Pathogenesis of segmental glomerular changes at the tubular origin, as in the glomerular tip lesion.

Segmental abnormalities at the glomerulo-tubular junction, or tip changes, are a common and early feature in several experimental and human renal disorders. Scanning and transmission electron microscopic study of an experimental model, Lewis rats given anti-glomerular basement membrane antibodies, showed that at 5 days there were monocytes/macrophages in glomerular capillary loops next to the tubular origin, with abnormalities of visceral epithelium, including prolapse of groups of these cells into the tubular origin. At 12 days, there was contact and adhesion between glomerular capillary loops and Bowman's capsule. Transmission electron microscopic study of human renal biopsies showed that the human tip changes resembled the later lesions seen in rats, with intracapillary foam cells confirmed by immunohistological study to be monocytes/macrophages. These findings show that abnormalities of the glomerular tuft precede adhesion to Bowman's capsule and that the earliest changes recognized by light microscopy in human renal biopsies are relatively late in their natural history, meaning at least several days old. Prolapse of visceral epithelial cells into the tubular origin may explain the characteristic site of tip changes.

The mammalian glomerulotubular junction studied by scanning and transmission electron microscopy.

The structure of the junction of glomerulus and tubule was investigated in man and 5 other mammalian species (rat, mouse, ferret, rabbit and pig) by scanning and transmission electron microscopy. The junction between parietal epithelium and proximal tubular epithelium was usually abrupt but varied in position: inside Bowman's capsule, especially in the male mouse; at the anatomical tubular origin, in the rat, ferret and man; and down the tubule, in the rabbit. All animals but especially the pig had cells intermediate in appearance between parietal and tubular cells at the junction. Serial sections of 3 rat junctions studied by transmission electron microscopy showed a variety of appearances of the arrangement of parietal and tubular cells, but the glomerular aspect of the first tubular cell up to its microvillous border was always covered by parietal epithelium, even though this was reduced to a thin sheet in places. This arrangement appeared to be the rule in all species studied.

Changes in the myelinated axons of femoral nerve in amyotrophic lateral sclerosis.

Myelinated fibres in femoral nerves removed from amyotrophic lateral sclerosis (ALS) cases at post mortem were compared with age matched controls. A technique for processing whole transverse sections of the nerves for osmication and subsequent morphometric analysis is described. Although areas depleted in myelinated fibres were seen in the nerves from the ALS group, no statistically significant difference was shown due to wide variations in the controls. However, the ALS nerves showed a degree of disruption in the myelin which was not apparent in the controls. The most obvious effect was widespread "wrinkling" of the myelin in both large and small fibres from the ALS nerves. This phenomenon is the initial stage of a process which eventually results in uneven myelin thickness and nodal swellings and finally myelin ovoids and balls. We illustrate the steps in the progression of this degeneration with teased nerve studies and electron microscopy and propose that there are qualitative changes in the myelin of peripheral nerve in ALS. It seems likely that these are secondary effects resulting from axonal degeneration caused by deterioration and loss of anterior horn cells in the spinal cord.

Morphometric correlates of renal excretory function.

There is often thought to be little or no correlation between renal excretory function and histological changes in the kidney, especially in acute renal failure and in the kidney examined post-mortem. We studied the relationship between renal function and structure in 28 patients at necropsy and in 41 patients who had a renal biopsy. A point-counting method was used on kidney stained by an immunoperoxidase method using an antiserum to proximal tubule brush border; an antiserum to Tamm-Horsfall protein, which is a marker of thick limbs of the loop of Henle; and a monoclonal antibody to epithelial membrane antigen, normally a marker of all parts of the tubule except proximal tubule. There was a correlation between the reciprocal of plasma creatinine concentration, which is a measure of renal function, and the ratio of brush border positive tubules to negative tubules. There was also a less strong correlation between renal function and ratios of Tamm-Horsfall positive tubules to negative tubules and of cast-containing tubules to others. There was no correlation between renal function and the ratio of tubules expressing epithelial membrane antigen to those not expressing it. The method of point-counting tubules stained by the brush border antiserum was a useful, practical way of correlating renal function and structure which could be used even on post-mortem kidney.