Kidneys have been recognized as an easy target for the toxicity of a number of chemicals and paharmacologically active substances. Over the last few decades it has become increasingly evident that kidneys may be exposed to harm by a variety of substances, including environmental, industrial and naturally occurring chemicals as well as an array of medicines which are used for different ailments. The dose of the chemical may be small and for a prolonged period leading to chronic nephrotoxicity, or it may be heavy and for a short period leading to acute nephrotoxicity1. Small size of the kidneys relative to their blood supply and diversity of their functions makes them easy targets not only for the harmful effects of toxic chemicals, but also for the pharmacologically active substances.
Most of the cases of end-stage renal disease brought to nephrology and dialysis units may be the consequence of chemical exposure1. Epidemiological evidence indicates that nephrotoxicity leading to acute and/or chronic renal failure represents a substantial financial burden to society2. If we need to avoid this burden, we must assume some prophylactic measures to avoid injury to the kidneys in the first place. This may be achieved by avoiding exposure to toxic substances. However, if the exposure is unavoidable, or we have already been exposed to the culprit agent, then we need to use something which can protect us from the harmful effects of the toxic substance. The present study focuses at finding the ameliorating effects of ginkgo biloba extract on lead induced nephrotoxicity.
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Among the pharmacologically active chemicals responsible for nephrotoxicity are the non-steroidal anti-inflamatory drugs (NSAIDS), antibiotics like aminoglycosides, cephaloceporins, amphotericin-B and tetracyclines, penicillamine, lithium, urograhic contrast media, anti- cancer drugs like cisplatin, adriamycin, and immune-suppressants like cyclosporin A. Other chemicals concerned with nephrotoxicity include ethylene glycol, organic chemicals and solvents like volatile hydrocarbons, chloroform, halogenated alkenes, hydrocarbons etc., silicon and mycotoxins.1
Heavy metals are also among the important offending agents capable of producing nephrotoxicity. People continue to be exposed to heavy metals in the environment. In many parts of the world, food and water are contaminated with heavy metals. Metal leaches from cooking utensils and is added to our food3. Modern era of industries and lot of mining of heavy metals has resulted in a great deal of environmental pollution, which is responsible for many occupational diseases due to various chemical toxins4. Some of the most important sources of heavy metal poisoning in this modern era are from burning of fossil fuels containing heavy metals, tetra-ethyl lead addition to gasoline, and increased industrial uses of metals4. Toxic metals are widely distributed in our environment, and humans are exposed to the toxic effects of these metals from water, soil, air and food contamination5.
Damage to the kidneys is one of the primary toxic effects of metals, and heavy metal induced nephrotoxicity has been extensively studied. Studies show that low dose mercury exposure can result in degenerative changes in mice kidney6. Nephritic syndrome as well as membranous nephritis may occur in humans who are exposed to mercury and its salts for a long time.7-8 Another study has shown glomerular and tubular alterations in workers who are chronically exposed to mercury, particularly its fumes.9 Similarly, cadmium toxicity in sufficient cumulative dosage leads to the development of Fanconi syndrome which is characterized by generalized proximal tubular reabsorptive defect related to both ATP production and Na-K-ATPase activity.10 Another study has shown that histological examination of kidneys of rats treated with cisplatin revealed significant proximal tubular lesions varying from minimal changes to severe toxicity.11 When more than one toxic agents are involved, the damaging effects are exaggerated. For example the histopathologic changes in kidneys were aggravated when lead was administered concomitantly with cadmium.12
Lead is a ubiquitous metal present everywhere on the earth. It is found in all soils, rivers, seawater, even in sea spray and dust in the air.13 Lead toxicity may affect virtually every organ of the body, but the effects on kidneys are the most insidious. Acute nephrotoxicity may result in cytosolic and nuclear inclusion bodies which can be seen microscopically. The intracellular lead is associated with high affinity proteins and may combine with metallothionein. Acute exposure is associated with proximal tubular dysfunction with Fanconi type syndrome, and alterations in the structure of mitochondria14.
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Metals and other substances that are considered to be toxic to humans produce their toxic effects by virtue of producing oxidative stress. This involves the production of reactive oxygen species which can overwhelm cell's intrinsic antioxidant defense mechanisms. Cells which undergo oxidative stress display dysfunctions of lipid, proteins and DNA5. Oxidative stress is involved in acute renal toxicities induced by substances like lead, gentamicin, cisplatin, glycerol, cyclosporine and others15.
Ginkgo biloba extract is well known for its free radical scavengering ability. Many studies have shown the anti-oxidant effect of ginkgo biloba extract. It has been proved to be effective in preventing ethanol induced gastric ulcer, which is most probably due to its inhibitory effect on lipid peroxidation and cell apoptosis16. Zhu and others have conducted a study in which they proved protective anti-oxidant effect of ginkgo biloba extract on early diabetic nephropathy17. In another study, it has shown a delaying effect on the development of glomerulosclerosis in diabetic nephropathy18-19.
Present study deals with the ameliorating effect of ginkgo biloba extract on lead-induced nephrotoxicity. Until now, both the anti-oxidant effects of ginkgo biloba extract and lead-induced nephrotoxicity have been studied separately several times, but this study is unique in a sense that this combination has never been studied before to the best of our knowledge.
REVIEW OF LITERATURE
Lead has been known as a poison since ancient times. It is classified as one of the most serious threats to human wellbeing particularly in developing countries like ours. Greek poet and philosopher Nikander was the first who discovered the clinical syndrome of lead poisoning in 200 BCE. The high lead concentration in Roman wine was claimed to be one of the important factors which contributed to the downfall of Roman Empire20. Portuguese wine was once used to be transported with lead bars submerged in it to increase its flavor and durability. The use of this was responsible for several incidences of lead poisoning among the English aristocracy21.
Although use of lead has been known since ancient times, its massive consumption came into existence in the 20th century. More than 300 million tons of lead has been mined out between 1920 and 2000, and has been added to the atomosphere due to combustion activities and applied to the surfaces in the form of leaded paints.
Lead is the heaviest of all non-radioactive metals which are found in significant quantities in earth's crust13. It is bluish gray in color and has a low melting point. It is usually found combined with other elements to form lead compounds.
Sources of lead
Lead compounds are used as a pigment in paints, dyes, and ceramic glazes and in caulk. Lead, being a ubiquitous metal, is found everywhere. Even natural soil is not totally lead free13. Soil is a major source of lead, and blood lead levels are higher in children living in areas having lead contaminated soil22.
The most obvious and hazardous spread of lead in the environment has been due to the use of leaded gasoline, lead being in the form of tetraethyle and tetramethyle lead, starting from 1923, that has caused release of billions of tons of lead into the environment from vehicle exhausts. Lead was used in gasoline to increase octane rating and to act as anti-knocking agent. In most of the developed countries, use of lead has been phased out starting from 1980, and it was banned for use in vehicles in U.S.A starting from January 1991. In Pakistan, however, lead has been phased out from gasoline staring from October 2001 and was completed in July 200323. This has led to decrease in blood levels of lead in Pakistani children, but not to the desired level. It will take time to get the desired level because lead once emitted in the environment is not destroyed and remains in soil for long times. Moreover, it has been observed that even when lead additives are removed from gasoline, smaller amounts of lead continue to be emitted from automobiles, trucks, and other vehicles. In addition to some natural lead in gasoline, the gradual loss of fine particles of metal, rubber, and other components that contain lead contribute to pollution, particularly in urban areas with high traffic density13.
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Lead-glazed ceramics are also important source of lead. Lead exposure due to use of lead-glazed ceramics can result in elevated blood lead levels in people of relatively high socio-economic status24. Acidic foods and beverages like tomato juice, fruit juice, carbonated drinks, cider, michels etc, that are contained in improperly glazed containers, can absorb lead and lead to subsequent lead poisoning in the consumers4.
An earlier nationwide survey in UK has shown that 10% of the urban population was exposed to lead levels in excess of 2,000 Âµg /g in house-hold dust. Approximately 50% of lead intake in 2 year old children was from dust ingested as a result of hand-to-mouth activity. Important sources of dust lead included lead-based paint, road dust and soils. It appears that although lead of minewaste origin may be present at elevated levels in dusts and soils, it does not necessarily contribute to elevated blood lead levels when the lead is present in relatively insoluble form.25 The dust in houses which are close to roads may be contaminated with metals. Metals in houses may travel from the roads, through the windows and balconies. The houses where windows and doors are kept closed, and there is regular sweeping and vacuum cleaning, levels of contaminants are low. The color of the wall paint used in the house may be another factor influencing the contamination levels26. . While adults are exposed particularly due to their profession, children are usually affected by their exposure to the lead dust and paint flakes from old houses, especially during renovation27.
A study conducted in Karachi showed that 80% of the children had a blood lead concentration of more than 10Âµg/dl. Father's education and his exposure to lead at his workplace, the child's habit of eating food from street vendors, the child's hand-to-mouth activity, the use of metal cooking utensils and living in "west-open" houses were identified as independent factors associated with elevated blood lead concentrations in children in Karachi28.
Lead used in ammunition is a significant non-battery end-use and has been quite a common source of lead in recent years29. Shooting range soils have been investigated for lead contamination from Pb bullets and the soil has been found to be heavily contaminated30. Spitz et al have described a case of bullet retention in which symptoms of lead toxicity in the form of choreoathetosis were seen after 7 years of initial exposure31. Firearm projectiles have been found to be rare cause of lead toxicity. Spitz et al have described a case of bullet retention in which symptoms of lead toxicity in the form of choreoathetosis were seen after 7 years of initial exposure31.
Lead is also an important component of batteries and the workers in battery manufacturing factories and repair shops are easy victims of lead exposure32. People living near such plants are also at risk of getting exposed to high levels of lead33. Children of the workers in battery manufacturing factories and workshops are particularly liable to get exposed to the high levels of lead which their fathers bring home in their clothes34. Sathye et al have reported a case of a child who suffered from lead poisoning, the source of lead being the lead dust on clothes of his father who worked in a brass industry where brass alloys contained lead in substantial amounts 35.
Kohl and surma are eye cosmetics which are commonly used in India, Pakistan, Near East, Middle East and North Africa. Their use has even spread to the western countries. The main ingredient of these cosmetics is lead sulphide, and their use is associated with increased blood lead levels particularly in children, who are the main users of these cosmetics36. However, according to another study, "relation between Kohl and toxicity or increased blood lead concentration upon its application to eyes as reported elsewhere is likely to be more of theoretical nature rather than a practical health hazard"37.
Kushta is a traditional medicine used as an aphrodisiac in the indo-pak subcontinent, and contains harmful metals like mercury, lead and antimony mixed with certain traditional herbs. Consumption of such medicines is also associated with the risk of getting exposed to lead and other metal poisoning38.
Absorption of lead
Elemental lead and non-organic lead compounds are usually absorbed either through ingestion or inhalation. Organic lead like tetraethyl lead as well as inorganic lead oxide can be absorbed through skin as well 39. Rate of absorption of lead is more in children as compared to adults. When ingested, lead is absorbed primarily in the duodenum. Zinc, iron and calcium are competitors of lead for the shared receptors for absorption in the duodenal epithelium. Thus the absorption of lead is reduced in the presence of these substances. Iron deficiency and periods of rapid growth in children are associated with greater absorption of lead 40-41 and children who have iron deficiency anemia are more prone to have subsequent lead toxicity when exposed42. Low calorie and high fat intake is also associated with enhanced absorption of lead21. Dietary phosphate deficiency leads to increased absorption of lead in the intestine and hence increased body burden of lead in bones43. Rate of absorption of lead particles also depends upon the size of the particles. Smaller particles that are dispersed in the air and are therefore respireable, are absorbed 10 times faster as compared to larger ingestable particles44. The respirable particles are more numerous in industrial areas, and people, particularly children living nearby, are more prone to inhale these particles and get affected by the harmful effects of lead45. Workers of a lead factory were investigated for blood lead levels. It was found that those who were exposed to lead fumes, had higher blood lead levels than those who were simply involved in handling lead materials46.
Distribution and excretion of lead
Once absorbed, about 99% of lead binds to hemoglobin in erythrocytes. Only about 1% remains free in serum. Inorganic lead is first distributed to soft tissues like the tubular epithelium of kidneys and liver. Eventually however, most of lead is redistributed and deposited in bone, teeth and hair. Bone is the major store house of lead and contains about 95% of body lead burden. Small amounts of inorganic lead are also stored in gray mater and basal ganglia of brain4.
Factors which govern the distribution of lead are similar to those for calcium. High phosphate intake is associated with increased deposition of lead in bone and low concentration in soft tissue. Conversely, low intake of phosphate results in mobilization of lead from bone to the soft tissues. Lead is deposited in bone as tertiary lead phosphate, which does not contribute to toxicity. High calcium intake in the presence of low phosphate results in mobilization of lead from bone into soft tissues. Vitamin D tends to enhance the deposition of lead into bone in the presence of sufficient phosphate. However, where there is deficiency of phosphate, calcium competes for the available phosphate, and lead is mobilized to the soft tissues. Parathyroid hormone leads to mobilization of lead into soft tissues, and enhances its excretion in urine4. Deficiency of micronutrients like zinc may result in increased retension of lead in tissues47.
The excretion of lead is limited, therefore it tends to accumulate in the body, particularly in bones41. In experimental animals the route of excretion is mainly bile and hence the feces48. In humans however, urinary excretion is more important as compared to bile49. Since most of lead in circulation is in erythrocytes, only small quantities are filtered in urine. Other routes of excretion include sweat and milk, and placental transfer is also observed4.
The biological half-life of lead in erythrocytes is about 35 days. In soft tissues like liver, kidney and brain it is about 40 days, whereas in bone it ranges between 20 to 30 years50.
Several mechanisms have been proposed for lead induced oxidative stress. These include the direct effect of lead on the cell membranes, interaction with hemoglobin, 5-Aminolevulinic acid induced generation of reactive oxygen species, suppressing the tissue's anti-oxidant defense system5.
Anti oxidants work because most of the toxic effects involve the oxidative stress as the mechanism of injury.
As far as the preventive measures against the toxic effects of these environmental and occupational pollutants are concerned, they are only effective if we know these effects at a time when they are reversible, and have not compromised the kidney's functions. This unfortunately is not always possible. The symptoms of renal damage usually occur at a time when massive damage to the kidneys has already been done.
Nephrotoxic effects of lead ingestion have been shown in an experimental study by Antonio Garcia, T. and L. Corredor, in which they demonstrated that lead and cadmium are associated with lowering of the enzymes alkaline and acid phosphatase, Mg(2+)/Ca(2+)-dependent ATPase, and Na(+)/K(+)-dependent ATPase. The ATPases are necessary for secretory and absorptive functions whereas phosphatases are involved in differentiation of proximal convoluted tubules. This means that lead toxicity leads to biochemical alterations in kidneys leading to their malfunction51.
A study in India has shown that neurodevelopmental risk in children is directly related to the blood lead levels27. So higher blood levels are usually associated with low IQ.
Sources of lead toxicity, absorption of lead, its metabolism and toxic effects are not the same in children and adults. Children are more sensitive to the harmful effects of lead particularly as far as the relatively immature nervous system is concerned52.
Lead exposure results in accumulation of lead in the lining epithelium of proximal convoluted tubules in the form of inclusion bodies. These inclusion bodies are lead-protein complexes which can be seen microscopically10, 53.
Lead exposure of pregnant rats was found to cause hydropic degeneration of renal proximal tubules of the fetuses in a dose dependant manner54
Although acute nephrotoxicity with lead can be reversed by prophylactic measures and drugs like chelating agents, the chronic lead induced nephropathy may be irreversible. It may be associated with interstitial fibrosis, proximal tubular hyperplasia as well as atrophy, glomerulonephritis and ultimately chronic renal failure leading to end-stage renal disease14.
Children who live close to the areas of lead smelter show slight deterioration in the proximal convoluted tubules, as demonstrated by a study conducted by Bernard et al55.
Studies in individuals with low-level lead exposure have shown a correlation between blood lead levels and serum creatinine or creatinine clearance.
Exposure to lead (Pb) has been shown to disrupt developmental processes in the brain and to result in impaired brain function. Studies have suggest that exposure to Pb may selectively interfere with critical developmental gene expression56.
Acute exposure to high concentrations of lead can result in proximal tubular damage with characteristic histologic features and manifested by glycosuria and aminoaciduria. Chronic occupational exposure to lead, or consumption of illicit alcohol adulterated with lead, has also been linked to a high incidence of renal dysfunction, which is characterized by glomerular and tubulointerstitial changes resulting in chronic renal failure, hypertension, hyperuricemia, and gout 57.
Lead nephropathy in adults is silent and insidious, characterized by the absence of proteinuria in its early phase58
Damage to the kidneys is one of the primary toxic actions of metals. Nephrotoxic substances not only cause renal disease directly, but they can also destroy renal reserve capacity, potentially placing those people with additional risk factors, such as diabetes, hypertension, cardiovascular disease, and genetic predispositions, at greater risk59.
Chronic occupational exposure to inorganic mercury (mainly mercury vapor) may result in renal alterations affecting both tubules and glomeruli9
The main health problems in children with blood lead levels as low as 6ïg/dl are neurological deficits. In adults, main health problem may be the occurrence of hypertension at levels above 25-30 ïg/dl. Moreover, chronic lead exposure in pregnant women can result in spontaneous abortion and potential damage to the fetus13
Policemen are easy victims of toxicity from lead, released from automobile exhaust. Markers of renal damage have been found in them 60.
A study on the effects of EGB761 on bleomycin induced lung fibrosis has shown that it can reverse the toxic effects of bleomycin61
The efficacy of ginkgo biloba extract in the treatment of Alzheimer's disease has been studied and positive results found62.
First report of lead induced nephrotoxicity was published in 1863 by Lancereaux in which he noted atrophy of renal cortex and tubular fibrosis in a painter who had the habit of keeping paint brushes in his mouth21
Lead may act as a cofactor with more established risk factors associated with chronic renal diseases even at a lower level than is needed to produce lead nephropathy. In fact, blood lead levels as low as 5mcg/dl may be associated with adverse renal effects21.
Even in developed countries like USA, where proportion of children having blood lead level of more than 10mcg/dl has dropped by 80%, lead toxicity remains a problem in poor localities and in upper class children living in older houses which are being renovated63.
Lead acetate and cadmium acetate impair renal function by producing biochemical changes like decrease in alkaline and acid phosphatases and different ATPases. However when administered together, they seem to protect against each other's toxicity51
Treatment of choice in heavy metal poisoning is by chelating agents. Flora et al have shown in a study that plumbism can be treated more effectively by combining an anti-oxidant moiety like melatonin or N-acetylcysteine with thiol-chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA)64.
Lead exposure has been found to be a significant health problem in indian children, being associated with higher neurodevelopmental risk in many of them27.
Celik et all did a study regarding protective effects of ginkgo biloba extract and other anti oxidants on vancomycin induced nephrotoxicity in rats. They found potential protective effect of ginkgo biloba extract on this nephrotoxicity65.
Environmental lead exposure in children is associated with intellectual deficit66.
Zhu and other others have conducted a study in which they have seen that ginkgo biloba extract has a protective effect on early diabetic nephropathy17. Ginkgo biloba extract can delay the development of glomerulosclerosis in diabetic nephropathy18-19
Although various measures have been adopted to decline the level of lead in the environment, but still we cannot deny its adverse effects. Indeed, blood lead levels as low as 5 Âµg/dl may be associated with nephrotoxicity in susceptible population, especially those who are already hypertensive or diabetic67.
shown to protect against cisplatin-induced nephrotoxicity68.
Lead appears to be a risk factor in language disorders due probably to its negative impact on neuropsychological functions69
Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to hyperuricaemia and gout, presumably by inhibiting uric acid secretion, and diminished glomerular filteration rate
Lead accumulation in the proximal tubule leads to hyperuricaemia and gout, probably due to inhibition of uric acid secretion and diminished glomerular filteration rate.10
A recent study conducted by Jusko et al has shown that children's intellectual functioning at the age of 6 years can be affected and impaired by blood lead levels well below 10Âµg/dl70
Kadir et al have published a review according to which blood lead level in Pakistani children has declined from 38Âµg/dl in 1989 to 15Âµg/dl in 2002. Sources of lead which they found were the leaded petrol, father's occupation in lead based industries, leaded paint, different house remedies and cosmetics71.
Studies of children's blood lead levels has shown that cognitive impairments are becoming apparent at increasingly lower blood lead levels. More drastic measures have to be taken to avoid the risk of lead exposure. The strategy can involve identifying the source, eliminating or limiting the exposure to the source, and monitoring the environmental exposures and hazards72
Chronic lead exposure induces severe hepato- and nephrotoxicity depending upon the dose, and the age of the animal and the target organ involved73.
Ginkgo biloba extract is found to improve vascular endothelial function in patients with early diabetic nephropathy by decreasing the plasma level of von Willebrand factor, raising the plasma nitric oxide level and improving the endothelium dependent vascular dilating function74.
Genetic polymorphism may play a role in the development of lead induced nephrotoxicity in high lead exposed workers. Polymorphisms of ALAD and VDR gene have been studied in this respect 75.
Exposure of rat proximal tubular cells to low dose lead was associated with cell death which was mediated through cell apoptosis and necrosis. The chief mechanism of this apoptotic cell death was oxidative stress76
CONTEXT: EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior. OBJECTIVE: To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia. DESIGN: A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study. PATIENTS: Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions. INTERVENTION: Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks. PRIMarY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC). RESULTS: From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events. CONCLUSIONS: EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.