Lead nephropathy

Renal Effects. The characteristics of early or acute lead-induced nephropathy in humans include nuclear inclusion bodies, mitochondrial changes, and cytomegaly of the proximal tubular epithelial cells dysfunction of the proximal tubules (Fanconi s syndrome) manifested as aminoaciduria, glucosuria, and phosphaturia with hypophosphatemia and increased sodium and decreased uric acid excretion. These effects appear to be reversible. Characteristics of chronic lead nephropathy include progressive interstitial fibrosis, dilation of tubules and atrophy or hyperplasia of the tubular epithelial cells, and few or no nuclear inclusion bodies, reduction in glomerular filtration rate, and azotemia. These effects are irreversible. The acute form is reported in lead-intoxicated children, whose primary exposure is via the oral route, and sometimes in lead workers. The chronic form is reported mainly in lead workers, whose primary exposure is via inhalation. Animal studies provide evidence of nephropathy similar to that which occurs in humans, particularly the acute form (see Section 2.2.3.2). 

In a study of lead workers, Wedeen et al. (1979) identified 15 who had no other risk factors for renal disease and who had previously unsuspected lead nephropathy (detected as reduced glomerular filtration... 

The lead-induced nephropathy observed in humans and rodents shows a comparable early pathology (Goyer 1993). However, in rodents, proximal tubular cell injury induced by lead can progress to adenocarcinomas of the kidney (see Section 2.2.3.8). The observation of lead-induced kidney tumors in rats may not be relevant to humans. Conclusive evidence for lead-induced renal cancers (or any other type of cancer) in humans is lacking, even in populations in which chronic lead nephropathy is evident. 

Baker EL, GoyerRA, Fowler BA, etal. 1980. Occupational lead nephropathy and renal cancer. Am J IndMed 1 138-148. 

WedeenRP. 1988. Bone lead, hypertension, and lead nephropathy. Environ Health Perspect 78 57-60. 

Wedeen RP, Mallik DK. Batuman V. 1979. Detection and treatment of occupational lead nephropathy. Arch Intern Med 139 53-57. 

Chronic high-dose lead exposure, usually associated with months to years of blood lead concentrations in excess of 80 g/dL, may result in renal interstitial fibrosis and nephrosclerosis. Lead nephropathy may have a latency period of years. Lead may alter uric acid excretion by the kidney, resulting in recurrent bouts of gouty arthritis ("saturnine gout"). Acute high-dose lead exposure sometimes produces transient azotemia, possibly as a consequence of intrarenal vasoconstriction. 

The exposure to lead based paints and subsequent lead nephropathy and encephalopathy, in the USA, is concentrated in substandard housing [162]. Individuals at the lower end of our economic ladder often are denied access to preventative health care thus putting them at additional risk for toxin exposure. Another example is the consumption of "moonshine" whiskey that has been associated with the development of lead nephropathy [167]. 

Morgan JM, Hartley MW. Etiologic factors in lead nephropathy. South Med J 1976 69 1445-1449. 

In the past, lead nephropathy was identified in individuals who had repeated episodes of symptomatic lead intoxicahon [1]. The classic symptoms of... 

In children with lead encephalopathy, proximal tubule reabsorptive defects characterized by the Fanconi syndrome have been observed [13]. The Fanconi syndrome appears when blood lead levels approach 150 //g/ dL. It is rapidly reversed by chelation therapy designed to treat the far more dangerous lead encephalopathy. The proximal tubule reabsorptive defect can regularly be induced experimentally in rats fed dietary lead [14]. In both children and experimental animals, acute lead nephropathy is consistently associated with acid-fast intranuclear inclusions in proximal tubule... 

Chronic lead nephropathy from moonshine came to medical attention because of the dramatic symptoms of acute lead poisoning. Lead colic and anemia were... 

Chronic lead nephropathy in moonshiners, more often than not, is accompanied by gout and hypertension, in accord with 19 century descriptions of plumbism and reports from Austraha [1]. A statistically significant odds ratio of 2.4 has been reported for moonshine consumption and end-stage renal disease, suggesting a causal association with lead in fhe absence of symptomatic lead poisoning [31]. 

Renal biopsies in chronic lead nephropathy show nonspecific tubular atrophy and interstitial fibrosis with minimal inflammatory response as well as mitochondrial swelling, loss of cristae, and increased lysosomal dense bodies within proximal tubule cells [4,18]. (Figure 1)... 

Figure 1. Tubular atrophy and interstitial fibrosis in a case of chronic lead nephropathy.

The functional changes in chronic lead nephropathy appear to be less specific than those observed in acute poisoning. As in other forms of interstitial nephritis, proteinuria and glycosuria are initially absent. In contrast to cadmium nephropathy, the excretion of a large array of urinary marker proteins such as retinal binding protein, lysozyme, and iriicroglobulin [33, 34] is not increased in the absence of a reduced GFR. 

The increase in urinary N-acetyl- -D-glucosamini-dase (NAG) with increasing blood lead concentrations reflects the proximal tubule dysfunction seen in acute lead nephropathy rather than the chronic interstitial nephritis associated with occupational lead exposure [35, 36]. NAG excretion correlates positively with the blood lead concentration but not with the bone lead concentration [37]. Eicosanoid excretion in lead workers is similar to that in patients with essential... 

In contrast to the reabsorptive defect of acute lead nephropathy, saturnine gout is characterized by renal retention of uric acid [18]. The clearance (Cp ) and maximal secretion rate (Tmp ) for p-aminohippurate (PAH) have been found to be variable in patients with occupational lead nephropathy. 

Hyperuricemia and gout are common among individuals with excessive exposure to lead, apparently the result of decreased excretion and increased production of uric acid. Although hyperuricemia invariably accompanies azotemia, gout is uncommon in patients with renal failure except in those with lead nephropathy. Half of uremic patients with lead nephropathy have clinical gout [18] but in the absence of renal failure, gout cannot usually be attributed to lead despite coexisting hypertension [23, 37]. 

Lead-induced hyperuricemia may contribute to chronic lead nephropathy. Uric acid per se induces endothelial cell injury, renal microvascular disease, and hypertension, at least in part mediated by oxidative stress [38]. Independent of uric acid, reactive oxygen species induced by lead have been imphcated in endothelial cell injury, increased vascular reactivity, and the production of hypertension in humans and experimental animals [39]. 

Lead nephropathy does not account for renal failure in all hypertensives with kidney disease any more than it accounts for renal failure in all gout patients with kidney disease. The heavy metal may, however, contribute to the association of gout with hypertension, as well as to the variable incidence of renal failure in each of these conditions. 

Lead nephropathy is important because it is one of the few renal diseases that is preventable. Moreover, lead-induced acute renal dysfunction can sometimes be reversed by chelation therapy [19, 28, 63]. The salutary effect of chelation therapy appears to be on the acute reduction in GFR and the acute elevation of blood pressure associated with elevated blood lead concentration rather than on the long-term effects of cumulative exposure associated with endothelial dysfunction, hypertension, and interstitial nephritis. There is no evidence that such therapy reverses established interstitial nephritis. The partial remission achieved among moonshiners and lead workers appears to represent reversal of the physiologic effects of acute poisoning superimposed on chronic lead nephropathy. No improvement in renal function has been observed once advanced interstitial nephritis is present and the steady-state serum creatinine concentration exceeds about 3 mg/ dL [64]. 

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