicity of uranium in humans. However, the information from this population should be taken with caution because it is now known that diabetes is the main cause of chronic kidney disease in developed countries (Molitch et al., 2004). Another factor that further complicates the issue is the documented fact that hyperglycaemia per se reduces the renal damage caused by metals (Jin et al., 1996; Shyh et al., 1984), although diabetic nephropathy caused by chronic diabetes increases the susceptibility to metal nephrotoxicity (Jin et al., 1994, 1999). Several independent studies have provided evidence of humans (totaling ∼24 people) treated orally with soluble uranyl nitrate, at 3 doses of 2 g daily (6 g/day) over months or even years (Bond, 1898; Bradbury, 1896; Duncan, 1897; Wilcox, 1917). No kind of renal damage was reported in any of these cases (Wilcox, 1917). Nevertheless, it is not possible to rule out that the patients treated with these concentrations of uranium might have suffered some type of kidney lesion. In the 19th century, there was no pathological or diagnostic information available that would allow a slight or moderate degree of damage to be detected, unlike current diagnostic techniques that allow specific aspects of such damage to be determined. The highest concentrations of natural uranium present in water are found in mountainous regions of countries, such as Finland (Kurttio et al., 2002; Vesterbacka et al., 2005), Norway (Frengstad et al., 2000), Canada (Mao et al., 1995; Zamora et al., 1998, 2009), Sweden (Selden et al., 2009), and the United States (Hakonson-Hayes et al., 2002; Magdo et al., 2007; Orloff et al., 2004). Accordingly, in these zones, population epidemiological studies on oral exposure to uranium have been conducted. One important bias common to such studies is that it is extremely difficult to establish the number of years over which the people surveyed have been exposed. It has generally been assumed that this would be proportional to the time of residence in the place affected. Table 4 shows the most significant data of these and other studies addressing chronic exposure to uranium, specifying the available data concerning renal effects, which are evaluated in the next section. Pathophysiological Picture from Human Studies The documented cases of chronic intoxication in humans indicate that there are few situations in which uranium produces symptoms of a reduction in glomerular filtration and azotemia, such as a decrease in the GFR (McDiarmid et al., 2001), and an increase in plasma creatinine and urea concentrations (Wyatt et al., 2008). In most studies, no reports have been made of alterations in these parameters, although a few authors have described alterations in parameters related to the function and integrity of the kidney structures, especially the tubular compartment, although inconsistently among the different studies. However, it is necessary to take into account that such inconsistency could be because of strong biases among them as regards the dose, duration and route of exposure, the time of diagnosis, sex, age, and other determinant factors. Nonetheless, as discussed below and reflected in Figure 2, it is interesting to note that the same changes have also been observed in laboratory animals exposed chronically to the metal (“Pathological Studies with Animal Models” section) and that the pattern of damage is similar to that produced by acute overexposure (with much higher doses—“Nephrotoxicity because of Acute Overexposure” section). FIG. 2. Open in new tabDownload slide Simptomatology after Chronic Exposure to Uranium. Comparison between Humans and Animals. BUN, blood urea nitrogen; Ca, calcium; ALP, alkaline phosphatase; GGT, gamma-glutamyl-transpeptidase; NAG, N-actetyl-β-D-glucosaminidase, ▴, increase; ▾, decrease; ---, no change. FIG. 2. Open in new tabDownload slide Simptomatology after Chronic Exposure to Uranium. Comparison between Humans and Animals. BUN, blood urea nitrogen; Ca, calcium; ALP, alkaline phosphatase; GGT, gamma-glutamyl-transpeptidase; NAG, N-actetyl-β-D-glucosaminidase, ▴, increase; ▾, decrease; ---, no change. In some studies, reports have been made of proteinuria or the excretion of certain specific proteins, such as albumin (retinol-binding protein [RBP] and β-2-microglobulin, Magdo et al., 2007; Pinney et al., 2003), after uranium exposure. These findings are inconsistent with those obtained by other authors (Kurttio et al., 2006; McDiarmid et al., 2001, 2006, 2007; Zamora et al., 1998). In part, this may be also because of differences in sampling, the analytical method used, the statistical analyses applied, or the level of exposure to uranium. It is not known whether the observed general or selective proteinuria is of glomerular or tubular origin. As in the case of acute nephrotoxicity, studies have also measured a series of kidney enzymes used as markers of tissue damage, including ALP, GGT, LDH, and NAG (Kurttio et al., 2002, 2006; McDiarmid et al., 2006; Zamora et al., 1998). In these studies, it was not possible to relate alterations in these enzymes to the ingestion of uranium. Nevertheless, in rats, a decrease in the activity of GGT in urine has been observed following chronic ingestion of the metal (Niwa et al., 1993), possibly because of the fact that the activity of this enzyme is inhibited by uranium (Nechay et al., 1980). ALP activity seems to be related to the chronic ingestion of uranium because a tendency for it to increase in urine has been observed (Kurttio et al., 2006; Zamora et al., 1998, 2009), although in other studies, it seems to be unaltered (McDiarmid et al., 2006; Squibb and McDiarmid, 2006; Squibb et al., 2005). A tendency for LDH activity to increase after chronic exposure to uranium in humans has also been reported (Zamora et al., 1998, 2009). Some studies have reported alterations of other tubular functions, such as increases in the excretion of calcium (Kurttio et al., 2002; Squibb and McDiarmid, 2006), glucose (Kurttio et al., 2002, 2006; Zamora et al., 1998), and phosphate (Kurttio et al., 2002; McDiarmid et al., 2001). However, no increases in calcium or phosphate levels have been observed in other studies (McDiarmid et al., 2006; Selden et al., 2009). However, no clear relation between exposure level, duration of exposure, and observed renal effects can be drawn from the available studies in humans (Table 3). Just as an example, whereas Wyatt et al. (2008) found increased serum creatinine in 156 people 1 year after the cessation of a chronic overexposure of years to drinking water containing over 30 μg U/l, Kurttio et al. (2002) found no alterations in this parameter in 325 people during an overexposure of years to water containing over 100 μg U/l. Together with the results obtained in animal models (“Pathological Studies with Animal Models” section), the available information indicates that chronic exposure to uranium may lead to a variable degree of renal damage, which in general terms ranges from no detectable alterations to a mild injury mostly of tubular origin. However, undetermined comorbidity factors seem to play an important role at determining the final effect of uranium in the kidneys. Recent studies suggest that chronic exposure to uranium would be associated with an increase in plasma renin concentrations, which would result in an elevation of blood pressure and hence a predisposition to hypertension in subjects exposed to uranium (Kurttio et al., 2006). As commented above (“Nephrotoxicity because of Chronic Overdose” section), this effect has also been reported in acute overexposure to uranium. A new hypothesis has associated the kidney damage produced by chronic ingestion of uranium with the induction of renal anemia (anemia because of renal disease), which has been described as an early symptom in the progression of chronic renal disease (Berradi et al., 2008). This conclusion was reached after the discovery, in laboratory animals, of low red blood cell levels following chronic exposure to the metal (Berradi et al., 2008). However, this has not been corroborated in uranium workers (Shawky et al., 2002), although it has been observed in people living close to nuclear power plants (Pinney et al., 2003) and in soldiers exposed to uranium (Squibb and McDiarmid, 2006). Finally, studies have been carried out to determine whether age influences renal damage. This aspect is of special relevance because children may be at a greater risk of developing renal damage after uranium exposure because they drink more water and food per kilogram of body weight than adults (Ershow and Cantor, 1989). In one study, it was found that chronic ingestion of uranium by a 3-year-old boy caused a much greater increase in the urinary excretion of β-2-microglobulin than the other individuals exposed to the same amount of the metal (Magdo et al., 2007). Moreover, adults with impaired renal function may also be at greater risk. In these, a decrease in creatinine clearance together with an increase in serum cystatin C levels has been reported (Kurttio et al., 2006). Regarding the possible increase in blood pressure because of increases in plasma renin concentrations, a correlation has been found between exposure to uranium and increased blood pressure (Kurttio et al., 2006). Histological Alterations There is little histological information in humans following chronic uranium exposure, and in a review of the literature, we have only been able to find a few studies performed on uranium workers. In one case, an autopsy was performed on a miner who had been exposed to uranium for years. The mean uranium content in was 2 ng U/g kidney, and his annual uranium excretion calculated with several data was 14.3 mg U/year (0.04 mg U/day). Sclerotic zones were observed in the glomeruli, together with lymphocyte infiltration and zones of arteriosclerosis (Russell and Kathren, 2004). In another work, the authors performed an autopsy on seven uranium workers together with another six people not known to have been exposed to the element. In this case, no histological differences were observed between both groups (Russell et al., 1996). Studies have been carried out on chronic exposure in laboratory animals and the third segment of the proximal tubule (S3) has been established as the site mainly affected (Gilman et al., 1998a,b,c; Mao et al., 1995). Apical nuclear displacement, cytoplasmic vacuolization, and tubular dilation were observed, although a certain degree of glomerular damage, such as adherences and focal sclerosis, was also found (Gilman et al., 1998c). The histological data obtained to date in human beings do not allow a clear idea to be gained of the type of damage caused by uranium through chronic exposure nor in which part of the kidney such damage is caused. However, several investigations carried out in animals suggest that the proximal tubule is the one most affected by exposure to uranium, a result that has been reproduced in both acute and chronic intoxications. In both cases, tubular dilation, cytoplasmic vacuolization, and apical nuclear displacement have been reported. However, the corticomedullary necrosis observed after acute intoxications is not observed after a chronic exposure to uranium. This metal has also been linked to the production of glomerular damage, although in this case, the evidence is not as clear because this kind of damage has only been observed in a few studies. As in the case of acute exposure, renal tissue tends to regenerate after exposure to high and repeated doses of the metal, pointing to the development of resistance to the toxic effects of uranium (Bentley et al., 1985; Durbin et al., 1997; Dygert, 1949; Maynard and Hodge, 1949; Pozzani, 1949; Yuile, 1973). The mechanism through which this tolerance is acquired is based on the morphological effects observed in regenerated cells of the proximal tubule (Leggett, 1989; MacNider, 1929), which appear swollen, without microvilli on the luminal surface and with a reduced number of mitochondria. It has been suggested that this reduction in microvilli could give rise to a decrease in the binding of uranium to the renal cell surface and hence reduce its toxic action at this site (,Gilman et al., 1998c). Another possible tolerance mechanism is related to the increase in heat-shock proteins (HSPs) (Ciocca et al., 1992; Elliott et al., 1982; Honda and Sudo, 1982; Salminen et al., 1997). In in vitro studies, it has been observed that renal tubular cells express high levels of HSPs in response to uranyl nitrate (Goering et al., 2000; Mizuno et al., 1997). In particular, the HSP25 and HSP70i proteins have been associated with cytoprotection against other renal toxic agents, among which are mercury and gentamicin (Elliott et al., 1982; Goering et al., 2000; Zager et al., 1994). HSP induction seems to be different in the case of uranium (Goering et al., 2000) because exposure to this metal has mainly been linked to an increase in HSP73 expression in kidney cells (Mizuno et al., 1997) as well as increases in the levels of HSP25, HSP32, and HSP70i. In contrast, in in vivo studies, no increases in the levels of these proteins have been reported (Ananthan et al., 1986), such that it has not been possible to corroborate this hypothesis. Conclusions and Perspectives All the above suggests that chronic exposure to uranium cannot be easily linked to the occurrence of nephrotoxicity and that, in the event of the metal being responsible for it, it may revert with time. In studies on exposure performed only a short time after the ingestion or inhalation of uranium, some urinary markers of renal damage have been found to be altered, such as urinary β-2-microglobulin, although some years after exposure to the metal has ceased, the renal parameters studied seem to return to normal values and only an increased urinary excretion of uranium is observed. It has been proposed that such excretion could be a marker of exposure to the metal. However, it is difficult to associate uranium excretion with nephrotoxicity because despite the excretion of the metal in the urine, in most cases, no nephrotoxicity is observed. This therefore indicates that (1) the risk of renal damage in humans because of chronic exposure to uranium is at most uncertain and variable and (2) even if in some cases chronic exposure produces an undetermined level of renal injury, it reverts with time, suggesting that people exposed chronically to uranium do not develop a typical chronic renal disease. Our impression is that a very long period of overexposure (many years) would be necessary for uranium to accumulate in target organs (in this case, the kidneys) at levels above the toxicity threshold and to cause tangible deleterious effects. Studies with an exposure time of months carried out on animals require higher doses to produce similar effects to those detected in humans subjected to years of low-dose exposure. Figure 2 shows a comparison of the changes observed in different markers following chronic exposure in humans and animals. In sum, by integrating the information concerning acute and chronic overexposure, it may be deduced that uranium nephrotoxicity probably derives from tissue accumulation above certain levels, which can be attained with different combinations of exposure time and dose, such that the greater the dose, the shorter the time and vice versa. However, further information is needed together with new studies to determine correctly the profile of uranium nephrotoxicity because of both chronic and acute overexposure. An emerging issue to be considered is the possibility that chronic exposure to uranium, in stages in which it still does not cause any renal alteration, might be able to predispose subjects to develop acute renal impairment (including acute renal failure) because of exposure to other potentially nephrotoxic environmental or therapeutic agents that under normal conditions would not cause renal damage. In this sense, data from our own laboratory (unpublished) indicate that chronic exposure of rats to high doses of the metal over some months, without eliciting symptoms of nephrotoxicity by itself, reduces the threshold of nephrotoxicity and enhances the nephrotoxic effects of certain drugs, such as the aminoglycoside antibiotic gentamicin. Were it to be confirmed, this situation would be of huge clinical relevance because, in an occult and nondiagnosable way, chronic overexposure could render the sector of the population in contact with the metal more susceptible to renal failure. We believe that this is an issue requiring further research effort in the near future, especially within the context of the detection of this potential situation. MECHANISMS OF NEPHROTOXIC ACTION Although uranium is widely used as an experimental nephrotoxic agent, the underlying physiological mechanism responsible for renal damage has not been fully elucidated. One limitation to our knowledge about this issue is that most of the information has been obtained in acute studies with animals (Diamond et al., 1989; Haley, 1982, Haley et al., 1982; Morrow et al., 1982; Rothstein, 1949; Stokinger et al., 1953; Taylor and Taylor, 1997; Thun et al., 1985). The first issue that has not been suitably clarified is whether uranium needs to penetrate cells to exert its toxic effect. Some authors have proposed that this would not be necessary because its effects (or a large part of them) derive from binding to certain components of the cell membrane (Leggett, 1989; Muller et al., 2006). According to those authors, such effects would be based on interference with the reabsorption of glucose, sodium, amino acids, proteins, water, and other substances, which would lead to a slow cell death because of the suppression of cell respiration (Hori et al., 1985; Leggett, 1989; Nechay et al., 1980). However, others have proposed that the metal does need to enter cells to exert its toxic effects. This has been observed in LLC-PK1 cells of the proximal tubules in studies aimed at determining whether there are differences in the toxicity of the U-bicarbonate and U-citrate complexes (L’Azou et al., 2002; Mirto et al., 1999). In these studies, it was possible to correlate the presence of the uranium complex inside the cells and the toxic effect. Thus, it was observed that the U-citrate complex entered the cells and exerted a significant toxic effect in them, whereas the U-bicarbonate complex, which did not enter the cells, exerted a much lower toxic effect (Mirto et al., 1999). Accordingly, the authors concluded that as regards its toxic effects, the entry of uranium into cells is very important. Below, we detail some of the aspects related to the mechanism involved in uranium nephrotoxicity. Alterations in Solute Transport In studies of brush border membrane vesicles from rat renal tubular cells, it has been observed that uranyl acetate produces a decrease in glucose transport because of a reduction in the number of sodium-glucose transporters (SGLT) (Goldman et al., 2006). Hori et al. (1985) also reported a decrease in the sodium-dependent glucose gradient that led them to suspect that the enzymatic activity of Na+ K+, adenosine triphosphatase (Na+, K+ ATPase, or sodium pump) could be inhibited by uranyl nitrate. Similar results were obtained by Brady et al. (1989) in rabbit kidney cells. Those authors suggested that uranyl nitrate would inhibit both the sodium-dependent and the sodium-independent ATP utilization and mitochondrial oxidative phosphorylation. Muller et al. (2006) reported that the cytotoxicity of uranium for LLC-PK1 cells would depend on the extracellular concentration of phosphate. High concentrations of phosphate in the medium gave rise to the formation of uranium-phosphate complexes, which inhibited the Na/Pi II transporter participating in the reabsorption of organic phosphate. Oxidative Stress Oxidative stress has been proposed as a possible mediator of renal damage because of exposure to uranium. In the rat renal proximal tubular cell line (NRK-52E), uranium stimulates the production of reactive oxygen species (ROS), caspases 9 and 3, and cell death because of apoptosis (Thiebault et al., 2007). In studies carried out on rat renal tissue (Linares et al., 2006), an increase was observed in ROS levels, in oxidized glutathione (GSSG), and in the activity of SOD. An increase in thiobarbituric acid–reactive substances, indicative of lipid peroxidation and oxidative stress, was also observed. It has also been suggested that uranium could act as a catalyst in the Fenton/Haber-Weiss reaction (Kovacic and Jacintho, 2001), which would facilitate the conversion of the superoxide anion and hydrogen peroxide into hydroxyl radicals, believed to be responsible for initiating lipid peroxidation (Linares et al., 2006; Stohs and Bagchi, 1995; Taulan et al., 2004). In other studies, the pro-oxidant action of uranium has been related to a disturbance in the activity of acetyl cholinesterase and of monoamine metabolism (Kurttio et al., 2002; Linares et al., 2006; Sanchez et al., 2001) and to an increase in mitochondrial oxidative phosphorylation in the proximal tubule (Brady et al., 1989). These results indicate that uranium could produce oxidative stress, inducing, at least in part, the death of target cells (Sabolic, 2006). Figure 3 shows the possible mechanism responsible for renal damage caused by uranium. FIG. 3. Open in new tabDownload slide Absorption, distribution, accumulation, and excretion of uranium in the human body. FIG. 3. Open in new tabDownload slide Absorption, distribution, accumulation, and excretion of uranium in the human body. Alterations in Gene Expression Chronic exposure to uranium in animals elicits changes in the profiles of the renal expression of genes related to oxidative stress, cellular metabolism, solute transport, and signal transduction, among other processes (Taulan et al., 2004, 2006). As seen in Table 5, some of these changes in renal gene expression are correlated with the appearance of pathological effects, such as inflammation, apoptosis, oxidative stress, and alterations in cellular homeostasis. However, the role of these genes in the initiation and development of such effects, as well as their causal relationships with them, have not yet been clarified. TABLE 5 Modifications in Renal Gene Expression Profiling (ARNm) after an Acute and Chronic Exposure to Uranium in Mice Gen Physiological process Acute exposure Chronic exposure Observed effect Na-Pi II Solute transporters < — Hypophosphatemia Na/K ATPase Solute transporters — < Decreased sodium reabsorption SOD Oxidative stress < > Induction of ROS GPx Oxidative stress > > Induction of ROS Fau Ribosomal protein synthesis > > Perturbation in protein synthesis Odc Cellular metabolism < < Arrest of the cell cycle Umod Tamm Horsfall protein synthesis > < Inflammation Tctp Apoptosis, inflammation > > Apoptosis, inflammation Gal-3 Apoptosis, inflammation > — Apoptosis, inflammation Opn Inflammation, proximal tubules regeneration > — Inflammation, tissular regeneration MT-2 Metallothionein synthesis > — Uranium detoxification Igfbp7 Cellular proliferation > — Not established Rps 29 Apoptosis > — Not established Octs 2 Organic cation transport < — Decreased of organic cation transport Gen Physiological process Acute exposure Chronic exposure Observed effect Na-Pi II Solute transporters < — Hypophosphatemia Na/K ATPase Solute transporters — < Decreased sodium reabsorption SOD Oxidative stress < > Induction of ROS GPx Oxidative stress > > Induction of ROS Fau Ribosomal protein synthesis > > Perturbation in protein synthesis Odc Cellular metabolism < < Arrest of the cell cycle Umod Tamm Horsfall protein synthesis > < Inflammation Tctp Apoptosis, inflammation > > Apoptosis, inflammation Gal-3 Apoptosis, inflammation > — Apoptosis, inflammation Opn Inflammation, proximal tubules regeneration > — Inflammation, tissular regeneration MT-2 Metallothionein synthesis > — Uranium detoxification Igfbp7 Cellular proliferation > — Not established Rps 29 Apoptosis > — Not established Octs 2 Organic cation transport < — Decreased of organic cation transport Note. This table was performed with data from Taulan et al. (2004) (chronic) and Taulan et al. (2006). <, decreased; >, increased; – unchanged. Modified genes: Fau, Finkel-Biskis-Reilly murine sarcoma virus; Odc, ornithine decarboxylase; Umod, uromoduline; Tctp, translationally regulated transcript; Gal-3, galactose binding, soluble 3; Opn, osteopontin; MT-2, metallothionein 2; Igfbp7, insulin-like growth factor binding protein 7; Octs 2, organic cation transporter 2. Open in new tab TABLE 5 Modifications in Renal Gene Expression Profiling (ARNm) after an Acute and Chronic Exposure to Uranium in Mice Gen Physiological process Acute exposure Chronic exposure Observed effect Na-Pi II Solute transporters < — Hypophosphatemia Na/K ATPase Solute transporters — < Decreased sodium reabsorption SOD Oxidative stress < > Induction of ROS GPx Oxidative stress > > Induction of ROS Fau Ribosomal protein synthesis > > Perturbation in protein synthesis Odc Cellular metabolism < < Arrest of the cell cycle Umod Tamm Horsfall protein synthesis > < Inflammation Tctp Apoptosis, inflammation > > Apoptosis, inflammation Gal-3 Apoptosis, inflammation > — Apoptosis, inflammation Opn Inflammation, proximal tubules regeneration > — Inflammation, tissular regeneration MT-2 Metallothionein synthesis > — Uranium detoxification Igfbp7 Cellular proliferation > — Not established Rps 29 Apoptosis > — Not established Octs 2 Organic cation transport < — Decreased of organic cation transport Gen Physiological process Acute exposure Chronic exposure Observed effect Na-Pi II Solute transporters < — Hypophosphatemia Na/K ATPase Solute transporters — < Decreased sodium reabsorption SOD Oxidative stress < > Induction of ROS GPx Oxidative stress > > Induction of ROS Fau Ribosomal protein synthesis > > Perturbation in protein synthesis Odc Cellular metabolism < < Arrest of the cell cycle Umod Tamm Horsfall protein synthesis > < Inflammation Tctp Apoptosis, inflammation > > Apoptosis, inflammation Gal-3 Apoptosis, inflammation > — Apoptosis, inflammation Opn Inflammation, proximal tubules regeneration > — Inflammation, tissular regeneration MT-2 Metallothionein synthesis > — Uranium detoxification Igfbp7 Cellular proliferation > — Not established Rps 29 Apoptosis > — Not established Octs 2 Organic cation transport < — Decreased of organic cation transport Note. This table was performed with data from Taulan et al. (2004) (chronic) and Taulan et al. (2006). <, decreased; >, increased; – unchanged. Modified genes: Fau, Finkel-Biskis-Reilly murine sarcoma virus; Odc, ornithine decarboxylase; Umod, uromoduline; Tctp, translationally regulated transcript; Gal-3, galactose binding, soluble 3; Opn, osteopontin; MT-2, metallothionein 2; Igfbp7, insulin-like growth factor binding protein 7; Octs 2, organic cation transporter 2. Open in new tab Diagnosis of Intoxication by Uranium The diagnosis of nephrotoxicity because of uranium requires two components: (1) the detection of overexposure to the metal and (2) determination of the renal toxic effects. Detection of the latter indicates that the former has occurred at a specific moment. It is also possible that subnephrotoxic chronic exposure could lead to a hidden predisposition to acute renal failure because of other agents or that it might in some way cooperate or increase the effect of other causes of CRI. As commented in “Conclusions and Perspectives” section under “Nephrotoxicity because of Chronic Overexposure” section, some results obtained by us indicate that chronic treatment with uranyl nitrate predisposes individuals to the acute renal failure elicited by other potentially nephrotoxic drugs, such as gentamicin. Detection of Overexposure To date, the most efficient way of diagnosing exposure to uranium is its detection in urine (Ballou et al., 1986; Cooper et al., 1982; Downs et al., 1967; Morrow et al., 1982; Stradling et al., 1981, 1991). According to the United States Nuclear Regulatory Commission guide, acceptable methods for quantifying uranium in urine should have a limit of 5 μg/kg and a precision of 30% (Kressin, 1984). Different methods for detecting the metal are available, such as kinetic fluorescence analysis (Hooper et al., 1999; Price, 1989), alpha spectrometry (Beyer et al., 1993; Chalabreysse et al., 1989; Harduin et al., 1994; Sachett et al., 1984; Spencer et al., 1990; Wreen et al., 1992), inductively coupled plasma mass spectrometry (Baglan et al., 1999; Ejnik et al., 2000; Krystek and Ritsema, 2009; Lorber et al., 1996; Paquet et al., 2006; Zamora et al., 1998), neutron activation (Sansone et al., 2001), and atomic absorption (Wessman, 1984). Besides uranium determination, of all the other markers studied only an increase in renal glucose excretion has been linked to exposure to uranium in the human being (Kurttio et al., 2002, 2006; Zamora et al., 1998), in agreement with experimental studies carried out on different animal species (,Gilman et al., 1998c; Martinez et al., 2003; Ortega et al., 1989). Detection of Nephrotoxicity For the detection of renal toxicity, there are no specific biomarkers for diagnosing that it has been produced by uranium; thus, general markers of nephrotoxicity are used when a person is suspected to have been exposed to the metal (Saccomanno et al., 1982; Thun et al., 1985; Zamora et al., 1998). As in any situation in which there is suspicion of renal damage, the most common diagnosis involves measurement of the plasma creatinine concentration, which increases with the decrease in the GFR. From the plasma creatinine concentration, together with certain common anthropometric data (weight, sex, age, etc.), by using established algorithms such as the Modification in Diet in Renal Disease equation or the Cockroft-Gault equation (Snively and Gutierrez, 2004; Snyder and Pendergraph, 2005), it is possible to obtain an estimation of the GFR. A slight proteinuria and amino aciduria are also indicative of this damage (Saccomanno et al., 1982; Thun et al., 1985), together with other markers of tubular damage, such as urinary glucose, ALP, and β-2-microglobulin (Zamora et al., 1998). Presently, the most serious problem in the diagnosis of renal impairment, both chronic and acute, is that it is based on the detection of the consequences of renal dysfunction, which only occur when the kidney damage is in a very advanced stage. At that time, both the possibility of intervening and the prognosis are poor (Vaidya et al., 2008). The future of the diagnosis of these kidney diseases will require the identification of markers, preferentially urinary markers, able to detect damage in the early stages (Vaidya et al., 2008). In the case of acute renal impairment, some urinary markers that appear in the urine a few hours after the start of the damage have been identified. Among them is neutrophil gelatinase–associated lipocalin (lipocalin 2), Kidney Injury Molecule 1 (KIM-1), interleukin 18, and cystatin C, to mention but a few, that are in an advanced stage of validation (reviewed in Vaidya et al., 2008). The next step in the refinement of the capacity to diagnose acute renal damage will be the discovery of markers (or sets of markers—fingerprints) that as well as being detected early are able to discern the cause of the damage. This, then, is also a matter pending in the diagnosis of acute renal impairment because of uranium exposure. Regarding chronic renal disease, there are not even any good early markers of the disease. In the case of some chronic renal conditions with a given etiology, such as diabetes, the possible role of microalbuminuria in the early diagnosis and prognosis of the evolution of the disease is currently being discussed (Parving et al., 2002; Schena and Gesualdo, 2005). In diabetic nephropathy, microalbuminuria occurs prior to the appearance of signs of kidney dysfunction, such as the increase in plasma creatinine concentrations. However, its value as a marker is debatable and it probably does not occur early enough to be of use (Parving et al., 2002). In the case of chronic intoxication with uranium, it remains to be seen whether the gradual accumulation of the metal will lead to a subacute kidney lesion. This difference is not trivial in the diagnosis of nephrotoxicity because of chronic exposure because CRI is a disease that, when the no-return point has been passed, enters a vicious degenerative cycle and progresses irreversibly and independently of the initial cause of the damage (Compton, 2004). Conclusions and Perspectives Accordingly, the perspectives for improving the diagnosis of this condition are necessarily based on a better understanding of the renal pathology associated with chronic intoxication with the metal. In the case of chronic uranium exposure producing CRI, it would be necessary to identify very early general and specific markers of this type of lesion. In the case of chronic exposure inducing a subacute lesion, improvements in diagnosis will probably involve the identification of urinary markers that afford information about the level of uranium accumulation in the kidney. In this sense, it will be necessary to determine whether the urinary excretion of the element could fulfill this function or whether it would be necessary to identify other markers that are more tightly correlated with the physiopathological outcomes of increased levels of accumulation of the metal in renal structures. TREATMENT OF INTOXICATION BY URANIUM Therapy for intoxication with uranium has a dual mission. On one hand, it must attempt to palliate the intoxication by halting the absorption, distribution, or the action of the metal or by accelerating its excretion, and—on the other—it must take into account the repair of the toxic damage caused. Prevention of Intoxication Prevention of intoxication is attempted at two nonexcluding levels aimed at preventing absorption and, if this has already occurred, at preventing uranium action on target organs. Prevention of Absorption The main objective in treating patients overexposed to uranium is to prevent or minimize absorption from the site of entry and distribution and to increase its removal from the blood or target organs by favoring its excretion (Cronin and Heinrich, 2000). When acute intoxication occurs through the oral route, the usual measures stipulated for the treatment of the ingestion of toxic substances must be brought into play with a view to lowering intestinal absorption. Among such measures are (1) stomach gastric lavage; (2) the use of emetics, such as oral ipecacuana; (3) laxatives; (4) ion exchange agents; and (5) the administration of antacids containing salts of aluminium, barium sulfate, sodium phytate, and salts of glucuronic and maluronic acid (ICRP, 1991). When intoxication has occurred through the inhalation route, the therapeutic agents include pancreatic dornase, Triton, or Tween-90, which decrease the viscosity of the endobronchial mucosa and act on the mucopolysaccharides and nucleoproteins of the respiratory tree, favor the elimination of uranium through coughing, and prevent its pulmonary absorption (ICRP, 1991). Prevention of Action If it is suspected or known that the uranium has reached the blood stream, complex-forming agents are employed, such as bicarbonate, citrate, lactate, and fumarate. Of these, bicarbonate is the one reported to have the highest elimination efficiency (Neuman et al., 1948) because it binds to uranium to form ring-shaped complexes, which are excreted in the urine. Additionally, bicarbonate alkalinizes the urine, which improves renal uranium excretion. This treatment must be applied as soon as possible after exposure, before the uranium has a chance to be incorporated into the target organs. Generally, it is administered 24 h after exposure (Domingo et al., 1992; Ortega et al., 1989), but its use is limited because of the possible adverse effects of hypocalcaemia and alkalosis (Bhattacharyya et al., 1992; NCRP, 1980; WHO, 1984). Classic chelating agents. If uranium has already entered the target organs, therapy with chelating agents is initiated. In clinical practice, these agents are usually used as antidotes in intoxications, both acute and chronic, with metals. These compounds bind to the metal and improve its excretion. Moreover, in some cases, they decrease the toxicity of the metal because they prevent it from binding to its target cells. To obtain the best effects in therapy with chelating agents, it is necessary to adjust the length of the treatment (Basinger and Jones, 1981; Domingo et al., 1990; Henge-Napoli et al., 1995, 1999) and the doses of the chelating agents (Henge-Napoli et al., 1999) and to take into account the route of entry and the chemical form of the uranium involved (Houpert et al., 2003). In humans, the chelating agents used are EDTA and diethylene triamine pentaacetic acid (DTPA) (Basinger and Jones 1981; Dagimanjian et al., 1956; Domingo et al., 1989, 1990; Durbin et al., 1997; Henge-Napoli et al., 1995, 1998, 1999; Houpert et al., 2001; Martinez et al., 2000, 2003; Stradling et al., 1991; Ubios et al., 1994). EDTA has been used both in human medicine and in experimentation with animals for the treatment of intoxications by inorganic substances (Hammond and Beliles, 1980). In intoxications with uranium, both acute and chronic, it is administered iv dissolved in 5% glucose or in physiological saline. It is crucial to assess kidney function before starting treatment because the use of EDTA is contraindicated in patients with established renal disease. EDTA is also used in combination with sodium (Na-EDTA), although this may give rise to hypocalcaemia, and thus, the use of EDTA associated with calcium is preferred (Ca-EDTA). DTPA is a chelating agent belonging to the polyaminocarboxylate series that forms highly stable water-soluble complexes that are excreted by the kidney. The U.S. Food and Drug Administration approves the use of calcium and zinc salts with DTPA in cases of human contamination with transuranic elements. Ca-DTPA provides efficient treatment of contamination with actinides (Rosen et al., 1989). The therapeutic efficiency of both (Ca-DTPA and Zn-DTPA) depends on the chemical form and solubility of the transuranic element. Both agents are useful for the elimination of soluble uranium salts, such as nitrates and chlorides, but their efficiency with sparingly soluble salts such as oxides is somewhat weaker (Catsch, 1959). They are injected or infused iv, injected im, or are administered in aerosol form for inhalation. The route of administration depends on the circumstances of the intoxication by uranium, its chemical form, and the route of contamination. Ca-DTPA is more efficient than Zn-DTPA if used early on after the contamination has occurred (Lloyd et al., 1977), but the efficiency of both is the same if they are administered later. The injection of 1 g of Ca-DTPA per week in long-term treatments does not elicit toxic effects in patients contaminated with actinides (Ballou, 1962). In contrast, a constant infusion of Ca-DTPA did cause severe toxic effects in animals, which led to death after a few days (Taylor and Mays, 1979). The toxicity of Zn-DTPA is 30-fold lower than that of its Ca-DTPA counterpart in fractionated doses (Lushbaugh and Washburn, 1979). Although DTPA is the recommended treatment after accidental exposures to uranium, derivatives, it is very risky to use this substance because at high doses, it is nephrotoxic (Diamond et al., 1989; Doolan et al., 1967). In addition, (1) in certain studies with laboratory animals, the use of DTPA has not proved to be useful (Archimbaud et al., 1994; Domingo et al., 1989, 1990; Ubios et al., 1994); and (2) more recently, in vitro, it has been observed that the administration of DTPA increases the cytotoxicity of uranium in LLC-PK1 cells (Houpert et al., 2003). DTPA together with EDTA were used in the treatment of a patient who ingested a large amount of uranium. This treatment was inefficient at increasing the excretion of the metal (Pavlakis et al., 1996). New chelating agents. Apart from the classic chelating agents, others have also been studied in animal experimentation, among which is sodium-4,5-dihydroxybenzene-1,3-disulphonate (Tiron), which has been seen to decrease uranium toxicity in mice (Domingo et al., 1989, 1990, 1992; Gomez et al., 1991; Ortega et al., 1989). In this species, Tiron has been found to be useful at doses of 1500 mg/kg/day (Bosque et al., 1993; Ortega et al., 1991), whereas in rats, it has not been reported to be so efficient (Zalups, 1991). For treatment with Tiron to be effective, early administration is crucial, such that its use would only be of value in acute intoxications. Another chelating agent used in experimental rodents is ethane-1-hydroxy-1,1-biphosphonate. This is a drug used in the treatment of osteoporosis and when administered ip is useful in the treatment of uranium intoxication (Henge-Napoli et al., 1999; Houpert et al., 2001; Martinez et al., 2000, 2003; Ubios et al., 1994). Catechol-3, 6-bismethylaminodiacetic acid (CBMIDA) has also been found to be effective in the experimental setting (Fukuda et al., 2001). Studies have been performed to determine whether the administration of this chelating agent together with bicarbonate might improve the toxic effects. The results obtained to date suggest that this is not the case, and additionally, bicarbonate has adverse effects when coadministered with ethane-1-hydroxy-1, 1-bisphosphonate (EHBP) (,Fukuda et al., 2005a). Furthermore, a series of chelating agents with which no beneficial effects have been obtained has been removed from the therapeutic arsenal, among which are triethylene tetraamino hexaacetic acid (TTHA) and diamine diethylthioether tetraacetic acid (DDTA) (Ivannikov, 1966). The affinity of uranium for phosphoric acid molecules is known, and for this reason, the efficacy of polyaminophosphoric acids, bisphosphonates, and phosphoalkylpolyphosphates has been investigated (Bailly et al., 1994; Bulman, 1987; Dagimanjian et al., 1956; Ebetino and Jamieson, 1990; Ebetino et al., 1990; Gillard et al., 1989) because these substances complex uranium (Bulman, 1987; Ebetino and Jamieson, 1990; Ebetino et al., 1990). In some cases, a strong reduction in uranium contents in kidney and bone was observed when administration was performed rapidly after exposure to the metal (Gray et al., 1992; Henge-Napoli et al., 1998; Ubios et al., 1994). The problem with polyphosphates is that although they reduce the mortality caused by poisoning with uranium, they also elicit metabolic acidosis and hypocalcaemia, which makes their use impractical in the treatment of uranium contamination (Dagimanjian et al., 1956). In the same sense, studies have been conducted with hydroxyaspartate, citrate (Rajan and Martell, 1964), and catechol disulphonate (Lusky and Braun, 1950). Of these, multidentate catecholate and ligands of hydroxyaspartate administered rapidly after iv or ip injection of uranium decrease the renal content of the metal to a considerable extent (Henge-Napoli et al., 1995, 1998). However, the treatment is not successful if administered more than 30 min after the initial exposure to this substance (Durbin et al., 1997; Henge-Napoli et al., 1995), such that its behavior can be said to be similar to that of phosphonates and hence of no use in clinical practice (Gray et al., 1992; Henge-Napoli et al., 1998; Ubios et al., 1994). Several attempts have been made to produce a lipophilic chelating agent that will allow better access to the intracellular medium through the membrane lipid layer. Among such compounds, a lipophilic compound called Puchel, produced at Harwell (United Kingdom), was observed to be more effective than DTPA when administered through the inhalation route (Stradling et al., 1981), with better therapeutic effects when used in combination with DTPA, but this combination has not proved useful in clinical practice. For the treatment of chronic intoxication with uranium, studies have also been carried out regarding the possibility of inducing the mobilization of uranium from bone structures by means of parathyroid hormone. This has been studied in several experimental models, but this technique does not seem to offer a practical alternative for decreasing contamination by uranium in the organism (Durakovic et al., 1973). Repair of Renal Damage As mentioned above, another important therapeutic aspect is the repair of the damage produced, involving the regeneration of kidney tissues. Thus, cessation of exposure to the metal should favor the process of tissue regeneration discussed in “Treatment of Intoxication by Uranium” section. Because to date no treatments that favor renal tissue regeneration after damage because of any etiology are available, this remains a challenge for the future. In this sense, although still in an experimental context, some regenerative therapeutic strategies that could possibly be applied in uranium-induced nephrotoxicity are currently being tested. On one hand, investigators are developing treatment with growth factors that regulate the viability, proliferation, and migration of cells, among which hepatic growth factor (reviewed in Matsumoto et al., 2000, and Nigam and Lieberthal, 2000), but also insulin-like growth factor and epidermal growth factor (reviewed in Nigam and Lieberthal, 2000), are of interest. Exogenous administration of these factors to laboratory animals has demonstrated their ability to improve the repair of acute and chronic renal damage. A new cell-based repair strategy consists of (1) stimulation of resident renal stem cells (Oliver et al., 2004) and (2) exogenous injection of kidney stem cells or bone marrow stem cells with transdifferentiation capacity (e.g., mesenchymal cells or haematopoietic stem cells, Anglani et al., 2004) to achieve the re-epithelialization of lost tissues, especially damaged tubules. In one experimental study, mesenchymal cells from bone marrow were used (reviewed in Brodie and Humes, 2005) owing to their known ability to differentiate into epithelial tubular cells (Herrera et al., 2004; Kale et al., 2003) and mesangial (Masuya et al., 2003) and endothelial cells for neovascularization (Patschan et al., 2006; Takahashi et al., 1999). This type of cell has been used to repair the damage caused by drugs or ischemia (Herrera et al., 2004), although its efficacy has also been questioned (reviewed in Brodie and Humes, 2005). Finally, other systems are being developed including (1) a bioartificial kidney consisting of a dialysis system formed by a tubular structure containing ∼1 billion tubular cells (Humes et al., 2004) and (2) implants of encapsulated cells with a view to removing uraemic toxins and for drug administration (see Brodie and Humes, 2005). We thank Nicholas S. Skinner from the Servicio de Idiomas, Universidad de Salamanca (Spain), for his assistance on the English version of the manuscript. References Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention (ATSDR/CDC) Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention 1990 Subcommittee Report on Biological Indicators of Organ Damage, Atlanta, GA. 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TI - Nephrotoxicity of Uranium: Pathophysiological, Diagnostic and Therapeutic Perspectives
JF - Toxicological Sciences
DO - 10.1093/toxsci/kfq178
DA - 2010-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/nephrotoxicity-of-uranium-pathophysiological-diagnostic-and-mBP1OBsL06
SP - 324
EP - 347
VL - 118
IS - 2
DP - DeepDyve
ER -