Lead nephropathy toxicity

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

Clinically, lead nephropathy is seen as either reversible tubular dysfunction or as an irreversible interstitial nephropathy. Tubular toxicity occurs most commonly in children following acute exposure and is characterized by glucosuria, phosphaturia, aminoaciduria, and occasionally proteinuria. One unique morphological feature of lead exposure is the formation of nuclear inclusion bodies within renal tubular cells. These bodies are complexes between lead... 

Lead nephropathy as a toxicological topic has presented various interpretive clinical and empirical dilemmas. Some appear to have resolved to some extent. Some are mainly confined to nephropathic responses per se. Some are shared with other lead-associated toxic endpoints. A classical endpoint in Pb-induced nephropathy is a reduced estimated or measured glomerular filtration rate (GFR), typically employing creatinine clearance rates, in tandem with measurements of blood urea nitrogen (BUN) and serum creatinine levels. Such declines in GFR are proportional to the level of PbB in chronic injury, subsequent to any transitory hyperfiltration. 

Unlike the neurotoxicological, developmental, and other toxic effects of lead, chronic lead nephropathy was historically viewed as a disease of adults, particularly lead workers, and children were generally considered to be at low risk. The exception to this view was kidney tubular injury in early, acute childhood Pb poisoning in the form of Fanconi Syndrome. 

Lead worker nephropathy has comprised a sizeable hterature, at least in quantitative terms, within the earlier toxic nephropathy database. Illustrative smdies are summarized in Table 15.3. Such nephropathy has typically, but not always, presented histopathologicaUy as a focal interstitial nephritis and functionally as reduced GFR. Lead nephropathy has been documented in many countries, including the United States (Baker et al., 1979 Wedeen et al., 1975, 1979), Romania (LUis et al., 1968), Brazil (Pinto de Almeida et al., 1987), Japan (Omae et al., 1990), Singapore (Chia et al., 1995a), and Belgium (Buchet et al., 1980). 

The alimentary symptoms may be overshadowed by neuromuscular dysfunction, accompanied by signs of motor weakness that may progress to paralysis of the exterior muscles or the wrist (wrist drop), and less often, of the ankles (foot drop). Encephalopathy, the most serious result of lead poisoning, frequendy occurs in children as a result of pica, ie, ingestion of inorganic lead compounds in paint chips this rarely occurs in adults. Nephropathy has also been associated with chronic lead poisoning (147). The toxic effects of lead may be most pronounced on the developing fetus. Consequendy, women must be particulady cautious of lead exposure (148). The U.S. Center for Disease Control recommends a blood level of less than 10 p.m per 100 mL for children. 

Several studies conducted in children known to have lead toxicity, indicate that nephropathy occurs in children only at PbB >80 pg/dL, and usually exceeding 120 pg/dL (NAS 1972). 

Lead Inorganic lead oxides and salts Gastrointestinal, respiratory Soft tissues redistributed to skeleton (> 90% of adult body burden) CNS deficits peripheral neuropathy anemia nephropathy hypertension reproductive toxicity Inhibits enzymes interferes with essential cations alters membrane structure Renal (major) feces and breast milk (minor)... 

Cyclosporine is a macrolide antibiotic and has been used as an immunosuppressive agent. Cyclosporine can cause both renal and nonrenal toxicity. Clinically renal toxicity consists of four discrete syndromes which include acute reversible renal functional impairment, delayed renal allograft function, acute vasculopathy, and chronic nephropathy with interstitial fibrosis. Proximal tubular epithelium is uniquely sensitive to the toxic effect. The toxic effect is characterized by isometric cytoplasmic vacuolations (several small equally sized vacuoles in cytoplasm), necrosis with or without subsequent mineralization, inclusion bodies (giant mitochondria), and giant lysosomes. Acute vasculopathy consists of vacuolization of the arteriolar smooth muscles and endothelial cells leading to necrosis. In some cases, thrombotic microangiopathy develops, characterized by thrombosis of the renal micro vasculature. Long-term treatment with cyclosporine results in chronic nephropathy with interstitial fibrosis (Chamey et al., 2004). 

Several adulterants added to nonherbal supplements, vitamins, and herbal medicine preparations can cause renal dysfunction and renal failure. Aristolochic acid is used as a herbal remedy for weight loss and has been reported to cause Chinese herb nephropathy characterized by extensive interstitial fibrosis with tubular atrophy and loss. Herbal medicine preparations produced in South Asia contain potentially harmful levels of lead, mercury, and/or arsenic which can lead to renal toxicity. 

Saccharated ferric oxide, an intravenous formulation of iron that is used when oral iron is not effective in anemia, can cause osteomalacia during long-term use. The underlying mechanism of nephropathy leading to bone toxicity has recently been reviewed (34). 

Answer E. The profile of lead toxicity includes decreased heme synthesis, anemia, nephropathy, and peripheral neuropathy, the last leading to foot drop or wrist drop. Garlic breath and watery stools are associated with arsenic poisoning. Chronic gingivitis and loose teeth are features of mercury poisoning. 

A two-thirds reduction in absorption has been described in 6 other subjects given penicillamine 500 mg and ferrous sulfate 300 mg. Other studies confirm this interaction. There is also evidence that the withdrawal of iron from patients stabilised on penicillamine can lead to the development of toxicity (nephropathy) unless the penicillamine dosage is reduced. ... 

A number of complications and empirical conundrums also arise in assessing lead worker cohorts with reference to endpoints such as morbidity and mortality associated with Pb nephropathy. There is the weU-recognized and general healthy worker effect, where the healthiest and/or least adversely responsive workers exposed to toxics are most likely to remain at the job over time, potentially biasing the overall dose—toxic response relationships for various endpoints in humans to a less robust relationship. Survivor bias is related to this phenomenon in mortality studies. That is, those workers leaving employment within shorter time periods are not likely included in the statistical analyses of survival rates. 

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