Interstitial fibrosis 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). 

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. 

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. 

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.

Chronic exposure to low levels of lead results in lead accumulation within the body. Workers who have been chronically exposed to lead develop interstitial fibrosis, vascular and glomerular sclerosis, and tubular atrophy and/or hypertrophy. Although acute lead nephropathy is reversible with chelator therapy and/or removal from exposure, chronic effects may be irreversible. In addition, chronic exposure to lead may result in a gouty nephropathy as lead reduces uric acid excretion and elevates blood uric acid levels. 

Lead-induced nephropathy was first reported more than a century ago. However, the condition remains to be clearly defined. A study from Queensland, Australia, described 34 patients with a chronic nephropathy who had suffered from lead palsy in childhood following exposure to lead paints (Nye, 1933). Interstitial fibrosis, tubular atrophy and dilation have been observed in workers with heavy long-term exposure to lead. Renal tubular dysfunction characterized by glycosuria and aminoaciduria has been observed in lead-exposed children (Chisholm and Leahy, 1962). Lead exposure should be considered in the differential diagnosis of glycosuria occurring in childhood. 

Acute exposure to inorganic lead can cause reversible damage to the kidneys, manifested as tubular dysfunction. Chronic exposure to lead, however, causes permanent interstitial nephropathy, which involves tubular cell atrophy, pathological changes in the vasculature, and fibrosis. The most pronounced changes occur in the proximal tubules. Indeed, lead-protein complexes are seen as inclusion bodies in tubular cells, and the mitochondria in such cells have been shown to be altered with impaired oxidative phosphorylation. Clearly, this will influence the function of the proximal tubular cells in reabsorption and secretion of solutes and metabolites. Consequently, one indication of renal dysfunction is amino aciduria, glycosuria, and impairment of sodium reabsorption. 

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