Kidney International, Vol. 7 (1975), p. 254—270 U1rastructure of glomerular disease: A review JACOB CHURG and EDITH GRISHMAN Division of RenalPathology, Department of Pathology, Mount Sinai School of Medicine, New York, New York Electron microscopy was first applied to the study of on the luminal aspect, by the layer of endothelium with the kidney some 25 yr ago. In the early 1950's the nor- numerous perforations, around 100 nm in diameter. It mal ultrastructure was established [1, 21 providing a is likely that these perforations are closed by very basis for the studies of abnormal morphology. A large thin diaphragms [7] which prevent direct contact be- number of papers dealing with human and experi- tween blood and basement membrane. The basement mental renal disease appeared during the next 15 yr membrane consists of three layers: lamina densa, and several comprehensive reviews were published lamina rara externa and lamina rara interna. Lamina in the late 1960's [3—6]. The high resolution of the densa is composed mainly of collagen; it often appears electron microscope enabled the investigators to shed homogeneous, but in good preparations it is found to light on many problems which had caused controversy contain fibrils about 10 nm and also 3 nm in diameter. among the light microscopists, among them the struc- The lamina rara consists mainly of glycoproteins. The ture of the capillary wall in the glomerulus, the nature lamina rara interna apparently corresponds to, and of the mesangium and its behavior in disease and the possibly represents, the remnant of pericapillary mes- nature and location of "fibrinoid" deposits in various angium, which in certain species (toads, some fishes) glomerular diseases. Electron microscopic studies con- encircles the entire capillary. In man and higher verte- tributed significantly to the understanding of the patho- brates, lamina rara interna may be viewed as a poten- genesis and the morphogenesis of the disease process in tial pericapillary space, which is brought into being by the glomeruli and to a lesser extent in the tubules, the expansion and ingrowth of the mesangium into the interstitial tissue and the blood vessels. Tt also proved to capillary wall or by formation of deposits which may have definite diagnostic value. attain considerable bulk. On the contrary, the epithe- In this review only the more important contributions hal foot processes are firmly anchored to the basement of the earlier periods will be discussed and will be membrane by perpendicular fibers running across supplemented by the more recent information covering lamina rara externa. Subepithelial deposits tend to be approximately the last ten years. small and discontinuous in any plane of section. The foot processes of the podocytes are separated by nar- row slits (filtration slits) bridged by a thin layer of Normal ultrastructure cytoplasm (filtration slit membrane) (Fig. 1). The sur- Electron microscopy has clarified the fine details of faces of the epithehial cells, including that of the filtra- structural elements of the glomerulus—capillary wall, tion slit membranes, are covered by a thick coat of mesangium and Bowman's capsule. This is important sialic acid, stainable with collodial iron [8] and ruthe- because all pathological processes in the glomerulus nium red [9]. In addition to the usual cell organelles, can be localized to one or more of these elements and the cytoplasm of the epithelial cells contains many to the spaces defined by them—the capillary lumina microtubules as well as microfibrils. The latter form a and the Bowman's or urinary space. loose network or, in the foot process, dense bundles. As is well known, the capillary wall consists of the The microfibrils resemble myofilaments of smooth basement membrane lined on the urinary aspect by the muscle cells and may possibly endow the cell with epithelial podocytes, which attach to the basement ability to contract [10]. membrane by means of pedicels or foot processes; and Despite much speculation, the specific role of each of the components of the capillary wall and that of the © 1975, by theInternationalSociety of Nephrology. sialic acid coat in the process of filtration have not been 254 Ultrastructure of glo,nerular disease 255 definitely established. The main filtration barriers are brane causing wrinkling and collapse of capillaries [16] probably the basement membrane and the plasma (Fig. 16). membrane of the podocytes, but sialic acid coat may Intracytoplasmic crystals in podocytes have been re- also play a role. ported in some cases of multiple myeloma [17, 18] and Electron microscopy has confirmed the existence of cystinosis [19]. the glomerular mesangium and has defined its structure Basement membrane. Thickening of the basement [11]. Normal mesangial cell differs from endothelial membrane occurs in a variety of diseases, among them cell in certain structural aspects; e.g., the presence of diabetes mellitus (Fig. 12), systemic lupus erythemato- fine fibrils arranged perpendicularly to the cell mem- sus and glomerulonephritis. The thickening may reach brane. However, these distinctions often disappear in striking proportions, the membrane attaining ten times disease. More characteristic is the relationship of and more of normal thickness. There may be focal mesangial cells to mesangial matrix which forms a rarefaction (mottling), layering (splitting) or protru- meshwork separating the cells from each other and sions on the endothelial aspect. The latter are common from endothelial cells. This relationship persists and is in nephrotic syndrome with minimal glomerular even accentuated in pathologic states. Mesangial disease. Focal splitting may be seen in a variety of matrix is similar in composition to that of basement diseases, but extensive splitting into multiple layers is membrane, but is not identical; witness its response to characteristic of certain forms of hereditary nephritis certain toxins such as Habu snake poison which dis- [20] (Fig. 19). Occasionally, basement membranes solves mesangial matrix but does not affect basement show gaps or breaks which are particularly frequent in membrane [12]. rapidly progressive (extracapillary) glomerulonephritis (Fig. 4). Segments of broken membrane may be phago- cytosed by adjacent cells of a crescent [21]. Gaps may General pathology of the glomerulus also be observed in association with necrosis or poly- Podocytes. The most conspicuous change of the morphonuclear leukocytic infiltration [22]. podocytes is the loss or fusion of their foot processes, Striking protrusions alternating with electron-dense with replacement by a continuous sheet of cytoplasm deposits on the epithelial surface of the basement [13J (Fig. 15).' This change is apparently due to swell- membrane produce a characteristic picture known as ing of cytoplasm which fills the spaces between foot "membranous transformation" (Fig. 17). This trans- processes [5], and retraction of swollen foot processes formation eventually results in a very thick, nonhomo- as seen by scanning electron microscopy [14]. Despite geneous, irregular and later increasingly uniform the swelling the foot processes retain their dense basement membrane. Such change may occur in certain material; i.e., dense bundles of microfibrils. Loss of forms of idiopathic nephrotic syndrome, in systemic foot processes is usually accompanied by the appear- lupus erythematosus, in subacute and chronic glomer- ance of numerous villi projecting from the free surface ulonephritis and in diabetes mellitus. Severe damage of the cells (Fig. 15). The loss may be limited to a few is repaired by a process akin to scarring, with resultant short stretches or may involve the entire capillary sur- permanent decrease in the capillary permeability. face. It is particularly prominent in the presence of Endothelial cells. A common response to injury is severe proteinuria and the nephrotic syndrome; abate- diffuse edema, which causes obliteration of the pores ment of proteinuria coincides with reappearance of and formation of large loose structureless blebs. In foot processes. It is possible that in some instances of acute glomerulonephritis, as well as in toxemia of preg- proteinuria the primary injury occurs in the basement nancy, the edematous cells may completely fill the membrane, in others in the epithelial cells. lumen, interfering with glomerular blood flow and Cell bodies of podocytes respond to disease stimuli filtration. by developing abundant cell organelles [15]. Intracyto- Severe endothelial injury leads to formation of gaps plasmic vesicles and inclusions increase in size and between adjoining cells and separation of the cell from number. Conversely, there may be swelling of the the basement membrane. The latter process occurs in cytoplasm with a diminished number of cell organelles the hemolytic-uremic syndrome [23, 24] (Fig. 18) or ra- indicating hypoactivity. We have observed degenera- diation nephritis [25] (Fig. 11). Crystalline inclusions tion and breakdown of podocytes shortly after the on- in endothelial cells have been seen in a few cases of set of proteinuria. In other instances podocytes may dysproteinemia [26, 27]. become detached from the underlying basement mem- Deposits. Deposits found in the walls of glomerular capillaries and in the mesangium consist of accumula- 1Illustrationsfor this section will be found under Specific tion of poorly soluble organic or inorganic material. Diseases. Most deposits are probably derived from the blood 256 Churg/Grishman