Role of ultrastructural techniques in understanding mechanisms of metal-induced nephrotoxicity

The combined use of ultrastructural morphometry and X-ray microanalysis in conjunction with biochemical analysis is one approach to elucidating mechanisms of metal nephrotoxicity at the cellular level. Ultrastructural morphometry conducted on proximal tubule cells of rats exposed to low levels of methyl mercury for prolonged periods of time showed statistically significant increases in the volume densities of the lysosomal and mitochondrial compartments. These findings were associated with marked changes in lysosomal marker enzymes and mitochondrial heme biosynthesis enzymes leading to the detection of a renal porphyrinuria that occurred before changes in standard tests of renal function. Ultrastructural morphometry, X-ray microanalysis, and biochemical studies of the low-molecular-weight tubular proteinuria produced by injection of cadmium metallothionein (CdMT) showed a rapid proximal tubule cell lysosome uptake and degradation of the CdMT complex, which led to a subsequent decrease in the numerical density (Nv) and average diameter of lysosomes and to an increase in the Nv of apical pinocytolic vesicles with time. The data indicate disruption of the normal primary lysosome-pinocytolic vesicle fusion process and related development of tubular proteinuria. Ultrastructural techniques may provide information useful in elucidating mechanisms of ongoing metal-induced nephrotoxic processes when consideration is given to sampling strategies for morphometric analysis and the inherent detection limits, elemental volatility, translocation effects, and limitations of quantification for X-ray microanalysis in soft biological tissues.